Lord Nelson's (1758-1805) left eye.

Following the loss of his right eye at Calvi in 1794, Lord Nelson suffered increasing left-sided visual loss, here considered most likely to have been due to the ocular inflammatory condition 'sympathetic ophthalmia'. It is also argued that his succeeding episodes of violent headaches with nausea and prostration, and possible depigmentation of hair, reflected the development of an uveomeningoencephalitic syndrome akin to that of Vogt-Koyanagi-Harada disease, which is best regarded as the same condition with a different aetiology.

VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families.

Our group previously described and mapped to chromosomal region 12p13 a form of dominantly inherited hereditary spastic ataxia (HSA) in three large Newfoundland (Canada) families. This report identifies vesicle-associated membrane protein 1 (VAMP1), which encodes a critical protein for synaptic exocytosis, as the responsible gene. In total, 50 affected individuals from these families and three independent probands from Ontario (Canada) share the disease phenotype together with a disruptive VAMP1 mutation that affects a critical donor site for the splicing of VAMP1 isoforms. This mutation leads to the loss of the only VAMP1 isoform (VAMP1A) expressed in the nervous system, thus highlighting an association between the well-studied VAMP1 and a neurological disorder. Given the variable phenotype seen in the affected individuals examined here, we believe that VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.

A quantitative analysis of suspected environmental causes of MS.

BACKGROUND: Multiple sclerosis (MS) is a disease with purported environmental causes. Consistent correlations have been found in various settings for latitude, smoking exposure, sunlight, and vitamin D deficiency. We analysed the contribution of various environmental factors to the risk of developing MS from a population perspective. METHODS: We collated global data of MS prevalence from 54 studies over the previous ten years and calculated the degree of risk contributed by latitude, longitude, ultraviolet radiation (from NASA satellite data and formulae for available sunlight hours), population smoking rates (from WHO data), gender, study date, study demographics, and several socioeconomic factors. We report a very significant negative correlation between MS prevalence and available ultraviolet (UV) radiation. RESULTS: The lack of available UV radiation outweighs other factors by at least 20 fold (p < 10⁻8) from single variate regression analysis. Multiple regression analysis revealed that latitude and longitude are also significant factors; smoking may also provide a very minimal role. The eight prevalence studies from Scandinavia produced prevalences that were lower than expected, given their global geospatial positioning. CONCLUSIONS: The available ultraviolet radiation is a significant environmental factor, more so than all the other factors examined.

Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. DESIGN: Case-control study with replication. SETTING: Memory referral clinics in Canada and the United Kingdom. PARTICIPANTS: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. RESULTS: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). CONCLUSIONS: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.

A clinical study of migraine evolution.

BACKGROUND: The buildup time of migraine headaches has not been well delineated in publications to date and we are aware of patients whose migraines last well over 72 hours. More concentration on these factors in the assessment of patients might lead to more appropriate therapeutic choices. METHOD: Prospective ascertainment of such data through a questionnaire completed by 253 informed and willing patients with IHS migraine with or without aura consulting Canadian headache specialists. Data were electronically sent to a central computer from each center, tabulated and analyzed using standard statistical parameters. RESULTS: In 253 patients with migraine ascertained using applied IHS criteria, nausea was a feature in over 90% of cases, especially in those with aura. This inhibited the ingestion of oral medications in about a quarter of all subjects. The time to build from no pain to moderate/severe pain was shorter in subjects with auras and was less than 2 hours in 97% of those with and 86% of those without auras. However, we also identified a group of subjects with migraine (over 10% of all) in whom the build time to maximum pain is delayed for over 2 hours. Nausea was experienced by 91.7% of subjects, slightly but significantly later in those without auras. While most headaches in each group lasted from 4 to 72 hours, 24.3% of those with and 20.6% of those without aura expected to experience pain for more than 72 hours, while in untreated cases disability due to pain, nausea, or malaise usually persisted for over 3 days in 24.3% and 16.7% of those with and without aura, respectively. One-fifth of migraineurs may be in pain and/or disabled by accompanying symptoms for over 3 days in a typical migraine attack. Over half of our subjects reported that their medications worked well or excellently. CONCLUSIONS: Attacks of migraine in real-life clinical situations vary somewhat from the IHS criteria in that they are more often associated with nausea that interferes with oral therapy; can persist for over 72 hours; may have slow (>2 hours) buildup to maximum pain in 10% of cases; and may cause disability for over 3 days. Nevertheless, current therapeutic regimens (including prescribed medications) work well for a substantial majority.

Rasmussen's encephalitis in a 58-year-old female: still a variant?

BACKGROUND: We report the case of a 58-year-old female with clinical, radiological, and histopathological evidence of Rasmussen's encephalitis, representing the oldest confirmed case to date. CASE SUMMARY: The patient presented with complex partial seizures characterized by numbness of the left face and staring spells. These progressed to a state of epilepsia partialis continua with jerking of the left face, as well as severe cognitive impairment and loss of all communication. The patient responded well to Intravenous Immunoglobulin (IVIG) therapy despite early complications and with ongoing treatment is living independently with minimal cognitive impairment. CONCLUSIONS: This represents the oldest confirmed case of Rasmussen's encephalitis and suggests that this diagnosis should be considered in patients of any age with an appropriate clinical picture. We recommend IVIG as a first line therapy for adult cases of Rasmussen's encephalitis.

Pain free efficacy of sumatriptan in the early treatment of migraine.

BACKGROUND: There is evidence that headache response rates may be higher if triptans are used early when a migraine attack is still mild, as compared to when it is treated after pain has reached moderate or severe intensity. METHODS: In this randomized, double blind, placebo controlled, parallel group clinical trial, 361 patients took either placebo, sumatriptan 50 mg, or sumatriptan 100 mg in a single attack study. The primary outcome measure was pain-free status at two hours. RESULTS: In the intention to treat group, two hour pain free rates were 16%, 40%, and 50% in the placebo group, sumatriptan 50 mg group, and the sumatriptan 100 mg group respectively (p < 0.001, active treatment groups vs. placebo). CONCLUSIONS: Both sumatriptan 50 mg and 100 mg were significantly superior to placebo for the pain-free end point at two hours. The pain-free response rates in this trial where sumatriptan was taken while the headache was still mild were generally higher than in older clinical trials where headache was treated after reaching a moderate or severe intensity.

Assessment and management of disability in chronic daily headache.

The problem of chronic daily headache is ubiquitous and affects up to 5% of the world's population. In most cases, it is associated with the overuse of symptomatic medications in patients with a history of migraine or tension-type headaches, indicating an urgent need for intensive public and professional education. In a minority, it develops de novo from episodic migraine without excessive drug intake. The condition is likely to have a biologic (rather than psychologic) basis. The degree with which it negatively impacts patients and their family is reviewed. Current treatment regimes are described, but it is noted that those currently employed are seldom adequate in the long term, possibly because of the unavailability of nonpharmacologic treatments to most people or because of the low frequency of use of preventative pharmacologic and lifestyle measures.

Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed "HSN2," consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.

A headache diagnosis project.

BACKGROUND: Despite the availability of objective criteria, the diagnosis of migraine is thought to be missed frequently in primary practice. OBJECTIVE: To determine the most important questions assisting in the clinical diagnosis of migraine headache. METHODS: A cohort of 461 patients referred to headache specialists in Canada was assessed using a pro-forma questionnaire that was completed by the patients alone or administered by the physicians themselves. A final clinical diagnosis was recorded after a complete clinical evaluation. In a subsequent validation study, three questions derived from the results of the first phase of the study were administered to a new cohort of 128 patients, and diagnoses of "migraine" or "not migraine" were recorded according to the decision generated in the first part of the study. The final clinical diagnosis was taken as the "gold standard" for diagnosis, and the results from the two independently derived diagnostic methods were compared. RESULTS: Statistical analysis of the responses from part 1 of the study yielded three questions (related to daily occurrence, unilaterally, and functional impairment) that distinguished between pure migraine and other headache diagnoses with high reliability and validity. The sensitivity and selectivity of the three-question protocol exceeded 91%. CONCLUSIONS: The use of three questions related to headache frequency, laterality, and impact on functioning may represent an attractive screening instrument in primary care practice, alerting physicians to the diagnosis of migraine in patients or to the possibility of a second or alternative headache diagnosis in patients in whom their diagnosis of migraine previously has been made. The presence of multiple headache syndromes in individual patients, as is common in tertiary referral practice, may reduce the discriminating power of the three-question protocol.

Evaluating migraine disability: the headache impact test instrument in context.

Migraine impairs physical, social and emotional functioning but the diagnosis is not always made despite the availability of helpful tools. Poor patient-physician communication is one reason cited for this. It is arguable that if the impact that headaches are having on a person's life can be communicated adequately to the physician, the likelihood of appropriate management will increase. The tools currently employed for assessing headache impact are reviewed briefly and the Headache Impact Test (HIT) and HIT-6 described as validated and reliable measures of the effect that headaches are having on patients. The availability of the standard test on the internet, with feedback provided, indicates that this is a potentially useful tool enabling headache sufferers to realize the extent of the burden of migraine and empowering them to seek appropriate management strategies.

Management of acute stroke.

Preview Regardless of cause, acute stroke is a devastating illness that demands immediate treatment to contain neurologic damage, plus long-term management to assure utmost rehabilitation. In this article, the authors describe the features of stroke from various causes and discuss current therapy.

Estudo randomizado comparativo entre o cloridrato de ticlopidina e a aspirina, na prevencao de acidente vascular cerebral em paciente de alto risco

Este artigo relata os resultados do Estudo Ticlopidina-Aspirina em AVC, estudo duplo-cego realizado em 56 centros norte-americanos com o objetivo de comparar os efeitos do cloridrato de ticlopidina (500mg ao dia) com os da aspirina (1300mg ao dia) sobre o risco de acidente vascular cerebral ou morte. Os dois tratamentos foram distribuidos aleatoriamente entre os 3.069 pacientes, que apresentavam quadro recente transitorio, ou leve e persistente de isquemia retiniana ou cerebral focal. O periodo de acompanhamento variou de dois a seis anos. A incidencia de acidente vascular cerebral nao fatal ou de morte por qualquer causa apos tres anos foi de 17 por cento no grupo tratado com ticlopidina e de 19 por cento no grupo aspirina - houve reducao de 12 por cento do risco (intervalo de confianca 95 por cento, -2 a 26 por cento) com a ticlopidina (p=0,048 na estimativa acumulada de Kaplan-Meier). A incidencia de acidente vascular cerebral fatal e nao-fatal apos tres anos foi de 10 por cento no grupo de ticlopidina e de 13 por cento no grupo aspirina - reducao de 21 por cento no risco (intervalo de confianca 95 por cento, 4 a 38 por cento) com a ticlopidina (p=0,024 na analise acumulada de kaplan-Meier). a ticlopidina mostrou eficacia superior a da aspirina em ambos os sexos. Os efeitos adversos da aspirina foram diarreia (10 por cento), erupcao cutanea (5,5 por cento), ulcera (3 por cento), gastrite (2 por cento) e sangramento gastrointestinal (1 por cento). Com a ticlopidina foram observados os seguintes efeitos colaterais: diarreia (20 por cento), erupcao cutanea (14 por cento) e neutropenia acentuada porem reversivel (menos de 1 por cento). A relacao entre os niveis de lipoproteinas de alta e baixa densidade e o colesterol total foi a mesma nos dois grupos. O aumento medio dos niveis de colesterol total foi de 9 por cento com a ticlopidina e 2 por cento com a aspirina (p>0,01). Concluimos que a aspirina na prevencao de acidente vascular cerebral na populacao estudada, embora tenha provocado maior incidencia de efeitos colaterais.