Alexander De Nesnera, MD

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.