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.     

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.     

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.     

Parasympathetic function in Huntington's disease

Parasympathetic function in 7 Huntington's chorea patients with a duration of the disease ranging from 1 to 20 years, was evaluated by studying R-R intervals during quiet and deep breathing and Valsalva manoeuvre. All 7 patients were free of neuropathy, orthostatic hypotension, heart or lung disease and had had no medication for at least 15 days prior to hospitalization. Seven normal subjects served as controls. On the whole, the responses of the Huntington's chorea patients were not significantly different from those of the controls. Abnormal responses to all the tests were received in only one patient and a low R-R variability during deep breathing in the youngest patients. Unlike other Central Nervous System degenerative disorders, in Huntington's disease parasympathetic autonomy seems to be sufficiently preserved.     

Growth hormone and prolactin response to bromocriptine in patients with Huntington''s chorea.

The growth hormone (hGH) and prolactin (hPRL) responses to oral bromocriptine were studied in two groups of patients with Huntington's chorea and in seven healthy control subjects. The patients included six patients who had previously been treated with phenothiazines and six patients who had not received phenothiazine treatment. All medication was stopped 72 hours before the investigation which involved taking blood samples for up to 210 minutes after taking bromocriptine (2.5 mg). Plasma samples were analysed for hGH and hPRL. There was no significant difference in basal hGH concentrations between the patients and control subjects. The hGH response to bromocriptine varied in the individual patients but the concentrations were significantly lower in the patients compared with the controls between 160 and 210 minutes. The basal concentrations of hPRL were also not different, apart from the findings of elevated hPRL concentrations in three patients previously treated with phenothiazines. The patients and control subjects showed a consistent fall in hPRL concentrations after taking bromocriptine. The lower peak hGH response to bromocriptine found in the patients suggests that there may be an alteration of dopaminergic neurones mediating hGH release.     

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.     

Regional distribution of choline acetyltransferase in the human brain: changes in Huntington''s chorea.

A stereotaxic method of tissue sampling has been developed permitting detailed studies of the distribution of choline acetyltransferase (CAT) in brains from controls and from patients suffering from Huntington's chorea. The characteristic pattern of CAT distribution within extra-pyramidal structures is described. In Huntington's chorea, CAT is unevenly reduced in several brain regions particularly in the rostromedial part of the caudate nucleus. The results indicate a preferential degeneration of neostriatal cholinergic neurones in Huntington's chorea.     

Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson''s disease and Huntington''s chorea.

Lumbar cerebrospinal fluid (CSF) acetylcholine (ACh) and choline (Ch) levels were measured in patients with Huntington's chorea (N=11), Parkinson's disease (N=8), and subjects at risk for Huntington's chorea (N=4), and all three groups were found not to differ significantly from normal controls (N=10). The values found for lumbar CSF ACh and Ch levels in the normal subjects were comparable with previously reported values. The use of physostigmine, a cholinesterase inhibitor, in collecting the CSF samples did not appear to make a difference with regard to ACh and Ch concentrations. Evidence suggesting a ventricular-lumbar gradient, with lumbar CSF Ch concentration being less than ventricular CSF Ch concentration, was found. Finally, ACh levels in CSF did not correlate with corresponding Ch levels.     

Medication effect on lymphocyte morphology in schizophrenia

Past studies on the occurrence of atypical lymphocytes in the blood of individuals with schizophrenia are contradictory; some researchers have argued that such cells are a genetic marker of the disease while others have explained the cells simply as an effect of antipsychotic drugs. The present study blindly measured atypical lymphocytes in 14 schizophrenics on medication for at least 6 weeks and off medication for at least 4 weeks, ten Huntington's disease patients on antipsychotic medication, and ten normal controls. The patients with schizophrenia (P less than 0.05) and those with Huntington's disease (P less than 0.02) both had significantly more atypical lymphocytes than the normal controls. However no difference was found in the percentage of atypical lymphocytes in patients with schizophrenia on and off medication. The authors cite the need for studies of first-admission, never-tested patients to definitively settle this question.     

Acoustic analysis of prosody in Sydenham's chorea

There are few studies of language and speech in patients with Sydenham's chorea (SC). We have done an acoustic analysis of fundamental frequency (F0), duration and intensity of declarative and interrogative sentences made by 20 SC patients, 20 patients with rheumatic fever (RF) without chorea, and compared them with 20 healthy age-matched controls (CO). Each group included 12 females. We found that there is no difference between the RF and CO groups in all studied parameters. Patients with SC, however, presented with a speech characterized by decreased F0 range (difference between minimum and maximum F0), shorter duration of sentences, and higher intensity of the first syllable of sentences. The findings were not influenced by the nature of the sentences (i.e. , declarative or interrogative), but for all variables they were significantly more severe in males than females. In conclusion, we have demonstrated that patients with acute SC have an impairment of modulation of F0 and longer duration of emission of sentences, resulting in a monotone and slow speech. This pattern is similar to what has been described in other basal ganglia illnesses, such as Parkinson's disease, Huntington's disease and Wilson's disease.     

A blinded study of the suppressibility of involuntary movements in Huntington's chorea, tardive dyskinesia, and L-dopa-induced chorea

Videotapes of patients with Huntington's chorea, tardive dyskinesia (TD), and L-DOPA-induced chorea in Parkinson's disease were taken while the patients were seated with their legs dangling. The videotapes were scored in a blinded fashion for suppressibility of dyskinesias. Most patients with TD or L-DOPA-induced chorea substantially suppressed their involuntary movements, whereas most patients with Huntington's chorea did not. There was a small overlap between the TD and Huntington's chorea groups and suppressibility therefore could not absolutely distinguish between them. Suppressibility testing may nonetheless be a valuable clinical tool since a good, excellent, or complete suppressibility rating was highly suggestive of TD but not Huntington's chorea. TD and L-DOPA-induced chorea may be more pathophysiologically similar to each other than either is to Huntington's chorea.     

Plasma glutamate decarboxylase activity in neuropsychiatry

Plasma glutamate decarboxylase (GAD) activity was measured in patients with endogenous psychoses and neurologic diseases. Unmedicated schizophrenic patients showed no difference in plasma GAD levels compared to controls. Administration of neuroleptics together with anticholinergic agents increased plasma GAD activity in schizophrenic patients. Compared to controls, patients with major depression and bipolar illness showed significantly lower GAD activity. No effect of antidepressants and minor tranquilizers on plasma GAD activity was found. Relatively lower GAD activity was shown in neurotic patients. The enzyme activity in plasma of patients with Huntington's chorea (HC) was lower than control levels. The plasma GAD concentrations correlated with cerebrospinal fluid concentrations in five HC patients.     

Platelet dopamine uptake in Huntington's chorea and Gilles de la Tourette's syndrome: effect of haloperidol.

Uptake of 14C-dopamine by human platelets has been studied in two diseases, namely Gilles de la Tourette's syndrome and Huntington's chroea, in which abnormal metabolism of dopamine has been implicated. Platelets from untreated Huntington's chorea patients showed a small increase in Km and Vmax.; platelets from patients in all other groups showed an uptake identical with the controls. Haloperidol (10(-5)M) was also shown to be a strong non-competitive inhibitor of 14C-DA uptake by platelets. This property is probably unrelated to the drugs' action in ameliorating the symptoms of Huntington's chorea which is likely related to the increase in cholinergic neuronal activity produced by neuroleptic blockade of dopamine receptors.     

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.     

Habituation of the orbicularis oculi reflex in dementia and dyskinetic states.

The habituation index is a quantitative expression of the ability of the orbicularis oculi (blink reflex) to adapt to a series of electrical stimuli applied to the supraorbital region. This parameter has been studied in a group of normal control subjects, and the results compared with those in cases of idiopathic and drug-induced Parkinsonism, states of dementia, and dyskinesias such as Huntington's chorea and senile chorea. Patients with Huntington's chorea showed a tendency for the reflex to habituate readily in contrast to patients with dementia caused by cortical atrophy and those with Parkinson's disease. Younger patients with Huntington's chorea had indices within the normal range. It seems unlikely that this test will prove of value in the detection of clinically unaffected relatives. Where dementia was associated with a reversible intracranial lesion, the habituation index was studied before and after treatment. Failure of habituation in this condition appears to be due to the release of a primitive protective reflex.     

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.     

Short-term variability in amplitude and motor topography of whole-body involuntary movements in Parkinson's disease dyskinesias and in Huntington's chorea

OBJECTIVES: Clinical observations have noted variability in amplitude of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) and chorea in Huntington's disease (HD) during the day. However, no studies have examined whether both the amplitude and body location (motor topography) of whole-body involuntary movement (WBIM) varied over short periods of time (seconds or minutes), which may have a distinct and significant effect on how disruptive these WBIM may be. The present study quantified the variability of WBIM amplitude and motor topography in patients with PD having LID and in patients with HD having chorea. PATIENTS AND METHODS: WBIM was quantified using the MotionMonitor magnetic motion tracker system. Five patients in each group were tested in two conditions: sitting and standing. RESULTS: WBIM increased from sitting to standing, more so in choreic patients. WBIM varied from 17% to 102% of total WBIM amplitude. Chorea tended to present with greater variability than LID in absolute terms in the standing condition, but not when the mean WBIM amplitude was taken into consideration. Motor topography of WBIM also varied more in the HD group, but mostly in the seated condition where more limbs were free to move. Neither group expressed any laterality of involuntary movement, with amplitude being equally distributed on both sides of the body. CONCLUSION: Results show significant short-term variability in amplitude of chorea and LID, as well as, variability in location of these involuntary movements, illustrating the complexity of the adaptations required to live and be active with involuntary movements such as HD chorea or PD dyskinesias.     

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.     

Depressive symptoms and the glucose tolerance test and insulin tolerance test.

Patients with severe depression have been observed previously to have a reduced rate of glucose utilization accompanied by elevated serum insulin levels during the intravenous glucose tolerance test (GTT) and a reduced metabolic responsiveness to exogenous insulin during the insulin tolerance test (ITT). These abnormalities were less obvious in patients with neurotic depression as compared to patients with severe endogenous or "psychotic" depression. To evaluate more fully the relationships of depressive symptomatology to these metabolic abnormalities, patients were rated by nursing staff on a short clinical rating scale (SCRS) and by a psychiatrist on the Brief Psychiatric Rating Scale (BPRS) at the time the metabolic measurements were made. Patients were given the GTT and the ITT once when they were off medication and symptomatic and then again 3 to 8 weeks later when symptoms had decreased following amitriptyline treatment. Fasting serum-free fatty acid levels (FFA) had a significant positive correlation to rating of anxiety. Fasting levels of glucose, insulin, and human growth hormone (HGH) did not significantly correlate to any of the ratings. A decreased rate of glucose utilization (k) correlated significantly with increased ratings of motor retardation, emotional withdrawal, and blunt affects, but not to other depressive symptoms. The responsiveness of FFA and HGH during the ITT was significantly less in patients with more severe symptomatology; responsiveness improved when those patients improved. Neither incorrelated to the ratings. These data suggest that within the sydrome of depression, increased FFA is realated to anxiety, decreased glucose utilization is related to motor retardation, emotional withdrawal, and blunt affect, and that decreased FFA and HGH responsiveness to insulin is a nonspecific correlate of the general depressive syndrome.     

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.