Dementia due to Huntington' disease.
- Clinical features and course of illness
- Pathology and genetics
- Diagnosis of patients with early symptoms
- Diagnosis of patients with well-established signs and symptoms
- Diagnosis of patients with advanced disease
- Differential diagnosis
- Treatment and management
- Helping persons at risk for Huntington' disease
Huntington' disease was first described in 1872 by an American physician who lived on Long Island, New York. His father and grandfather practised medicine in the same community, and thus he had access to case notes from several generations of families living in the area. This long period of record keeping allowed him to document a hereditary form of chorea, similar to ‘common (Sydenham') chorea', but progressing over many years to death. Its sufferers had a tendency to insanity and suicide. Huntington' brief essay, which also included a clear description of the autosomal dominant inheritance of this disorder, remains one of the classical descriptions of a medical disorder. (1)
Clinical features and course of illness
Huntington' disease is an inherited neuropsychiatric disorder mainly affecting the striatum and its direct connections. It is characterized by a triad of clinical features that are common to most diseases of the striatum and its direct connections: a non-aphasic dementia, depression and other disorders of mood, and a variety of dyskinesias, most typically chorea. (2,3) Chorea, from the Greek word for ‘dance', describes involuntary non-stereotyped jerky movements. The illness, insidious in onset, may begin with any of these three features. Patients who present initially to psychiatrists usually have depression, often with suicidal thoughts or attempts, dementia, or loss of temper. The onset may occur at any time from early childhood to old age, most frequently between 35 and 45 years of age. Once the illness begins, sufferers gradually deteriorate over many years in their cognitive and motor functioning and end in a persistent vegetative state with almost complete loss of voluntary motor function. Death occurs after about 16 years (although some patients live much longer) and is usually caused by inanition or aspiration pneumonia. Some patients die earlier from suicide or subdural haematoma caused by a fall.
Pathology and genetics
The earliest visible neuropathology is in the striosomes of the caudate/putamen, (4) followed by a dorsal-to-ventral progressive loss of almost all striatal output neurones. There can also be milder neuronal loss in some brainstem nuclei and the deep layers of cortex.
The disorder, with a point prevalence of about 6/100 000, (5) is caused by the expansion of an unstable triplet repeat sequence (CAG) in the first exon of a gene near the telomere of chromosome 4p. (6) Normally, this triplet sequence contains from about 7 to 30 repeats; when the number rises above 37, Huntington' disease occurs. The abnormal gene is transcribed and appears to function abnormally, causing a ‘gain of function'. It is transmitted as an autosomal dominant trait; if one parent is affected, each offspring (regardless of sex) has an independent 50 per cent chance of having inherited the abnormal gene. Those who inherit the gene will almost certainly develop Huntington' disease. The mutation rate is low, so that most patients will have an affected parent. However, it can be difficult to obtain an accurate family history. The pathophysiology may be related to the accumulation of fragments of the abnormal huntington protein (called ‘huntingtin') in the nucleus of striatal neurones or the protein' abnormal interaction with other proteins. (7)
Like most disorders caused by the expansion of unstable trimeric repeat sequences, the number does not remain stable at meiosis. In Huntington' disease, the number of CAG repeats is more likely to increase when the gene is transmitted by fathers. As the number of repeats increases, the age at onset is earlier. Thus paternal transmission is often associated with ‘anticipation', earlier onset in subsequent generations, and most cases with childhood onset have affected fathers. (8)
Despite the availability of genetic testing, the diagnosis of Huntington' disease remains dependent on a thorough psychiatric history, including a detailed family history and history of changes in social adjustment, neurological examination, and mental state examination, including a cognitive examination. The clinical presentation changes as the disease progresses. (9)
Diagnosis of patients with early symptoms
Patients with Huntington' disease who initially consult psychiatrists usually present with depression or irritability, and occasionally with bipolar disorder, obsessive–compulsive disorder, schizophrenia, or excessive anxiety. When associated with Huntington' disease, these psychiatric syndromes are clinically indistinguishable from idiopathic psychiatric disorders and may persist as the only manifestation of the illness for several years. It is often during this prodromal phase that patients commit suicide, which may occur even if the patient does not know of his risk for Huntington' disease. (10) Additional presenting symptoms must often be elicited from an informant because the patient minimizes them or is embarrassed about them. These include loss of efficiency at work, which may have precipitated demotion or warnings from superiors stemming from loss of work speed and accuracy; a tendency to become irritated or physically aggressive in response to annoying stimuli that would not have elicited such a response in the past; and a decrease in interest in activities.
Most of these symptoms and behaviours are common in psychiatric disorders, but the cognitive inefficiency and irritability may seem to be out of proportion in their severity, relative to the patient' other symptoms. On cognitive examination, the patient may have difficulty recalling dates of important life events and more difficulty than expected with ‘serial sevens'. There may be motor restlessness (easily misinterpreted as a manifestation of anxiety), as well as motor signs on neurological examination, but these may be subtle: slightly slow saccadic eye movements, (11) writhing movements of the protruded tongue or of the fingertips when the arms are held at 90°, or mild disdiadochokinesis. Diagnosis can be further complicated by the apparent lack of a family history of Huntington' disease. The family may not have been informed about the affected parent' diagnosis even if it had been made, or may know only that a parent died in a psychiatric institution or committed suicide.
Usually, the cognitive changes are easier to notice after the psychiatric disorder is treated, which can usually be accomplished using standard medications. However, unlike idiopathic disorders, cognitive inefficiency and difficulties at work, apathy (if present), and sometimes irritability remain even after the patient' mood, energy, and sleep patterns have returned to normal. When this happens in the course of treatment of depression, a dementia work-up should be considered and the family history further scrutinized through hospital records and other family informants. If the family history is actually negative (this is quite uncommon for Huntington' disease) or unobtainable (often the case for adopted individuals who frequently present in childhood), the diagnosis may be confirmed by testing the patient' DNA for the expanded trimeric repeat in the Huntington' disease gene.
When Huntington' disease starts in childhood or early adolescence, (12) motor signs are limited to voluntary, parkinsonian-like motor slowness, with lead pipe or cogwheel rigidity and very slow saccades. Occasional children have a coarse tremor, and later myoclonus is seen. Cognitively, there is slowing in the rate of learning in school, deterioration of handwriting, and often loss of interest in school and social activities. (13) Of the patients who present with a schizophrenic syndrome, most are adolescents. Psychosis and loss of cognitive capacity may be the only clinical feature for several years before motor impairment begins. Children with Huntington' disease may have seizures, which are usually grand mal. Sometimes myoclonus is mistaken for seizures.
It is important to make the diagnosis of Huntington' disease as early as possible in persons who are employed. Poor function at work (or in schoolwork or household duties) occurs early in the illness, and patients are at risk of losing their jobs, often on suspicion of drug or alcohol abuse. This can usually be avoided if the diagnosis is made known to the family and employer, allowing the patient to retire on disability grounds. Prompt diagnosis does not mean that the patient needs to be informed of the diagnosis at that same time. Some patients are too depressed to do this safely; others indicate that they do not wish to be told. Treatment can usually proceed despite the patient' reluctance to label the disorder.
Diagnosis of patients with well-established signs and symptoms
After a few years of illness, diagnosis is easier. The signs and symptoms will have worsened, and usually the motor disorder has become obvious. A typical patient who has been ill for about 5 to 7 years is unable to work or manage finances, but lives at home and is able to handle personal needs. Some patients remain active and energetic, continuing to participate as fully in life as their cognitive and motor disabilities allow; others are apathetic most of the time, but irritable when disturbed; still others have severe depression with delusions, obsessions, or compulsions, and most are anxious and easily upset by changes of routine. An uncommon, but very troublesome, feature of Huntington' disease is sexual abnormality. While most patients become impotent or uninterested in sex, a few are hypersexual and may develop paraphilias. (14) While these may begin in the early years of illness, they are usually most troublesome in the middle stages.
Cognitively, patients complain of forgetfulness and becoming easily distracted. Thinking is slow; patients have difficulty following a conversation and cannot complete a multistaged task. On cognitive examination, Mini Mental State Examination scores (15) may still be above the usual 23 cut-off score, but serial sevens will be very poor, and one or two items will be missed on recalling words after a distraction. On neuropsychological testing, IQ will be lower than expected for education, and there will be difficulty learning word lists and on tests that require changing sets.
Most patients will have obvious involuntary choreic movements, as well as difficulty with control of voluntary motor movements, as seen by clumsiness, slowness, dysarthria, and an unsteady gait. The involuntary movements will wax and wane with the level of arousal. Speech will have an irregular staccato, often laboured, quality. Saccadic eye movements will be slow or irregular, and the patient will be obviously clumsy on diadochokinesis and finger–thumb tapping, although finger-to-nose testing is normal. Gait will be wide based and irregular, with difficulty with tandem walking. Reflexes are usually brisk.
Diagnosis of patients with advanced disease
After 10 years of illness, dementia is more severe, with poor performance on all aspects of the cognitive examination except naming. Speech is dysfluent with long lapses between the examiner' question and the patient' reply, rather like Brocca' aphasia. Some patients will be virtually unable to speak, although language is relatively preserved. Patients (if they are co-operative) can carry out commands and will recognize relatives and nursing staff. Often irritability and depression have improved, but some patients continue to make suicide attempts or be physically aggressive. Physical disabilities are much worse. Patients often need to be fed, toileted, and helped with most daily needs. They have difficulty in walking and are at risk for falls that can cause further disability through broken limbs or subdural haematomas. Chorea often stabilizes and may even subside, (9) but the ability to carry out voluntary movements is more severely impaired. If they survive long enough, patients become unable to initiate speech, swallow with great difficulty, are unable to walk, and have such severely rigid muscle tone that they may be nearly unable to move their bodies. Clonus and positive Babinski signs are present. Patients in this sort of ‘persistent vegetative state' (16) are difficult to distinguish from individuals with other movement disorders or dementias; as in early disease, eliciting a positive family history may be the only way to make a confident diagnosis without genetic testing.
The differential diagnosis of Huntington' disease is theoretically quite large, (3) but only a few of the disorders for which it can be mistaken are very common. (2) This includes other dementias, other movement disorders, and other psychiatric disorders. The most frequent subcortical dementia is Parkinson' disease, which has a similar motor slowness, but a pill-rolling tremor and festinating gait are rare in Huntington' disease. The dementia associated with late-life depression can look very similar to Huntington' disease. Alzheimer' disease is easily distinguished by the lack of motor signs during the first several years of illness and more prominent difficulty with memory and language, as opposed to attention and calculation. Perhaps most difficult to distinguish clinically are the frontal dementias, which present with prominent behavioural disturbances and a positive family history. The clinical resentation may be insufficient to distinguish these various dementias in patients with advanced disease, since they may all progress to a persistent vegetative state. The family history and the duration of illness (which is longer for Huntington' disease than Alzheimer' disease or frontal dementia) can be helpful.
Several other diseases classified as movement disorders include all the features of the subcortical triad. They often have an autosomal dominant inheritance pattern, and some are caused by expansion of unstable trimeric repeat sequences. These include Fahr' syndrome (calcification of the striatum), some forms of spinocerebellar degeneration, chorea acanthocytosis, and dentato–rubral–pallido–lusian atrophy ( DRPLA). The latter two disorders, while much rarer than Huntington' disease, can look so similar that they can only be diagnosed confidently by genetic testing (in the case of DRPLA) and by a blood smear for acanthocytes (in the case of chorea acanthocytosis). The most common movement disorder that resembles Huntington' disease is tardive dyskinesia. Patients with Huntington' disease occasionally have several years of a schizophrenia syndrome before the movement disorder begins. If they have been treated with neuroleptics, the involuntary movements of Huntington' disease are often mistaken for tardive dyskinesia. On the other hand, the choreoathetotic involuntary movements of severe tardive dyskinesia often involve the trunk and extremities as well as the face and look very much like Huntington' disease. Usually, it is possible to distinguish the patients with tardive dyskinesia by their normal saccadic eye movements, normal tandem gait, and fluid and fluent speech. (17) However, DNA testing for Huntington' disease is sometimes appropriate. Wilson' disease also presents with the subcortical triad and should be considered when neither parent is affected. It is inherited as a recessive, so that the only affected relatives are siblings. Very-late-onset Huntington' disease may be diagnosed as ‘senile chorea' because the family history appears to be negative. Family members will also present symptoms only late in life and may have died before their manifestation.
The differential diagnosis of nearly all psychiatric disorders includes Huntington' disease. The first clinical manifestation can be bipolar affective disorder, unipolar depression, schizophrenia (particularly in adolescents), obsessive–compulsive disorder, or anxiety disorder. As described above, the differential diagnosis is aided by a family history of Huntington' disease, but some families only know that a parent committed suicide or died in an institution, a history that is equally compatible with Huntington' disease or other psychiatric disorders.
Treatment and management
Currently, no treatment influences the course of illness of Huntington' disease, although advances in research on the function of the Huntington' disease gene may change that. Nevertheless, psychiatric treatments can relieve some of the troublesome symptoms. Clinical experience suggests that the depression, anxiety, and obsessive–compulsive disorder associated with Huntington' disease usually respond to the pharmacological treatments used for the similar idiopathic disorders. Because some patients seem unaware of their depressed mood (just as they can be unaware of their involuntary movements) an informant is needed to elicit the symptoms. It is also important to distinguish depression (from which the patient is miserable and sleepless) and apathy, which does not cause the patient distress. Occasionally, mood and anxiety disorders are chronic and unresponsive to treatment. Severe, unresponsive depression can be treated successfully with electroconvulsive therapy. (18) Bipolar disorder in patients with Huntington' disease does not usually respond to lithium, but may improve with carbamazepine or valproic acid, which is also helpful for severely irritable patients. Lithium is difficult to administer because Huntington' disease patients require high volumes of liquid and easily become lithium toxic if fluid intake is insufficient. In one case report, high doses of sertraline were very effective for intractable aggression. (19) Schizophrenic symptoms can be relatively unresponsive to treatment. Sometimes a combination of clozaril and antidepressants can provide some relief. Small doses of neuroleptics can be helpful in decreasing involuntary movements in the first stages of the illness. (20) Persons with advanced disease are often unresponsive to most medication, probably because few striatal receptors remain.
As with most dementias, psychopathology influences, and is influenced by, the patient' environment. Patients do best in a calm highly predictable environment. Patients whose jobs have become cognitively taxing can be irritable, especially towards their family. Often stopping work will alleviate this almost entirely. Huntington' disease seriously damages family relationships, which in turn affects the patient. The well spouse becomes responsible for supporting the family, caring for children and the patient, and making family and financial decisions. Spouses naturally find this very burdensome and may become irritable and resentful. Some patients are unwilling to give up financial and family decision making, even though they may make very poor decisions that damage family relationships and finances. Some patients neglect their children or treat them badly. If the other parent cannot prevent this, it is wisest to remove the patient from the home. There is no research on the treatment of sexual aggression, but the author has successfully treated a few males using progesterone.
Helping persons at risk for Huntington' disease
People at risk for Huntington' disease vary in their abilities to deal with the burden of uncertainty, depending on their personal attributes and their personal experience with the illness in a relative. A few consult physicians for reassurance, but most avoid doctors until they become ill, and even then many resist medical attention, claiming against all evidence that they are perfectly well. Relatively few persons at risk decide to have genetic testing to see whether they have the Huntington' disease gene, but persons who choose testing usually handle the results well, regardless of the test outcome. (21) They are often people who like to plan for the future; for them uncertainty is worse than bad news. Testing should always be preceded by genetic counselling that includes a discussion of the person' motivations. These usually include childbearing, educational and job decisions, or providing the information to their young adult offspring. Many individuals who come for testing have not seriously considered the possibility that they will have a bad outcome test, so that role playing about various outcome scenarios is important. Occasionally, persons request testing who have recently been told about Huntington' disease in their families or who are depressed or under unusual stress for other reasons. Such persons should be encouraged to delay testing until their situation becomes more settled. Finally, some people who request testing already have symptoms of Huntington' disease, yet do not wish to have a diagnosis. Considerable care is required to decide how best to support individuals in this situation, and family members or other close friends of the person should be consulted. (22)
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