Time interval from a brain insult to the onset of infantile spasms.

The temporal latency between an encephalopathic event and the onset of infantile spasms cannot be determined in the majority of symptomatic cases (e.g. genetic conditions, cerebral malformations). However, we can measure this interval when a previously normal infant sustains brain injury followed by infantile spasms. This information has implications for understanding the underlying pathophysiologic basis for infantile spasms and, also, is germane to allegations that a close temporal relationship between vaccination and the onset of this seizure disorder establishes causation. We identified 19 published cases with sufficient information. The interval between brain injury and the onset of infantile spasms ranged from 6 weeks to 11 months (mean = 5.1 months). A similar temporal latency occurs in children with perinatal cerebral infarction and infantile spasms. We conclude that infantile spasms do not occur acutely following an encephalopathic event. This interval of weeks to months is consistent with prior studies indicating temporal latency between brain injury and the onset of other types of epilepsy, as well as with the previously proposed developmental desynchronization hypothesis. The findings refute claims that a close temporal association between an immunization and the onset of infantile spasms establishes causation.

Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.

Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.