Neurology September 2009 Volume 73 Issue 10

Objective: To define distinctive features of nodular heterotopia in specimens derived from drug-resistant patients with epilepsy by evaluating mRNA expression of three different layer-specific markers: Ror[beta], Er81, and Nurr1.Methods: We analyzed the expression profile of these genes, recognized as markers mainly expressed in layer IV for Ror[beta], in layer V for Er81, and in layer VI for Nurr1, in surgical samples from 14 epileptic patients, using in situ hybridization. Six patients had subcortical nodular heterotopia and 8 patients were controls. The intrinsic organization of nodular formations and of the overlaying neocortex was assessed.Results: In all patients, the 3 selected genes showed high cortical laminar specificity. In subcortical nodular heterotopia, the different gene expression profiles revealed a rudimentary laminar organization of the nodules. In the overlaying cortex, fewer cells expressed the 3 genes in the appropriate specific layer as compared to controls.Conclusions: These data provide new insights into possible ontogenetic mechanisms of nodular heterotopia formation and show the potential role of layer-specific markers to elucidate the neuropathology of malformations of cortical development.(C)2009AAN Enterprises, Inc.

Objective: To evaluate the influence of the single nucleotide polymorphism rs1080985 in the cytochrome P450 2D6 (CYP2D6) gene on the efficacy of donepezil in patients with mild to moderate Alzheimer disease (AD).Methods: This was a multicenter, prospective cohort study of 127 white patients with AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil 5-10 mg/daily for 6 months. Cognitive and functional statuses were evaluated at baseline and at 6-month follow-up. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Compliance and drug-related adverse events were also evaluated. The analyses identifying the CYP2D6 and APOE polymorphisms were performed in blinded fashion.Results: At 6-month follow-up, 69 of 115 patients (60%) were responders and 46 patients (40%) were nonresponders to donepezil treatment. A significantly higher frequency of patients with the G allele of rs1080985 was found in nonresponders than in responders (58.7% vs 34.8%, p = 0.013). Logistic regression analysis adjusted for age, sex, Mini-Mental State Examination score at baseline, and APOE demonstrated that patients with the G allele had a significantly higher risk of poor response to donepezil treatment (odds ratio 3.431, 95% confidence interval 1.490-7.901).Conclusions: The single nucleotide polymorphism rs1080985 in the CYP2D6 gene may influence the clinical efficacy of donepezil in patients with mild to moderate Alzheimer disease (AD). The analysis of CYP2D6 genotypes may be useful in identifying subgroups of patients with AD who have different clinical responses to donepezil.(C)2009AAN Enterprises, Inc.

Background: Although ultrasound-activated microbubbles (MB) accelerate clot lysis, MB activation has shown to promote blood barrier disruption and bleeding in animal models. We conducted a case-control study aimed to investigate the risk of hemorrhagic transformation (HT) after MB-enhanced sonothrombolysis in acute stroke.Methods: We evaluated a total of 296 patients with acute stroke treated with IV tissue plasminogen activator (tPA) <3 hours after stroke onset. One hundred eighty-eight patients received continuous 2-hour TCD monitoring plus 3 doses of 2.5 g of MB after tPA bolus (MB group). These patients were compared with 98 historic stroke patients (control group). The presence and extent of HT on 24-hour CT were blindly assessed.Results: Recanalization rates were higher in the MB compared with the control group at 1, 2, 6, and 12 hours (p < 0.05). MB administration was associated with an increased risk of hemorrhagic infarction (HI)1-HI2 (21% vs 12%, p = 0.026) and a higher degree of clinical improvement at 24 hours (54.9% vs 31.1%, p = 0.004). Parenchymal hematoma (PH)1-PH2 and symptomatic intracranial hemorrhage rates were similar in both groups. Moreover, the extent of bleeding after MB-enhanced sonothrombolysis was correlated with the time to reperfusion. Early (<6 hours) recanalization independently predicted HI in the MB group (odds ratio 6.3, 95% confidence interval 2.3-56) but not in the control group. Delayed (>6 hours) or no recanalization was associated with PH1-PH2 in both the MB group (p = 0.024) and the control group (p = 0.045).Conclusion: This hypothesis-generating study shows that microbubble administration was associated with early recanalization and a high rate of hemorrhagic transformation but does not seem to increase the risk of symptomatic intracranial hemorrhage. However, definitive conclusions cannot be made based on these data.(C)2009AAN Enterprises, Inc.

Background: We previously reported the occurrence of myelitis in patients with atopic disorders (atopic myelitis [AM]). To uncover the spectrum of neural damage associated with atopy, we conducted a cross-sectional nationwide survey of AM and atopy-related peripheral neuritis (APN), including Churg-Strauss syndrome (CSS), in individuals with atopic diathesis.Method: Cases with AM diagnosed between 1996 and 2006 and cases with APN between 2000 and 2006 were collected from all over Japan. Detailed data on 109 patients with AM and 133 patients with APN were collated.Results: Patients with APN showed a preponderance of women, higher age at onset, and greater eosinophil counts than patients with AM. Patients with AM most commonly showed cervical cord involvement, whereas patients with APN preferentially exhibited mononeuritis multiplex predominantly affecting the lower limbs. Among patients with AM, motor weakness and muscle atrophy were significantly more frequent in those with bronchial asthma than in those with other atopic disorders. Patients with APN who met the criteria for CSS showed a higher age at onset, higher frequencies of systemic organ involvement, and greater disability than those who did not. Abnormalities suggesting peripheral nervous system involvement were seen in 25.7% of patients with AM, whereas 18.8% of patients with APN had abnormalities indicating CNS involvement. Multiple logistic regression analyses revealed that atopic dermatitis increased the risk of myelitis, whereas high age at onset and bronchial asthma decreased that risk.Conclusions: Atopy-related neural inflammation multifocally affects CNS and peripheral nervous system tissues. Both preceding atopic disorders and age seem to influence the distribution of neural damage.(C)2009AAN Enterprises, Inc.

Heterogeneity of motor phenotypes is a clinically well-recognized fundamental aspect of amyotrophic lateral sclerosis (ALS) and is determined by variability of 3 independent primary attributes: body region of onset; relative mix of upper motor neuron (UMN) and lower motor neuron (LMN) deficits; and rate of progression. Motor phenotypes are determined by the anatomy of the underlying neuropathology and the common defining elements underlying their heterogeneity are that motor neuron degeneration is fundamentally a focal process and that it spreads contiguously through the 3-dimensional anatomy of the UMN and LMN levels, thus causing seemingly complex and varied clinical manifestations. This suggests motor neuron degeneration in ALS is in actuality a very orderly and actively propagating process and that fundamental molecular mechanisms may be uniform and their chief properties deduced. This also suggests opportunities for translational research to seek pathobiology directly in the less affected regions of the nervous system.(C)2009AAN Enterprises, Inc.

Objective: Telephone medicine is part of clinical practice, but there are no published data on the volume, nature, and time allocation of patient-related telephone calls received in a movement disorders center. Such data might provide insights which augment patient care, and may be instructive regarding medical education, since patient-related telephone calls are often addressed by physicians-in-training.Methods: Characteristics of patient-related calls to a movement disorders center were prospectively recorded during a 2-month period.Results: A total of 633 calls were generated by 397 patients. The average time per call was 6.6 +/- 4.7 minutes. Disease-related questions (35.1%), treatment-related questions (21.3%), and side effect reports (15.3%) represented the majority of calls. Patients with Parkinson disease, Tourette syndrome (TS), and atypical parkinsonism (AP) called more frequently, while patients with dystonia and tremor called less frequently.Conclusion: Patient telephone calls contribute substantially to the patient care in a movement disorders center and represent an important aspect of training, providing an opportunity for movement disorders fellows to develop independent decision-making skills and monitor effectiveness of their physician-patient counseling. Parkinson disease, Tourette syndrome (TS), and atypical parkinsonism (AP) contribute disproportionately to the total patient telephone volume, possibly due to coexisting obsessive-compulsive and impulse-control comorbidities in patients with TS, and complications or a change of diagnosis and prognosis in patients with AP. Emphasis on the management of these specific diagnostic groups early in fellowship training may be warranted.(C)2009AAN Enterprises, Inc.