Idiopathic Central Nervous System Research Articles

Autoimmunity and neurological disease: antibody modulation of synaptic transmission.

Over the past three decades, compelling evidence has emerged that the immune system can attack the nervous system with devastating consequences for human health. Either cell-mediated or humoral (antibody-mediated) autoimmune mechanisms may predominate in effecting a given disease, and either glia or neurons may fall under immune attack. A subset of these diseases has been particularly useful for understanding fundamental neuroscience as well as mechanisms of human disease. This subset involves humoral autoimmune attack on cell surface molecules subserving transmembrane signaling of excitable cells; special emphasis is placed here on proteins involved in synaptic transmission. We begin by reviewing the prototypic humoral autoimmune disease of synaptic transmission, myasthenia gravis. This provides a context for insights obtained from the study of diseases targeting molecules that regulate synaptic transmission at the neuromuscular junction and in the central nervous system. We also explore a disease where autoimmunity produces agonist antibodies acting at two distinct G-protein-coupled receptors. We conclude with an exploration of the vital issue of access of antibodies to targets within the central nervous system and the implications that such access may have in the pathogenesis of poorly understood idiopathic central nervous system diseases.

Blood pressure effects of long-term stimulant use in disorders of hypersomnolence.

Untoward cardiovascular effects have been implicated as a deterrent to long-term central nervous system (CNS) stimulant use in disorders of hypersomnolence. In this study, we reviewed the relationship between blood pressure and long-term stimulant use. Medical records of 54 patients with narcolepsy and idiopathic CNS hypersomnolence (ICH) were reviewed. The overall mean number of months of follow-up for the entire group was 45.6 (95% CI: 42-49). Both simple linear regression and multiple regression utilizing generalized estimating equations were used to show relationships between blood pressure (BP), time and other covariates. In the simple linear regression model, the average slope of the line of systolic BP (SBP) on time for the entire group was 0.06 (95% CI: -0.09, 0.13) and the line of diastolic BP (DBP) on time was 0.01 (95% CI: -0.05, 0.07). Two multiple regression equations were fitted for the continuous response variables SBP and DBP. Covariates in the model included: time, hypertension, weight at baseline, weight, SBP baseline (SBPBL), DBP baseline (DBPBL), high vs. low dose stimulant therapy and age at starting treatment. For SBP, the covariates weight at baseline, weight and SBPBL were significant (P < 0.05) predictors. For DBP, covariates reaching statistical significance (P < 0.05) included weight and DBPBL. There was no significant change in SBP or DBP over time in either model. Two different statistical models support the conclusion that there was no significant change in SBP or DBP over time in this population.

Etiologies and sequelae of excessive daytime sleepiness

Excessive dynamic sleepiness (EDS), the primary complaint of patients seen in sleep clinics, affects up to 12% of the general population. The effects of EDS can be debilitating and even life threatening. Patients with EDS may exhibit psychosocial distress, decreased work or school performance, and increased risk for accidents. The differential diagnosis of EDS requires objective assessments, such as polysomnography and the Multiple Sleep Latency Test. There are four major causes of EDS: (1) central nervous system (CNS) pathologic abnormalities, such as narcolepsy and idiopathic CNS hypersomnia; (2) qualitative or quantitative sleep deficiencies, such as sleep apnea and insufficient nocturnal sleep; (3) misalignments of the body's circadian pacemaker with the environment (eg, jet lag or shift work); and (4) drugs, which can increase sleepiness either therapeutically or as a side effect. Depending on etiology, management strategies for EDS include extension of time in bed, naps, surgery, various medical devices (eg, oral appliances, continuous positive airway pressure), and pharmacotherapy. Pharmacotherapy is generally achieved with stimulants, such as amphetamine sulfate, methylphenidate, and pemoline or newer, safer compounds like modafinil.

Association Between HLA Antigens and Different Types of Hypersomnia

<h3>To the Editor.—</h3> A close association has been reported between HLA antigens and narcolepsy.^1-3Over the past two years we compared various types of hypersomnia in 56 patients. Thirty-four narcoleptics and 13 patients with idiopathic central nervous system hypersomnia, all unrelated and white, were included in the statistics (Table). These patients were diagnosed on the basis of a clinical interview and polygraphic recordings of at least five daytime naps. Polygraphic recordings were scored blind with regard to the results of HLA determinations. All narcoleptics exhibited excessive daytime sleepiness, cataplexy, and sleep-onset rapid eye movement periods during nap recordings. All idiopathic hypersomniacs had severe excessive daytime sleepiness without cataplexy and short sleep latencies but no sleep-onset rapid eye movement periods during naprecordings. Sleep apnea and nocturnal myoclonus were ruled out in all idiopathic hypersomniac patients by two all-night polygraphic recordings. Fifty-four HLA antigens of loci A, B, C, and

HLA antigens in narcolepsy and idiopathic central nervous system hypersomnolence.

Several studies have shown familial incidence of narcolepsy and idiopathic central nervous system (CNS) hypersomnia. HLA antigen studies performed in mongoloid and caucasoid narcoleptic patients on the A, B, and C loci have yielded conflicting results. The aim of this study is to document a possible association between the HLA system, including the DR locus and excessive daytime somnolence. Thirty-one narcoleptic patients and 10 idiopathic hypersomniac patients were selected and typed for 54 HLA antigens. A family with narcoleptic members in 3 generations was also studied. HLA-DR2 was found in 100% of narcoleptic patients. The frequency of HLA-A3 and B7, which are in linkage disequilibrium with DR2 was also increased in this group. Idiopathic hypersomniac patients showed an increase of HLA-Cw2, DR5, and B27, three antigens known to be in linkage disequilibrium. In the family study, narcoleptic patients were also HLA-DR2; moreover, 3 subjects, one of whom was narcoleptic, were HLA-DR2 as a result of recombination (i.e., genetic crossing-over). These results locate the hypothetic gene associated with narcolepsy more precisely, and indicate that narcolepsy and idiopathic CNS hypersomnolence are two different entities.

The Concurrence of Multiple Sclerosis and Amyotrophic Lateral Sclerosis

We report the clinical and pathological findings of the unusual combination of two idiopathic central nervous system diseases, multiple sclerosis and amyotrophic lateral sclerosis in a 56 year old physician with a twenty-seven year history of a disease initially characterized by relapses and remissions, followed by an eight year quiescent period. During the last year of life there was rapid deterioration with development of generalized weakness, atrophy, weight loss and fasciculations of body and tongue, and associated difficulty with swallowing and sudden respiratory failure. The autopsy confirmed characteristic "burned out" plaques of multiple sclerosis and anterior horn cell and axonal degeneration of amyotrophic lateral sclerosis.

Disorders of excessive daytime somnolence: polygraphic and clinical data for 100 patients.

A consecutive series of 100 sleep apnea free patients with the complaint of excessive daytime somnolence (EDS) were evaluated; data from medical histories, physical examination, personality inventories, and polysomnography [nocturnal polysomnography (NPSG) and daytime multiple sleep latency testing (MSLT)] were tabulated. Significant differences were found between narcoleptic and non-narcoleptic patients in a number of parameters, including EDS severity, mean sleep latency on MSLT, sleep latency on NPSG, latency to REM sleep at night, number of REM sleep at night, number of REM sleep segments throughout the night, the total number of nocturnal myoclonic jerks (as well as the number occurring per hour of NREM and REM sleep), and the number of arousals and wake periods preceded by a myoclonic jerk. Significant differences in sleep latency during MSLT and NPSG testing were found between different EDS diagnostic groups of non-narcoleptic patients. The majority of patients in the MSLT group with long sleep latencies were in the diagnostic groups of EDS associated with psychophysiological and/or psychiatric problems or with drug abuse; patients with a diagnosis of idiopathic central nervous system hypersomnia or EDS associated with disturbed nocturnal sleep formed the majority of the MSLT group with short sleep latencies. The non-narcoleptic patients in a MSLT group with short sleep latencies had significantly shorter sleep latencies at night, more sleep cycles, higher sleep efficiency, and earlier REM sleep than patients with long sleep latencies.