Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1-(entry expanded disability status scale, 3.0 -5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA-versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p ϭ 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p ϭ 0.0193). Interpretation:The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

Objective-To establish the

Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.

Objective-To investigate the clinical and demographic characteristics of primary progressive multiple sclerosis (PPMS) in Northern Ireland and to establish a database of such patients for genetic and immunological studies and future therapeutic trials. Methods-Diagnosis and categorisation were performed by two neurologists, potential cases being identified from the following sources: neurology outpatient clinics; neurology inpatients; a review of hospital discharges; and an ongoing epidemiological study of multiple sclerosis in Northern Ireland. Only those with a progressive course from onset and a clear history of no prior relapses were accepted. Potential cases were invited for interview and assessment, the minimal record of disability (MRD) being established. Results-One hundred and eleven cases of PPMS have been identified, 63 women and 48 men (ratio 1.3:1), with a mean age at onset of 39.5 (SD 11.0) (range 17-66)years, and mean disease duration of 13.6 (SD 9.3)years. The mean interval between onset and diagnosis was 4.7 (SD 4.2) years. Nineteen patients (17.1%) did not satisfy the requirements for any category in the Poser criteria. Motor disturbance was the commonest mode of onset (67.6%) with visual loss occurring only rarely at onset (3.6%). Kurtzke EDSS scores were concentrated at the upper end of the scale with a median of 6.0 and levels of unemployment and financial dependence were high. Conclusions-PPMS in Northern Ireland has a generally later age at onset, lower female preponderance, and predominantly motor onset compared with other subgroups of multiple sclerosis. The delay to diagnosis reflects the often insidious onset and the nature of the clinical course makes application of the Poser criteria diYcult. Levels of neurological impairment, disability, and handicap as measured by the MRD are high. (J Neurol Neurosurg Psychiatry 1998;64:451-454)

The results of this small study suggest a positive effect of the intervention on the symptoms of constipation, and support the feasibility of a substantive trial of abdominal massage for the alleviation of the symptoms of constipation in people with MS.

A female with the Brown-Vialetto-Van Laere syndrome is described. The patient's father, a paternal uncle, and possibly a paternal first cousin had neurosensory deafness and a paternal aunt had clinical symptoms indicative of the syndrome. This family raises the possibility that the. disorder is genetically heterogeneous with autosomal recessive and autosomal dominant forms. Alternatively, it could be caused by a mutant gene on the X chromosome.The Brown-Vialetto-Van Laere syndrome is a rare condition characterised by bilateral nerve deafness accompanied by cranial nerve disorders, usually involving the motor components of the seventh, and ninth to twelfth nerves.'5 In some cases, there is involvement of the spinal motor nerves and less commonly of upper motor neurones. The onset of the disease is usually in childhood. Although most reported cases are sporadic,' 3-`1 0 familial cases have been described.2 3 11 12The present paper describes an affected girl whose father and a paternal uncle had bilateral neurosensory deafness, and whose paternal aunt had bilateral neurosensory deafness and muscle weakness. It is suggested in this family that inheritance may be autosomal dominant or, alternatively, X linked. Case report The proband was born at term after a normal delivery. There was no history of adverse factors during the antenatal period. Development was normal. She was a healthy, athletic young girl who was a good swimmer with no neuromuscular problems before the onset of her illness. At the age of 12 years, over the course of a few weeks, she experienced rapid onset neurosensory deafness. The following year she developed rapidly progressive weakness with clumsiness of her upper limbs and difficulty in washing, dressing, writing, and combing her hair. At that time her mother noted she tended to shake and twitch particular at night. During the day she was sleepy. She also complained of shortness of breath. It was also noticed that she was unable to rise from lying, her speech was soft, and she had difficulty with swallowing.When aged 131/2 years, she was treated with steroids for 12 months, during which time her condition improved. When she was 15 years old she began to deteriorate again. On clinical examination of the cranial nerves the fields of vision were full and the pupillary responses were normal. The optic discs were pale but the optic fundi were normal. Visual acuity was normal. The external ocular movements were full. There was no ptosis. There was unsustained nystagmus on lateral gaze. The corneal responses were present. The jaw jerk was not obtained. There was weakness of the orbicularis oculi but muscles around the mouth had normal power. There was severe neurosensory deafness. The gag reflex was normal. The sternomastoid muscles were weak. The tongue was was small, wasted, and fasciculating.There was marked wasting of the muscles of the hands and forearms, more severe distally (MRC grade 2) than proximally (MRC grade 3/4). Power in the legs was grade 4-proximally and normal distally. The ten...