Christopher Kenney

CSF Multianalyte Profile Distinguishes Alzheimer and Parkinson Diseases

The therapeutic imperative for Alzheimer disease (AD) and Parkinson disease (PD) calls for discovery and validation of biomarkers. Increased cerebrospinal fluid (CSF) tau and decreased amyloid (A) beta42 have been validated as biomarkers of AD. In contrast, there is no validated CSF biomarker for PD. We validated our proteomics-discovered multianalyte profile (MAP) in CSF from 95 control subjects, 48 patients with probable AD, and 40 patients with probable PD. An optimal 8-member MAP agreed with expert diagnosis for 90 control subjects (95%), 36 patients with probable AD (75%), and 38 patients with probable PD (95%). This MAP consisted of the following (in decreasing order of contribution): tau, brain-derived neurotrophic factor, interleukin 8, Abeta42, beta2-microglobulin, vitamin D binding protein, apolipoprotein (apo) AII, and apoE. This first large-scale validation of a proteomic-discovered MAP suggests a panel of 8 CSF proteins that are highly effective at identifying PD and moderately effective at identifying AD.

GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities

Tourette syndrome (TS) is characterized by phonic and motor tics and psychiatric comorbidities including attention-deficit (± hyperactivity) disorder (AD/HD), obsessive-compulsive behavior (OCB), anxiety, depression, and others.1 The efficacy and safety of deep brain stimulation (DBS) in movement disorders are established, and their applicability to neuropsychiatric conditions is expanding. We describe the results of bilateral DBS of the globus pallidus interna (GPi) in a 16-year-old boy with severe, medication-refractory TS. This left-handed boy presented at age 15 years for evaluation of escalating TS. Tics began at age 3, OCB by age 5, and AD/HD, coprolalia, copropraxia, and loud screaming by age 7. Haloperidol, pimozide, fluphenazine, benzodiazepines, guanfacine, selective serotonin reuptake inhibitors, tetrabenazine, and botulinum toxin injections (vocal cords) failed to relieve symptoms, including touching and grabbing others, self-gagging until emesis, eye poking, facial self-excoriations, self-hitting, and screaming until hoarse. Anxiety, depression, hyperactivity, and impulsivity were notable, while inattention and opposition were less problematic. His marked academic and social impairment prompted consideration of DBS surgery. Neuropsychological evaluation assessed suitability …

Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders

We sought to review the long‐term tolerability of tetrabenazine (TBZ) and seek determinants of tolerability in the treatment of hyperkinetic movement disorders. A retrospective chart review was performed on patients treated with TBZ between 1997 and 2004. Efficacy of TBZ was assessed by a 1‐ to 5‐point response scale (1 = marked reduction in abnormal movements, 5 = worsening). All adverse events (AEs) were captured according to their relationship with study drug. A total of 448 patients (42% male) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19). The mean age at onset of the movement disorder was 43.0 ± 24.2 years, with TBZ starting at a mean age of 50.0 ± 22.3 years. Patients remained on treatment for a mean of 2.3 ± 3.4 years. An efficacy response rating of 1 or 2 was sustained in the majority of patients between the first and last visit. Common AEs included drowsiness (25.0%), Parkinsonism (15.4%), depression (7.6%), and akathisia (7.6%). Comparison of log‐likelihood ratios revealed that age was a reliable predictor of Parkinsonism (P < 0.0001). TBZ is a safe and effective drug for the long‐term treatment of hyperkinetic movement disorders.

Tetrabenazine in the treatment of hyperkinetic movement disorders

Tetrabenazine, a dopamine-depleting agent first synthesized half a century ago, was initially developed for the treatment of schizophrenia. Although psychotic disorders have since been treated more successfully with other neuroleptic medications, many studies have shown this drug to be effective in the treatment of hyperkinetic movement disorders (hyperkinesias). Hyperkinesias are neurologic disorders characterized by abnormal involuntary movements such as chorea associated with Huntington’s disease, tics in Tourette’s syndrome and stereotypies in tardive dyskinesia. Recently, clinical trials investigating tetrabenazine for the treatment of chorea associated with Huntington’s disease found the drug to be safe and efficacious, making approval by the US Food and Drug Administration for this indication a distinct possibility.

Botulinum toxin in the treatment of blepharospasm and hemifacial spasm

SummaryBlepharospasm and hemifacial spasm are the two most common craniofacial movement disorders. Blepharospasm is a syndrome characterized by excessive or continuous eye closure related to overactivity of the orbicularis oculi and adjacent muscles bilaterally. Hemifacial spasm is a peripherally-induced movement disorder typically caused by vascular compression of cranial nerve VII (CN VII) leading to involuntary unilateral contractions of muscles used in facial expression. Treatment options for both conditions include medications, botulinum toxin, and various surgical interventions. This article summarizes the existing medical literature which indicates that botulinum toxin is the treatment of choice for blepharospasm and hemifacial spasm.

AFQ056 in Parkinson Patients With Levodopa-Induced Dyskinesia: 13-Week, Randomized, Dose-Finding Study

AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinsons disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinsons Disease Dyskinesia Scale, the Patients/Clinicians Global Impression of Change, and the Unified Parkinsons Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinsons Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinsons Disease Dyskinesia Scale, the Unified Parkinsons Disease Rating Scale part IV item 33 or items 32 and 33, or the Patients/Clinicians Global Impression of Change. Unified Parkinsons Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials.

Autopsy-proven Huntington's disease with 29 trinucleotide repeats

Huntingtons 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.

Bilateral pedunculopontine nuclei strokes presenting as freezing of gait

The penduculopontine nucleus (PPN) has been suggested to play an important role in locomotion, based on animal studies, but its function in humans has not been well defined. Autopsy studies have suggested that PPN pathology correlates with gait dysfunction in Parkinsons disease and in progressive supranuclear palsy but direct clinical evidence is lacking. We report a patient with bilateral PPN infarcts whose dominant clinical feature was freezing of gait, thus providing evidence that PPN is involved in human locomotion and that damage to the PPN may lead to abnormal gait.

Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias

BACKGROUND Modulation of metabotropic glutamate receptors may be a novel therapeutic approach to manage L-Dopa-induced dyskinesias in patients with Parkinsons disease. This article reviews the rationale for use of metabotropic glutamate 5-receptor antagonists in experimental and clinical L-Dopa-induced dyskinesias. METHODS Systematic literature searches were performed (between May 2012-March 2014) for relevant English language articles using PubMed. Additional articles of interest were identified from reference lists of included publications. Relevant clinical abstracts from Movement Disorder Society meetings were included. RESULTS 16 preclinical studies of metabotropic glutamate 5-receptor antagonists in animal models of L-Dopa-induced dyskinesias and 7 clinical studies in patients with Parkinsons disease and L-Dopa-induced dyskinesias were included. Anti-dyskinetic effects of metabotropic glutamate 5-receptor blockade (MPEP, MTEP, fenobam, or MRZ-8676) were reported in dyskinetic 6-hydroxydopamine-lesioned rats. Studies in MPTP-lesioned non-human primates reported anti-dyskinetic effects of MPEP, MTEP, fenobam and mavoglurant (AFQ056). Three randomized, double-blind clinical trials reported anti-dyskinetic efficacy of mavoglurant, without effects on anti-parkinsonian therapy, with dizziness the most common adverse event. However, two further studies failed to demonstrate significant anti-dyskinetic efficacy. A randomized, double-blind, placebo-controlled safety study of dipraglurant (ADX48621) demonstrated tolerability and positive exploratory secondary outcomes of reduced dyskinesia. CONCLUSIONS Animal model studies provide evidence for anti-dyskinetic efficacy of metabotropic glutamate 5-receptor antagonists. Initial proof-of-concept clinical trials of mavoglurant and dipraglurant showed positive results; anti-dyskinetic efficacy was not supported by two recent mavoglurant trials. Further evaluations of optimal dosage and long-term efficacy and safety of metabotropic glutamate 5-receptor antagonists for management of L-Dopa-induced dyskinesias in Parkinsons disease are required.

Metoclopramide, an Increasingly Recognized Cause of Tardive Dyskinesia

T dyskinesia (TD), a hyperkinetic movement disorder causally related to dopamine receptorblocking drug (DRBD) exposure, is a well-recognized iatrogenic disorder in adults and less commonly seen in children and infants. Although the literature on TD mainly focuses on patients treated with DRBDs used as antipsychotics, DRBDs are also used to treat a wide array of medical, chiefly gastrointestinal, conditions. Although most of the drugs that cause TD are DRBDs that antagonize dopamine D2 receptors, other classes of drugs have the potential to cause TD, including antidepressants and calcium channel blockers. The reported lifetime prevalence of TD in patients treated with traditional DRBDs has varied greatly, with an average of about 25% of exposed adults. Risk factors associated with the development of TD include advanced age, female gender, and, more important, total cumulative drug exposure. We sought to determine which drugs most commonly cause TD in patients referred to our clinic.