Pallidal GABA and chorea in Huntington's disease

Summary Neurochemical correlates of chorea in Huntington's disease were studied using striatal and pallidal tissue taken post mortem from patients with mild and severe chorea. While GABA was decreased in all these areas in Huntington's disease, patients with mild chorea had significantly less GABA in the medial pallidum than did those with severe chorea. There was no relationship between the degree of chorea and concentrations of dopamine or its metabolite. Thus the chorea of Huntington's disease may relate to the balance of residual GABAergic innervation between specific areas of the basal ganglia, consistent with primate models of dyskinesias.     

The EEG in Huntington''s chorea: a clinical and neuropathological study

The EEGs are reported on a group of 95 patients with Huntington's chorea. Thirty one showed little activity of any kind, and in particular no alpha rhythm above 10 μV in amplitude was seen. Only those records which still met these criteria when re-examined were included in the `low voltage' category. EEGs in this category occurred significantly more frequently in institutionalized patients and in those with a positive family history of Huntington's chorea, dementia, and choreiform movements together. Computer averaged responses to light and sound were found in the three patients examined, though their routine EEGs were low voltage. Neuropathological examination confirmed a clinical diagnosis of Huntington's chorea in 14 patients investigated. There was a statistically significant association between cortical atrophy, including the frontal lobe, and a `low voltage' EEG. It was concluded that the low voltage record, though not specific for Huntington's chorea, was rare in other neurological disorders. The EEG is therefore of value in patients suspected of having Huntington's chorea as well as in various presenile dementias.     

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.     

Hepatic morphology in Huntington''s chorea.

Liver biopsy specimens from six patients with Huntington's chorea were examined locally and referred with clinical information to three colleagues abroad experienced in the interpretation of liver biopsy specimens. The minor and inconsistent abnormalities reported upon were of non-specific character. The suggested interrelation between damage to cerebral neurones and hepatocytes in Huntington's chorea was not substantiated by this study.     

Altered growth hormone release in Huntington''s chorea.

Glucose tolerance tests have been performed on five patients with Huntington's chorea and no difference in response has been observed compared with seven controls. Insulin tolerance tests have been performed on 12 patients with Huntington's chorea and 10 controls. Blood samples were taken at regular intervals for 75 minutes and analysed for blood glucose, insulin, and growth hormone (HGH). There was no difference between the groups in the hypoglycaemia which developed. The patients, however, had an earlier elevation of HGH than the controls. The difference was highly significant (P less than 0.001, P less than 0.02) 30 and 35 minutes after the intravenous injection of insulin. The patients, although awake, ceased to have choreiform movements for at least the last 60 minutes of the insulin tolerance tests. Our observations of HGH release imply that hypothalamic activity is altered in Huntington's chorea. Further observations of HGH release may therefore be of value in its diagnosis.     

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.     

Lithium treatment of Huntington's chorea. A placebo-controlled clinical trial.

The therapeutic effect of lithium in Huntington's chorea was tested in six patients through a double-blind cross-over comparison of lithium and placebo, each administered for 6 weeks. Four of the patients received neuroleptic drugs at the same time. Lithium and placebo periods did not differ as regards motor skills, hyperkinesias, or total ward situation, all rated quantitatively with the use of scales. Lithium does not seem to be of therapeutic value in Huntington's chorea.     

Somatosensory evoked potentials in Huntington's chorea

Somatosensory evoked potentials were measured in 21 patients with Huntington's chorea and 12 controls. Central brain conduction time was normal. Early cortical component amplitudes were reduced in the patient group, latencies were normal. These abnormalities probably can be attributed to cortical dysfunction in Huntington's chorea. No indication of brain-stem dysfunction was found.     

Respiration during sleep in Huntington's chorea

In view of recent reports on lower brainstem dysfunction in Huntington's chorea, we studied respiration during sleep in 12 patients with Huntington's chorea (HC) and in controls. There were no statistically significant differences between patients and controls with respect to apnea periods, respiratory frequency and time elapsed between minimal and maximal value of the respiratory curve. No statistically significant differences in respiratory variability were observed between patients and controls. In the present study, no indication was found for dysfunction of lower brainstem structures involved in respiration in HC.     

Evidence of genetic heterogeneity in Huntington''s chorea

In an extensive study of Huntington's chorea in Queensland evidence was found to support an old observation that the magnitude of the variation in the symptom complex of the disease between different families is sufficient to suggest that there may be more than one form of Huntington's chorea allele present in the community. Analysis of data concerning age at onset indicates that at least two separate forms of the disorder may exist.     

Reduced density of striatal somatostatin receptors in Huntington's chorea

A marked increase of the endogenous somatostatin has been reported in the striatum in Huntington's chorea by radioimmunoassay and immunohistochemistry. Using quantitative receptor autoradiography we examined the density and distribution of somatostatin receptors in the striatum of 6 patients dying from Huntington's chorea degree 3, in 12 control healthy patients dying without neurological diseases and 7 schizophrenic patients, using the stable somatostatin octapeptide analogue [¹²⁵I]204-090 as a radioligand. Marked reductions of the density of somatostatin binding sites were observed in the caudate and putamen of all patients with Huntington's chorea. However, these receptors were well preserved in the nucleus accumbens and in the ventral aspects of the anterior putamen. No alteration of somatostatin receptors was observed in other brain areas. These results suggest that somatostatin receptors in the human striatum are markedly down-regulated or localized on a population of neurons which is at risk in Huntington's chorea and questions the postulated role for the elevated somatostatin levels in choreiform movements.     

Cause and course in a series of patients with sporadic chorea

OBJECTIVE: To identify correlations between clinical and neuroimaging features in sporadic chorea and to explicate the evolution of choreas of differing aetiologies. METHODS: We analysed the clinical and neuroimaging data of 51 consecutive cases (17 males, 34 females; age 16-95 years) of sporadic chorea admitted to the neurology departments of two general hospitals from January 1994 to December 1999, and two neurological institutes from January 1997. Six months later the patients were reassessed clinically and those still with chorea (20 cases) were asked to undergo the genetic tests for Huntington's disease and dentatorubropallidoluysian atrophy. RESULTS: There were 9 cases of focal dyskinesias, 18 of hemichorea, and 24 of generalised chorea; onset was acute in 17, subacute in 27, and insidious in seven. Analysis permitted classification as follows: vascular-related (21 cases); vasculitis (1 case); hypoxia (2 cases); drug-induced (7 cases); AIDS-related (5 cases), borreliosis (1 case); Sydenham's chorea (1 case); hyperglycaemia (2 cases); hyponatraemia (2 cases); Huntington's disease (HD) (5 cases) and acanthocytosis (1 case). In 3 patients neither etiological factors nor neuroradiological alterations were found. CONCLUSIONS: Although a convincing concordance between choreic signs and neuroradiological findings was possible in 4 patients only, it was possible to assign an aetiology in most cases with vascular related causes the most frequent and metabolic factors often participating. Huntington's disease is not unusual as a cause of sporadic choreas. HIV infection is an emerging cause of chorea and AIDS-related disease should be considered in young patients presenting without a family history of movement disorders. We emphasize the importance of follow-up to identify persistent chorea for which genetic testing is mandatory.     

The treatment of Huntington's chorea with belladonna alkaloids

Conclusions Although the series of cases presented is very small, the consistently beneficial results obtained by the use of belladonna alkaloids in the treatment of Huntington's chorea is most encouraging. It cannot be claimed that the belladonna alkaloids will prevent or arrest the chronic progressive degeneration. However, they do offer marked relief from the incapacitating neurological symptoms. This improvement in the somatic sphere is reflected in the psychic sphere. Personality changes are less prominent, and there is lessening in the apparent emotional and intellectual deterioration. Hospitalization does not become necessary so early and possibly may be prevented entirely. Hospitalized patients may be improved to the point where they can again return to the community. Further, it is believed that this treatment will prolong the lives of individuals suffering with Huntington's chorea by deferring the inevitable terminal complications.Presented at the interhospital conference, Syracuse Psychopathic Hospital, April 22, 1947.     

Amine metabolites in the cerbrospinal fluid in Huntington''s chorea

The amine metabolites HVA and 5-HIAA in the lumbar CSF of 15 patients with Huntington's chorea were determined. A negative correlation was found between the severity of symptoms and the CSF HVA, but not 5-HIAA levels. The mean HVA concentration was lower than that of a group of patients with miscellaneous neurological disorders, similar to that of a group with miscellaneous psychiatric disorders and higher than that of a group with Parkinson's disease. The mean 5-HIAA concentration was similar to that of the neurological group and higher than those of the groups with psychiatric disorders or Parkinson's disease. CSF HVA and 5-HIAA concentrations of a single patient with severe akinetic rigid Huntington's chorea were similar to those found in Parkinson's disease. The findings are discussed in relation to previous neuropathological observations and to reported effects of drugs on the choreic symptoms.     

Biochemical markers for Huntington's chorea

The uptake of dopamine (DA) by platelet rich plasma was assayed in 11 patients with Huntington's chorea (H.C.). The results confirmed the previous observation that platelets from H.C. patients take up, at equilibrium, more dopamine than do platelets from normal control subjects. The mean difference was 50% higher at DA substrate concentrations of 0.11 mM. However, attempts to confirm the higher Na+ - K+ ATPase activity of erythrocyte ghosts from Huntington's chorea patients were unsuccessful.     

Open-label pilot study of levetiracetam (Keppra) for the treatment of chorea in Huntington's disease.

The objective of this study is to evaluate the tolerability and preliminary efficacy of levetiracetam (LEV) in reducing chorea in Huntington's disease (HD) patients in a prospective open-label pilot study. Nine HD patients with chorea were treated with LEV in doses up to 3,000 mg/day for up to 48 days. The primary endpoint measure was the Unified Huntington's Disease Rating Scale (UHDRS) chorea subscore. The mean dose (+/-SD) of LEV at endpoint was 2,583.3 +/- 1,020.6 mg/day. Mean UHDRS chorea score decreased from 12.6 +/- 3.0 at baseline to 6.7 +/- 4.3 at endpoint (P = 0.01). There was no significant change in UHDRS total motor scores (38.8 +/- 11.4 at baseline and 33.6 +/- 26.7 at endpoint; P = 0.24). Somnolence contributed to a 33% drop-out rate, and 3 patients developed Parkinsonism. Results of this open label study suggest that LEV may be efficacious in reducing chorea in HD patients.     

Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome

Huntington's disease is characterised by hyperkinetic movements, mainly chorea, cognitive dysfunction, and psychiatric abnormalities. Non-dopa responsive parkinsonism occurs in the later stages of choreic disease or as the predominant feature of juvenile patients (Westphal variant). Late onset Huntington's disease presenting as levodopa responsive parkinsonism is rare. A series of four patients with late onset Huntington's disease presenting as levodopa responsive parkinsonism and cardiovascular dysautonomia, initially misdiagnosed as multiple system atrophy (MSA) in three patients, is reported. Levodopa treatment did not unmask significant chorea. These cases suggest the presence of a distinct phenotypic variant of Huntington's disease to be added to the differential diagnosis of other akinetic rigid syndromes.     

Brainstem reflexes and brainstem auditory evoked responses in Huntington''s chorea.

Blink reflex, corneal reflex, jaw reflex, exteroceptive suppression in masseter muscles and brainstem auditory evoked potentials were measured in 20 patients with Huntington's chorea and 12 controls. A significantly increased latency of the second component of the homolateral and heterolateral blink reflex was found in the patient group as compared with the controls. The other investigations revealed no significant differences between patients and controls except for some facilitation of the jaw reflex in the patient group. Increase of second component latency of the blink reflex in the presence of normal corneal reflexes is suggestive of functional impulse conduction disturbance in the lower brainstem. It is discussed whether in Huntington's chorea this is to be attributed to alterations of cortical or striatal influence or to local brainstem abnormalities.     

A case of Huntington's chorea with unilateral ectopic gray matter

The authors report a single case of Huntington's chorea associated with a unilateral focus of ectopic gray matter. The patient's symptoms began at age 45 and included typical involuntary jerking movements of all extremities and face. Mental deterioration may have proceeded the choreiform movements. The family history was positive for Huntington's chorea. Pneumoencephalogram showed atrophy of the caudate nuclei bilaterally early in the disease. The patient improved transiently with haloperidol therapy. The major pathologic features included mild generalized cerebral atrophy with marked atrophy of the caudate nuclei and putamen. Within the white matter of the left frontal lobe, there were irregular nodules of ectopic gray matter with an overall diameter of 2 cm. The rarity of either unilateral ectopia or Huntington's chorea alone, makes it impossible to judge if the two lesions might be linked by a common pathologic mechanism. The significance such a linkage might hold is discussed in light of several currently postulate pathologic mechanisms.     

Subcortical afferent projection systems in Huntington's chorea

Summary The number and nucleolar volume of nerve cells within the nucleus basalis of Meynert, locus caeruleus, substantia nigra and dorsal raphe were examined in five patients with Huntington's chorea. No significant changes in nerve cell number were noted in any area in any patient and, although nucleolar volume was reduced in nerve cells of locus caeruleus and substantia nigra in four patients, this was considered to reflect medication rather than to be related to the disease process itself. It is concluded that the subcortical afferent projection systems of the mid-brain and brain stem are unaffected in Huntington's chorea and that the dementia in such patients most likely relates to changes within the cerebral cortex and/or damage to corticopetal pathways within the basal ganglia.Supported in part by the North Western Regional Health Authority