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.     

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.     

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.     

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.     

Regional Specificity of Brain Atrophy in Huntington''s Disease

The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntington's disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntington's disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntington's disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntington's disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntington's disease.     

Cerebrospinal fluid levels of diazepam-binding inhibitor in neurodegenerative disorders with dementia

We investigated CSF levels of diazepam-binding inhibitor (DBI), a recently discovered neuropeptide that allosterically modulates GABAergic transmission, in various neurodegenerative disorders with dementia (28 patients with Parkinson's disease, 10 with Alzheimer's disease, 7 with Huntington's chorea). We applied a battery of neuropsychological tests to determine the degree of dementia and to exclude the presence of mood alterations. CSF DBI levels were elevated in parkinsonian subjects with dementia and in patients with Alzheimer's disease, but decreased in Huntington's chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic system.     

Role of autonomic nerve functions in patients with familial amyloidotic polyneuropathy as analyzed by laser Doppler flowmetry, capsule hydrograph, and cardiographic R-R interval.

Laser Doppler flowmetry (LDF) was conducted on familial amyloidotic polyneuropathy (FAP) patients and asymptomatic carriers of FAP. Vasoconstrictive responses in the 11 FAP patients tested, induced by deep inspiration, were markedly depressed compared with those of the healthy controls. The responses decreased with the progression of FAP, with no responses being elicited from the 7 patients in stages 2 (moderate) to 4 (terminal). Interestingly, vasoconstrictive responses following deep inspiration also were depressed in 3 of 4 asymptomatic carriers of FAP who showed no clinical sign of FAP, and who had normal sensory nerve conduction velocity. Patients who had such diseases as Shy-Drager's disease, spinocelebellar degeneration, and pandysautonomia showed no decrease in blood flow for various stimulations. In contrast, patients with primary amyloidosis, who had no autonomic dysfunction, showed a normal pattern. Detection of the autonomic functions in FAP patients and asymptomatic carriers by capsule polyhydrography and computer analysis of the cardiographic R-R interval revealed that the asymptomatic carriers of FAP, as well as the FAP patients, had disordered peripheral autonomic functions. Our results suggest that the autonomic nervous system is first affected during the very early stage of FAP.     

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.     

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.     

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.     

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.     

Features of the blink reflex in individuals at risk for Huntington's disease.

The aim of the study was to correlate the features of the blink reflex (BR) with the genetic abnormalities and the clinical findings in patients with Huntington's disease (HD) and asymptomatic gene carriers. Twenty patients with HD and 20 relatives were studied. Mutation analysis was performed for the CAG expansion within the HD gene using HD 333-HD 447 as oligonucleotide primers. The BR was elicited transcutaneously by electrical stimulation of the right supraorbital nerve. The recovery curve of the R2 and R3 responses after a conditioning stimulus was evaluated. R2 latency and duration and R3 duration were significantly increased in HD patients and in presymptomatic carriers in comparison with controls; reduced R2 recovery was also clear in both HD and gene-carrier relatives. In HD patients, the R2 latency increase correlated significantly with the severity of facial chorea. The R2 abnormalities are probably caused by impaired suprasegmental control by the basal ganglia over brainstem interneurons, which may precede the onset of involuntary movements, probably conditioning the severity of facial chorea during development of the disease.     

Cerebrospinal fluid choline in extrapyramidal disorders

Cerebrospinal fluid from patients with Parkinson's disease and Huntington's chorea has been investigated with regard to the concentration of choline. In Parkinson's disease the choline concentration of lumbar spinal fluid was not different from that of a control group, nor was it related to medication, duration of illness, or severity of symptoms. A comparison between choline in ventricular cerebrospinal fluid from patients with Parkinson's disease and with intention tremor showed no significant differences. Patients with Huntington's chorea had a lower concentration of choline in lumbar spinal fluid as compared with a control group. The results are discussed in relation to the possible sources of cerebrospinal fluid choline.     

Chorea. Causes, diagnosis, and therapy

The differential diagnosis of chorea includes a growing number of rare diseases. This article gives hints on clinical differences and possible laboratory investigations which may help to identify the underlying disease. The majority of hereditary chorea cases are caused by Huntington's disease. Different courses of disease can be distinguished depending on age at disease onset. The diagnosis can be confirmed genetically. Predictive testing is also possible but should be applied with caution only following internationally accepted guidelines. Our knowledge about treatment of chorea is limited, and studies have focused on the use of neuroleptics only. Their value is often outweighed by serious side effects. All efforts to find disease-modifying therapies for Huntington's disease had negative outcomes so far. To face these therapeutic limitations, the European Huntington's Disease Network was formed as a platform supporting the development and undertaking of clinical studies in Huntington's disease to improve care for these patients.     

Enhanced associated movements in the contralateral limbs elicited by brisk voluntary contraction in choreic disorders.

OBJECTIVES: To study the deficit of inhibition of excessive motor drive generated in the central nervous system in chorea. METHODS: Identical associated movements in the contralateral limb elicited by rapid hand squeezing were measured in 6 patients with Huntington's disease, 7 patients with peak-dose dyskinesia, 10 patients with Parkinson's disease, 8 patients with spinocerebellar degeneration and in 8 normal subjects. The intensity of associated movements was assessed by the EMG amplitude ratio of associated contractions to active contractions. RESULTS: The associated movement ratios were larger in Huntington's disease and peak-dose dyskinesia as compared to other groups. The ratios in akinetic "off" phase were smaller than those in dyskinetic "on" phase in all peak-dose dyskinesia patients. CONCLUSIONS: Enhanced associated movements support a possible common mechanism that chorea may result from failure in inhibition of phasic neural activity pathologically generated in the brain.     

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.     

Beta-adrenergic receptor subtypes in the basal ganglia of patients with Huntington's chorea and Parkinson's disease.

The density of [125I]iodo-cyanopindolol binding to beta-1 and beta-2 adrenergic receptors was studied in post mortem basal ganglia samples of Huntington's chorea and Parkinson's disease patients using autoradiography. Whereas no significant changes were observed in sections from Parkinson's and Huntington's chorea grade 2 patients, a nearly complete loss of beta-1 binding sites was observed in the basal ganglia of Huntington patients at later stages of the disease. The concentration of beta-2 receptors was increased by a factor 2 in the posterior putamen of all choreic cases. These results are consistent with the view that beta-1 receptors are predominantly located on a subpopulation of neurons which degenerate at late stages of Huntington's chorea, while beta-2 receptors are present mainly on glial elements.     

Long-term treatment of sleep breathing disorder in a patient with Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. An association with sleep breathing disorder has not previously been established in the literature. We report the case of a 45-year-old woman with HD, presenting with snoring and observed apnea. Polysomnography showed obstructive sleep apnea with an apnea-hypopnea index (AHI) of 6.6 per hour including events up to 57 s long during rapid eye movement (REM) sleep. A trial of continuous positive airway pressure (CPAP) resulted in significant improvement in sleep structure, nocturnal respiration, daytime alertness, and subjective memory. Snoring, apneas, and respiratory arousals were abolished on CPAP. HD patients may suffer from sleep breathing disorder, and in spite of potential chorea, CPAP is feasible and may significantly improve their quality of life.     

Orthostatic intolerance in the chronic fatigue syndrome

This study aims to investigate the prevalence and pathophysiology of orthostatic intolerance (OI) and its potential contribution to symptoms of a group of unselected patients with chronic fatigue syndrome (CFS). Seventy five patients (65 women, 10 men) with CFS were evaluated. During an initial visit, a clinical suspicion as to the likelihood of observing laboratory evidence of OI was assigned. Laboratory investigation consisted of beat-to-beat recordings of heart rate, blood pressure (Finapres), and stroke volume (impedance cardiograph) while supine and during 80 degrees head-up tilt (HUT), during rhythmic deep breathing (6 breaths/min) and during the Valsalva maneuver. The responses of 48 age-matched healthy controls who had no history of OI were used to define the range of normal responses to these three maneuvers. Forty percent of patients with CFS had OI during head-up tilt. Sixteen exhibited neurally-mediated syncope alone, seven tachycardia (> 35 bpm averaged over the whole of the head-up tilt) and six a mixture of tachycardia and syncope. Eight of 48 controls exhibited neurally-mediated syncope. The responses to the Valsalva maneuver and to deep breathing were similar in controls and patients. On average, the duration of disease and patient age were significantly less and the onset of symptoms was more often subacute in patients with OI than in those without OI. We conclude that there exists a clinically identifiable subgroup of patients with CFS and OI that differs from control subjects and from those with CFS without OI for whom treatment specifically aimed at improving orthostatic tolerance may be indicated.     

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.