Huntington Disease Dementia 

Updated: Sep 11, 2018
Author: Idan Sharon, MD; Chief Editor: David Bienenfeld, MD 

Overview

Background

Key features

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.

Case study

The progressive nature of the disorder, the variation in symptoms, and the complexity of diagnosis and treatment is well portrayed in a case study published by Lipe and Bird. They reviewed clinical and genetic features in 34 cases of late-onset Huntington disease.[1]

Among the cases reviewed was a 74-year-old male who presented with mild chorea, memory problems, and anxiety at the age of 61 years. Though his family had no known history of HD, a number of family members were believed to have been afflicted by dementia, a staggering gait, emphysema, and Parkinson disease. Genetic testing revealed 43 CAG repeats in the HD gene. His motor and cognitive function deteriorated over several years following diagnosis. Mild depression progressed to severe depression and suicidal thoughts, followed by psychosis including delusions and hallucinations, requiring multiple psychiatric hospitalizations.

Pathophysiology

Huntington disease (HD) is associated with an excessive sequence of CAG repeats in the 5' end of HTT (alias IT15- interesting transcript number 15), a 350-kD gene located on the short arm of chromosome 4.[2] Healthy individuals may have between 9 and 35 CAG repeats, while patients diagnosed with HD, as well as carriers, have an abnormal expansion accommodating 36 or more CAG repeats.[3] The HTT gene, or HD gene, codes for a protein called huntingtin. This protein is found in neurons throughout the brain; its normal function is unknown. In affected patients, neuronal degeneration initiates in the striatum and progresses to the cerebral cortex, following a pattern that correlates to clinical progression of HD.[2]

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 HD 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).

The role of mitochondrial dysfunction in HD has been under investigation. Quintanilla et al published the results of a study that focused on the contribution of mitochondrial dysfunction and transcriptional dysregulation to the pathogenesis of HD and the possibility of therapeutic intervention. The authors note that impaired energy generally precedes clinical diagnosis of HD, suggesting that the disruption of energy homeostasis is linked to the pathogenesis of HD. Based on their findings, Quintanilla et al suggest the possibility that the effects of mutant HD can be reduced by increasing the availability and activity of PGC-1 α, a co-activator involved in mitochondrial function and glucose, lipid, and energy homeostasis, the function of which seems to be disrupted by mutant HD interactions that interfere with signaling pathways.[2]

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 persons 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.

Epidemiology

Frequency

United States

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

Recent estimates of the prevalence of HD in the United States are between 5 and 10 people per 100,000.[4]

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. The prevalence of HD in the United Kingdom is currently estimated at 8 cases per 100,000 individuals. In a 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. The prevalence in Japan is estimated at 1 case per 100,000 people.[4]

Mortality/Morbidity

HD is a progressive disorder, typically lasting approximately 15–20 years from onset of symptoms until death.

  • 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.

Demographics

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.

HD affects males and females in relatively equal numbers.

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).

 

Presentation

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 a study conducted by Jason et al, cognitive manifestations were examined in relation to age, clinical onset, progression, and genetic analysis.[5] Evidence showed an inverse correlation between the age of 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.

  • The prevalence of apathy (Apathy Scale score 14 points) in patients with Huntington Disease is independently associated with male sex, worse global functioning, and the higher use of neuroleptics and benzodiazepines.[6]

  • 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.

Causes

HD is a genetic autosomal dominant disorder. Persons who have 36 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.

Physical Examination

See the list below:

  • 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.

    • Solomon et al found that verbal episodic memory function is affected in patients with HD CAG expansion, in a manner that is consistent with the profile of subcortical dementias, prior to manifestation of HD.[7]  The authors concluded that impairments in verbal learning and memory are detectable prior to clinical diagnosis of HD. Identifying the presentation of such features early provides clinicians with the opportunity to monitor the course of progression. The study was part of the ongoing Predict-HD project through which researchers are seeking to identify markers that will enable tracking of the disease from its earliest stages.

  • 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.

 

DDx

Diagnostic Considerations

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.

As Peavy et al discussed in a study published in 2008, the criteria for diagnosing HD dementia has centered on the memory deficit characteristics of AD.[8] The authors of the study sought to propose criteria for the diagnosis of HD that focused more on functional impairment than on memory loss. The implementation of such criteria would allow for diagnosis in earlier stages, as functional deficits usually present well in advance of memory loss in the patient with HD. Peavy et al suggest that criteria for diagnosis of HD dementia include evidence of impaired speed of processing, as well as any of the following: executive function, visuospatial ability, or attention or memory deficits. Such features will follow a deteriorating course.

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.

Differential Diagnoses

 

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.[9] 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.[10] 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. A recent review detailing all studies investigating the effectiveness of acetylcholinesterase inhibitors revealed that there is little evidence of the benefit of such medications.[11]

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.[12]

  • 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

Medication Summary

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.

In 2008, Adam and Jankovic published a review of therapies for the treatment of motor, psychiatric, behavioral, and cognitive symptoms of HD. They developed a clear visual to depict the suggested algorithm for symptomatic treatment of HD.[13]

There is only one FDA-approved medication for Huntington's disease. Xenazine (tetrabenazine) was approved by the FDA in 2008 and is indicated for treatment of movement disorder (chorea) caused by Huntington's disease. This drug has no impact on dementia or cognitive decline associated with the disease.

Antipsychotics

Class Summary

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.

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.

Quetiapine (Seroquel)

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

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.

Clozapine (Clozaril)

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

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.

Benzodiazepines

Class Summary

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.

Anticonvulsants

Class Summary

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.

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.

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.

Antidepressants

Class Summary

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.

Venlafaxine (Effexor)

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

Duloxetine (Cymbalta)

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

 

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

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.[15]

There is evidence that individuals with a family history of HD are discriminated against in various ways, contributing to psychological distress.[16]

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.

Coulson et al discussed the use of online support groups as a resource for those affected by HD.[17] The authors analyzed the content of more than 1000 postings on a support group's message board. They found that those diagnosed with HD, we well as those affected by HD, use the online group to exchange information on the disease and networking information, such as referrals, and to offer and seek empathy, emotional, and esteem support. Online support groups can lessen feelings of isolation by providing a community for those who are facing the unique challenges of HD. Further investigation is needed to evaluate the accuracy of informational exchanges.

For patient education resources, see the Dementia Center, as well as Huntington Disease Dementia, Dementia Overview, and Dementia Medication Overview.

Other useful websites for the patient and the family are as follows:

  • National Institute of Neurological Disorders and Stroke Huntington's Disease Information Page

  • Huntington's Disease Society of America

  • Medline Plus - Huntington's Disease