Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease.

We evaluated the tolerability and preliminary efficacy of levetiracetam (LEV; Keppra) in reducing levodopa-induced dyskinesias in Parkinson's disease (PD) in an open-label pilot study. Nine PD patients who were experiencing peak-dose dyskinesias for at least 25% of the awake day and were at least moderately disabling were treated with LEV in doses up to 3,000 mg for up to 60 days. The primary outcome measure was the percent of the awake day that patients spent on without dyskinesia or with nontroublesome dyskinesia (good on time). The mean dose of LEV at endpoint was 625+/-277 mg/day. LEV significantly improved percent of the awake day on without dyskinesia or with nontroublesome dyskinesia at endpoint compared to baseline (43% +/- 12% vs. 61% +/- 17%; P=0.02). Percent on time with troublesome dyskinesia decreased from 23% +/- 10% at baseline to 11% +/- 6% at endpoint, although not significantly. There was no significant increase in off time from baseline to endpoint. There was a 56% dropout rate, mostly due to somnolence. In PD patients who experienced peak-dose dyskinesia for at least 25% of the awake day, LEV significantly improved on time without dyskinesia or with nontroublesome dyskinesia.     

Short-term effects of tetrabenazine on chorea associated with Huntington's disease.

We sought to assess the short-term clinical effects of tetrabenazine (TBZ) on choreic movements in Huntington's disease patients. A total of 10 patients on stable doses of TBZ were enrolled in this observational study. Patients took their evening dose of TBZ and presented the next day to the Baylor College of Medicine Movement Disorders Clinic without taking the usual morning dose. They were assessed using the Unified Huntington's Disease Rating Scale (UHDRS) motor assessment and Beck Depression Inventory. The usual morning dose of TBZ was then administered and patients were followed with serial UHDRS motor examinations approximately every 2 hours until choreic movements subsided and then returned. TBZ decreased the UHDRS chorea score on average 42.4% +/- 17.8%. The duration of effect varied from a minimum of 3.2 hours to a maximum of 8.1 hours (mean = 5.4 +/- 1.3). No patient experienced an adverse event related to TBZ or its withdrawal. During short-term follow-up after a single dose, TBZ improves chorea for approximately 5 hours.     

A pilot study using nabilone for symptomatic treatment in Huntington's disease

Pilot study of nabilone in Huntington's disease (HD). Double‐blind, placebo‐controlled, cross‐over study of nabilone versus placebo. Primary outcome, Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Secondary measures: UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI). 44 randomized patients received either nabilone (1 or 2 mg) followed by placebo (n = 22), or placebo followed by nabilone (n = 22). Recruiting was straightforward. Nabilone safe and well tolerated, no psychotic episodes. Assessment of either dose of nabilone versus placebo showed a treatment difference of 0.86 (95% CI: ?1.8 to 3.52) for total motor score; 1.68 (95% CI: 0.44 to 2.92) for chorea; 3.57 (95% CI: ?3.41 to 10.55) for UHDRS cognition; 4.01 (95% CI: ?0.11 to 8.13) for UHDRS behavior, and 6.43 (95% CI: 0.2 to 12.66) for the NPI. Larger longer RCT of nabilone in HD is feasible and warranted. © 2009 Movement Disorder Society     

Nuclear membrane indentations in Huntington's chorea

Electron-microscopical examination of the nucleus accumbens, caudate nucleus and frontal cortex was performed in 21 patients with Huntington's disease (HD) and 21 age-matched controls. In HD, nuclear membrane indentations (NMI) were found in 25%, 29% and 20%, respectively, of the neurons of these areas. In the control group these figures were 4%, 4% and 38%, respectively. Possible pathogenetic mechanisms of the NMI are discussed.     

Pharmacological treatment of chorea in Huntington's disease–good clinical practice versus evidence‐based guideline

Recently, the American Academy of Neurology published an evidence‐based guideline for the pharmacological treatment of chorea in Huntington's disease. Although the progress in medical care because of the implementation of criteria of evidence‐based medicine is undisputed, the guideline classifies the level of evidence for drugs to reduce chorea based on anchors in the Unified Huntington's Disease Rating Scale‐Total Motor Score chorea sum score, which were chosen arbitrarily and do not reflect validated or generally accepted levels of clinical relevance. Thus, the guideline faces several serious limitations and delivers clinical recommendations that do not represent current clinical practice; these are reviewed in detail, and arguments are presented why these recommendations should not be followed. To remedy the lack of evidence‐based recommendations and provide guidance to a pragmatic symptomatic therapy of chorea in HD, a flow‐chart pathway that follows currently established clinical standards based on expert opinion is presented. © 2013 Movement Disorder Society     

Chorea in a patient with cerebral palsy: treatment with levetiracetam.

We report on the case of an adult cerebral palsy patient who developed severe chorea coincident with a febrile illness from a nonstreptococcal infection. The chorea improved markedly with the use of levetiracetam (LEV, Keppra).     

Minocycline in Huntington's disease: a pilot study.

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase (iNOS), and has been shown to delay disease progression in the mouse model R6/2 of Huntington's disease (HD). This safety and tolerability study included 30 patients with HD who were given minocycline over a 6-month period and underwent assessments every 2 months with laboratory studies, the Abnormal Involuntary Movements Scale, the Unified Huntington's Disease Rating Scale, and the Mini-Mental State Examination. Minocycline was well tolerated during this study period and no serious adverse events were noted.     

Substantial improvement in a Meige's syndrome patient with levetiracetam treatment.

We report on a woman with idiopathic Meige's syndrome whose dystonia improved with the use of levetiracetam (LEV, Keppra, UCB Pharma, Smyrna, GA). This report and data from an animal model of paroxysmal dystonia suggest that LEV might be helpful in the treatment of dystonia.     

Autopsy-proven Huntington's disease with 29 trinucleotide repeats.

Huntington's disease (HD) is a neurodegenerative disorder associated with expansion of CAG trinucleotide repeats in the huntingtin gene. A minimum of 36 CAG repeats is usually reported in patients with clinical features of HD; 30 to 35 repeats represent an intermediate range. Here we report a 65-year-old male with autopsy-proven HD and 29 CAG repeats.     

Tongue force analysis assesses motor phenotype in premanifest and symptomatic Huntington's disease

Motor symptoms in Huntington's Disease (HD) are commonly assessed by the Unified Huntington's Disease Rating Scale‐Total Motor Score (UHDRS‐TMS). However, the UHDRS‐TMS is limited by interrater variability, its categorical nature, and insensitivity in premanifest subjects. More objective and quantitative measures of motor phenotype may complement the use of the UHDRS‐TMS as outcome measure and increase the power and sensitivity of clinical trials. Deficits in tongue protrusion are well acknowledged in HD and constitute a subitem of the UHDRS‐TMS. We, therefore, investigated whether objective and quantitative assessment of tongue protrusion forces (TPF) provides measures that (1) correlate to the severity of motor phenotype detected in the UHDRS‐TMS in symptomatic HD, (2) detect a motor phenotype in premanifest HD gene‐carriers, and (3) exhibit a correlation to the genotype as assessed by a disease burden score (based on CAG‐repeat length and age). Using a precalibrated force transducer, the ability of premanifest gene carriers (n = 15) and subjects with symptomatic HD (n = 20) to generate and maintain isometric TPF at three target force levels (0.25, 0.5, and 1.0 N) was assessed and compared with age‐matched controls (n = 20) in a cross‐sectional study. Measures of variability of TPF and tongue contact time distinguished controls, premanifest, and symptomatic HD groups and correlated to the UHDRS‐TMS and disease burden score, suggesting a strong genotype‐phenotype correlation. Group distinction was most reliable at the lowest target force level. We conclude that assessment of TPF may be a useful objective and quantitative marker of motor dysfunction in premanifest and symptomatic HD. © 2010 Movement Disorder Society     

Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington's disease.

Cystamine, an inhibitor of transglutaminases, slows progression of Huntington's disease in the murine model by approximately 20%. Cysteamine, the dimer of cystamine, is an orphan drug approved for the treatment of nephropathic cystinosis and has a similar benefit in the murine model but with a narrower therapeutic window. In a single-center open-label study, we determined the maximum tolerable dose (MTD) and side effects of cysteamine in people with Huntington's disease. Cysteamine was started at a dose of 10 mg/kg per day, divided into four doses, and increased by 10 mg/kg per day weekly until the development of intolerable side effects or a maximum dose of 70 mg/kg per day. Of the 9 subjects, 1 had an MTD of 10 mg/kg per day, 1 had an MTD of 20 mg/kg per day, the maximum dose was 30 mg/kg per day for 2, 40 mg/kg per day for 2, and 50 mg/kg per day for 3. Dose-limiting side effects were motoric impairment in 5 and nausea in 4. The dose found tolerable by 8 of the subjects was 20 mg/kg per day. All had a noticeable hydrogen sulfide odor at doses of 40 mg/kg per day or higher. We conclude that, at a dose of 20 mg/kg per day, cysteamine was tolerable in people with Huntington's disease. Nausea and motoric impairment were the dose-limiting side effects.     

Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized cross-over trial.

We evaluated tolerability and the efficacy of continuous infusion of apomorphine hydrochloride on involuntary movements and mood disorder in Huntington's disease (HD) patients in a pilot, single center, double-blind, randomized, crossover, and controlled versus placebo study. Nine patients with a molecular diagnosis of HD were screened for response to acute apomorphine injection. Four of them, not ameliorating at the acute test, were discontinued. Five patients, responding to acute apomorphine, received continuous infusion of either apomorphine or placebo for 5 days. After 2 days of washout, the alternative treatment was administered. Primary endpoint measures were scores of the Unified Huntington's Disease Rating Scale (UHDRS "motor section") and of the Abnormal Involuntary Movement Scale (AIMS). Secondary endpoint measures were the Hamilton Depression Rating Scale (HAD) score and safety parameters. Both UHDRS and AIMS scores significantly decreased in all patients after apomorphine. The beneficial effect of apomorphine was recorded throughout the 5 treatment days. The HAD score did not change after infusion of either treatment. No serious adverse events were reported by either group during the study. Our results suggest that continuous infusion of apomorphine might be considered for the treatment of involuntary movements in some HD patients.     

Phenotypic features of Huntington's disease-like 2.

Huntington's disease-like 2 is an autosomal dominantly inherited disorder due to an expansion of trinucleotide repeats. It resembles classic Huntington's disease in clinical phenotype, inheritance pattern, and neuropathological features. We highlight the clinical features of this disorder, including chorea, dystonia, parkinsonism, and cognitive deficits.     

Reduced Purkinje cell density in Huntington's disease

We studied, in a "blind" and quantitative fashion, the density of cerebellar Purkinje cells in 17 adult cases of Huntington's disease (HD), 17 patients with other movement disorders, 17 with schizophrenia, and 23 normal controls. There was a highly significant reduction in Purkinje cell density in HD compared with any of the other three groups. A much smaller difference in neuronal density between patients with other movement disorders and normal controls was barely significant. Eight of the 17 HD patients and only 1 of the other 57 subjects had Purkinje cell density less than 50% of the mean for the normal controls. The low density of Purkinje cells in HD could not be attributed to aging, seizures, or cause of death, nor was it merely a part of a generalized brain atrophy. The loss of large Purkinje cells suggests that the neuronal loss in HD may not be restricted to small and medium-size neurons.     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society