Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

Dr. Mulchahey reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

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

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

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

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

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

Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Symptoms of obstructive sleep apnea (OSA) often mimic psychopathology. Because of this, patients with OSA who exhibit these symptoms often are misdiagnosed as having a psychiatric disorder.

Consider OSA in the differential diagnosis of:

• depression. Sleep-disordered breathing is five times more prevalent in adults and children with depression than in nondepressed patients. Psychotic features also positively correlate with OSA.¹
• anxiety. Physiologic and hormonal changes associated with OSA can cause panic attacks.
• attention-deficit/hyperactivity disorder (ADHD). Attention, concentration, and vigilance are often impaired in adults and children with OSA. Up to one-third of children with frequent, loud snoring display inattention and hyperactivity.²
• memory impairment. Deficits in working and long-term episodic memory are common in OSA.
• executive dysfunction. Patients with OSA often cannot sustain an organized, goal-directed, flexible approach to problem solving.
• erectile dysfunction. Pathologic processes activated by OSA may predispose men to impaired erectile function.³
• School phobia. Poor academic functioning is common in children with OSA. These children resist going to school because of a resultant loss of self-esteem. Excessive daytime sleepiness also contributes to poor academic performance.²
• Behavioral problems in children. Sleep deprivation often manifests as irritability and oppositional behavior.

Disturbances in intellectual and executive functioning are strongly correlated with hypoxemia. Deficits in vigilance, alertness, and memory correlate with measures of sleep fragmentation.⁴

When to suspect sleep apnea

Refer patients to a pulmonologist, ENT specialist, or sleep disorders center if the history and physical exam reveal excessive daytime sleepiness, frequent nocturia, morning headaches, nasal quality to the voice, enlarged tonsils and adenoids in children, or loud snoring or gasping sounds during sleep (consider interviewing the patient’s bed partner).

Risk factors such as family history, recessed chin, smoking, neck size >16 inches, male gender, enlarged tonsils and adenoids, and age >40 may also point to OSA. Also watch for:

• ethnicity. OSA is most prevalent among Pacific Islanders, Hispanics, and African-Americans.
• BMI >25 in adults younger than age 65. However, OSA is often missed in young people who are not obese.

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia

Summit Directors and Editors:
Michael A. DeGeorgia, MD; Derk Krieger, MD, PhD; and Anthony Furlan, MD

Contents

Foreword
Michael DeGeorgia, MD

Historical Perspectives: Neurointensive Care

The development of neurologic intensive care
Allan H. Ropper, MD, St. Elizabeth's Medical Center and Tufts University School of Medicine, Boston, MA

Intracranial Pressure

The pathophysiology of brain edema and elevated intracranial pressure
Anthony Marmarou, PhD, Virginia Commonwealth University Medical Center, Richmond, VA

Hypertonic saline for cerebral edema and elevated intracranial pressure
José I. Suarez, MD, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH

Every breath you take: Hyperventilation and intracranial pressure
Claudia Robertson, MD, Baylor College of Medicine, Houston, TX

Multimodal monitoring in neurocritical care
Michael A. DeGeorgia, MD, The Cleveland Clinic Foundation, Cleveland, OH

Hemorrhagic Stroke

Endovascular coiling: The end of conventional neurosurgery?
Peter A. Rasmussen, MD, The Cleveland Clinic Foundation, Cleveland, OH

Fundamentals of Cricital Care

Lessons from the medical and surgical ICU
J. Javier Provencio, MD, The Cleveland Clinic Foundation, Cleveland, OH

Historical Perspectives: Cerebrovascular Disease

Cerebrovascular disease: Historical background, with an eye to the future
Louis R. Caplan, MD, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA

Acute Ischemic Stroke

Pathophysiology of acute ischemic stroke
Midori A. Yenari, MD, Stanford University, Stanford, CA

Intravenous thrombolysis for acute stroke
Joseph P. Broderick, MD, University of Cincinnati College of Medicine, Cincinnati, OH

Intra-arterial thrombolysis for acute stroke
Anthony Furlan, MD, The Cleveland Clinic Foundation, Cleveland, OH

Therapeutic hypothermia may enhance reperfusion in acute ischemic stroke
Derk W. Krieger, MD, PhD, The Cleveland Clinic Foundation, Cleveland, OH

Stem cell transplantation for stroke
Lawrence R. Wechsler, MD, University of Pittsburgh Medical School, Pittsburgh, PA

Extracranial Disease

Carotid artery disease: From knife to stent
Marc R. Mayberg, MD, The Cleveland Clinic Foundation, Cleveland, OH

Carotid stenting in high-risk patients: Design and rationale of the SAPPHIRE trial
Jay S. Yadav, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial Disease

Medical management of intracranial atherosclerosis: Current state of the art
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Intracranial stentings: Which patients and when?
Randall T. Higashida, MD, University of California, San Francisco, Medical Center, San Francisco, CA

Antithrombotic Therapy

Anticoagulation for stroke prevention: Yes, no, maybe
J.P. Mohr, MD, The Neurological Institute, New York, NY

Antiplatelet therapy for acute stroke: Aspirin and beyond
Cathy A. Sila, MD, The Cleveland Clinic Foundation, Cleveland, OH

Abstracts/Poster Presentations

Abstract 1: Hyponatremia-related focal cerebral edema, a mimic of worsening cerebral edema due to intracerebral hemorrhage
P. Widdes-Walsh, V. Sabharwal

Abstract 2: Suboccipital craniectomy for acute cerebellar ischemic stroke
B.R. Cohen, G.L. Bernardini, D. Friedlich, A.J. Popp

Abstract 3: The feasibility and safety of mild brain hypothermia obtained by local surface cooling in acute stroke
K. Yamada, H. Moriwaki, H. Oe, K. Miyashita, K. Nagatsuka, T. Yamawaki, H. Naritomi

Abstract 4: The Diverter, a novel permanent arterial diversion device
J. Leor, Y. Grad, O. Oz, Y. Assaf

Abstract 5: Fatal arrhythmia in an anxious patient during recovery from lateral medullary infarction
J.G. Lattore

Abstract 6: Motor, behavioral, and cognitive changes in patients with thalamic lesions
A.V. Srinivasan, B.S. Virudhagirinathan, C.U. Velmurugendran

Abstract 7: Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA
K.E. Wartenberg, N.S. Janjua, S.A. Mayer, P. Meyers

Abstract 8: Dantrolene reduces the threshold and gain for shivering
R. Lenhardt

Abstract 9: Predicting outcome after subarachnoid hemorrhage: Comparison of different grading systems
M. Berker, A. Deogaonkar, V. Sabharwal, P. Rasmussen, M. Mayberg, M. DeGeorgia

Abstract 10: Integrative monitoring methods in neurocricital care
A. Deogaonkar, A. Vander Kouwe, K. Horning, R. Burgess, M. DeGerogia