Progress in understanding Huntington's chorea.

The present paper analyses the new data accumulated since 1972 concerning the etiology and pathogenesis of Huntington's chorea. Particular attention is paid to the respective roles of the dopaminergic and GABA-ergic systems.     

Sodium valproate in Huntington's chorea.

In a single-case study of Huntington's Chorea the effect of sodium valproate on motor behaviour was first compared with that of L-Dopa and than investigated further alone. Drug effect was assessed in terms of number of EMG-bursts with concurrent determinations of serum-levels of sodium valproate. The main result of this study was the development of a state of tolerance to sodium valproate.     

Huntington's chorea and tryptophan

Daily use of 7 g l-tryptophan and 70 mg pyridoxine for 14 days led to no deterioration of objectively measured manual motor skills in a small group of patients with Huntington''s chorea.     

Glutamatergic therapy of Huntington's chorea.

Preclinical evidence suggests that hypofunction of the glutamatergic subthalamopallidal tract may contribute to the hyperkinesis in Huntington's chorea. The clinical effects of milacemide, a glycine prodrug, were studied in seven patients with Huntington's disease under double-blind, placebo-controlled conditions. Oral doses of 1,200 mg/day did not alter chorea or cognitive dysfunction. Specific modulatory effects of glycine on the NMDA subtype of glutamate receptors, rather than the AMPA receptors, which may predominate among target neurons of the subthalamus, may explain the therapeutic failure of milacemide.     

Huntington's chorea. A random process.

The purpose of the present study was to investigate statistically the irregular nature of the choreatic jerks in Huntington's Chorea. EMG-bursts of certain muscles in a patient with Huntington's Chorea were taken as a measure of the jerks. Statistical analysis of the measurements, i.e. durations of bursts and intervals between bursts, revealed that the irregular nature of the choreatic jerks originate from a random process. Each choreatic jerk appears to be an entirely independent and unpredictable event.     

Homovanilic acid in Huntington's disease and Sydenham's chorea.

Homovanilic acid (HVA) was determined in the lumbar CSF of 12 patients with Huntington's disease and 12 with Sydenham's chorea before and after probenecid administration. The means of HVA concentration (basal and after probenecid) were lower in those with Huntington's disease than in controls, and were even lower in a sub-group characterised by increased tone and slowness of voluntary movement. There was no correlation between CSF HVA values and the severity of abnormal movements, nor with length of the illness and age of the patients with Huntington's disease. The mean basal HVA concentration did not differ from controls in those with Sydenham's chorea but the accumulation with probenecid was significantly lower. These results suggest a decrease in cerebral dopamine release in both forms of chorea.     

Pathophysiology of chorea and bradykinesia in Huntington's disease.

This article reviews the neurophysiological abnormalities described in Huntington's disease. Among the typical features of choreic movements are variable and random patterns of electromyographic (EMG) activity, including cocontraction of agonist and antagonist muscles. Studies of premotor potentials show that choreic movements are not preceded by a Bereitschaftspotential, therefore demonstrating that choreic movement is involuntary. Early cortical median-nerve somatosensory-evoked potentials have reduced amplitudes and the reduction correlates with reduced glucose consumption in the caudate nucleus. Long-latency stretch reflexes evoked in the small hand muscles are depressed. These findings may reflect failed thalamocortical relay of sensory information. In Huntington's disease, the R2 response of the blink reflex has prolonged latencies, diminished amplitudes, and greater habituation than normal. These abnormalities correlate with the severity of chorea in the face. Patients with Huntington's disease perform simple voluntary movements more slowly than normal subjects and with an abnormal triphasic EMG pattern. Bradykinesia is also present during their performance of simultaneous and sequential movements. Eye movements show abnormalities similar to those seen in arm movements. In Huntington's disease, arm movement execution is associated with reduced PET activation of cortical frontal areas. Studies using transcranial magnetic stimulation show that patients with Huntington's disease have normal corticospinal conduction but some patients have a prolonged cortical silent period. Bradykinesia results from degeneration of the basal ganglia output to the supplementary motor areas concerned with the initiation and maintenance of sequential movements. The coexisting hyperkinetic and hypokinetic movement disorders in patients with Huntington's disease probably reflect the involvement of direct and indirect pathways in the basal ganglia-thalamus-cortical motor circuit.     

Iatrogenic parkinsonism in Huntington's chorea

This case report describes a 63 year old woman with a nineteen year history of Huntington's Chorea who had been successfully treated with tetrabenazine for 9 years. During a hospital admission for an unrelated medical illness, she was given two doses of chlorpromazine 25 mg for a vascular headache and within hours became mute, extremely rigid, and unable to move or swallow. The consultation psychiatrist confirmed the diagnosis of severe drug-induced parkinsonism by intramuscular injection of benztropine mesylate which resulted in a dramatic immediate improvement. Both chlorpromazine and tetrabenazine were discontinued and the patient's severe parkinsonian symptoms completely abated on oral benztropine mesylate. Tetrabenazine alone, was restarted after 48 hours to control her Huntington's Chorea and there was no recurrence of parkinsonism. (Past history revealed the patient to have tolerated the same doses of chlorpromazine and tetrabenazine when given separately.) Previous literature reports concurrent safe use of antipsychotics with tetrabenazine, but this case report would suggest caution, and early discontinuance in the event of parkinsonism.     

Kluver-Bucy syndrome in Huntington's chorea

In this paper the first case of Kluver-Bucy syndrome (KBS) in Huntington's chorea is reported. The patient, a 46-year-old man with advanced Huntington's disease, displayed prosopagnosia, oral tendencies, emotional changes, hypersexual behavior, and hyperphagia associated with severe dementia. Haloperidol in moderate doses controlled both the KBS and the chorea, suggesting a possible role for the dopaminergic system in the pathogenesis of KBS in Huntington's disease. The presence of profound dementia in our patient supports the previous assertion that human cases of KBS are invariably associated with severe cognitive dysfunction. Since KBS was established as an entity, a great deal of attention has been directed to its neuroanatomical basis. However, due to the multidetermined nature of human behavior, the role of physiological, psychological, and environmental factors should also be taken into consideration with regard to the pathogenesis of this syndrome.     

Studies of hypothalamic function in Huntington's chorea.

In eight patients with classical Huntington''s chorea hypothalamic function was assessed by the insulin tolerance test, the thyrotrophin releasing hormone test, the gonadotrophin releasing hormone test and water deprivation and the results compared with those of 10 control subjects. All patients ceased to have choreiform movements for approximately 60 minutes during the insulin tolerance test. Four of the patients failed to show clinical features of stress in response to hypoglycaemia. The fasting blood glucose level and blood glucose response to insulin were similar for the two groups. However, the response of plasma cortisol (p less than 0.05) and of growth hormone (p less than 0.05) to hypoglycaemia was earlier in patients than controls, though peak responses were the same for each group. The thyrotrophin releasing hormone test revealed no difference in basal levels of thyroid stimulating hormone in either group, or in peak response to thyrotrophin releasing hormone or in the increment at 20 minutes. One of the patients had a delayed response typical of a hypothalamic disorder, whereas none of the controls had such a response. Mean free thyroxine index levels for each group were similar. There was no difference in basal prolactin level, or in the increment or in the peak level in response to thyrotrophin releasing hormone between each group as a whole or when the males and females were analysed separately. Because of small subgroups, the data from the gonadotrophin releasing hormone test were difficult to analyse, but no clear differences or obvious abnormalities emerged. Water deprivation revealed no evidence of inability to concentrate urine in either group and hence no indication of impaired antidiuretic hormone function. The study supports previous findings of altered hypothalamic function in patients with Huntington''s chorea but further suggests that serotoninergic rather than dopaminergic mechanisms may be altered.