Lawrence Z. Stern

Controlled clinical trial of cannabidiol in Huntington's disease

Based on encouraging preliminary findings, cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntingtons Disease (HD). The effects of oral CBD (10 mg/kg/day for 6 weeks) and placebo (sesame oil for 6 weeks) were ascertained weekly under a double-blind, randomized cross-over design. A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables, and on a Cannabis side effect inventory, clinical lab tests and other safety outcome variables, indicated no significant (p greater than 0.05) or clinically important differences. Correspondingly, plasma levels of CBD were assayed by GC/MS, and the weekly levels (mean range of 5.9 to 11.2 ng/ml) did not differ significantly over the 6 weeks of CBD administration. In summary, CBD, at an average daily dose of about 700 mg/day for 6 weeks, was neither symptomatically effective nor toxic, relative to placebo, in neuroleptic-free patients with HD.

Neurobiology and pharmacology of Huntington's disease

Abstract Huntingtons disease (HD) is an autosomal dominant, symptomatically complex neurological disorder which, although normally manifested in the adult years, has been reported at all ages (1). Because of the dominant nature of the disorder, offsprings of an effected individual have a 50% probability of developing the disease at some time in their life. At present it is neither possible to accurately predict which at-risk individuals possess the gene for HD nor is it possible to prevent the onset of the disease or arrest its progress. In the past few years research on HD has yielded significant information about the neuroanatomical and neurochemical deficits present in the disorder. As a result of these studies, it is probable that in the near future more specific and effective pharmacological agents will be developed to help ameliorate the symptoms of this disease. In addition, these investigations have also yielded new insights into the interneuronal relationships which exist in the normal human brain and thus the findings are of fundamental importance in neurobiology. This review is intended to briefly summarize the clinical, neuropathological, neurochemical and pharmacological features of HD with special emphasis on more recent findings. Interested readers are urged to consult other sources for more comprehensive discussions of these topics. (1–3,8).

Alterations in dopaminergic receptors in Huntington's disease.

To detect variations in dopaminergic receptors and cholinergic activity in regions of postmortem Huntingtons diseased brains, 3H-spiroperidol binding assays and choline acetyltransferase (ChAc) activities were carried out. A significant reduction in 3H-spiroperidol binding in the caudate nucleus, putamen and frontal cortex of choreic brains was detected which appeared to be due to a decrease in the total number of binding sites rather than to a decrease in affinity of 3H-spiroperidol for the dopaminergic receptor. In choreic brains, there were also significant reductions in ChAc activity in the caudate nucleus and putamen. The decreases of both 3H-spiroperidol binding and ChAc activity in the neostriatum suggest that the dopaminergic receptors are localized postsynaptically on cholinergic interneurons. Dopaminergic receptor alterations in the basal ganglia may be one of the causes of the abnormal motor movements found in HD while alterations of these receptors in the frontal cortex may be associated with the neuronal degeneration found in that area of choreic brains.

Localization of the gene for X‐linked spinal muscular atrophy

We used probes for DNA polymorphisms on the X chromosome to study genetic linkage in seven families with X-linked adult-onset spinal muscular atrophy. We found significant linkage to the marker DXYS1 on the proximal X chromosome long arm and loose linkage or nonlinkage to markers elsewhere. Our analysis localizes the gene defect for this form of anterior horn cell disease.

Investigation of Sounds Produced by Healthy and Diseased Human Muscular Contraction

Muscle sounds were recorded from the medial biceps of 37 subjects as they pressed against a stationary object. The recordings were analyzed with a digital computer for frequency content. 20 subjects had some form of neuromuscular disorder, while 17 had no known muscle impairment.

Chronic myopathy induced by repeated bupivacaine injections

The effect of recurrent cycles of muscle fiber degeneration-regeneration was studied by repeated bupivacaine injections into the rat anterior tibial muscle. Injections of 0.6 ml of 0.75% bupivacaine were performed weekly for 6 months. The rats were allowed to recover for another 2 months and then killed. Histological and histochemical stains showed striking changes, including marked variability in fiber size, numerous internal nuclei, extensive fiber splitting and many whorled fibers. Combined staining for end-plate cholinesterase and terminal axons showed a markedly enlarged zone of terminal innervation. These findings suggest that the observed morphological changes usually attributed to a primary myopathic process may instead be the manifestations of impaired and incomplete regeneration occurring after cycles of degeneration-regeneration.

CMT4A: identification of a Hispanic GDAP1 founder mutation.

Mutations of the ganglioside‐induced differentiation‐associated protein 1 gene (GDAP1) cause autosomal recessive Charcot–Marie–Tooth disease type 4A. We report four additional families with recessive mutations (487C→T, Q163X; 359G→A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina. Ann Neurol 2003;53:400–405

Huntington's disease: regional alteration in muscarinic cholinergic receptor binding in human brain.

Abstract Huntingtons Disease, an autosomal dominant neurological disorder, is characterized by diffuse neuronal degeneration particularly in the basal ganglia and cerebral cortex. The purpose of this study was to examine various discrete regions of choreic and control brains for alterations in muscarinic cholinergic receptor binding and choline acetyltransferase (ChAc) activity. Nine postmortem brains, three from patients with Huntingtons Disease and six controls, were dissected into 17 discrete regions. Each regional homogenate was assayed for muscarinic receptor concentration by measuring specific membrane binding of [3H]-QNB, a potent muscarinic antagonist which selectively labels brain muscarinic receptors. Aliquots from each brain region were also assayed for ChAc activity. Of significance was the marked reduction in specific [3H]-QNB receptor binding in the caudate nucleus, putamen and globus pallidus of choreic brain while no significant alterations were detected in other brain regions. Significant decreases in ChAc activity were found in the caudate nucleus, putamen, and globus pallidus with no alterations in ChAc activity in the rest of the brain regions examined. The tissues were chosen such that protein levels were similar in both choreic and normal brain samples. The apparent reduction in the number of muscarinic cholinergic receptors in the choreic brains suggests that treatment with cholinomimetic drugs might be beneficial in Huntingtons Disease.

L-dopa in uremic patients with the restless legs syndrome

Restless legs syndrome (RLS) is a poorly understood, often distressing condition that is particularly prevalent among patients with chronic renal failure. A wide variety of medications have been used to treat RLS with variable results. In order to evaluate the efficacy of carbidopa/levodopa therapy, eight consecutive uremic patients with RLS on maintenance hemodialysis were treated with doses ranging from 25/100 to 25/250 twice daily. Six of eight patients obtained satisfactory relief which has continued for 3 months follow-up. Carbidopa-levodopa appears to be an effective opinion in management of RLS in patients with chronic rental failure.

Serial two-dimensional echocardiography in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) are known to have progressive epicardial fibrosis of the free wall of the left ventricle, but standard noninvasive M-mode echocardiographic tests of left ventricular function are relatively insensitive detectors of this cardiomyopathy. We therefore used two-dimensional echocardiography to record three short axis levels of the left ventricle in 13 Duchenne patients. Serial studies were separated by 2 years for most patients. The two-dimensional echocardiographic technique allows qualitative evaluation of segmental contraction of the left ventricle. Four general principles were found during this study: (1) Obvious contraction abnormalities of the left ventricle were present in most patients with DMD. (2) In most patients, the contraction deficit was first noted in the left ventricular posterior free wall behind the mistral valve. (3) Once a contraction deficit was observed, the area of abnormal contraction progressed inferiorly to include additional areas of the left ventricular posterior free wall. (4) Standard M-mode left ventricular function techniques were unreliable for detecting individuals with segmental contraction abnormalities.