Michael C. Huang

Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset motor neuron disease that arises as a dominantly inherited trait in approximately 10% of ALS cases. Mutations in one gene, cytosolic Cu/Zn superoxide dismutase (SOD1), account for approximately 25% of familial ALS (FALS) cases. We have performed a genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene and have identified novel ALS loci on chromosomes 16 and 20. The analysis of these genes will delineate pathways implicated as determinants of motor-neuron viability and provide insights into possible therapies for ALS.

Coagulopathy After Traumatic Brain Injury

Traumatic brain injury has long been associated with abnormal coagulation parameters, but the exact mechanisms underlying this phenomenon are poorly understood. Coagulopathy after traumatic brain injury includes hypercoagulable and hypocoagulable states that can lead to secondary injury by either the induction of microthrombosis or the progression of hemorrhagic brain lesions. Multiple hypotheses have been proposed to explain this phenomenon, including the release of tissue factor, disseminated intravascular coagulation, hyperfibrinolysis, hypoperfusion with protein C activation, and platelet dysfunction. The diagnosis and management of these complex patients are difficult given the lack of understanding of the underlying mechanisms. The goal of this review is to summarize the current knowledge regarding the mechanisms of coagulopathy after blunt traumatic brain injury. The current and emerging diagnostic tools, radiological findings, treatment options, and prognosis are discussed.

Identification of p18INK4c as a Tumor Suppressor Gene in Glioblastoma Multiforme

Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16(INK4a) and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c) cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) often occurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but not p18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identify p18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.

DPL-1 DP, LIN-35 Rb and EFL-1 E2F Act With the MCD-1 Zinc-Finger Protein to Promote Programmed Cell Death in Caenorhabditis elegans

The genes egl-1, ced-9, ced-4, and ced-3 play major roles in programmed cell death in Caenorhabditis elegans. To identify genes that have more subtle activities, we sought mutations that confer strong cell-death defects in a genetically sensitized mutant background. Specifically, we screened for mutations that enhance the cell-death defects caused by a partial loss-of-function allele of the ced-3 caspase gene. We identified mutations in two genes not previously known to affect cell death, dpl-1 and mcd-1 (modifier of cell death). dpl-1 encodes the C. elegans homolog of DP, the human E2F-heterodimerization partner. By testing genes known to interact with dpl-1, we identified roles in cell death for four additional genes: efl-1 E2F, lin-35 Rb, lin-37 Mip40, and lin-52 dLin52. mcd-1 encodes a novel protein that contains one zinc finger and that is synthetically required with lin-35 Rb for animal viability. dpl-1 and mcd-1 act with efl-1 E2F and lin-35 Rb to promote programmed cell death and do so by regulating the killing process rather than by affecting the decision between survival and death. We propose that the DPL-1 DP, MCD-1 zinc finger, EFL-1 E2F, LIN-35 Rb, LIN-37 Mip40, and LIN-52 dLin52 proteins act together in transcriptional regulation to promote programmed cell death.

182 Ultra-Early (<12 Hours) Decompression Improves Recovery After Spinal Cord Injury Compared to Early (12-24 Hours) Decompression.

INTRODUCTION:Spinal cord injury (SCI) is a devastating condition with very few treatment options. Surgical decompression of the spine after injury has been shown to improve outcomes; however, the optimal timing of surgery is a matter of debate.METHODS:We collected data from 78 patients with SCI. Bas

Cervicomedullary neurocysticercosis causing obstructive hydrocephalus

We present a 45-year-old man with tussive headache and blurred vision found to have obstructive hydrocephalus from a neurocysticercal cyst at the cervicomedullary junction who underwent surgical removal of the cyst. We performed a suboccipital craniectomy to remove the cervicomedullary cyst en bloc. Cyst removal successfully treated the patients headaches without necessitating permanent cerebrospinal fluid diversion. Neurocysticercosis is the most common parasite infection of the central nervous system causing seizures and, less commonly, hydrocephalus. Intraventricular cysts or arachnoiditis usually cause hydrocephalus in neurocysticercosis but craniocervical junction cysts causing obstructive hydrocephalus are rare. Neurocysticercosis at the craniocervical junction may cause Chiari-like symptoms. In the absence of arachnoiditis and leptomeningeal enhancement, surgical removal of the intact cyst can lead to favorable outcomes.

Aneurysm of the Posterior Meningeal Artery Embedded Within a Dorsal Exophytic Medullary Hemangioblastoma: Surgical Management and Review of Literature

Hemangioblastomas are World Health Organization (WHO) Grade I neoplasms of the hindbrain and spinal cord, whose management can be complicated by preoperative hemorrhage. We report on a case of a young female in extremis with posterior fossa hemorrhage following rupture of a fusiform posterior meningeal artery aneurysm embedded within a medullary hemangioblastoma. We discuss management options, including operative staging and embolization, and review similar cases of hemangioblastoma associated with aneurysm.

Placement of a subdural evacuating port system for management of iatrogenic hyperacute subdural hemorrhage following intracranial monitor placement

A 22-year-old man was admitted with a severe traumatic brain injury developed a hyperacute subdural hematoma (SDH) following attempted brain tissue oxygen monitor placement. This patient was successfully treated by placement of a subdural evacuation portal system (SEPS). The patient presented to a Level I trauma center after a severe bike versus auto accident. On admission, he was found to have a Glasgow Coma Scale (GCS) score of 3. The patient had small areas of intraparechymal hemorrhage as well as suspicion for diffuse axonal injury in the midbrain. Based on the patients GCS score, neurological monitoring was indicated as a part of his intensive care unit treatment, however a SDH occurred during an attempted placement of a brain tissue oxygen monitor. This iatrogenic hyperacute SDH after burr hole monitoring device placement was treated with a SEPS drain. The SEPS drain has been shown to provide complete and/or temporary decompression of liquefied SDH. To our knowledge, this is the first report of using the SEPS to treat iatrogenic SDH associated with an intracranial monitoring device. This technique should be added to the armament of treatment options for a neurosurgeon to treat or temporize a hyperacute SDH with increased intracranial pressure in specific patients.

Concordance of common data elements for assessment of subjective cognitive complaints after mild-traumatic brain injury: a TRACK-TBI Pilot Study

ABSTRACT Objective: To determine characteristics and concordance of subjective cognitive complaints (SCCs) 6 months following mild-traumatic brain injury (mTBI) as assessed by two different TBI common data elements (CDEs). Research design: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot Study was a prospective observational study that utilized the NIH TBI CDEs, Version 1.0. We examined variables associated with SCC, performance on objective cognitive tests (Wechsler Adult Intelligence Scale, California Verbal Learning Test, and Trail Making Tests A and B), and agreement on self-report of SCCs as assessed by the acute concussion evaluation (ACE) versus the Rivermead Post Concussion Symptoms Questionnaire (RPQ). Results: In total, 68% of 227 participants endorsed SCCs at 6 months. Factors associated with SCC included less education, psychiatric history, and being assaulted. Compared to participants without SCC, those with SCC defined by RPQ performed significantly worse on all cognitive tests. There was moderate agreement between the two measures of SCCs (kappa = 0.567 to 0.680). Conclusion: We show that the symptom questionnaires ACE and RPQ show good, but not excellent, agreement for SCCs in an mTBI study population. Our results support the retention of RPQ as a basic CDE for mTBI research. Abbreviations: BSI-18: Brief Symptom Inventory; 18CDEs: common data elements; CT: computed tomography; CVLT: California Verbal Learning Test; ED: emergency department; GCS: Glasgow coma scale; LOC: loss of consciousnessm; TBI: mild-traumatic brain injury; PTA: post-traumatic amnesia; SCC: subjective cognitive complaints; TBI: traumatic brain injury; TRACK-TBI: Transforming Research and Clinical Knowledge in Traumatic Brain Injury; TMT: Trail Making Test; WAIS-PSI: Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index

Treatment of recurrent, multiloculated, obstructive hydrocephalus with suprahepatic peritoneal catheter placement

The suprahepatic space represents a potential reservoir for cerebrospinal fluid absorption and becomes critical when extensive abdominal adhesions prevent passage of a peritoneal shunt catheter toward the pelvis. We present a patient with refractory hydrocephalus in which a multishunt system with drainage into the suprahepatic space was ultimately successful in decompressing the patients trapped ventricular spaces.