Vishal Vashistha, MD

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

figure_1.png

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

figure_2.png

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

figure_3.png

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

figure_1.png

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

figure_2.png

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

figure_3.png

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

figure_1.png

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

figure_2.png

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

figure_3.png

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

fdp03801040_t.png

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

fdp03801040_f.png

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

fdp03801040_t.png

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

fdp03801040_f.png

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

fdp03801040_t.png

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

fdp03801040_f.png

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

wang_serotoninsyndrome_t1.gif

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

wang_serotoninsyndrome_t2.gif

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

wang_serotoninsyndrome_f1.gif

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

wang_serotoninsyndrome_t3.gif

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

wang_serotoninsyndrome_t1.gif

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

wang_serotoninsyndrome_t2.gif

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

wang_serotoninsyndrome_f1.gif

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

wang_serotoninsyndrome_t3.gif

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

wang_serotoninsyndrome_t1.gif

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

wang_serotoninsyndrome_t2.gif

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

wang_serotoninsyndrome_f1.gif

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

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The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.