Evidence-Based Reviews

Four principles of treating delirium can help protect medical/surgical patients at risk for morbidity and functional decline. These principals—which I call the “four Ps”—are prompt identification, protection, pragmatic intervention, and pharmacotherapy.

This article describes an up-to-date, “four-Ps” approach to treating delirium—including use of antipsychotics and supportive care—and offers evidence and case reports to address these clinical questions:

• What causes delirium?
• Does delirium worsen prognosis?
• Can delirium be prevented?

FOUR ‘Ps’ FOR TREATING DELIRIUM

When a patient’s mental status changes dramatically (Box 1),¹ identifying potential delirium causes requires careful medical, psychiatric, and neurologic assessment. Assimilating this information is as essential to positive outcomes as are intensive nursing care and appropriate interventions.

Box 1

Prompt identification. Delirium often goes unrecognized, delaying treatment. Easily administered rating scales—such as the Delirium Rating Scale (DRS)² and the Confusion Assessment Method (CAM)³ —can help detect emerging symptoms.

Patient protection. Provide intensive nursing care—often one-to-one observation and containment—and, where possible, enlist the family in reassuring and calming the patient. Restraints may be needed to safeguard against injury and to prevent the patient from removing or dislocating monitoring equipment and IV access.

Pragmatic intervention. With medical colleagues, begin treating biochemical and physiologic abnormalities that are the most likely and most remediable contributors (Box 2).^2,4-6 Review the patient’s medications and discontinue or replace any that may be causing delirium.

Pharmacotherapy. Based on clinical studies, antipsychotics appear to possess antidelirium properties and may be considered as one part of a patient’s treatment plan. Interpreting these studies is complicated, however, by delirium’s complexity, numerous causes, and presumed mechanisms, as well as the transience of some forms. For ethical reasons, no placebo-controlled studies of delirium treatment have been done.

EVIDENCE ON ANTIPSYCHOTICS

Haloperidol has been the drug of choice for managing delirium because it is less likely to cause hypotension and sedation than other neuroleptics. Optimum haloperidol dosing in delirium has not been established, but the usual range is 2 to 6 mg every 4 to 6 hours, depending on the patient’s age and delirium severity.

Instances of QTc interval prolongation have been reported with high-dose IV haloperidol (> 100 mg). This life-threatening effect—which can induce torsades de pointes dysrhythmia, ventricular tachycardias, and fibrillation—is very rare, quite variable, and unpredictable. It probably is a function of total dose and neuroleptic administration rate.

Atypical antipsychotics share haloperidol’s advantages over first-generation neuroleptics, with lower potential for dystonic reactions, parkinsonian side effects, and tardive dyskinesia. Preliminary evidence suggests that atypicals may be safe and effective in treating delirium, although no randomized controlled trials have been done and accurate dose-response curves have not been established. Low to modest dosages have been used in case series.

Risperidone. Two prospective, open-label trials—each with 10 patients—suggest that low-dose risperidone is effective for treating delirium:

• In one trial, risperidone given at an average dosage of 1.7 mg/d was effective in 80% of patients with delirium, and one patient responded to 0.5 mg/d. Some patients experienced sleepiness or mild drug-induced parkinsonism.⁷
• In the other trial, risperidone was started at 0.5 mg twice daily, with additional doses allowed on day 1 for cognitive and behavioral symptoms. This dosage was maintained until DRS scores declined to ≤12, then was reduced by 50% and continued until day 6. Mean maintenance dosage was 0.75 mg/d. Two patients discontinued risperidone because of sedation or hypotension.⁸

Box 2

In a larger prospective study, 64 patients (mean age 67) with delirium were treated with risperidone, given at a mean dose of 2.6 +/- 1.7 mg/d at day 3. This dosage was effective in 90% of patients and significantly improved all symptoms, as measured with scales including the DRS. Two patients (3%) experienced adverse effects.⁹

No significant differences in response frequency were seen in a 7-day, double-blind comparison of flexibly-dosed risperidone (starting at 0.5 mg bid) and haloperidol (starting at 0.75 mg bid) in 28 patients with delirium. Symptom severity decreased for each group, as measured with the Memorial Delirium Assessment Scale. One patient receiving haloperidol experienced mild akathisia, but no others reported clinically significant side effects.¹⁰

Quetiapine. In a retrospective review, the charts of 11 patients who received quetiapine for delirium were compared with those of 11 similar patients treated with haloperidol. DRS scores improved by >50% in 10 of 11 patients in both groups, with similar onset of effect, treatment duration, and overall clinical improvement.¹¹ Small prospective trials with flexible dosing schedules have reported similar results.^12,13

In a study of 12 older hospitalized patients with delirium, quetiapine at a mean dosage of 93.75 +/-23.31 mg/d was associated with significant DRS score improvements. Interestingly, patients’ Mini-Mental State Examination and Clock-Drawing Test scores continued to improve 3 months after their delirium symptoms stabilized.¹⁴

Olanzapine. In a prospective trial, hospitalized patients with delirium were randomly assigned to receive enteral olanzapine or haloperidol. Delirium symptoms decreased across 5 days in both groups, and clinical improvement was similar. Some patients receiving haloperidol reported extrapyramidal symptoms, whereas those receiving olanzapine reported no adverse effects.¹⁵

Parenteral forms of some atypicals (aripiprazole, olanzapine, and ziprasidone) have become available and may increase this class’ usefulness in treating delirium.

Other drugs. Benzodiazepines appear ineffective and generally play only an adjunctive role in treating delirium. An exception may be delirium induced by acute alcohol or benzodiazepine withdrawal. Sedating antidepressants have been used as hypnotics in patients with delirium, but supporting evidence is lacking.

Other drug classes—general anesthetics, narcotics, cholinomimetics—may help manage the dangerously hyperactive delirious patient, but the literature contains no systematic analyses.

WHAT CAUSES DELIRIUM?

Delirium’s pathophysiology is not completely understood, although most authors believe several mechanisms are involved.

The brain’s exclusively oxidative metabolism and its systems’ hierarchical vulnerability to substrate deficiency—as might occur in even transient hypoxia or hypotension—appear to play important roles. Factors such as fever and stress that increase metabolic demand on the brain intensify the effects of oxygen deficiency or circulatory compromise.

At least three molecular mechanisms have been proposed for delirium, including cholinergic transmission disruption, monoaminergic dysfunction, and cytokine release ( Box 3).^16-19 These mechanisms may interact, cascading into a common final pathway that results in delirium.

Features not considered essential to delirium’s diagnosis—such as visual hallucinations or aggressive behaviors—indicate that additional cortical and subcortical systems are involved.

CASE REPORT: DRUG-DRUG INTERACTION

Three days after hip replacement surgery, Mr. S, age 64, becomes confused, distractible, and combative. He is alert one minute and somnolent the next. His arms and legs jerk involuntarily, and his muscle tone is diffusely increased. He talks with absent friends and family as though they are present in his hospital room. His body temperature and blood pressure fluctuate widely, despite no evidence of infection.

Box 3

Table

Drugs whose anticholinergic effects may increase the risk of delirium

For several years, Mr. S has been taking the monoamine oxidase inhibitor (MAOI) phenelzine, 30 mg/d, for depression maintenance treatment. On admission, he insisted that the MAOI be continued during hospitalization because it had relieved his severe depressions.

Within 24 hours of surgery, he was given the skeletal muscle relaxant cyclobenzaprine, 5 mg tid, for painful muscle spasms in the operated hip. When this brought little relief, the dosage was increased to 10 mg tid. Delirium and autonomic instability developed approximately 4 hours after the first 10-mg dose and gradually worsened.

The two drugs are discontinued, and Mr S. gradually recovers after several days of physiologic support, protection, and sedation in the intensive-care unit.

Discussion. Mr. S developed serotonin syndrome from a drug-drug interaction. Phenelzine inhibited serotonin metabolism, and cyclobenzaprine—a drug chemically similar to tricyclic antidepressants—inhibited serotonin reuptake, resulting in substantially increased CNS serotonergic activity.²⁰ Serotonin syndrome symptoms include delirium, autonomic dysfunction, and neurologic signs such as myoclonus and rigidity when patients are taking drugs that enhance serotonergic transmission.

DOES DELIRIUM WORSEN PROGNOSIS?

In the largest study of delirium in older patients, Inouye et al²¹ examined outcomes of 727 consecutive patients age 65 and older with various medical diagnoses who were admitted to three teaching hospitals. Delirium was diagnosed in 88 patients (12%) at admission.

Within 3 months of hospital discharge, 165 (25%) of 663 patients had died or been newly admitted to a nursing home. After the authors controlled the data for age, gender, dementia, illness severity, and functional status, they found that delirium:

• tripled the likelihood of nursing home placement at hospital discharge and after 3 months (adjusted odds ratio [OR] for delirium 3.0)
• more than doubled the likelihood of death or new nursing home placement at discharge (OR for delirium 2.1) and after 3 months (OR for delirium 2.6).

They concluded that delirium was a significant predictor of functional decline at hospital discharge and also at follow-up in older patients.

Interestingly, although these authors did not find a statistically significant association between delirium and death alone, the risk of death was particularly strong for patients who were not demented (OR for delirium, 3.77). Similarly, Rabins and Folstein²² found higher mortality rates in medically ill patients diagnosed with delirium on hospital admission than in demented, cognitively intact, or depressed patients. After 1 year, the death rate remained higher in those who had been delirious than in those with dementia.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

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

Four principles of treating delirium can help protect medical/surgical patients at risk for morbidity and functional decline. These principals—which I call the “four Ps”—are prompt identification, protection, pragmatic intervention, and pharmacotherapy.

This article describes an up-to-date, “four-Ps” approach to treating delirium—including use of antipsychotics and supportive care—and offers evidence and case reports to address these clinical questions:

• What causes delirium?
• Does delirium worsen prognosis?
• Can delirium be prevented?

FOUR ‘Ps’ FOR TREATING DELIRIUM

When a patient’s mental status changes dramatically (Box 1),¹ identifying potential delirium causes requires careful medical, psychiatric, and neurologic assessment. Assimilating this information is as essential to positive outcomes as are intensive nursing care and appropriate interventions.

Box 1

Prompt identification. Delirium often goes unrecognized, delaying treatment. Easily administered rating scales—such as the Delirium Rating Scale (DRS)² and the Confusion Assessment Method (CAM)³ —can help detect emerging symptoms.

Patient protection. Provide intensive nursing care—often one-to-one observation and containment—and, where possible, enlist the family in reassuring and calming the patient. Restraints may be needed to safeguard against injury and to prevent the patient from removing or dislocating monitoring equipment and IV access.

Pragmatic intervention. With medical colleagues, begin treating biochemical and physiologic abnormalities that are the most likely and most remediable contributors (Box 2).^2,4-6 Review the patient’s medications and discontinue or replace any that may be causing delirium.

Pharmacotherapy. Based on clinical studies, antipsychotics appear to possess antidelirium properties and may be considered as one part of a patient’s treatment plan. Interpreting these studies is complicated, however, by delirium’s complexity, numerous causes, and presumed mechanisms, as well as the transience of some forms. For ethical reasons, no placebo-controlled studies of delirium treatment have been done.

EVIDENCE ON ANTIPSYCHOTICS

Haloperidol has been the drug of choice for managing delirium because it is less likely to cause hypotension and sedation than other neuroleptics. Optimum haloperidol dosing in delirium has not been established, but the usual range is 2 to 6 mg every 4 to 6 hours, depending on the patient’s age and delirium severity.

Instances of QTc interval prolongation have been reported with high-dose IV haloperidol (> 100 mg). This life-threatening effect—which can induce torsades de pointes dysrhythmia, ventricular tachycardias, and fibrillation—is very rare, quite variable, and unpredictable. It probably is a function of total dose and neuroleptic administration rate.

Atypical antipsychotics share haloperidol’s advantages over first-generation neuroleptics, with lower potential for dystonic reactions, parkinsonian side effects, and tardive dyskinesia. Preliminary evidence suggests that atypicals may be safe and effective in treating delirium, although no randomized controlled trials have been done and accurate dose-response curves have not been established. Low to modest dosages have been used in case series.

Risperidone. Two prospective, open-label trials—each with 10 patients—suggest that low-dose risperidone is effective for treating delirium:

• In one trial, risperidone given at an average dosage of 1.7 mg/d was effective in 80% of patients with delirium, and one patient responded to 0.5 mg/d. Some patients experienced sleepiness or mild drug-induced parkinsonism.⁷
• In the other trial, risperidone was started at 0.5 mg twice daily, with additional doses allowed on day 1 for cognitive and behavioral symptoms. This dosage was maintained until DRS scores declined to ≤12, then was reduced by 50% and continued until day 6. Mean maintenance dosage was 0.75 mg/d. Two patients discontinued risperidone because of sedation or hypotension.⁸

Box 2

In a larger prospective study, 64 patients (mean age 67) with delirium were treated with risperidone, given at a mean dose of 2.6 +/- 1.7 mg/d at day 3. This dosage was effective in 90% of patients and significantly improved all symptoms, as measured with scales including the DRS. Two patients (3%) experienced adverse effects.⁹

No significant differences in response frequency were seen in a 7-day, double-blind comparison of flexibly-dosed risperidone (starting at 0.5 mg bid) and haloperidol (starting at 0.75 mg bid) in 28 patients with delirium. Symptom severity decreased for each group, as measured with the Memorial Delirium Assessment Scale. One patient receiving haloperidol experienced mild akathisia, but no others reported clinically significant side effects.¹⁰

Quetiapine. In a retrospective review, the charts of 11 patients who received quetiapine for delirium were compared with those of 11 similar patients treated with haloperidol. DRS scores improved by >50% in 10 of 11 patients in both groups, with similar onset of effect, treatment duration, and overall clinical improvement.¹¹ Small prospective trials with flexible dosing schedules have reported similar results.^12,13

In a study of 12 older hospitalized patients with delirium, quetiapine at a mean dosage of 93.75 +/-23.31 mg/d was associated with significant DRS score improvements. Interestingly, patients’ Mini-Mental State Examination and Clock-Drawing Test scores continued to improve 3 months after their delirium symptoms stabilized.¹⁴

Olanzapine. In a prospective trial, hospitalized patients with delirium were randomly assigned to receive enteral olanzapine or haloperidol. Delirium symptoms decreased across 5 days in both groups, and clinical improvement was similar. Some patients receiving haloperidol reported extrapyramidal symptoms, whereas those receiving olanzapine reported no adverse effects.¹⁵

Parenteral forms of some atypicals (aripiprazole, olanzapine, and ziprasidone) have become available and may increase this class’ usefulness in treating delirium.

Other drugs. Benzodiazepines appear ineffective and generally play only an adjunctive role in treating delirium. An exception may be delirium induced by acute alcohol or benzodiazepine withdrawal. Sedating antidepressants have been used as hypnotics in patients with delirium, but supporting evidence is lacking.

Other drug classes—general anesthetics, narcotics, cholinomimetics—may help manage the dangerously hyperactive delirious patient, but the literature contains no systematic analyses.

WHAT CAUSES DELIRIUM?

Delirium’s pathophysiology is not completely understood, although most authors believe several mechanisms are involved.

The brain’s exclusively oxidative metabolism and its systems’ hierarchical vulnerability to substrate deficiency—as might occur in even transient hypoxia or hypotension—appear to play important roles. Factors such as fever and stress that increase metabolic demand on the brain intensify the effects of oxygen deficiency or circulatory compromise.

At least three molecular mechanisms have been proposed for delirium, including cholinergic transmission disruption, monoaminergic dysfunction, and cytokine release ( Box 3).^16-19 These mechanisms may interact, cascading into a common final pathway that results in delirium.

Features not considered essential to delirium’s diagnosis—such as visual hallucinations or aggressive behaviors—indicate that additional cortical and subcortical systems are involved.

CASE REPORT: DRUG-DRUG INTERACTION

Three days after hip replacement surgery, Mr. S, age 64, becomes confused, distractible, and combative. He is alert one minute and somnolent the next. His arms and legs jerk involuntarily, and his muscle tone is diffusely increased. He talks with absent friends and family as though they are present in his hospital room. His body temperature and blood pressure fluctuate widely, despite no evidence of infection.

Box 3

Table

Drugs whose anticholinergic effects may increase the risk of delirium

For several years, Mr. S has been taking the monoamine oxidase inhibitor (MAOI) phenelzine, 30 mg/d, for depression maintenance treatment. On admission, he insisted that the MAOI be continued during hospitalization because it had relieved his severe depressions.

Within 24 hours of surgery, he was given the skeletal muscle relaxant cyclobenzaprine, 5 mg tid, for painful muscle spasms in the operated hip. When this brought little relief, the dosage was increased to 10 mg tid. Delirium and autonomic instability developed approximately 4 hours after the first 10-mg dose and gradually worsened.

The two drugs are discontinued, and Mr S. gradually recovers after several days of physiologic support, protection, and sedation in the intensive-care unit.

Discussion. Mr. S developed serotonin syndrome from a drug-drug interaction. Phenelzine inhibited serotonin metabolism, and cyclobenzaprine—a drug chemically similar to tricyclic antidepressants—inhibited serotonin reuptake, resulting in substantially increased CNS serotonergic activity.²⁰ Serotonin syndrome symptoms include delirium, autonomic dysfunction, and neurologic signs such as myoclonus and rigidity when patients are taking drugs that enhance serotonergic transmission.

DOES DELIRIUM WORSEN PROGNOSIS?

In the largest study of delirium in older patients, Inouye et al²¹ examined outcomes of 727 consecutive patients age 65 and older with various medical diagnoses who were admitted to three teaching hospitals. Delirium was diagnosed in 88 patients (12%) at admission.

Within 3 months of hospital discharge, 165 (25%) of 663 patients had died or been newly admitted to a nursing home. After the authors controlled the data for age, gender, dementia, illness severity, and functional status, they found that delirium:

• tripled the likelihood of nursing home placement at hospital discharge and after 3 months (adjusted odds ratio [OR] for delirium 3.0)
• more than doubled the likelihood of death or new nursing home placement at discharge (OR for delirium 2.1) and after 3 months (OR for delirium 2.6).

They concluded that delirium was a significant predictor of functional decline at hospital discharge and also at follow-up in older patients.

Interestingly, although these authors did not find a statistically significant association between delirium and death alone, the risk of death was particularly strong for patients who were not demented (OR for delirium, 3.77). Similarly, Rabins and Folstein²² found higher mortality rates in medically ill patients diagnosed with delirium on hospital admission than in demented, cognitively intact, or depressed patients. After 1 year, the death rate remained higher in those who had been delirious than in those with dementia.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

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

Four principles of treating delirium can help protect medical/surgical patients at risk for morbidity and functional decline. These principals—which I call the “four Ps”—are prompt identification, protection, pragmatic intervention, and pharmacotherapy.

This article describes an up-to-date, “four-Ps” approach to treating delirium—including use of antipsychotics and supportive care—and offers evidence and case reports to address these clinical questions:

• What causes delirium?
• Does delirium worsen prognosis?
• Can delirium be prevented?

FOUR ‘Ps’ FOR TREATING DELIRIUM

When a patient’s mental status changes dramatically (Box 1),¹ identifying potential delirium causes requires careful medical, psychiatric, and neurologic assessment. Assimilating this information is as essential to positive outcomes as are intensive nursing care and appropriate interventions.

Box 1

Prompt identification. Delirium often goes unrecognized, delaying treatment. Easily administered rating scales—such as the Delirium Rating Scale (DRS)² and the Confusion Assessment Method (CAM)³ —can help detect emerging symptoms.

Patient protection. Provide intensive nursing care—often one-to-one observation and containment—and, where possible, enlist the family in reassuring and calming the patient. Restraints may be needed to safeguard against injury and to prevent the patient from removing or dislocating monitoring equipment and IV access.

Pragmatic intervention. With medical colleagues, begin treating biochemical and physiologic abnormalities that are the most likely and most remediable contributors (Box 2).^2,4-6 Review the patient’s medications and discontinue or replace any that may be causing delirium.

Pharmacotherapy. Based on clinical studies, antipsychotics appear to possess antidelirium properties and may be considered as one part of a patient’s treatment plan. Interpreting these studies is complicated, however, by delirium’s complexity, numerous causes, and presumed mechanisms, as well as the transience of some forms. For ethical reasons, no placebo-controlled studies of delirium treatment have been done.

EVIDENCE ON ANTIPSYCHOTICS

Haloperidol has been the drug of choice for managing delirium because it is less likely to cause hypotension and sedation than other neuroleptics. Optimum haloperidol dosing in delirium has not been established, but the usual range is 2 to 6 mg every 4 to 6 hours, depending on the patient’s age and delirium severity.

Instances of QTc interval prolongation have been reported with high-dose IV haloperidol (> 100 mg). This life-threatening effect—which can induce torsades de pointes dysrhythmia, ventricular tachycardias, and fibrillation—is very rare, quite variable, and unpredictable. It probably is a function of total dose and neuroleptic administration rate.

Atypical antipsychotics share haloperidol’s advantages over first-generation neuroleptics, with lower potential for dystonic reactions, parkinsonian side effects, and tardive dyskinesia. Preliminary evidence suggests that atypicals may be safe and effective in treating delirium, although no randomized controlled trials have been done and accurate dose-response curves have not been established. Low to modest dosages have been used in case series.

Risperidone. Two prospective, open-label trials—each with 10 patients—suggest that low-dose risperidone is effective for treating delirium:

• In one trial, risperidone given at an average dosage of 1.7 mg/d was effective in 80% of patients with delirium, and one patient responded to 0.5 mg/d. Some patients experienced sleepiness or mild drug-induced parkinsonism.⁷
• In the other trial, risperidone was started at 0.5 mg twice daily, with additional doses allowed on day 1 for cognitive and behavioral symptoms. This dosage was maintained until DRS scores declined to ≤12, then was reduced by 50% and continued until day 6. Mean maintenance dosage was 0.75 mg/d. Two patients discontinued risperidone because of sedation or hypotension.⁸

Box 2

In a larger prospective study, 64 patients (mean age 67) with delirium were treated with risperidone, given at a mean dose of 2.6 +/- 1.7 mg/d at day 3. This dosage was effective in 90% of patients and significantly improved all symptoms, as measured with scales including the DRS. Two patients (3%) experienced adverse effects.⁹

No significant differences in response frequency were seen in a 7-day, double-blind comparison of flexibly-dosed risperidone (starting at 0.5 mg bid) and haloperidol (starting at 0.75 mg bid) in 28 patients with delirium. Symptom severity decreased for each group, as measured with the Memorial Delirium Assessment Scale. One patient receiving haloperidol experienced mild akathisia, but no others reported clinically significant side effects.¹⁰

Quetiapine. In a retrospective review, the charts of 11 patients who received quetiapine for delirium were compared with those of 11 similar patients treated with haloperidol. DRS scores improved by >50% in 10 of 11 patients in both groups, with similar onset of effect, treatment duration, and overall clinical improvement.¹¹ Small prospective trials with flexible dosing schedules have reported similar results.^12,13

In a study of 12 older hospitalized patients with delirium, quetiapine at a mean dosage of 93.75 +/-23.31 mg/d was associated with significant DRS score improvements. Interestingly, patients’ Mini-Mental State Examination and Clock-Drawing Test scores continued to improve 3 months after their delirium symptoms stabilized.¹⁴

Olanzapine. In a prospective trial, hospitalized patients with delirium were randomly assigned to receive enteral olanzapine or haloperidol. Delirium symptoms decreased across 5 days in both groups, and clinical improvement was similar. Some patients receiving haloperidol reported extrapyramidal symptoms, whereas those receiving olanzapine reported no adverse effects.¹⁵

Parenteral forms of some atypicals (aripiprazole, olanzapine, and ziprasidone) have become available and may increase this class’ usefulness in treating delirium.

Other drugs. Benzodiazepines appear ineffective and generally play only an adjunctive role in treating delirium. An exception may be delirium induced by acute alcohol or benzodiazepine withdrawal. Sedating antidepressants have been used as hypnotics in patients with delirium, but supporting evidence is lacking.

Other drug classes—general anesthetics, narcotics, cholinomimetics—may help manage the dangerously hyperactive delirious patient, but the literature contains no systematic analyses.

WHAT CAUSES DELIRIUM?

Delirium’s pathophysiology is not completely understood, although most authors believe several mechanisms are involved.

The brain’s exclusively oxidative metabolism and its systems’ hierarchical vulnerability to substrate deficiency—as might occur in even transient hypoxia or hypotension—appear to play important roles. Factors such as fever and stress that increase metabolic demand on the brain intensify the effects of oxygen deficiency or circulatory compromise.

At least three molecular mechanisms have been proposed for delirium, including cholinergic transmission disruption, monoaminergic dysfunction, and cytokine release ( Box 3).^16-19 These mechanisms may interact, cascading into a common final pathway that results in delirium.

Features not considered essential to delirium’s diagnosis—such as visual hallucinations or aggressive behaviors—indicate that additional cortical and subcortical systems are involved.

CASE REPORT: DRUG-DRUG INTERACTION

Three days after hip replacement surgery, Mr. S, age 64, becomes confused, distractible, and combative. He is alert one minute and somnolent the next. His arms and legs jerk involuntarily, and his muscle tone is diffusely increased. He talks with absent friends and family as though they are present in his hospital room. His body temperature and blood pressure fluctuate widely, despite no evidence of infection.

Box 3

Table

Drugs whose anticholinergic effects may increase the risk of delirium

For several years, Mr. S has been taking the monoamine oxidase inhibitor (MAOI) phenelzine, 30 mg/d, for depression maintenance treatment. On admission, he insisted that the MAOI be continued during hospitalization because it had relieved his severe depressions.

Within 24 hours of surgery, he was given the skeletal muscle relaxant cyclobenzaprine, 5 mg tid, for painful muscle spasms in the operated hip. When this brought little relief, the dosage was increased to 10 mg tid. Delirium and autonomic instability developed approximately 4 hours after the first 10-mg dose and gradually worsened.

The two drugs are discontinued, and Mr S. gradually recovers after several days of physiologic support, protection, and sedation in the intensive-care unit.

Discussion. Mr. S developed serotonin syndrome from a drug-drug interaction. Phenelzine inhibited serotonin metabolism, and cyclobenzaprine—a drug chemically similar to tricyclic antidepressants—inhibited serotonin reuptake, resulting in substantially increased CNS serotonergic activity.²⁰ Serotonin syndrome symptoms include delirium, autonomic dysfunction, and neurologic signs such as myoclonus and rigidity when patients are taking drugs that enhance serotonergic transmission.

DOES DELIRIUM WORSEN PROGNOSIS?

In the largest study of delirium in older patients, Inouye et al²¹ examined outcomes of 727 consecutive patients age 65 and older with various medical diagnoses who were admitted to three teaching hospitals. Delirium was diagnosed in 88 patients (12%) at admission.

Within 3 months of hospital discharge, 165 (25%) of 663 patients had died or been newly admitted to a nursing home. After the authors controlled the data for age, gender, dementia, illness severity, and functional status, they found that delirium:

• tripled the likelihood of nursing home placement at hospital discharge and after 3 months (adjusted odds ratio [OR] for delirium 3.0)
• more than doubled the likelihood of death or new nursing home placement at discharge (OR for delirium 2.1) and after 3 months (OR for delirium 2.6).

They concluded that delirium was a significant predictor of functional decline at hospital discharge and also at follow-up in older patients.

Interestingly, although these authors did not find a statistically significant association between delirium and death alone, the risk of death was particularly strong for patients who were not demented (OR for delirium, 3.77). Similarly, Rabins and Folstein²² found higher mortality rates in medically ill patients diagnosed with delirium on hospital admission than in demented, cognitively intact, or depressed patients. After 1 year, the death rate remained higher in those who had been delirious than in those with dementia.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

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

Trichotillomania (TTM) is distressing to pediatric patients who pull their hair and to their parents who feel helpless to stop the destructive behavior. Hair-pulling with psychiatric comorbidity requires comprehensive assessment and treatment, but we have found that cognitive-behavioral therapy (CBT) alone can help children and adolescents with uncomplicated TTM.

This article describes a typical patient with adolescent-onset mild-to-moderate TTM and the three-step CBT approach—awareness training, stimulus control, and habit reversal—that we find effective in reducing pediatric hair pulling.

Jane, age 12, was referred to our clinic by her primary doctor after an 8-week trial of fluoxetine, 80 mg/d, failed to stop her hair pulling. Jane, who is right-handed, has been pulling her hair for 2 years, mostly in the right front scalp. Her shame over the hair loss makes her reluctant to participate in social activities. A dermatologist found no medical cause for her behavior, such as alopecia or folliculitis.

Jane’s parents say she has no history of a major mood disorder or anxiety. Her hair pulling causes significant “tension and stress” for all family members.

WHY DO PATIENTS PULL HAIR?

Cognitive-behavioral theory suggests that chronic TTM originates as a normal response to stress that often escapes personal and social awareness but gradually increases in frequency and severity (Box).^1-8 Thus, hair pulling becomes associated with internal and external cues through conditioning and is maintained primarily by positive reinforcement. Hair-pulling urges that are reinforced by pulling intensify the need to pull, perpetuating the behavioral cycle.

A genetic link? Familial research has associated TTM with increased rates of obsessive-compulsive disorder (OCD) or other excessive habits—such as nail biting or skin picking—among first-degree relatives.^6,9,10 Neuroimaging of persons with TTM has shown hyperactivity in the left cerebellum and right superior parietal lobe¹¹ as well as possible structural abnormalities in the left putamen,¹² left inferior frontal gyrus, and right cluneal cortex.¹³

These findings do not necessarily indicate pre-existing brain pathology, however. Perhaps TTM leads to changes in brain structure or function, or both TTM and the brain abnormalities may be caused by another as-yet-unknown variable.

Decreased pain sensitivity. Patients with TTM often report that hair pulling is not painful,² though we suspect that persons without TTM would disagree and derive no pleasure from it. Changes in pain sensitivity may influence the reinforcing quality of pulling behavior. One possible mechanism for such alterations is upregulation of the endogenous opioid system; some intriguing evidence suggests that opioid receptor antagonists such as naltrexone may reduce pulling.¹⁴

Box

Pain tolerance at the preferred pulling site has not been studied, however. For patients who feel pain from hair pulling, the pain itself may reinforce the behavior by distracting the individual from negative emotional or physiologic states.¹⁵

CASE CONTINUED: COUNTING THE WAYS

Jane and her parents agree that she pulls her hair 5 to 8 times daily, one hair at a time with her right index finger and thumb while doing homework or watching TV. The trigger, she says, is “an itch” on her scalp; “sometimes pulling relieves the itch.” She fails to resist pulling her hair 9 out of 10 times.

Table 1

Defining hair pulling: What to ask the pediatric patient

Psychiatric comorbidity is common—if not the norm—in adults with TTM. Although axis I comorbidity is also seen in children and adolescents, their hair pulling is frequently uncomplicated. Jane meets criteria for TTM, as determined by the Trichotillomania Diagnostic Interview,¹⁶ but her history does not support a comorbid disorder. After discussing the diagnosis with Jane and her parents, the psychiatrist begins treatment with CBT alone.

MEDICATION OR CBT?

SSRIs. Literature on TTM pharmacotherapy is very limited and equivocal. Medications that have helped adults with TTM have been described,¹⁷ but the lack of a single, randomized, controlled trial in pediatric TTM severely limits treatment recommendations for children.

Selective serotonin reuptake inhibitors (SSRIs) have shown efficacy for treating anger and other impulse control problems but not for TTM. Some practitioners use SSRIs for TTM because of the belief that TTM is a variant of OCD. However, TTM may be maintained by positive reinforcement rather than compulsive tendencies and thus may not respond to SSRIs.

CBT. Evidence on CBT justifies cautious recommendations for pediatric TTM. In randomized trials, CBT reduced hair pulling in adults and was more effective than SSRIs or placebo.^18,19

REDUCING THE URGE

Obtain detailed information about a child or adolescent’s hair-pulling episodes (Table 1), as recognizing triggers and reactions is vital to effective CBT. Explain to the patient that:

• the pleasure or satisfaction she derives from pulling reinforces the urge to pull
• she can reduce the urge by learning and using awareness training, stimulus control, and habit reversal (Table 2).

Awareness training involves patient self-monitoring to gain awareness of urges to pull and of pulling behavior. The child must become alert to every hair pulled and to response precursors, such as placing her hand on her head. For a patient such as Jane, a useful technique is to post reminders on the TV and school notebook and in the bedroom and bathroom—wherever pulling typically occurs.

A “PULLING CALENDAR”

Jane begins a daily “pulling calendar” in which she records each time she pulls a hair while watching TV or doing homework. She is asked to include the total number of hairs pulled and the intensity of the “itch to pull” on a scale of 1 to 10.

Stimulus control. Most patients can identify high-risk situations, such as time in the bathroom, talking on the phone, watching TV, driving, reading, or while falling asleep. Boredom, frustration, anxiety, and sadness may serve as pulling cues.

With stimulus control, the patient tries to reduce her ability to freely engage in pulling behavior in high-risk situations. For instance, you might encourage a child who pulls hairs while doing homework to stick Band-Aid^®-type adhesive strips on her thumb and index finger tips before she starts studying as an impediment to gripping hairs. Such “speed bumps” may allow her to delay pulling and reach for tools that assist in habit reversal.

TREATMENT THAT APPEALS

Jane agrees to apply adhesive strips to her fingers and understands why. Because she is a fan of Peter Pan, we place Peter Pan stickers on her books and notebooks and on the TV remote control as reminders not to pull.

Table 2

CBT strategies to reduce the hair-pulling urge

Habit reversal and competing response procedures provide pleasurable physical stimulation as an alternative to pulling. The most effective methods engage the same motions as used in hair pulling. Examples include sculpting with clay, hulling sunflower seeds, and playing with Koosh^® balls—small rubbery balls filled with a jellylike plasma and covered with hundreds of soft “tentacles.”

‘CALMER, HAPPIER’

We explain habit reversal to Jane and instruct her to use the Koosh ball a few times a day. She enjoys pulling its rubber strands, an action that uses the same muscles as hair pulling. Because she will need Koosh balls during all identified high-risk situations, we instruct her to buy one for her book bag and to leave one near the couch where she watches TV.

Over time, Jane reports a gradual decrease of hair pulling with the use of awareness training and stimulus control techniques. Using the Koosh ball (habit reversal) helps her improve. By the 10th week, Jane and her parents report a 70% decrease in hair pulling, based on the pulling calendar entries and other objective evidence of treatment response. All report feeling “calmer and happier.”

CONCLUSION

Cognitive and behavioral strategies are useful and safe for treating pediatric TTM. Enlisting the parents and patient in identifying problem situations and applying creative solutions may increase the chances of success.

Follow-up is important for maintaining new cognitive and behavioral patterns. We recommend that you see patients monthly for at least 3 months, depending on how the patient feels about additional sessions. We encourage families to call and report on progress or relapses. Booster CBT sessions can help deal with setbacks.

Related resources

• Trichotillomania Learning Center, Inc.; devoted to improving TTM understanding and providing access to treatments and support groups. www.trich.org. Accessed Sept. 17, 2004.
• Golomb RG, Vavrichek SM. The hair pulling “habit” and you: how to solve the trichotillomania puzzle (rev ed). Silver Spring, MD: Writer’s Cooperative of Greater Washington; 2000. Book for children and teenagers.

Drug brand names

• Fluoxetine • Prozac
• Naltrexone • Depade, ReVia

Disclosure

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

Acknowledgment

Preparation of this article was supported in part by a grant from the National Institute of Mental Health (MH61457).

Trichotillomania (TTM) is distressing to pediatric patients who pull their hair and to their parents who feel helpless to stop the destructive behavior. Hair-pulling with psychiatric comorbidity requires comprehensive assessment and treatment, but we have found that cognitive-behavioral therapy (CBT) alone can help children and adolescents with uncomplicated TTM.

This article describes a typical patient with adolescent-onset mild-to-moderate TTM and the three-step CBT approach—awareness training, stimulus control, and habit reversal—that we find effective in reducing pediatric hair pulling.

Jane, age 12, was referred to our clinic by her primary doctor after an 8-week trial of fluoxetine, 80 mg/d, failed to stop her hair pulling. Jane, who is right-handed, has been pulling her hair for 2 years, mostly in the right front scalp. Her shame over the hair loss makes her reluctant to participate in social activities. A dermatologist found no medical cause for her behavior, such as alopecia or folliculitis.

Jane’s parents say she has no history of a major mood disorder or anxiety. Her hair pulling causes significant “tension and stress” for all family members.

WHY DO PATIENTS PULL HAIR?

Cognitive-behavioral theory suggests that chronic TTM originates as a normal response to stress that often escapes personal and social awareness but gradually increases in frequency and severity (Box).^1-8 Thus, hair pulling becomes associated with internal and external cues through conditioning and is maintained primarily by positive reinforcement. Hair-pulling urges that are reinforced by pulling intensify the need to pull, perpetuating the behavioral cycle.

A genetic link? Familial research has associated TTM with increased rates of obsessive-compulsive disorder (OCD) or other excessive habits—such as nail biting or skin picking—among first-degree relatives.^6,9,10 Neuroimaging of persons with TTM has shown hyperactivity in the left cerebellum and right superior parietal lobe¹¹ as well as possible structural abnormalities in the left putamen,¹² left inferior frontal gyrus, and right cluneal cortex.¹³

These findings do not necessarily indicate pre-existing brain pathology, however. Perhaps TTM leads to changes in brain structure or function, or both TTM and the brain abnormalities may be caused by another as-yet-unknown variable.

Decreased pain sensitivity. Patients with TTM often report that hair pulling is not painful,² though we suspect that persons without TTM would disagree and derive no pleasure from it. Changes in pain sensitivity may influence the reinforcing quality of pulling behavior. One possible mechanism for such alterations is upregulation of the endogenous opioid system; some intriguing evidence suggests that opioid receptor antagonists such as naltrexone may reduce pulling.¹⁴

Box

Pain tolerance at the preferred pulling site has not been studied, however. For patients who feel pain from hair pulling, the pain itself may reinforce the behavior by distracting the individual from negative emotional or physiologic states.¹⁵

CASE CONTINUED: COUNTING THE WAYS

Jane and her parents agree that she pulls her hair 5 to 8 times daily, one hair at a time with her right index finger and thumb while doing homework or watching TV. The trigger, she says, is “an itch” on her scalp; “sometimes pulling relieves the itch.” She fails to resist pulling her hair 9 out of 10 times.

Table 1

Defining hair pulling: What to ask the pediatric patient

Psychiatric comorbidity is common—if not the norm—in adults with TTM. Although axis I comorbidity is also seen in children and adolescents, their hair pulling is frequently uncomplicated. Jane meets criteria for TTM, as determined by the Trichotillomania Diagnostic Interview,¹⁶ but her history does not support a comorbid disorder. After discussing the diagnosis with Jane and her parents, the psychiatrist begins treatment with CBT alone.

MEDICATION OR CBT?

SSRIs. Literature on TTM pharmacotherapy is very limited and equivocal. Medications that have helped adults with TTM have been described,¹⁷ but the lack of a single, randomized, controlled trial in pediatric TTM severely limits treatment recommendations for children.

Selective serotonin reuptake inhibitors (SSRIs) have shown efficacy for treating anger and other impulse control problems but not for TTM. Some practitioners use SSRIs for TTM because of the belief that TTM is a variant of OCD. However, TTM may be maintained by positive reinforcement rather than compulsive tendencies and thus may not respond to SSRIs.

CBT. Evidence on CBT justifies cautious recommendations for pediatric TTM. In randomized trials, CBT reduced hair pulling in adults and was more effective than SSRIs or placebo.^18,19

REDUCING THE URGE

Obtain detailed information about a child or adolescent’s hair-pulling episodes (Table 1), as recognizing triggers and reactions is vital to effective CBT. Explain to the patient that:

• the pleasure or satisfaction she derives from pulling reinforces the urge to pull
• she can reduce the urge by learning and using awareness training, stimulus control, and habit reversal (Table 2).

Awareness training involves patient self-monitoring to gain awareness of urges to pull and of pulling behavior. The child must become alert to every hair pulled and to response precursors, such as placing her hand on her head. For a patient such as Jane, a useful technique is to post reminders on the TV and school notebook and in the bedroom and bathroom—wherever pulling typically occurs.

A “PULLING CALENDAR”

Jane begins a daily “pulling calendar” in which she records each time she pulls a hair while watching TV or doing homework. She is asked to include the total number of hairs pulled and the intensity of the “itch to pull” on a scale of 1 to 10.

Stimulus control. Most patients can identify high-risk situations, such as time in the bathroom, talking on the phone, watching TV, driving, reading, or while falling asleep. Boredom, frustration, anxiety, and sadness may serve as pulling cues.

With stimulus control, the patient tries to reduce her ability to freely engage in pulling behavior in high-risk situations. For instance, you might encourage a child who pulls hairs while doing homework to stick Band-Aid^®-type adhesive strips on her thumb and index finger tips before she starts studying as an impediment to gripping hairs. Such “speed bumps” may allow her to delay pulling and reach for tools that assist in habit reversal.

TREATMENT THAT APPEALS

Jane agrees to apply adhesive strips to her fingers and understands why. Because she is a fan of Peter Pan, we place Peter Pan stickers on her books and notebooks and on the TV remote control as reminders not to pull.

Table 2

CBT strategies to reduce the hair-pulling urge

Habit reversal and competing response procedures provide pleasurable physical stimulation as an alternative to pulling. The most effective methods engage the same motions as used in hair pulling. Examples include sculpting with clay, hulling sunflower seeds, and playing with Koosh^® balls—small rubbery balls filled with a jellylike plasma and covered with hundreds of soft “tentacles.”

‘CALMER, HAPPIER’

We explain habit reversal to Jane and instruct her to use the Koosh ball a few times a day. She enjoys pulling its rubber strands, an action that uses the same muscles as hair pulling. Because she will need Koosh balls during all identified high-risk situations, we instruct her to buy one for her book bag and to leave one near the couch where she watches TV.

Over time, Jane reports a gradual decrease of hair pulling with the use of awareness training and stimulus control techniques. Using the Koosh ball (habit reversal) helps her improve. By the 10th week, Jane and her parents report a 70% decrease in hair pulling, based on the pulling calendar entries and other objective evidence of treatment response. All report feeling “calmer and happier.”

CONCLUSION

Cognitive and behavioral strategies are useful and safe for treating pediatric TTM. Enlisting the parents and patient in identifying problem situations and applying creative solutions may increase the chances of success.

Follow-up is important for maintaining new cognitive and behavioral patterns. We recommend that you see patients monthly for at least 3 months, depending on how the patient feels about additional sessions. We encourage families to call and report on progress or relapses. Booster CBT sessions can help deal with setbacks.

Related resources

• Trichotillomania Learning Center, Inc.; devoted to improving TTM understanding and providing access to treatments and support groups. www.trich.org. Accessed Sept. 17, 2004.
• Golomb RG, Vavrichek SM. The hair pulling “habit” and you: how to solve the trichotillomania puzzle (rev ed). Silver Spring, MD: Writer’s Cooperative of Greater Washington; 2000. Book for children and teenagers.

Drug brand names

• Fluoxetine • Prozac
• Naltrexone • Depade, ReVia

Disclosure

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

Acknowledgment

Preparation of this article was supported in part by a grant from the National Institute of Mental Health (MH61457).

Trichotillomania (TTM) is distressing to pediatric patients who pull their hair and to their parents who feel helpless to stop the destructive behavior. Hair-pulling with psychiatric comorbidity requires comprehensive assessment and treatment, but we have found that cognitive-behavioral therapy (CBT) alone can help children and adolescents with uncomplicated TTM.

This article describes a typical patient with adolescent-onset mild-to-moderate TTM and the three-step CBT approach—awareness training, stimulus control, and habit reversal—that we find effective in reducing pediatric hair pulling.

Jane, age 12, was referred to our clinic by her primary doctor after an 8-week trial of fluoxetine, 80 mg/d, failed to stop her hair pulling. Jane, who is right-handed, has been pulling her hair for 2 years, mostly in the right front scalp. Her shame over the hair loss makes her reluctant to participate in social activities. A dermatologist found no medical cause for her behavior, such as alopecia or folliculitis.

Jane’s parents say she has no history of a major mood disorder or anxiety. Her hair pulling causes significant “tension and stress” for all family members.

WHY DO PATIENTS PULL HAIR?

Cognitive-behavioral theory suggests that chronic TTM originates as a normal response to stress that often escapes personal and social awareness but gradually increases in frequency and severity (Box).^1-8 Thus, hair pulling becomes associated with internal and external cues through conditioning and is maintained primarily by positive reinforcement. Hair-pulling urges that are reinforced by pulling intensify the need to pull, perpetuating the behavioral cycle.

A genetic link? Familial research has associated TTM with increased rates of obsessive-compulsive disorder (OCD) or other excessive habits—such as nail biting or skin picking—among first-degree relatives.^6,9,10 Neuroimaging of persons with TTM has shown hyperactivity in the left cerebellum and right superior parietal lobe¹¹ as well as possible structural abnormalities in the left putamen,¹² left inferior frontal gyrus, and right cluneal cortex.¹³

These findings do not necessarily indicate pre-existing brain pathology, however. Perhaps TTM leads to changes in brain structure or function, or both TTM and the brain abnormalities may be caused by another as-yet-unknown variable.

Decreased pain sensitivity. Patients with TTM often report that hair pulling is not painful,² though we suspect that persons without TTM would disagree and derive no pleasure from it. Changes in pain sensitivity may influence the reinforcing quality of pulling behavior. One possible mechanism for such alterations is upregulation of the endogenous opioid system; some intriguing evidence suggests that opioid receptor antagonists such as naltrexone may reduce pulling.¹⁴

Box

Pain tolerance at the preferred pulling site has not been studied, however. For patients who feel pain from hair pulling, the pain itself may reinforce the behavior by distracting the individual from negative emotional or physiologic states.¹⁵

CASE CONTINUED: COUNTING THE WAYS

Jane and her parents agree that she pulls her hair 5 to 8 times daily, one hair at a time with her right index finger and thumb while doing homework or watching TV. The trigger, she says, is “an itch” on her scalp; “sometimes pulling relieves the itch.” She fails to resist pulling her hair 9 out of 10 times.

Table 1

Defining hair pulling: What to ask the pediatric patient

Psychiatric comorbidity is common—if not the norm—in adults with TTM. Although axis I comorbidity is also seen in children and adolescents, their hair pulling is frequently uncomplicated. Jane meets criteria for TTM, as determined by the Trichotillomania Diagnostic Interview,¹⁶ but her history does not support a comorbid disorder. After discussing the diagnosis with Jane and her parents, the psychiatrist begins treatment with CBT alone.

MEDICATION OR CBT?

SSRIs. Literature on TTM pharmacotherapy is very limited and equivocal. Medications that have helped adults with TTM have been described,¹⁷ but the lack of a single, randomized, controlled trial in pediatric TTM severely limits treatment recommendations for children.

Selective serotonin reuptake inhibitors (SSRIs) have shown efficacy for treating anger and other impulse control problems but not for TTM. Some practitioners use SSRIs for TTM because of the belief that TTM is a variant of OCD. However, TTM may be maintained by positive reinforcement rather than compulsive tendencies and thus may not respond to SSRIs.

CBT. Evidence on CBT justifies cautious recommendations for pediatric TTM. In randomized trials, CBT reduced hair pulling in adults and was more effective than SSRIs or placebo.^18,19

REDUCING THE URGE

Obtain detailed information about a child or adolescent’s hair-pulling episodes (Table 1), as recognizing triggers and reactions is vital to effective CBT. Explain to the patient that:

• the pleasure or satisfaction she derives from pulling reinforces the urge to pull
• she can reduce the urge by learning and using awareness training, stimulus control, and habit reversal (Table 2).

Awareness training involves patient self-monitoring to gain awareness of urges to pull and of pulling behavior. The child must become alert to every hair pulled and to response precursors, such as placing her hand on her head. For a patient such as Jane, a useful technique is to post reminders on the TV and school notebook and in the bedroom and bathroom—wherever pulling typically occurs.

A “PULLING CALENDAR”

Jane begins a daily “pulling calendar” in which she records each time she pulls a hair while watching TV or doing homework. She is asked to include the total number of hairs pulled and the intensity of the “itch to pull” on a scale of 1 to 10.

Stimulus control. Most patients can identify high-risk situations, such as time in the bathroom, talking on the phone, watching TV, driving, reading, or while falling asleep. Boredom, frustration, anxiety, and sadness may serve as pulling cues.

With stimulus control, the patient tries to reduce her ability to freely engage in pulling behavior in high-risk situations. For instance, you might encourage a child who pulls hairs while doing homework to stick Band-Aid^®-type adhesive strips on her thumb and index finger tips before she starts studying as an impediment to gripping hairs. Such “speed bumps” may allow her to delay pulling and reach for tools that assist in habit reversal.

TREATMENT THAT APPEALS

Jane agrees to apply adhesive strips to her fingers and understands why. Because she is a fan of Peter Pan, we place Peter Pan stickers on her books and notebooks and on the TV remote control as reminders not to pull.

Table 2

CBT strategies to reduce the hair-pulling urge

Habit reversal and competing response procedures provide pleasurable physical stimulation as an alternative to pulling. The most effective methods engage the same motions as used in hair pulling. Examples include sculpting with clay, hulling sunflower seeds, and playing with Koosh^® balls—small rubbery balls filled with a jellylike plasma and covered with hundreds of soft “tentacles.”

‘CALMER, HAPPIER’

We explain habit reversal to Jane and instruct her to use the Koosh ball a few times a day. She enjoys pulling its rubber strands, an action that uses the same muscles as hair pulling. Because she will need Koosh balls during all identified high-risk situations, we instruct her to buy one for her book bag and to leave one near the couch where she watches TV.

Over time, Jane reports a gradual decrease of hair pulling with the use of awareness training and stimulus control techniques. Using the Koosh ball (habit reversal) helps her improve. By the 10th week, Jane and her parents report a 70% decrease in hair pulling, based on the pulling calendar entries and other objective evidence of treatment response. All report feeling “calmer and happier.”

CONCLUSION

Cognitive and behavioral strategies are useful and safe for treating pediatric TTM. Enlisting the parents and patient in identifying problem situations and applying creative solutions may increase the chances of success.

Follow-up is important for maintaining new cognitive and behavioral patterns. We recommend that you see patients monthly for at least 3 months, depending on how the patient feels about additional sessions. We encourage families to call and report on progress or relapses. Booster CBT sessions can help deal with setbacks.

Related resources

• Trichotillomania Learning Center, Inc.; devoted to improving TTM understanding and providing access to treatments and support groups. www.trich.org. Accessed Sept. 17, 2004.
• Golomb RG, Vavrichek SM. The hair pulling “habit” and you: how to solve the trichotillomania puzzle (rev ed). Silver Spring, MD: Writer’s Cooperative of Greater Washington; 2000. Book for children and teenagers.

Drug brand names

• Fluoxetine • Prozac
• Naltrexone • Depade, ReVia

Disclosure

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

Acknowledgment

Preparation of this article was supported in part by a grant from the National Institute of Mental Health (MH61457).

Primary care doctors refer patients with dementia to psychiatrists when the diagnosis or disease course is unclear. Psychiatrists thus must often discern non-Alzheimer’s dementias— particularly the vascular and Lewy body types— from Alzheimer’s dementia. This article describes:

• features that distinguish vascular, Lewy body, and Alzheimer’s dementias
• cognitive and medical tests to help determine dementia type and facilitate treatment
• risk factors that promote cognitive and functional decline
• strategies for using medication while minimizing side-effect risks.

CASE REPORT: DISRUPTIVE IN DAY CARE

Ms. Z, age 82, is referred to a psychiatrist after numerous failed attempts by her primary care physician to stop her medical and psychiatric deterioration.

Table 1

Estimated dementia type prevalence among patients with dementia

The patient was functioning well at home until 6 months ago, when her husband’s death triggered a dramatic functional decline. She has Parkinson’s disease and has had dementia symptoms for 3 years, but family members do not recall a dementia diagnosis.

Ms. Z has become increasingly disruptive in day care; she yelled at and slapped a staff member during one episode. Her son is concerned that additional outbursts will prompt her dismissal. Her Mini-Mental State Examination (MMSE) score is 19, indicating moderate dementia.

Donepezil, 10 mg/d across 2 years, has not slowed Ms. Z’s memory decline. Carbidopa/levadopa, 25/250 mg tid over 1 year, has not improved her Parkinson’s symptoms. Risperidone, 0.5 mg bid, caused marked sedation and unsteady gait and was stopped after 4 weeks. She also is taking hydrocodone/acetaminophen, 5/500 mg/d for osteoarthritis, and lisinopril/hydrochlorothiazide, 10/12.5 mg/d for hypertension.

Discussion. As with Ms. Z, a significant other can mask a dementia patient’s cognitive deficits, but these deficits become apparent after the partner dies. Family members then discover that a parent or sibling cannot function independently.

Treatment should target Ms. Z’s aggression to allow her to stay in day care and her son to care for her at home. Determining the dementia type is crucial to planning treatment and preserving function.

WHICH DEMENTIA IS WHICH?

Non-Alzheimer’s dementias account for up to 35% of dementia cases (Table 1).¹ The pathologic correlations separating Alzheimer’s, vascular, and Lewy body dementias are often confusing:

• Beta-amyloid plaques are common in Alzheimer’s and Lewy body dementias, although neurofibrillary tangles are much less common in the Lewy body type.
• Synaptic cholinergic deficiencies are seen in Alzheimer’s and vascular dementias.
• Hypertension and hyperlipidemia—both traditional vascular risk factors—also appear to contribute to Alzheimer’s dementia.

Vascular dementia. Large, single-vessel hemispheric infarcts cause substantial damage, whereas multiple small vascular lesions (such as lacunae or mini-infarcts) can have more-subtle effects when strategically located, such as in the basal ganglia, hippocampus, or thalamus. These smaller lesions can disrupt frontal cortical-subcortical neural pathways and contribute to difficulties with executive functions (judgment, insight), emotional control, and behavior.

Lesions from a cerebrovascular accident, however, do not necessarily cause dementia, and the mechanism by which lesions cause dementia is not fully understood. Post-stroke dementia sometimes is progressive, suggesting a degenerative rather than vascular cause.

Lewy body dementia is associated with Parkinson’s disease, as Lewy body inclusion deposits are common to both disorders. The deposits typically appear in the cerebral cortex in Lewy body dementia but not in Parkinson’s.

Amyloid protein deposits alter the clinical presentation. Patients with these lesions have fewer visual hallucinations and motor problems, making diagnosis more difficult.

Lewy body dementia, like all major dementias, usually surfaces after age 75. Its clinical course generally is considered worse than that of Alzheimer’s dementia, but these two dementia types do not differ substantially in age of onset, age of death, or survival rates.

Table 2

Clinical features that characterize Lewy body dementia

FEATURES OF VASCULAR DEMENTIA

Onset can be gradual but is more often sudden— usually occurring shortly after an ischemic stroke. Disease progression can be gradual or dramatic, depending on the vascular event type. Cognitive and physical decline in vascular dementia usually is stepwise over time, whereas decline in Alzheimer’s dementia is more gradual with progressive severity.

Patients with vascular dementia classically present with memory loss temporally associated with other typical stroke stigmata. Brain imaging often uncovers evidence of stroke that is otherwise not clinically evident.

CNS manifestations of vascular dementia often include memory loss, emotional lability (including depression), and executive-task dysfunction. Patients usually have atrial fibrillation or vascular risk factors, including diabetes mellitus, hypertension, hyperlipidemia, obesity, or tobacco use. Patients with previous stroke, coronary artery disease, or peripheral vascular disease are at increased risk.

Vascular dementia is categorized by stroke type:

Embolic infarct. Emboli, typically cardiac in origin, can occlude small or large cerebral arteries, resulting in correspondingly sized infarcts. Atrial fibrillation can promote areas in the atria with relatively low flow turbulence. Blood clots can form that eventually embolize via the carotid arteries. Multiple emboli can occur, causing progressive dementia.

Cerebral hemorrhage —small or large—can be devastating. Hypertension is the major risk factor for this form of stroke.

Multi-infarct dementia. Multiple cerebral blood vessel infarcts classically lead to stepwise functional decline after each event. Multiple small infarcts can occur in various brain regions, including the cortex and basal ganglia. Binswanger’s disease, a variant of vascular dementia in which incomplete ischemia is limited to the hemispheric white matter, tends to be fairly progressive.²

Small-vessel disease. Reduced blood flow and tissue perfusion can cause small-vessel disease. Often the ischemia is “silent,” detectable only on MRI or CT. The infarcts typically cause lacunar lesions, nerve demyelination, and gliosis.³ These can occur to some extent in nondemented patients but become significant with more-extensive disease.

FEATURES OF LEWY BODY DEMENTIA

As with all dementias, permanent memory loss must be present to diagnose this dementia sub-type. Overall cognitive deficits may be more prominent than memory loss, however. The patient may have trouble performing cognitive tasks that employ visuospatial abilities, executive functions, and attention. Neuropsychiatric symptoms that overlap with Alzheimer’s dementia include apathy, anxiety, agitation, depression, anhedonia, and paranoia.

The presence of visual hallucinations, fluctuating cognition, or extrapyramidal symptoms (EPS) distinguish Lewy body from Alzheimer’s dementia.

Visual hallucinations are prominent in Lewy body dementia and often prompt psychiatric referral (Table 2). They usually surface early in the disease course and tend to persist. Other sensory hallucinations also can occur.

The hallucinations often are detailed and vivid and the patient may be aware they are occurring, especially if the dementia is not advanced. Treatment might not be necessary for mild hallucinations, which can concern the caregiver more than the patient.

Antipsychotics paradoxically worsen hallucinations in Lewy body dementia, and many patients present to psychiatrists after failing an empiric trial. A failed antipsychotic course in a patient diagnosed with Alzheimer’s dementia could indicate that the diagnosis is incorrect.

Fluctuating cognition occurs in 50% to 75% of Lewy body cases. Alertness, attention, and concentration are variable and can cycle within hours to weeks. The patient often is fairly interactive and social for a time, then has periods of diminished function and being “out of it.” Some patients have recurrent delirium and undergo multiple workups in search of a cause.

EPS. As many as 75% of Lewy body patients have parkinsonian motor features.⁴ Because these features are not essential to the diagnosis, their absence is the most common reason Lewy body dementia goes unrecognized.¹

Motor involvement varies and can be worsened by antipsychotics. Overuse of antipsychotics in Alzheimer’s or vascular dementia also can cause motor symptoms that mimic Lewy body features.

EPS orientation tends to be axial, showing less facial expressivity and more postural imbalance. Peripheral signs such as tremor and extremity rigidity tend to be less dominant.

MAKING THE DIAGNOSIS

Vascular and Lewy body dementia diagnoses are primarily based on clinical features and findings. Memory loss is necessary for either diagnosis.

Vascular dementia. Most consensus criteria require presence of dementia, physical or radiologic signs of a stroke, and a temporal relationship between the stroke and the dementia for a vascular dementia diagnosis.

Hachinski’s “ischemia scale” can help differentiate multi-infarct from Alzheimer’s dementia.⁵ Cases are scored on a 0-to-9 scale, with point values for abrupt onset; stepwise course; history of stroke; and presence of somatic complaints, emotional lability, hypertension, and focal neurologic signs. A score ≥4 suggests vascular dementia.

The scale, however, does not account for imaging studies, vascular risk factors other than hypertension, or repeated silent strokes that can cause symptoms. Also, some patients who score below the cutoff have strategic infarct dementias.

Lewy body dementia. Clinical consensus guidelines developed by McKeith et al⁶ can help clinicians recognize and categorize this dementia type (Table 2). Several studies of diagnostic criteria have shown very good specificity but variable sensitivity.⁷ Because no standard imaging modalities or serum markers exist, presence of progressive memory loss, fluctuating cognition, visual hallucinations, and EPS should drive the diagnosis.

Lewy body dementia is commonly misdiagnosed as Parkinson’s dementia. The two types are readily differentiated by onset of memory loss, which emerges late in Parkinson’s dementia but is early and prominent in Lewy body dementia.

CASE CONTINUED: HISTORY LEADS TO DIAGNOSIS

Ms. Z was diagnosed as having Lewy body dementia, as her cognitive decline clearly preceded her motor deficits. Further questioning revealed fluctuating attention levels and a history of visual hallucinations.

TESTING PATIENT FUNCTION

Neuropsychiatric tests. DSM-IV recommends testing memory, orientation, language, praxis, constructional ability, and executive control function in patients with dementia. Numerous tests can aid in diagnosis, but they generally are too lengthy to be practical. The MMSE takes 5 to 10 minutes, but it might miss mild memory loss or executive dysfunction.

Giving a quick clock-drawing test in tandem with the MMSE can help measure basic executive control and constructional ability. Also, patients with Lewy body or vascular dementia often are more proficient than patients with Alzheimer’s dementia on verbal memory tests but less proficient on visuospatial performance. Consider referring clinically challenging patients for more-extensive neuropsychiatric testing.

Lab tests. Blood tests including TSH and B¹²/folate screens are usually performed but rarely positive. Rapid plasma reagin testing for syphilis is no longer recommended unless syphilis is suspected.

Table 3

Potential cognitive side effects associated with psychotropic classes*

Radiologic imaging. Radiologic imaging (MRI or CT) can show infarcts in vascular dementia and can rule out:

• a brain tumor
• a subdural hemorrhage after recent head trauma
• or normal-pressure hydrocephalus in patients with dementia, gait instability, and/or urinary incontinence.

Brain imaging in Lewy body dementia can show hippocampal preservation⁸ but is not specific and does not significantly support the diagnosis. Specialized tests such as single-photon emission computed tomography or positron-emission tomography show occipital hypoperfusion⁹ but are expensive, not sufficiently specific, and do not add substantial value over clinical criteria.

MANAGING SYMPTOMS

Medication may be necessary if the patient is frequently and significantly agitated. Consider prescribing a selective serotonin reuptake inhibitor, an anticonvulsant such as divalproex or carbamazepine as a mood stabilizer, or a short-acting benzodiazepine. Start low and titrate slowly if needed.

Find out if the patient is taking medications that may be causing bothersome side effects. Avoid agents with potential cognitive or anticholinergic effects (Table 3); the latter can cause confusion, sedation, and falls in the elderly.

Cholinesterase inhibitors, FDA-approved for use in Alzheimer’s dementia, have been shown to reduce cognitive and global functioning decline in vascular dementia.¹⁰ A cholinergic deficit present in vascular dementia may explain the drugs’ effectiveness. Donepezil, galantamine, and rivastigmine have all shown positive effects on cognition.

Because patients with Lewy body hallucinations have greater synaptic acetylcholine deficits, cholinesterase inhibitors tend to be more effective in Lewy body dementia than in other dementia subtypes. In small open-label studies, patients taking cholinesterase inhibitors for Lewy body dementia have shown sustained improvements (up to 96 months) in cognition and behavior. Wild et al,¹¹ however, concluded that the evidence supporting use of these agents—specifically rivastigmine—is weak.

Also, cholinesterase inhibitors offer fairly modest effectiveness, do not work for all patients, and do not prevent cognitive decline even when taken regularly. Because cholinesterase inhibitors are costly and most Medicare patients lack prescription medication coverage, an initial short (6-month) trial is recommended. Re-evaluate the patient periodically by using caregiver reports, caregiver assessment scales, and basic cognitive testing.

Cholinesterase inhibitor dosing is the same for vascular and Lewy body dementia as it is for Alzheimer’s disease. Tell patients to take the agents with food to minimize potential intestinal side effects.

Memantine. In European studies, memantine has shown positive effects on cognition and function in vascular dementia. Memantine, a N-methyl-D-aspartate receptor antagonist, is FDA-approved for moderate to severe Alzheimer’s dementia.¹²

DELAYING DECLINE

Controlling risk factors. Controlling vascular risk factors—especially high blood pressure—is the most effective way to prevent or treat vascular dementia. In primary prevention studies, patients with good hypertension and hyperlipidemia control developed dementia more slowly than did nontreated cohorts.

In patients with coronary artery disease, statins have been shown to lower cholesterol and stabilize pre-existing plaques in the arterial wall, reducing the risk of plaque rupture. Low-density lipoproteincholesterol goals vary according to vascular risk factors but should be <100 mg/dL for patients with vascular dementia, who are at highest risk. Blood pressure goals are ≤140 mm Hg (systolic) and ≤90 mm Hg (diastolic).

Glycemic control (fasting blood glucose <110 mg/dL) and smoking cessation can also reduce the risk of further vascular events. Most patients should be taking an antiplatelet medication, preferably aspirin, to reduce clotting risk.

Although Lewy body dementia has no known risk factors other than age, research will determine whether vascular or other factors contribute to its development.

CASE CONTINUED: TARGETING AGGRESSION

Ms. Z was given divalproex, 250 mg bid, to reduce her frequent aggression. Her visual hallucinations were considered mild and not problematic and therefore were not treated. She responded well to the medication, allowing her to remain in day care and avoid nursing home placement.

Related resources

• Alzheimer’s Association. http://www.alz.org
• American Geriatrics Society. http://www.americangeriatrics.org

Drug brand names

• Carbamazepine • Tegretol, others
• Carbidopa/Levodopa • Various
• Divalproex • Depakote
• Donepezil • Aricept
• Galantamine • Reminyl
• Hydrocodone/acetaminophen • Vicodin, others
• Lisinopril/hydrochlorothiazide • Prinzide, Zestoretic
• Memantine • Namenda
• Risperdone • Risperdal
• Rivastigmine • Exelon

Disclosure

Dr. Bartz is a speaker for Forest Pharmaceuticals and Novartis Pharmaceuticals Corp.

Primary care doctors refer patients with dementia to psychiatrists when the diagnosis or disease course is unclear. Psychiatrists thus must often discern non-Alzheimer’s dementias— particularly the vascular and Lewy body types— from Alzheimer’s dementia. This article describes:

• features that distinguish vascular, Lewy body, and Alzheimer’s dementias
• cognitive and medical tests to help determine dementia type and facilitate treatment
• risk factors that promote cognitive and functional decline
• strategies for using medication while minimizing side-effect risks.

CASE REPORT: DISRUPTIVE IN DAY CARE

Ms. Z, age 82, is referred to a psychiatrist after numerous failed attempts by her primary care physician to stop her medical and psychiatric deterioration.

Table 1

Estimated dementia type prevalence among patients with dementia

The patient was functioning well at home until 6 months ago, when her husband’s death triggered a dramatic functional decline. She has Parkinson’s disease and has had dementia symptoms for 3 years, but family members do not recall a dementia diagnosis.

Ms. Z has become increasingly disruptive in day care; she yelled at and slapped a staff member during one episode. Her son is concerned that additional outbursts will prompt her dismissal. Her Mini-Mental State Examination (MMSE) score is 19, indicating moderate dementia.

Donepezil, 10 mg/d across 2 years, has not slowed Ms. Z’s memory decline. Carbidopa/levadopa, 25/250 mg tid over 1 year, has not improved her Parkinson’s symptoms. Risperidone, 0.5 mg bid, caused marked sedation and unsteady gait and was stopped after 4 weeks. She also is taking hydrocodone/acetaminophen, 5/500 mg/d for osteoarthritis, and lisinopril/hydrochlorothiazide, 10/12.5 mg/d for hypertension.

Discussion. As with Ms. Z, a significant other can mask a dementia patient’s cognitive deficits, but these deficits become apparent after the partner dies. Family members then discover that a parent or sibling cannot function independently.

Treatment should target Ms. Z’s aggression to allow her to stay in day care and her son to care for her at home. Determining the dementia type is crucial to planning treatment and preserving function.

WHICH DEMENTIA IS WHICH?

Non-Alzheimer’s dementias account for up to 35% of dementia cases (Table 1).¹ The pathologic correlations separating Alzheimer’s, vascular, and Lewy body dementias are often confusing:

• Beta-amyloid plaques are common in Alzheimer’s and Lewy body dementias, although neurofibrillary tangles are much less common in the Lewy body type.
• Synaptic cholinergic deficiencies are seen in Alzheimer’s and vascular dementias.
• Hypertension and hyperlipidemia—both traditional vascular risk factors—also appear to contribute to Alzheimer’s dementia.

Vascular dementia. Large, single-vessel hemispheric infarcts cause substantial damage, whereas multiple small vascular lesions (such as lacunae or mini-infarcts) can have more-subtle effects when strategically located, such as in the basal ganglia, hippocampus, or thalamus. These smaller lesions can disrupt frontal cortical-subcortical neural pathways and contribute to difficulties with executive functions (judgment, insight), emotional control, and behavior.

Lesions from a cerebrovascular accident, however, do not necessarily cause dementia, and the mechanism by which lesions cause dementia is not fully understood. Post-stroke dementia sometimes is progressive, suggesting a degenerative rather than vascular cause.

Lewy body dementia is associated with Parkinson’s disease, as Lewy body inclusion deposits are common to both disorders. The deposits typically appear in the cerebral cortex in Lewy body dementia but not in Parkinson’s.

Amyloid protein deposits alter the clinical presentation. Patients with these lesions have fewer visual hallucinations and motor problems, making diagnosis more difficult.

Lewy body dementia, like all major dementias, usually surfaces after age 75. Its clinical course generally is considered worse than that of Alzheimer’s dementia, but these two dementia types do not differ substantially in age of onset, age of death, or survival rates.

Table 2

Clinical features that characterize Lewy body dementia

FEATURES OF VASCULAR DEMENTIA

Onset can be gradual but is more often sudden— usually occurring shortly after an ischemic stroke. Disease progression can be gradual or dramatic, depending on the vascular event type. Cognitive and physical decline in vascular dementia usually is stepwise over time, whereas decline in Alzheimer’s dementia is more gradual with progressive severity.

Patients with vascular dementia classically present with memory loss temporally associated with other typical stroke stigmata. Brain imaging often uncovers evidence of stroke that is otherwise not clinically evident.

CNS manifestations of vascular dementia often include memory loss, emotional lability (including depression), and executive-task dysfunction. Patients usually have atrial fibrillation or vascular risk factors, including diabetes mellitus, hypertension, hyperlipidemia, obesity, or tobacco use. Patients with previous stroke, coronary artery disease, or peripheral vascular disease are at increased risk.

Vascular dementia is categorized by stroke type:

Embolic infarct. Emboli, typically cardiac in origin, can occlude small or large cerebral arteries, resulting in correspondingly sized infarcts. Atrial fibrillation can promote areas in the atria with relatively low flow turbulence. Blood clots can form that eventually embolize via the carotid arteries. Multiple emboli can occur, causing progressive dementia.

Cerebral hemorrhage —small or large—can be devastating. Hypertension is the major risk factor for this form of stroke.

Multi-infarct dementia. Multiple cerebral blood vessel infarcts classically lead to stepwise functional decline after each event. Multiple small infarcts can occur in various brain regions, including the cortex and basal ganglia. Binswanger’s disease, a variant of vascular dementia in which incomplete ischemia is limited to the hemispheric white matter, tends to be fairly progressive.²

Small-vessel disease. Reduced blood flow and tissue perfusion can cause small-vessel disease. Often the ischemia is “silent,” detectable only on MRI or CT. The infarcts typically cause lacunar lesions, nerve demyelination, and gliosis.³ These can occur to some extent in nondemented patients but become significant with more-extensive disease.

FEATURES OF LEWY BODY DEMENTIA

As with all dementias, permanent memory loss must be present to diagnose this dementia sub-type. Overall cognitive deficits may be more prominent than memory loss, however. The patient may have trouble performing cognitive tasks that employ visuospatial abilities, executive functions, and attention. Neuropsychiatric symptoms that overlap with Alzheimer’s dementia include apathy, anxiety, agitation, depression, anhedonia, and paranoia.

The presence of visual hallucinations, fluctuating cognition, or extrapyramidal symptoms (EPS) distinguish Lewy body from Alzheimer’s dementia.

Visual hallucinations are prominent in Lewy body dementia and often prompt psychiatric referral (Table 2). They usually surface early in the disease course and tend to persist. Other sensory hallucinations also can occur.

The hallucinations often are detailed and vivid and the patient may be aware they are occurring, especially if the dementia is not advanced. Treatment might not be necessary for mild hallucinations, which can concern the caregiver more than the patient.

Antipsychotics paradoxically worsen hallucinations in Lewy body dementia, and many patients present to psychiatrists after failing an empiric trial. A failed antipsychotic course in a patient diagnosed with Alzheimer’s dementia could indicate that the diagnosis is incorrect.

Fluctuating cognition occurs in 50% to 75% of Lewy body cases. Alertness, attention, and concentration are variable and can cycle within hours to weeks. The patient often is fairly interactive and social for a time, then has periods of diminished function and being “out of it.” Some patients have recurrent delirium and undergo multiple workups in search of a cause.

EPS. As many as 75% of Lewy body patients have parkinsonian motor features.⁴ Because these features are not essential to the diagnosis, their absence is the most common reason Lewy body dementia goes unrecognized.¹

Motor involvement varies and can be worsened by antipsychotics. Overuse of antipsychotics in Alzheimer’s or vascular dementia also can cause motor symptoms that mimic Lewy body features.

EPS orientation tends to be axial, showing less facial expressivity and more postural imbalance. Peripheral signs such as tremor and extremity rigidity tend to be less dominant.

MAKING THE DIAGNOSIS

Vascular and Lewy body dementia diagnoses are primarily based on clinical features and findings. Memory loss is necessary for either diagnosis.

Vascular dementia. Most consensus criteria require presence of dementia, physical or radiologic signs of a stroke, and a temporal relationship between the stroke and the dementia for a vascular dementia diagnosis.

Hachinski’s “ischemia scale” can help differentiate multi-infarct from Alzheimer’s dementia.⁵ Cases are scored on a 0-to-9 scale, with point values for abrupt onset; stepwise course; history of stroke; and presence of somatic complaints, emotional lability, hypertension, and focal neurologic signs. A score ≥4 suggests vascular dementia.

The scale, however, does not account for imaging studies, vascular risk factors other than hypertension, or repeated silent strokes that can cause symptoms. Also, some patients who score below the cutoff have strategic infarct dementias.

Lewy body dementia. Clinical consensus guidelines developed by McKeith et al⁶ can help clinicians recognize and categorize this dementia type (Table 2). Several studies of diagnostic criteria have shown very good specificity but variable sensitivity.⁷ Because no standard imaging modalities or serum markers exist, presence of progressive memory loss, fluctuating cognition, visual hallucinations, and EPS should drive the diagnosis.

Lewy body dementia is commonly misdiagnosed as Parkinson’s dementia. The two types are readily differentiated by onset of memory loss, which emerges late in Parkinson’s dementia but is early and prominent in Lewy body dementia.

CASE CONTINUED: HISTORY LEADS TO DIAGNOSIS

Ms. Z was diagnosed as having Lewy body dementia, as her cognitive decline clearly preceded her motor deficits. Further questioning revealed fluctuating attention levels and a history of visual hallucinations.

TESTING PATIENT FUNCTION

Neuropsychiatric tests. DSM-IV recommends testing memory, orientation, language, praxis, constructional ability, and executive control function in patients with dementia. Numerous tests can aid in diagnosis, but they generally are too lengthy to be practical. The MMSE takes 5 to 10 minutes, but it might miss mild memory loss or executive dysfunction.

Giving a quick clock-drawing test in tandem with the MMSE can help measure basic executive control and constructional ability. Also, patients with Lewy body or vascular dementia often are more proficient than patients with Alzheimer’s dementia on verbal memory tests but less proficient on visuospatial performance. Consider referring clinically challenging patients for more-extensive neuropsychiatric testing.

Lab tests. Blood tests including TSH and B¹²/folate screens are usually performed but rarely positive. Rapid plasma reagin testing for syphilis is no longer recommended unless syphilis is suspected.

Table 3

Potential cognitive side effects associated with psychotropic classes*

Radiologic imaging. Radiologic imaging (MRI or CT) can show infarcts in vascular dementia and can rule out:

• a brain tumor
• a subdural hemorrhage after recent head trauma
• or normal-pressure hydrocephalus in patients with dementia, gait instability, and/or urinary incontinence.

Brain imaging in Lewy body dementia can show hippocampal preservation⁸ but is not specific and does not significantly support the diagnosis. Specialized tests such as single-photon emission computed tomography or positron-emission tomography show occipital hypoperfusion⁹ but are expensive, not sufficiently specific, and do not add substantial value over clinical criteria.

MANAGING SYMPTOMS

Medication may be necessary if the patient is frequently and significantly agitated. Consider prescribing a selective serotonin reuptake inhibitor, an anticonvulsant such as divalproex or carbamazepine as a mood stabilizer, or a short-acting benzodiazepine. Start low and titrate slowly if needed.

Find out if the patient is taking medications that may be causing bothersome side effects. Avoid agents with potential cognitive or anticholinergic effects (Table 3); the latter can cause confusion, sedation, and falls in the elderly.

Cholinesterase inhibitors, FDA-approved for use in Alzheimer’s dementia, have been shown to reduce cognitive and global functioning decline in vascular dementia.¹⁰ A cholinergic deficit present in vascular dementia may explain the drugs’ effectiveness. Donepezil, galantamine, and rivastigmine have all shown positive effects on cognition.

Because patients with Lewy body hallucinations have greater synaptic acetylcholine deficits, cholinesterase inhibitors tend to be more effective in Lewy body dementia than in other dementia subtypes. In small open-label studies, patients taking cholinesterase inhibitors for Lewy body dementia have shown sustained improvements (up to 96 months) in cognition and behavior. Wild et al,¹¹ however, concluded that the evidence supporting use of these agents—specifically rivastigmine—is weak.

Also, cholinesterase inhibitors offer fairly modest effectiveness, do not work for all patients, and do not prevent cognitive decline even when taken regularly. Because cholinesterase inhibitors are costly and most Medicare patients lack prescription medication coverage, an initial short (6-month) trial is recommended. Re-evaluate the patient periodically by using caregiver reports, caregiver assessment scales, and basic cognitive testing.

Cholinesterase inhibitor dosing is the same for vascular and Lewy body dementia as it is for Alzheimer’s disease. Tell patients to take the agents with food to minimize potential intestinal side effects.

Memantine. In European studies, memantine has shown positive effects on cognition and function in vascular dementia. Memantine, a N-methyl-D-aspartate receptor antagonist, is FDA-approved for moderate to severe Alzheimer’s dementia.¹²

DELAYING DECLINE

Controlling risk factors. Controlling vascular risk factors—especially high blood pressure—is the most effective way to prevent or treat vascular dementia. In primary prevention studies, patients with good hypertension and hyperlipidemia control developed dementia more slowly than did nontreated cohorts.

In patients with coronary artery disease, statins have been shown to lower cholesterol and stabilize pre-existing plaques in the arterial wall, reducing the risk of plaque rupture. Low-density lipoproteincholesterol goals vary according to vascular risk factors but should be <100 mg/dL for patients with vascular dementia, who are at highest risk. Blood pressure goals are ≤140 mm Hg (systolic) and ≤90 mm Hg (diastolic).

Glycemic control (fasting blood glucose <110 mg/dL) and smoking cessation can also reduce the risk of further vascular events. Most patients should be taking an antiplatelet medication, preferably aspirin, to reduce clotting risk.

Although Lewy body dementia has no known risk factors other than age, research will determine whether vascular or other factors contribute to its development.

CASE CONTINUED: TARGETING AGGRESSION

Ms. Z was given divalproex, 250 mg bid, to reduce her frequent aggression. Her visual hallucinations were considered mild and not problematic and therefore were not treated. She responded well to the medication, allowing her to remain in day care and avoid nursing home placement.

Related resources

• Alzheimer’s Association. http://www.alz.org
• American Geriatrics Society. http://www.americangeriatrics.org

Drug brand names

• Carbamazepine • Tegretol, others
• Carbidopa/Levodopa • Various
• Divalproex • Depakote
• Donepezil • Aricept
• Galantamine • Reminyl
• Hydrocodone/acetaminophen • Vicodin, others
• Lisinopril/hydrochlorothiazide • Prinzide, Zestoretic
• Memantine • Namenda
• Risperdone • Risperdal
• Rivastigmine • Exelon

Disclosure

Dr. Bartz is a speaker for Forest Pharmaceuticals and Novartis Pharmaceuticals Corp.

Primary care doctors refer patients with dementia to psychiatrists when the diagnosis or disease course is unclear. Psychiatrists thus must often discern non-Alzheimer’s dementias— particularly the vascular and Lewy body types— from Alzheimer’s dementia. This article describes:

• features that distinguish vascular, Lewy body, and Alzheimer’s dementias
• cognitive and medical tests to help determine dementia type and facilitate treatment
• risk factors that promote cognitive and functional decline
• strategies for using medication while minimizing side-effect risks.

CASE REPORT: DISRUPTIVE IN DAY CARE

Ms. Z, age 82, is referred to a psychiatrist after numerous failed attempts by her primary care physician to stop her medical and psychiatric deterioration.

Table 1

Estimated dementia type prevalence among patients with dementia

The patient was functioning well at home until 6 months ago, when her husband’s death triggered a dramatic functional decline. She has Parkinson’s disease and has had dementia symptoms for 3 years, but family members do not recall a dementia diagnosis.

Ms. Z has become increasingly disruptive in day care; she yelled at and slapped a staff member during one episode. Her son is concerned that additional outbursts will prompt her dismissal. Her Mini-Mental State Examination (MMSE) score is 19, indicating moderate dementia.

Donepezil, 10 mg/d across 2 years, has not slowed Ms. Z’s memory decline. Carbidopa/levadopa, 25/250 mg tid over 1 year, has not improved her Parkinson’s symptoms. Risperidone, 0.5 mg bid, caused marked sedation and unsteady gait and was stopped after 4 weeks. She also is taking hydrocodone/acetaminophen, 5/500 mg/d for osteoarthritis, and lisinopril/hydrochlorothiazide, 10/12.5 mg/d for hypertension.

Discussion. As with Ms. Z, a significant other can mask a dementia patient’s cognitive deficits, but these deficits become apparent after the partner dies. Family members then discover that a parent or sibling cannot function independently.

Treatment should target Ms. Z’s aggression to allow her to stay in day care and her son to care for her at home. Determining the dementia type is crucial to planning treatment and preserving function.

WHICH DEMENTIA IS WHICH?

Non-Alzheimer’s dementias account for up to 35% of dementia cases (Table 1).¹ The pathologic correlations separating Alzheimer’s, vascular, and Lewy body dementias are often confusing:

• Beta-amyloid plaques are common in Alzheimer’s and Lewy body dementias, although neurofibrillary tangles are much less common in the Lewy body type.
• Synaptic cholinergic deficiencies are seen in Alzheimer’s and vascular dementias.
• Hypertension and hyperlipidemia—both traditional vascular risk factors—also appear to contribute to Alzheimer’s dementia.

Vascular dementia. Large, single-vessel hemispheric infarcts cause substantial damage, whereas multiple small vascular lesions (such as lacunae or mini-infarcts) can have more-subtle effects when strategically located, such as in the basal ganglia, hippocampus, or thalamus. These smaller lesions can disrupt frontal cortical-subcortical neural pathways and contribute to difficulties with executive functions (judgment, insight), emotional control, and behavior.

Lesions from a cerebrovascular accident, however, do not necessarily cause dementia, and the mechanism by which lesions cause dementia is not fully understood. Post-stroke dementia sometimes is progressive, suggesting a degenerative rather than vascular cause.

Lewy body dementia is associated with Parkinson’s disease, as Lewy body inclusion deposits are common to both disorders. The deposits typically appear in the cerebral cortex in Lewy body dementia but not in Parkinson’s.

Amyloid protein deposits alter the clinical presentation. Patients with these lesions have fewer visual hallucinations and motor problems, making diagnosis more difficult.

Lewy body dementia, like all major dementias, usually surfaces after age 75. Its clinical course generally is considered worse than that of Alzheimer’s dementia, but these two dementia types do not differ substantially in age of onset, age of death, or survival rates.

Table 2

Clinical features that characterize Lewy body dementia

FEATURES OF VASCULAR DEMENTIA

Onset can be gradual but is more often sudden— usually occurring shortly after an ischemic stroke. Disease progression can be gradual or dramatic, depending on the vascular event type. Cognitive and physical decline in vascular dementia usually is stepwise over time, whereas decline in Alzheimer’s dementia is more gradual with progressive severity.

Patients with vascular dementia classically present with memory loss temporally associated with other typical stroke stigmata. Brain imaging often uncovers evidence of stroke that is otherwise not clinically evident.

CNS manifestations of vascular dementia often include memory loss, emotional lability (including depression), and executive-task dysfunction. Patients usually have atrial fibrillation or vascular risk factors, including diabetes mellitus, hypertension, hyperlipidemia, obesity, or tobacco use. Patients with previous stroke, coronary artery disease, or peripheral vascular disease are at increased risk.

Vascular dementia is categorized by stroke type:

Embolic infarct. Emboli, typically cardiac in origin, can occlude small or large cerebral arteries, resulting in correspondingly sized infarcts. Atrial fibrillation can promote areas in the atria with relatively low flow turbulence. Blood clots can form that eventually embolize via the carotid arteries. Multiple emboli can occur, causing progressive dementia.

Cerebral hemorrhage —small or large—can be devastating. Hypertension is the major risk factor for this form of stroke.

Multi-infarct dementia. Multiple cerebral blood vessel infarcts classically lead to stepwise functional decline after each event. Multiple small infarcts can occur in various brain regions, including the cortex and basal ganglia. Binswanger’s disease, a variant of vascular dementia in which incomplete ischemia is limited to the hemispheric white matter, tends to be fairly progressive.²

Small-vessel disease. Reduced blood flow and tissue perfusion can cause small-vessel disease. Often the ischemia is “silent,” detectable only on MRI or CT. The infarcts typically cause lacunar lesions, nerve demyelination, and gliosis.³ These can occur to some extent in nondemented patients but become significant with more-extensive disease.

FEATURES OF LEWY BODY DEMENTIA

As with all dementias, permanent memory loss must be present to diagnose this dementia sub-type. Overall cognitive deficits may be more prominent than memory loss, however. The patient may have trouble performing cognitive tasks that employ visuospatial abilities, executive functions, and attention. Neuropsychiatric symptoms that overlap with Alzheimer’s dementia include apathy, anxiety, agitation, depression, anhedonia, and paranoia.

The presence of visual hallucinations, fluctuating cognition, or extrapyramidal symptoms (EPS) distinguish Lewy body from Alzheimer’s dementia.

Visual hallucinations are prominent in Lewy body dementia and often prompt psychiatric referral (Table 2). They usually surface early in the disease course and tend to persist. Other sensory hallucinations also can occur.

The hallucinations often are detailed and vivid and the patient may be aware they are occurring, especially if the dementia is not advanced. Treatment might not be necessary for mild hallucinations, which can concern the caregiver more than the patient.

Antipsychotics paradoxically worsen hallucinations in Lewy body dementia, and many patients present to psychiatrists after failing an empiric trial. A failed antipsychotic course in a patient diagnosed with Alzheimer’s dementia could indicate that the diagnosis is incorrect.

Fluctuating cognition occurs in 50% to 75% of Lewy body cases. Alertness, attention, and concentration are variable and can cycle within hours to weeks. The patient often is fairly interactive and social for a time, then has periods of diminished function and being “out of it.” Some patients have recurrent delirium and undergo multiple workups in search of a cause.

EPS. As many as 75% of Lewy body patients have parkinsonian motor features.⁴ Because these features are not essential to the diagnosis, their absence is the most common reason Lewy body dementia goes unrecognized.¹

Motor involvement varies and can be worsened by antipsychotics. Overuse of antipsychotics in Alzheimer’s or vascular dementia also can cause motor symptoms that mimic Lewy body features.

EPS orientation tends to be axial, showing less facial expressivity and more postural imbalance. Peripheral signs such as tremor and extremity rigidity tend to be less dominant.

MAKING THE DIAGNOSIS

Vascular and Lewy body dementia diagnoses are primarily based on clinical features and findings. Memory loss is necessary for either diagnosis.

Vascular dementia. Most consensus criteria require presence of dementia, physical or radiologic signs of a stroke, and a temporal relationship between the stroke and the dementia for a vascular dementia diagnosis.

Hachinski’s “ischemia scale” can help differentiate multi-infarct from Alzheimer’s dementia.⁵ Cases are scored on a 0-to-9 scale, with point values for abrupt onset; stepwise course; history of stroke; and presence of somatic complaints, emotional lability, hypertension, and focal neurologic signs. A score ≥4 suggests vascular dementia.

The scale, however, does not account for imaging studies, vascular risk factors other than hypertension, or repeated silent strokes that can cause symptoms. Also, some patients who score below the cutoff have strategic infarct dementias.

Lewy body dementia. Clinical consensus guidelines developed by McKeith et al⁶ can help clinicians recognize and categorize this dementia type (Table 2). Several studies of diagnostic criteria have shown very good specificity but variable sensitivity.⁷ Because no standard imaging modalities or serum markers exist, presence of progressive memory loss, fluctuating cognition, visual hallucinations, and EPS should drive the diagnosis.

Lewy body dementia is commonly misdiagnosed as Parkinson’s dementia. The two types are readily differentiated by onset of memory loss, which emerges late in Parkinson’s dementia but is early and prominent in Lewy body dementia.

CASE CONTINUED: HISTORY LEADS TO DIAGNOSIS

Ms. Z was diagnosed as having Lewy body dementia, as her cognitive decline clearly preceded her motor deficits. Further questioning revealed fluctuating attention levels and a history of visual hallucinations.

TESTING PATIENT FUNCTION

Neuropsychiatric tests. DSM-IV recommends testing memory, orientation, language, praxis, constructional ability, and executive control function in patients with dementia. Numerous tests can aid in diagnosis, but they generally are too lengthy to be practical. The MMSE takes 5 to 10 minutes, but it might miss mild memory loss or executive dysfunction.

Giving a quick clock-drawing test in tandem with the MMSE can help measure basic executive control and constructional ability. Also, patients with Lewy body or vascular dementia often are more proficient than patients with Alzheimer’s dementia on verbal memory tests but less proficient on visuospatial performance. Consider referring clinically challenging patients for more-extensive neuropsychiatric testing.

Lab tests. Blood tests including TSH and B¹²/folate screens are usually performed but rarely positive. Rapid plasma reagin testing for syphilis is no longer recommended unless syphilis is suspected.

Table 3

Potential cognitive side effects associated with psychotropic classes*

Radiologic imaging. Radiologic imaging (MRI or CT) can show infarcts in vascular dementia and can rule out:

• a brain tumor
• a subdural hemorrhage after recent head trauma
• or normal-pressure hydrocephalus in patients with dementia, gait instability, and/or urinary incontinence.

Brain imaging in Lewy body dementia can show hippocampal preservation⁸ but is not specific and does not significantly support the diagnosis. Specialized tests such as single-photon emission computed tomography or positron-emission tomography show occipital hypoperfusion⁹ but are expensive, not sufficiently specific, and do not add substantial value over clinical criteria.

MANAGING SYMPTOMS

Medication may be necessary if the patient is frequently and significantly agitated. Consider prescribing a selective serotonin reuptake inhibitor, an anticonvulsant such as divalproex or carbamazepine as a mood stabilizer, or a short-acting benzodiazepine. Start low and titrate slowly if needed.

Find out if the patient is taking medications that may be causing bothersome side effects. Avoid agents with potential cognitive or anticholinergic effects (Table 3); the latter can cause confusion, sedation, and falls in the elderly.

Cholinesterase inhibitors, FDA-approved for use in Alzheimer’s dementia, have been shown to reduce cognitive and global functioning decline in vascular dementia.¹⁰ A cholinergic deficit present in vascular dementia may explain the drugs’ effectiveness. Donepezil, galantamine, and rivastigmine have all shown positive effects on cognition.

Because patients with Lewy body hallucinations have greater synaptic acetylcholine deficits, cholinesterase inhibitors tend to be more effective in Lewy body dementia than in other dementia subtypes. In small open-label studies, patients taking cholinesterase inhibitors for Lewy body dementia have shown sustained improvements (up to 96 months) in cognition and behavior. Wild et al,¹¹ however, concluded that the evidence supporting use of these agents—specifically rivastigmine—is weak.

Also, cholinesterase inhibitors offer fairly modest effectiveness, do not work for all patients, and do not prevent cognitive decline even when taken regularly. Because cholinesterase inhibitors are costly and most Medicare patients lack prescription medication coverage, an initial short (6-month) trial is recommended. Re-evaluate the patient periodically by using caregiver reports, caregiver assessment scales, and basic cognitive testing.

Cholinesterase inhibitor dosing is the same for vascular and Lewy body dementia as it is for Alzheimer’s disease. Tell patients to take the agents with food to minimize potential intestinal side effects.

Memantine. In European studies, memantine has shown positive effects on cognition and function in vascular dementia. Memantine, a N-methyl-D-aspartate receptor antagonist, is FDA-approved for moderate to severe Alzheimer’s dementia.¹²

DELAYING DECLINE

Controlling risk factors. Controlling vascular risk factors—especially high blood pressure—is the most effective way to prevent or treat vascular dementia. In primary prevention studies, patients with good hypertension and hyperlipidemia control developed dementia more slowly than did nontreated cohorts.

In patients with coronary artery disease, statins have been shown to lower cholesterol and stabilize pre-existing plaques in the arterial wall, reducing the risk of plaque rupture. Low-density lipoproteincholesterol goals vary according to vascular risk factors but should be <100 mg/dL for patients with vascular dementia, who are at highest risk. Blood pressure goals are ≤140 mm Hg (systolic) and ≤90 mm Hg (diastolic).

Glycemic control (fasting blood glucose <110 mg/dL) and smoking cessation can also reduce the risk of further vascular events. Most patients should be taking an antiplatelet medication, preferably aspirin, to reduce clotting risk.

Although Lewy body dementia has no known risk factors other than age, research will determine whether vascular or other factors contribute to its development.

CASE CONTINUED: TARGETING AGGRESSION

Ms. Z was given divalproex, 250 mg bid, to reduce her frequent aggression. Her visual hallucinations were considered mild and not problematic and therefore were not treated. She responded well to the medication, allowing her to remain in day care and avoid nursing home placement.

Related resources

• Alzheimer’s Association. http://www.alz.org
• American Geriatrics Society. http://www.americangeriatrics.org

Drug brand names

• Carbamazepine • Tegretol, others
• Carbidopa/Levodopa • Various
• Divalproex • Depakote
• Donepezil • Aricept
• Galantamine • Reminyl
• Hydrocodone/acetaminophen • Vicodin, others
• Lisinopril/hydrochlorothiazide • Prinzide, Zestoretic
• Memantine • Namenda
• Risperdone • Risperdal
• Rivastigmine • Exelon

Disclosure

Dr. Bartz is a speaker for Forest Pharmaceuticals and Novartis Pharmaceuticals Corp.