Genetics of schizophrenia in the South African Xhosa.

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

Multiple Sclerosis impact on employment and income in New Zealand.

BACKGROUND AND OBJECTIVES: We investigated the demographic, social and clinical characteristics associated with employment status and income for people with multiple sclerosis (MS) in New Zealand (NZ). METHODS: The NZ National MS Prevalence study included all persons resident in NZ on census day 2006 diagnosed with MS (96.7% coverage). Factors associated with employment and income status among the working age population (25-64 years) were identified by linear regression. RESULTS: Over 90% of working age people with MS (n=1727) had a work history, but 54% were not working. Work loss occurred early in the disease course, and at low disability (P<.001). Advancing age, progressive disease, longer disease duration, higher disability levels, partner loss and lower education were associated with work loss (P<.001). Working age people with MS had lower income than the NZ population (P<.0001). Higher qualifications yielded no additional income for MS females and about half the additional income for MS males (P<.0001). CONCLUSIONS: MS profoundly reduces employment and income early in the disease course, and at low levels of disability, however, unemployment is not entirely accounted for by clinical, social and demographic factors. These findings suggest social supports should be explored early in the disease course to reduce loss of income and unemployment for people with MS.

Development of recombinant rabies viruses vectors with Gaussia luciferase reporter based on Chinese vaccine strain CTN181.

UNLABELLED: The recombinant rabies virus (RV) vectors encoding the secreted gene marker Gaussia luciferase (Gluc) were generated based on Chinese vaccine strain CTN181. Vectors included replication competent CTN-Gluc, CTN/G(Q333R)-Gluc, in which the amino acid in position 333 of glycoprotein was mutated from glutamine (Q) to arginine (R), and replication constrained CTNΔG-Gluc, in which the glycoprotein encoding gene (G) was deleted. The growth of recombinant RVs in transfected cells was confirmed through biochemical assays of Gluc activities. Gluc expression in recombinant CTNΔG-Gluc virus was highest while that in CTN/G(Q333R)-Gluc virus was lowest. The optimal time to harvest recombinant RVs was determined and the function of pathogenic and nonpathogenic rabies glycoprotein in virus recovery was examined. The addition of glycoprotein was slightly beneficial for virus recovery and the titer of rescued virus was lowered even when the amino acid in G333 position of glycoprotein was mutated from nonpathogenic Gln to pathogenic Arg. CONCLUSIONS: Viral vectors based on a human rabies vaccine strain CTN181 were successful. Gluc was useful as an in vitro gene marker for monitoring the growth of recombinant RVs iteratively in cell culture.

American Academy of Neurology (AAN) 60th Annual Meeting. 12 to 19 April 2008.

The Annual Meeting of the AAN is the major meeting in the USA covering all aspects of neurology and attracts a large number of international presenters. At the 2008 meeting in Chicago, as has been the case in recent years, multiple sclerosis (MS) was the neurological disorder that attracted the most extensive contributions and interest. Aspects of MS that were most actively addressed were trials of treatment with new agents (oral immune-modulating medications and monoclonal antibodies), further assessment of established immune-modulating agents particularly head-to-head trials, Devics disease (neuromyelitis optica) and its relationship to MS, and MS in children. In addition to about 300 poster and platform presentations on MS topics, MS therapy was reviewed at a 2-hour evening meeting. Space does not allow acknowledgement of most of the individual reports of particular interest and the following is a general overview.

Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Rizatriptan Wafer Protocol 049 Study Group.

Rizatriptan is a potent, highly selective 5HT1B/1D agonist with rapid onset of action for acute treatment of migraine. Rizatriptan wafer is a novel, freeze-dried dosage formulation of rizatriptan which rapidly disintegrates on the tongue, is swallowed with saliva, and may be taken without liquids. The efficacy and tolerability of rizatriptan wafer were examined in a placebo-controlled, double-blind, outpatient study in 555 migraineurs. The primary efficacy endpoint was pain relief at 2 h. From 30 min onwards, significantly more patients experienced pain relief and became pain-free after rizatriptan 10-mg wafer compared to placebo. At 2 h, the percentage of patients with pain relief was significantly higher after rizatriptan 10-mg wafer (74%), 5-mg wafer (59%) compared with placebo (28%). Rizatriptan 10-mg wafer was superior to rizatriptan 5-mg wafer on pain relief at 1.5 and 2 h (p < 0.05). Significantly more patients were pain-free at 2 h after rizatriptan 10-mg wafer (42%), 5-mg wafer (35%) compared with placebo (10%). Both doses of rizatriptan wafer were well tolerated. Rizatriptan wafer is a convenient, highly effective new formulation for acute treatment of migraine.

Development of a multiple sclerosis functional composite as a clinical trial outcome measure.

The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Rizatriptan 022 Study Group.

Rizatriptan is a novel 5-HT1B/1D agonist which is rapidly absorbed after oral administration. The efficacy and tolerability of oral rizatriptan (5 mg and 10 mg) were examined in this multicenter, double-blind, outpatient study of 1473 migraineurs which featured randomized, placebo-controlled treatment of migraine recurrences. On experiencing moderate or severe migraine headaches, patients rated headache severity prior to dosing and at 30-minute intervals for 2 hours after dosing. Onset of effect was seen as early as 30 minutes after dosing with rizatriptan 10 mg. At 2 hours postdose, the percentage of patients with pain relief was significantly higher after rizatriptan 5 mg (62%) or 10 mg (71%) compared with placebo (35%). Complete relief was also significantly higher after rizatriptan 5 mg (33%) and 10 mg (42%) compared with placebo (10%). In patients experiencing headache recurrence after initial benefit, further relief was obtained in 71% with rizatriptan 5 mg (placebo 54%) and in 82% with rizatriptan 10 mg (placebo 44%). Complete relief of recurrent headache was obtained in 36% with rizatriptan 5 mg, 49% with rizatriptan 10 mg, and 15% with placebo (P < 0.05). The most common drug-related adverse experiences were dizziness, somnolence, asthenia/fatigue, and nausea (the incidences of which were low and dose related). There was no increase in the incidence of adverse experiences after use of up to three doses of rizatriptan within 24 hours. We conclude that both doses of rizatriptan are effective and well tolerated in the acute treatment of migraine and migraine recurrence, with the 10-mg dose preferred as it is more effective with a faster onset of action.

Idiopathic steroid responsive chronic lymphocytic meningitis--clinical features and long-term outcome in 17 patients.

BACKGROUND: Some patients with chronic lymphocytic meningitis appear to respond to corticosteroid treatment, but investigations fail to identify the cause. The use of corticosteroids in patients with chronic meningitis is controversial and the long-term outcome is unclear. AIM: To review the long-term outcome in 17 patients with the syndrome of idiopathic steroid responsive chronic lymphocytic meningitis. METHODS: Review of patients' records and examination of surviving patients 1.5 to 17.5 years (median 8.8 years) after presentation. RESULTS: The cause of the steroid responsive chronic meningitis was found during follow up in two of the 17 patients: Wegener's granulomatosis and multiple sclerosis in one patient each. A cause was not found in the other 15 patients. Seven of these patients eventually recovered and corticosteroids were withdrawn after six weeks to six years without a recurrence of symptoms. Four patients improved transiently, but died six months to 26 years after starting treatment; in two, steroids were withdrawn a few weeks before death. Four patients had active chronic meningitis and reduction in the dose of corticosteroids was associated with a recurrence of symptoms. Leptomeningeal and brain biopsy in eight patients showed non-specific abnormalities which were not helpful in the diagnosis. CONCLUSIONS: A subgroup of patients with idiopathic chronic lymphocytic meningitis responds to corticosteroids. Leptomeningeal biopsy and long-term follow up seldom identify the underlying cause in these patients. Steroid treatment must be undertaken with caution, even after infective causes of chronic meningitis have been excluded.

Recommendations from the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force.

This article provides recommendations from the National Multiple Sclerosis Society's Clinical Outcomes Assessment Task Force. The Task Force was appointed in 1994 and charged with recommendending improved approaches for clinical outcomes assessment in future controlled clinical trials. The recommendations herein follow extensive deliberation and data analysis during 2.5 years. General principles and desirable measurement attributes were used to assess alternative measurement techniques and clinical scales. On the basis of the analysis of existing multiple sclerosis (MS) data sets, a new measurement approach is proposed. The approach is based on quantitative functional composites that consist of simple quantitative measures from the major clinical dimensions of MS combined into a single score. Quantitative functional composites are likely to provide improved precision and sensitivity in future MS clinical trials. Studies necessary to further refine quantitative functional composites as useful MS clinical trial outcomes are delineated.

Late recurrence of postdural puncture headache.

BACKGROUND AND OBJECTIVES: Postdural puncture headache can recur following an epidural blood patch but usually does so within the first week. However, a late recurrence was encountered in a 31-year-old woman with probable lupus vasculitis. METHODS: The patient underwent a diagnostic lumbar puncture and suffered a postdural puncture headache. She was treated with an epidural blood patch and had complete resolution of her headache. Five weeks later, she suffered a sudden recurrence of an identical headache and underwent a repeat epidural blood patch. RESULTS: The second headache, like the first, was immediately and completely resolved. CONCLUSIONS: A review of risk factors for postdural puncture headache and the role of an epidural blood patch suggests a possible explanation for the late recurrence in this case.

Clinical outcomes assessment in multiple sclerosis.

This article represents initial deliberation of an international task force appointed by the US National Multiple Sclerosis Society to develop recommendations for optimal clinical assessment tools for multiple sclerosis clinical trials. Presented within this article are the key issues identified by the task force during its initial year of deliberation. These include the precise purpose for a clinical assessment tool, the clinical dimensions to be measured in a multidimensional outcome measure, desirable attributes of an optimal clinical outcome measure, the complexities of multidimensional outcome measures, the relative merits of categorical clinical ratings and quantitative functional assessments, and a number of other important design issues that relate to the use of a multidimensional outcome measure. An action plan for analysis of existing data is summarized, as are the plans for more detailed recommendations from the task force.

Leptomeningeal and brain biopsy in chronic meningitis.

BACKGROUND: The cause is not found in one third of patients presenting with chronic meningitis. Biopsy of the leptomeninges and brain is often recommended in these patients, but the value of a biopsy is uncertain. AIMS: To review the results of leptomeningeal and brain biopsies and their effect on diagnosis and management in patients with chronic meningitis, if the diagnosis was uncertain after clinical assessment, lumbar puncture and radiological investigations. METHODS: The clinical features, investigations and the results of leptomeningeal and brain biopsies were reviewed retrospectively in 25 patients presenting with chronic meningitis between 1967 and 1990. RESULTS: The biopsy identified the cause of the chronic meningitis in five patients (neoplastic meningitis in three, tuberculous meningitis in one, granulomatous angiitis in one). In 17 patients the biopsy was abnormal but it did not identify the cause (non-granulomatous lymphocytic meningitis in eight, granulomatous meningitis in two, non-specific abnormalities in seven). In two patients the biopsy was normal and in one patient the tissue was used only for culture. The results of the biopsy led to a beneficial change in treatment in two patients but did not influence management in the other patients. CONCLUSIONS: A leptomeningeal and brain biopsy was of limited practical value in diagnosis and management in most patients with chronic meningitis.

A structured panel interview and group exercise in the selection of medical students.

The selection of entrants for medical school, as now widely agreed, should include measurements of non-academic as well as academic attributes. The authors have developed a process to assess the personal attributes of applicants. This included a structured panel interview carried out twice on each applicant by independent interviewers and a group exercise in which several applicants were observed whilst discussing a problem. Training for interviewers took the form of a half-day interactive workshop. One hundred and forty-one school-leaving applicants completed the new assessment. No relationship was found between academic achievement as reflected by marks in a national examination and scores in the panel interview, the group exercise, or the school principal's report. However, significant intercorrelations were found between the panel interview, group exercise and school report. The results of this experience have encouraged the Auckland School to continue to explore methods to measure these attributes in a carefully controlled study.

Brain biopsy in the management of focal encephalitis.

The value of a brain biopsy in diagnosis and management of suspected herpes simplex encephalitis was studied in 29 patients (16 prospectively and 13 retrospectively). The biopsy showed herpes simplex encephalitis in eight, culture-negative encephalitis in 14, and was normal in three patients. It provided an alternative diagnosis in four patients, for two of whom curative treatment was available. The biopsy was complicated by a fatal intracranial haemorrhage in one patient. The low yield of alternative diagnoses suggests that a brain biopsy is not justified in the routine investigation of focal encephalitis.

Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients.

A prospective study of serial magnetic resonance (MR) scans of the brain was carried out every 2 weeks for 4 to 6 months in 9 patients with mild, clinically definite, relapsing/remitting multiple sclerosis (MS). Six of the 9 patients developed a total of 12 asymptomatic new lesions in various parts of the brain. In none of the patients were the changes on MR scan accompanied by relevant new neurological symptoms or signs. New MR lesions had a characteristic temporal profile, reaching a maximum size in approximately 4 weeks before gradually shrinking, usually leaving a small residual abnormality indistinguishable from chronic MS lesions. The frequent occurrence of new asymptomatic lesions indicates that MS may be a more active process even in mildly affected asymptomatic patients than has been previously realized. The results emphasize the potential importance of using MR scanning to measure disease activity in laboratory studies of MS and in the assessment of treatment, particularly in asymptomatic patients in the early stages. We suggest that the expanding and contracting new lesions are the basic or primary lesion in MS, that the characteristic demyelinated plaque is represented by the small residual area that these lesions shrink down to, and that the typical collection of scattered white matter lesions in chronic MS may represent the accumulated residua of dozens or more of these active lesions occurring over many years.

Scales for rating impairment in multiple sclerosis: a critique.

We reviewed scales proposed over the past 35 years for the rating of neurologic impairment in MS. We focused on the Expanded Disability Status Scale (EDSS) which has been recommended as the most useful scale for rating impairment by the International Federation of Multiple Sclerosis Societies in its Minimal Record of Disability for Multiple Sclerosis. We consider that the EDSS has important flaws that seriously limit its usefulness. In light of the widely accepted three-tier classification of dysfunction developed by the World Health Organization, the title is inappropriate. More substantial problems include inadequate precision in defining the degree of impairment in some functional categories of the scale, and the use of a mixture of neurologic signs elicited on examination and subjective information obtained from the patient in defining the overall scale. We suggest guidelines for developing a "Neurologic Impairment Scale" to rate impairment in MS.