Prevalence of MRI abnormalities in people with epilepsy in rural China.

OBJECTIVE: To assess the prevalence of brain MRI abnormalities in people with epilepsy in rural China and to compare it with that of individuals in the United Kingdom. METHODS: Brain MRI scans were obtained in people with epilepsy who participated in a rural community-based program in China between July 2010 and December 2012. Individual epileptogenic lesion types were reviewed and their associations with seizure control examined. The MRI findings were compared with 2 previous similar studies in the United Kingdom. RESULTS: Among the 597 individuals (58% male, median age 38 years) with MRI scans analyzed, 488 (82%) had active epilepsy. The MRI was abnormal in 389 individuals (65%), with potentially epileptogenic lesion in 224 (38%) and nonspecific abnormalities in 165 (28%), and 108 (18%) were potentially resectable. The potentially epileptogenic lesions were less frequently detected in children (<18 years old, 12 of 68, 18%) than in adults (212 of 529, 40%; p < 0.001). In people with potentially epileptogenic lesions, 67% (150 of 224) had failed ≥2 antiseizure medications. They had higher risk of uncontrolled epilepsy than those with normal MRI (risk ratio [RR] 1.25; p < 0.001) and those with nonspecific abnormality (RR 1.15; p = 0.002) after adjustment for age and sex. The diagnostic yield of MRI was similar to that reported in community- and hospital-based studies in the United Kingdom. CONCLUSIONS: More than one-third of people with chronic epilepsy in rural China have potentially epileptogenic lesions identifiable on brain MRI, with two-thirds fulfilling the definition of pharmacoresistance. These findings highlight the magnitude of the unmet needs for epilepsy surgery in China.

Chronic Hyperglycemia before Spinal Cord Injury Increases Inflammatory Reaction and Astrogliosis after Injury: Human and Rat Studies.

Traumatic spinal cord injury (SCI) can cause permanent disabilities that seriously reduce quality of life. We evaluated the effects of chronic hyperglycemia before SCI on inflammatory markers and functional recovery after SCI in human patients and a rat model. In the human study, multivariate logistical regression analysis revealed that hemoglobin A1c (HbA1c) values, reflecting average plasma glucose concentration over a 3 month period, at admission were a significant risk factor for poor functional recovery. Moreover, patients with chronic hyperglycemia (HbA1c ≥ 6.5%) had high concentrations of inflammatory biomarkers (interleukin [IL]-6 and IL-8) of cerebrospinal fluid after SCI. Consistent with patient findings, chronic hyperglycemia before SCI in rats was associated with increased inflammatory responses and oxygen-free radicals in the spinal cord and blood, thus resulting in poor functional recovery and histological outcomes. Tight glucose control before SCI decreased the harmful effects of hyperglycemia after SCI in both human and rat studies. Our findings suggest that chronic hyperglycemia before SCI may be a significant prognostic factor with a negative impact on functional and histological outcomes, highlighting the importance of tight glucose control before SCI.

Medullary Astrogliosis in Sudden Infant Death Syndrome Varies With Sleeping Environment: Evidence for Different Mechanisms of Death in Alone Versus Co-sleepers?

Sudden infant death syndrome remains the leading cause of death in infants under 1 year, and underlying pathophysiological mechanisms are poorly understood. The current study investigated the hypothesis that co-sleepers die more rapidly from causes such as suffocation from overlaying by comparing levels of reactive astrogliosis in the medulla of infants who died sleeping alone to those who died co-sleeping. The amount of glial fibrillary acidic protein (GFAP) staining in alone sleepers was significantly higher than shared sleepers in 3 specific areas of the medulla, the inferior vestibular nucleus, the medial vestibular nucleus and the cochlear nucleus. Given that glial fibrillary acidic protein elevations follow a delayed time course, this suggests that death in co-sleepers was more rapid, not allowing for reactive gliosis to occur. This provides evidence of pathological differences in mechanisms of death in infants who are classified as having died from sudden infant death syndrome, suggesting potential need for refinement of categorization of these cases.

(Epi)Genetic analyses of age-related macular degeneration: case-control and discordant twin studies.

BACKGROUND/AIMS: Phenotypic discordance in monozygotic (MZ) twin pairs can have an epigenetic or genetic basis. Although age-related macular degeneration (AMD) has a strong genetic component, few studies have addressed its epigenetic basis. METHODS: Using SNP arrays, we evaluated differences in copy number variation (CNV) and allele-specific methylation (ASM) patterns (via methyl-sensitive restriction enzyme digestion of DNA) in MZ twin pairs from the US Twin Study of AMD. Further analyses examined the relationship between ASM and CNVs with AMD by both case/control analysis of ASM at candidate regions and by analysis of ASM and CNVs in twins discordant for AMD. RESULTS: The frequency of ASM sites differs between cases and controls in regions surrounding the AMD candidate genes CFH, C2 and CFB. While ASM patterns show a substantial dependence on local sequence polymorphisms, we observed dissimilar patterns of ASM between MZ twins. The genes closest to the sites where discordant MZ twins have dissimilar patterns of ASM are enriched for genes implicated in gliosis, a process associated with neovascular AMD. Similar twin-based analyses revealed no AMD-associated CNVs. CONCLUSIONS: Our results provide evidence of epigenetic influences beyond the known genetic susceptibility and implicate inflammatory responses and gliosis in the etiology of AMD.

Primary epileptogenic unruptured intracranial aneurysms: incidence and effect of treatment on epilepsy.

BACKGROUND: Seizures as the unique initial manifestation of unruptured intracranial aneurysms have rarely been documented and not systematically described until now. OBJECTIVE: The purpose of this large retrospective analysis was to focus on the incidence of primary epileptogenic aneurysms and the influence of treatment on epilepsy. METHODS: Within a 16-year period, 347 unruptured aneurysms were surgically treated at centers in Munich (1992-2002) and Düsseldorf (2003-2008), Germany. Of this patient population, 9 patients presented exclusively with epileptic seizures or epileptic equivalents. In 3 of them, a high-lying internal carotid artery aneurysm was diagnosed that was buried in the parahippocampal gyrus. In 4 patients, a middle cerebral artery aneurysm also created contact with the mediotemporal lobe adjacent to the parahippocampal gyrus. An anterior communicating artery aneurysm and a pericallosal artery aneurysm were diagnosed in 2 additional patients. Two patients with a middle cerebral artery aneurysm were initially incompletely occluded with Guglielmi detachable coils and continued to have epilepsy after the intervention. In all but 1 patient, the aneurysms were clipped and completely removed. RESULTS: In all 8 patients operated on, there was no sign of hemorrhage intraoperatively but cortical gliosis was seen around the dome of the aneurysm. In all cases, the aneurysm and the surrounding gliosis, if existent, were surgically removed. Freedom from seizures without medication resulted for all patients after microsurgery. DISCUSSION: Seizures as a presenting symptom of unruptured intracranial aneurysms are rare. There seems to be a preponderance of aneurysms anatomically related to the temporomedial region. Elimination of the aneurysm and perifocal gliosis provides the possibility of a cure for the epilepsy.

Pathologic findings in prospectively ascertained essential tremor subjects.

OBJECTIVE: To assess pathologic changes in prospectively characterized subjects with essential tremor (ET). METHODS: Subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program were examined annually by a movement disorders neurologist, and semiannually by a behavioral neurologist and neuropsychologist. Twenty-four subjects without a prior diagnosis of dementia or other major movement disorder met clinical criteria for ET and came to autopsy. Subjects with mild cognitive impairment (n = 3) were included. These subjects were compared with 21 controls. Brains were examined postmortem according to standardized protocols for assessment of age-related changes and specific pathologic conditions (e.g., Parkinson disease, Alzheimer disease). RESULTS: Subjects had a mean age of 86.2 years and a mean duration of tremor of 11.1 years. Seven subjects had evidence for cerebellar pathology (Purkinje cell loss, cerebellar cortical sclerosis, and proliferation of Bergmann glia). Pigmented neurons were qualitatively depleted in the locus ceruleus in eight subjects and in the substantia nigra in five subjects. Of these, three had Lewy bodies, one subject had brainstem predominant disease, and two had limbic stage. Three subjects had a nonspecific cerebral tauopathy and another met pathologic criteria for progressive supranuclear palsy. However, when compared with controls, only changes in the locus ceruleus and gliosis of the cerebellum remained significant findings. CONCLUSIONS: This study supports previous findings of heterogenous pathology in essential tremor (ET). There is an increased frequency of cerebellar gliosis and locus ceruleus depletion. We did not find an increased incidence of Lewy bodies in subjects with ET.

Multiple sclerosis and Alzheimer's disease.

OBJECTIVE: Chronic inflammation with microglia activation is thought to play a major role in the formation or clearance of Alzheimer's disease (AD) lesions, as well as in the induction of demyelination in multiple sclerosis (MS). In MS, the cortex is severely affected by chronic, long-lasting inflammation, microglia activation, and demyelination. To what extent chronic inflammation in the cortex of MS patients influences the development of AD lesions is so far unresolved. METHODS: The study was performed on autopsy tissue of 45 MS cases, 9 AD cases, and 15 control subjects. We analyzed lymphocyte and plasma cell infiltration in relation to microglia activation, to the presence of beta-amyloid plaques and (AT8+) neurofibrillary tangles, and to myelin pathology. RESULTS: Profound microglia activation, determined by a broad spectrum of markers, was found in both MS and AD cortices, and the patterns of microglia activation were closely similar. Microglia activation in MS cortex, in contrast with that in AD and control cortex, correlated with lymphocyte and plasma-cell infiltrates in the meninges. MS cases older than 64 years experienced development of AD pathology in comparable incidence as seen in the course of normal aging. The density of beta-amyloid plaques and neurofibrillary tangles did not differ between demyelinated and nondemyelinated cortical areas. CONCLUSIONS: Our data suggest that microglia activation in the MS cortex alone has little or no influence on the development of cortical AD pathology.

A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD.

There is biochemical and animal model evidence supporting a pathological role of the ACT gene in AD. However, direct genetic evidence remains controversial and has been mostly limited to individual single nucleotide polymorphism (SNP) analysis. To resolve this apparent conflict we have used a high-density ACT SNP map, constructed haplotypes and explored correlations with phenotype. SNPs were identified by sequencing and used to construct haplotypes in 668 AD patients and 419 controls and a case-control association study was performed. Five SNPs, comprising five common haplotypes, represented 93% of ACT gene variation. Although no single SNP or haplotype was associated with AD status, a SNP in intron 2 was associated with later onset and more rapid cognitive decline (P=0.04). This SNP was both individually associated with severe astrocytosis (P=0.004) in AD patients and when combined with the signal sequence SNP (P=0.002). This suggests that astrocytosis may have a protective function for a limited period in some patients. These SNP associations either support a direct role for the ACT gene, in AD pathology or alternatively reflect linkage with polymorphisms in other genes nearby.

Gray matter injury associated with periventricular leukomalacia in the premature infant.

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histology: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diffuse white matter gliosis (DWMG) (n = 17) without necrosis; and "Negative" group (n = 7) with no abnormalities. Neuronal loss was found almost exclusively in PVL, with significantly increased incidence and severity in the thalamus (38%), globus pallidus (33%), and cerebellar dentate nucleus (29%) compared to DWMG cases. The incidence of gliosis was significantly increased in PVL compared to DWMG cases in the deep gray nuclei (thalamus/basal ganglia; 50-60% of PVL cases), and basis pontis (100% of PVL cases). Thalamic and basal ganglionic lesions occur almost exclusively in infants with PVL. Gray matter lesions occur in a third or more of PVL cases suggesting that white matter injury generally does not occur in isolation, and that the term "perinatal panencephalopathy" may better describe the scope of the neuropathology.

Cerebral MRI findings in very-low-birth-weight and small-for-gestational-age children at 15 years of age.

BACKGROUND: A high prevalence of abnormal cerebral MRI findings has been reported in low-birth-weight children. OBJECTIVE: To compare MRI findings in very-low-birth-weight (VLBW) and term small-for-gestational-age (SGA) children with controls in early adolescence. MATERIALS AND METHODS: Cerebral MRI was used to examine 55 VLBW, 54 SGA and 66 controls at 15 years of age. The MR images were qualitatively assessed, and size of ventricles, white-matter and grey-matter abnormalities were reported. RESULTS: The VLBW teenagers had a higher prevalence of various MRI abnormalities than SGA children and controls. Dilation of the ventricular system, especially of the occipital horns, was found in 82% of the VLBW group, in 19% of the SGA group and in 21% of controls. White-matter reduction was found in 53% of the VLBW, in 6% of the SGA and in 2% of controls. Corpus callosum thinning was found in 47% of the VLBW, in 2% of the SGA and in 6% of controls. Periventricular gliosis was found in 29% of the VLBW, in 4% of the SGA and in 8% of controls. CONCLUSIONS: Cerebral MRI pathology in white matter is a common finding in VLBW teenagers. The findings may indicate minor perinatal PVL with resulting loss of white-matter tissue and ventricular dilation.

Temporal lobe epilepsy after prolonged febrile convulsions: excellent outcome after surgical treatment.

We studied 47 consecutive patients who underwent temporal resection for seizure control. Nineteen (40%) had febrile convulsions preceding onset of their habitual seizures. In 17 of 18 patients whose disease duration was known, the febrile convulsions were prolonged (mean 4 h). As compared with patients without preceding febrile convulsions, patients with antecedent febrile convulsions had a significantly higher prevalence of positive family history of febrile convulsions, an increased incidence of retrospectively identified gestational or perinatal complications, and no foreign tissue lesions. Pathologic studies showed gliosis and cell loss in mesiotemporal structures, usually moderate, in addition to usually mild gliosis in lateral temporal cortex. These patients had an excellent outcome after temporal resection: 84% were seizure-free, had residual auras only, or occasional convulsions with medication discontinuation. One patient (5%) had > 90% improvement. Two patients (11%) in whom the hippocampus was totally spared continued to have complex partial seizures: in both, seizures stopped after reoperation and hippocampal resection. Thus, 95% of these patients had an excellent result. Only 16% required invasive preoperative studies to confirm lateralization. These results were significantly better than those of the group without preceding febrile convulsions (p = 0.0013).

The incidence of idiopathic preretinal macular gliosis.

A series of 1,000 consecutive routine eye examinations performed on patients over the age of 50 was evaluated with particular reference to the presence of idiopathic preretinal macular gliosis (IPMG). In this group, there were 64 patients with IPMG (6.4%), 13 (20%) of whom had bilateral IPMG. The large majority of cases (63%), however, had only minor visual disability as a result of this disorder.

Viral infections and malformations of the nervous system.

Experimental viral infections are described which cause malformations of the developing nervous system. These include influenza virus infection of chick embryos causing defects in neural tube closure and flexion, parvovirus infections of rodents and cats resulting in a granuloprival cerebellar malformation, and myxovirus infections of rodents inducing stenosis of the aqueduct of Sylvius. In each experimental model the pathogenesis of the malformation is different, but in each the resultant noninflammatory malformation bears resemblances to malformations in man considered to have a genetic basis.