Methods: A sample of 140 consecutive patients with MS were interviewed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Axis I disorders (SCID-IV) from which details of cannabis use were recorded. Cognition was assessed using the Neuropsychological Battery for MS supplemented with the Symbol Digit Modalities Test (SDMT), an index of information processing speed, working memory, and sustained attention.

Results: Ten subjects (7.7%) were defined as current cannabis users based on use within the last month. Compared to non-cannabis users (n = 130), they were younger (p = 0.001). Each of the 10 current cannabis users was matched on demographic and disease variables to four subjects with MS who did not use cannabis (total control sample n = 40). Group comparisons revealed that the proportion of patients meeting DSM-IV criteria for a psychiatric diagnosis was higher in cannabis users (p = 0.04). In addition, on the SDMT, cannabis users had a slower mean performance time (p = 0.006) and a different pattern of response compared to matched controls (group x time interaction; p = 0.001).

Conclusions: Inhaled cannabis is associated with impaired mentation in patients with multiple sclerosis, particularly with respect to cognition. Future studies are required to clarify the direction of this relationship.

GLOSSARY: 7/24 = 7/24 Spatial Learning Test; BSS = Beck Suicide Scale; COWAT = Controlled Oral Word Association Test; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders; EDSS = Expanded Disability Status Scale; HADS = Hospital Anxiety and Depression Scale; MS = multiple sclerosis; NPBMS = Neuropsychological Battery for MS; PASAT = Paced Auditory Serial Addition Task; SCID-IV = Structured Clinical Interview for DSM-IV Axis I disorders; SDMT = Symbol Digit Modalities Test; SRT = Selective Reminding Test; SSSI = Social Stress and Support Inventory.

Methods: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the statistic.

Results: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2°F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%.

Conclusions: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

GLOSSARY: ED = emergency department; FS = febrile seizures; FSE = febrile status epilepticus; HHV = human herpesvirus; ILAE = International League Against Epilepsy; IQR = interquartile range; MTLE = mesial temporal lobe epilepsy; MTS = mesial temporal sclerosis.

Methods: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case–control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls.

Results: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004).

Conclusion: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

GLOSSARY: BNFC = benign neonatal familial convulsions; bp = base pair; cRNA = complementary RNA; IAE = idiopathic absence epilepsy; IE = idiopathic epilepsy; IGE = idiopathic generalized epilepsy; JME = juvenile myoclonic epilepsy; OR = odds ratio; RE = rolandic epilepsy; SNP = single nucleotide polymorphism; WT = wild type.

Methods: One hundred five patients with acute left hemisphere ischemic stroke had diffusion-weighted imaging, perfusion-weighted imaging, a test of picture naming, and other language tests at admission and 2 to 4 days later. Linear regression was used to determine whether diffusion–perfusion mismatch in any BA in language cortex, total volume of mismatch, or diffusion or perfusion abnormality predicted degree of improvement in naming by days 3 to 5.

Results: The presence of >20% diffusion–perfusion mismatch in left BA 37 and total volumes of diffusion and perfusion abnormality at day 1 each independently predicted degree of improvement in naming. Mismatch in this area did not predict the degree of improvement in other language tests or the NIH Stroke Scale in this study.

Conclusions/Relevance: Diffusion–perfusion mismatch in left Brodmann area 37 was strongly associated with acute improvement in naming, independently of volume or percentage of total mismatch or diffusion or perfusion abnormality. These data indicate that mismatch in a particular area is a marker of salvageable tissue and an important predictor of potential for recovery of functions that depend on that area. Location of mismatch before treatment may help to predict potential benefits of reperfusion.

GLOSSARY: ADC = apparent diffusion coefficient; BA = Brodmann area; DWI = diffusion-weighted imaging; NIHSS = NIH Stroke Scale; PWI = perfusion-weighted imaging; TE = echo time; TR = repetition time; TTP = time to peak.

Methods: We studied 100 consecutive patients with ischemic stroke with MCA occlusions on prebolus transcranial Doppler (TCD) examination treated with tPA following SITS-MOST criteria. MetS was diagnosed following AHA/NHLBI-2005 criteria. Resistance to thrombolysis was defined as the absence of TCD-assessed complete MCA recanalization 24 hours after tPA infusion. Infarct volume was measured on CT scans. Long-term clinical outcome was evaluated by the modified Rankin scale (mRS) score at day 90.

Results: Fifty-eight (58%) patients fulfilled MetS criteria. Median prebolus NIH Stroke Scale score was 17. Forty (42%) patients showed resistance to clot dissolution, and 53 (53%) had poor clinical outcomes (mRS > 2). A multivariable-adjusted logistic regression model identified MetS as independently associated with resistance to thrombolysis (OR 4.7, 95% CI [1.7–13.6], p = 0.004). In the whole sample, MetS was associated with mRS > 2 (OR 2.4 [1.1–5.4], p = 0.03), although this association was no longer significant after multivariable adjustment. However, in patients with atherothrombotic stroke, MetS emerged as an independent predictor of poor long-term outcome (adjusted OR 13.9 [1.3–148.7], p = 0.02).

Conclusion: In our series, the metabolic syndrome was associated with a poor response to thrombolysis in patients with acute middle cerebral artery occlusions, as reflected by a higher resistance to clot dissolution.

GLOSSARY: AHA/NHLBI = American Heart Association & National Heart, Lung and Blood Institute; BMI = body mass index; HDL = high-density lipoprotein; MCA = middle cerebral artery; MetS = metabolic syndrome; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale; TCD = transcranial Doppler; TIBI = Thrombolysis in Brain Ischemia; tPA = tissue-type plasminogen activator.

Objective: To investigate whether the reactivities of anti-GD1b IgG to such complexes are different between ataxic and nonataxic patients.

Methods: The authors examined sera from 17 patients with GBS (9 with ataxia and 8 without ataxia) who had GD1b-mono IgG, with the use of an ELISA in which wells were coated with a mixture of GD1b and each of nine gangliosides (GM1, GM2, GM3, GD1a, GD3, GT1a, GT1b, GQ1b, and GalNAc-GD1a). The binding activities of the anti-GD1b IgG antibodies against such mixture antigens were compared between ataxic and nonataxic patients.

Results: The reactivities to antigens, such as GD1b combined with GD1a, GT1b, GQ1b, and GalNAc-GD1a, were significantly reduced in ataxic compared with nonataxic patients. Sera from all nonataxic patients had antibody activities to GSCs not containing GD1b.

Conclusions: The addition of another ganglioside may cause conformational change of GD1b. Given the inhibition of the binding ability of the anti-GD1b IgG antibodies by such a conformational change, the anti-GD1b IgG antibodies in ataxic patients may interact closely with GD1b. IgG antibodies highly specific for GD1b may induce ataxia in Guillain-Barré syndrome.

GLOSSARY: GBS = Guillain-Barré syndrome; GSCs = ganglioside complexes; OD = optical density.

Objective: This prospective, randomized, double-blinded, placebo-controlled trial evaluated the safety and effectiveness of a surgically implanted shunt in subjects with probable AD.

Methods: A total of 215 subjects with probable AD by National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria received either a low-flow ventriculoperitoneal shunt or a sham (occluded) shunt for 9 months. Longitudinal CSF sampling was performed in both active and control subjects. Primary outcome measures were the Mattis Dementia Rating Scale and the Global Deterioration Scale. CSF Aβ_(1-42) and MAP- also were assayed.

Results: After a planned interim analysis, the study was halted for futility. Using the intent-to-treat population, no between-group differences were observed in the primary outcome measures. The surgical procedure and device were associated with 12 CNS infections, some temporally associated with CSF sampling. All were treated successfully.

Conclusions: We found no benefit to low-flow CSF shunting in subjects with mild to severe Alzheimer disease. CSF infections, while treatable, occurred more frequently than expected, in some cases likely related to CSF sampling.

GLOSSARY: Aβ = amyloid beta-peptides; AD = Alzheimer disease; ADCS-ADL = AD Cooperative Study Activities of Daily Living; BBB = blood–brain barrier; CP = choroid plexus; FDA = Food and Drug Administration; GDS = Global Deterioration Scale; GEE = Generalized Estimating Equations; IA = interim analysis; ISF = interstitial fluid; ITT = intent-to-treat; LRP-1 = lipoprotein receptor-related protein-1; MAP- = microtubule-associated-protein tau; MDRS = Mattis Dementia Rating Scale; MMSE = Mini-Mental State Examination; NAART = North American Adult Reading Test; NINCDS-ADRDA = National Institutes of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Disorders Association; NPH = normal-pressure hydrocephalus; PHF = perihippocampal fissures; RAGE = receptor for advanced glycation end-products; SADAS-Cog = Standardized AD Assessment Scale–Cognitive; SAE = serious adverse events.

Background: In normal aging physical fitness appears to mitigate functional and structural age-related brain changes. Whether this is observed in AD is not known.

Methods: Subjects without dementia (n = 64) and subjects with early-stage AD (n = 57) had MRI and standard clinical and psychometric evaluations. Peak oxygen consumption (VO₂^peak), the standard measure of cardiorespiratory fitness, was assessed during a graded treadmill test. Normalized whole brain volume, a brain atrophy estimate, was determined by MRI. Pearson correlation and linear regression were used to assess fitness in relation to brain volume and cognitive performance.

Results: Cardiorespiratory fitness (VO₂^peak) was modestly reduced in subjects with AD (34.7 [5.0] mL/kg/min) vs subjects without dementia (38.1 [6.3] mL/kg/min, p = 0.002). In early AD, VO₂^peak was associated with whole brain volume (beta = 0.35, p = 0.02) and white matter volume (beta = 0.35, p = 0.04) after controlling for age. Controlling for additional covariates of sex, dementia severity, physical activity, and physical frailty did not attenuate the relationships. VO₂^peak was associated with performance on delayed memory and digit symbol in early AD but not after controlling for age. In participants with no dementia, there was no relationship between fitness and brain atrophy. Fitness in participants with no dementia was associated with better global cognitive performance (r = 0.30, p = 0.02) and performance on Trailmaking A and B, Stroop, and delayed logical memory but not after controlling for age.

Conclusions: Increased cardiorespiratory fitness is associated with reduced brain atrophy in Alzheimer disease (AD). Cardiorespiratory fitness may moderate AD-related brain atrophy or a common underlying AD-related process may impact both brain atrophy and cardiorespiratory fitness.

GLOSSARY: AD = Alzheimer disease; CDR = Clinical Dementia Rating; MMSE = Mini-Mental State Examination; PASE = Physical Activity Scale in the Elderly.

Objectives: To compare the effects of various STN-DBS parameters on freezing of gait and to determine whether such effects are more related to stimulation energy (usual voltages vs high voltages at 130 Hz) or frequency (130 Hz vs approximately half this frequency: 60 Hz).

Methods: We blindly assessed STN-DBS parameters in 13 PD patients reporting severe gait disorders. We compared the effects on gait of two different voltages (the patient’s usual voltage [median 3 volts] and a high voltage [median 3.7 volts]) and two different frequencies (60 and 130 Hz, while maintaining the same total energy delivered) vs "off-stimulation" conditions.

Results: The number of freezing episodes was significantly lower at the 60-Hz "high voltage/equivalent energy" and higher at the 130-Hz/high voltage than for "off stimulation." The slight improvement in the Unified Parkinson’s Disease Rating Scale motor score observed (at 130 Hz) did not achieve statistical significance.

Conclusions: Our results prompt consideration of a new strategy for two-stage subthalamic nucleus deep brain stimulation (STN-DBS) frequency optimization, with stimulation at 130 Hz and the usual voltage during the initial years of STN-DBS and then at 60 Hz at a high voltage in Parkinson disease patients who develop severe gait disorders.

Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Aβ₄₀, Aβ₄₂, F₂-isoprostanes) and CSF (F₂-isoprostanes, t-tau, p-tau₁₈₁, Aβ₄₀, Aβ₄₂, and Aβ₄₂/Aβ₄₀ ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs).

Results: Plasma Aβ₄₂ levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Aβ₄₂/Aβ₄₀ (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Aβ₄₂ levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Aβ₄₂ to Aβ₄₀ was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau₁₈₁ levels were elevated in presymptomatic FAD MCs. CSF levels of F₂-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031).

Conclusions: Our data indicate that Aβ₄₂ is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Aβ₄₂ to Aβ₄₀ was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau₁₈₁ are sensitive indicators of presymptomatic disease. Our finding of elevated F₂-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

Methods: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58.

Results: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4–18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months).

Conclusions: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Methods: MA+ patients were consecutively enrolled as part of the Shunt Associated Migraine (SAM) study. Patients underwent a standardized headache and vascular risk factors questionnaire, contrast-enhanced transcranial Doppler, blood coagulation tests, and brain MRI. RLS was categorized into four grades: no shunt, <10 microbubbles (mb), >10 mb single spikes pattern, and >10 mb shower/curtain pattern. Standard and fluid-attenuated inversion recovery T2-weighted MRI sequences were inspected for WMLs by three independent raters blinded to RLS grade. WML load was scored in the periventricular areas (PV-WMLs) with the Fazekas scale and in the deep white matter (D-WMLs) with the Scheltens scale. Interobserver agreement was good to excellent ( = 0.64 to 0.96, p < 0.0001). WML load was then correlated between patients with and without RLS.

Results: One hundred eighty-five patients (77% women) were included. PV-WML load was similar between patients with and without RLS. D-WML load decreased in patients with RLS (p = 0.045). On logistic regression analysis, only age was associated with WMLs (p < 0.001).

Conclusions: The presence of right-to-left shunt does not increase white matter lesion load in patients who have migraine with aura.

Methods: One hundred four cognitively intact men and women followed longitudinally for up to 13 years underwent at least three MRIs with corresponding annual cognitive and neurologic assessments. Brain volume, ventricular CSF (vCSF), and total periventricular (PV) and subcortical WMH volumes were measured. Progression of MRI volumes was examined in relation to rates of cognitive, motor, and cerebral volume change based on slopes of outcomes.

Results: Higher initial total and PV WMH volume was associated with total WMH, PV WMH, and vCSF progression, and with increased time and number of steps to walk 30 feet. Progression of PV WMH volume was associated with increased time to walk 30 feet. Progression of subcortical WMH volume was associated with decreased performance on logical memory testing and increased rate of vCSF volume change.

Conclusion: Increased total and periventricular (PV) white matter hyperintensity (WMH) burden and progression of PV WMH burden are associated with decreased gait performance over time, while progression of subcortical WMH volume is associated with memory decline in cognitively intact elderly. Greater progression of WMH burden is associated with an increased risk of memory and gait dysfunction, and thus should not be considered a benign process.

Objective: To investigate the efficacy and tolerability of a fixed-dose, single-tablet formulation of sumatriptan 85 mg, formulated with RT Technology, and naproxen sodium 500 mg (sumatriptan/naproxen) as early intervention acute therapy for migraine.

Methods: Patients (aged 18 to 65 years) with International Headache Society–defined migraine with or without aura were enrolled in one of two identically designed, randomized, double-blind, parallel group, placebo-controlled studies. Patients treated a single migraine within 1 hour of onset of migraine head pain and while the pain was mild with either sumatriptan/naproxen or placebo. The primary efficacy measure was the percentage of patients who became pain-free 2 hours postdose.

Results: Intent-to-treat analyses consisted of 576 and 535 migraineurs. At 2 hours, 52% and 51% of sumatriptan/naproxen-treated patients were pain free, as compared to 17% and 15% of placebo-treated patients (p < 0.001). Significant pain-free responses in favor of sumatriptan/naproxen were demonstrated as early as 30 minutes, maintained at 1 hour, and sustained from 2 to 24 hours. At 2 and 4 hours, sumatriptan/naproxen provided significantly lower rates of traditional migraine-associated symptoms (nausea, photophobia, and phonophobia) and nontraditional migraine-associated symptoms (neck pain/discomfort and sinus pain/pressure). The most commonly reported adverse events were nausea (≤4%) and dizziness (≤2%).

Conclusion: The fixed-dose single-tablet formulation of sumatriptan/naproxen was effective and well tolerated in an early intervention paradigm for the acute treatment of migraine, including traditional and nontraditional symptoms.

Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of BtA (Dysport) for leg spasticity in 64 children with cerebral palsy. For 2 years, the children received trial injections of up to 30 mu/kg every 3 months if clinically indicated.

Results: For the primary endpoints of Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Index (PEDI) scaled scores at 2 years (trough rather than peak effect), there were no differences between the mean change scores of each group. For the GMFM total score, the 95% CI of –4.81 to 1.90 excluded a 5-point difference in either direction, and a 2-point benefit with 95% confidence. There were no differences in adverse events.

Conclusions: There was no evidence of cumulative or persisting benefit from repeated botulinum toxin A (BtA) at the injection cycle troughs at 1 year or 2 years. The dose was not enough to change spasticity measures and thus GMFM in this heterogeneous group. Ceiling effects in GMFM and Pediatric Evaluation of Disability Index (PEDI) may have reduced responsiveness. This finding does not deny the value, individually, of single injection cycles or prove that repeating them is unhelpful. In this regard, BtA treatment can be viewed in the same light as other temporary measures to relieve spasticity, such as oral or intrathecal agents: there is no evidence of continuing benefit if the treatment ceases. The study provides long-term, fully controlled adverse event data and has not revealed any long-term adverse effects.

Methods: Systematic review of incidence studies of MS published in Medline between 1966 and February 2007. Age- and sex-specific incidence rates were collected from eligible publications. We computed age-adjusted rates using the world population as standard, and assessed differences in rates according to latitude and period of case ascertainment. Additionally, we evaluated the association between period of case ascertainment and the female-to-male ratio.

Results: The overall incidence rate of MS was 3.6 cases per 100,000 person-years (95% CI 3.0, 4.2) in women and 2.0 (95% CI 1.5, 2.4) in men. Higher latitude was associated with higher MS incidence, though this latitude gradient was attenuated after 1980, apparently due to increased incidence of MS in lower latitudes. The female-to-male ratio in MS incidence increased over time, from an estimated 1.4 in 1955 to 2.3 in 2000.

Conclusion: The latitude gradient present in older incidence studies of multiple sclerosis (MS) is decreasing. The female-to-male MS ratio has increased in the last five decades.

Methods: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting.

Results: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35–85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative.

Conclusions: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

Methods: The cost-of-illness method was used to determine the costs of medical care and lost productivity, and a modified value of a statistical life approach was used to determine the cost of premature deaths. Data were obtained from the Nationwide Inpatient Sample, the Medical Expenditure Panel Survey, the Compressed Mortality File, a telephone survey of 180 adult patients with GBS, and other sources.

Results: The estimated annual cost of GBS was $1.7 billion (95% CI, $1.6 to 1.9 billion), including $0.2 billion (14%) in direct medical costs and $1.5 billion (86%) in indirect costs. Most of the medical costs were for community hospital admissions. Most of the indirect costs were due to premature deaths. The mean cost per patient with GBS was $318,966 (95% CI, $278,378 to 359,554).

Conclusions: The economic cost of Guillain-Barré syndrome (GBS) was substantial, and largely due to disability and death. The cost estimate summarizes the lifetime health burden due to GBS in monetary terms, and provides some of the information needed to assess the cost-effectiveness of health measures that affect GBS.

Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR.

Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT.

Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

Methods: We performed Western blots on CSF from patients with MS and controls with the commercially available Nogo-A antibody and secondary antibody used in a prior report. We used densitometry to measure band density on Western blot. Controls included blots without primary antibody, samples without dithiothreitol (DTT), CSF passed through a protein G column, and Western blots with anti-Ig-light chain antibody. IgG concentration in CSF was measured by ELISA.

Results: A band at about 25 kD band was detectable in almost all CSF specimens, but was darker in samples from patients with MS. The density relative to a reference sample (mean ± SD) was 0.84 ± 0.67 for relapsing MS (n = 17), 1.16 ± 0.74 for primary progressive MS (n = 11), and 0.49 ± 0.22 in controls (n = 12). This band was still present when the primary antibody was omitted, but was absent if the sample buffer did not include DTT or if the CSF was first adsorbed with protein G. IgG concentration was higher in MS CSF and correlated closely with the 25 kD band density (r = 0.78).

Conclusions: A 25 kD band is detectable on Western blots stained with Nogo-A antibody in almost all CSF specimens, but is darker in MS specimens. Our results suggest this band is immunoglobulin light chains rather than Nogo-A. It is not likely to be a useful biomarker for multiple sclerosis.

Objective: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen.

Methods: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model.

Results: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours.

Conclusions: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2–3 weeks.

Methods: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging (¹H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine.

Results: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units ± SD, patients vs controls): frontal white matter (0.051 ± 0.010 vs 0.064 ± 0.010; p = 0.001), lenticular nucleus (0.056 ± 0.011 vs 0.069 ± 0.009; p < 0.001), and thalamus (0.063 ± 0.010 vs 0.071 ± 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed.

Conclusion: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

Methods: Between July 2005 and March 2006, we undertook a cross-sectional study at 10 sentinel sites within eight Asia-Pacific countries to determine the prevalence of moderate to severe HIV-related neurocognitive impairment and symptomatic sensory neuropathy. We clinically assessed and administered sensitive neuropsychological and peripheral neuropathy screening tools to 658 patients infected with HIV. Univariate and logistic regression analyses were applied to the data.

Results: The results showed that 76 patients (11.7%) (95% CI 9.3–14.2) were significantly neurocognitively impaired, 235 patients (36.4%) (95% CI 32.7–40.2) were depressed, and 126 patients (19.7%) (95% CI 16.6–22.8) had either definite or probable symptomatic sensory neuropathy; 63% of this last group had exposure to stavudine, didanosine, or zalcitabine. Several potential confounders including depression (OR 1.49, 95% CI 0.88–2.51, p = 0.11) and prior CNS AIDS illness (OR 1.28, 95% CI 0.50–2.89, p = 0.54) were not significantly associated with neurocognitive impairment.

Conclusions: A total of 12% of patients had moderate to severe HIV-related neurocognitive impairment, 20% of patients had symptomatic sensory neuropathy, and 36% of patients had evidence of depression. This study provides a broad regional estimate of the burden of HIV-related neurologic disease and depression in the Asia-Pacific region.

Objective: To explore the extent and scope of American Academy of Neurology (AAN) guideline author reported COI and implications for management; and to review process of AAN guideline COI management to highlight challenges, establish comparative benchmarks, and identify areas to be improved.

Methods: Authors of AAN clinical practice guidelines with an active membership panel completed a COI reporting form. Authors were asked to report current interests including the 1 year prior to the date of completing the form. Interests include personal income relationships (consulting, speaker’s bureaus, advisory boards), equity (stocks/stock options), patent/royalties, research, clinical practice, fiduciary interest in a company, and expert testimony. Comparisons were made between the two committees that oversee CPG development at the AAN: the Quality Standards Subcommittee (QSS) and the Therapeutics and Technology Assessment (TTA) Subcommittee.

Results: There were 50 CPG with an average of 8.5 authors per CPG. There were a total of 425 available authors, 351 of whom completed a COI reporting form (83% response rate). Forty-six of the 50 guidelines had at least one author with a COI. The most commonly reported COIs were research-related (45% of authors), clinical practice–related (42%), and personal income relationships (33%). Authors of QSS guidelines were more likely to have personal income COIs with pharmaceutical and medical device companies (39% vs 24%, p < 0.01), whereas authors of TTA guidelines were more likely to have clinical practice–related COIs (50% vs 38%, p < 0.05). A minority of authors had individual COIs exceeding >$25,000 or had multiple interests (>10) that overlapped with content of the guidelines.

Conclusion: Conflicts of interest are common for authors of American Academy of Neurology clinical practice guidelines across many domains of personal and professional interests. More research is needed to improve the methods to identify and quantify the types of conflicts and their potential biasing effects on selecting guideline topics, grading research evidence, and formulating practice recommendations.

Methods: We previously showed that the inheritance pattern of MMD is autosomal dominant with incomplete penetrance. Here, we report the genome-wide parametric linkage analysis for MMD in 15 extended Japanese families. We conducted linkage analyses under two diagnostic classifications: narrow and broad. Affected member-only analysis was applied due to incomplete and age-dependent penetrance of the disease.

Results: Under both classifications, significant evidence of linkage was only observed on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) scores of 6.57 (under the narrow classification) and 8.07 (under the broad classification) at D17S704. Haplotype analysis revealed segregation of a disease haplotype in all families but one, and informative crossovers enabled mapping of the MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, encompassing 94 annotated genes.

Conclusions: Our data suggest that there is a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.

Methods: We explored the relationships between hemorrhage risk and treatment, baseline patient characteristics, most recent blood pressure, and most recent low-density lipoprotein (LDL) cholesterol levels prior to the hemorrhage.

Results: Of 4,731 patients, 67% had ischemic strokes, 31% TIAs, and 2% hemorrhagic strokes as entry events. In addition to atorvastatin treatment (HR 1.68, 95% CI 1.09 to 2.59, p = 0.02), Cox multivariable regression including baseline variables significant in univariable analyses showed that hemorrhagic stroke risk was higher in those having a hemorrhagic stroke as the entry event (HR 5.65, 95% CI 2.82 to 11.30, p < 0.001), in men (HR 1.79, 95% CI 1.13 to 2.84, p = 0.01), and with age (10y increments, HR 1.42, 95% CI 1.16 to 1.74, p = 0.001). There were no statistical interactions between these factors and treatment. Multivariable analyses also found that having Stage 2 (JNC-7) hypertension at the last study visit before a hemorrhagic stroke increased risk (HR 6.19, 95% CI 1.47 to 26.11, p = 0.01), but there was no effect of most recent LDL-cholesterol level in those treated with atorvastatin.

Conclusions: Hemorrhagic stroke was more frequent in those treated with atorvastatin, in those with a hemorrhagic stroke as an entry event, in men, and increased with age. Those with Stage 2 hypertension at the last visit prior to the hemorrhagic stroke were also at increased risk. Treatment did not disproportionately affect the hemorrhagic stroke risk associated with these other factors. There were no relationships between hemorrhage risk and baseline low-density lipoprotein (LDL) cholesterol level or recent LDL cholesterol level in treated patients.

Methods: A total of 310 consecutive patients hospitalized within 3 days after the onset of an ischemic stroke were prospectively enr