Faculty Bibliography

We report a case with therapeutic hypothermia after cardiac arrest where meaningful recovery far exceeded anticipated negative endpoints following cardiac arrest with loss of brainstem reflexes and subsequent status epilepticus. This man survived and recovered after an out-of-hospital cardiac arrest followed by a 6-week coma with absent motor responses and 5 weeks of burst suppression. Standard criteria suggested no chance of recovery. His recovery may relate to the effect of burst-suppression on EEG to rescue neurons near neuronal cell death. Further research to understand the mechanisms of therapeutic hypothermia and late restoration of neuronal functional capacity may improve prediction and aid end-of-life decisions after cardiac arrest.

OBJECTIVES: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC. The impact of genotype on these early manifestations of CKD has not been investigated. DESIGN: Retrospective chart review of 84 children and young adults with TSC. MEASUREMENTS: This study assessed the prevalence of hypertension, renal impairment, and proteinuria, as well as the genotype-phenotype correlations. RESULTS: Children and young adults with TSC2 mutations had a significantly higher rate of renal lesions, hypertension (36% vs 14%), and decreased renal function than those with TSC1 mutations. CONCLUSION: On the basis of estimated glomerular filtration rate and blood pressure, our findings are consistent with the hypothesis that TSC2 mutations are associated with more severe early renal involvement in children. There is a compelling need for close collaboration of nephrologists and neurologists to provide care to pediatric patients with TSC to improve screening and management of early manifestations of renal disease.

Purpose: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability (ID). Related female carriers were unaffected (Van Maldergem L et al. Hum Mol Genet 2013;22:3306-3314). Here, we report 12 female patients who carry a heterozygous de novo mutation of KIAA2022 and share a phenotype characterized by ID and epilepsy. Method: The 12 reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation-And expression studies were performed when possible. Clinical data were collected from medical records. Results: All mutations were predicted to result in a frameshift or premature stop. Ten out of 12 patients had intractable epilepsy with myoclonic and/or absence seizures, generalized in 9. Eleven patients had mild to severe ID. This female phenotype partially overlaps with the reported male phenotype, which consists of more severe ID, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation (XCI), complete absence of RNA expression in blood, and a phenotype similar to male patients. In five other tested patients XCI was random, confirmed by a non-significant two-To threefold decrease of RNA expression in blood, and consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. Conclusion: De novo truncating mutations in the KIAA2022 gene can lead to a phenotype not only in males, but also in females. While males have more pronounced ID and dysmorphic features, females affected by KIAA2022 mutations show variable symptoms seemingly related to XCI skewing. Females with 100% XCI skewing and absent KIAA2022 expression show a phenotype similar to affected males. Females with random XCI tend to have a more prominent epilepsy phenotype, with predominant generalized myoclonic and/or absence seizures. Mechanisms underlying the female phenotype may be both cellular mosaicism and reduced protein expression

BACKGROUND: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy. METHODS: Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible. RESULTS: All mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. CONCLUSIONS: Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

OBJECTIVE: To characterize the frequency of and risk factors for out-of-hospital sudden neurologic deaths. METHODS: During the initial 25 months (February 1, 2011-March 1, 2013) of the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study, we captured incident WHO criteria sudden cardiac deaths (SCDs) through active surveillance of consecutive out-of-hospital deaths, which must be reported to the medical examiner by law. All cases were referred for full autopsy with detailed examination of the heart and cranial vault, toxicology, and histology. A multidisciplinary committee adjudicated a final cause of death. RESULTS: Of 352 incident SCDs, 335 (95%) underwent systematic evaluation including full autopsy. Of these 335 cases, 18 (5.4%) were sudden neurologic deaths (mean age 60.6 years [SD 17.6, range 27-87]; 67.7% female), which accounted for 14.9% of the 121 noncardiac sudden deaths. The risk of sudden neurologic death compared to non-neurologic SCD was lower in male and white participants (p < 0.01). Neurologic causes included intracranial hemorrhage (8), sudden unexpected death in epilepsy (6, including 2 with juvenile myoclonic epilepsy), aneurysmal subarachnoid hemorrhage (2), acute ischemic stroke (1), and aspiration from Huntington disease (1). Most deaths were unwitnessed (16; 89%) with asystole at presentation (17; 94%). Prior stroke/TIA was not associated with risk of stroke (odds ratio [OR] 1.4 [95% confidence interval (CI) 0.18-11.8], p = 0.73), but antithrombotic medication use was (OR 3.9 [95% 1.01-15.5], p = 0.05). CONCLUSIONS: Sudden neurologic death is an important cause of out-of-hospital apparent SCDs. Low prevailing autopsy rates may result in systematic misclassification of apparent SCDs and underestimation of the incidence of sudden neurologic death.