Hot off the presses! Apr 07 Neurology

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Latest Articles Include:

• This week in Neurology(R): Highlights of the April 7 issue
  - Neurology 72(14):1199 (2009)
  
• Skin biopsy for peripheral neuropathy: Is it better to punch or to blister?
  - Neurology 72(14):1200-1201 (2009)
  
• Dyskinesia in Parkinson disease: Back for the future?
  - Neurology 72(14):1202-1203 (2009)
  
• Invited Article: Human natural autoantibodies in the treatment of neurologic disease
  - Neurology 72(14):1269-1276 (2009)
  Naturally occurring autoantibodies are molecules that are part of the normal immunoglobulin repertoire. This review focuses on three distinct groups of human monoclonal antibodies (mAb). These are human natural autoantibodies that, when injected into an animal model of human disease, stimulate remyelination in CNS demyelinating diseases, protect neurons and extend neuronal processes in CNS axonal disorders, and activate immune dendritic cells to produce cytotoxic T cells to clear metastatic tumors. Natural autoantibodies react to self antigens and are of relatively low affinity. They are derived from germline immunoglobulin genes and are usually polyreactive. Our experiments demonstrated CNS entry by autoradiography of labeled mAb and by MRI. Remyelinating mAb rHIgM22 clusters beta-integrin and mouse mAb O4 recognizes sulfatide. Neuronal outgrowth mAbs sHIgM42 and sHIgM12 appear to target carbohydrates on the surface of neurons. The mAb sHIgM12 (B7-DC-Xab) also is prom! ising as therapeutic against metastatic tumors. It functions by binding and cross-linking the antigen B7-DC on dendritic cells, inducing tumor-specific cytotoxic T cells. All these mAbs activate a transient increase in intracellular calcium, signal via NF{kappa}b, and prevent apoptosis. The mAbs engage downstream signaling events that induce the primary function of the cell (that is, remyelination for oligodendrocytes, axonal preservation and neurite extension for neurons, or antigen presentation for dendritic cells). Natural human auto mAbs are a potentially important therapeutic technique in combating a wide spectrum of disease processes. Ig = immunoglobulin; mAb = monoclonal antibodies; MS = multiple sclerosis.
• Daniel Carleton Gajdusek, MD (1923-2008)
  - Neurology 72(14):1204 (2009)
  
• Skin blister and skin biopsy to quantify epidermal nerves: A comparative study
  - Neurology 72(14):1205-1210 (2009)
  Background: Skin biopsy is an important procedure for the diagnosis of peripheral neuropathy. The main indicators of unmyelinated nerve involvement are decreased density and abnormal morphology of epidermal nerve fibers (ENFs). The suction skin blister is an alternative, less invasive method to visualize and quantify ENFs. The blister roof provides an integrated bird's eye view of all ENFs within one tissue specimen. Objective: We compared the suction skin blister method to the punch skin biopsy for evaluation of ENFs. Methods: Twenty-five volunteers, 35 to 62 years old, without symptoms or history of peripheral neuropathy, and normal by neurologic examination and nerve conduction tests, were studied. One 3 mm punch biopsy and two 3 mm suction blister specimens were collected from the right foot and calf. Comparison between blister and biopsy ENF density was assessed by repeated measures analysis of covariance, accounting for age, gender, and specimen's location. Re! sults: The epidermal roof of the suction skin blister permitted detailed analyses of ENF density, morphology, and distribution across the epidermis and observation of ENF branching pattern. No systematic differences of ENF density were found between skin blisters and biopsies (p = 0.29) or between pairs of blisters from the same location (p = 0.15). ENF density was lower for older subjects (p < 0.01). Conclusions: The suction skin blister method has potential as a diagnostic tool to investigate small fiber neuropathies. It is a minimally invasive and reliable technique, comparable to skin biopsy for determining epidermal nerve fiber density. BMI = body mass index; ENF = epidermal nerve fiber; PBS = phosphate buffered saline.
• PET demonstrates reduced dopamine transporter expression in PD with dyskinesias
  - Neurology 72(14):1211-1216 (2009)
  Objective: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. Methods: Thirty-six patients with PD with motor fluctuations were assessed with PET using [11C]-d-threo-methylphenidate (MP) and [11C]-({+/-}) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. Results: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between ! groups (nondyskinesia 1.54 {+/-} 0.36, dyskinesia 1.39 {+/-} 0.28; mean {+/-} SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 {+/-} 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 {+/-} 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. Conclusions: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias. BP = binding potential; COMTi = catechol-O-methyl transferase inhibitors; CR = controlled release; DA = dopamine; DAT = D! A transporter; DTBZ = [11C]-({+/-}) dihydrotetrabenazine; DVR ! = distribution volume; MF = motor fluctuation; MP = [11C]-d-threo-methylphenidate; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson's Disease Rating Scale.
• Bevacizumab and chemotherapy for recurrent glioblastoma: A single-institution experience
  - Neurology 72(14):1217-1222 (2009)
  Objective: Bevacizumab has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials. Methods: We conducted a retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients, comparing progression-free survival (PFS) and overall survival (OS) between the two groups, and performed subgroup analysis based on age and performance status. Expression of vascular endothelial growth factor (VEGF) based on age was examined using DNA microarray analysis. We also evaluated the impact of bevacizumab on quality of life. Results: We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab. There was a significant improvement in PFS and OS in the bevacizumab-treated group. Patients of older age ([≥]55 years) and poor performance status (Karnofsky Performance Status [≤]80! ) had significantly better PFS when treated with bevacizumab, and bevacizumab-treated older patients had significantly increased OS. VEGF expression was significantly higher in older glioblastoma patients (aged [≥]55 years). Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group. Conclusions: Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor. GBM = glioblastoma; HR = hazard ratio; KPS = Karnofsky Performance Status; OS = overall survival; PFS = progression-free survival; VEGF = vascular endothelial growth factor.
• Adverse antiepileptic drug effects: Toward a clinically and neurobiologically relevant taxonomy
  - Neurology 72(14):1223-1229 (2009)
  Background: Adverse effects (AEs) of antiepileptic drugs (AEDs) are a major impediment to optimal dosing for seizure control. Better understanding of clinical properties of AEs is a prerequisite for systematic research of their neurobiological underpinnings. This study aimed to define specific patterns of AE occurrence and determine their clinical relevance based on their association with subjective health status. Methods: Two hundred subjects with epilepsy completed validated self-report health assessments, including the Adverse Event Profile (AEP) and Quality of Life in Epilepsy Inventory (QOLIE)-89. Factor analysis was performed on the 19 AEP items to identify distinct classes of AEs. Correlations between AE class scores and QOLIE-89 scores were evaluated. Multivariate analysis was used to assess contributions of AE class scores to QOLIE-89 scores after controlling for depression and seizure frequency. Relationships between changes in AE class scores and changes in! QOLIE-89 scores were also investigated in a subgroup of 62 subjects enrolled in a randomized trial. Results: The mean number of AEs per subject was 6.5. AEs were segregated into five classes: Cognition/Coordination, Mood/Emotion, Sleep, Weight/Cephalgia, and Tegument/Mucosa. Higher scores in each AE class were associated with lower QOLIE-89 scores. Cognition/Coordination scores were the strongest predictor of QOLIE-89 scores. Improvements in Cognition/Coordination, Mood/Emotion, and Tegument/Mucosa scores were associated with improvements in QOLIE-89 scores. Improved Cognition/Coordination was the only predictor of improved QOLIE-89. Conclusion: Adverse effects (AEs) of antiepileptic drugs can be classified in five biologically plausible factors. When specific classes of AEs are identified and attempts are made to reduce them, quality of life is significantly improved. AE = adverse effect; AED = antiepileptic drug; AEP = Adverse Event Profile; BDI = Beck Depression Inve! ntory; GABA = {gamma}-aminobutyric acid; HRQOL = Health-Relate! d Quality of Life; QOLIE = Quality of Life in Epilepsy Inventory.
• Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy
  - Neurology 72(14):1230-1235 (2009)
  Background: Neuropathologic studies suggest an association between cerebral amyloid angiopathy (CAA) and small ischemic infarctions as well as hemorrhages. We examined the prevalence and associated risk factors for infarcts detected by diffusion-weighted imaging (DWI). Methods: We performed retrospective analysis of MR images from 78 subjects with a diagnosis of probable CAA and a similar aged group of 55 subjects with Alzheimer disease or mild cognitive impairment (AD/MCI) for comparison. DWI and apparent diffusion coefficient (ADC) maps were inspected for acute or subacute infarcts. We also examined the association between DWI lesions and demographic variables, conventional vascular risk factors, and radiographic markers of CAA severity such as number of hemorrhages on gradient-echo MRI and volume of T2-hyperintense white matter lesions. Results: Twelve of 78 subjects with CAA (15%) had a total of 17 DWI-hyperintense lesions consistent with subacute cerebral infarc! tions vs 0 of 55 subjects with AD/MCI (p = 0.001). The DWI lesions were located primarily in cortex and subcortical white matter. CAA subjects with DWI lesions had a higher median number of total hemorrhages (22 vs 4, p = 0.025) and no difference in white matter hyperintensity volume or conventional vascular risk factors compared to subjects with CAA without lesions. Conclusions: MRI evidence of small subacute infarcts is present in a substantial proportion of living patients with advanced cerebral amyloid angiopathy (CAA). The presence of these lesions is associated with a higher burden of hemorrhages, but not with conventional vascular risk factors. This suggests that advanced CAA predisposes to ischemic infarction as well as intracerebral hemorrhage. AD = Alzheimer disease; ADC = apparent diffusion coefficient; CAA = cerebral amyloid angiopathy; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; GRE = gradient-echo; HTN = hypertension; ICH =! intracerebral hemorrhage; MCI = mild cognitive impairment; MG! H = Massachusetts General Hospital; nWMH = normalized white matter hyperintensity volumes; WMH = white matter T2-hyperintense lesions.
• Brain atrophy in primary lateral sclerosis
  - Neurology 72(14):1236-1241 (2009)
  Background: Primary lateral sclerosis (PLS) is an idiopathic upper motor neuron degenerative disorder. The aim of this study was to compare brain volumes in patients with PLS and controls and determine whether differences were due to loss of gray matter (GM), white matter (WM), or both. Methods: T1-weighted images were acquired in patients with PLS and controls. Freesurfer was used for volumetric segmentation of whole brain, cortical GM, precentral and postcentral cortex, WM, corpus callosum, basal ganglia, thalamus, cerebellum, and CSF. Relationships were sought between disease severity, disease duration, age and brain volumes. Results: Eleven patients with PLS and 10 age-matched healthy controls were included in this study. Compared to control subjects, patients with PLS had significantly smaller whole brain (p = 0.043), frontal lobe (p = 0.036), precentral cortex (p = 0.016), and corpus callosum (p = 0.036) volumes. There was a trend toward a smaller thalamus (p =! 0.051). Disease severity correlated with ventricular CSF volume (rho = -0.604, p = 0.025) and precentral cortex volume loss (rho = 0.599, p = 0.026). Disease duration tended to correlate with a loss of WM (rho = -0.636, p = 0.063). Conclusions: Our results suggest that there is focal atrophy in patients with primary lateral sclerosis compared with controls especially in the precentral cortex and the corpus callosum, specifically where there is transfer of motor fibers. ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale; fSPGR = fast spoiled gradient echo sequence; GM = gray matter; PLS = primary lateral sclerosis; TE = echo time; TR = repetition time; WM = white matter.
• The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome
  - Neurology 72(14):1242-1247 (2009)
  Background: Rett syndrome (RTT) is caused by mutations in the transcriptional repressor methyl CpG-binding protein 2 (MECP2). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis, and plasticity, and it has been shown that BDNF expression is regulated by MeCP2 through a complex interaction. A common polymorphism of BDNF (Val66Met [p.V66M]) has been found to correlate with severity and course of several neuropsychiatric disorders. Methods: We examined the association between disease severity score, assessed by the modified Percy score, and BDNF polymorphism, using regression methods, in 125 mutation-positive patients with RTT from the Australian Rett Syndrome Database and an Israeli cohort. Results: Those who were heterozygous (Val/Met) had slightly more severe disease than those who were homozygous for the wild-type (Val/Val) BDNF polymorphism (increased severity score 2.1, p = 0.09). In those with ! p.R168X, a commonly occurring MECP2 mutation in RTT, there was a 6-point increase in severity score for those who were heterozygous for the BDNF polymorphism, both unadjusted (p = 0.02) and adjusted for age (p = 0.03). Individuals with the p.R168X mutation and heterozygous for the BDNF polymorphism were also at an increased risk of seizure onset (hazard ratio 5.3, 95% confidence interval 1.6-17.7) compared with those homozygous for the wild-type BDNF allele. Conclusions: In addition to mutation type and degree of X-chromosome skewing, the common brain-derived neurotrophic factor (BDNF) polymorphism appears to be another genetic modifier of Rett syndrome (RTT) severity. This suggests that BDNF function may play a significant role in the pathogenesis of RTT. ARSD = Australian Rett Syndrome Database; BDNF = brain-derived neurotrophic factor; CI = confidence interval; HR = hazard ratios; MECP2 = methyl CpG-binding protein 2; Met = methionine; NAA = N-acetylaspartate; RTT = Re! tt syndrome; Val = valine.
• Etiology of musician's dystonia: Familial or environmental?
  - Neurology 72(14):1248-1254 (2009)
  Objective: To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician's dystonia (MD) and to identify possible environmental triggers. Methods: The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH-]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD. Results: A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias! : n = 2), 5 of whom were members of FH- families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members. Conclusion: Our results suggest a genetic contribution to musician's dystonia with phenotypic variability including focal task-specific dystonia. BIDS = Beth Israel Dystonia Screen; FH+ = reported positive family history of focal task-specific dystonia; FH- = no known family history of focal task-specific dystonia; FTSD = focal task-specific dystonia; MD = musician's dy! stonia; WC = writer's cramp.
• Obesity and restless legs syndrome in men and women
  - Neurology 72(14):1255-1261 (2009)
  Background: Obesity and restless legs syndrome (RLS) are both associated with hypofunction of dopamine in the CNS. We therefore examined whether individuals who are obese have an increased risk of RLS in two ongoing US cohorts, the Nurses' Health Study II and the Health Professional Follow-up Study. Methods: We included 65,554 women and 23,119 men free of diabetes, arthritis, and pregnancy in the current analyses. Information on RLS was assessed using a set of standardized questions. Participants were considered to have RLS if they met four RLS diagnostic criteria recommended by the International RLS Study Group and had restless legs [≥]5 times/month. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression models adjusting for age, smoking, use of antidepressant, phobic anxiety score, and other covariates. Log ORs from the two cohorts were pooled by a fixed-effects model. Results: There were 6.4% of women and 4.1% of men who we! re considered to have RLS. Multivariate adjusted ORs for RLS were 1.42 (95% CI: 1.3, 1.6; p trend <0.0001) for participants with body mass index (BMI) >30 vs <23 kg/m2 and 1.60 (95% CI: 1.5, 1.8; p trend <0.0001) for highest vs lowest waist circumference quintiles. Greater BMI in early adulthood (age 18-21 years) and weight gain were also associated with a higher prevalence of RLS (p trend <0.01 for both). Conclusions: Both overall and abdominal adiposity are associated with increased likelihoods of having restless legs syndrome (RLS). Further prospective studies are warranted to clarify causative association between obesity and risk of developing RLS. BMI = body mass index; CI = confidence interval; HPFS = Health Professionals Follow-up Study; NHS II = Nurses' Health Study II; OR = odds ratios; RLS = restless legs syndrome.
• A 41-year-old woman with progressive leg weakness and numbness, dizziness, and myalgia
  - Neurology 72(14):1262-1268 (2009)
  
• HEMISPHERIC STROKE DOES NOT MOBILIZE CD34+ HEMATOPOIETIC STEM CELLS INTO THE PERIPHERAL BLOOD
  - Neurology 72(14):1277-1278 (2009)
  
• EFFICACY OF LAMOTRIGINE IN DISABLING MYOCLONUS IN A PATIENT WITH AN mtDNA A3243G MUTATION
  - Neurology 72(14):1279-1280 (2009)
  
• The beautiful feet of neuropathy
  - Neurology 72(14):1281 (2009)
  
• Teaching Video NeuroImages: Tongue myokymia following head and neck radiotherapy for nasopharyngeal carcinoma
  - Neurology 72(14):e65 (2009)
  
• Teaching NeuroImages: Sinus pericranii
  - Neurology 72(14):e66 (2009)
  
• ECONOMIC COST OF GUILLAIN-BARRE SYNDROME IN THE UNITED STATES
  - Neurology 72(14):1282 (2009)
  
• NEUROPATHIC PAIN: REDEFINITION AND A GRADING SYSTEM FOR CLINICAL AND RESEARCH PURPOSES
  - Neurology 72(14):1282-a-1283 (2009)
  
• CONFLICTS OF INTEREST FOR AUTHORS OF AMERICAN ACADEMY OF NEUROLOGY CLINICAL PRACTICE GUIDELINES
  - Neurology 72(14):1283-1284 (2009)
  
• CORRECTION
  - Neurology 72(14):1284 (2009)
  
• HEADACHE SIMPLIFIED
  - Neurology 72(14):1285 (2009)
  
• Calendar
  - Neurology 72(14):1286-1287 (2009)
  
• Changes * People * Comments
  - Neurology 72(14):1288-1290 (2009)