Objective  To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD.

Design, Setting, and Participants  Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects.

Main Outcome Measures  Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial.

Results  The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by -tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with -tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with -tocopherol.

Conclusions  Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Published online October 12, 2009 (doi:10.1001/archneurol.2009.247).

Design  Observational and retrospective case series.

Setting  Keio University, Hanamaki General Hospital, Kanazawa University, Nagasaki University, and Juntendo University.

Patients  A cohort of 8 patients with MG with clinically defined inflammatory myopathies.

Interventions  Clinical and histological features were described. Serological analyses included MG-related antistriational autoantibodies (those to titin, ryanodine receptor, muscular voltage-gated potassium channel Kv1.4) and myositis-specific autoantibodies.

Results  Of 924 patients with MG, 8 (0.9%) had inflammatory myopathies. The mean (SD) onset age of MG was 55.3 (10.3) years. All patients showed severe symptoms with bulbar involvement; 5 patients had myasthenic crisis and 4 had invasive thymoma. Myocarditis was found in 3 patients and myositis in 6. Myocarditis, developing 13 to 211 months after the MG onset, was characterized by heart failure and arrhythmias. Myositis, developing before or at the same time as MG, affected limb and paraspinal muscles. Histological findings of skeletal muscles showed CD8⁺ lymphocyte infiltration. Seven patients had 1 of these antistriational autoantibodies but not myositis-specific autoantibodies. Immunomodulatory therapy was required for all patients and was effective for both MG and inflammatory myopathies, although 1 patient died.

Conclusions  Heart and skeletal muscles are autoimmune targets in some patients with MG. This autoimmunity has a broad clinical spectrum with antistriational autoantibodies.

Published online September 14, 2009 (doi:10.1001/archneurol.2009.229).

Objective  To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting.

Design  The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples.

Setting  Outpatient units in Germany.

Patients  Untreated and interferon beta–treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study.

Main Outcome Measures  Gene expression and serum chemokine protein levels.

Results  CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta–treated, NAB-negative MS patients. In contrast, gene expression in interferon beta–treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta–treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta–treated, NAB-positive MS patients.

Conclusions  We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta.

Published online August 10, 2009 (doi:10.1001/archneurol.2009.138).

Methods  A previously published, biophysically realistic model of the dentate gyrus that included mossy fiber sprouting between granule cells was used to model putative environmental changes associated with temporal lobe epilepsy. Properties of voltage-gated ion channels, either 1 at a time or in combinations, were varied systematically to determine their effect on network excitability.

Results  We found that the network is most sensitive to changes in steady-state voltage dependence of activation and relatively insensitive to changes in inactivation. Changes in sodium channels had the greatest effect on excitability, followed by changes in fast-delayed rectifier potassium channels and then N-type calcium channels. We also investigated the effects of simultaneous small changes in several ion channels, modeling a complex genetic background expected for common epilepsies. A combination of 2 or 3 simultaneous voltage shifts in steady-state activation as small as 2 mV could produce large changes in network excitability.

Conclusion  Statistical power calculations indicate that changes this small are effectively undetectable with current experimental practices, thus posing new challenges for the functional analysis and validation of epilepsy genes.

Design  Prospective cohort study.

Setting  Epilepsy Center, Rambam Medical Center.

Patients  Two hundred fifty-six consecutive patients who entered long-term (>1 year) antiepileptic drug–induced seizure remission were followed up prospectively for 2 years or more.

Main Outcome Measures  Seizure relapse and development of drug-resistant epilepsy.

Results  Five years after entering seizure remission, 40.2% of patients experienced seizure relapse and 25.3% of patients developed drug-resistant epilepsy. The Kaplan-Meier curves could be fitted by monoexponential functions, with a maximal seizure relapse rate of 43.6%, maximal drug-resistance rate of 27.4%, and half-decay constant of 21.5 months for both curves. Treatment history served as a significant independent prognostic risk factor for both seizure relapse and development of drug resistance. The preremission seizure frequency and duration of epilepsy were also identified as significant prognostic risk factors in the univariant analysis but failed to reach statistical significance in the multivariate analysis.

Conclusion  Seizure relapse commonly occurs in patients following long-term seizure remission. Treatment history and duration of epilepsy are predictive risk factors for both seizure relapse and development of drug resistance.

Objective  To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration.

Design  Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype.

Setting  Alzheimer disease research center.

Participants  Two generations of a family.

Main Outcome Measures  Clinical, biochemical, and neuropathologic observations in 2 generations of a family.

Results  In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children.

Conclusions  To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrP^E200K may result in increased Aβ deposition.

Objective  To relate midlife plasma Aβ measures and 10-year change in plasma Aβ measures since midlife to late-life cognitive decline.

Design  Prospective study of a population-based sample.

Setting  Academic research.

Participants  Plasma Aβ40 and Aβ42 levels were measured in 481 Nurses' Health Study participants in late midlife (mean age, 63.6 years) and again 10 years later (mean age, 74.6 years). Cognitive testing also began 10 years after the initial blood draw. Participants completed 3 repeated telephone-based assessments (mean span, 4.1 years). Multivariable linear mixed-effects models were used to estimate relations of midlife plasma Aβ40 to Aβ42 ratios and Aβ42 levels to late-life cognitive decline, as well as relations of 10-year change in Aβ40 to Aβ42 ratios and Aβ42 levels to cognitive decline.

Main Outcome Measures  The 3 primary outcomes were the Telephone Interview for Cognitive Status (TICS) findings, a global score averaging the results of all tests (TICS, immediate and delayed verbal recall, category fluency, and attention), and a verbal memory score averaging the results of 4 tests of verbal recall.

Results  Higher midlife plasma Aβ40 to Aβ42 ratios were associated with worse late-life decline on the global score (P = .04 for trend). Furthermore, increase in Aβ40 to Aβ42 ratios since midlife predicted greater decline in the global score (P = .03 for trend) and in the TICS (P = .02 for trend). There was no association of cognitive decline with midlife plasma Aβ42 levels alone or with change in Aβ42 levels since midlife.

Conclusion  In this large community-dwelling sample, higher plasma Aβ40 to Aβ42 ratios in late midlife and increases in Aβ40 to Aβ42 ratios 10 years later were significantly associated with greater decline in global cognition at late life.

Objective  To model the cognitive decline in preclinical Alzheimer disease.

Design  Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory.

Setting  Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri.

Participants  One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented.

Main Outcome Measures  Inflection point in longitudinal cognitive performance.

Results  The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease.

Conclusions  There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.

Design  We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a case-control association study.

Participants  The sample included 708 Italian subjects: 251 unrelated, sporadic patients with LOAD, 99 sporadic patients with early-onset Alzheimer disease (AD), and 358 healthy controls.

Main Outcome Measures  We analyzed the 13 SNPs in the SORL1 gene that had been studied in previous reports using case-control methods and included sex, apolipoprotein E (APOE) genotype, and age at AD onset as covariates.

Results  The SNPs 4 (rs661057), 7 (rs12364988), and 10 (rs641120) were significantly associated with LOAD compared with controls. We found an association between these 3 variants and sex, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. Of interest, the association of these SNPs with LOAD was confined to APOE 4 noncarriers. Several haplotypic associations at the 5' end of SORL1 were found, including the previously associated CGC haplotype at SNPs 8 through 10.

Conclusions  Our results confirm the association of SORL1 with AD and show a possible effect of female sex, suggesting that this gene may be a promising susceptibility factor for LOAD. Further studies to detect pathogenic variants and further elucidate the effect of SORL1 on the development of AD are necessary.

Design  Case-control association study.

Setting  Movement disorder clinic in Montreal.

Subjects  We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects.

Main Outcome Measures  Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder.

Results  The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (² = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (² = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score.

Conclusion  Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Design  Case-control and cross-sectional study.

Participants  Forty-eight patients with CBS and 14 control subjects.

Intervention  Administration of the Test of Oral and Limb Apraxia.

Main Outcome Measures  Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS.

Results  Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis.

Conclusions  In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.

Objective  To investigate whether patients with amputation experience the sensations of another person in their own phantom limb during the mere observation of someone else being touched, owing to removal of the inhibition of the mirror neuron system that would have occurred had the limb been intact.

Design  Case report.

Setting  University campus, academic setting.

Patients  Four patients with upper-limb amputation.

Main Outcome Measures  The subjective reports of patients.

Results  We report that 4 individuals with arm amputation, the mere watching of the intact hand of another being touched evokes vivid, precisely localized sensations in their own phantom hands.

Conclusions  We suggest these evoked sensations are owing to removal of neural signals from the hand that would have ordinarily inhibited the response of the mirror neurons and prevented their activity from reaching the threshold of conscious awareness.

Design  Case report with video.

Setting  University hospitals.

Patient  A 69-year-old woman presented with subacute onset of whole-body tremulousness and laryngospasm attributed to gastroesophageal reflux.

Results  Further evaluation revealed polymyoclonus, cerebellar ataxia, and laryngospasm suspicious of an underlying malignant neoplasm. Surface electromyography of multiple limb muscles confirmed the presence of polymyoclonus. The patient was seropositive for P/Q-type voltage-gated calcium channel antibody; subsequently, whole-body fluorine 18 fluorodeoxyglucose positron emission tomography and cervical lymph node biopsy revealed widespread metastatic adenocarcinoma. Follow-up serologic evaluation revealed calcium channel antibodies (P/Q type and N type) and potassium channel antibody.

Conclusions  We highlight the importance of recognizing polymyoclonus. To our knowledge, this is also the first description of a syndrome of polymyoclonus, laryngospasm, and ataxia associated with adenocarcinoma and these cation channel antibodies.

Data Sources  The MEDLINE (1966-February 2009) and Cochrane databases and reference lists of retrieved articles.

Study Selection  Randomized controlled trials on preventive antibiotic treatment in stroke. For inclusion, at least case fatality or infection rate had to be recorded.

Data Extraction  Each study was scored for methodological key issues and appraised by the Jadad scale. We extracted the data using a predetermined protocol and included all patients who were randomized or who started therapy in an intent-to-treat analysis.

Data Synthesis  We identified 4 randomized clinical trials including 426 patients; 94% had ischemic stroke. Study interventions were fluoroquinolones in 2 and tetracycline or a combination of β-lactam antibiotic with β-lactamase inhibitor in 1. Therapy was started within 24 hours of stroke onset. Duration of therapy varied between 3 and 5 days. The methodological quality ranged from 2 to 5 on the Jadad scale, and studies were subject to potential bias. The proportion of patients with infection was significantly smaller in the antibiotic group than in the placebo/control group (32 of 136 [23.5%] vs 53 of 139 [38.1%] patients). The pooled odds ratio for infection was 0.44 (95% confidence interval, 0.23-0.86). Ten of 210 patients (4.8%) in the antibiotic group died, compared with 13 of 216 (6.0%) in the placebo/control group. The pooled odds ratio for mortality was 0.63 (95% confidence interval, 0.22-1.78). No major harm or toxicity was reported.

Conclusions  In adults with acute stroke, preventive antibiotics reduced the risk of infection, but did not reduce mortality. The observed effect warrants evaluation of preventive antibiotics in large stroke trials.

Design  Retrospective cohort study.

Setting  Single tertiary care hospital.

Participants  A total of 4335 patients undergoing coronary artery bypass grafting, aortic valve replacement, or both.

Main Outcome Measures  Incidence, subtype, and arterial distribution of stroke.

Results  Clinically definite stroke was detected in 1.8% of patients undergoing cardiac operations during the same admission. Only 5.3% of these strokes were of the large-vessel type, and most strokes (76.3%) occurred without significant carotid stenosis. In 60.0% of cases, strokes identified via computed tomographic head scans were not confined to a single carotid artery territory. According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis. Undergoing combined carotid and cardiac operations increases the risk of postoperative stroke compared with patients with a similar degree of carotid stenosis but who underwent cardiac surgery alone (15.1% vs 0%; P = .004).

Conclusions  There is no direct causal relationship between significant carotid stenosis and postoperative stroke in patients undergoing cardiac operations. Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis.

Design  Inception cohort analysis.

Setting  Ambulatory population from multiple sites in the United States and Canada.

Participants  Four hundred thirteen patients with early, untreated PD who participated in 2 double-blind trials that assessed the potential of experimental drugs to serve as disease-modifying agents in PD.

Intervention  Participants were randomized into treatment groups: creatine (n = 67), minocycline (n = 66), coenzyme Q10 (n = 71), GPI-1485 (n = 71), and placebo (n = 138).

Main Outcome Measure  Time between baseline assessment and need for the initiation of symptomatic treatment for PD. The following baseline variables were assessed for their relation to the main outcome measure, while adjusting for possible treatment effect: sex; age; level of education; race/ethnicity; disease duration; occupational status; and Unified Parkinson Disease Rating Scale (UPDRS), Medical Outcomes Study Short Form Survey, Modified Rankin Scale, Schwab and England Activities of Daily Living Scale, Total Functional Capacity Scale, 39-item Parkinson Disease Questionnaire, and Geriatric Depression Scale scores. Variables reaching statistical threshold in univariate analyses ( = .15) were entered into a multivariable Cox proportional hazards regression model using time to symptomatic treatment as the dependent variable.

Results  Approximately half (48.5%) of the participants reached end point within 12 months. Higher baseline impairment and disability, as determined by UPDRS III (motor section), UPDRS II (activities of daily living section, participant rating), and Modified Rankin Scale scores and level of education were independently associated with an earlier need for symptomatic treatment.

Conclusions  In early PD, greater impairment and disability and higher level of education are independently associated with an earlier need for symptomatic treatment.

Published online July 13, 2009 (doi:10.1001/archneurol.2009.159).

Objective  To investigate occupations, specific job tasks, or exposures and risk of parkinsonism and clinical subtypes.

Design  Case-control.

Setting  Eight movement disorders centers in North America.

Participants  Inclusion criteria were parkinsonism (≥2 cardinal signs), diagnosis within 8 years of recruitment (to minimize survival bias), and ability to participate in detailed telephone interviews. Control subjects were primarily nonblood relatives or acquaintances of patients.

Main Outcome Measures  This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis ≤50 years).

Results  Findings in 519 cases and 511 controls were analyzed. Work in agriculture, education, health care, or welding was not associated with increased risk of parkinsonism. Unexpected increased risks associated with legal, construction and extraction, or religious occupations were not maintained after adjustment for duration. Risk of parkinsonism increased with pesticide use (odds ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75), and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48). None of the specific occupations, job tasks, or task-related exposures were associated with younger age at diagnosis (≤50 years). Ever working in business and finance, legal occupations, construction and extraction, or transportation and material moving was associated with postural instability and gait difficulty subtype of parkinsonism. Tobacco use was inversely associated with parkinsonism risk.

Conclusion  The association of disease risk with pesticides support a toxicant-induced cause of parkinsonism.

Design  Brain autopsy study (1988-2004) of subjects without evidence of neurodegenerative disease or tremor who were evaluated by at least 1 physician within 1 year of death. Researchers analyzed incidental Lewy pathology blinded to clinical abstraction.

Setting  Olmsted County, Minnesota.

Subjects  Residents of Olmsted County and the immediate vicinity aged older than 60 years.

Main Outcome Measures  Whether risk factors previously associated with PD in Olmsted County are also associated with iLBD.

Results  Of 235 subjects, 34 had iLBD (14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the 2 sets of odds ratio (OR) estimates, with 11 of 16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for physician occupation and caffeine intake, the ORs for iLBD were in the same direction and statistically significant, whereas for education, head injury, and number of children, they were in the same direction but not significant; they were in the opposite direction but not statistically significant for depression and anxiety. Incidental Lewy body disease was not associated with various end-of-life conditions or causes of death, though these patients were slightly older and more likely cachectic.

Conclusions  Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of iLBD could represent preclinical PD, arrested PD, or a partial syndrome due to a lesser burden of causative factors. Incidental Lewy body disease is not explained by nonspecific end-of-life brain insults.

Objective  To examine rates of occurrence and risk factors for all types of EPSs and to describe the impact of EPSs over time on the clinical course of AD.

Design  Longitudinal study.

Setting  The Washington Heights Hamilton Heights Inwood Columbia Aging Project.

Patients  A total of 388 patients with incident AD (mean age, 79 years; 71.4% female).

Main Outcome Measures  Extrapyramidal signs rated by means of a standardized portion of the Unified Parkinson's Disease Rating Scale; prevalence and incidence rates and cumulative risk for non–drug-induced EPSs; and rates of change in EPSs over time, taking into account potential covariates.

Results  Extrapyramidal signs were detected in 12.3% of patients at first evaluation and 22.6% at last evaluation. In a multivariate-adjusted generalized estimating equation model of change, total EPS score increased at an annual rate of 1.3%. Women (relative risk [RR], 1.57; P = .03), older patients (RR, 1.03; P = .02), and those with EPSs at baseline (RR, 2.07; P = .001) had greater rates of cognitive decline.

Conclusions  Extrapyramidal signs occur frequently and progress significantly in AD. Patients with incident AD and concomitant EPSs have a greater rate of cognitive decline than do patients with incident AD but without EPSs.

Objective  To evaluate the efficacy and safety of mycophenolate mofetil therapy in NMO spectrum disorders.

Design  Retrospective case series with prospective telephone follow-up.

Setting  Mayo Clinic Health System.

Patients  Twenty-four patients with NMO spectrum disorders (7 treatment-naive).

Intervention  Mycophenolate mofetil (median dose of 2000 mg per day).

Main Outcome Measures  Annualized relapse rates and disability (Expanded Disability Status Scale).

Results  At a median follow-up of 28 months (range, 18-89 months), 19 patients (79%) were continuing treatment. The median duration of treatment was 27 months (range, 1-89 months). The median annualized posttreatment relapse rate was lower than the pretreatment rate (0.09; range, 0-1.5; and 1.3; range, 0.23-11.8, respectively; P < .001). Disability stabilized or decreased in 22 of 24 patients (91%). One patient died of disease complications during follow-up. Six patients (25%) noted adverse effects during treatment with mycophenolate.

Conclusion  Mycophenolate is associated with reduction in relapse frequency and stable or reduced disability in patients with NMO spectrum disorders.

Design  Case-control study.

Setting  Mayo Clinic Neuroimmunology Laboratory (Rochester, Minnesota) and Departments of Neurology (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida).

Patients  Group 1, 835 Mayo Clinic patients, 100 with a neuromyelitis optica (NMO) spectrum disorder diagnosis and 735 without NMO spectrum disorder; group 2, 5500 non–Mayo Clinic patients.

Main Outcome Measure  Sensitivity and specificity of each assay for NMO or NMO spectrum disorder, individually and combined.

Results  In group 1, the sensitivity rates for NMO were IF, 58%; IP, 33%; and combined assays, 63%. The sensitivity rates for relapsing longitudinally extensive transverse myelitis were IF, 29%; IP, 6%; and combined assays, 29%. The specificity rates for NMO and relapsing longitudinally extensive transverse myelitis were IF, 99.6%; IP, 99.3%; and combined assays, 99.2%. In group 2, NMO-IgG was detected by IF in 498 of 5500 patients (9.1%) and by IP in 331 patients (6.0%); 76 of the 331 patients seropositive by IP (23%) were negative by IF. Clinical information was available for 124 patients (including 16 of those seropositive by IP only); 123 had a definite NMO spectrum disorder and 1 was at risk for NMO (monophasic optic neuritis).

Conclusions  In this large, clinical practice-based study, NMO-IgG detected by IF or IP was highly specific for NMO spectrum disorders. The IP assay was significantly less sensitive than IF. Combined testing improved sensitivity by 5%.

Design  Retrospective case series.

Setting  Tertiary referral center.

Patients  Patients were identified through the Mayo Clinic data retrieval system (1996-2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course, and radiological features.

Main Outcome Measures  Demographic, clinical, and radiological characteristics of the disease.

Results  Twelve patients were men. The median age of the first clinical symptom suggestive of central nervous system demyelination was 33 years, and severe MS-related cognitive impairment developed at a median age of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n = 9) or chronic progressive (n = 14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%), and cortical symptoms and signs (eg, seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain magnetic resonance imaging demonstrated diffuse cerebral atrophy in 16 and gadolinium-enhancing lesions in 11. Asymptomatic spinal cord magnetic resonance imaging lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients.

Conclusions  We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be overrepresented in this phenotype.

Objective  To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS.

Design  Cross-sectional survey.

Setting  Referral, hospital-based MS clinic.

Patients  Seventy patients with relapsing-remitting MS.

Main Outcome Measures  Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed.

Results  Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (β = 0.228; P = .02), CL volume (β = 0.452; P < .001), and normalized neocortical gray matter volume (β = 0.349; P < .001) were independent predictors of the cognitive impairment index (r² = 0.55; F = 23.903; P < .001).

Conclusion  The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.

Objectives  To establish whether the rates of conversion from mild cognitive impairment to dementia differed according to recruitment source and, if so, to investigate factors that might explain this discrepancy.

Design  Rates and predictors of conversion were examined in a prospective longitudinal study at a single center.

Setting  Among the participants, 46% were recruited from a clinical setting and 54% were recruited directly through community outreach.

Participants  One hundred eleven individuals with mild cognitive impairment were followed up longitudinally for an average of 2.4 years (range, 0.5-4.0 years).

Main Outcome Measures  Conversion from mild cognitive impairment to dementia.

Results  During the follow-up period, 28 individuals progressed to dementia with a mean (SD) time to conversion of 2.19 (0.72) years. The clinic sample had an annual conversion rate of 13%, whereas the community sample had an annual conversion rate of 3%. In a Cox proportional hazards model, clinic recruitment source alone was associated with an increased hazard of incident dementia (hazard ratio = 3.50; 95% confidence interval, 1.31-9.18; P = .01). When other variables were added to the model, only baseline functional impairment as measured by the Clinical Dementia Rating Scale (and no demographic, cognitive, or neuroimaging variables or mild cognitive impairment subtype) accounted for the differences in conversion rates across the 2 cohorts.

Conclusions  These findings add to the growing literature to suggest that the degree of functional impairment at baseline is an important predictor of conversion to dementia and may help explain differences in findings between epidemiological and clinic-based studies.

Design  Case report.

Setting  An outpatient neurorheumatology clinic at the Johns Hopkins Hospital devoted to care of patients with neurological manifestation of rheumatic diseases.

Patient  A woman with NMO and SLE.

Intervention  Rituximab therapy.

Main Outcome Measures  Clinical and neuroimaging features of relapsing disease.

Results  Recurrent and increasingly severe myelitis attacks still occurred after treatment with rituximab.

Conclusions  It may be progressively more difficult to prevent relapses and commensurate disability in patients with later stages of relapsing NMO. Recognition of NMO as a distinct diagnostic entity in patients with SLE and other rheumatic diseases is crucial, in that institution of earlier targeted immunosuppressant treatment may be more effective than later targeted immunosuppression. The cellular arm of the immune system may be recruited by pathogenic B cells and may explain why relapses may occur after treatment with B cell–depleting therapy.

Objective  To compare the prognostic utility of NMO-IgG titer and quantitative measures of complement-mediated injury to AQP4-expressing cells in NMO attacks.

Design, Setting, and Participants  A retrospective clinical-serological correlative study at Mayo Clinic's Neuroimmunology Laboratory was undertaken. Over an 18-month period, we identified NMO-IgG–seropositive patients in whom sufficient serum and adequate clinical information pertaining to NMO attacks (6 severe, 6 mild) were available to analyze clinical-serological correlations. Sera from 9 patients with multiple sclerosis and 9 healthy subjects (all NMO-IgG seronegative) served as controls. Complement activation was measured by quantifying the number of green fluorescent protein–AQP4–transfected HEK 293 cells permeable to the viability dye propidium iodide after exposure to patient serum and active complement.

Main Outcome Measures  Attack severity (mild or severe), percentage of AQP4-transfected cells lesioned, and NMO-IgG titer.

Results  The median percentage of AQP4-transfected cells lesioned by complement in the presence of serum from patients with NMO was 14% for patients with mild attacks and 54% for patients with severe attacks (P = .005). Median complement activation values for sera from healthy subjects and patients with multiple sclerosis were 8% and 12%, respectively. Patients with mild NMO attacks and patients with severe NMO attacks did not differ significantly with respect to NMO-IgG titer (P = .089).

Conclusions  A laboratory measure of complement-mediated cell injury may serve as a prognostic biomarker in NMO. Larger prospective studies are required to validate this observation.

Design  We used cell lines "poisoned" with oligomycin, the specific inhibitor of ATP synthase, and "natural" models, including transmitochondrial human cell lines (cybrids) harboring 2 different pathogenic mutations associated with the NARP/MILS phenotypes.

Main Outcome Measures  Cell survival, morphology, and ATP content.

Results  When normal human fibroblasts cultured in glucose-free medium were forced to increase energy consumption by exposure to the ionophore gramicidin or were energy challenged by oligomycin inhibition, their survival at 72 hours was 5%, but this increased to 70% when the medium was supplemented with -ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation. Homoplasmic cybrids harboring the 8993T->G NARP mutation were also protected from death (75% vs 15% survival at 72 hours) by the supplemented medium and their ATP content was similar to controls.

Conclusions  These results show that ATP synthase–deficient cells can be rescued by increasing mitochondrial substrate-level phosphorylation and suggest potential dietary or pharmacological therapeutic approaches based on the supplementation of -ketoglutarate/aspartate to patients with impaired ATP synthase activity.

Design  We conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age.

Setting  Kaiser Permanente Northern California and Stanford University.

Participants  We prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls.

Main Outcome Measure  Postpartum relapse.

Results  Of the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01).

Conclusions  Our findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study.

Published online June 8, 2009 (doi:10.1001/archneurol.2009.132).

Objective  To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD.

Design  Descriptive historical cohort.

Setting  Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota.

Patients  Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay.

Main Outcome Measures  Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review.

Results  Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis.

Conclusion  Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.

Design  Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS.

Setting  A pediatric and an adult MS center.

Patients  Patients with pediatric-onset <18 years) and adult-onset (≥18 years) MS.

Main Outcome Measures  We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (≥1cm), or enhancing.

Results  We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals.

Conclusion  While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.

Objective  To identify allelic variants that influence response to interferon beta therapy in patients with MS.

Design  Genome-wide scan.

Setting  Academic research.

Patients  Two hundred patients having relapsing-remitting MS treated with interferon beta and having a follow-up period of at least 2 years were classified as responders or nonresponders to treatment based on stringent clinical criteria.

Main Outcome Measures  In the first phase of the study, a pooling-based genome-wide association study of 428 867 single-nucleotide polymorphisms (SNPs) was performed in 53 responders and 53 nonresponders to interferon beta therapy. After applying several selection criteria, 383 SNPs were individually genotyped in an independent validation cohort of 49 responders and 45 nonresponders to interferon beta therapy using a different genotyping platform.

Results  Eighteen SNPs had uncorrected P < .05 associated with interferon beta responder status in the validation cohort. Of these, 7 SNPs were located in genes that code for alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid–type glutamate receptor GRIA3, type 1 interferon–related proteins ADAR and IFNAR2, cell cycle–dependent protein CIT, zinc finger proteins ZFAT and ZFHX4, and guanosine triphosphatase–activating protein STARD13.

Conclusions  This study supports an underlying polygenic response to interferon beta treatment in MS and highlights the importance of the glutamatergic system in patient response to interferon beta therapy.

Design  A retrospective cross-sectional study.

Setting  Taiwan.

Patients  This study linked 2 nationwide population-based data sets: Taiwan's birth certificate registry and the Taiwan National Health Insurance Research Data set. A total of 1016 women with epilepsy were selected who had single births from 2001 to 2003 and who had been diagnosed with epilepsy within 2 years prior to their index delivery, together with 8128 matched women without chronic disease as a comparison cohort. Women with epilepsy were further stratified into 2 groups for analysis: women who did and did not have seizures during pregnancy.

Main Outcome Measures  Low-birth-weight infants, preterm delivery, and infants who are small for gestational age (SGA).

Results  Compared with women without epilepsy, epileptic seizures during pregnancy were independently associated with a 1.36-fold (95% confidence interval [CI], 1.01-1.88), 1.63-fold (95% CI, 1.21-2.19), and 1.37-fold (95% CI, 1.09-1.70) increased risk of low-birth-weight infants, preterm delivery, and SGA, respectively, after adjusting for family income and parental and infant characteristics. Further, the risk of SGA increased significantly (odds ratio, 1.34; 95% CI, 1.01-1.84) for women with seizures during pregnancy compared with women with epilepsy who did not have seizures during pregnancy.

Conclusion  We suggest preventing seizures during pregnancy as an essential step to reduce risk of adverse pregnancy outcomes.

Objective  To investigate long-term outcome in patients with PEDs.

Design  We retrospectively analyzed the outcomes of patients who had PEDs diagnosed during a 7-year period. We abstracted and tabulated clinical parameters from the time of EEG, imaging findings, EEG measurements, and subsequent clinical outcome from medical records. We used descriptive, inferential, and logistic regression analysis to determine the factors associated with clinical outcomes in patients with PEDs. We divided PEDs into the following subgroups: periodic lateralized epileptiform discharges (PLEDs), generalized PEDs, and bilateral PEDs and analyzed these subgroups individually.

Setting  University-affiliated teaching hospital.

Subjects  One hundred sixty-two patients with PEDs.

Results  We obtained complete clinical, neuroimaging, neurophysiologic, and long-term outcome data in 118 patients. In the subgroup of patients with PLEDs, absence of seizures at onset (odds ratio, 0.21 per point; 95% confidence interval, 0.04-0.97) and an acute etiology for the PLEDs (odds ratio, 0.14 per point; 95% confidence interval, 0.03-0.72) were associated with death. A nonneoplastic cause for PLEDs was associated with independent functionality (odds ratio, 0.45 per point; 95% confidence interval, 0.3-0.67).

Conclusion  In patients with PLEDs, the absence of clinical seizures at the time of detection and presumed acute etiology are associated with death, whereas a nonneoplastic etiology was associated with a good clinical outcome.

Objective  To determine the incidence and predictors of new-onset unprovoked seizures.

Design  Prospective cohort study.

Setting  Three academic centers.

Patients  Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992.

Main Outcome Measure  Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or "funny" spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance,  = 0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings.

Results  Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08-1.41; P = .003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23-16.61).

Conclusions  Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.

Design  Case-control study.

Setting  Referral center.

Participants  Ninety referred patients with MS and 29 healthy volunteers.

Main Outcome Measures  Magnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36).

Results  All tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P < .001) and (r = –0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness >80 µm), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), (r = –0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = –0.69; P < .001).

Conclusions  Fractional anisotropy and are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.

Design  Retrospective study.

Subjects  A total of 63 patients with posteriorly predominant lissencephaly.

Interventions  Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined.

Results  Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly.

Conclusion  Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.

Objective  To determine the effect of rituximab on the presence of B cells in cerebral perivascular spaces.

Design, Setting, and Patients  Case report from a tertiary academic medical center. Cerebral white matter from autopsy material of a patient with gastrointestinal mantle-cell lymphoma who developed progressive multifocal leukoencephalopathy following rituximab therapy was evaluated by immunohistochemistry. Location-matched brain sections of patients with multiple sclerosis not treated with rituximab, patients without central nervous system disease, and patients with progressive multifocal leukoencephalopathy not associated with rituximab were used as controls.

Main Outcome Measures  Assessment of the number of B lymphocytes in cerebral perivascular spaces in a patient with gastrointestinal mantle-cell lymphoma treated with rituximab, patients with multiple sclerosis, patients with progressive multifocal leukoencephalopathy not associated with rituximab, and healthy control subjects.

Results  We were unable to detect B cells in cerebral perivascular spaces of the patient who developed progressive multifocal leukoencephalopathy following rituximab therapy 8 months after her last dose. In contrast, B cells were detectable in all control brain tissues.

Conclusions  To our knowledge, this is the first report to show B-lymphocyte depletion from brain tissue following rituximab therapy. A reduction in B-cell numbers may be an important contributing factor in the pathogenesis of central nervous system infections.

Design  Case report.

Setting  Tertiary referral center.

Patient  A 72-year-old man with myelofibrosis and mild leukopenia experienced progressive limb weakness and dysarthria.

Results  Imaging revealed almost complete sparing of the white matter with isolated involvement of the brainstem and deep gray matter. Postmortem examination led to definitive diagnosis of progressive multifocal leukoencephalopathy and demonstrated an unusual miliary pattern of disease rather than the typical confluent involvement. Genetic analysis revealed a mutation in the transcription control region of the JC polyomavirus, prompting speculation about the pathogenesis of progressive multifocal leukoencephalopathy.

Conclusions  Leukopenia may render patients effectively immunosuppressed. The differential diagnosis should include progressive multifocal leukoencephalopathy even in patients with atypical clinical and radiologic features.

Objective  To describe an individual after gastric bypass surgery who developed a chronic progressive myeloneuropathy, an acute optic neuropathy, along with anemia and leukopenia.

Design  Case report.

Setting  Academic center.

Patient  A 55-year-old woman, following gastric bypass surgery 22 years earlier, developed progressive numbness, weakness, and sphincter disturbance over 6 years. She awoke one morning with bilateral blindness. Examination findings showed evidence of severe myelopathy and peripheral neuropathy.

Main Outcome Measures  Magnetic resonance imaging, optical coherence tomography, electrophysiologic studies, nerve and muscle biopsy specimens, and vision testing.

Results  Over 1 year of follow-up, copper infusion therapy seemed to stabilize the progressive myeloneuropathy and improved leukopenia and anemia. It had no effect on the optic neuropathy. Optic nerve tissue injury was observed on magnetic resonance diffusion tensor imaging and on optical coherence tomography.

Conclusions  Copper deficiency should be considered in cases of atypical optic neuropathy. Serum copper levels should be monitored in patients with a compatible neurologic syndrome who have undergone gastric bypass surgery. Although visual acuity did not improve after copper infusion in our patient, prompt recognition of copper deficiency may prevent further deterioration.

Objective  To investigate the molecular basis of MNGIE in a patient with a normal plasma thymidine level.

Design  Clinical, neurophysiological, and histopathological examinations as well as molecular and genetic analyses.

Setting  Nerve and muscle center and genetic clinic.

Patient  A 42-year-old woman with clinical findings strongly suggestive for MNGIE.

Main Outcome Measures  Clinical description of the disease and its novel genetic cause.

Results  Identification of mitochondrial DNA depletion in muscle samples (approximately 12% of the control mean content) prompted us to look for other causes of our patient's condition. Sequencing of genes associated with mitochondrial DNA depletion—POLG, PEO1, ANT1, SUCLG1, and SUCLA2—did not reveal deleterious mutations. Results of sequencing and array comparative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle were negative. Sequencing of RRM2B, a gene encoding cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, c.329G>A (p.R110H) and c.362G>A (p.R121H). These mutations are predicted to affect the docking interface of the RIR2B homodimer and likely result in impaired enzyme activity.

Conclusions  This study expands the clinical spectrum of impaired RIR2B function, challenges the notion of locus homogeneity of MNGIE, and sheds light on the pathogenesis of conditions involved in the homeostasis of the mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine levels should be tested for RRM2B mutations.

Objective  To validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard.

Design, Setting, and Participants  Community-based cohort study of nondemented, ethnically diverse elderly persons in northern Manhattan.

Methods  High-resolution quantitative MRIs were acquired for 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the ² test. Putative relationships between factors potentially influencing the reporting of stroke, including memory performance, cognitive function, and vascular risk factors, were assessed using logistic regression models. Subsequently, all analyses were repeated, stratified by age, sex, ethnic group, and level of education.

Results  In analyses of the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4%, and specificity was 78.9%. In analyses stratified by median age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity and specificity, 36.7% and 81.3% vs 27.6% and 26.2%; P = .02). Impaired memory, cognitive skills, or language ability and the presence of hypertension or myocardial infarction were associated with higher rates of false-negative results.

Conclusions  Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease, and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.

Published online May 11, 2009 (doi:10.1001/archneurol.2009.83).

Objective  To describe the clinical and magnetic resonance imaging (MRI) follow-up of patients with subclinical demyelinating lesions that fulfill the Barkhof/Tintoré criteria.

Design  Prospective study.

Setting  University-affiliated teaching hospitals.

Patients  Fifty-three women and 17 men with subclinical demyelinating lesions (mean age, 35.63 years).

Main Outcome Measures  Cerebrospinal fluid, MRI, and visual evoked potential measurements.

Methods  All patients underwent their first brain MRI for various medical problems that were not suggestive of multiple sclerosis (MS). The patients' physicians proposed that they undergo paraclinical studies (blood, cerebrospinal fluid, and visual evoked potential analysis) and follow-up with MRI.

Results  Twenty-three patients (33%) had clinical conversion: 6 to optic neuritis, 6 to myelitis, 5 to brainstem symptoms, 4 to sensitive symptoms, 1 to cerebellar symptoms, and 1 to cognitive deterioration. The mean time between the first brain MRI and the first clinically isolated syndrome was 2.3 years (range, 0.8-5.0 years). Twelve patients had been treated with immunomodulators after a clinically isolated syndrome. Examination of pejorative markers for clinical conversion showed that sex, number of T2 lesions, presence of oligoclonal bands, and IgG index were not statistically different in patients with MS determined by MRI compared with clinically definite MS. Visual evoked potential abnormalities, young age, and gadolinium enhancement on follow-up MRI were more frequent in clinically definite MS than in MS determined by MRI.

Conclusions  In this cohort, we determined the rate of clinical conversion (33%) during a mean follow-up of 5.2 years. To our knowledge, this is the first clinically isolated syndrome cohort with preclinical follow-up. Early treatment of these patients with MS determined by MRI should be discussed.

Design, Setting, and Patients  We determined brain, ventricular, and leukoaraiosis volumes from axial fluid-attenuated inversion recovery MRI; we calculated brain atrophy as the difference between total intracranial and brain volumes. Microsatellite markers (n = 451) distributed across the 22 autosomes were genotyped, and we used variance components methods to estimate heritability and assess evidence of genetic linkage for each MRI measure.

Main Outcome Measures  Brain atrophy ventricular volume, and leukoaraiosis determined from fluid-attenuated inversion recovery MRI.

Results  In both races, the heritability of each MRI measure was statistically greater than 0 (P < .001), ranging in magnitude from 0.42 (for ventricular volume in blacks) to 0.69 (for brain atrophy in blacks). Based on multipoint logarithm of odds scores (MLS), the strongest evidence of genetic linkage was observed for brain atrophy on chromosomes 1 (MLS, 3.49 at 161 cM; P < .001) and 17 (MLS, 3.08 at 18 cM; P < .001) in whites; for ventricular volume on chromosome 12 (MLS, 3.67 at 49 cM; P < .001) in blacks and chromosome 10 (MLS, 2.47 at 110 cM; P < .001) in whites; and for leukoaraiosis on chromosome 11 (MLS, 2.21 at 118 cM; P < .001) in whites and chromosome 22 (MLS, 2.02 at 36 cM; P = .001) in blacks.

Conclusions  The MRI measures of structural brain injury are heritable in non-Hispanic black and white sibships ascertained through hypertensive sibling pairs. The susceptibility loci for brain atrophy, ventricular volume, and leukoaraiosis identified by linkage analyses differ among MRI measures and between races.

Objective  To establish the relationship between cigarette smoking and progression of MS using clinical and magnetic resonance imaging outcomes

Design  Cross-sectional survey and longitudinal follow-up for a mean of 3.29 years, ending January 15, 2008.

Setting  Partners MS Center (Boston, Massachusetts), a referral center for patients with MS.

Patients  Study participants included 1465 patients with clinically definite MS (25.1% men), with mean (range) age at baseline of 42.0 (16-75) years and disease duration of 9.4 (0-50.4) years. Seven hundred eighty patients (53.2%) were never-smokers, 428 (29.2%) were ex-smokers, and 257 (17.5%) were current smokers.

Main Outcome Measures  Smoking groups were compared for baseline clinical and magnetic resonance imaging characteristics as well as progression and sustained progression on the Expanded Disability Status Scale at 2 and 5 years and time to disease conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction and T2 hyperintense lesion volume were compared.

Results  Current smokers had significantly worse disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (adjusted P < .001), Multiple Sclerosis Severity Score (adjusted P < .001), and brain parenchymal fraction (adjusted P = .004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio, 2.41; 95% confidence interval, 1.09-5.34). At longitudinal analyses, MS in smokers progressed from relapsing-remitting to secondary progressive disease faster than in never-smokers (hazard ratio for current smokers vs never-smokers, 2.50; 95% confidence interval, 1.42-4.41). In addition, in smokers, the T2-weighted lesion volume increased faster (P = .02), and brain parenchymal fraction decreased faster (P = .02).

Conclusion  Our data suggest that cigarette smoke has an adverse influence on the progression of MS and accelerates conversion from a relapsing-remitting to a progressive course.

Design  Retrospective medical record analysis of cardiac patients treated with amiodarone between January 1, 1996, and July 31, 2008.

Setting  Residents of Olmsted County, Minnesota, treated at the Mayo Clinic.

Patients  The Mayo Clinic medical records of all adult Olmsted County residents prescribed amiodarone between January 1, 1996, and July 31, 2008, were reviewed and all possible neurologic adverse effects that might be attributable to amiodarone were tabulated.

Main Outcome Measures  Risk factors and clinical characteristics of patients developing neurologic problems were compared with those who did not.

Results  Over the 151 months of analysis, 707 patients were treated with amiodarone. Among these patients, the cumulative incidence of likely amiodarone neurotoxic effects was 2.8%; 1.6% of all amiodarone-treated patients were referred to Neurology for a neurotoxic reaction. Neurologic problems included tremor, gait ataxia, peripheral neuropathy, and cognitive impairment. The primary risk factor for amiodarone neurotoxic effects was duration of treatment, not age, drug dose, sex, or indication for therapy. Where this could be assessed, the adverse effects were usually but not always reversible.

Conclusions  Amiodarone infrequently causes clinically significant neurologic toxic effects. Substantially higher estimates of neurotoxic effects in the early amiodarone era may be related to a much higher daily dose.

Objective  To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD.

Design  Case-control study.

Setting  An academic medical center.

Participants:  Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease.

Main Outcome Measures  Levels of 16 organochlorine pesticides in serum samples.

Results  β-Hexachlorocyclohexane (β-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of β-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of β-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67-11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum β-HCH and PD.

Conclusions  These data suggest that β-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of β-HCH as a etiologic agent for some cases of PD.

Design  We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed.

Setting  Tertiary outpatient clinic.

Participants  Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls.

Main Outcome Measure  Cortical deactivations.

Results  Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD.

Conclusions  We describe specific malfunctioning of the default mode network during an executive task in PD. This finding is plausibly linked to dopamine depletion and may critically contribute to the understanding of executive deficits in PD.

Objective  To summarize for the neurologist the knowledge about fistula between the left atrium and esophagus occurring after RAF.

Design, Setting, and Patients  Using a MEDLINE search, we collected reports about AEF after RAF in 28 patients.

Main Outcome Measures  From the collected reports, the description of symptoms, diagnostic investigations, therapy, and outcome of the 28 patients were summarized.

Results  In 28 cases, AEF developed 3 to 38 days after RAF. Confusion, grand mal seizures, meningitis, focal cortical signs, and postprandial transient ischemic attacks associated with fever were the leading manifestations in 21 of 28 patients. Blood tests showed leukocytosis, elevated serum C-reactive protein levels, and thrombocytopenia. Blood cultures were frequently positive for bacteria. Lumbar puncture revealed pleocytosis, elevated protein levels, increased lactate levels, and bacteria. Diagnosis was established by thoracic contrast computed tomography. Endoscopy, insertion of nasogastric tubes, and transesophageal echocardiography were detrimental, leading to an increase in fistula size and food or air embolism. Therapy comprised surgery (n = 11) or temporary esophageal stenting (n = 1). The remaining patients died before attempted surgery or confirmation of the diagnosis. A neurological deficit persisted in 3 of the 9 surviving patients.

Conclusions  In patients with meningitis, stroke, seizures, or impaired consciousness and fever, it should be determined whether they have had a previous RAF. In cases with a history of recent RAF, AEF should be strongly considered, especially if there are also symptoms such as dysphagia or chest pain. After RAF, the patient, his or her family, and his or her treating physicians should be informed about the signs of AEF, which may occur even weeks after RAF.

Objectives  To explore whether the apathy manifested in frontotemporal dementia (FTD), with its predominantly anterior brain neuropathologic features, differs from the apathy in dementia of Alzheimer type (DAT), with its predominantly hippocampal- and temporoparietal-based neuropathologic features, and to determine whether other behavioral disturbances reported in frontosubcortical circuit syndromes correlate with apathy.

Design  Analyses included individual items within Neuropsychiatric Inventory subscale items. Items of the apathy/indifference subscale were designated by consensus as affective (lacking in emotions), behavioral (inactive, chores abandoned), or cognitive (no interest in the activities of others). Proportions of correlated nonapathy Neuropsychiatric Inventory items were calculated.

Setting  Several neurology specialty clinics contributed to our data set.

Participants  A total of 92 participants with FTD and 457 with DAT.

Main Outcome Measures  The Neuropsychiatric Inventory was analyzed.

Results  Apathy was more prevalent in patients with FTD than in those with DAT, but when present, the specific apathy symptoms associated with both types of dementia were rarely restricted to 1 of the 3 domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in the FTD group. Participants with affective apathy more frequently copresented with an orbital frontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also copresented with uncooperative agitation, anger, and physical agitation in both types of dementia.

Conclusions  Apathy is common in patients with FTD and DAT, although it is more common in those with FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to affect patient safety, independence, and quality of life.

Objective  To report priapism as a unique clinical manifestation of infantile transverse myelitis.

Design  Case series.

Setting  Transverse Myelitis Center at Johns Hopkins, Johns Hopkins Hospital, Baltimore, Maryland.

Patients  Three infants younger than 12 months.

Interventions  Intravenous corticosteroids, intravenous immunoglobulin, physical therapy, and rehabilitation.

Main Outcome Measure  Clinical outcomes in infants with priapism and transverse myelitis.

Results  All 3 infants demonstrated rapidly progressive quadriplegia that resulted in substantial disability and proved fatal for 1 infant.

Conclusion  Priapism in infants with transverse myelitis may be an indication of severe inflammation and neural injury that necessitates immediate and aggressive treatment.

Objective  To report a novel PME syndrome.

Design  Case report.

Setting  Epilepsy service in a tertiary care urban medical center.

Patient  A 24-year-old man with progressive myoclonus, seizures, and unique features of preserved intellect and demyelinating peripheral neuropathy.

Main Outcome Measure  Detailed clinical assessment, electrophysiologic studies, and survey of the literature.

Results  We characterize an unusual PME phenotype with unique features of preserved intellect and electrophysiologic evidence of a generalized demyelinating peripheral neuropathic condition. An extensive diagnostic evaluation did not reveal an underlying cause, and a literature survey did not identify other, similar clinical reports.

Conclusion  We describe a novel PME syndrome with preserved intellect and demyelinating peripheral neuropathy.