Perinatal stroke commonly causes childhood neurological morbidity. Presumed perinatal ischemic stroke (PPIS) defines children presenting outside a normal perinatal period with chronic, focal infarction on neuroimaging. Infarcts are assumed to represent arterial strokes, but recent evidence suggests the periventricular venous infarction (PVI) of infants born preterm may also occur in utero and present as PPIS. Using the largest published cohort, we aimed to define arterial and PVI PPIS syndromes and their outcomes.A PPIS consecutive cohort was identified (SickKids Children's Stroke Program, 1992-2006). Systematic neuroradiological scoring executed by blinded investigators included previously defined arterial stroke syndromes. PVI criteria included unilateral injury with at least four of the following conditions: (1) focal periventricular encephalomalacia, (2) internal capsule T2 prolongation, (3) cortical and (4) relative basal ganglia sparing, and (5) remote hemorrhage. Arterial and PVI classifications were validated and correlated with neurological outcomes (Pediatric Stroke Outcome Measure).In 59 PPISs (64% male), 94% of lesions fell within potential middle cerebral artery territories. Although arterial proximal M1 infarction was most common (n = 19; 35%), venous PVI was second (n = 12; 22%) and accounted for 75% of subcortical injuries. Motor outcomes (mean follow-up, 5.3 years) were predicted by basal ganglia involvement including leg hemiparesis, spasticity, and need for assistive devices (p < 0.01). Nonmotor outcomes were associated with cortical involvement, including cognitive/behavioral outcomes, visual deficits, and epilepsy (p < 0.01). Classification interrater reliability was excellent (correlation coefficients > 0.975).Recognizable PPIS patterns predict long-term morbidity and may guide surveillance, therapy, and counseling. PVI is an underrecognized cause of PPIS and congenital hemiplegia. Ann Neurol 2008
Several autoimmune myelopathies are recognized clinically. We describe 57 patients in whom serological evaluation for myelopathy of uncertain cause demonstrated collapsin response-mediator protein 5 IgG. Most had spinal imaging and cerebrospinal fluid abnormalities and insidiously progressive presentation; some had acute monophasic or relapsing myelopathy. Initial diagnoses included multiple sclerosis, transverse myelitis, and unspecified neurodegenerative myelopathy. Most were smokers; neoplasia was discovered in 68% (most commonly small-cell lung carcinoma and after collapsin response-mediator protein-5 IgG detection). Collapsin response-mediator protein-5 autoimmune myelopathy and occult neoplasia are important considerations in patients with insidiously progressive myelopathy, especially with known cancer risk. Ann Neurol 2008
We evaluated the incidence, volume, and spatial distribution of T2-weighted magnetic resonance imaging lesions in 58 children with clinically isolated syndromes at risk for multiple sclerosis compared with 58 adults with relapsing-remitting multiple sclerosis. Pediatric patients with clinically isolated syndromes who had brain lesions had supratentorial lesion volumes similar to adult multiple sclerosis patients, but greater infratentorial lesion volumes (p < 0.009), particularly in the pons of male patients. The predilection for infratentorial lesions the pediatric patients with clinically isolated syndromes may reflect immunological differences or differences in myelin, possibly related to the caudorostral temporal gradient in myelin maturation. Ann Neurol 2008
Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A2A receptor antagonist, istradefylline, shows promise for the treatment of PD.Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring.After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (± standard deviation) of -10.8 ± 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 ± 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 ± 2.8 hours for istradefylline and -0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild.Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia. Ann Neurol 2008
Complex I deficiency is the most common respiratory chain defect, clinically manifesting by severe neonatal lactic acidosis, Leigh's disease, or various combinations of cardiac, hepatic, and renal disorders. Using homozygosity mapping, we identified a splice-site mutation in the NDUFA11 gene in six patients from three unrelated families. The patients presented with encephalocardiomyopathy or fatal infantile lactic acidemia. The mutation is predicted to abolish the first transmembrane domain of the gene product, thereby destabilizing the enzymatic complex. Mutation analysis of the NDUFA11 is warranted in isolated complex I deficiency presenting with infantile lactic acidemia or encephalocardiomyopathy. Ann Neurol 2008
The mitochondrial energy-generating system (MEGS) encompasses the mitochondrial enzymatic reactions from oxidation of pyruvate to the export of adenosine triphosphate. It is investigated in intact muscle mitochondria by measuring the pyruvate oxidation and adenosine triphosphate production rates, which we refer to as the "MEGS capacity." Currently, little is known about MEGS pathology in patients with mutations in the mitochondrial DNA. Because MEGS capacity is an indicator for the overall mitochondrial function related to energy production, we searched for a correlation between MEGS capacity and 3243A[rarr]G mutation load in muscle of patients with the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome.In muscle tissue of 24 patients with the 3243A[rarr]G mutation, we investigated the MEGS capacity, the respiratory chain enzymatic activities, and the 3243A[rarr]G mutation load. To exclude coinciding mutations, we sequenced all 22 mitochondrial transfer RNA genes in the patients, if possible.We found highly significant differences between patients and control subjects with respect to the MEGS capacity and complex I, III, and IV activities. MEGS-related measurements correlated considerably better with the mutation load than respiratory chain enzyme activities. We found no additional mutations in the mitochondrial transfer RNA genes of the patients.The results show that MEGS capacity has a greater sensitivity than respiratory chain enzymatic activities for detection of subtle mitochondrial dysfunction. This is important in the workup of patients with rare or new mitochondrial DNA mutations, and with low mutation loads. In these cases we suggest to determine the MEGS capacity. Ann Neurol 2008
Recent studies in peripheral blood mononuclear cells (PBMCs) have indicated that exacerbations of multiple sclerosis (MS) could be associated with the reactivation of latent varicella-zoster virus (VZV).Ultrastructural observations for viral particles were made by electron microscopy in cerebrospinal fluid (CSF) from 15 MS patients during relapse, 19 MS patients during remission, and 28 control subjects. Initial findings were reproduced in a confirmation cohort. In addition, DNA from VZV was quantified by real-time polymerase chain reaction in PBMCs and CSF from a large number of MS patients (n = 78).We found by electron microscopy the presence of abundant viral particles identical to VZV in CSF obtained from MS patients within the first few days of an acute relapse. In contrast, viral particles were not seen in CSF samples from MS patients in remission or from neurological control subjects. Also, DNA from VZV was present in CSF and in PBMCs during relapse, disappearing in most patients during remission. The mean viral load was 542 times greater in CSF at relapse than in CSF at remission and 328 times greater in CSF at relapse than in PBMCs at relapse.The ultrastructural finding of viral particles identical to VZV, together with the simultaneous presence of large quantities of DNA from VZV in the subarachnoid space, almost restricted to the periods of exacerbation, as well as its steady diminution and eventual disappearance from clinical relapse to clinical remission are surprising and constitute the strongest evidence to support the participation of VZV in the pathogenesis of MS. Ann Neurol 2008
Dysferlin (DYSF) gene mutations cause limb girdle muscular dystrophy type 2B and Miyoshi's myopathy. The consequences of DYSF mutations on protein structure are poorly understood.The gene encoding dysferlin was sequenced in patients with suspected dysferlin-deficient muscular dystrophy. Muscle biopsy specimens were analyzed by histochemistry, immunohistochemistry, and electron microscopy. Antibodies against N-terminal dysferlin-peptides were raised.We found three families with muscular dystrophy caused by homozygous or compound heterozygous DYSF mutations featuring sarcolemmal and interstitial amyloid deposits. These mutations were all located in the N-terminal region of the protein. Dysferlin was a constituent of the amyloid deposits.Limb girdle muscular dystrophy type 2B is the first muscular dystrophy associated with amyloidosis. Molecular treatment strategies will necessarily have to consider the presence of amyloidogenesis. Ann Neurol 2008