Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert–Eaton syndrome. The calcium-channel subtype that is responsible is not known. We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced ⁴⁵Ca influx in cultured small-cell carcinoma cell lines. Anti–P/Q-type calcium-channel antibodies were found in serum from all 32 patients with the Lambert–Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with the Lambert–Eaton syndrome without cancer. Anti–N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert–Eaton syndrome. Lower titers of anti–P/Q-type and anti–N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. The high frequency of P/Q-type calcium-channel antibodies found in patients with the Lambert–Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.

Time-frequency analysis methods were applied to surface EMG records of patients with tremor. Variation in tremor frequency over time and between muscles was measured in subjects with Parkinson's disease (n = 20), essential tremor (n = 8) and psychogenic tremor (n = 7). The effect of externally paced voluntary contractions on tremor frequency was also characterized. Psychogenic tremor involved fewer limbs and fewer limb segments than Parkinson's disease rest tremor and essential tremor, and its frequency was less consistent. In all subject groups, muscles within a single extremity generally had identical instantaneous frequencies. Frequency dissociation, used here to describe a modal contemporaneous frequency difference of more than 0.1 Hz between two extremities, was demonstrated for symptomatic tremors in 17 subjects with Parkinson's disease, in four subjects with essential tremor and in none of the subjects with psychogenic tremor. Dissociation between tapping and tremor limbs was demonstrated in an additional two subjects with Parkinson's disease and in all four remaining essential tremor subjects but in none of the psychogenic tremor subjects. Tremor maintained a different frequency from the tapping limb in Parkinson's disease and essential tremor, and its frequency in many cases shifted by at least 0.3 Hz compared with the non-tapping condition. For example, arm and leg tremors at 5.2 and 3.8 Hz, respectively, shifted to a common frequency of 4.6 Hz in one Parkinson's disease patient while using the contralateral arm to perform a tapping movement in time with a metronome at 2 Hz. These observations suggest the existence of distinct oscillator systems projecting to each tremoring limb, which can be linked to a variable degree, and which can be modulated by voluntary activation of another limb. Psychogenic tremor was not maintained while tapping with the contralateral arm: tremor either dissipated or shifted to the metronome's frequency. The latter response was also seen in normal volunteers mimicking tremor, but not in Parkinson's disease or essential tremor. We suggest that maintenance of phasic contraction in psychogenic tremor is not due to intrinsic instability of the motor system and that muscle activation in involved limbs may instead be synchronized to a common oscillator. As in voluntary movements, only a single rhythm may be easily followed at a time. Coexistence of muscle groups phasically contracting at consistently different instantaneous frequencies is evidence against a psychogenic aetiology of tremor.

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD. ClinicalTrials.gov identifier: NCT00608881. Classification of evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

The rate of progression of Parkinson disease (PD) varies widely. The change in the motor score of the Unified Parkinson's Disease Rating Scale during the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) trial is an example: for subjects randomized to placebo, the 9-point standard deviation was the same as the mean change.¹One fifth of PD patients develop dementia in the first 5 years of the disease,² while many patients observed for more than a decade remain free of dementia. Approximately one third of patients become disabled within 5 years, another third within 10 years, and many of the others go more than 15 years without becoming disabled.³ Most of the variance in rate and extent of neurodegeneration in patients with PD is unexplained.

Background Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), can present with parkinsonism. However, classically, atypical features, including pyramidal and cerebellar signs, peripheral neuropathy, and/or anterior horn cell dysfunction, are also seen. Levodopa responsiveness is unusual in this disorder. Objective To determine the cause of apparent parkinsonism suggestive of Parkinson disease (PD) in a large family of African origin. Methods We studied a large family in which apparent autosomal dominant parkinsonism suggestive of PD occurs in order to find the causal genetic mutation. Affected and unaffected family members were screened for the presence of a pathogenic expansion at theMJD/SCA3locus using a polymerase chain reaction polyacrylamide gel electrophoresis–based assay. Results Three of the 4 individuals who were examined have a phenotype reminiscent of PD. Specifically, they have at least 2 of the cardinal features, are levodopa responsive, and have no atypical features. All affected family members were shown to possess pathogenic expansions in theMJD/SCA3gene. Conclusions Parkinsonism suggestive of PD due to MJD/SCA3 has not been previously reported, to our knowledge. However, atypical, though also levodopa-responsive, parkinsonism has been previously reported to occur in African American families, suggesting that that this phenotype is associated with African ancestry. In this regard, it is perhaps significant that all the individuals with parkinsonism have relatively low numbers of repeats (normal, 16-34; pathologic, 60-84). In families in which linkage analysis is being performed to determine a locus for autosomal dominant parkinsonism suggestive of PD, evaluation for theMJD/SCA3mutation is indicated.