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The angry disciple
CASE Disorganized thoughts and grandiose delusions
Mr. J, age 54, presents to the psychiatric emergency department (ED) with agitation and disruptive behavior. He claims that he is “the son of Jesus Christ” and has to travel to the Middle East to be baptized. Mr. J is irritable, shouting, and threatening staff members. He receives
The next day, he is calm and cooperative, but continues to express the same religious delusions. Mr. J is admitted to the psychiatric inpatient unit for further evaluation.
On the unit, Mr. J is pleasant and cooperative, but tangential in thought process. He reports he was “saved” by God 4 years ago, and that God communicates with him through music. Despite this, he denies having auditory or visual hallucinations.
Approximately 3 months earlier, Mr. J had stopped working and left his home and family in another state to pursue his “mission” of being baptized in the Middle East. Mr. J has been homeless since then. Despite that, he reports that his mood is “great” and denies any recent changes in mood, sleep, appetite, energy level, or psychomotor agitation. Although no formal cognitive testing is performed, Mr. J is alert and oriented to person, place, and time with intact remote and recent memory, no language deficits, and no lapses in concentration or attention throughout interview.
Mr. J says he has been drinking alcohol regularly throughout his adult life, often a few times per week, up to “a case and a half” of beer at times. He claims he’s had multiple periods of sobriety but denies having experienced withdrawal symptoms during those times. Mr. J reports 1 prior psychiatric hospitalization 25 years ago after attempting suicide by overdose following the loss of a loved one. At that time, he was diagnosed with posttraumatic stress disorder (PTSD). During this admission, he denies having any symptoms of PTSD or periods of mania or depression, and he has not undergone psychiatric treatment since he had been diagnosed with PTSD. He denies any family history of psychiatric illness as well as any medical comorbidities or medication use.
[polldaddy:10279202]
The authors’ observations
Mr. J’s presentation had a wide differential diagnosis (Table 1). The initial agitation Mr. J displayed in the psychiatric ED was likely secondary to acute alcohol intoxication, given that he was subsequently pleasant, calm, and cooperative after the alcohol was metabolized. Despite this, Mr. J continued to demonstrate delusions of a religious and somewhat grandiose nature with tangential thought processes, which made substance-induced psychosis less likely to be the sole diagnosis. Although it is possible to develop psychotic symptoms due to severe alcohol withdrawal (alcoholic hallucinosis), Mr. J’s vital signs remained stable, and he demonstrated no other signs or symptoms of withdrawal throughout his hospitalization. His presentation also did not fit that of delirium tremens because he was not confused or disoriented, and did not demonstrate perceptual disturbance.
While delusions were the most prominent feature of Mr. J’s apparent psychosis, the presence of disorganized thought processes and impaired functioning, as evidenced by Mr. J’s unemployment and recent homelessness, were more consistent with a primary psychotic disorder than a delusional disorder.1
Continue to: Mr. J began to exhibit...
Mr. J began to exhibit these psychotic symptoms in his early 50s; because the average age of onset of schizophrenia for males is approximately age 20 to 25, the likelihood of his presentation being the result of a primary psychotic disorder was low.1 Although less common, it was possible that Mr. J had developed late-onset schizophrenia, where the first episode typically occurs after approximately age 40 to 45. Mr. J also described that he was in a “great” mood but had grandiose delusions and had made recent impulsive decisions, which suggests there was a possible mood component to his presentation and a potential diagnosis of schizoaffective disorder or bipolar disorder with psychotic symptoms. However, before any of these diagnoses could be made, a medical or neurologic condition that could cause his symptoms needed to be investigated and ruled out. Further collateral information regarding Mr. J’s history and timeline of symptoms was required.
EVALUATION Family history reveals clues
All laboratory studies completed during Mr. J’s hospitalization are unremarkable, including complete blood count, basic metabolic panel, hepatic function panel, gamma-glutamyl transferase test, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, thiamine, folate, urinalysis, and urine drug screen. Mr. J does not undergo any head imaging.
Mr. J has not been in touch with his family since leaving his home approximately 3 months before he presented to the ED, and he gives consent for the inpatient team to attempt to contact them. One week into hospitalization, Mr. J’s sibling informs the team of a family history of genetically confirmed Huntington’s disease (HD), with psychiatric symptoms preceding the onset of motor symptoms in multiple first-degree relatives. His family says that before Mr. J first developed delusions 4 years ago, he had not exhibited any psychotic symptoms during periods of alcohol use or sobriety.
Mr. J does not demonstrate any overt movement symptoms on the unit and denies noting any rigidity, change in gait, or abnormal/uncontrolled movements. The inpatient psychiatric team consults neurology and a full neurologic evaluation is performed. The results are unremarkable outside of his psychiatric symptoms; specifically, Mr. J does not demonstrate even subtle motor signs or cognitive impairment. Given Mr. J’s family history, unremarkable lab findings, and age at presentation, the neurology team and inpatient psychiatry team suspect that his psychosis is likely an early presentation of HD.
[polldaddy:10279212]
The authors’ observations
Genetics of Huntington’s disease
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats within the Huntingtin (HTT) gene on chromosome 4, which codes for the huntingtin protein.2,3 While the function of “normal” huntingtin protein is not fully understood, it is known that CAG repeat expansion in the HTT gene of >35 repeats codes for a mutant huntingtin protein.2,3 The mutant huntingtin protein causes progressive neuronal loss in the basal ganglia and striatum, resulting in the clinical Huntington’s phenotype.3 Notably, the patient’s age at disease onset is inversely correlated with the number of repeats. For example, expansions of approximately 40 to 50 CAG repeats often result in adult-onset HD, while expansions of >60 repeats are typically associated with juvenile-onset HD (before age 20). CAG repeat lengths of approximately 36 to 39 demonstrate reduced penetrance, with some individuals developing symptomatic HD while others do not.2 Instability of the CAG repeat expansion can result in genetic “anticipation,” wherein repeat length increases between generations, causing earlier age of onset in affected offspring. Genetic anticipation in HD occurs more frequently in paternal transmission—approximately 80% to 90% of juvenile HD cases are inherited paternally, at times with the number of CAG repeats exceeding 200.3
Continue to: Psychiatric manifestations of Huntington's disease
Psychiatric manifestations of Huntington’s disease
Huntington’s disease is characterized by motor, cognitive, and behavioral disturbances (Table 22,4). Motor symptoms include a characteristic and well-recognized chorea, often predominating earlier in HD, that progresses to rigidity, spasticity, and bradykinesia later in the disease course.2 Cognitive impairments develop in a similar progressive manner and can often precede the onset of motor symptoms, beginning with early executive dysfunction. Thinking often becomes more rigid and less efficient, causing difficulty with multi-tasking and concentration, and often progressing to subcortical dementia.2
Psychiatric symptoms have long been recognized as a feature of HD; the estimated lifetime prevalence in patients with HD ranges from approximately 33% to 76%.4 Depressed mood, anxiety, irritability, and apathy are the most commonly reported symptoms, while a smaller percentage of patients with HD can experience obsessive-compulsive disorder (10% to 52%) or psychotic symptoms (3% to 11%).4 A more specific schizophrenia-like psychosis occurs in approximately 3% to 6% of patients, and often is a paranoid type.5,6 Positive psychotic symptoms, such as hallucinations and delusions, typically become less overt as HD progresses and cognitive impairments worsen.7
Although the onset of motor symptoms leads to diagnosis in the majority of patients with HD, many patients present with psychiatric symptoms—most commonly depression—prior to motor symptoms.8 An increasing body of literature details instances of psychosis preceding motor symptom onset by up to 10 years.6,9-12 In many of these cases, the patient has a family history of HD-associated psychosis. Family history is a major risk factor for HD-associated psychosis, as is early-onset HD.7,9
TREATMENT Antipsychotics result in some improvement
On Day 1 or 2, Mr. J is started on risperidone, 1 mg twice daily, to manage his symptoms. He shows incremental improvement in thought organization. Although his religious and grandiose delusions persist, they become less fixed, and he is able to take the team’s suggestion that he reconnect with his family.
Mr. J is aware of his family history of HD and acknowledges that multiple relatives had early psychiatric manifestations of HD. Despite this, he still has difficulty recognizing any connection between other family members’ presentation and his own. The psychiatry and neurology teams discuss the process, ethics, and implications of genetic testing for HD with Mr. J; however, he is ambivalent regarding genetic testing, and states he would consider it after discussing it with his family.
Continue to: The neurology team recommends...
The neurology team recommends against imaging for Mr. J because HD-related changes are not typically seen until later in the disease progression. On Day 9, they recommend changing from risperidone to quetiapine (50 mg every night at bedtime) due to evidence of its effectiveness specifically for treating behavioral symptoms of HD.13
While receiving quetiapine, Mr. J experiences significant drowsiness. Because he had experienced improvement in thought organization while he was receiving risperidone, he is switched back to risperidone.
[polldaddy:10279220]
The authors’ observations
Currently, no treatments are available to prevent the development or progression of HD. However, symptomatic treatment of motor and behavioral disturbances can lead to functional improvement and improved quality of life for individuals affected by HD.
There are no extensive clinical trials to date, but multiple case reports and studies have shown second-generation antipsychotics (SGAs), including quetiapine, olanzapine,
OUTCOME Discharge despite persistent delusions
Mr. J’s religious and grandiose delusions continue throughout hospitalization despite treatment with antipsychotics. However, because he remains calm and cooperative and demonstrates improvement in thought organization, he is deemed safe for discharge and instructed to continue risperidone. The team coordinates with Mr. J’s family to arrange transportation home and outpatient neurology follow-up.
Bottom Line
Psychiatric manifestations, including psychosis, are prominent symptoms of Huntington’s disease (HD) and may precede the onset of more readily recognized motor symptoms. This poses a diagnostic challenge, and clinicians should remain cognizant of this possibility, especially in patients with a family history of HD-associated psychosis.
Related Resources
- Huntington’s Disease Society of America. http://hdsa.org.
- National Institute of Neurological Disorders and Stroke. Huntington’s disease information page: What research is being done? https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page.
- Scher LM. How to target psychiatric symptoms of Huntington’s disease. Current Psychiatry. 2012;11(9):34-39.
Drug Brand Names
Aripiprazole • Abilify
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
2. Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol. 2011;98:297-323.
3. Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington’s disease. Int Rev Neurobiol. 2011;98:325-372.
4. van Duijn E, Kingma EM, Van der mast RC. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci. 2007;19(4):441-448.
5. Naarding P, Kremer HP, Zitman FG. Huntington’s disease: a review of the literature on prevalence and treatment of neuropsychiatric phenomena. Eur Psychiatry. 2001;16(8):439-445.
6. Xu C, Yogaratnam J, Tan N, et al. Psychosis, treatment emergent extrapyramidal events, and subsequent onset of Huntington’s disease: a case report and review of the literature. Clin Psychopharmacol Neurosci. 2016;14(3):302-304.
7. Mendez MF. Huntington’s disease: update and review of neuropsychiatric aspects. Int J Psychiatry Med. 1994;24(3):189-208.
8. Di Maio L, Squitieri F, Napolitano G, et al. Onset symptoms in 510 patients with Huntington’s disease. J Med Genet. 1993;30(4):289-292.
9. Jauhar S, Ritchie S. Psychiatric and behavioural manifestations of Huntington’s disease. Adv Psychiatr Treat. 2010;16(3):168-175.
10. Nagel M, Rumpf HJ, Kasten M. Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis. Gen Hosp Psychiatry. 2014;36(3):361.e3-e4. doi: 10.1016/j.genhosppsych.2014.01.008.
11. Corrêa BB, Xavier M, Guimarães J. Association of Huntington’s disease and schizophrenia-like psychosis in a Huntington’s disease pedigree. Clin Pract Epidemiol Ment Health. 2006;2:1.
12. Ding J, Gadit AM. Psychosis with Huntington’s disease: role of antipsychotic medications. BMJ Case Rep. 2014: bcr2013202625. doi: 10.1136/bcr-2013-202625.
13. Alpay M, Koroshetz WJ. Quetiapine in the treatment of behavioral disturbances in patients with Huntington’s disease. Psychosomatics. 2006;47(1):70-72.
14. Duff K, Beglinger LJ, O’Rourke ME, et al. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington’s disease. Ann Clin Psychiatry. 2008;20(1):1-3.
15. Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease. Acta Neurol Scand. 2002;105(6):441-444.
16. Lin W, Chou Y. Aripiprazole effects on psychosis and chorea in a patient with Huntington’s disease. Am J Psychiatry. 2008;165(9):1207-1208.
17. van Vugt JP, Siesling S, Vergeer M, et al. Clozapine versus placebo in Huntington’s disease: a double blind randomized comparative study. J Neurol Neurosurg Psychiatr. 1997;63(1):35-39.
CASE Disorganized thoughts and grandiose delusions
Mr. J, age 54, presents to the psychiatric emergency department (ED) with agitation and disruptive behavior. He claims that he is “the son of Jesus Christ” and has to travel to the Middle East to be baptized. Mr. J is irritable, shouting, and threatening staff members. He receives
The next day, he is calm and cooperative, but continues to express the same religious delusions. Mr. J is admitted to the psychiatric inpatient unit for further evaluation.
On the unit, Mr. J is pleasant and cooperative, but tangential in thought process. He reports he was “saved” by God 4 years ago, and that God communicates with him through music. Despite this, he denies having auditory or visual hallucinations.
Approximately 3 months earlier, Mr. J had stopped working and left his home and family in another state to pursue his “mission” of being baptized in the Middle East. Mr. J has been homeless since then. Despite that, he reports that his mood is “great” and denies any recent changes in mood, sleep, appetite, energy level, or psychomotor agitation. Although no formal cognitive testing is performed, Mr. J is alert and oriented to person, place, and time with intact remote and recent memory, no language deficits, and no lapses in concentration or attention throughout interview.
Mr. J says he has been drinking alcohol regularly throughout his adult life, often a few times per week, up to “a case and a half” of beer at times. He claims he’s had multiple periods of sobriety but denies having experienced withdrawal symptoms during those times. Mr. J reports 1 prior psychiatric hospitalization 25 years ago after attempting suicide by overdose following the loss of a loved one. At that time, he was diagnosed with posttraumatic stress disorder (PTSD). During this admission, he denies having any symptoms of PTSD or periods of mania or depression, and he has not undergone psychiatric treatment since he had been diagnosed with PTSD. He denies any family history of psychiatric illness as well as any medical comorbidities or medication use.
[polldaddy:10279202]
The authors’ observations
Mr. J’s presentation had a wide differential diagnosis (Table 1). The initial agitation Mr. J displayed in the psychiatric ED was likely secondary to acute alcohol intoxication, given that he was subsequently pleasant, calm, and cooperative after the alcohol was metabolized. Despite this, Mr. J continued to demonstrate delusions of a religious and somewhat grandiose nature with tangential thought processes, which made substance-induced psychosis less likely to be the sole diagnosis. Although it is possible to develop psychotic symptoms due to severe alcohol withdrawal (alcoholic hallucinosis), Mr. J’s vital signs remained stable, and he demonstrated no other signs or symptoms of withdrawal throughout his hospitalization. His presentation also did not fit that of delirium tremens because he was not confused or disoriented, and did not demonstrate perceptual disturbance.
While delusions were the most prominent feature of Mr. J’s apparent psychosis, the presence of disorganized thought processes and impaired functioning, as evidenced by Mr. J’s unemployment and recent homelessness, were more consistent with a primary psychotic disorder than a delusional disorder.1
Continue to: Mr. J began to exhibit...
Mr. J began to exhibit these psychotic symptoms in his early 50s; because the average age of onset of schizophrenia for males is approximately age 20 to 25, the likelihood of his presentation being the result of a primary psychotic disorder was low.1 Although less common, it was possible that Mr. J had developed late-onset schizophrenia, where the first episode typically occurs after approximately age 40 to 45. Mr. J also described that he was in a “great” mood but had grandiose delusions and had made recent impulsive decisions, which suggests there was a possible mood component to his presentation and a potential diagnosis of schizoaffective disorder or bipolar disorder with psychotic symptoms. However, before any of these diagnoses could be made, a medical or neurologic condition that could cause his symptoms needed to be investigated and ruled out. Further collateral information regarding Mr. J’s history and timeline of symptoms was required.
EVALUATION Family history reveals clues
All laboratory studies completed during Mr. J’s hospitalization are unremarkable, including complete blood count, basic metabolic panel, hepatic function panel, gamma-glutamyl transferase test, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, thiamine, folate, urinalysis, and urine drug screen. Mr. J does not undergo any head imaging.
Mr. J has not been in touch with his family since leaving his home approximately 3 months before he presented to the ED, and he gives consent for the inpatient team to attempt to contact them. One week into hospitalization, Mr. J’s sibling informs the team of a family history of genetically confirmed Huntington’s disease (HD), with psychiatric symptoms preceding the onset of motor symptoms in multiple first-degree relatives. His family says that before Mr. J first developed delusions 4 years ago, he had not exhibited any psychotic symptoms during periods of alcohol use or sobriety.
Mr. J does not demonstrate any overt movement symptoms on the unit and denies noting any rigidity, change in gait, or abnormal/uncontrolled movements. The inpatient psychiatric team consults neurology and a full neurologic evaluation is performed. The results are unremarkable outside of his psychiatric symptoms; specifically, Mr. J does not demonstrate even subtle motor signs or cognitive impairment. Given Mr. J’s family history, unremarkable lab findings, and age at presentation, the neurology team and inpatient psychiatry team suspect that his psychosis is likely an early presentation of HD.
[polldaddy:10279212]
The authors’ observations
Genetics of Huntington’s disease
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats within the Huntingtin (HTT) gene on chromosome 4, which codes for the huntingtin protein.2,3 While the function of “normal” huntingtin protein is not fully understood, it is known that CAG repeat expansion in the HTT gene of >35 repeats codes for a mutant huntingtin protein.2,3 The mutant huntingtin protein causes progressive neuronal loss in the basal ganglia and striatum, resulting in the clinical Huntington’s phenotype.3 Notably, the patient’s age at disease onset is inversely correlated with the number of repeats. For example, expansions of approximately 40 to 50 CAG repeats often result in adult-onset HD, while expansions of >60 repeats are typically associated with juvenile-onset HD (before age 20). CAG repeat lengths of approximately 36 to 39 demonstrate reduced penetrance, with some individuals developing symptomatic HD while others do not.2 Instability of the CAG repeat expansion can result in genetic “anticipation,” wherein repeat length increases between generations, causing earlier age of onset in affected offspring. Genetic anticipation in HD occurs more frequently in paternal transmission—approximately 80% to 90% of juvenile HD cases are inherited paternally, at times with the number of CAG repeats exceeding 200.3
Continue to: Psychiatric manifestations of Huntington's disease
Psychiatric manifestations of Huntington’s disease
Huntington’s disease is characterized by motor, cognitive, and behavioral disturbances (Table 22,4). Motor symptoms include a characteristic and well-recognized chorea, often predominating earlier in HD, that progresses to rigidity, spasticity, and bradykinesia later in the disease course.2 Cognitive impairments develop in a similar progressive manner and can often precede the onset of motor symptoms, beginning with early executive dysfunction. Thinking often becomes more rigid and less efficient, causing difficulty with multi-tasking and concentration, and often progressing to subcortical dementia.2
Psychiatric symptoms have long been recognized as a feature of HD; the estimated lifetime prevalence in patients with HD ranges from approximately 33% to 76%.4 Depressed mood, anxiety, irritability, and apathy are the most commonly reported symptoms, while a smaller percentage of patients with HD can experience obsessive-compulsive disorder (10% to 52%) or psychotic symptoms (3% to 11%).4 A more specific schizophrenia-like psychosis occurs in approximately 3% to 6% of patients, and often is a paranoid type.5,6 Positive psychotic symptoms, such as hallucinations and delusions, typically become less overt as HD progresses and cognitive impairments worsen.7
Although the onset of motor symptoms leads to diagnosis in the majority of patients with HD, many patients present with psychiatric symptoms—most commonly depression—prior to motor symptoms.8 An increasing body of literature details instances of psychosis preceding motor symptom onset by up to 10 years.6,9-12 In many of these cases, the patient has a family history of HD-associated psychosis. Family history is a major risk factor for HD-associated psychosis, as is early-onset HD.7,9
TREATMENT Antipsychotics result in some improvement
On Day 1 or 2, Mr. J is started on risperidone, 1 mg twice daily, to manage his symptoms. He shows incremental improvement in thought organization. Although his religious and grandiose delusions persist, they become less fixed, and he is able to take the team’s suggestion that he reconnect with his family.
Mr. J is aware of his family history of HD and acknowledges that multiple relatives had early psychiatric manifestations of HD. Despite this, he still has difficulty recognizing any connection between other family members’ presentation and his own. The psychiatry and neurology teams discuss the process, ethics, and implications of genetic testing for HD with Mr. J; however, he is ambivalent regarding genetic testing, and states he would consider it after discussing it with his family.
Continue to: The neurology team recommends...
The neurology team recommends against imaging for Mr. J because HD-related changes are not typically seen until later in the disease progression. On Day 9, they recommend changing from risperidone to quetiapine (50 mg every night at bedtime) due to evidence of its effectiveness specifically for treating behavioral symptoms of HD.13
While receiving quetiapine, Mr. J experiences significant drowsiness. Because he had experienced improvement in thought organization while he was receiving risperidone, he is switched back to risperidone.
[polldaddy:10279220]
The authors’ observations
Currently, no treatments are available to prevent the development or progression of HD. However, symptomatic treatment of motor and behavioral disturbances can lead to functional improvement and improved quality of life for individuals affected by HD.
There are no extensive clinical trials to date, but multiple case reports and studies have shown second-generation antipsychotics (SGAs), including quetiapine, olanzapine,
OUTCOME Discharge despite persistent delusions
Mr. J’s religious and grandiose delusions continue throughout hospitalization despite treatment with antipsychotics. However, because he remains calm and cooperative and demonstrates improvement in thought organization, he is deemed safe for discharge and instructed to continue risperidone. The team coordinates with Mr. J’s family to arrange transportation home and outpatient neurology follow-up.
Bottom Line
Psychiatric manifestations, including psychosis, are prominent symptoms of Huntington’s disease (HD) and may precede the onset of more readily recognized motor symptoms. This poses a diagnostic challenge, and clinicians should remain cognizant of this possibility, especially in patients with a family history of HD-associated psychosis.
Related Resources
- Huntington’s Disease Society of America. http://hdsa.org.
- National Institute of Neurological Disorders and Stroke. Huntington’s disease information page: What research is being done? https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page.
- Scher LM. How to target psychiatric symptoms of Huntington’s disease. Current Psychiatry. 2012;11(9):34-39.
Drug Brand Names
Aripiprazole • Abilify
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
CASE Disorganized thoughts and grandiose delusions
Mr. J, age 54, presents to the psychiatric emergency department (ED) with agitation and disruptive behavior. He claims that he is “the son of Jesus Christ” and has to travel to the Middle East to be baptized. Mr. J is irritable, shouting, and threatening staff members. He receives
The next day, he is calm and cooperative, but continues to express the same religious delusions. Mr. J is admitted to the psychiatric inpatient unit for further evaluation.
On the unit, Mr. J is pleasant and cooperative, but tangential in thought process. He reports he was “saved” by God 4 years ago, and that God communicates with him through music. Despite this, he denies having auditory or visual hallucinations.
Approximately 3 months earlier, Mr. J had stopped working and left his home and family in another state to pursue his “mission” of being baptized in the Middle East. Mr. J has been homeless since then. Despite that, he reports that his mood is “great” and denies any recent changes in mood, sleep, appetite, energy level, or psychomotor agitation. Although no formal cognitive testing is performed, Mr. J is alert and oriented to person, place, and time with intact remote and recent memory, no language deficits, and no lapses in concentration or attention throughout interview.
Mr. J says he has been drinking alcohol regularly throughout his adult life, often a few times per week, up to “a case and a half” of beer at times. He claims he’s had multiple periods of sobriety but denies having experienced withdrawal symptoms during those times. Mr. J reports 1 prior psychiatric hospitalization 25 years ago after attempting suicide by overdose following the loss of a loved one. At that time, he was diagnosed with posttraumatic stress disorder (PTSD). During this admission, he denies having any symptoms of PTSD or periods of mania or depression, and he has not undergone psychiatric treatment since he had been diagnosed with PTSD. He denies any family history of psychiatric illness as well as any medical comorbidities or medication use.
[polldaddy:10279202]
The authors’ observations
Mr. J’s presentation had a wide differential diagnosis (Table 1). The initial agitation Mr. J displayed in the psychiatric ED was likely secondary to acute alcohol intoxication, given that he was subsequently pleasant, calm, and cooperative after the alcohol was metabolized. Despite this, Mr. J continued to demonstrate delusions of a religious and somewhat grandiose nature with tangential thought processes, which made substance-induced psychosis less likely to be the sole diagnosis. Although it is possible to develop psychotic symptoms due to severe alcohol withdrawal (alcoholic hallucinosis), Mr. J’s vital signs remained stable, and he demonstrated no other signs or symptoms of withdrawal throughout his hospitalization. His presentation also did not fit that of delirium tremens because he was not confused or disoriented, and did not demonstrate perceptual disturbance.
While delusions were the most prominent feature of Mr. J’s apparent psychosis, the presence of disorganized thought processes and impaired functioning, as evidenced by Mr. J’s unemployment and recent homelessness, were more consistent with a primary psychotic disorder than a delusional disorder.1
Continue to: Mr. J began to exhibit...
Mr. J began to exhibit these psychotic symptoms in his early 50s; because the average age of onset of schizophrenia for males is approximately age 20 to 25, the likelihood of his presentation being the result of a primary psychotic disorder was low.1 Although less common, it was possible that Mr. J had developed late-onset schizophrenia, where the first episode typically occurs after approximately age 40 to 45. Mr. J also described that he was in a “great” mood but had grandiose delusions and had made recent impulsive decisions, which suggests there was a possible mood component to his presentation and a potential diagnosis of schizoaffective disorder or bipolar disorder with psychotic symptoms. However, before any of these diagnoses could be made, a medical or neurologic condition that could cause his symptoms needed to be investigated and ruled out. Further collateral information regarding Mr. J’s history and timeline of symptoms was required.
EVALUATION Family history reveals clues
All laboratory studies completed during Mr. J’s hospitalization are unremarkable, including complete blood count, basic metabolic panel, hepatic function panel, gamma-glutamyl transferase test, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, thiamine, folate, urinalysis, and urine drug screen. Mr. J does not undergo any head imaging.
Mr. J has not been in touch with his family since leaving his home approximately 3 months before he presented to the ED, and he gives consent for the inpatient team to attempt to contact them. One week into hospitalization, Mr. J’s sibling informs the team of a family history of genetically confirmed Huntington’s disease (HD), with psychiatric symptoms preceding the onset of motor symptoms in multiple first-degree relatives. His family says that before Mr. J first developed delusions 4 years ago, he had not exhibited any psychotic symptoms during periods of alcohol use or sobriety.
Mr. J does not demonstrate any overt movement symptoms on the unit and denies noting any rigidity, change in gait, or abnormal/uncontrolled movements. The inpatient psychiatric team consults neurology and a full neurologic evaluation is performed. The results are unremarkable outside of his psychiatric symptoms; specifically, Mr. J does not demonstrate even subtle motor signs or cognitive impairment. Given Mr. J’s family history, unremarkable lab findings, and age at presentation, the neurology team and inpatient psychiatry team suspect that his psychosis is likely an early presentation of HD.
[polldaddy:10279212]
The authors’ observations
Genetics of Huntington’s disease
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats within the Huntingtin (HTT) gene on chromosome 4, which codes for the huntingtin protein.2,3 While the function of “normal” huntingtin protein is not fully understood, it is known that CAG repeat expansion in the HTT gene of >35 repeats codes for a mutant huntingtin protein.2,3 The mutant huntingtin protein causes progressive neuronal loss in the basal ganglia and striatum, resulting in the clinical Huntington’s phenotype.3 Notably, the patient’s age at disease onset is inversely correlated with the number of repeats. For example, expansions of approximately 40 to 50 CAG repeats often result in adult-onset HD, while expansions of >60 repeats are typically associated with juvenile-onset HD (before age 20). CAG repeat lengths of approximately 36 to 39 demonstrate reduced penetrance, with some individuals developing symptomatic HD while others do not.2 Instability of the CAG repeat expansion can result in genetic “anticipation,” wherein repeat length increases between generations, causing earlier age of onset in affected offspring. Genetic anticipation in HD occurs more frequently in paternal transmission—approximately 80% to 90% of juvenile HD cases are inherited paternally, at times with the number of CAG repeats exceeding 200.3
Continue to: Psychiatric manifestations of Huntington's disease
Psychiatric manifestations of Huntington’s disease
Huntington’s disease is characterized by motor, cognitive, and behavioral disturbances (Table 22,4). Motor symptoms include a characteristic and well-recognized chorea, often predominating earlier in HD, that progresses to rigidity, spasticity, and bradykinesia later in the disease course.2 Cognitive impairments develop in a similar progressive manner and can often precede the onset of motor symptoms, beginning with early executive dysfunction. Thinking often becomes more rigid and less efficient, causing difficulty with multi-tasking and concentration, and often progressing to subcortical dementia.2
Psychiatric symptoms have long been recognized as a feature of HD; the estimated lifetime prevalence in patients with HD ranges from approximately 33% to 76%.4 Depressed mood, anxiety, irritability, and apathy are the most commonly reported symptoms, while a smaller percentage of patients with HD can experience obsessive-compulsive disorder (10% to 52%) or psychotic symptoms (3% to 11%).4 A more specific schizophrenia-like psychosis occurs in approximately 3% to 6% of patients, and often is a paranoid type.5,6 Positive psychotic symptoms, such as hallucinations and delusions, typically become less overt as HD progresses and cognitive impairments worsen.7
Although the onset of motor symptoms leads to diagnosis in the majority of patients with HD, many patients present with psychiatric symptoms—most commonly depression—prior to motor symptoms.8 An increasing body of literature details instances of psychosis preceding motor symptom onset by up to 10 years.6,9-12 In many of these cases, the patient has a family history of HD-associated psychosis. Family history is a major risk factor for HD-associated psychosis, as is early-onset HD.7,9
TREATMENT Antipsychotics result in some improvement
On Day 1 or 2, Mr. J is started on risperidone, 1 mg twice daily, to manage his symptoms. He shows incremental improvement in thought organization. Although his religious and grandiose delusions persist, they become less fixed, and he is able to take the team’s suggestion that he reconnect with his family.
Mr. J is aware of his family history of HD and acknowledges that multiple relatives had early psychiatric manifestations of HD. Despite this, he still has difficulty recognizing any connection between other family members’ presentation and his own. The psychiatry and neurology teams discuss the process, ethics, and implications of genetic testing for HD with Mr. J; however, he is ambivalent regarding genetic testing, and states he would consider it after discussing it with his family.
Continue to: The neurology team recommends...
The neurology team recommends against imaging for Mr. J because HD-related changes are not typically seen until later in the disease progression. On Day 9, they recommend changing from risperidone to quetiapine (50 mg every night at bedtime) due to evidence of its effectiveness specifically for treating behavioral symptoms of HD.13
While receiving quetiapine, Mr. J experiences significant drowsiness. Because he had experienced improvement in thought organization while he was receiving risperidone, he is switched back to risperidone.
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The authors’ observations
Currently, no treatments are available to prevent the development or progression of HD. However, symptomatic treatment of motor and behavioral disturbances can lead to functional improvement and improved quality of life for individuals affected by HD.
There are no extensive clinical trials to date, but multiple case reports and studies have shown second-generation antipsychotics (SGAs), including quetiapine, olanzapine,
OUTCOME Discharge despite persistent delusions
Mr. J’s religious and grandiose delusions continue throughout hospitalization despite treatment with antipsychotics. However, because he remains calm and cooperative and demonstrates improvement in thought organization, he is deemed safe for discharge and instructed to continue risperidone. The team coordinates with Mr. J’s family to arrange transportation home and outpatient neurology follow-up.
Bottom Line
Psychiatric manifestations, including psychosis, are prominent symptoms of Huntington’s disease (HD) and may precede the onset of more readily recognized motor symptoms. This poses a diagnostic challenge, and clinicians should remain cognizant of this possibility, especially in patients with a family history of HD-associated psychosis.
Related Resources
- Huntington’s Disease Society of America. http://hdsa.org.
- National Institute of Neurological Disorders and Stroke. Huntington’s disease information page: What research is being done? https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page.
- Scher LM. How to target psychiatric symptoms of Huntington’s disease. Current Psychiatry. 2012;11(9):34-39.
Drug Brand Names
Aripiprazole • Abilify
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
2. Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol. 2011;98:297-323.
3. Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington’s disease. Int Rev Neurobiol. 2011;98:325-372.
4. van Duijn E, Kingma EM, Van der mast RC. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci. 2007;19(4):441-448.
5. Naarding P, Kremer HP, Zitman FG. Huntington’s disease: a review of the literature on prevalence and treatment of neuropsychiatric phenomena. Eur Psychiatry. 2001;16(8):439-445.
6. Xu C, Yogaratnam J, Tan N, et al. Psychosis, treatment emergent extrapyramidal events, and subsequent onset of Huntington’s disease: a case report and review of the literature. Clin Psychopharmacol Neurosci. 2016;14(3):302-304.
7. Mendez MF. Huntington’s disease: update and review of neuropsychiatric aspects. Int J Psychiatry Med. 1994;24(3):189-208.
8. Di Maio L, Squitieri F, Napolitano G, et al. Onset symptoms in 510 patients with Huntington’s disease. J Med Genet. 1993;30(4):289-292.
9. Jauhar S, Ritchie S. Psychiatric and behavioural manifestations of Huntington’s disease. Adv Psychiatr Treat. 2010;16(3):168-175.
10. Nagel M, Rumpf HJ, Kasten M. Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis. Gen Hosp Psychiatry. 2014;36(3):361.e3-e4. doi: 10.1016/j.genhosppsych.2014.01.008.
11. Corrêa BB, Xavier M, Guimarães J. Association of Huntington’s disease and schizophrenia-like psychosis in a Huntington’s disease pedigree. Clin Pract Epidemiol Ment Health. 2006;2:1.
12. Ding J, Gadit AM. Psychosis with Huntington’s disease: role of antipsychotic medications. BMJ Case Rep. 2014: bcr2013202625. doi: 10.1136/bcr-2013-202625.
13. Alpay M, Koroshetz WJ. Quetiapine in the treatment of behavioral disturbances in patients with Huntington’s disease. Psychosomatics. 2006;47(1):70-72.
14. Duff K, Beglinger LJ, O’Rourke ME, et al. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington’s disease. Ann Clin Psychiatry. 2008;20(1):1-3.
15. Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease. Acta Neurol Scand. 2002;105(6):441-444.
16. Lin W, Chou Y. Aripiprazole effects on psychosis and chorea in a patient with Huntington’s disease. Am J Psychiatry. 2008;165(9):1207-1208.
17. van Vugt JP, Siesling S, Vergeer M, et al. Clozapine versus placebo in Huntington’s disease: a double blind randomized comparative study. J Neurol Neurosurg Psychiatr. 1997;63(1):35-39.
1. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
2. Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol. 2011;98:297-323.
3. Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington’s disease. Int Rev Neurobiol. 2011;98:325-372.
4. van Duijn E, Kingma EM, Van der mast RC. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci. 2007;19(4):441-448.
5. Naarding P, Kremer HP, Zitman FG. Huntington’s disease: a review of the literature on prevalence and treatment of neuropsychiatric phenomena. Eur Psychiatry. 2001;16(8):439-445.
6. Xu C, Yogaratnam J, Tan N, et al. Psychosis, treatment emergent extrapyramidal events, and subsequent onset of Huntington’s disease: a case report and review of the literature. Clin Psychopharmacol Neurosci. 2016;14(3):302-304.
7. Mendez MF. Huntington’s disease: update and review of neuropsychiatric aspects. Int J Psychiatry Med. 1994;24(3):189-208.
8. Di Maio L, Squitieri F, Napolitano G, et al. Onset symptoms in 510 patients with Huntington’s disease. J Med Genet. 1993;30(4):289-292.
9. Jauhar S, Ritchie S. Psychiatric and behavioural manifestations of Huntington’s disease. Adv Psychiatr Treat. 2010;16(3):168-175.
10. Nagel M, Rumpf HJ, Kasten M. Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis. Gen Hosp Psychiatry. 2014;36(3):361.e3-e4. doi: 10.1016/j.genhosppsych.2014.01.008.
11. Corrêa BB, Xavier M, Guimarães J. Association of Huntington’s disease and schizophrenia-like psychosis in a Huntington’s disease pedigree. Clin Pract Epidemiol Ment Health. 2006;2:1.
12. Ding J, Gadit AM. Psychosis with Huntington’s disease: role of antipsychotic medications. BMJ Case Rep. 2014: bcr2013202625. doi: 10.1136/bcr-2013-202625.
13. Alpay M, Koroshetz WJ. Quetiapine in the treatment of behavioral disturbances in patients with Huntington’s disease. Psychosomatics. 2006;47(1):70-72.
14. Duff K, Beglinger LJ, O’Rourke ME, et al. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington’s disease. Ann Clin Psychiatry. 2008;20(1):1-3.
15. Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease. Acta Neurol Scand. 2002;105(6):441-444.
16. Lin W, Chou Y. Aripiprazole effects on psychosis and chorea in a patient with Huntington’s disease. Am J Psychiatry. 2008;165(9):1207-1208.
17. van Vugt JP, Siesling S, Vergeer M, et al. Clozapine versus placebo in Huntington’s disease: a double blind randomized comparative study. J Neurol Neurosurg Psychiatr. 1997;63(1):35-39.
