eMedicine Specialties > Psychiatry > Adult

Huntington Disease Dementia

Idan Sharon, MD, Consulting Staff, Departments of Neurology and Psychiatry, Cornell New York Methodist Hospital; Private Practice
Tulay Ersan, MD, Chief of Geriatrics, Department of Internal Medicine, Division of Geriatrics, Monmouth Medical Center; Roni Sharon, University of Michigan

Updated: Aug 20, 2007

Introduction

Background

Huntington disease (HD) is a genetic, autosomal dominant, neurodegenerative disorder characterized clinically by disorders of movement, progressive dementia, and psychiatric and/or behavioral disturbance. In 1872, George Huntington, MD, presented a disease featuring "hereditary nature, adult onset, chorea, mind impairment," and "with a tendency to insanity and suicide." Although Huntington was not the first to describe this "dancing mania," his account was so comprehensive that he received international recognition. In the following 128 years, HD has inspired thousands of research papers in which elucidation of this unrelenting neurodegenerative disorder has been attempted.

Pathophysiology

HD is associated with an excessive sequence of CAG repeats in the IT15 (interesting transcript number 15) gene located on arm 4p; researchers are looking into which chromosome contains that gene. The HD gene codes for a protein called huntingtin. This protein is found in neurons throughout the brain; its normal function is unknown. Possibly, the abnormal huntingtin protein undergoes proteolysis and is then transported to the nucleus, where it undergoes aggregation. Transport to the nucleus may involve specific protein-to-protein interactions that occur in certain cell types only, possibly explaining the selective neuronal vulnerability present in patients with HD. The genetic mutation is theorized to cause an imbalance between free radical production and removal, resulting in the subsequent neuronal degeneration and neurotransmitter decline.

Great insight has been shed on the IT15 gene on a molecular level; however, if and how this leads to the clinical symptoms of HD still are not clear. Evidence also indicates the presence of inappropriate neuronal apoptosis in persons with HD. Symptoms result from the selective loss of neurons, mostly in the caudate nucleus and putamen. Vonsattel et al devised a neural pathologic grading system that scaled the microscopic and gross striatum changes. The grades of this scale range from 0 (normal) to 4 (severe neuronal loss; astrocytosis; and atrophy of the globus, pallidus, and caudate putamen).

Neurochemically, levels of transmitter substances (eg, GABA and its synthetic enzyme glutamic acid decarboxylase) are markedly decreased throughout the basal ganglia. Levels of acetylcholine, substance P, and enkephalins are also reduced. Nuclear magnetic resonance spectroscopy in living subjects with HD has shown elevated levels of lactate in the basal ganglia.

HD supposedly can cause psychiatric disorders in 2 ways, (1) by the direct action of the gene on striatal neurons and (2) by the indirect effect of the disordered family environment on the children regardless of whether they inherited the HD gene.

Frequency

United States

Several epidemiological studies in the United States, conducted from 1945-1980, show consistent statistics stating that approximately 30,000 people have HD.

International

HD occurs in various geographic and cultural ethnicities worldwide. The worldwide prevalence of this disorder is 5-10 cases per 100,000 persons. In North America and Europe, HD has a prevalence of 0.5-9.95 cases per 100,000 individuals. In a particular study by Walker et al in South Wales, a prevalence of 7.61 cases per 100,000 persons was reported. This study was reanalyzed in 1988 and showed the prevalence to be higher (8.85 cases per 100,000 persons), indicating a slight rise over the years.

Mortality/Morbidity

HD is a progressive disorder, typically lasting approximately 15 years.

• Early onset affecting patients younger than 20 years (juvenile HD) is associated with rigidity, ataxia, cognitive decline, and more rapid progression. The typical duration is approximately 8 years. Seizures are more common with juvenile-onset disease than other forms.
• Individuals who inherit the disease from their fathers tend to become symptomatic much earlier in life than those who inherit it from their mothers.
• Death is usually secondary to pneumonia, cardiopulmonary failure, trauma, or suicide.

Race

• No significant differences exist among national and ethnic groups in the number of CAG repeats; however, the higher frequency of HD among white persons and its lower prevalence in other populations, including black persons and Japanese persons, has led to the hypothesis that the mutation responsible for the disease was carried to different parts of the world by immigrant European settlers.
• This theory is further supported by the suggestion that the mutation rate in the HD gene is exceedingly low, perhaps the lowest such rate for any human genetic disease. The fact that the mutation rate for HD is higher than previously estimated and that new mutations may account for as many as 3% of the cases is now apparent; therefore, new mutations, in addition to European migration, may account for the disease's presence in many different and sometimes isolated communities.

Sex

HD affects males and females in relatively equal numbers.

Age

• The onset of disease usually occurs in the fourth or fifth decade of life, with a wide range in age from childhood to later years in life. Juvenile onset has a large repeat expansion and occurs most often when the father is the affected parent (a form of genetic anticipation).

Clinical

History

The first symptoms typically are choreic movements or psychiatric disorders, whereas global cognitive decline generally becomes obvious later and eventually expresses itself as a triad of disordered movement, cognitive decline, and psychiatric disturbance. Clinically, the cognitive deterioration of HD is generally thought to correlate with the number of years affected rather than the age of onset. In an interesting study conducted by Jason et al in 1997, cognitive manifestations were examined in relation to age, clinical onset, progression, and genetic analysis. Evidence showed an inverse correlation between the onset of cognitive impairment and the number of trinucleotide repeats in the HD gene. Additionally, this study showed that although a statistically significant correlation exists between the number of repeats and the progressive dementia, the relationship is tenuous.

• Psychiatric symptoms are prominent in patients with HD, as follows:
  • Symptoms range from personality alterations to mood disorders, aggressiveness, hypersexuality or impotence, alcoholism, and psychosis, including schizophrenia.
  • Psychiatric disorders may occur in 35-73% of patients with HD, and behavioral changes may represent the initial manifestation of the disease in one third to one half of the cases.
  • Depression is the most common psychiatric condition.
  • Mania occurs in 2-12% of patients, whereas suicide occurs in nearly 6% of patients.
  • Eccentricity, inappropriateness, loss of social amenities, excess irritability, and sexual hyperactivity can mark the early stages.
  • Occasionally, a schizophreniform illness precedes the motor abnormality by several years.
  • Depression, apathy, social withdrawal, and intermittent disinhibition are common.
  • Suicide occurs frequently, partially because the progressing dementia often fails to blunt insight.
• When HD starts as subtle fidgeting, it may be unrecognized by the patient and family. Patients have a history of progressive generalized choreiform activity accompanied by behavioral or personality changes, especially in those with a family history. Sporadic cases are also possible.

Physical

• Early motor symptoms often include dystonic posturing and rigidity, but these changes give way to prominent choreiform activity in most affected adults.
• Frequent, irregular, and sudden jerks and movements of any of the limbs or trunk occur.
• Grimacing, grunting, and poor articulation of speech may be prominent.
• Mental status exam 
  • The patient appears older than stated age. 
  • Patient is well oriented in all spheres.
  • Patient appears alert.
  • Affect is appropriate.
  • Mood is euthymic. 
  • Presents self in a disheveled and sloppy fashion.
  • Eye contact can be described as limited.
  • Speech is illogical, incoherent, garbled, and not goal-directed. 
  • An increased risk for suicidal and homicidal thinking occurs due to the poor prognosis and erratic thinking, which can be accompanied by paranoia. 
  • Recent memory appears moderately to severely impaired. Remote memory is not impaired.
  • Psychomotor activity can be characterized by choreic movements and hyperactivity.
  • A negligible to severe degree of conceptual disorganization is evident. 
  • Thought content is characterized by delusions, hallucinations, and violent ideation at times.
  • Regarding perceptual functioning, the patient has hallucinations and none are evident.
  • Attitude can be described as cooperative but disinterested. 
  • The patient verbalizes no awareness of problems and does not see consequences. Judgment is poor.
  • Attention/concentration is characterized by an inability to attend and maintain focus.
  • The patient is not reflective and unable to resist urges.
• The gait is disjointed and poorly coordinated. Patients with HD, like healthy subjects, depend more on proprioceptive cues than on visual cues to maintain balance; however, patients with HD develop more sway compared with healthy subjects when proprioceptive cues and vision are altered.
• Given the presence of choreiform movement and subcortical neuropathology, performance on manual dexterity tasks is impaired.
• Cognitive symptoms include the following:
  • Memory frequently is not impaired until late in the disease, but attention, judgment, and executive functions may be seriously deficient at an early stage.
  • Early signs of dementia often include forgetfulness, disorganization, and affective disorders.
  • Free recall may be severely impaired.
  • Memory deficits involve both recent and remote function. Studies show that patients with HD can accurately recognize recently presented verbal material only when cues are used in memory retrieval. Other studies show that the patients sometimes recall words the next day that they had not recalled during testing sessions, further supporting a delayed-retrieval hypothesis.
  • Patients have significant problems with frontal executive functions, such as problems with maintenance, cognitive flexibility, abstraction, judgment, reasoning, sequencing, organizing, planning, and adapting.
  • Skilled motor-procedural learning deficits are reported. Working memory may be affected in patients with HD because of frontal lobe dysfunction associated with the bidirectional connections with the caudate.
  • Insight, orientation, factual information, and overall intelligence quotient scores are preserved relatively well into the disease process.
• Verbal skills are discussed as follows:
  • Verbal skills are the least impaired in patients with HD.
  • Reduced fluency in the face of preserved confrontation naming occurs.
  • Letter and category fluency are also impaired.
  • Sensory motor deficits occur, such as poor olfactory perception, slow sequential or graphomotor movements, and impaired prism adaptation.
• Spatial disorientation, specifically the inability to identify position relative to a fixed point, is another characteristic impairment in patients with HD. In a landmark study conducted by Podegil et al, patients with HD were asked to remember the position of a fixed target and then were asked to identify the point after being blindfolded. The patients were able to identify the markings in this setting; yet, when a variation of position was incorporated (ie, sidestepping after being blindfolded), patients showed significant impairment in target localization.
• Patients with HD have difficulty in sustaining their performance in a variety of everyday tasks that require both cognitive and motor function. Performance on the Stroop test and the Trail-Making Test are highly sensitive to these deficits, which encompass activities associated with mental arithmetic, digit or symbol matching, and reaction time.

Causes

HD is a genetic autosomal dominant disorder. Persons who have 38 or more CAG repeats in the HD gene have inherited the disease mutation and eventually develop symptoms if they live to an advanced age. Each of their children has a 50% risk of inheriting the abnormal gene. Also, rare sporadic cases without any family history occur.

Differential Diagnoses

Alzheimer Disease
Parkinson Disease Dementia
Tourette Syndrome
Wilson Disease

Other Problems to Be Considered

The differential diagnosis of HD depends on the presenting symptoms and family history. The dementia of patients with HD, although characteristic, is not unique. Many conditions must be considered when diagnosing Huntington dementia, as follows:

Genetic disorders

Genetic disorders to consider in the differential of an adult patient who has cognitive impairment with chorea include dentatorubropallidoluysian and neuroacanthocytosis. Dentatorubropallidoluysian is rare in the United States; however, it may be considered in patients of Japanese descent. Patients with neuroacanthocytosis also may present with dementia and chorea, yet the acanthocyte hallmark pathology helps differentiate this disease.

Other genetic conditions that may be considered include Wilson disease, hereditary ataxias, benign hereditary ataxia, and mitochondrial disorders.

Gilles de la Tourette syndrome

Gilles de la Tourette syndrome is most often transmitted in an autosomal dominant pattern, but such patients have an earlier onset, show motor ticks rather than chorea, and lack the behavioral and mental changes.

Chorea

Senile chorea is a rare disorder beginning in persons older than 60 years. The abnormal movements are usually less prominent than in patients with HD, and no comparable degree of dementia develops.

A reversible adult chorea can also develop in association with lupus erythematosus or thyrotoxicosis. Reversible adult chorea has an abrupt onset and gradually disappears within weeks or months. Also, disorders that may mimic HD (eg, schizophrenia, benign familial chorea, inherited ataxias, neural acanthocytosis, familial Alzheimer disease [AD]) do not show the CAG expansion in the HD gene.

Other conditions associated with dementia

When classifying degenerative dementias, 2 major profiles may be considered. The subcortical type primarily affects attention, judgment, and behavior. This dementia pattern resembles such pathologies as HD, Parkinson disease (PD), supranuclear palsy, and dementia of the frontal lobe. Cortical dementias (eg, AD) involve the gray matter cortex and manifest with early-onset memory losses and language disturbances. Patients with subcortical dementias (eg, HD, PD, subcortical vascular dementias) have more motor symptoms than those with temporoparietal or frontal dementias. Unfortunately, clinical characteristics of cortical and subcortical dementias show a subtle overlap, which complicates a distinct diagnosis.

Patients with AD and HD can be differentiated on the basis of specific neurocognitive deficits that are independent of severity. Using the Mattis Dementia Rating Scale, at all levels of severity, patients with HD are found to be more impaired on initiation and perseveration but less impaired on memory. At moderate and severe levels of dementia, patients with HD are more impaired in constructional praxis than patients with AD. These differences relate to the cortical involvement of AD versus the subcortical involvement of HD.

Patients with HD perform better than patients with AD on the immediate and delayed trials of logical memory and on the delayed trial of visual reproduction, but only at the mild stage. Patients with HD have better retention of a word list than patients with AD relative to age- and education-matched control groups. While patients with AD do poorly on the Mini-Mental State Examination, patients with HD may do as well as controls. In particular, patients with AD are impaired in learning or encoding and retention. Patients with HD show better retention and fewer tendencies toward cued intrusions. While patients with AD show deficient word storage, they tend to show particular difficulty with word retrieval in the face of relatively better word storage.

When patients with HD and patients with PD are compared, patients with HD are more impaired than patients with PD in immediate free recall and they do not exhibit the expected learning curve across trials. Patients with HD tend to exhibit a strong recency effect (ie, recalling more items from the end of the stimulus list than from the middle or beginning). Patients with PD make slightly fewer so-called errors of perseveration (ie, repetition), which is significantly fewer than the patients with HD. Patients with HD demonstrate significantly more improvement on recognition testing.

Pick disease

Pick disease affects the frontal and temporal lobes and also features more frontal or cortical signs. Clinically, it resembles HD; however, the age of onset is usually later in life and with a different underlying pathology. Early manifestations show personality and behavior changes with progressive involvement of memory and intellectual facets.

Workup

Laboratory Studies

• DNA repeat expansion
  • This study forms the basis of a diagnostic blood test for the HD gene. Direct gene testing via polymerase chain reaction can identify the HD gene and carrier states.
  • In addition to being a sensitive indicator of the inheritance of HD, CAG expansion is also highly specific because it is not observed in other neuropsychiatric disorders with which HD frequently is confused.
• Dopamine homovanillic acid
  • In 1986, Stahl et al measured the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid (CSF) before and after probenecid administration in healthy controls and in patients with HD. Baseline CSF-HVA concentrations correlated positively with age in healthy control subjects. Baseline CSF-HVA concentrations were reduced in patients with HD, and the degree of this reduction correlated with the severity of dementia and with the duration of the disease.
  • In 1995, a study conducted in Spain also showed that the mean levels of HVA in the CSF of patients with HD were reduced significantly compared with those from healthy controls, patients with dystonia, individuals with other neurologic diseases, and even patients with untreated PD. The clinical relevance and practicality of these findings need further research. Data suggest reduced dopamine neurotransmission in persons with HD, and this may account for the bradykinesia observed in these patients.

Imaging Studies

• Computed tomography or magnetic resonance imaging
  • In fully developed cases, these studies show cerebral atrophy, especially of the caudate and putamen, to a degree that is almost specific to the disease.
  • In patients with mild-to-moderate HD, subcortical atrophy observed on an MRI is significantly correlated with specific cognitive deficits and demonstrates that cortical atrophy has an important association with the cognitive deficits in patients with HD.
  • Radiographically, caudate atrophy leads to the typical dilation of the frontal horns of the lateral ventricles; however, the sensitivity of a CT scan is insufficient to justify its role in the investigation of patients with suspected HD, unless genetic test findings and other diagnoses need to be excluded.
• Single-photon emission computed tomography scanning
  • Studies using single-photon emission computed tomography scans show a decrease in glucose metabolism and cerebral blood flow in the caudate nucleus greater than that of the putamen.
  • Additionally, position emission tomography scanning shows decreased D1 and D2 dopamine receptor binding sites in patients with HD. This study may provide a means to track early signs of decline in individuals with the HD gene mutation prior to clinical onset.

Other Tests

• Wechsler Memory Scale-Revised
  • Verbal and visual delayed recall on the logical memory and visual reproduction subtests of the Wechsler Memory Scale-Revised test are the 2 most sensitive neuropsychological tasks for indexing cognitive dysfunction in patients with HD.
  • Contrary to the poor performance of patients with AD on both recall and recognition measures, the pattern of results suggests that patients with HD have only mild-to-moderate memory impairment that results from a retrieval deficit due to frontal-striatal dysfunction.
• Wisconsin Card Sorting Test: Performance on the Wisconsin Card Sorting Test has shown to be able to discriminate approximately 82% of patients with HD from healthy controls. In keeping with the clinical and neuropathological features of HD, this pattern is consistent with the widespread cognitive alterations expected from frontal-subcortical circuit dysfunction.
• Trail-Making Test parts A and B versus Stroop tests: Results from tests of attention (eg, Trail-Making Test parts A and B) show moderate impairment in patients with HD. Performance on the Stroop test is more sensitive than the Trail-Making Test to attention and/or concentration deficit in patients with HD.
• In summary, patients with HD are most deficient on tests of delayed recall, followed by performance on measures of memory acquisition, cognitive flexibility and abstraction, manual dexterity, attention and/or concentration, performance skills, and verbal skills.

Histologic Findings

The disease predominantly strikes the striatum. Gliosis and neuronal loss occur, especially of medium-sized spiny neurons in the caudate and putamen. Relative sparing of large, cholinergic, aspiny neurons occurs.

Treatment

Medical Care

Acetylcholinesterase inhibitors (eg, rivastigmine, memantine) may have positive effects on cognition, although no treatment halts the progression of this illness. Symptomatic treatment is aimed at minimizing the distressing movements. Pharmacological intervention is available for the behavior and/or psychologic disturbances, chorea, and weight loss. Psychologic symptoms may require major antipsychotic drugs for control. Treatment for patients with depression is used to improve mood, functional status, and quality of life. Research has shed greater understanding on the disease mechanism; however, promising avenues in gene therapy and neurotransplantation are still only in their incipient stages.

• Cognitive impairment
  • Patients who are cognitively impaired require a multidisciplinary treatment approach, which must be based on a solid alliance with the patient and family.
  • Ongoing assessment should include periodic monitoring of the development and evolution of cognitive and noncognitive psychiatric symptoms and their response to intervention.
  • Safety measures include (1) evaluation of suicidal tendency and the potential for violence; (2) recommendations regarding providing adequate supervision, preventing falls, and limiting the hazards of wandering; (3) vigilance regarding neglect or abuse; and (4) restrictions on driving and the use of other dangerous equipment.
  • Also, helping patients and their families plan for financial and legal issues is important.
• Psychosis
  • Intervention should be guided by the patient's level of distress and risk to the patient or caregivers.
  • In addition to distress, if agitation, combativeness, or violent behavior is causing danger to the patient or others, psychopharmacologic treatment is indicated with atypical neuroleptics and mood stabilizers (anticonvulsants known as GABA agents).

Surgical Care

One experimental strategy that may offer hope in the neurodegenerative disorder of HD has been neural transplantation. Fetal human striatal implants to replace lost neurons and/or prevent the degeneration of neurons destined to die most likely will be the first transplantation strategy attempted in clinical trials.

• A study conducted in France examined whether grafts of human fetal striatal tissue could survive and have detectable effects in 5 patients with mild-to-moderate HD.
  • After 2 years of preoperative assessment, patients were grafted with human fetal neuroblasts into the right striatum then, after a year, the left striatum.
  • Final results were assessed 1 year later on the basis of neurological, neuropsychological, neurophysiological, and psychiatric test results.
  • The final position emission tomography scan assessment showed increased metabolic activity in various subnuclei of the striatum in 3 of 5 patients, contrasting with the progressive decline recorded in the other 2 patients in the series, as seen in patients with untreated HD. Motor and cognitive functions were improved or maintained within the normal range, and functional benefits were seen in activities of daily living in these 3 patients but not in the other 2.
  • Fetal neural allografts could be associated with functional, motor, and cognitive improvements in patients with HD.

Consultations

Consultation with social service agency personnel is warranted. As the patient's dependency increases, caregivers may begin to feel more burdened. Families should be counseled regarding when to consider and plan for additional support at home or for possible transfer to a long-term care facility. A referral for some form of respite care (eg, home health aid, daycare, brief nursing home stay) with the help of social service agency personnel may be helpful.

Medication

Drugs used to manage psychosis and agitation in patients with dementia are intended to decrease psychotic symptoms (eg, paranoia, delusions, hallucinations) and associated or independent agitation, screaming, combativeness, or violence. The therapeutic goal is increased comfort and safety of patients, families, and caregivers.

Antipsychotics

Choice of agent is based on adverse-effect profile (patient specific). Atypical neuroleptics such as quetiapine and aripiprazole are the best studied. They are initiated at low doses and are given as standing doses rather than as needed. Use the lowest effective dose, and treat emergent adverse effects first by dose reduction. Younger and less frail individuals may tolerate and respond to somewhat higher doses. Periodically consider reducing or withdrawing antipsychotic medications.

Seroquel (Quetiapine)

Highly effective with data that indicates it has a low EPS profile (similar to placebo). Flipside is its initial sedating effect.

Dosing

Adult

50-300 mg PO bid; give higher dose in PM or HS Dosages do not have to equal or exceed dosage regimens for bipolar disorders or the psychotic disorders

Pediatric

Not applicable

Interactions

Contraindications

Warnings of use in the elderly as a class effect

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sedation, dizziness, unsteadiness, hypotension

Aripiprazole (Abilify)

Mechanism of action is unknown, but is hypothesized to work differently than other antipsychotics. Thought to be a partial dopamine (D2) and serotonin (5HT-1A) agonist, and antagonize serotonin (5HT-2A). Additionally, no QTc interval prolongation noted in clinical trials.

Dosing

Adult

10-15 mg PO qd; if needed, may increase dose gradually q2wk, not to exceed 30 mg/d

Pediatric

Not established

Interactions

CYP450 3A4 and 2D6 isoenzyme substrate, thus, inhibitors (ie, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (ie, carbamazepine) may increase or decrease serum levels, respectively

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include headache, anxiety, somnolence, or insomnia; rare reports of tardive dyskinesia and neuroleptic malignant syndrome; may cause orthostatic hypotension, seizure, dysphagia, or suicidal ideation; hyperglycemia may occur and in some cases be extreme, resulting in ketoacidosis, hyperosmolar coma, or death

Quetiapine (Seroquel)

Indicated for schizophrenia. May act by antagonizing dopamine and serotonin effects.

Dosing

Adult

Initial: 25 mg PO bid/tid and increase to a range of 300-400 divided bid/tid by fourth day
Maintenance: 150-750 mg/d

Pediatric

Not established

Interactions

May antagonize levodopa and dopamine agonists; phenytoin, thioridazine, and other liver enzyme inducers may reduce levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May induce orthostatic hypotension associated with dizziness, tachycardia, and syncope; has been associated with neuroleptic malignant syndrome

Risperidone (Risperdal)

Effective against agitation and psychosis in elderly patients, even at very low doses, which may limit EPS. Binds to dopamine D2 receptor with 20 times lower affinity than for 5-HT2 receptor. Improves negative symptoms of psychoses and reduces incidence of EPS.

Dosing

Adult

0.5-2 mg PO qd; titrate at 1-wk intervals prn; not to exceed 16 mg/d

Pediatric

Not established

Interactions

Avoid alcohol; caution with other drugs that may prolong QT interval; coadministration with carbamazepine may decrease effects; may inhibit effects of levodopa; clozapine may increase levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause extrapyramidal reactions, hypotension, tachycardia, and arrhythmias

Clozapine (Clozaril)

May be a good choice for individuals who cannot tolerate EPS of conventional antipsychotic agents. May inhibit serotonin, muscarinic, and dopamine effects.

Dosing

Adult

25 mg PO qd/bid; then increase to a therapeutic target dose of 300-450 mg/d after 2 wk

Pediatric

Not established

Interactions

Epinephrine and phenytoin may decrease effects; TCAs, neuroleptics, CNS depressants, guanabenz, and anticholinergics may increase effects; do not use with bone marrow depressants

Contraindications

Documented hypersensitivity; WBC count <3500/µL before or during therapy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not discontinue abruptly; perform WBC testing q2wk for duration of therapy

Thioridazine (Mellaril)

Medium-potency antipsychotic with less EPS but more sedation than haloperidol. More sedating and may be given at bedtime for a patient with difficulty falling asleep. First-line drug for treatment of evening psychosis (sundowning) or multiple affective symptoms (eg, agitation, anxiety, depressed mood, tension, sleep disturbance, fears) in elderly patients, patients with dementia, or both.

Dosing

Adult

25-100 mg PO qd

Pediatric

<2 years: Not recommended
>2 years: 25 mg PO qd; not to exceed 3 mg/kg/d

Interactions

May cause false-positive pregnancy test result; some anticholinergics may reduce effects of medication; may increase toxicity of CNS depressants, TCAs, and antihypertensives (eg, propranolol, pindolol); may decrease effects of guanethidine

Contraindications

Documented hypersensitivity; severely depressed state

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients may experience thermoregulatory changes and stomach upset; orthostasis may lead to falls in elderly patients; caution in narrow-angle glaucoma and severe cardiac or liver disease

Benzodiazepines

Sometimes not ideal agents for geriatric patients. May have higher likelihood of adverse effects and potentially fewer benefits than antipsychotics; however, can be useful in treating agitation when anxiety is prominent. Most common adverse effects are sedation, ataxia, amnesia, confusion, and paradoxical anxiety. Long-acting agents must be used with caution, and dose increases should be gradual. If benzodiazepines are used for an extended period (eg, 1 mo), they should be tapered rather than stopped abruptly, owing to the risk of withdrawal.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Does not require oxidative metabolism in the liver and has no active metabolites.
Benzodiazepine of choice in the ED; can be given PO, SL (for rapid effect in panic attack), and IM or IV (mixed in same syringe with antipsychotic). Has longer CNS effects than diazepam and is preferred over antipsychotics for treatment of psychosis secondary to acute intoxication with hallucinogens, cocaine, PCP, and stimulants. Can be used as adjunctive therapy in nonorganic acute psychosis in which DOC is a high potency antipsychotic.

Dosing

Adult

0.5-2 mg PO/IV/IM q6-8h

Pediatric

0.02-0.05 mg/kg PO/IV/IM; not to exceed 4 mg/dose

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or PD; drug or alcohol abuse; suicidal tendencies

Anticonvulsants

Given the limited data, cannot be recommended with confidence for treatment of agitation in patients with dementia. Nonetheless, a therapeutic trial of one of these agents may be appropriate for some patients who are nonpsychotic, especially those who are mildly agitated or unresponsive to antipsychotics. Monitoring patients for symptoms of toxicity and discontinuing administration if a toxic symptom is identified or if no improvement is observed are critical. The more efficacious agents have been the newer ones (ie, zonisamide, oxcarbazepine, levetiracetam), which are GABA modulators and have less toxicity, with no need to monitor levels.

Zonisamide (Zonegran)

Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Evidence indicates that it is also effective in myoclonic and other generalized seizure types.

Dosing

Adult

100 mg/d PO for 2 wk, then increase by 100 mg/d PO q2wk; not to exceed 400 mg/d; may be given qd or bid

Pediatric

Not established

Interactions

May increase serum carbamazepine levels; carbamazepine may increase concentrations; phenobarbital may decrease levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause drowsiness, weight loss, ataxia, nausea, and slowing of mental activity

Oxcarbazepine (Trileptal)

Indicated for treatment of seizures. Pharmacological activity is primarily by the 10-monohydroxy metabolite (MHD) of oxcarbazepine. May block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. Anticonvulsant effect also may occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children <8 y) have a 30-40% increased clearance compared with older children and adults. Children <2 y have not been studied in controlled clinical trials.

Dosing

Adult

Adjunctive therapy: 600 mg/d PO divided bid initially; may increase by a maximum of 600 mg/d qwk; recommended daily dose is 1200 mg/d; monitor patients for adverse anticonvulsant effects
Conversion to monotherapy: 600 mg/d PO divided bid initially; gradually reduce dose of concomitant anticonvulsants in approximately 3-6 wk and gradually increase oxcarbazepine dose in 2-4 wk; may increase oxcarbazepine dose prn by maximum increment of 600 mg/d qwk; monitor patients closely during transition phase for adverse anticonvulsant effects
Initiation of monotherapy: 600 mg/d PO divided bid initially; increase dose by 300 mg/d PO q3d to 1200 mg/d; monitor patients for adverse anticonvulsant effects

Pediatric

Adjunctive therapy
<4 years: Not established
4-16 years: 8-10 mg/kg/d PO divided bid, not to exceed 600 mg/d; gradually increase to target dose over 2 wk
Target dose (based on body weight)
20-29 kg: 900 mg/d
29.1-39 kg: 1200 mg/d
>39 kg: 1800 mg/d

Interactions

May decrease levels of dihydropyridine calcium antagonists and oral contraceptives; can reduce serum concentrations of carbamazepine, phenobarbital, phenytoin, and valproic acid; when given in doses >1200 mg/d, may significantly increase phenytoin and phenobarbital serum concentrations; can reduce serum concentrations of oral contraceptives and make them ineffective; can increase clearance of felodipine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Can cause adverse cognitive effects (eg, psychomotor slowing, impaired concentration, impaired speech and language); in persons with impaired renal function (CrCl <30 mL/min), begin at half usual starting dose; dose increments should be made more slowly; can cause hyponatremia (sodium <125 mmol/L); among persons with hypersensitivity to carbamazepine, 25-30% will have hypersensitivity to oxcarbazepine; rapid withdrawal can cause exacerbation of seizures; observe for adverse effects and monitor plasma levels of concomitant anticonvulsants during dose titration

Levetiracetam (Keppra)

Used as add-on therapy for partial seizures. Mechanism of action unknown. Has favorable adverse effect profile, with no life-threatening toxicity reported.

Dosing

Adult

1000 mg/d PO bid (500 mg bid); may increase 1000 mg/d q2wk to maximum recommended daily dose of 3000 mg; long-term experience at doses >3000 mg/d is relatively minimal, and no evidence indicates doses >3000 mg/d offer additional benefit

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment; major adverse effects include somnolence, asthenia, incoordination, mild leukopenia (3%), and behavioral changes (eg, anxiety, hostility, emotional lability, depression and psychosis [1-2%], depersonalization)

Antidepressants

Patients with depression should be considered for treatment even when the diagnostic criteria for major depression are not met. Evaluate patient for neurovegetative signs, suicidal ideation, and other indicators of major depression because these may indicate a need for safety measures. Successful treatment of depression, partially or fully, can resolve cognitive deficits. SSRIs tend to have a more favorable adverse effect profile than cyclic agents. The choice of an antidepressant generally is based on adverse effect profile and general medical and psychiatric status of each patient. SNRIs, which now include venlafaxine (Effexor XR) and duloxetine (Cymbalta), are first-choice agents.

Paroxetine mesylate (Paxil)

Selectively inhibits presynaptic serotonin reuptake. Besides use in patients with depression, Ranen et al used sertraline in the treatment of severe aggressiveness in HD. Complete cessation of agitative behavior was maintained on follow-up studies.

Dosing

Adult

10-40 mg PO qd, usually dosed PM secondary to sedating effects

Pediatric

Not established

Interactions

Increases toxicity of MAOIs, diazepam, tolbutamide, and warfarin; avoid alcohol; may be potentiated by cimetidine; caution with other CNS drugs and drugs metabolized by CYP2D6 isoenzyme (eg, TCAs, flecainide, propafenone)

Contraindications

Documented hypersensitivity; during or within 14 d of MAOIs

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in preexisting seizure disorders and recent myocardial infarction, unstable heart disease, and hepatic or renal impairment; monitor for mania or hypomania; suicidal tendencies

Venlafaxine (Effexor)

Indicated for treatment of depression. May treat depression by inhibiting neuronal serotonin and norepinephrine reuptake. In addition, causes beta-receptor down-regulation.

Dosing

Adult

IR: 75 mg/d PO divided bid/tid with food; increase in 75-mg/d increments q4d to 225-375 mg/d
ER: 75 mg/d PO with food; increase in 75-mg/d increments q4d to 225 mg/d

Pediatric

Not established

Interactions

Cimetidine, MAOIs, sertraline, fluoxetine class IC antiarrhythmics, TCAs, and phenothiazine may increase effects

Contraindications

Documented hypersensitivity; patients taking MAOIs or have taken them within 14 d of initiating therapy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients may experience hypertension; fatal reaction may occur if taken concurrently with an MAOI; exercise caution in patients with cardiovascular disorders

Duloxetine (Cymbalta)

Potent inhibitor of neuronal serotonin and norepinephrine reuptake. Antidepressive action is theorized to be due to serotonergic and noradrenergic potentiation in CNS.

Dosing

Adult

20 mg PO bid; may increase to 60 mg/d administered qd or divided as 30 mg bid

Pediatric

Not established

Interactions

Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase blood levels and toxicity; moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, TCAs, phenothiazines [eg, thioridazine], type IC antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAOIs may cause serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes including extreme agitation, delirium, and coma (see Contraindications)

Contraindications

Documented hypersensitivity; uncontrolled narrow-angle glaucoma; do not administer with 14 days after stopping MAOI or initiate MAOIs within 5 d after stopping duloxetine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Observe closely for clinical worsening and suicidal ideation when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence and increased sweating

Follow-up

Prognosis

• HD has a great impact on patients' physical and psychosocial well-being, the latter being more severely affected. Even though the symptoms of HD are fairly well characterized, their progression, especially in the early and middle stages, remains unpredictable. With the approach of late-stage HD, affected individuals begin to experience speech difficulty and weight loss. In the late stage, patients lose bowel and bladder control. Clarification of disease progression is vital to improved understanding of the pathogenesis of HD and to the evaluation of therapeutic agents that are designed to slow the progression of disease.
• In longitudinal analyses, longer disease duration and better neuropsychological performance at baseline were associated with a less rapid rate of decline in the Total Functional Capacity Scale score, whereas depressive symptomatology at baseline was associated with a more rapid decline in the Independence Scale score. These rates of functional decline and the co-variates that modify them should be considered in estimating statistical power and designing future therapeutic trials involving patients with HD who have early or moderately severe disease.

Patient Education

• Genetic testing has been available for HD for longer than any other adult-onset genetic disorder.
  • Predictive genetic testing presents unique issues in the legal and ethical debate concerning disclosure of information within the physician-patient relationship.
  • A duty to disclose information to family members has been found when the disclosure is likely to result in the ability to mitigate the damaging effects of the disease.
  • When evaluating a situation in which an individual is at risk of HD, the analysis must be different and necessitates an ethical and legal examination of the consequences of receipt of the information on family members, ie, those known to be at risk but who may not know they are at risk of inheriting a genetic disease.
  • The situation presented by HD is unique and demands a different framework for analysis, given the late onset and lack of curative or ameliorative treatment. Also, the ethical standards should be invoked when considering violating the privacy of a patient or a family member. The principles of autonomy and self-determination of family members are considered, compared with the risk of harm and the privacy interest in not knowing potentially devastating information.
  • The discovery of the genetic mutation causing HD made possible the use of predictive testing to identify currently unaffected carriers. Concerns have been raised that predictive testing may lead to an increase in deaths by suicide among identified carriers.
• A fact that might be comforting to patients with HD (or family members) is the significantly lower prevalence of cancer among these patients. The lower prevalence of cancer among patients with HD seems to be related to intrinsic biologic factors. One explanation may be that the modified protein, huntingtin, encountered in patients with HD protects against cancer by inducing or increasing the rate of naturally occurring programmed cell death in preneoplastic cells.
• When possible, the patient and the family members/caregivers should be prepared for the HD progression, from early involuntary movements and emotional changes to more overt motor symptoms and difficulty with activities of daily living.
• Family therapy, support groups, and caregiver education is extremely important due to the degenerative and emotionally exhausting course of the disorder.  Family therapy may encourage genetic testing and provide for support functionality to the families and caregivers. It provides for a deeper understanding of the condition and ways to deal with the deterioration as it comes about.
• For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education articles Huntington Disease Dementia, Dementia Overview, and Dementia Medication Overview.

Miscellaneous

Medicolegal Pitfalls

Because the general appreciation of the role of genes in diseases is growing, the demand for genetic counseling has increased. Patients who are concerned about their own risk for a genetic disorder or about the risk of genetic disease (eg, HD) in their offspring should consult their physician with questions and expect explanations; therefore, all physicians should be familiar with the principles of medical genetics and should use this knowledge to counsel patients, which may help avoid medical or legal problems.

• The essentials, explained in language understandable to those being counseled, provides effective communication.
• Written notes and diagrams frequently are helpful.
• Summary letters and reviews at subsequent visits help to correct misconceptions and to increase retention of the information.

Special Concerns

Adolescents who are actively requesting HD predictive testing of their own accord pose dilemmas to those providing testing. Asymptomatic adult children at risk for HD should receive careful genetic counseling prior to DNA testing because a positive result may have serious emotional and social consequences. Adhering to published testing and counseling protocols is recommended.

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Keywords

Huntington disease, dementia, HD, Huntington's disease, movement disorders, progressive dementia, psychiatric illness, behavioral disturbance, mental illness, psychosis, depression, schizophrenia, benign familial chorea, inherited ataxias, neural acanthocytosis, familial Alzheimer disease, AD, Parkinson disease, Parkinsonism, PD

Contributor Information and Disclosures

Author

Idan Sharon, MD, Consulting Staff, Departments of Neurology and Psychiatry, Cornell New York Methodist Hospital; Private Practice
Idan Sharon, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Medical Society of the State of New York
Disclosure: Nothing to disclose.

Coauthor(s)

Tulay Ersan, MD, Chief of Geriatrics, Department of Internal Medicine, Division of Geriatrics, Monmouth Medical Center
Tulay Ersan, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Geriatrics Society, and American Medical Association
Disclosure: Nothing to disclose.

Roni Sharon, University of Michigan
Disclosure: Nothing to disclose.

Medical Editor

Alan D Schmetzer, MD, Professor and Vice-Chair for Education, Department of Psychiatry, Director of Residency Training, Indiana University School of Medicine
Alan D Schmetzer, MD is a member of the following medical societies: American Medical Association and American Psychiatric Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

David Bienenfeld, MD, Vice-Chair, Program Director, Professor, Department of Psychiatry, Wright State University School of Medicine
David Bienenfeld, MD is a member of the following medical societies: American Medical Association, American Psychiatric Association, and Association for Academic Psychiatry
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; BMS Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Other; Northstar Grant/research funds Other; Novartis  Other

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration
Disclosure: Nothing to disclose.

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