Neurology June 2009 Volume 72 Issue 22

Objective: A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2, result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding.Methods: We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD.Results: We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 (p = 0.28).Conclusions: We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37.GLOSSARY: GDS = Geriatric Depression Scale; MMSE = Mini-Mental State Examination; NCRAD = National Cell Repository for Alzheimer's Disease; PD = Parkinson disease; PSG = Parkinson Study Group; UPDRS = Unified Parkinson's Disease Rating Scale.(C)2009AAN Enterprises, Inc.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent Alzheimer dementia (AD).Methods: We analyzed the association of prior NSAID exposure with incident dementia and AD in the Adult Changes in Thought population-based cohort aged >=65 years (median 74.8) at enrollment. Participants were members of Group Health, which provided computerized pharmacy dispensing records from 1977 onward. We studied 2,736 dementia-free enrollees with extensive prior pharmacy data, following them biennially for up to 12 years to identify dementia and AD. Cox proportional hazards regression assessed association of dementia or AD with NSAID use graded in standard daily doses (SDD) dispensed over 2 years (e.g., heavy use = 500+ SDD), with some analyses also adding consecutive biennial self-reports of NSAID use.Results: Pharmacy records identified 351 participants (12.8%) with history of heavy NSAID use at enrollment. Another 107 became heavy users during follow-up. Some 476 individuals developed incident dementia, 356 with AD (median onset ages 83.5 and 83.8 years). Contrary to the hypothesis that NSAIDs protect against AD, pharmacy-defined heavy NSAID users showed increased incidence of dementia and AD, with adjusted hazard ratios of 1.66 (95% confidence interval, 1.24-2.24) and 1.57 (95% confidence interval, 1.10-2.23). Addition of self-reported exposure data did not alter these results.Conclusions: These findings differ from those of other studies with younger cohorts. The results observed elsewhere may reflect delayed onset of Alzheimer dementia (AD) in nonsteroidal anti-inflammatory drug (NSAID) users. Conceivably, such delay could result in increased AD incidence in late old age. The relation of NSAID use and AD pathogenesis needs further investigation.GLOSSARY: ACT = Adult Changes in Thought; AD = Alzheimer dementia; ADL = activities of daily living; aHR = adjusted hazard ratio; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; GH = Group Health; HR = hazard ratio; NSAID = nonsteroidal anti-inflammatory drug; OR = odds ratio; SDD = standard daily dose.(C)2009AAN Enterprises, Inc.

Objective: To analyze and compare the extent of remyelination in lesions from patients with multiple sclerosis (MS) who have a short (early MS lesions) or a long (chronic MS lesions) disease duration and to determine the influence of anatomic localization on the extent of remyelination. In early MS lesions, remyelination has been described as a relatively frequent event, in contrast to chronic MS lesions, where remyelination is absent or limited to the lesion border in the majority of lesions. However, no studies have been published that have quantified and compared the extent of remyelination in early and chronic MS lesions.Methods: We analyzed the occurrence of remyelination in 52 biopsies from 51 patients (early MS) and in 174 lesions from 36 autopsy cases (chronic MS) by immunohistochemistry for myelin proteins, and correlated our findings with anatomic localization, sex, age, and disease duration.Results: Significantly more lesions were remyelinated in early than in chronic MS (80.7% vs 60%). In chronic MS, subcortical lesions showed more extensive remyelination than periventricular lesions. The majority of cerebellar lesions were completely demyelinated.Conclusion: In summary, our data demonstrate that remyelination is a frequent event in early multiple sclerosis lesions. Furthermore, the anatomic localization of a lesion might influence the extent of remyelination.GLOSSARY: CNPase = 2,3-cyclic nucleotide 3-phosphodiesterase; LFB = Luxol fast blue; MBP = myelin basic protein; MOG = myelin oligodendrocyte protein; MS = multiple sclerosis; OPC = oligodendrocyte progenitor cell; PAS = periodic acid-Schiff; PBS = phosphate-buffered saline; PLP = proteolipid protein.(C)2009AAN Enterprises, Inc.

Background: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA.Methods: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12-24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner.Results: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen.Conclusions: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening.GLOSSARY: BS = burst suppression; CA = cardiac arrest; CPR = cardiopulmonary resuscitation; DD = developmental delay; FEN = fentanyl; FOS = fosphenytoin; HIE = hypoxic ischemic encephalopathy; LEV = levetiracetam; LZP = lorazepam; MDZ = midazolam; NCS = nonconvulsive seizures; NCSE = nonconvulsive status epilepticus; NPV = negative predictive value; PB = phenobarbital; PED = periodic epileptiform discharge; PICU = pediatric intensive care unit; PPV = positive predictive value; SE = status epilepticus; SIDS = sudden infant death syndrome; sz = seizures; TH = therapeutic hypothermia; VEC = vecuronium; VPA = valproic acid; VT = ventricular tachycardia.(C)2009AAN Enterprises, Inc.

Objective: To determine how clinical features at the first evaluation and in follow-up can be used to suggest a diagnostic outcome for patients with only upper motor neuron (UMN) signs at disease onset.Methods: We reviewed the records of 34 patients (9 primary lateral sclerosis [PLS], 15 UMN-dominant amyotrophic lateral sclerosis [ALS], and 10 randomly selected control patients with ALS) seen in 1984-2007. Analysis of variance F tests for continuous variables and [chi]2 tests for categorical variables analyzed differences in baseline data among the diagnostic categories. Linear and generalized mixed effects models assessed the relation between examination data and diagnostic group over time.Results: At first examination, the lowest score of the weakest muscle (p < 0.001), the site of onset (p = 0.041), and time to evaluation (p = 0.05) discriminated between eventual diagnostic group; patients with PLS were stronger, slower in progressing, and more likely to have limb onset than the other groups. Strength <=4 on any muscle was associated with the diagnosis of ALS (p = 0.0001), but not PLS. Across all visits, muscle strength (p = 0.003), ALS Functional Rating Scale score (p = 0.009), and vital capacity (p = 0.026) predicted group assignment. UMN-dominant and ALS groups had more weight loss (p = 0.004), even when controlled for dysphagia (p = 0.021) and muscle atrophy (p = 0.009), and patients with ALS were more likely to have hyporeflexia (p = 0.001).Conclusions: Features at baseline most suggestive of eventual lower motor neuron signs were focal muscle weakness or bulbar onset. Later, weight loss, reduced forced vital capacity, and limb weakness predicted lower motor neuron dysfunction. We suggest that patients with only upper motor neuron signs have periodic evaluations of strength, weight, forced vital capacity, Amyotrophic Lateral Sclerosis Functional Rating Scale score, and EMG, because a change in any can signal the imminent development of lower motor neuron signs.GLOSSARY: ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale; FVC = forced vital capacity; LMN = lower motor neuron; MMT = manual muscle testing; MRC = Medical Research Council; MRS = magnetic resonance spectroscopy; PLS = primary lateral sclerosis; UMN = upper motor neuron; UMN-D = upper motor neuron dominant.(C)2009AAN Enterprises, Inc.