Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice.

Approximately 40-50% of individuals affected by tuberous sclerosis (TSC) develop autism spectrum disorders (ASDs). One possible explanation for this partial penetrance is an interaction between TSC gene mutations and other risk factors such as gestational immune activation. In this study, we report the interactive effects of these two ASD risk factors in a mouse model of TSC. Combined, but not single, exposure had adverse effects on intrauterine survival. Additionally, provisional results suggest that these factors synergize to disrupt social approach behavior in adult mice. Moreover, studies in human populations are consistent with an interaction between high seasonal flu activity in late gestation and TSC mutations in ASD. Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.

Surgery for the treatment of medically intractable infantile spasms: a cautionary case.

UNLABELLED: The most appropriate time to consider cortical resection to treat medically intractable infantile spasms has not been clearly defined. The risks that need to be reconciled to make this decision are: What is the risk of loss of developmental potential if surgery is delayed too long versus what is the risk of unnecessary surgery if it is done too soon. We propose that, in addition to evaluation of seizures, developmental assessment is a key factor in the surgical decision. The case report illustrates this concept. CASE REPORT: HC had onset of seizures at 9 days of age and developed infantile spasms due to mild right hemimegancephaly. At 19 months, she was having up to 50 seizures/day and was evaluated and approved for right hemispherectomy but surgery was delayed. Despite the seizures, her development had been much better than most patients with hemimegencephaly and infantile spasms. At 25 months her seizure control was much improved but she had several seizures/week. EcoG at the time of surgery did not demonstrate the usual abnormalities so no resection was performed. She has had only 5 seizures in the 2(1/2) year since. CONCLUSIONS: (a) Hemimegalencephaly is not always associated with severe mental retardation; (b) normal or near-normal development may, in some cases, indicate the possibility of medical control of seizures as the child grows; (c) a localized developmental brain abnormality in a child with intractable seizures should not necessarily lead to cortical resection; and (d) when a child meets developmental milestones, it may be appropriate to delay surgical intervention.

Incidence of death in patients with intractable epilepsy during nitrazepam treatment.

PURPOSE: Increased risk of death has been reported in patients with intractable epilepsy (IE) taking nitrazepam (NZP). METHODS: Between January 1983 and March 1994, 302 patients with IE were entered into a NZP compassionate-plea protocol. NZP was discontinued if there was < 50% seizure reduction or significant side effects. In some patients with > 50% reduction, it also was discontinued for lack of sufficient effect. At the end of follow-up for this study, 62 patients remained taking NZP. Patients took NZP from 3 days to 10 years. RESULTS: Twenty-one of 302 patients died after institution of NZP. Fourteen of 21 of these were taking NZP at death, and in five of 21, the NZP had been discontinued. Two patients were excluded from analysis, because it is unclear whether NZP had been discontinued before death. Six other patients were lost from follow-up. Of the 14 deaths with NZP, seven were sudden, six were of pneumonia, and one was of cystinosis. Nine had at least one contributing factor, such as dysphagia, gastroesophageal reflux, or recurrent aspirations. The 294 patients took NZP for a total of 704 patient years (ptyrs), and were discontinued for a total of 856 ptyrs. There were 1.98 deaths/ 100 ptyrs on NZP compared with 0.58 deaths/100 ptyrs without NZP, most of the former being associated with side effects of NZP. Mortality in patients younger than 3.4 years was 3.98 with NZP compared with 0.26 deaths/100 ptyrs without NZP (p = 0.0002). Corresponding figures in patients 3.4 years or older were 0.50 and 0.86 deaths/100 ptyrs, respectively. CONCLUSIONS: NZP therapy for epilepsy apparently increases the risk of death, especially in young patients with IE. This should be considered in antiepileptic drug (AED) management decisions.