Rajesh R. Tampi, MD, MS

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  

Disclosure

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

Acknowledgment

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the BPHr, HRSA, DHHS or the U.S. Government.”

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  

Disclosure

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

Acknowledgment

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the BPHr, HRSA, DHHS or the U.S. Government.”

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  

Disclosure

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

Acknowledgment

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the BPHr, HRSA, DHHS or the U.S. Government.”

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.