Showing papers in "Neurology in 2012"

Patterns of treatment response in newly diagnosed epilepsy

Abstract: Objective: To delineate the temporal patterns of outcome and to determine the probability of seizure freedom with successive antiepileptic drug regimens in newly diagnosed epilepsy. Methods: Patients in whom epilepsy was diagnosed and the first antiepileptic drug prescribed between July 1, 1982, and April 1, 2006, were followed up until March 31, 2008. Outcomes were categorized into 4 patterns: A) early and sustained seizure freedom; B) delayed but sustained seizure freedom; C) fluctuation between periods of seizure freedom and relapse; and D) seizure freedom never attained. Probability of seizure freedom with successive drug regimens was compared. Seizure freedom was defined as no seizures for ≥1 year. Results: A total of 1,098 patients were included (median age 32 years, range 9–93). At the last clinic visit, 749 (68%) patients were seizure-free, 678 (62%) on monotherapy. Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients. There was a higher probability of seizure freedom in patients receiving 1 compared to 2 drug regimens, and 2 compared to 3 regimens ( p Conclusions: Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.

Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society

Abstract: Objective: To provide updated evidence-based recommendations for the preventive treatment of migraine headache The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention? Methods: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention Results and Recommendations: The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that are reviewed herein Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A) Frovatriptan is effective for prevention of menstrual migraine (Level A) Lamotrigine is ineffective for migraine prevention (Level A)

The good, bad, and ugly? How blood nutrient concentrations may reflect cognitive performance.

Abstract: A growing body of evidence is supportive of the influence of nutritional factors on cognitive health. There is evidence relating nutrition to cognitive measures to assess cognitive change over time, but such functional changes may not reflect the neuroanatomic or pathologic alterations that have occurred. Brain imaging may complement clinical assessment of dementia and hence, an understanding of how nutrients alter brain structure, specifically volumes, is key. The scarcity of such information is due in part to costs of brain imaging as well as the reluctance of participants to undergo these tests. Further, the complexity of dietary exposures or behaviors, and how best to characterize or quantify their diversity, are not only demanding of the respondent, but also demand a level of expertise in the investigator that is often overlooked. Most efforts have been directed to examining associations between single nutrients and cognitive status. More recently, nutritional epidemiologists have described dietary pattern—disease associations using a variety of approaches. These include a posteriori methods, such as factor or cluster analyses, that reduce nutrient data into investigator-named dietary patterns based on the intercorrelations between food/nutrient items or for cluster analyses on the differences1; a comparison of a priori patterns, such as the Mediterranean pattern2,3; and reduced rank regression, which is a combination of the 2 methods.4 All of these approaches are highly dependent on the performance characteristics (validity and reliability) of the dietary instruments used in the intended population. Application of one of these analytical approaches is appealing because extraction of dietary patterns can distill the synergistic and sometimes antagonistic metabolic influences of food groups or nutrients (even anti-nutrients) within foods. Additional advantages of such methods include the ability to summarize dietary behavior when examined in the context of other health behaviors, the avoidance of type I (false-positive) error inflation when many nutrients are examined, and an alternative way to account for redundancy in contribution that several nutrients have on the outcomes (here, cognitive performance, brain volumes).1–4 Moreover, if a dietary pattern is highly predictive of improved health outcomes, it may be easier to translate that pattern into practice, as has been reported for the Dietary Approaches to Stop Hypertension (DASH) diet plan.5 People eat foods, not nutrients, and they eat them in combination, not in isolation.

Tafamidis for transthyretin familial amyloid polyneuropathy A randomized, controlled trial

Abstract: Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this rando ...

Age at stroke: temporal trends in stroke incidence in a large, biracial population.

Abstract: Objectives: We describe temporal trends in stroke incidence stratified by age from our population-based stroke epidemiology study. We hypothesized that stroke incidence in younger adults (age 20–54) increased over time, most notably between 1999 and 2005. Methods: The Greater Cincinnati/Northern Kentucky region includes an estimated population of 1.3 million. Strokes were ascertained in the population between July 1, 1993, and June 30, 1994, and in calendar years 1999 and 2005. Age-, race-, and gender-specific incidence rates with 95 confidence intervals were calculated assuming a Poisson distribution. We tested for differences in age trends over time using a mixed-model approach, with appropriate link functions. Results: The mean age at stroke significantly decreased from 71.2 years in 1993/1994 to 69.2 years in 2005 ( p p = 0.002), characterized as a shift to younger strokes in 2005 compared with earlier study periods. Stroke incidence rates in those 20–54 years of age were significantly increased in both black and white patients in 2005 compared to earlier periods. Conclusions: We found trends toward increasing stroke incidence at younger ages. This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable.

Extreme delta brush A unique EEG pattern in adults with anti-NMDA receptor encephalitis

Abstract: Objectives: To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder. Methods: We evaluated the clinical and EEG data of 23 hospitalized adult patients with anti-NMDAR encephalitis who underwent cEEG monitoring between January 2005 and February 2011 at 2 large academic medical centers. Results: Twenty-three patients with anti-NMDAR encephalitis underwent a median of 7 (range 1−123) days of cEEG monitoring. The median length of hospitalization was 44 (range 2−200) days. Personality or behavioral changes (100%), movement disorders (82.6%), and seizures (78.3%) were the most common symptoms. Seven of 23 patients (30.4%) had a unique electrographic pattern, which we named “extreme delta brush” because of its resemblance to waveforms seen in premature infants. The presence of extreme delta brush was associated with a more prolonged hospitalization (mean 128.3 ± 47.5 vs 43.2 ± 39.0 days, p = 0.008) and increased days of cEEG monitoring (mean 27.6 ± 42.3 vs 6.2 ± 5.6 days, p = 0.012). The modified Rankin Scale score showed a trend toward worse scores in patients with the extreme delta brush pattern (mean 4.0 ± 0.8 vs 3.1 ± 1.1, p = 0.089). Conclusions: Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome.

Total daily physical activity and the risk of AD and cognitive decline in older adults

Abstract: Objective: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Methods: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. Results: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273–0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). Conclusions: A higher level of total daily physical activity is associated with a reduced risk of AD.

Reducing in-hospital delay to 20 minutes in stroke thrombolysis

Abstract: Objectives: Efficacy of thrombolytic therapy for ischemic stroke decreases with time elapsed from symptom onset. We analyzed the effect of interventions aimed to reduce treatment delays in our single-center observational series. Methods: All consecutive ischemic stroke patients treated with IV alteplase (tissue plasminogen activator [tPA]) were prospectively registered in the Helsinki Stroke Thrombolysis Registry. A series of interventions to reduce treatment delays were implemented over the years 1998 to 2011. In-hospital delays were analyzed as annual median door-to-needle time (DNT) in minutes, with interquartile range. Results: A total of 1,860 patients were treated between June 1995 and June 2011, which included 174 patients with basilar artery occlusion (BAO) treated mostly beyond 4.5 hours from symptom onset. In the non-BAO patients, the DNT was reduced annually, from median 105 minutes (65–120) in 1998, to 60 minutes (48–80) in 2003, further on to 20 minutes (14–32) in 2011. In 2011, we treated with tPA 31% of ischemic stroke patients admitted to our hospital. Of these, 94% were treated within 60 minutes from arrival. Performing angiography or perfusion imaging doubled the in-hospital delays. Patients with in-hospital stroke or arriving very soon from symptom onset had longer delays because there was no time to prepare for their arrival. Conclusions: With multiple concurrent strategies it is possible to cut the median in-hospital delay to 20 minutes. The key is to do as little as possible after the patient has arrived at the emergency room and as much as possible before that, while the patient is being transported.

Neurodegenerative causes of death among retired National Football League players

Abstract: Objective:Toanalyzeneurodegenerativecausesofdeath,specificallyAlzheimerdisease(AD),Parkinson disease, and amyotrophic lateral sclerosis (ALS), among a cohort of professional football players. Methods:This was a cohort mortality study of 3,439 National Football League players with at least 5 pension-credited playing seasons from 1959 to 1988. Vital status was ascertained through 2007. For analysis purposes, players were placed into 2 strata based on characteristics of position played: nonspeed players (linemen) and speed players (all other positions except punter/kicker). External comparisons with the US population used standardized mortality ratios (SMRs); internal comparisons between speed and nonspeed player positions used standardized rate ratios (SRRs). Results:Overall player mortality compared with that of the US population was reduced (SMR 0.53, 95% confidence interval [CI] 0.48!0.59). Neurodegenerative mortality was increased using both underlying cause of death rate files (SMR 2.83, 95% CI 1.36!5.21) and multiple cause of death (MCOD) rate files (SMR 3.26, 95% CI 1.90!5.22). Of the neurodegenerative causes, results were elevated (using MCOD rates) for both ALS (SMR 4.31, 95% CI 1.73!8.87) and AD (SMR 3.86, 95% CI 1.55!7.95). In internal analysis (using MCOD rates), higher neurodegenerative mortality was observed among players in speed positions compared with players in nonspeed positions (SRR 3.29, 95% CI 0.92!11.7). Conclusions:The neurodegenerative mortality of this cohort is 3 times higher than that of the general US population; that for 2 of the major neurodegenerative subcategories, AD and ALS, is 4 times higher. These results are consistent with recent studies that suggest an increased risk of neurodegenerative disease among football players.Neurology ® 2012;79:1‐1

Comparative safety of antiepileptic drugs during pregnancy

Abstract: Objective: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy. Methods: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months9 gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression. Results: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0–8.5) for valproate, 2.9 (1.4–5.8) for phenobarbital, and 2.2 (1.2–4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip. Conclusions: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology

Abstract: Objective: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. Methods: Drawing from larger calibrated item banks, we developed short measures (8–9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. Results: Internal consistency (Cronbach α) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82–0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1–2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. Conclusion: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function.

Serologic diagnosis of NMO: A multicenter comparison of aquaporin-4-IgG assays

Abstract: Objectives: Neuromyelitis optica (NMO) immunoglobulin G (IgG) (aquaporin-4 [AQP4] IgG) is highly specific for NMO and related disorders, and autoantibody detection has become an essential investigation in patients with demyelinating disease. However, although different techniques are now used, no multicenter comparisons have been performed. This study compares the sensitivity and specificity of different assays, including an in-house flow cytometric assay and 2 commercial assays (ELISA and transfected cell-based assay [CBA]). Methods: Six assay methods (in-house or commercial) were performed in 2 international centers using coded serum from patients with NMO (35 patients), NMO spectrum disorders (25 patients), relapsing-remitting multiple sclerosis (39 patients), miscellaneous autoimmune diseases (25 patients), and healthy subjects (22 subjects). Results: The highest sensitivities were yielded by assays detecting IgG binding to cells expressing recombinant AQP4 with quantitative flow cytometry (77; 46 of 60) or visual observation (CBA, 73%; 44 of 60). The fluorescence immunoprecipitation assay and tissue-based immunofluorescence assay were least sensitive (48%–53%). The CBA and ELISA commercial assays (100% specific) yielded sensitivities of 68% (41 of 60) and 60% (36 of 60), respectively, and sensitivity of 72% (43 of 60) when used in combination. Conclusions: The greater sensitivity and excellent specificity of second-generation recombinant antigen-based assays for detection of NMO-IgG in a clinical setting should enable earlier diagnosis of NMO spectrum disorders and prompt initiation of disease-appropriate therapies.

Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304

Abstract: Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures Methods: This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrialsgov identifier: NCT00699972) Patients (12 years, with ongoing seizures despite 1–3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration Results: Of 388 patients randomized and treated, 387 provided seizure frequency data Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was 210%, 263%, and 345% for placebo and perampanel 8 and 12 mg, respectively (p 00261 and p 00158 for 8 and 12 mg vs placebo, respectively) Fifty percent responder rates during the maintenance period were 264%, 376%, and 361%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p 00760) or 12 mg (p 00914) Sixty-eight (175%) patients discontinued, including 40 (103%) for adverse events Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia Conclusions: This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable Classification of evidence: This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures Neurology ® 2012;79:589–596

Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype

Abstract: Objectives: To report an association of myelin-oligodendrocyte glycoprotein (MOG) antibodies with aquaporin-4 (AQP4) antibody–seronegative neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) in adults. Methods: We describe the clinical and serologic features of 4 adult patients with an NMO/NMOSD phenotype who had antibodies to MOG. Results: Twenty-seven adult AQP4-seronegative NMO/NMOSD patients were tested for MOG antibodies. Four patients (3 male, 1 female) with severe optic neuritis and/or longitudinally extensive transverse myelitis were positive. All 4 made good recoveries with steroids or plasma exchange. Two patients experienced recurrence of symptoms when corticosteroids were withdrawn quickly but none have experienced further relapses over a mean follow-up of 12 months, although 3 patients remain on treatment. Imaging abnormalities resolved fully following clinical recovery and MOG antibody titers fell in all 4 patients. MOG antibodies were not found in 44 AQP4 antibody–positive NMO/NMOSD patients, 75 adult patients with multiple sclerosis, or 47 healthy individuals. Conclusions: MOG antibody–associated NMO/NMOSD could account for some cases thought previously to be AQP4-seronegative NMO/NMOSD. Our 4 patients appear to have more favorable clinical outcomes than those with typical AQP4 antibody–mediated disease. However, further studies of NMO/NMOSD and other demyelinating conditions are required to help clarify the diagnostic and prognostic relevance of MOG antibodies.

Blood–brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke

Abstract: It has been more than a century since Paul Ehrlich, in 1885, and later his student Edwin Goldmann, proposed that a barrier existed between the CNS and the peripheral circulation.1 While studying the limited permeation of potassium ferrocyanate into the brain in 1900, Lewandowsky coined the term bluthirnschranke, blood–brain barrier (BBB).1 The BBB is considered the gatekeeper of the CNS, whose main role is to maintain the fragile homeostasis of the brain designed by segregating the CNS from the systemic circulation. The BBB is composed of endothelial cells, pericytes, astrocytes, neurons, and the extracellular matrix (ECM), which are collectively known as the neurovascular unit (NVU). BBB endothelial cells lack fenestrations, have tight junctions (TJs), have minimal pinocytotic activity, and express a number of enzymes capable of degrading both harmful and therapeutic molecules. They also have increased mitochondrial content, which is required for the multiple energy-dependent processes involved in nutrient support and protection of the brain.1,–,3 Pericytes are vascular smooth-muscle-lineage cells that occur as solitary cells embedded in the basement membrane of microvessels and have their own characteristic morphology.4 Both the endothelial cells and pericytes are surrounded by the basal lamina, which is 30- to 40-nm contiguous with the plasma membranes of astrocyte end-feet. The basal lamina supports and anchors cells via adhesion receptors and regulates intercellular communication. Astrocytes play a very important role not only in BBB support and its maintenance but also in neuron–NVU interactions. Under conditions of ischemia, there is a disruption of the bidirectional communication between microvessels and neurons with the participation of the intervening astrocytes.3 The greater the distance between the microvessels and the neurons [(m − n) distance], the higher the likelihood of being prone to ischemic injury.3 Microglial cells are basically the macrophages of …

Vitamin D, cognition, and dementia: a systematic review and meta-analysis.

Abstract: Objective: To examine the association between cognitive function and dementia with vitamin D concentration in adults. Methods: Five databases were searched for English-language studies up to August 2010, and included all study designs with a comparative group. Cognitive function or impairment was defined by tests of global or domain-specific cognitive performance and dementia was diagnosed according to recognized criteria. A vitamin D measurement was required. Two authors independently extracted data and assessed study quality using predefined criteria. The Q statistic and I 2 methods were used to test for heterogeneity. We conducted meta-analyses using random effects models for the weighted mean difference (WMD) and Hedge9s g . Results: Thirty-seven studies were included; 8 contained data allowing mean Mini-Mental State Examination (MMSE) scores to be compared between participants with vitamin D I 2 = 0.65; p = 0.002). The small positive effect persisted despite several sensitivity analyses. Six studies presented data comparing Alzheimer disease (AD) to controls but 2 utilized a method withdrawn from commercial use. For the remaining 4 studies the AD group had a lower vitamin D concentration compared to the control group (WMD = −6.2 nmol/L, 95% CI −10.6 to −1.8) with no heterogeneity ( I 2 p = 0.53). Conclusion: These results suggest that lower vitamin D concentrations are associated with poorer cognitive function and a higher risk of AD. Further studies are required to determine the significance and potential public health benefit of this association.

Randomized phase III study 306 Adjunctive perampanel for refractory partial-onset seizures

Abstract: Objective: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1–3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1–3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. Results: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency—the primary efficacy endpoint—was −10.7%, −13.6%, −23.3%, and −30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day ( p = 0.0026) and 8 mg/day ( p p = 0.0132) and 8 mg/day ( p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. Conclusions: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. Classification of Evidence: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

Is dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam Study.

Abstract: Objective: To investigate whether dementia incidence has changed over the last 2 decades. Methods: We compared dementia incidence in 2 independent subcohorts of persons aged 60–90 years from the Rotterdam Study, a population-based cohort study. The first subcohort started in 1990 (n = 5,727), the second in 2000 (n = 1,769). Participants were dementia-free at baseline and followed for at maximum 5 years. We calculated age-adjusted dementia incidence rates for the 2 subcohorts in total, in 10-year age strata, and for men and women separately. We also compared mortality rates, differences in prevalence of vascular risk factors, and medication use. Finally, we compared brain volumes and the extent of cerebral small vessel disease in participants who underwent brain imaging 5 years after the baseline examinations. Results: In the 1990 subcohort (25,696 person-years), 286 persons developed dementia, and in the 2000 subcohort (8,384 person-years), 49 persons. Age-adjusted dementia incidence rates were consistently, yet nonsignificantly, lower in the 2000 subcohort in all strata, reaching borderline significance in the overall analysis (incidence rate ratio 0.75, 95% confidence interval [CI] 0.56–1.02). Mortality rates were also lower in the 2000 subcohort (rate ratio 0.63, 95% CI 0.52–0.77). The prevalence of hypertension and obesity significantly increased between 1990 and 2000. This was paralleled by a strong increase in use of antithrombotics and lipid-lowering drugs. Participants in 2005–2006 had larger total brain volumes ( p Conclusions: Although the differences in dementia incidence were nonsignificant, our study suggests that dementia incidence has decreased between 1990 and 2005.

β-Amyloid burden in healthy aging Regional distribution and cognitive consequences

Abstract: Objective: Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of β-amyloid (Aβ) in a healthy adult lifespan sample (aged 30–89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. Methods: A total of 137 well-screened and cognitively normal adults underwent Aβ PET imaging with radiotracer 18 F-florbetapir. Aβ load was estimated from 8 cortical regions. Participants were genotyped for A PO E and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability. Results: Aβ deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE e4 (38%) than nonelevated adults (19%). Aβ burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. Conclusions: Even in a highly selected lifespan sample of adults, Aβ deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses.

Primary progressive aphasia: A tale of two syndromes and the rest

Abstract: Objective: Primary progressive aphasia (PPA) has been proposed to comprise 3 discrete clinical subtypes: semantic, agrammatic/nonfluent, and logopenic. Recent consensus recommendations suggest a diagnostic framework based primarily on clinical and neuropsychological findings to classify these variants. Our objective was to evaluate the extent to which patients with PPA would conform to the proposed tripartite system and whether the clustering pattern of elements of the linguistic profile suggests discrete clinical syndromes. Methods: A total of 46 patients with PPA were prospectively recruited to the Cambridge Longitudinal Study of PPA. Sufficient data were collected to assess all consensus-proposed diagnostic domains. By comparing patients9 performances against those of 30 age- and education-matched healthy volunteers, z scores were calculated, and values of 1.5 SDs outside control participants9 means were considered abnormal. Raw test scores were used to undertake a principal factor analysis to identify the clustering pattern of individual measures. Results: Of the patients, 28.3%, 26.1%, and 4.3% fitted semantic, nonfluent/agrammatic, and logopenic categories respectively, and 41.3% did not fulfill the diagnostic recommendations for any of the 3 proposed variants. There was no significant between-group difference in age, education, or disease duration. Furthermore, the outcome of the factor analysis was in keeping with discrete semantic and nonfluent/agrammatic syndromes but did not support a logopenic variant. Conclusion: Taken together, the results of this prospective data-driven study suggest that although a substantial proportion of patients with PPA have neither the semantic nor the nonfluent variants, they do not necessarily conform to a discrete logopenic variant.

Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes.

Abstract: Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinson9s Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p p p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients ( p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology ® 2012;79:55–65

Total daily physical activity and the risk of AD and cognitive decline in older adultsAuthor Response

Abstract: Editors' Note: In reference to “Total daily physical activity and the risk of AD and cognitive decline in older adults” by Buchman et al., Dr. Abe points out that many subjects at the beginning of the study already had mild cognitive impairment, which could affect their activity level and likelihood of developing Alzheimer disease. He suggests that a longer observational period might have helped to compensate. The authors agree with Dr. Abe that an ideal study would only include subjects without cognitive impairment. Drs. Deisenhammer and Hegen lament that neutralizing antibodies against …

Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study.

Abstract: Objective: Cerebral microbleeds are frequently found in the general elderly population and may reflect underlying vascular disease, but their role in cognitive function is unknown. Methods: We investigated the association between cerebral microbleeds and performance in multiple cognitive domains in 3,979 persons without dementia (mean age, 60.3 years). Mini-Mental State Examination (MMSE) score and neuropsychological tests were used to assess global cognition and the following cognitive domains: memory, information processing speed, executive function, and motor speed. We used number of microbleeds as continuous variable, and additionally distinguished between persons with no microbleeds, 1 microbleed, 2–4 microbleeds, and ≥5 microbleeds. The association of microbleeds with different cognitive domains was estimated using linear regression models. Additional adjustments were made for vascular risk factors, brain atrophy, and other imaging markers of cerebral small vessel disease. We stratified analyses by location of microbleeds. Results: A higher number of microbleeds was associated with lower MMSE score and worse performance on tests of information processing speed and motor speed. When analyzed per category, presence of 5 or more microbleeds was associated with worse performance in all cognitive domains, except memory. These associations were most robust in participants with strictly lobar microbleeds, whereas after additional adjustments associations disappeared for deep or infratentorial microbleeds. Conclusions: Presence of numerous microbleeds, especially in a strictly lobar location, is associated with worse performance on tests measuring cognitive function, even after adjustments for vascular risk factors and other imaging markers of small vessel disease. These results suggest an independent role for microbleed-associated vasculopathy in cognitive impairment.

Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis

Abstract: Objective: This study aims to evaluate protective effects of brief repetitive bilateral arm ischemic preconditioning (BAIPC) on stroke recurrence in patients with symptomatic atherosclerotic intracranial arterial stenosis (IAS). Methods: A total of 68 consecutive cases with symptomatic IAS, diagnosed by imaging, were enrolled in this prospective and randomized study. All patients received standard medical management. Patients in the BAIPC group (n = 38) underwent 5 brief cycles consisting of bilateral upper limb ischemia followed by reperfusion. The BAIPC procedure was performed twice daily over 300 consecutive days. Incidence of recurrent stroke and cerebral perfusion status in BAIPC-treated patients were compared with the untreated control group (n = 30). Results: In the control group, incidence of recurrent stroke at 90 and 300 days were 23.3% and 26.7%, respectively. In the BAIPC group, incidence of recurrent stroke was reduced to 5% and 7.9% at 90 and 300 days ( p p Conclusion: This study provides a proof-of-concept that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS. Further investigation of this therapeutic approach is warranted as some patients were excluded after randomization.

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

Abstract: Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a wellbehaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology ® 2012;78:690–695

Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sampleAuthor Response

Abstract: # {#article-title-2} Rossetti et al.1 reported a population-based study of scores on the Montreal Cognitive Assessment (MoCA) in Texas. Compared to our study2 in Montreal, the Caucasian group of normal controls in the Rossetti et al. study was considerably younger (52.9 vs 72.8 years) and had slightly lower mean MoCA scores (25.6 vs 26.9). In the other ethnic groups, they found substantial effects of age and education on their MoCA scores. Subjects in our study were excluded if they had subjective complaints …

Long-lasting treatment effect of rituximab in MuSK myasthenia

Abstract: Objective: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients. Methods: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. Results: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3. Conclusion: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. Classification of evidence: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant

Abstract: Objective: To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia. Methods: We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep. Results: Suvorexant showed significant ( p values Conclusions: The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia. Classification of evidence: This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society

Abstract: The 2012 AAN guideline “Evidence-based guideline update: NSAIDS and other complementary treatments for episodic migraine prevention in adults” has been retired by the AAN Board of Directors on September 16, 2015, due to serious safety concerns with a preventative treatment, butterbur,

Evidence-based guideline update: Medical treatment of infantile spasms Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Abstract: Objective: To update the 2004 American Academy of Neurology/Child Neurology Society practice parameter on treatment of infantile spasms in children. Methods: MEDLINE and EMBASE were searched from 2002 to 2011 and searches of reference lists of retrieved articles were performed. Sixty-eight articles were selected for detailed review; 26 were included in the analysis. Recommendations were based on a 4-tiered classification scheme combining pre-2002 evidence and more recent evidence. Results: There is insufficient evidence to determine whether other forms of corticosteroids are as effective as adrenocorticotropic hormone (ACTH) for short-term treatment of infantile spasms. However, low-dose ACTH is probably as effective as high-dose ACTH. ACTH is more effective than vigabatrin (VGB) for short-term treatment of children with infantile spasms (excluding those with tuberous sclerosis complex). There is insufficient evidence to show that other agents and combination therapy are effective for short-term treatment of infantile spasms. Short lag time to treatment leads to better long-term developmental outcome. Successful short-term treatment of cryptogenic infantile spasms with ACTH or prednisolone leads to better long-term developmental outcome than treatment with VGB. Recommendations: Low-dose ACTH should be considered for treatment of infantile spasms. ACTH or VGB may be useful for short-term treatment of infantile spasms, with ACTH considered preferentially over VGB. Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome. A shorter lag time to treatment of infantile spasms with either hormonal therapy or VGB possibly improves long-term developmental outcomes.