Medical Forum

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

Case Presentation: A 39-year-old Air Force veteran was admitted to the US Department of Veterans Affairs Boston Healthcare System (VABHS) for evaluation of recurrent, painful right knee effusions. On presentation, his vital signs were stable, and the examination was significant for a right knee with a large effusion and tenderness to palpation without erythema or warmth. His white blood cell count was 12.0 cells/L with an erythrocyte sedimentation rate of 23 mm/h and C-reactive protein of 11.87 mg/L. He was in remission from alcohol use but had relapsed on alcohol in the past day to treat the pain. He had a history of IV drug use but was in remission. He was previously active and enjoyed long hikes. Nine months prior to presentation, he developed his first large right knee effusion associated with pain. He reported no antecedent trauma. At that time, he presented to another hospital and underwent arthrocentesis with orthopedic surgery, but this did not lead to a diagnosis, and the effusion reaccumulated within 24 hours. Four months later, he received a corticosteroid injection that provided only minor, temporary relief. He received 5 additional arthrocenteses over 9 months, all without definitive diagnosis and with rapid reaccumulation of the fluid. His most recent arthrocentesis was 3 weeks before admission.

►Lauren E. Merz, MD, MSc, Chief Medical Resident, VABHS: Dr. Jindal, what is your approach and differential diagnosis for joint effusions in hospitalized patients?

►Shivani Jindal, MD, MPH, Hospitalist, VABHS, Instructor in Medicine, Boston University School of Medicine (BUSM): A thorough history and physical examination are important. I specifically ask about chronicity, pain, and trauma. A medical history of potential infectious exposures and the history of the present illness are also important, such as the risk of sexually transmitted infections, exposure to Lyme disease or other viral illnesses. Gonococcal arthritis is one of the most common causes of nontraumatic monoarthritis in young adults but can also present as a migratory polyarthritis.¹

It sounds like he was quite active and liked to hike so a history of tick exposure is important to ascertain. I would also ask about eye inflammation and back pain to assess possible ankylosing spondyarthritis. Other inflammatory etiologies, such as gout are common, but it would be surprising to miss this diagnosis on repeated arthocenteses. A physical examination can confirm monoarthritis over polyarthritis and assess for signs of inflammatory arthritis (eg, warmth and erythema). The most important etiology to assess for and rule out in a person admitted to the hospital is septic arthritis. The severe pain, mild leukocytosis, and mildly elevated inflammatory markers could be consistent with this diagnosis but are nonspecific. However, the chronicity of this patient’s presentation and hemodynamic stability make septic arthritis less likely overall and a more indolent infection or other inflammatory process more likely.

►Dr. Merz: The patient’s medical history included posttraumatic stress disorder (PTSD) and antisocial personality disorder with multiple prior suicide attempts. He also had a history of opioid use disorder (OUD) with prior overdose and alcohol use disorder (AUD). Given his stated preference to avoid opioids and normal liver function and liver chemistry testing, the initial treatment was with acetaminophen. After this failed to provide satisfactory pain control, IV hydromorphone was added.

Dr. Jindal, how do you approach pain control in the hospital for musculoskeletal issues like this?

►Dr. Jindal: Typically, nonsteroidal anti-inflammatory medications (NSAIDs) are most effective for musculoskeletal pain, often in the form of ketorolac or ibuprofen. However, we are often limited in our NSAID use by kidney disease, gastritis, or cardiovascular disease. Selective COX-2 inhibitors (eg, celecoxib) have the advantage of a lower risk of gastrointestinal bleeding. Topical formulations (eg, diclofenac) may also come with a lower adverse effect profile. Corticosteroids are also an option but come with their own adverse effect profile. This patient does not have any of these comorbidities. Adjuvant therapies such as lidocaine patches or capsaicin cream can also provide relief. Gabapentin or pregabalin are indicated for any component of neuropathic pain. Opioids can be helpful for acute musculoskeletal pain, but there is no long-term benefit in chronic musculoskeletal pain.² The experience of pain is also multifactorial so ensuring that anxiety and insomnia are addressed is key.

►Dr. Merz: On hospital day 1, the patient asked to leave to consume alcohol to ease unremitting pain. He also expressed suicidal ideation and discharge was therefore felt to be unsafe. He was reluctant to engage with psychiatry and became physically combative while attempting to leave the hospital, necessitating the use of sedating medications and physical restraints.

Dr. Shahal, what factors led to the decision to place an involuntary hold, and how do you balance patient autonomy and patient safety?

►Dr. Talya Shahal, MD, Consult-Liaison Psychiatry Service, VABHS, Instructor in Psychiatry, Harvard Medical School: This is a delicate balance that requires constant reassessment. The patient initially presented to the emergency department with suicidal ideation, stating he was not able to tolerate the pain and thus resumed alcohol consumption after a period of nonuse. He had multiple risk factors for suicide, including 9 prior suicide attempts with the latest less than a year before presentation, active substance use with alcohol and other recreational drugs, PTSD, pain, veteran status, male sex, single status, and a history of trauma.^3,4 He was also displaying impulsivity and limited insight, did not engage in his psychiatric assessment, and attempted to assault staff. As such, his suicide risk was assessed to be high at the time of the evaluation, which led to the decision to place an involuntary hold. However, we reevaluate this decision at least daily in order to reassess the risk and ensure that the balance between patient safety and autonomy are maintained.

►Dr. Merz: The involuntary hold was removed within 48 hours as the patient remained calm and engaged with the primary and consulting teams. He requested escalating doses of opioids as he felt the short-acting IV medications were not providing sustained relief. However, he was also noted to be walking outside of the hospital without assistance, and he repeatedly declined nonopioid pain modalities as well as buprenorphine/naloxone. The chronic pain service was consulted but was unable to see the patient as he was frequently outside of his room.

Dr. Shahal, how do you address OUD, pain, and stigma in the hospital?

►Dr. Shahal: It is important to remember that patients with substance use disorder (SUD) and mental illness frequently have physical causes for pain and are often undertreated.⁵ Patients with SUD may also have higher tolerance for opioids and may need higher doses to treat the pain.⁵ Modalities like buprenorphine/naloxone can be effective to treat OUD and pain, but these usually cannot be initiated while the patient is on short-acting opioids as this would precipitate withdrawal.⁶ However, withdrawal can be managed while inpatient, and this can be a good time to start these medications as practitioners can aggressively help with symptom control. Proactively addressing mental health concerns, particularly anxiety, AUD, insomnia, PTSD, and depression, can also have a direct impact on the perception of pain and assist with better control.² In addition, nonpharmacologic options, such as meditation, deep breathing, and even acupuncture and Reiki can be helpful and of course less harmful to treat pain.²

► Dr. Merz: An X-ray of the knee showed no acute fracture or joint space narrowing. Magnetic resonance imaging confirmed a large knee effusion with no evidence of ligament injury. Synovial fluid showed turbid, yellow fluid with 14,110 nucleated cells (84% segmented cells and 4000 RBCs). Gram stain was negative, culture had no growth, and there were no crystals. Anticyclic citrullinated peptide (anti-CCP), rheumatoid factor, HIV testing, and HLA-B27 were negative.

Dr. Serrao, what do these studies tell us about the joint effusion and the possible diagnoses?

► Dr. Richard Serrao, MD, Infectious Disease, VABHS, Clinical Associate Professor in Medicine, BUSM: I would expect the white blood cell (WBC) count to be > 50,000 cells with > 75% polymorphonuclear cells and a positive Gram stain if this was a bacterial infection resulting in septic arthritis.⁷ This patient’s studies are not consistent with this diagnosis nor is the chronicity of his presentation. There are 2 important bacteria that can present with inflammatory arthritis and less pronounced findings on arthrocentesis: Borrelia burgdorferi (the bacteria causing Lyme arthritis) and Neisseria gonorrhea. Lyme arthritis could be consistent with this relapsing remitting presentation as you expect a WBC count between 3000 and 100,000 cells with a mean value between 10,000 and 25,000 cells, > 50% polymorphonuclear leukocytes, and negative Gram stains.⁸ Gonococcal infections often do not have marked elevations in the WBC count and the Gram stain can be variable, but you still expect the WBC count to be > 30,000 cells.⁷ Inflammatory causes such as gout or autoimmune conditions such as lupus often have a WBC count between 2000 and 100,000 with a negative Gram stain, which could be consistent with this patient’s presentation.⁷ However, the lack of crystals rules out gout and the negative anti-CCP, rheumatoid factor, and HLA-B27 make rheumatologic diseases less likely.

►Dr. Merz: The patient received a phone call from another hospital where an arthrocentesis had been performed 3 weeks before. The results included a positive polymerase chain reaction (PCR) test for Lyme disease in the synovial fluid. A subsequent serum Lyme screen was positive for 1 of 3 immunoglobulin (Ig) M bands and 10 of 10 IgG bands.

Dr. Serrao, how does Lyme arthritis typically present, and are there aspects of this case that make you suspect the diagnosis? Does the serum Lyme test give us any additional information?

►Dr. Serrao: Lyme arthritis is a late manifestation of Lyme disease. Patients typically have persistent or intermittent arthritis, and large joints are more commonly impacted than small joints. Monoarthritis of the knee is the most common, but oligoarthritis is possible as well. The swelling usually begins abruptly, lasts for weeks to months, and effusions typically recur quickly after aspiration. These findings are consistent with the patient’s clinical history.

For diagnostics, the IgG Western blot is positive if 5 of the 10 bands are positive.⁹ This patient far exceeds the IgG band number to diagnose Lyme disease. All patients with Lyme arthritis will have positive IgG serologies since Lyme arthritis is a late manifestation of the infection. IgM reactivity may be present, but are not necessary to diagnose Lyme arthritis.¹⁰ Synovial fluid is often not analyzed for antibody responses as they are susceptible to false positive results, but synovial PCR testing like this patient had detects approximately 70% of patients with untreated Lyme arthritis.¹¹ However, PCR positivity does not necessarily equate with active infection. Serologic testing for Lyme disease by enzyme-linked immunosorbent assay and Western blot as well as careful history and the exclusion of other diagnoses are usually sufficient to make the diagnosis.

► Dr. Merz: On further history the patient reported that 5 years prior he found a tick on his skin with a bull’s-eye rash. He was treated with 28 days of doxycycline at that time. He did not recall any tick bites or rashes in the years since.

Dr. Serrao, is it surprising that he developed Lyme arthritis 5 years after exposure and after being treated appropriately? What is the typical treatment approach for a patient like this?

►Dr. Serrao: It is atypical to develop Lyme arthritis 5 years after reported treatment of what appeared to be early localized disease, namely, erythema migrans. This stage is usually cured with 10 days of treatment alone (he received 28 days) and is generally abortive of subsequent stages, including Lyme arthritis. Furthermore, the patient reported no symptoms of arthritis until recently since that time. Therefore, one can argue that the excessively long span of time from treatment to these first episodes of arthritis suggests the patient could have been reinfected. When available, comparing the types and number of Western blot bands (eg, new and/or more bands on subsequent serologic testing) can support a reinfection diagnosis. A delayed postinfectious inflammatory process from excessive proinflammatory immune responses that block wound repair resulting in proliferative synovitis is also possible.¹² This is defined as the postinfectious, postantibiotic, or antibiotic-refractory Lyme arthritis, a diagnosis of exclusion more apparent only after patients receive appropriate antibiotic courses for the possibility of untreated Lyme as an active infection.¹²

Given the inherent diagnostic uncertainty between an active infection and posttreatment Lyme arthritis syndromes, it is best to approach most cases of Lyme arthritis as an active infection first especially if not yet treated with antibiotics. Diagnosis of postinflammatory processes should be considered if symptoms persist after appropriate antibiotics, and then short-term use of disease-modifying antirheumatic drugs, rather than further courses of antibiotics, is recommended.

► Dr. Merz: The patient was initiated on doxycycline with the plan to transition to ceftriaxone if there was no response. One day after diagnosis and treatment initiation and in the setting of continued pain, the patient again asked to leave the hospital to drink alcohol. After eloping and becoming intoxicated with alcohol, he returned to his room. He remained concerned about his continued pain and lack of adequate pain control. At the time, he was receiving hydromorphone, ketorolac, lorazepam, gabapentin, and quetiapine.

Dr. Serrao, do you expect this degree of pain from Lyme arthritis?

► Dr. Serrao: Lyme arthritis is typically less painful than other forms of infectious or inflammatory arthritis. Pain is usually caused by the pressure from the acute accumulation and reaccumulation of fluid. In this case, the rapid accumulation of fluid that this patient experienced as well as relief with arthrocentesis suggests that the size and acuity of the effusion was causing great discomfort. Repeated arthrocentesis can prove to be a preventative strategy to minimize synovial herniation.

►Dr. Merz: Dr. Shahal, how do you balance the patient subjectively telling you that they are in pain with objective signs that they may be tolerating the pain like walking around unassisted? Is there anything else that could have been done to prevent this adverse outcome?

►Dr. Shahal: This is one of the hardest pieces of pain management. We want to practice beneficence by believing our patients and addressing their discomfort, but we also want to practice nonmaleficence by avoiding inappropriate long-term pain treatments like opioids that have significant harm as well as avoiding exacerbating this patient’s underlying SUD. An agent like buprenorphine/naloxone could have been an excellent fit to treat pain and SUD, but the patient’s lack of interest and the frequent use of short-acting opioids were major barriers. A chronic pain consult early on is helpful in cases like this as well, but they were unable to see him since he was often out of his room. Repeated arthrocentesis may also have helped the pain. Treatment of anxiety and insomnia with medications like hydroxyzine, trazodone, melatonin, gabapentin, or buspirone as well as interventions like sleep hygiene protocols or spiritual care may have helped somewhat as well.

We know that there is a vicious cycle between pain and poorly controlled mood symptoms. Many of our veterans have PTSD, anxiety, and SUD that are exacerbated by hospitalization and pain. Maintaining optimal communication between the patient and the practitioners, using trauma-informed care, understanding the patient’s goals of care, setting expectations and limits, and attempting to address the patient’s needs while attempting to minimize stigma might be helpful. However, despite optimal care, sometimes these events cannot be avoided.

►Dr. Merz: The patient was ultimately transferred to an inpatient psychiatric unit where a taper plan for the short-acting opioids was implemented. He was psychiatrically stabilized and discharged a few days later off opioids and on doxycycline. On follow-up a few weeks later, his pain had markedly improved, and the effusion was significantly reduced in size. His mood and impulsivity had stabilized. He continues to follow-up in the infectious disease clinic.

Case Presentation: A 39-year-old Air Force veteran was admitted to the US Department of Veterans Affairs Boston Healthcare System (VABHS) for evaluation of recurrent, painful right knee effusions. On presentation, his vital signs were stable, and the examination was significant for a right knee with a large effusion and tenderness to palpation without erythema or warmth. His white blood cell count was 12.0 cells/L with an erythrocyte sedimentation rate of 23 mm/h and C-reactive protein of 11.87 mg/L. He was in remission from alcohol use but had relapsed on alcohol in the past day to treat the pain. He had a history of IV drug use but was in remission. He was previously active and enjoyed long hikes. Nine months prior to presentation, he developed his first large right knee effusion associated with pain. He reported no antecedent trauma. At that time, he presented to another hospital and underwent arthrocentesis with orthopedic surgery, but this did not lead to a diagnosis, and the effusion reaccumulated within 24 hours. Four months later, he received a corticosteroid injection that provided only minor, temporary relief. He received 5 additional arthrocenteses over 9 months, all without definitive diagnosis and with rapid reaccumulation of the fluid. His most recent arthrocentesis was 3 weeks before admission.

►Lauren E. Merz, MD, MSc, Chief Medical Resident, VABHS: Dr. Jindal, what is your approach and differential diagnosis for joint effusions in hospitalized patients?

►Shivani Jindal, MD, MPH, Hospitalist, VABHS, Instructor in Medicine, Boston University School of Medicine (BUSM): A thorough history and physical examination are important. I specifically ask about chronicity, pain, and trauma. A medical history of potential infectious exposures and the history of the present illness are also important, such as the risk of sexually transmitted infections, exposure to Lyme disease or other viral illnesses. Gonococcal arthritis is one of the most common causes of nontraumatic monoarthritis in young adults but can also present as a migratory polyarthritis.¹

It sounds like he was quite active and liked to hike so a history of tick exposure is important to ascertain. I would also ask about eye inflammation and back pain to assess possible ankylosing spondyarthritis. Other inflammatory etiologies, such as gout are common, but it would be surprising to miss this diagnosis on repeated arthocenteses. A physical examination can confirm monoarthritis over polyarthritis and assess for signs of inflammatory arthritis (eg, warmth and erythema). The most important etiology to assess for and rule out in a person admitted to the hospital is septic arthritis. The severe pain, mild leukocytosis, and mildly elevated inflammatory markers could be consistent with this diagnosis but are nonspecific. However, the chronicity of this patient’s presentation and hemodynamic stability make septic arthritis less likely overall and a more indolent infection or other inflammatory process more likely.

►Dr. Merz: The patient’s medical history included posttraumatic stress disorder (PTSD) and antisocial personality disorder with multiple prior suicide attempts. He also had a history of opioid use disorder (OUD) with prior overdose and alcohol use disorder (AUD). Given his stated preference to avoid opioids and normal liver function and liver chemistry testing, the initial treatment was with acetaminophen. After this failed to provide satisfactory pain control, IV hydromorphone was added.

Dr. Jindal, how do you approach pain control in the hospital for musculoskeletal issues like this?

►Dr. Jindal: Typically, nonsteroidal anti-inflammatory medications (NSAIDs) are most effective for musculoskeletal pain, often in the form of ketorolac or ibuprofen. However, we are often limited in our NSAID use by kidney disease, gastritis, or cardiovascular disease. Selective COX-2 inhibitors (eg, celecoxib) have the advantage of a lower risk of gastrointestinal bleeding. Topical formulations (eg, diclofenac) may also come with a lower adverse effect profile. Corticosteroids are also an option but come with their own adverse effect profile. This patient does not have any of these comorbidities. Adjuvant therapies such as lidocaine patches or capsaicin cream can also provide relief. Gabapentin or pregabalin are indicated for any component of neuropathic pain. Opioids can be helpful for acute musculoskeletal pain, but there is no long-term benefit in chronic musculoskeletal pain.² The experience of pain is also multifactorial so ensuring that anxiety and insomnia are addressed is key.

►Dr. Merz: On hospital day 1, the patient asked to leave to consume alcohol to ease unremitting pain. He also expressed suicidal ideation and discharge was therefore felt to be unsafe. He was reluctant to engage with psychiatry and became physically combative while attempting to leave the hospital, necessitating the use of sedating medications and physical restraints.

Dr. Shahal, what factors led to the decision to place an involuntary hold, and how do you balance patient autonomy and patient safety?

►Dr. Talya Shahal, MD, Consult-Liaison Psychiatry Service, VABHS, Instructor in Psychiatry, Harvard Medical School: This is a delicate balance that requires constant reassessment. The patient initially presented to the emergency department with suicidal ideation, stating he was not able to tolerate the pain and thus resumed alcohol consumption after a period of nonuse. He had multiple risk factors for suicide, including 9 prior suicide attempts with the latest less than a year before presentation, active substance use with alcohol and other recreational drugs, PTSD, pain, veteran status, male sex, single status, and a history of trauma.^3,4 He was also displaying impulsivity and limited insight, did not engage in his psychiatric assessment, and attempted to assault staff. As such, his suicide risk was assessed to be high at the time of the evaluation, which led to the decision to place an involuntary hold. However, we reevaluate this decision at least daily in order to reassess the risk and ensure that the balance between patient safety and autonomy are maintained.

►Dr. Merz: The involuntary hold was removed within 48 hours as the patient remained calm and engaged with the primary and consulting teams. He requested escalating doses of opioids as he felt the short-acting IV medications were not providing sustained relief. However, he was also noted to be walking outside of the hospital without assistance, and he repeatedly declined nonopioid pain modalities as well as buprenorphine/naloxone. The chronic pain service was consulted but was unable to see the patient as he was frequently outside of his room.

Dr. Shahal, how do you address OUD, pain, and stigma in the hospital?

►Dr. Shahal: It is important to remember that patients with substance use disorder (SUD) and mental illness frequently have physical causes for pain and are often undertreated.⁵ Patients with SUD may also have higher tolerance for opioids and may need higher doses to treat the pain.⁵ Modalities like buprenorphine/naloxone can be effective to treat OUD and pain, but these usually cannot be initiated while the patient is on short-acting opioids as this would precipitate withdrawal.⁶ However, withdrawal can be managed while inpatient, and this can be a good time to start these medications as practitioners can aggressively help with symptom control. Proactively addressing mental health concerns, particularly anxiety, AUD, insomnia, PTSD, and depression, can also have a direct impact on the perception of pain and assist with better control.² In addition, nonpharmacologic options, such as meditation, deep breathing, and even acupuncture and Reiki can be helpful and of course less harmful to treat pain.²

► Dr. Merz: An X-ray of the knee showed no acute fracture or joint space narrowing. Magnetic resonance imaging confirmed a large knee effusion with no evidence of ligament injury. Synovial fluid showed turbid, yellow fluid with 14,110 nucleated cells (84% segmented cells and 4000 RBCs). Gram stain was negative, culture had no growth, and there were no crystals. Anticyclic citrullinated peptide (anti-CCP), rheumatoid factor, HIV testing, and HLA-B27 were negative.

Dr. Serrao, what do these studies tell us about the joint effusion and the possible diagnoses?

► Dr. Richard Serrao, MD, Infectious Disease, VABHS, Clinical Associate Professor in Medicine, BUSM: I would expect the white blood cell (WBC) count to be > 50,000 cells with > 75% polymorphonuclear cells and a positive Gram stain if this was a bacterial infection resulting in septic arthritis.⁷ This patient’s studies are not consistent with this diagnosis nor is the chronicity of his presentation. There are 2 important bacteria that can present with inflammatory arthritis and less pronounced findings on arthrocentesis: Borrelia burgdorferi (the bacteria causing Lyme arthritis) and Neisseria gonorrhea. Lyme arthritis could be consistent with this relapsing remitting presentation as you expect a WBC count between 3000 and 100,000 cells with a mean value between 10,000 and 25,000 cells, > 50% polymorphonuclear leukocytes, and negative Gram stains.⁸ Gonococcal infections often do not have marked elevations in the WBC count and the Gram stain can be variable, but you still expect the WBC count to be > 30,000 cells.⁷ Inflammatory causes such as gout or autoimmune conditions such as lupus often have a WBC count between 2000 and 100,000 with a negative Gram stain, which could be consistent with this patient’s presentation.⁷ However, the lack of crystals rules out gout and the negative anti-CCP, rheumatoid factor, and HLA-B27 make rheumatologic diseases less likely.

►Dr. Merz: The patient received a phone call from another hospital where an arthrocentesis had been performed 3 weeks before. The results included a positive polymerase chain reaction (PCR) test for Lyme disease in the synovial fluid. A subsequent serum Lyme screen was positive for 1 of 3 immunoglobulin (Ig) M bands and 10 of 10 IgG bands.

Dr. Serrao, how does Lyme arthritis typically present, and are there aspects of this case that make you suspect the diagnosis? Does the serum Lyme test give us any additional information?

►Dr. Serrao: Lyme arthritis is a late manifestation of Lyme disease. Patients typically have persistent or intermittent arthritis, and large joints are more commonly impacted than small joints. Monoarthritis of the knee is the most common, but oligoarthritis is possible as well. The swelling usually begins abruptly, lasts for weeks to months, and effusions typically recur quickly after aspiration. These findings are consistent with the patient’s clinical history.

For diagnostics, the IgG Western blot is positive if 5 of the 10 bands are positive.⁹ This patient far exceeds the IgG band number to diagnose Lyme disease. All patients with Lyme arthritis will have positive IgG serologies since Lyme arthritis is a late manifestation of the infection. IgM reactivity may be present, but are not necessary to diagnose Lyme arthritis.¹⁰ Synovial fluid is often not analyzed for antibody responses as they are susceptible to false positive results, but synovial PCR testing like this patient had detects approximately 70% of patients with untreated Lyme arthritis.¹¹ However, PCR positivity does not necessarily equate with active infection. Serologic testing for Lyme disease by enzyme-linked immunosorbent assay and Western blot as well as careful history and the exclusion of other diagnoses are usually sufficient to make the diagnosis.

► Dr. Merz: On further history the patient reported that 5 years prior he found a tick on his skin with a bull’s-eye rash. He was treated with 28 days of doxycycline at that time. He did not recall any tick bites or rashes in the years since.

Dr. Serrao, is it surprising that he developed Lyme arthritis 5 years after exposure and after being treated appropriately? What is the typical treatment approach for a patient like this?

►Dr. Serrao: It is atypical to develop Lyme arthritis 5 years after reported treatment of what appeared to be early localized disease, namely, erythema migrans. This stage is usually cured with 10 days of treatment alone (he received 28 days) and is generally abortive of subsequent stages, including Lyme arthritis. Furthermore, the patient reported no symptoms of arthritis until recently since that time. Therefore, one can argue that the excessively long span of time from treatment to these first episodes of arthritis suggests the patient could have been reinfected. When available, comparing the types and number of Western blot bands (eg, new and/or more bands on subsequent serologic testing) can support a reinfection diagnosis. A delayed postinfectious inflammatory process from excessive proinflammatory immune responses that block wound repair resulting in proliferative synovitis is also possible.¹² This is defined as the postinfectious, postantibiotic, or antibiotic-refractory Lyme arthritis, a diagnosis of exclusion more apparent only after patients receive appropriate antibiotic courses for the possibility of untreated Lyme as an active infection.¹²

Given the inherent diagnostic uncertainty between an active infection and posttreatment Lyme arthritis syndromes, it is best to approach most cases of Lyme arthritis as an active infection first especially if not yet treated with antibiotics. Diagnosis of postinflammatory processes should be considered if symptoms persist after appropriate antibiotics, and then short-term use of disease-modifying antirheumatic drugs, rather than further courses of antibiotics, is recommended.

► Dr. Merz: The patient was initiated on doxycycline with the plan to transition to ceftriaxone if there was no response. One day after diagnosis and treatment initiation and in the setting of continued pain, the patient again asked to leave the hospital to drink alcohol. After eloping and becoming intoxicated with alcohol, he returned to his room. He remained concerned about his continued pain and lack of adequate pain control. At the time, he was receiving hydromorphone, ketorolac, lorazepam, gabapentin, and quetiapine.

Dr. Serrao, do you expect this degree of pain from Lyme arthritis?

► Dr. Serrao: Lyme arthritis is typically less painful than other forms of infectious or inflammatory arthritis. Pain is usually caused by the pressure from the acute accumulation and reaccumulation of fluid. In this case, the rapid accumulation of fluid that this patient experienced as well as relief with arthrocentesis suggests that the size and acuity of the effusion was causing great discomfort. Repeated arthrocentesis can prove to be a preventative strategy to minimize synovial herniation.

►Dr. Merz: Dr. Shahal, how do you balance the patient subjectively telling you that they are in pain with objective signs that they may be tolerating the pain like walking around unassisted? Is there anything else that could have been done to prevent this adverse outcome?

►Dr. Shahal: This is one of the hardest pieces of pain management. We want to practice beneficence by believing our patients and addressing their discomfort, but we also want to practice nonmaleficence by avoiding inappropriate long-term pain treatments like opioids that have significant harm as well as avoiding exacerbating this patient’s underlying SUD. An agent like buprenorphine/naloxone could have been an excellent fit to treat pain and SUD, but the patient’s lack of interest and the frequent use of short-acting opioids were major barriers. A chronic pain consult early on is helpful in cases like this as well, but they were unable to see him since he was often out of his room. Repeated arthrocentesis may also have helped the pain. Treatment of anxiety and insomnia with medications like hydroxyzine, trazodone, melatonin, gabapentin, or buspirone as well as interventions like sleep hygiene protocols or spiritual care may have helped somewhat as well.

We know that there is a vicious cycle between pain and poorly controlled mood symptoms. Many of our veterans have PTSD, anxiety, and SUD that are exacerbated by hospitalization and pain. Maintaining optimal communication between the patient and the practitioners, using trauma-informed care, understanding the patient’s goals of care, setting expectations and limits, and attempting to address the patient’s needs while attempting to minimize stigma might be helpful. However, despite optimal care, sometimes these events cannot be avoided.

►Dr. Merz: The patient was ultimately transferred to an inpatient psychiatric unit where a taper plan for the short-acting opioids was implemented. He was psychiatrically stabilized and discharged a few days later off opioids and on doxycycline. On follow-up a few weeks later, his pain had markedly improved, and the effusion was significantly reduced in size. His mood and impulsivity had stabilized. He continues to follow-up in the infectious disease clinic.

Case Presentation: A 39-year-old Air Force veteran was admitted to the US Department of Veterans Affairs Boston Healthcare System (VABHS) for evaluation of recurrent, painful right knee effusions. On presentation, his vital signs were stable, and the examination was significant for a right knee with a large effusion and tenderness to palpation without erythema or warmth. His white blood cell count was 12.0 cells/L with an erythrocyte sedimentation rate of 23 mm/h and C-reactive protein of 11.87 mg/L. He was in remission from alcohol use but had relapsed on alcohol in the past day to treat the pain. He had a history of IV drug use but was in remission. He was previously active and enjoyed long hikes. Nine months prior to presentation, he developed his first large right knee effusion associated with pain. He reported no antecedent trauma. At that time, he presented to another hospital and underwent arthrocentesis with orthopedic surgery, but this did not lead to a diagnosis, and the effusion reaccumulated within 24 hours. Four months later, he received a corticosteroid injection that provided only minor, temporary relief. He received 5 additional arthrocenteses over 9 months, all without definitive diagnosis and with rapid reaccumulation of the fluid. His most recent arthrocentesis was 3 weeks before admission.

►Lauren E. Merz, MD, MSc, Chief Medical Resident, VABHS: Dr. Jindal, what is your approach and differential diagnosis for joint effusions in hospitalized patients?

►Shivani Jindal, MD, MPH, Hospitalist, VABHS, Instructor in Medicine, Boston University School of Medicine (BUSM): A thorough history and physical examination are important. I specifically ask about chronicity, pain, and trauma. A medical history of potential infectious exposures and the history of the present illness are also important, such as the risk of sexually transmitted infections, exposure to Lyme disease or other viral illnesses. Gonococcal arthritis is one of the most common causes of nontraumatic monoarthritis in young adults but can also present as a migratory polyarthritis.¹

It sounds like he was quite active and liked to hike so a history of tick exposure is important to ascertain. I would also ask about eye inflammation and back pain to assess possible ankylosing spondyarthritis. Other inflammatory etiologies, such as gout are common, but it would be surprising to miss this diagnosis on repeated arthocenteses. A physical examination can confirm monoarthritis over polyarthritis and assess for signs of inflammatory arthritis (eg, warmth and erythema). The most important etiology to assess for and rule out in a person admitted to the hospital is septic arthritis. The severe pain, mild leukocytosis, and mildly elevated inflammatory markers could be consistent with this diagnosis but are nonspecific. However, the chronicity of this patient’s presentation and hemodynamic stability make septic arthritis less likely overall and a more indolent infection or other inflammatory process more likely.

►Dr. Merz: The patient’s medical history included posttraumatic stress disorder (PTSD) and antisocial personality disorder with multiple prior suicide attempts. He also had a history of opioid use disorder (OUD) with prior overdose and alcohol use disorder (AUD). Given his stated preference to avoid opioids and normal liver function and liver chemistry testing, the initial treatment was with acetaminophen. After this failed to provide satisfactory pain control, IV hydromorphone was added.

Dr. Jindal, how do you approach pain control in the hospital for musculoskeletal issues like this?

►Dr. Jindal: Typically, nonsteroidal anti-inflammatory medications (NSAIDs) are most effective for musculoskeletal pain, often in the form of ketorolac or ibuprofen. However, we are often limited in our NSAID use by kidney disease, gastritis, or cardiovascular disease. Selective COX-2 inhibitors (eg, celecoxib) have the advantage of a lower risk of gastrointestinal bleeding. Topical formulations (eg, diclofenac) may also come with a lower adverse effect profile. Corticosteroids are also an option but come with their own adverse effect profile. This patient does not have any of these comorbidities. Adjuvant therapies such as lidocaine patches or capsaicin cream can also provide relief. Gabapentin or pregabalin are indicated for any component of neuropathic pain. Opioids can be helpful for acute musculoskeletal pain, but there is no long-term benefit in chronic musculoskeletal pain.² The experience of pain is also multifactorial so ensuring that anxiety and insomnia are addressed is key.

►Dr. Merz: On hospital day 1, the patient asked to leave to consume alcohol to ease unremitting pain. He also expressed suicidal ideation and discharge was therefore felt to be unsafe. He was reluctant to engage with psychiatry and became physically combative while attempting to leave the hospital, necessitating the use of sedating medications and physical restraints.

Dr. Shahal, what factors led to the decision to place an involuntary hold, and how do you balance patient autonomy and patient safety?

►Dr. Talya Shahal, MD, Consult-Liaison Psychiatry Service, VABHS, Instructor in Psychiatry, Harvard Medical School: This is a delicate balance that requires constant reassessment. The patient initially presented to the emergency department with suicidal ideation, stating he was not able to tolerate the pain and thus resumed alcohol consumption after a period of nonuse. He had multiple risk factors for suicide, including 9 prior suicide attempts with the latest less than a year before presentation, active substance use with alcohol and other recreational drugs, PTSD, pain, veteran status, male sex, single status, and a history of trauma.^3,4 He was also displaying impulsivity and limited insight, did not engage in his psychiatric assessment, and attempted to assault staff. As such, his suicide risk was assessed to be high at the time of the evaluation, which led to the decision to place an involuntary hold. However, we reevaluate this decision at least daily in order to reassess the risk and ensure that the balance between patient safety and autonomy are maintained.

►Dr. Merz: The involuntary hold was removed within 48 hours as the patient remained calm and engaged with the primary and consulting teams. He requested escalating doses of opioids as he felt the short-acting IV medications were not providing sustained relief. However, he was also noted to be walking outside of the hospital without assistance, and he repeatedly declined nonopioid pain modalities as well as buprenorphine/naloxone. The chronic pain service was consulted but was unable to see the patient as he was frequently outside of his room.

Dr. Shahal, how do you address OUD, pain, and stigma in the hospital?

►Dr. Shahal: It is important to remember that patients with substance use disorder (SUD) and mental illness frequently have physical causes for pain and are often undertreated.⁵ Patients with SUD may also have higher tolerance for opioids and may need higher doses to treat the pain.⁵ Modalities like buprenorphine/naloxone can be effective to treat OUD and pain, but these usually cannot be initiated while the patient is on short-acting opioids as this would precipitate withdrawal.⁶ However, withdrawal can be managed while inpatient, and this can be a good time to start these medications as practitioners can aggressively help with symptom control. Proactively addressing mental health concerns, particularly anxiety, AUD, insomnia, PTSD, and depression, can also have a direct impact on the perception of pain and assist with better control.² In addition, nonpharmacologic options, such as meditation, deep breathing, and even acupuncture and Reiki can be helpful and of course less harmful to treat pain.²

► Dr. Merz: An X-ray of the knee showed no acute fracture or joint space narrowing. Magnetic resonance imaging confirmed a large knee effusion with no evidence of ligament injury. Synovial fluid showed turbid, yellow fluid with 14,110 nucleated cells (84% segmented cells and 4000 RBCs). Gram stain was negative, culture had no growth, and there were no crystals. Anticyclic citrullinated peptide (anti-CCP), rheumatoid factor, HIV testing, and HLA-B27 were negative.

Dr. Serrao, what do these studies tell us about the joint effusion and the possible diagnoses?

► Dr. Richard Serrao, MD, Infectious Disease, VABHS, Clinical Associate Professor in Medicine, BUSM: I would expect the white blood cell (WBC) count to be > 50,000 cells with > 75% polymorphonuclear cells and a positive Gram stain if this was a bacterial infection resulting in septic arthritis.⁷ This patient’s studies are not consistent with this diagnosis nor is the chronicity of his presentation. There are 2 important bacteria that can present with inflammatory arthritis and less pronounced findings on arthrocentesis: Borrelia burgdorferi (the bacteria causing Lyme arthritis) and Neisseria gonorrhea. Lyme arthritis could be consistent with this relapsing remitting presentation as you expect a WBC count between 3000 and 100,000 cells with a mean value between 10,000 and 25,000 cells, > 50% polymorphonuclear leukocytes, and negative Gram stains.⁸ Gonococcal infections often do not have marked elevations in the WBC count and the Gram stain can be variable, but you still expect the WBC count to be > 30,000 cells.⁷ Inflammatory causes such as gout or autoimmune conditions such as lupus often have a WBC count between 2000 and 100,000 with a negative Gram stain, which could be consistent with this patient’s presentation.⁷ However, the lack of crystals rules out gout and the negative anti-CCP, rheumatoid factor, and HLA-B27 make rheumatologic diseases less likely.

►Dr. Merz: The patient received a phone call from another hospital where an arthrocentesis had been performed 3 weeks before. The results included a positive polymerase chain reaction (PCR) test for Lyme disease in the synovial fluid. A subsequent serum Lyme screen was positive for 1 of 3 immunoglobulin (Ig) M bands and 10 of 10 IgG bands.

Dr. Serrao, how does Lyme arthritis typically present, and are there aspects of this case that make you suspect the diagnosis? Does the serum Lyme test give us any additional information?

►Dr. Serrao: Lyme arthritis is a late manifestation of Lyme disease. Patients typically have persistent or intermittent arthritis, and large joints are more commonly impacted than small joints. Monoarthritis of the knee is the most common, but oligoarthritis is possible as well. The swelling usually begins abruptly, lasts for weeks to months, and effusions typically recur quickly after aspiration. These findings are consistent with the patient’s clinical history.

For diagnostics, the IgG Western blot is positive if 5 of the 10 bands are positive.⁹ This patient far exceeds the IgG band number to diagnose Lyme disease. All patients with Lyme arthritis will have positive IgG serologies since Lyme arthritis is a late manifestation of the infection. IgM reactivity may be present, but are not necessary to diagnose Lyme arthritis.¹⁰ Synovial fluid is often not analyzed for antibody responses as they are susceptible to false positive results, but synovial PCR testing like this patient had detects approximately 70% of patients with untreated Lyme arthritis.¹¹ However, PCR positivity does not necessarily equate with active infection. Serologic testing for Lyme disease by enzyme-linked immunosorbent assay and Western blot as well as careful history and the exclusion of other diagnoses are usually sufficient to make the diagnosis.

► Dr. Merz: On further history the patient reported that 5 years prior he found a tick on his skin with a bull’s-eye rash. He was treated with 28 days of doxycycline at that time. He did not recall any tick bites or rashes in the years since.

Dr. Serrao, is it surprising that he developed Lyme arthritis 5 years after exposure and after being treated appropriately? What is the typical treatment approach for a patient like this?

►Dr. Serrao: It is atypical to develop Lyme arthritis 5 years after reported treatment of what appeared to be early localized disease, namely, erythema migrans. This stage is usually cured with 10 days of treatment alone (he received 28 days) and is generally abortive of subsequent stages, including Lyme arthritis. Furthermore, the patient reported no symptoms of arthritis until recently since that time. Therefore, one can argue that the excessively long span of time from treatment to these first episodes of arthritis suggests the patient could have been reinfected. When available, comparing the types and number of Western blot bands (eg, new and/or more bands on subsequent serologic testing) can support a reinfection diagnosis. A delayed postinfectious inflammatory process from excessive proinflammatory immune responses that block wound repair resulting in proliferative synovitis is also possible.¹² This is defined as the postinfectious, postantibiotic, or antibiotic-refractory Lyme arthritis, a diagnosis of exclusion more apparent only after patients receive appropriate antibiotic courses for the possibility of untreated Lyme as an active infection.¹²

Given the inherent diagnostic uncertainty between an active infection and posttreatment Lyme arthritis syndromes, it is best to approach most cases of Lyme arthritis as an active infection first especially if not yet treated with antibiotics. Diagnosis of postinflammatory processes should be considered if symptoms persist after appropriate antibiotics, and then short-term use of disease-modifying antirheumatic drugs, rather than further courses of antibiotics, is recommended.

► Dr. Merz: The patient was initiated on doxycycline with the plan to transition to ceftriaxone if there was no response. One day after diagnosis and treatment initiation and in the setting of continued pain, the patient again asked to leave the hospital to drink alcohol. After eloping and becoming intoxicated with alcohol, he returned to his room. He remained concerned about his continued pain and lack of adequate pain control. At the time, he was receiving hydromorphone, ketorolac, lorazepam, gabapentin, and quetiapine.

Dr. Serrao, do you expect this degree of pain from Lyme arthritis?

► Dr. Serrao: Lyme arthritis is typically less painful than other forms of infectious or inflammatory arthritis. Pain is usually caused by the pressure from the acute accumulation and reaccumulation of fluid. In this case, the rapid accumulation of fluid that this patient experienced as well as relief with arthrocentesis suggests that the size and acuity of the effusion was causing great discomfort. Repeated arthrocentesis can prove to be a preventative strategy to minimize synovial herniation.

►Dr. Merz: Dr. Shahal, how do you balance the patient subjectively telling you that they are in pain with objective signs that they may be tolerating the pain like walking around unassisted? Is there anything else that could have been done to prevent this adverse outcome?

►Dr. Shahal: This is one of the hardest pieces of pain management. We want to practice beneficence by believing our patients and addressing their discomfort, but we also want to practice nonmaleficence by avoiding inappropriate long-term pain treatments like opioids that have significant harm as well as avoiding exacerbating this patient’s underlying SUD. An agent like buprenorphine/naloxone could have been an excellent fit to treat pain and SUD, but the patient’s lack of interest and the frequent use of short-acting opioids were major barriers. A chronic pain consult early on is helpful in cases like this as well, but they were unable to see him since he was often out of his room. Repeated arthrocentesis may also have helped the pain. Treatment of anxiety and insomnia with medications like hydroxyzine, trazodone, melatonin, gabapentin, or buspirone as well as interventions like sleep hygiene protocols or spiritual care may have helped somewhat as well.

We know that there is a vicious cycle between pain and poorly controlled mood symptoms. Many of our veterans have PTSD, anxiety, and SUD that are exacerbated by hospitalization and pain. Maintaining optimal communication between the patient and the practitioners, using trauma-informed care, understanding the patient’s goals of care, setting expectations and limits, and attempting to address the patient’s needs while attempting to minimize stigma might be helpful. However, despite optimal care, sometimes these events cannot be avoided.

►Dr. Merz: The patient was ultimately transferred to an inpatient psychiatric unit where a taper plan for the short-acting opioids was implemented. He was psychiatrically stabilized and discharged a few days later off opioids and on doxycycline. On follow-up a few weeks later, his pain had markedly improved, and the effusion was significantly reduced in size. His mood and impulsivity had stabilized. He continues to follow-up in the infectious disease clinic.

Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

*This article has been corrected to include a missing author.

Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?

► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.¹ In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.

► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?

► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.² Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).^3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.

Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.

► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).

Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?

► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.

► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.

Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?

► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.

► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.

Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?

► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.⁶ The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.⁷ Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.

If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.

► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?

► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.⁸ Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.^9,10

► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?

► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.^11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.^13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.¹⁵ As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).¹⁶ This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.

► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?

► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.⁹

His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.

► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.

Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?

► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.

Acknowledgments

The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.

*This article has been corrected to include a missing author.

Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?

► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.¹ In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.

► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?

► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.² Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).^3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.

Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.

► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).

Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?

► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.

► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.

Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?

► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.

► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.

Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?

► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.⁶ The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.⁷ Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.

If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.

► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?

► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.⁸ Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.^9,10

► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?

► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.^11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.^13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.¹⁵ As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).¹⁶ This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.

► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?

► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.⁹

His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.

► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.

Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?

► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.

Acknowledgments

The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.

*This article has been corrected to include a missing author.

Case Presentation. A 63-year-old male with well-controlled HIV (CD4 count 757, undetectable viral load), epilepsy, and hypertension presented to the VA Boston Healthcare System (VABHS) emergency department with 1 week of bilateral leg swelling and exertional shortness of breath. He reported having no fever, cough, chest pain, pain with inspiration and orthopnea. There was no personal or family history of pulmonary embolism. He reported weight gain but was unable to quantify how much. He also reported flare up of chronic knee pain, without swelling for which he had taken up to 4 tablets of naproxen daily for several weeks. His physical examination was notable for a heart rate of 105 beats per minute and bilateral pitting edema to his knees. Laboratory testing revealed a creatinine level of 2.5 mg/dL, which was increased from a baseline of 1.0 mg/dL (Table 1), and a urine protein-to-creatinine ratio of 7.8 mg/mg (Table 2). A renal ultrasound showed normal-sized kidneys without hydronephrosis or obstructing renal calculi. The patient was admitted for further workup of his dyspnea and acute kidney injury.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. William, based on the degree of proteinuria and edema, a diagnosis of nephrotic syndrome was made. How is nephrotic syndrome defined, and how is it distinguished from glomerulonephritis?

► Jeffrey William, MD, Nephrologist, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The pathophysiology of nephrotic disease and glomerulonephritis are quite distinct, resulting in symptoms and systemic manifestations that only slightly overlap. Glomerulonephritis is characterized by inflammation of the endothelial cells of the trilayered glomerular capillary, with a resulting active urine sediment with red blood cells, white blood cells, and casts. Nephrotic syndrome mostly affects the visceral epithelial cells of the glomerular capillary, commonly referred to as podocytes, and hence, the urine sediment in nephrotic disease is often inactive. Patients with nephrotic syndrome have nephrotic-range proteinuria (excretion of > 3.5 g per 24 h or a spot urine protein-creatinine ratio > 3.5 g in the steady state) and both hypoalbuminemia (< 3 g/dL) and peripheral edema. Lipiduria and hyperlipidemia are common findings in nephrotic syndrome but are not required for a clinical diagnosis.¹ In contrast, glomerulonephritis is defined by a constellation of findings that include renal insufficiency (often indicated by an elevation in blood urea nitrogen and creatinine), hypertension, hematuria, and subnephrotic range proteinuria. In practice, patients may fulfill criteria of both nephrotic and nephritic syndromes, but the preponderance of clinical evidence often points one way or the other. In this case, nephrotic syndrome was diagnosed based on the urine protein-to-creatinine ratio of 7.8 mg/mg, hypoalbuminemia, and edema.

► Dr. Li. What would be your first-line workup for evaluation of the etiology of this patient’s nephrotic syndrome?

► Dr. William. Rather than memorizing a list of etiologies of nephrotic syndrome, it is essential to consider the pathophysiology of heavy proteinuria. Though the glomerular filtration barrier is extremely complex and defects in any component can cause proteinuria, disruption of the podocyte is often involved. Common disease processes that chiefly target the podocyte include minimal change disease, primary focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy, all by differing mechanisms. Minimal change disease and idiopathic/primary FSGS are increasingly thought to be at differing points on a spectrum of the same disease.² Secondary FSGS, on the other hand, is a progressive disease, commonly resulting from longstanding hypertension, diabetes mellitus, and obesity in adults. Membranous nephropathy can also be either primary or secondary. Primary membranous nephropathy is chiefly caused by a circulating IgG4 antibody to the podocyte membrane antigen PLA2R (M-type phospholipase A2 receptor), whereas secondary membranous nephropathy can be caused by a variety of systemic etiologies, including autoimmune disease (eg, systemic lupus erythematosus), certain malignancies, chronic infections (eg, hepatitis B and C), and many medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).^3-5 Paraprotein deposition diseases can also cause glomerular damage leading to nephrotic-range proteinuria.

Given these potential diagnoses, a careful history should be taken to assess exposures and recent medication use. Urine sediment evaluation is essential in the evaluation of nephrotic syndrome to determine if there is an underlying nephritic process. Select serologies may be sent to look for autoimmune disease, such as systemic lupus erythematosus and common viral exposures like hepatitis B or C. Serum and urine protein electrophoreses would be appropriate initial tests of suspected paraprotein-related diseases. Other serologies, such as antineutrophil cytoplasmic antibodies or antiglomerular basement membrane antibodies, would not necessarily be indicated here given the lack of hematuria and presence of nephrotic-range proteinuria.

► Dr. Li. The initial evaluation was notable for an erythrocyte sedimentation rate > 120 (mm/h) and a weakly positive antinuclear antibody (ANA) titer of 1:40. The remainder of his initial workup did not reveal an etiology for his nephrotic syndrome (Table 3).

Dr. William, is there a role for starting urgent empiric steroids in nephrotic syndrome while workup is ongoing? If so, do the severity of proteinuria and/or symptoms play a role or is this determination based on something else?

► Dr. William. Edema is a primary symptom of nephrotic syndrome and can often be managed with diuretics alone. If a clear medication-mediated cause is suspected, discontinuation of this agent may result in spontaneous improvement without steroid treatment. However,in cases where an etiology is unclear and there are serious thrombotic complications requiring anticoagulation, and a renal biopsy is deemed to be too risky, then empiric steroid therapy may be necessary. Children with new-onset nephrotic syndrome are presumed to have minimal change disease, given its prevalence in this patient population, and are often given empiric steroids without obtaining a renal biopsy. However, in the adult population, a renal biopsy can typically be performed quickly and safely, with pathology results interpreted within days. In this patient, since a diagnosis was unclear and there was no contraindication to renal biopsy, a biopsy should be obtained before consideration of steroids.

► Dr. Li. Steroids were deferred in anticipation of renal biopsy, which showed stage I membranous nephropathy, suggestive of membranous lupus nephritis Class V. The deposits were strongly reactive for immunoglobuline G (IgG), IgA, and complement 1q (C1q), showed co-dominant staining for IgG1, IgG2, and IgG3, and were weakly positive for the PLA2 receptor. Focal intimal arteritis in a small interlobular vessel was seen.

Dr. William, the pathology returned suggestive of lupus nephritis. Does the overall clinical picture fit with lupus nephritis?

► Dr. William. Given the history and a rather low ANA, the diagnosis of lupus nephritis seems unlikely. The lack of IgG4 and PLA2R staining in the biopsy suggests that this membranous pattern on the biopsy is likely to be secondary to a systemic etiology, but further investigation should be pursued.

► Dr. Li. The patient was discharged after the biopsy with a planned outpatient nephrology follow-up to discuss results and treatment. He was prescribed an oral diuretic, and his symptoms improved. Several days after discharge, he developed blurry vision and was evaluated in the Ophthalmology clinic. On fundoscopy, he was found to have acute papillitis, a form of optic neuritis. As part of initial evaluation of infectious etiologies of papillitis, ophthalmology recommended testing for syphilis.

Dr. Strymish, when we are considering secondary syphilis, what is the recommended approach to diagnostic testing?

► Judith Strymish, MD, Infectious Diseases, BIDMC, Assistant Professor of Medicine, Harvard Medical School. The diagnosis of syphilis is usually made through serologic testing of blood specimens. Methods that detect the spirochete directly like dark-field smears are not readily available. Serologic tests include treponemal tests (eg, Treponema pallidum particle agglutination assay [TPPA]) and nontreponemal tests (eg, rapid plasma reagin [RPR]). One needs a confirmatory test because either test is associated with false positives. Either test can be done first. Most laboratories, including those at VABHS are now performing treponemal tests first as these have become more cost-effective.⁶ The TPPA treponemal test was found to have a lower false negative rate in primary syphilis compared with that of nontreponemal tests.⁷ Nontreponemal tests can be followed for response to therapy. If a patient has a history of treated syphilis, a nontreponemal test should be sent, since the treponemal test will remain positive for life.

If there is clinical concern for neurosyphilis, cerebrospinal fluid fluorescent (CSF) treponemal antibody needs to be sampled and sent for the nontreponemal venereal disease research laboratory (VDRL) test. The VDRL is highly specific for neurosyphilis but not as sensitive. Cerebrospinal fluid fluorescent treponemal antibody (CSF FTA) may also be sent; it is very sensitive but not very specific for neurosyphilis.

► Dr. Li. An RPR returned positive at 1:512 (was negative 14 months prior on a routine screening test), with positive reflex TPPA (Table 4). A diagnosis of secondary syphilis was made. Dr. Strymish, at this point, what additional testing and treatment is necessary?

► Dr. Strymish. With papillitis and a very high RPR, we need to assume that he has ophthalmic syphilis. This can occur in any stage of syphilis, but his eye findings and high RPR are consistent with secondary syphilis. Ophthalmic syphilis has been on the upswing, even more than is expected with recent increases in syphilis cases.⁸ Ophthalmic syphilis is considered a form of neurosyphilis. A lumbar puncture and treatment for neurosyphilis is recommended.^9,10

► Dr. Li. A lumbar puncture was performed, and his CSF was VDRL positive. This confirmed a diagnosis of neurosyphilis (Table 4). The patient was treated for neurosyphilis with IV penicillin. The patient shared that he had episodes of unprotected oral sexual activity within the past year and approximately 1 year ago, he came in close contact (but no sexual activity) with a person who had a rash consistent with syphilis.Dr. William, syphilis would be a potential unifying diagnosis of his renal and ophthalmologic manifestations. Is syphilis known to cause membranous nephropathy?

► Dr. William. Though it is uncommon, the nephrotic syndrome is a well-described complication of secondary syphilis.^11,12 Syphilis has been shown to cause nephrotic syndrome in a variety of ways. Case reports abound linking syphilis to minimal change disease and other glomerular diseases.^13,14 A case report from 1993 shows a membranous pattern of glomerular disease similar to this case.¹⁵ As a form of secondary membranous nephropathy, the immunofluorescence pattern can demonstrate staining similar to the “full house” seen in lupus nephritis (IgA, IgM, and C1q, in addition to IgG and C3).¹⁶ This explains the initial interpretation of this patient’s biopsy, as lupus nephritis would be a much more common etiology of secondary membranous nephropathy than is acute syphilis with this immunofluorescence pattern. However, the data in this case are highly suggestive of a causal relationship between secondary syphilis and membranous nephropathy.

► Dr. Li. Dr. Strymish, how should this patient be screened for syphilis reinfection, and at what intervals would you recommend?

► Dr. Strymish. He will need follow-up testing to make sure that his syphilis is effectively treated. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. He will also need follow-up for normalization of his RPR. Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy according to US Centers for Disease Control and Prevention guidelines.⁹

His treponemal test for syphilis will likely stay positive for life. His RPR should decrease significantly with effective treatment. It makes sense to screen with RPR alone as long as he continues to have risk factors for acquiring syphilis. Routine syphilis testing is recommended for pregnant women, sexually active men who have sex with men, sexually active persons with HIV, and persons taking PrEP (pre-exposure prophylaxis) for HIV prevention. He should be screened at least yearly for syphilis.

► Dr. Li. Over the next several months, the patient’s creatinine normalized and his proteinuria resolved. His vision recovered, and he has had no further ophthalmologic complications.

Dr. William, what is his long-term renal prognosis? Do you expect that his acute episode of membranous nephropathy will have permanent effects on his renal function?

► Dr. William. His rapid response to therapy for neurosyphilis provides evidence for this etiology of his renal dysfunction and glomerulonephritis. His long-term prognosis is quite good if the syphilis is the only reason for him to have renal disease. The renal damage is often reversible in these cases. However, given his prior extensive NSAID exposure and history of hypertension, he may be at higher risk for chronic kidney disease than an otherwise healthy patient, especially after an episode of acute kidney injury. Therefore, his renal function should continue to be monitored as an outpatient.

Acknowledgments

The authors thank this veteran for sharing his story and allowing us to learn from this unusual case for the benefit of our future patients.

Case Presentation. A 70-year-old US Marine Corps veteran of the Vietnam War with no significant past medical history was brought by ambulance to VA Boston Healthcare System (VABHS) after being found on the floor at home by his wife, awake, but with minimally coherent speech. He was moving all extremities, and there was no loss of bowel or bladder continence. He had last been seen well by his wife 30 minutes prior. When emergency medical services arrived, his finger stick blood glucose and vital signs were within normal range. In the emergency department, he was able to state his first name but then continuously repeated “7/11” to other questions. A neurologic examination revealed intact cranial nerves, full strength in all extremities, and normal reflexes. A National Institute of Health Stroke Scale (NIHSS) was 3, and a code stroke was activated. At the time of presentation, the patient was an active smoker of 15 cigarettes per day for 50 years and did not use alcohol or recreational drugs.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. Fehnel, the patient’s medical team was most worried about a transient ischemic attack (TIA) or cerebrovascular accident (CVA). Is his presentation consistent with these diagnoses, and what else is on your differential diagnosis?

►Corey R. Fehnel, MD, Neuro-Intensivist, BIDMC, and Assistant Professor of Neurology, Harvard Medical School. This patient is presenting with what appears to be an acute encephalopathy—a sudden onset of global alteration in mental status. The most worrisome underlying etiology for this presentation would be acute stroke, but this is an uncommon cause of acute encephalopathy. The differential diagnosis at this stage remains broad, but a careful neurologic examination can help narrow the possibilities. In particular, I would aim to differentiate an apparent language deficit (ie, aphasia) from a deficit of attention. A key finding that may help is the ability to name high- or low-frequency objects. If the patient can successfully name objects, aphasia is less likely. Based on the limited examination at present, the patient produces some normal speech, but perseverates; therefore, the finding remains nonspecific. My leading diagnoses are complex partial seizure and toxic/metabolic encephalopathy.

►Dr. Li. This patient’s NIHSS score is 3. How do you use this score in your management decisions for the patient?

►Dr. Fehnel. The NIHSS is a useful tool for gauging severity of ischemic and hemorrhagic stroke. However the score is not specific for establishing the diagnosis of stroke. Many common and chronic neurologic problems will score on the NIHSS, so it can never be interpreted in isolation. If the clinical history and complete neurologic examination support the diagnosis of stroke, then the NIHSS can be used with the understanding that it is biased toward anterior circulation strokes, and posterior circulation strokes will score lower even though they are potentially more life threatening.¹ In this case, even though a complex partial seizure appears more likely, it is difficult to rule out the possibility of an acute stroke affecting the thalamus or, less likely, a distal middle cerebral artery occlusion. I would consider IV thrombolysis pending further history and neuroimaging results.

►Dr. Li. Initial laboratory data include a hemoglobin of 12.8 mg/dL. The white cell count, platelet count, chemistry panel, liver function tests, thyroid-stimulating hormone, and troponin were within normal range (Table 1). 

Do you agree with inpatient workup for this patient whose mental status has now returned to baseline? If so, what workup would you pursue next?

►Dr. Fehnel. This patient requires inpatient admission to further evaluate the underlying etiology for his acute change in mental status. The improvement of his presenting deficit and largely normal neurovascular imaging make a neurovascular etiology less likely, but a careful risk factor evaluation for CVA/TIA should be performed, including continuous cardiac telemetry to detect atrial fibrillation. Magnetic resonance imaging (MRI) of the brain should be performed to rule out occult stroke and evaluate for a structural etiology given the more likely diagnosis of complex partial seizure. An electroencephalogram (EEG), preferably 24-hour continuous recording, should be performed. Without a clear toxic or metabolic etiology thus far to explain his acute global waxing-waning alteration in mental status and likely new-onset complex partial seizures, I would also pursue lumbar puncture for cerebrospinal fluid examination.

►Dr. Li. The hospital course was notable for episodes of acute combativeness and confusion. An MRI of the brain was deferred due to reports from the patient’s family of retained shrapnel in the lumbar spine. Routine EEG showed no seizure activity. This was followed by continuous video EEG monitoring, which showed subclinical seizure activity with a right temporal focus. He was started on valproic acid with improvement in his agitation, though confusion continued. He was discharged to an inpatient geriatric psychiatry nursing home with diagnosis of seizures and acute delirium.

Dr. Fehnel, seizures are often part of the workup for unexplained encephalopathy. In this case, the routine EEG was unrevealing, while the continuous video EEG proved valuable. In what situations would you pursue a continuous video EEG in addition to a routine EEG?

►Dr. Fehnel. EEG monitoring is only as good as the window of time during which the study is performed. If the suspicious clinical event is captured during a routine recording or an area of focal slowing is detected, a shorter study may be entirely sufficient. However, in cases where there is no clear alternative explanation, a patient’s mental status does not return to normal, or in the setting of mental status fluctuations without explanation, continuous video-EEG monitoring for at least 24 hours is indicated. While the prolonged study raises sensitivity, the exact duration of EEG recording required outside of the intensive care unit setting remains debated.²

►Dr. Li. If his encephalopathy were due to seizures alone, I would expect improvement in his mental status during interictal periods, which does not appear to be the case here. Do you feel the seizures alone can explain his encephalopathy?

►Dr. Fehnel. Complex partial seizures and the medications used to treat them can confound the examination of patients during the interictal period. We commonly debate postictal encephalopathy vs residual effect of benzodiazepines and rapid dose escalation of antiepileptic drugs as culprit in a patient’s prolonged alteration in mental status. Serial clinical examinations, continuous EEG monitoring to rule out ongoing subclinical seizures when appropriate, and judicious use of potentially sedating medications is the most helpful approach. The key issue here is the bimodal distribution of new-onset seizures. Among children there is a higher incidence of genetically related seizure disorders; whereas among adults, “acquired” and structural etiologies are more common. For this case, a more careful evaluation of acquired/structural etiologies for new-onset seizures is indicated.

►Dr. Li. At the geriatric psychiatry nursing home, the patient continued to be combative and refused medications. He was readmitted to the VABHS with encephalopathy of unclear etiology. An expanded encephalopathy workup was unrevealing (Table 2). 

Dr. Fehnel, this patient’s initial cerebrospinal fluid (CSF) cell count and chemistries were completely normal. Is this sufficient to rule out encephalitis? If not, what other diagnostic tests would you send?

►Dr. Fehnel. A fully normal CSF profile reduces the likelihood of a broad range of neuro-infectious etiologies but does not completely rule those out. For example, there are reports of herpes simplex virus (HSV) encephalitis producing relatively normal profiles and even negative polymerase chain reaction assays for antibodies to HSV if the specimen is obtained very early in the course of the disease.^3,4 That was not the case here as the CSF was obtained several days after his initial presentation. Given this patient’s clinical syndrome, normal CSF findings, and long smoking history without regular screening examinations, I would send a CSF specimen screening for paraneoplastic and autoimmune encephalitis. Most autoimmune encephalitis syndromes are associated with CSF lymphocytic pleocytosis or slight elevation in CSF protein levels. This patient’s diagnosis is most likely an anti-Hu paraneoplastic syndrome, which can be distinguished from other autoimmune and paraneoplastic processes by the characteristically normal CSF profile. Anti-Hu antibodies are strongly associated with non-small cell lung cancer (NSCLC). I would, therefore, also obtain more advanced chest imaging.

►Dr. Li. An autoimmune and paraneoplastic encephalitis panel was sent. While this send-out panel was pending, a CT torso was obtained to evaluate for occult malignancy in light of his significant smoking history. This showed a 3-cm spiculated mass originating from the left hilum. Bronchoalviolar lavage washings returned positive for small cell lung cancer. 

Dr. Fehnel, can you explain the mechanism by which certain neoplasms can cause encephalitis?

►Dr. Fehnel. Onconeuronal antibodies Hu (NSCLC) and Ma2 (testicular seminoma), when identified, are strongly associated with the presence of an underlying malignancy. The work of Dr. Josep Dalmau and others in this area has dramatically improved our understanding of these syndromes over the past 25 years.⁵ The exact mechanism is not fully understood but is thought to be mediated by cytotoxic T-cell response directed at the malignancy itself with homology to intraneuronal structures, which are readily absorbed and result in neuronal cell death.⁶

►Dr. Li. Is there a specific treatment for paraneoplastic encephalitis, other than treating the underlying malignancy?

►Dr. Fehnel. Early treatment is associated with improved outcome and should not be delayed while waiting for laboratory confirmation in cases of high clinical suspicion. Treatment directed at the underlying tumor is the mainstay along with less specific immunosuppressive agents. Unfortunately Anti-Hu (as well as Ma2) antibodies are intraneuronal and less responsive to standard treatments relative to other paraneoplastic auto-antibodies identified on the cell surface. Immunosuppressive agents typically used in this setting include high-dose IV methylprednisolone, IV immune globulin (IVIG), rituximab, and cyclophosphamide.⁷

►Dr. Li. The patient was started on IVIG, methylprednisolone, cisplatin, and etoposide. His course was complicated by aspiration pneumonia, autonomic dysfunction causing tachy- and brady-arrhythmias, urosepsis, worsening somnolence, chemotherapy-induced neutropenic fevers, and ultimately septic shock. The palliative care team was closely involved throughout the final stages of his hospital course. After multiple family meetings, the patient was transitioned to comfort-focused care per family discussion and died 6 weeks after his initial presentation.

This patient had a very atypical initial presentation of small cell lung cancer. Despite the fact that a diagnosis eluded his doctors, they persisted in a thoughtful and exhaustive workup and through this perseverance were able to make the final diagnosis, which serves as an important learning case for us all.

Acknowledgments

We thank the family of this veteran for sharing his story and allowing us to learn from this case for the benefit of our future patients. We also thank Dr. Michelle Hankins, who provided oncologic expertise.

Case Presentation. A 70-year-old US Marine Corps veteran of the Vietnam War with no significant past medical history was brought by ambulance to VA Boston Healthcare System (VABHS) after being found on the floor at home by his wife, awake, but with minimally coherent speech. He was moving all extremities, and there was no loss of bowel or bladder continence. He had last been seen well by his wife 30 minutes prior. When emergency medical services arrived, his finger stick blood glucose and vital signs were within normal range. In the emergency department, he was able to state his first name but then continuously repeated “7/11” to other questions. A neurologic examination revealed intact cranial nerves, full strength in all extremities, and normal reflexes. A National Institute of Health Stroke Scale (NIHSS) was 3, and a code stroke was activated. At the time of presentation, the patient was an active smoker of 15 cigarettes per day for 50 years and did not use alcohol or recreational drugs.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. Fehnel, the patient’s medical team was most worried about a transient ischemic attack (TIA) or cerebrovascular accident (CVA). Is his presentation consistent with these diagnoses, and what else is on your differential diagnosis?

►Corey R. Fehnel, MD, Neuro-Intensivist, BIDMC, and Assistant Professor of Neurology, Harvard Medical School. This patient is presenting with what appears to be an acute encephalopathy—a sudden onset of global alteration in mental status. The most worrisome underlying etiology for this presentation would be acute stroke, but this is an uncommon cause of acute encephalopathy. The differential diagnosis at this stage remains broad, but a careful neurologic examination can help narrow the possibilities. In particular, I would aim to differentiate an apparent language deficit (ie, aphasia) from a deficit of attention. A key finding that may help is the ability to name high- or low-frequency objects. If the patient can successfully name objects, aphasia is less likely. Based on the limited examination at present, the patient produces some normal speech, but perseverates; therefore, the finding remains nonspecific. My leading diagnoses are complex partial seizure and toxic/metabolic encephalopathy.

►Dr. Li. This patient’s NIHSS score is 3. How do you use this score in your management decisions for the patient?

►Dr. Fehnel. The NIHSS is a useful tool for gauging severity of ischemic and hemorrhagic stroke. However the score is not specific for establishing the diagnosis of stroke. Many common and chronic neurologic problems will score on the NIHSS, so it can never be interpreted in isolation. If the clinical history and complete neurologic examination support the diagnosis of stroke, then the NIHSS can be used with the understanding that it is biased toward anterior circulation strokes, and posterior circulation strokes will score lower even though they are potentially more life threatening.¹ In this case, even though a complex partial seizure appears more likely, it is difficult to rule out the possibility of an acute stroke affecting the thalamus or, less likely, a distal middle cerebral artery occlusion. I would consider IV thrombolysis pending further history and neuroimaging results.

►Dr. Li. Initial laboratory data include a hemoglobin of 12.8 mg/dL. The white cell count, platelet count, chemistry panel, liver function tests, thyroid-stimulating hormone, and troponin were within normal range (Table 1). 

Do you agree with inpatient workup for this patient whose mental status has now returned to baseline? If so, what workup would you pursue next?

►Dr. Fehnel. This patient requires inpatient admission to further evaluate the underlying etiology for his acute change in mental status. The improvement of his presenting deficit and largely normal neurovascular imaging make a neurovascular etiology less likely, but a careful risk factor evaluation for CVA/TIA should be performed, including continuous cardiac telemetry to detect atrial fibrillation. Magnetic resonance imaging (MRI) of the brain should be performed to rule out occult stroke and evaluate for a structural etiology given the more likely diagnosis of complex partial seizure. An electroencephalogram (EEG), preferably 24-hour continuous recording, should be performed. Without a clear toxic or metabolic etiology thus far to explain his acute global waxing-waning alteration in mental status and likely new-onset complex partial seizures, I would also pursue lumbar puncture for cerebrospinal fluid examination.

►Dr. Li. The hospital course was notable for episodes of acute combativeness and confusion. An MRI of the brain was deferred due to reports from the patient’s family of retained shrapnel in the lumbar spine. Routine EEG showed no seizure activity. This was followed by continuous video EEG monitoring, which showed subclinical seizure activity with a right temporal focus. He was started on valproic acid with improvement in his agitation, though confusion continued. He was discharged to an inpatient geriatric psychiatry nursing home with diagnosis of seizures and acute delirium.

Dr. Fehnel, seizures are often part of the workup for unexplained encephalopathy. In this case, the routine EEG was unrevealing, while the continuous video EEG proved valuable. In what situations would you pursue a continuous video EEG in addition to a routine EEG?

►Dr. Fehnel. EEG monitoring is only as good as the window of time during which the study is performed. If the suspicious clinical event is captured during a routine recording or an area of focal slowing is detected, a shorter study may be entirely sufficient. However, in cases where there is no clear alternative explanation, a patient’s mental status does not return to normal, or in the setting of mental status fluctuations without explanation, continuous video-EEG monitoring for at least 24 hours is indicated. While the prolonged study raises sensitivity, the exact duration of EEG recording required outside of the intensive care unit setting remains debated.²

►Dr. Li. If his encephalopathy were due to seizures alone, I would expect improvement in his mental status during interictal periods, which does not appear to be the case here. Do you feel the seizures alone can explain his encephalopathy?

►Dr. Fehnel. Complex partial seizures and the medications used to treat them can confound the examination of patients during the interictal period. We commonly debate postictal encephalopathy vs residual effect of benzodiazepines and rapid dose escalation of antiepileptic drugs as culprit in a patient’s prolonged alteration in mental status. Serial clinical examinations, continuous EEG monitoring to rule out ongoing subclinical seizures when appropriate, and judicious use of potentially sedating medications is the most helpful approach. The key issue here is the bimodal distribution of new-onset seizures. Among children there is a higher incidence of genetically related seizure disorders; whereas among adults, “acquired” and structural etiologies are more common. For this case, a more careful evaluation of acquired/structural etiologies for new-onset seizures is indicated.

►Dr. Li. At the geriatric psychiatry nursing home, the patient continued to be combative and refused medications. He was readmitted to the VABHS with encephalopathy of unclear etiology. An expanded encephalopathy workup was unrevealing (Table 2). 

Dr. Fehnel, this patient’s initial cerebrospinal fluid (CSF) cell count and chemistries were completely normal. Is this sufficient to rule out encephalitis? If not, what other diagnostic tests would you send?

►Dr. Fehnel. A fully normal CSF profile reduces the likelihood of a broad range of neuro-infectious etiologies but does not completely rule those out. For example, there are reports of herpes simplex virus (HSV) encephalitis producing relatively normal profiles and even negative polymerase chain reaction assays for antibodies to HSV if the specimen is obtained very early in the course of the disease.^3,4 That was not the case here as the CSF was obtained several days after his initial presentation. Given this patient’s clinical syndrome, normal CSF findings, and long smoking history without regular screening examinations, I would send a CSF specimen screening for paraneoplastic and autoimmune encephalitis. Most autoimmune encephalitis syndromes are associated with CSF lymphocytic pleocytosis or slight elevation in CSF protein levels. This patient’s diagnosis is most likely an anti-Hu paraneoplastic syndrome, which can be distinguished from other autoimmune and paraneoplastic processes by the characteristically normal CSF profile. Anti-Hu antibodies are strongly associated with non-small cell lung cancer (NSCLC). I would, therefore, also obtain more advanced chest imaging.

►Dr. Li. An autoimmune and paraneoplastic encephalitis panel was sent. While this send-out panel was pending, a CT torso was obtained to evaluate for occult malignancy in light of his significant smoking history. This showed a 3-cm spiculated mass originating from the left hilum. Bronchoalviolar lavage washings returned positive for small cell lung cancer. 

Dr. Fehnel, can you explain the mechanism by which certain neoplasms can cause encephalitis?

►Dr. Fehnel. Onconeuronal antibodies Hu (NSCLC) and Ma2 (testicular seminoma), when identified, are strongly associated with the presence of an underlying malignancy. The work of Dr. Josep Dalmau and others in this area has dramatically improved our understanding of these syndromes over the past 25 years.⁵ The exact mechanism is not fully understood but is thought to be mediated by cytotoxic T-cell response directed at the malignancy itself with homology to intraneuronal structures, which are readily absorbed and result in neuronal cell death.⁶

►Dr. Li. Is there a specific treatment for paraneoplastic encephalitis, other than treating the underlying malignancy?

►Dr. Fehnel. Early treatment is associated with improved outcome and should not be delayed while waiting for laboratory confirmation in cases of high clinical suspicion. Treatment directed at the underlying tumor is the mainstay along with less specific immunosuppressive agents. Unfortunately Anti-Hu (as well as Ma2) antibodies are intraneuronal and less responsive to standard treatments relative to other paraneoplastic auto-antibodies identified on the cell surface. Immunosuppressive agents typically used in this setting include high-dose IV methylprednisolone, IV immune globulin (IVIG), rituximab, and cyclophosphamide.⁷

►Dr. Li. The patient was started on IVIG, methylprednisolone, cisplatin, and etoposide. His course was complicated by aspiration pneumonia, autonomic dysfunction causing tachy- and brady-arrhythmias, urosepsis, worsening somnolence, chemotherapy-induced neutropenic fevers, and ultimately septic shock. The palliative care team was closely involved throughout the final stages of his hospital course. After multiple family meetings, the patient was transitioned to comfort-focused care per family discussion and died 6 weeks after his initial presentation.

This patient had a very atypical initial presentation of small cell lung cancer. Despite the fact that a diagnosis eluded his doctors, they persisted in a thoughtful and exhaustive workup and through this perseverance were able to make the final diagnosis, which serves as an important learning case for us all.

Acknowledgments

We thank the family of this veteran for sharing his story and allowing us to learn from this case for the benefit of our future patients. We also thank Dr. Michelle Hankins, who provided oncologic expertise.

Case Presentation. A 70-year-old US Marine Corps veteran of the Vietnam War with no significant past medical history was brought by ambulance to VA Boston Healthcare System (VABHS) after being found on the floor at home by his wife, awake, but with minimally coherent speech. He was moving all extremities, and there was no loss of bowel or bladder continence. He had last been seen well by his wife 30 minutes prior. When emergency medical services arrived, his finger stick blood glucose and vital signs were within normal range. In the emergency department, he was able to state his first name but then continuously repeated “7/11” to other questions. A neurologic examination revealed intact cranial nerves, full strength in all extremities, and normal reflexes. A National Institute of Health Stroke Scale (NIHSS) was 3, and a code stroke was activated. At the time of presentation, the patient was an active smoker of 15 cigarettes per day for 50 years and did not use alcohol or recreational drugs.

► Jonathan Li, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC). Dr. Fehnel, the patient’s medical team was most worried about a transient ischemic attack (TIA) or cerebrovascular accident (CVA). Is his presentation consistent with these diagnoses, and what else is on your differential diagnosis?

►Corey R. Fehnel, MD, Neuro-Intensivist, BIDMC, and Assistant Professor of Neurology, Harvard Medical School. This patient is presenting with what appears to be an acute encephalopathy—a sudden onset of global alteration in mental status. The most worrisome underlying etiology for this presentation would be acute stroke, but this is an uncommon cause of acute encephalopathy. The differential diagnosis at this stage remains broad, but a careful neurologic examination can help narrow the possibilities. In particular, I would aim to differentiate an apparent language deficit (ie, aphasia) from a deficit of attention. A key finding that may help is the ability to name high- or low-frequency objects. If the patient can successfully name objects, aphasia is less likely. Based on the limited examination at present, the patient produces some normal speech, but perseverates; therefore, the finding remains nonspecific. My leading diagnoses are complex partial seizure and toxic/metabolic encephalopathy.

►Dr. Li. This patient’s NIHSS score is 3. How do you use this score in your management decisions for the patient?

►Dr. Fehnel. The NIHSS is a useful tool for gauging severity of ischemic and hemorrhagic stroke. However the score is not specific for establishing the diagnosis of stroke. Many common and chronic neurologic problems will score on the NIHSS, so it can never be interpreted in isolation. If the clinical history and complete neurologic examination support the diagnosis of stroke, then the NIHSS can be used with the understanding that it is biased toward anterior circulation strokes, and posterior circulation strokes will score lower even though they are potentially more life threatening.¹ In this case, even though a complex partial seizure appears more likely, it is difficult to rule out the possibility of an acute stroke affecting the thalamus or, less likely, a distal middle cerebral artery occlusion. I would consider IV thrombolysis pending further history and neuroimaging results.

►Dr. Li. Initial laboratory data include a hemoglobin of 12.8 mg/dL. The white cell count, platelet count, chemistry panel, liver function tests, thyroid-stimulating hormone, and troponin were within normal range (Table 1). 

Do you agree with inpatient workup for this patient whose mental status has now returned to baseline? If so, what workup would you pursue next?

►Dr. Fehnel. This patient requires inpatient admission to further evaluate the underlying etiology for his acute change in mental status. The improvement of his presenting deficit and largely normal neurovascular imaging make a neurovascular etiology less likely, but a careful risk factor evaluation for CVA/TIA should be performed, including continuous cardiac telemetry to detect atrial fibrillation. Magnetic resonance imaging (MRI) of the brain should be performed to rule out occult stroke and evaluate for a structural etiology given the more likely diagnosis of complex partial seizure. An electroencephalogram (EEG), preferably 24-hour continuous recording, should be performed. Without a clear toxic or metabolic etiology thus far to explain his acute global waxing-waning alteration in mental status and likely new-onset complex partial seizures, I would also pursue lumbar puncture for cerebrospinal fluid examination.

►Dr. Li. The hospital course was notable for episodes of acute combativeness and confusion. An MRI of the brain was deferred due to reports from the patient’s family of retained shrapnel in the lumbar spine. Routine EEG showed no seizure activity. This was followed by continuous video EEG monitoring, which showed subclinical seizure activity with a right temporal focus. He was started on valproic acid with improvement in his agitation, though confusion continued. He was discharged to an inpatient geriatric psychiatry nursing home with diagnosis of seizures and acute delirium.

Dr. Fehnel, seizures are often part of the workup for unexplained encephalopathy. In this case, the routine EEG was unrevealing, while the continuous video EEG proved valuable. In what situations would you pursue a continuous video EEG in addition to a routine EEG?

►Dr. Fehnel. EEG monitoring is only as good as the window of time during which the study is performed. If the suspicious clinical event is captured during a routine recording or an area of focal slowing is detected, a shorter study may be entirely sufficient. However, in cases where there is no clear alternative explanation, a patient’s mental status does not return to normal, or in the setting of mental status fluctuations without explanation, continuous video-EEG monitoring for at least 24 hours is indicated. While the prolonged study raises sensitivity, the exact duration of EEG recording required outside of the intensive care unit setting remains debated.²

►Dr. Li. If his encephalopathy were due to seizures alone, I would expect improvement in his mental status during interictal periods, which does not appear to be the case here. Do you feel the seizures alone can explain his encephalopathy?

►Dr. Fehnel. Complex partial seizures and the medications used to treat them can confound the examination of patients during the interictal period. We commonly debate postictal encephalopathy vs residual effect of benzodiazepines and rapid dose escalation of antiepileptic drugs as culprit in a patient’s prolonged alteration in mental status. Serial clinical examinations, continuous EEG monitoring to rule out ongoing subclinical seizures when appropriate, and judicious use of potentially sedating medications is the most helpful approach. The key issue here is the bimodal distribution of new-onset seizures. Among children there is a higher incidence of genetically related seizure disorders; whereas among adults, “acquired” and structural etiologies are more common. For this case, a more careful evaluation of acquired/structural etiologies for new-onset seizures is indicated.

►Dr. Li. At the geriatric psychiatry nursing home, the patient continued to be combative and refused medications. He was readmitted to the VABHS with encephalopathy of unclear etiology. An expanded encephalopathy workup was unrevealing (Table 2). 

Dr. Fehnel, this patient’s initial cerebrospinal fluid (CSF) cell count and chemistries were completely normal. Is this sufficient to rule out encephalitis? If not, what other diagnostic tests would you send?

►Dr. Fehnel. A fully normal CSF profile reduces the likelihood of a broad range of neuro-infectious etiologies but does not completely rule those out. For example, there are reports of herpes simplex virus (HSV) encephalitis producing relatively normal profiles and even negative polymerase chain reaction assays for antibodies to HSV if the specimen is obtained very early in the course of the disease.^3,4 That was not the case here as the CSF was obtained several days after his initial presentation. Given this patient’s clinical syndrome, normal CSF findings, and long smoking history without regular screening examinations, I would send a CSF specimen screening for paraneoplastic and autoimmune encephalitis. Most autoimmune encephalitis syndromes are associated with CSF lymphocytic pleocytosis or slight elevation in CSF protein levels. This patient’s diagnosis is most likely an anti-Hu paraneoplastic syndrome, which can be distinguished from other autoimmune and paraneoplastic processes by the characteristically normal CSF profile. Anti-Hu antibodies are strongly associated with non-small cell lung cancer (NSCLC). I would, therefore, also obtain more advanced chest imaging.

►Dr. Li. An autoimmune and paraneoplastic encephalitis panel was sent. While this send-out panel was pending, a CT torso was obtained to evaluate for occult malignancy in light of his significant smoking history. This showed a 3-cm spiculated mass originating from the left hilum. Bronchoalviolar lavage washings returned positive for small cell lung cancer. 

Dr. Fehnel, can you explain the mechanism by which certain neoplasms can cause encephalitis?

►Dr. Fehnel. Onconeuronal antibodies Hu (NSCLC) and Ma2 (testicular seminoma), when identified, are strongly associated with the presence of an underlying malignancy. The work of Dr. Josep Dalmau and others in this area has dramatically improved our understanding of these syndromes over the past 25 years.⁵ The exact mechanism is not fully understood but is thought to be mediated by cytotoxic T-cell response directed at the malignancy itself with homology to intraneuronal structures, which are readily absorbed and result in neuronal cell death.⁶

►Dr. Li. Is there a specific treatment for paraneoplastic encephalitis, other than treating the underlying malignancy?

►Dr. Fehnel. Early treatment is associated with improved outcome and should not be delayed while waiting for laboratory confirmation in cases of high clinical suspicion. Treatment directed at the underlying tumor is the mainstay along with less specific immunosuppressive agents. Unfortunately Anti-Hu (as well as Ma2) antibodies are intraneuronal and less responsive to standard treatments relative to other paraneoplastic auto-antibodies identified on the cell surface. Immunosuppressive agents typically used in this setting include high-dose IV methylprednisolone, IV immune globulin (IVIG), rituximab, and cyclophosphamide.⁷

►Dr. Li. The patient was started on IVIG, methylprednisolone, cisplatin, and etoposide. His course was complicated by aspiration pneumonia, autonomic dysfunction causing tachy- and brady-arrhythmias, urosepsis, worsening somnolence, chemotherapy-induced neutropenic fevers, and ultimately septic shock. The palliative care team was closely involved throughout the final stages of his hospital course. After multiple family meetings, the patient was transitioned to comfort-focused care per family discussion and died 6 weeks after his initial presentation.

This patient had a very atypical initial presentation of small cell lung cancer. Despite the fact that a diagnosis eluded his doctors, they persisted in a thoughtful and exhaustive workup and through this perseverance were able to make the final diagnosis, which serves as an important learning case for us all.

Acknowledgments

We thank the family of this veteran for sharing his story and allowing us to learn from this case for the benefit of our future patients. We also thank Dr. Michelle Hankins, who provided oncologic expertise.

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.