R.A.C. Roos

Sleep, excessive daytime sleepiness and fatigue in Parkinson's disease

SummaryThe objective of this questionnaire-based survey was to evaluate the prevalence and causes of sleep disturbances in 90 nondepressive patients with Parkinsons disease (PD) and 71 age-matched healthy subjects. We also assessed the prevalence and characteristics of excessive daytime sleepiness (both groups) and excessive fatigue (PD patients).A high prevalence of sleep disturbances in PD patients was found; this is to a large extent probably the result of aging. As compared with controls, patients had a more severely disturbed sleep maintenance because of nycturia, pain, stiffness, and problems with turning in bed. The prevalence of excessive dreaming is similar in both groups, but altered dream experiences almost exclusively occurred in PD.Patients rated themselves more often to be morning-types than controls. This finding may account for the reported adaptation effects in experimental settings and the reduced REM latency in PD patients.The prevalence of daytime sleepiness was similar in both groups. Excessive daytime sleepiness showed a clear diurnal pattern with a peak in the early afternoon. As for excessive fatigue, the majority of the patients did not report a preferential time for this symptom. Our findings further argue against an association of fatigue with any circadian factor, and instead suggest a relationship with the motor deficits of PD.

Transient loss of consciousness: The value of the history for distinguishing seizure from syncope

SummaryWe studied 94 consecutive patients (age 15 or over) to investigate which aspects of the history and clinical findings help to distinguish seizures from synope and related conditions. Clonic movements or automatism observed by an eyewitness classified an event as a seizure. The seizure group consisted of 41 patients and the syncope group of 53 patients. The likelihood ratio was used to calculate the predictive power of single findings and logistic regression to analyse combinations of findings. The best discriminatory finding was orientation immediately after the event according to the eyewitness and the age of the patient in the absence of an eyewitness report (P<0.001). We found a seizure five times more likely than syncope if the patient was disoriented after the event and three times more likely if the patient was less than 45 years of age. Nausea or sweating before the event were useful to exclude a seizure. Incontinence and trauma were not discriminative findings.

Autonomic nervous system dysfunction in Parkinson's disease: relationships with age, medication, duration, and severity.

Heart rate variability at rest, during deep breathing, or standing up and with the Valsalva manoeuvre did not differ significantly between 67 patients with idiopathic Parkinsons disease (PD) and 31 healthy age matched controls. Blood pressure (BP) responses to standing up and sustained handgrip revealed diminished autonomic function in the PD group. In a preliminary analysis of the PD group older age, anti-Parkinson medication and higher Hoehn and Yahr (HY) stages were each associated with poor autonomic responsiveness. Disease duration was only related to the systolic BP fall on standing up. Multiple stepwise regression analysis showed that older age explained most of the variance of heart rate variability (up to 36%), and the only significant PD related factor was the use of medication, which explained less than 7%. The HY stage accounted for 12.7% of the variance in the standing up BP test, and the use of medication explained 10.6% of the variance of the systolic BP change in the sustained hand grip test. The unmedicated PD subgroup (n = 33), who had mild disease of short duration, showed no evidence of autonomic dysfunction. Cardiovascular autonomic dysfunction in PD is mild, mainly affects blood pressure responses, and occurs only in advanced cases.

Tapping linked to function and structure in premanifest and symptomatic Huntington disease

Objective: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntingtons Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. Methods: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. Results: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. Conclusion: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

Clozapine versus placebo in Huntington’s disease: a double blind randomised comparative study

OBJECTIVES To establish the effect of the atypical neuroleptic clozapine on chorea, voluntary motor performance, and functional disability in patients with Huntington’s disease. METHODS Thirty three patients with Huntington’s disease participated in a double blind randomised trial. A maximum of 150 mg/day clozapine or placebo equivalent was given for a period of 31 days. Assessments were performed in the week before and at the last day of the trial. Chorea was scored using the abnormal involuntary movement scale (AIMS), the chorea score of the unified Huntington’s disease rating scale (UHDRS), and judgement of video recordings. Voluntary motor performance was assessed using the UHDRS motor scale. Patients and their partners completed a questionnaire regarding functional disability. Twelve patients already used other neuroleptic medication, which was kept unchanged during the trial period. Results of neuroleptic naive and neuroleptic treated patients were analysed separately. RESULTS Clozapine tended to reduce chorea in neuroleptic naive patients only (AIMS); improvement seemed more pronounced in patients receiving higher doses of clozapine. Other measures of chorea (UHDRS chorea score, video ratings) showed no improvement. Clozapine had no beneficial effect on chorea in patients already receiving neuroleptic medication. Voluntary motor performance did not improve with clozapine. Neuroleptic naive patients reported aggravation of functional disability, possibly reflecting the frequent occurrence of side effects. Adverse reactions forced trial termination in six patients and dose reduction in another eight, and consisted mainly of drowsiness, fatigue, anticholinergic symptoms, and walking difficulties. CONCLUSIONS Clozapine has little beneficial effect in patients with Huntington’s disease, although individual patients may tolerate doses high enough to reduce chorea. Because adverse reactions are often encountered, clozapine should be used with restraint in this patient group.

Psychological effects of presymptomatic DNA testing for Huntington's disease in the Dutch program.

&NA; This study assessed the 6‐month follow‐up effects of presymptomatic DNA testing for Huntingtons disease (HD) in 73 individuals at 50% prior risk who were identified either as carriers of the HD gene (N = 29) or as noncarriers (N = 44). The subjects knowledge of being a gene carrier was expected to induce intrusive emotions, denial‐avoidance behavior, and pessimistic expectancies of the future and adjustment problems. The Impact of Event Scale, the Beck Hopelessness Scale, and the General Health Questionnaire were used as standard measures of psychological distress. At the disclosure of the test results, carriers had a strong increase in pessimistic expectations but showed a decline to baseline levels 6 months later. Noncarriers reported a steep decline in hopelessness compared with their pretest conditions but had increased scores after 6 months. Six months after the disclosure of the test results, both gene carriers and noncarriers reported a significant decrease in unwanted intrusive thoughts about HD. Carriers showed a slight increase in denial‐avoidance behavior, whereas noncarriers showed a clear decrease. Our observations might indicate that tested individuals found relief from the prior psychological distress and that they were able to acknowledge the impact of the test result on their future. An unresolved question is how the foreknowledge will affect carriers as they approach the impending onset of the disease. Longer observation periods (> 6 months after disclosure) are required to study changes of the impact of DNA test results over time.

Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

Objective: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. Methods: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3) basal ganglia volume on magnetic resonance images in 16 premanifest HD mutation carriers. Results: Normal and mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral, symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects, basal ganglia volumes (p < 0.05). In subjects with mutant CAG expansions in the low range, increasing size of the normal repeat correlated with more severe symptoms and pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat correlated with less severe symptoms and pathology. Conclusions: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials.

Electrophysiological correlates of postural instability in Parkinson's disease

Postural reflexes in response to sudden toe-up tilts of a supporting forceplate platform were studied in free-standing patients with stage III (N = 5) and stage IV (N = 5) Parkinsons disease and compared to 5 age- and sex-matched normals. Latencies of the short (SL), medium (ML) and long latency (LL) responses were normal in the patients. The normalized mean amplitudes of the ML responses were significantly increased only in the stage IV Parkinson patients (P less than 0.0005). The distal-proximal activation sequence of LL responses observed in all 5 controls was reversed in 1 of the stage III and 4 of the stage IV Parkinson patients. Both the enlargement of the ML response (P less than 0.01) and the inverted activation sequence of LL responses (P less than 0.01) were significantly correlated with severity of the disease. The data establish an association between abnormal modulation of postural reflexes in the lower extremity and clinically rated balance impairment in Parkinsons disease.

Syncope or seizure? The diagnostic value of the EEG and hyperventilation test in transient loss of consciousness.

In a prospective study of consecutive patients (age 15 or over) with transient loss of consciousness 45 patients had a history of seizure and 74 patients had a history of syncope. All patients had an EEG, ECG, laboratory tests and a hyperventilation test and were followed for an average of 14.5 months. Epileptiform activity in the interictal EEG had a sensitivity of 0.40 and a specificity of 0.95 for the diagnosis of a seizure. Epileptiform activity nearly doubled the probability of a seizure in doubtful cases. If no epileptiform activity was found, this probability remained substantially the same. The hyperventilation test had a sensitivity of 0.57 and a specificity of 0.84 for the diagnosis of syncope. A positive test increased the probability of syncope half as much in doubtful cases. A negative test did not exclude syncope. Laboratory tests were not helpful except for an ECG which was helpful in elderly patients.

Response fluctuations in Parkinson's disease

We studied the influence of several factors on the occurrence of response fluctuations in 91 Parkinsons disease patients. These included the age at onset, the presenting symptom, the duration of illness, and the stage of the disease at the time of initiation of levodopa treatment as time-independent covariates, and the mean and last dosage of levodopa as time-dependent covariates. Taken separately, none of the factors was related to the occurrence of response fluctuations. We found no evidence to delay levodopa treatment to a later stage of the disease. In the analysis of the combined influence of the age at onset and the interval before levodopa treatment, we noted a tendency for response fluctuations to occur less frequently in those patients with age at onset of 60 years and over who had started levodopa treatment more than 2 years after the 1st symptom. Our analysis of the combination of time-dependent factors suggests that response fluctuations are a likely event in those patients in whom the course of the disease recently necessitated an increase in the dosage of levodopa.