Not hysteria: ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis.

We report a case of a 33-year-old nulliparous woman who, following a short prodromal illness, experienced a series of psychiatric and behavioural symptoms. These included states of terror, insomnia, delirium, self-harm and suicidal ideation, facial dyskinesias, verbigeration, cognitive impairment, reduced responsiveness, violence and paranoia. A diagnosis of anti-N-methyl-d-aspartate (NMDAR) encephalitis was made 50 days after symptom onset. Early tumour removal is associated with an improved prognosis and a laparoscopic oophorectomy was performed following detection of a dermoid cyst. Within 24 hours of the operation there was marked improvement in cognitive function and appetite.

Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register.

BACKGROUND: The Scottish Motor Neurone Disease Register is a population based register of amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) in Scotland, with high case ascertainment levels. OBJECTIVE: To investigate the cause of death by autopsy and assess grading criteria in a cohort of cases of ALS from the Scottish MND Register. METHODS: The records of 44 patients undergoing autopsy were reviewed to determine the cause of death, clinical assessment (El Escorial and modified World Federation of Neurology criteria) during life and neuropathological autopsy findings. RESULTS: In a cohort of 44 cases undergoing autopsy between 1989 and 1998, the cause of death could be directly or indirectly (bronchopneumonia, aspiration/pneumonia and respiratory failure) attributed to MND in 32/44 (73%) cases. The clinical diagnosis of MND was confirmed at autopsy in 44/44 (100%) cases, 3/44 (7%) cases showed coexistent neurodegenerative disease and 5/44 (11%) were familial MND cases. CONCLUSIONS: Within our cohort, MND contributes to death in the majority of cases and there is excellent clinicopathological correlation, irrespective of the clinical grading criteria used. However, the autopsy rate is low (4%) and further larger studies are required to identify heterogeneity within the disease.

Increasing prevalence and incidence of multiple sclerosis in South East Wales.

BACKGROUND AND AIMS: Epidemiological studies of multiple sclerosis suggest a trend of increasing disease prevalence in susceptible populations. The reasons for this are unclear and may be the results of methodological differences between studies, incomplete ascertainment or advances in technologies that allow the increased identification of early or mild disease. In addition, direct comparison of cross sectional prevalence estimates performed in different epochs in ethnically and geographically distinct populations may be inappropriate. METHODS: Using detailed phenotypic information and standardised methodology, a geographically defined Welsh population was resurveyed after a significant interval, establishing contemporary prevalence rates and examining demographic and clinical data to determine causes of changing disease frequency. RESULTS: Disease prevalence increased 45% from 101 to 146 per 100,000 population over 20 years. The greatest increase was observed in women between the ages of 45 and 54 years. No significant increase in disease frequency was observed in the male population overall, or within specific age groups. There was no demographic evidence for a pattern of earlier age at onset or diagnosis to explain increased disease frequency or decrease in mean age of the prevalent population. In addition, we failed to identify a pattern of recognition of patients with less severe disability. Although there was a modest 13% increase of 2.2 years in mean disease duration, and eight new previously prevalent patients were identified, the main cause of rising disease frequency was related to a 2.8-fold increase in disease incidence for women over 23 years from 2.65 to 7.30/100,000/year increasing the sex ratio of incident patients from 1.8 to 4.3 (women:men). CONCLUSION: Recent change in disease incidence and prevalence in this population is likely to be the result of environmental factors that have been operative in the past few decades in women alone and infers avoidable risk factors. Modelling of current overall incidence suggests a further increase in prevalence to 260 per 100 000 population within the next 20-40 years. Further studies are needed in order to identify recent changes in sex specific environment and lifestyle that confer susceptibility.

Change in disability in patients with multiple sclerosis: a 20-year prospective population-based analysis.

BACKGROUND: In patients with multiple sclerosis (MS), the natural history of the disease is of considerable importance to predict and understand long-term outcome and inform choices made by patients and clinicians. This information should ideally be derived from data that reflects the entire disease course. METHODS: In this study, morbidity data from a prevalent cohort established in 1985 have been re-examined after an interval of 20 years to assess factors that may be important in determining outcome. RESULTS: Of 379 patients who fulfilled criteria for definite or probable MS in the original population-based cohort, 221 (58.3%) had died, 149 (39.3%) were alive and 9 (2.4%) were untraceable. Mean Expanded Disability Status Scale (EDSS) score in 1985 was 5.15 (SD 2.7, range 0-9.5) and 8.01 (SD 2.6, range 0-10) in those alive in 2005. Mean worsening of EDSS scores in surviving patients was +3.02 EDSS points, but 14.0% had worsened by <1 EDSS point over 20 years. 61.4% of patients with EDSS 3.5-5.5 and 82.2% of those with an EDSS of or=6 after 20 years. Lower baseline EDSS scores (p<0.0001), higher pyramidal functional system score (p = 0.02) and a greater number of functional systems involved (p = 0.001) were significantly more likely to be associated with greater worsening of disability. Of those with benign disease in 1985, only 19% remained benign after 20 years of follow-up; however, 12.6% of patients had minimal disability after at least 20 years after their disease onset and 14% of patients failed to worsen by >or=1 EDSS point. CONCLUSIONS: This study emphasises the importance of long-term epidemiological studies and the development of clinically relevant measures that effectively predict outcome and can guide decisions on therapeutic management.

Survival and cause of death in multiple sclerosis: a prospective population-based study.

BACKGROUND: Detailed studies of mortality in multiple sclerosis (MS) are limited. Studying death certificates in a prospective cohort of patients known to have MS is of value in establishing mortality data and can also provide important information on the accuracy and use of death certificates for epidemiological studies. METHODS: A population-based survey performed in South Wales in 1985 identified 441 patients. Cases were flagged with the Office of Population Censuses and Surveys and death certificates collected prospectively for more than 20 years. RESULTS: Median observed survival time was 38.0 years from symptom onset. Mean age at death was 65.3 for women and 65.2 years for men. Mean age at death in patients dying from MS-related causes was 62.5 and 69.3 years (p<0.001) for unrelated deaths. Those dying of MS-related causes had a younger age at disease onset (32.5) compared with those dying of unrelated causes (36.8 years) (p = 0.01). Cause of death was related to MS in 57.9% and unrelated in 42.1% of individuals. In 27% of patients, "MS" was absent from the death certificate. The most common cause of death was respiratory disease (47.5%). The standardised mortality ratio was 2.79 (95% CI 2.44 to 3.18) so that MS patients were almost three times more likely to die prematurely relative to the general population. CONCLUSIONS: These results confirm a continuing trend of premature death in patients with MS. Relying on data derived from death certificates will underestimate disease prevalence. Differences were identified between those dying from MS-related causes and those dying from other causes.

Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues.

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease.

OBJECTIVES: To describe survival of 1226 Scottish adults with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). METHODS: Ten year, prospective, population based disease register. Cox time dependent proportional hazards modelling for multivariate survival analyses. RESULTS: Median survival from onset was 25 months (interquartile range 16-34 months). In multivariate models we found an increased hazard with more recently diagnosed cases-that is, there was an unexpected decline in survival over the 10 year period (hazard ratio (HR) 1.06 (95% CI 1.04 to 1.09). Positive effects on survival were demonstrated for longer time from onset to diagnosis (HR 0.38 (95% CI 0.33 to 0.42), assessment by a neurological specialist (HR 0.56 (95% CI 0.40 to 0.77), and treatment with riluzole (HR 0.24 (95% CI 0.14 to 0.42). Poor prognosis was associated with bulbar onset (HR 1.25 (95% CI 1.09 to 1.46) and a mixed lower and upper motor neurone syndrome (HR 1.23 (95% CI 1.01-1.49) and increasing age. CONCLUSIONS: We found an unexpected decline in survival over the 10 year period, despite controlling for potential confounding variables. We would be cautious about over-interpreting these observations and suggest that further research is required to confirm or refute these findings.

Rapid mutation detection by the transgenomic wave analyser DHPLC identifies MYOC mutations in patients with ocular hypertension and/or open angle glaucoma.

AIMS: To rapidly screen Scottish patients with a family history of open angle glaucoma (OAG) or ocular hypertension (OHT) for mutations in the myocilin gene (MYOC) and develop a new rapid screening method for MYOC mutation detection. METHODS: All three exons of the MYOC gene were amplified by PCR from genomic DNA and subjected to direct DNA sequencing. Mutation detection methodology was also developed based on denaturing high performance liquid chromatography (DHPLC). A recurrent mutation was investigated by analysis of microsatellite haplotypes at the MYOC gene locus. RESULTS: Mutations were identified by DNA sequencing in four families. MYOC mutation Q368X was found in three kindreds and the fourth family carried the mutation G367R. The Q368X mutation was found to be associated with the same haplotype for markers closely flanking the MYOC gene. The mutations were identified by direct sequencing and were also readily detected by DHPLC analysis of PCR fragments, demonstrating that this is a robust method for MYOC analysis in future. CONCLUSIONS: Mutations in the MYOC gene were identified in patients presenting with highly variable phenotypes from normal through OHT to severe OAG. Haplotype analysis showed that mutation Q368X is likely to be an ancestral mutation in this population. DHPLC analysis is an accurate, rapid and cost effective method for MYOC mutation analysis in large population samples.

Early maternal and neonatal morbidity associated with operative delivery in second stage of labour: a cohort study.

BACKGROUND: A frequent dilemma for obstetricians is how to keep morbidity to a minimum when faced with arrested progress at full dilatation of the cervix. Our aim was to examine maternal and neonatal morbidity associated with vaginal instrumental delivery in theatre and caesarean section, at full dilatation. METHODS: We did a prospective cohort study of 393 women, who had term, singleton, liveborn, cephalic pregnancies requiring operative delivery in theatre at full dilatation for 1 year. FINDINGS: Factors increasing the likelihood of caesarean section included maternal body-mass index greater than 30 (adjusted odds ratio 2.4, 95% CI 1.2-4.9), neonatal birthweight greater than 4.0 kg (2.3, 1.3-3.8), and occipitoposterior position (2.5, 1.6-3.9). Women undergoing caesarean section were more likely to have a major haemorrhage (>1 L; 2.8, 1.1-7.6) and extended hospital stay (>/=6 days; 3.5, 1.6-7.6) than those with vaginal delivery. Babies delivered by caesarean section were more likely to require admission for intensive care (2.6, 1.2-6.0) but less likely to have trauma (0.4, 0.2-0.7) than babies delivered by forceps. Overall neonatal morbidity was low, but a few babies in each group had serious complications (serious trauma, eight vs three; sepsis, six vs 13; and jaundice, ten vs 12 after vaginal delivery and caesarean section, respectively). Major haemorrhage was less likely after delivery by a skilled obstetrician (0.5, 0.3-0.9). INTERPRETATION: The data lend support to an aim to deliver women vaginally, unless there are clear signs of cephalopelvic disproportion, and underline the importance of skilled obstetricians supervising complex operative deliveries.

Are the El Escorial and Revised El Escorial criteria for ALS reproducible? A study of inter-observer agreement.

INTRODUCTION: For accurate diagnosis, inter-observer agreement of criteria is important. METHODS: Using case records, the reproducibility of the original and revised El Escorial diagnostic criteria for amyotrophic lateral sclerosis were tested in a consecutive series of people referred to the Scottish Motor Neuron Disease Register. RESULTS: Agreement between independent observers was similar (weighted kappa: 0.783, 95% CI 0.656 to 0.911 (original criteria), 0.681, 95% CI 0.485 to 0.878 (revised)). CONCLUSIONS: Serious errors are unlikely, but the revised criteria may be less reproducible as they include more diagnostic categories. Revisions of diagnostic criteria should be tested for reproducibility and validity prior to widespread adoption.

Motor neuron disease--a review.

It is now clear that patients with MND are best managed using a multi-disciplinary approach conforming to evidence-based guidelines. Whilst scientific advances into the aetiology of MND have been of great importance in both the understanding of this and other neurodegenerative disease, they have only recently led to therapy directed at disease progression. The management of patients with MND remains largely supportive but it is hoped that the future may hold better prospects for those with the disease.

Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis.

OBJECTIVE: To evaluate the cost utility of interferon beta-1b in secondary progressive multiple sclerosis. DESIGN: Population based cost utility model (healthcare perspective). Data on use of health services were obtained from case records and routine morbidity data and utility values from a EuroQol survey. Local and published costs were used. Effectiveness was modelled using data on relative risk reductions from a randomised trial of interferon beta-1b. SETTING: Tayside region, 1993-5. SUBJECTS: 132 ambulatory people with secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year (QALY) gained. Rate of relapse and proportion becoming wheelchair dependent over three years. RESULTS: The number needed to treat for 30 months to delay time to wheelchair dependence in one person by nine months was 18 (95% confidence interval 5 to 26). For every 18 people treated for 30 months, six relapses would be prevented, gaining 0.397 discounted QALYs. The cost per QALY gained was 1 024 667 pounds sterling (276 466 pounds sterling to 485 499 pound sterling). If treatment was restricted to patients attending neurology services, the number needed to treat was 14 (cost per QALY gained 833 pounds sterling 514 (161 358 pounds sterling to infinity)). The cost per QALY gained was not sensitive to changes in cost which took account of a societal perspective. CONCLUSIONS: The cost per QALY gained from interferon beta is high because of the high drug cost and modest clinical effect. Resources could be used more efficiently elsewhere.

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Estimating the prevalence of multiple sclerosis in the United Kingdom by using capture-recapture methodology.

The geographic distribution of multiple sclerosis is nonrandom, as the disease is more prevalent in temperate than in tropical regions. Surveys conducted between 1970 and 1996 suggest that multiple sclerosis is more prevalent in the northern part of the United Kingdom than in the southern part. This north-south gradient ("the latitudinal gradient") might be a methodological artifact, because high prevalence figures from serial surveys of the northern part of the United Kingdom might have been the result of better ascertainment. By using capture-recapture methods, the authors found that case ascertainment was similar in the northern and southern parts of the United Kingdom. When prevalence figures for multiple sclerosis in the southern United Kingdom were increased to account for the number of unobserved cases, the difference persisted: The prevalence of multiple sclerosis in the northern part of the United Kingdom appeared to be at least 180 cases per 100,000 persons, whereas the maximum prevalence in the southern part of the United Kingdom was less than 160 cases per 100,000 persons. The distribution of multiple sclerosis in the United Kingdom is not uniform and is consistent with the hypothesis that populations with a high prevalence of multiple sclerosis may be genetically predisposed to the disease.

Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis.

We analyzed genomic DNA from ALS patients for mutations in the apurinic/apyrimidinic endonuclease (APEX nuclease) gene. We identified three rare polymorphisms in the untranslated region of the gene and one common two-allele polymorphism (D148E). The allelic frequency D148E was significantly different in sporadic ALS patients compared with controls. A conserved amino acid change and a 4-base pair deletion were also identified in sporadic ALS patients. These data suggest that APEX nuclease may contribute to the etiology of ALS.