James N. Scott

Idiopathic intracranial hypertension: The prevalence and morphology of sinovenous stenosis

Objective: To determine the prevalence and nature of sinovenous obstruction in idiopathic intracranial hypertension (IIH) using auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venography (ATECO MRV). Methods: In a prospective controlled study, 29 patients with established IIH as well as 59 control patients underwent ATECO MRV. In a randomized blinded fashion, three readers evaluated the images. Using a novel scoring system, each reader graded the degree of stenosis seen in the transverse and sigmoid sinuses of each patient. Results: There was excellent agreement across the three readers for application of the grading system. Substantial bilateral sinovenous stenoses were seen in 27 of 29 patients with IIH and in only 4 of 59 control patients. Conclusion: Using ATECO MRV and a novel grading system for quantifying sinovenous stenoses, the authors can identify IIH patients with sensitivity and specificity of 93%.

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

How often are nonenhancing supratentorial gliomas malignant? A population study.

Abstract—The presence of contrast enhancement in a brain tumor is often regarded as a sign of malignancy. The authors identified 314 patients with malignant and low-grade supratentorial glial neoplasms in an unselected population, 58 of which lacked contrast enhancement on preoperative neuroimaging. Nonenhancing gliomas were malignant in approximately one third of cases, especially in older patients. Histologic confirmation of the diagnosis is therefore important in all patients suspected of harboring a primary glial neoplasm.

Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging.

We examined whether the presence of diffusion‐weighted imaging (DWI) lesions and vessel occlusion on acute brain magnetic resonance images of minor stroke and transient ischemic attack patients predicted the occurrence of subsequent stroke and functional outcome. 120 transient ischemic attack or minor stroke (National Institutes of Health Stroke Scale ≤ 3) patients were prospectively enrolled. All were examined within 12 hours and had a magnetic resonance scan within 24 hours. Overall, the 90‐day risk for recurrent stroke was 11.7%. Patients with a DWI lesion were at greater risk for having a subsequent stroke than patients without and risk was greatest in the presence of vessel occlusion and a DWI lesion. The 90‐day risk rates, adjusted for baseline characteristics, were 4.3% (no DWI lesion), 10.8% (DWI lesion but no vessel occlusion), and 32.6% (DWI lesion and vessel occlusion) (p = 0.02). The percentages of patients who were functionally dependent at 90 days in the three groups were 1.9%, 6.2%, and 21.0%, respectively (p = 0.04). The presence of a DWI lesion and a vessel occlusion on a magnetic resonance image among patients presenting acutely with a transient ischemic attack or minor stroke is predictive of an increased risk for future stroke and functional dependence. Ann Neurol 2005;57:848–854

Which glioblastoma multiforme patient will become a long‐term survivor? A population‐based study

In this clinical and histopathological study, the frequency of long‐term glioblastoma multiforme (GBM) survivors (LTGBMSs) was determined in a population‐based study. The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in Alberta between January 1, 1975, and December 31, 1991. Patient charts were reviewed and histology reexamined. LTGBMSs were defined as GBM patients surviving 3 years after diagnosis. Each LTGBMS was compared with 3 age‐, sex‐, and year of diagnosis–matched controls, and patient/treatment or tumor characteristics that predicted long‐term survival were determined. There were 689 GBMs diagnosed in the study period; 15 (2.2%) of these patients survived 3 years. LTGBMSs (average age, 43.5 ± 3.3 years) were significantly younger when compared with all GBM patients (average age, 53.0 ± 0.56 years). LTGBMSs had a higher Karnofsky Performance Status score at diagnosis compared with controls. LTGBMSs were much more likely to have had a gross total resection and adjuvant chemotherapy than control GBM patients. Tumors from LTGBMSs tended to have fewer mitoses and a significantly lower Ki‐67 cellular proliferation index compared with controls. Radiation‐induced dementia was common and disabling in LTGBMSs. In conclusion, conventionally treated GBM patients in an unselected population have a very small chance of long‐term survival. The use of aggressive surgical resection and adjuvant chemotherapy may make long‐term survival more likely in GBM patients if their performance status is high at diagnosis. Ann Neurol 1999;47:183–188

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect.

Long-term Glioblastoma Multiforme Survivors: a Population-based Study

BACKGROUND Long-term glioblastoma multiforme survivors (LTGBMS) are uncommon. The frequency which these occur in an unselected population and factors which produce these unusually long survivors are unknown. OBJECTIVES To determine in a population-based study 1) the frequency of LTGBMS in a population and 2) identify which patient, treatment or tumor characteristics would predict which glioblastoma (GBM) patient would become a LTGBMS. METHODS The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in southern Alberta between 1/1/75-12/31/91. Patient charts were reviewed and histology re-examined by a blinded neuropathologist. LTGBMS were defined as GBM patients surviving > or = 3 years after diagnosis. Each LTGBMS was compared to three age-, gender-, and year of diagnosis-matched controls to compare patient, treatment, and tumor factors to GBM patients without long-term survival. RESULTS There were 279 GBMs diagnosed in the study period. Five (1.8%) survived > or = three years (range, 3.2-15.8 years). Seven additional long-term survivors, who carried a diagnosis of GBM, were excluded after neuropathologic review; the most common revised diagnosis was malignant oligodendroglioma. LTGBMS (avg. age = 45 years) were significantly younger when compared to all GBM patients (avg. age = 59 years, p = 0.0001) diagnosed in the study period. LTGBMS had a higher KPS at diagnosis (p = 0.001) compared to controls. Tumors from LTGBMS tended to have fewer mitoses and a lower Ki-67 cellular proliferative index compared to controls. Radiation-induced dementia was common and disabling in LTGBMS. CONCLUSIONS These data highlight the dismal prognosis for GBM patients who have both a short median survival and very small chance (1.8%) of long-term survival. The LTGBMS were younger, had a higher performance status, and their tumors tended to proliferate less rapidly than control GBM patients. When long-term survival does occur it is often accompanied by severe treatment-induced dementia.

Cerebral Microhemorrhages Predict New Disabling or Fatal Strokes in Patients With Acute Ischemic Stroke or Transient Ischemic Attack

Background and Purpose— Cerebral microhemorrhages (MHs) are common among patients presenting with acute ischemic stroke and may predict both subsequent ischemic and hemorrhagic strokes. Methods— We prospectively studied patients with and without MHs presenting within 12 hours of their ischemic stroke or transient ischemic attack (TIA). A magnetic resonance (MR) scan was performed within 24 hours of symptom(s) onset. The primary outcome was disabling or fatal stroke at 18 months. Results— An MR scan was done in 236 patients with acute ischemic stroke or TIA. Forty-five (19.1%) patients had an MH on a baseline MR scan. Patients with MHs were 2.8× (10.8% versus 4.0%; P=0.036) more likely to have a subsequent disabling or fatal stroke than patients without an MH. The risk of symptomatic intracerebral hemorrhage was not statistically significant among MH and non-MH patients (3.3% versus 0.8%; P=0.31). Conclusions— The presence of cerebral MH(s) in patients with acute ischemic stroke or TIA predicts recurrent disabling and fatal strokes. This risk is mainly assumed by recurrent ischemic strokes.

An improved scoring system for identifying patients at high early risk of stroke and functional impairment after an acute transient ischemic attack or minor stroke

Background Risk of a subsequent stroke following an acute transient ischemic attack (TIA) or minor stroke is high. The ABCD2 tool was proposed as a method to triage these patients using five clinical factors. Modern imaging of the brain was not included. The present study quantified the added value of magnetic resonance imaging (MRI) factors to the ABCD2 tool. Methods Patients with TIA or minor stroke were examined within 12 h and had a brain MRI within 24 h of symptom onset. Primary outcomes were recurrent stroke and functional impairment at 90 days. A new tool, ABCD2+ MRI, was created by adding diffusion-weighted imaging lesion and vessel occlusion status to the ABCD2 tool. The predictive accuracy of both tools was quantified by the area under the curve (AUC). Results One hundred and eighty patients were enrolled and 11·1% had a recurrent stroke within 90 days. The predictive accuracy of the ABCD2+MRI was significantly higher than ABCD2 (AUC of 0·88 vs. 0·78, P = 0·01). Those with a high score (7–9) had a 90-day recurrent stroke risk of 32·1%, moderate score (5–6) risk of 5·4%, and low score (0-4) risk of 0·0%. The ABCD2 tool did not predict risk of functional impairment at 90 days (P = 0·33), unlike the ABCD2+MRI (P = 0·02): high score (22·9%), moderate (7·5%), low (7·7%). Conclusions Risk of recurrent stroke and functional impairment after a TIA or minor stroke can be accurately predicted by a scoring system that utilizes both clinical and MRI information. The ABCD2+MRI score is simple and its components are commonly available during the time of admission.

β-Amyloid precursor protein gene is differentially expressed in axotomized sensory and motor systems

The beta-amyloid precursor protein (APP) is involved in the degenerative and regenerative neural changes associated with aging and Alzheimers disease. We studied the regulation of APP gene expression in a paradigm of degeneration and regeneration, the axotomized rat sciatic system. The sciatic nerves of rats were crushed and at intervals between 4 and 60 days, the affected dorsal root ganglia and spinal cord segments were processed for Northern analysis and in situ hybridization to evaluate various APP mRNA species. After nerve crush, dorsal root ganglia APP mRNA levels are increased for both APP695 (695 amino acids) and APPKPI (Kunitz protease inhibitor). Following reinnervation, APP695 returns to baseline but APPKPI remains elevated. In spinal cord there is a decrease of APP695, which returns to baseline following reinnervation. If regeneration is prevented, the initial phase of post-axotomy response for all APP forms persists for at least 60 days in both dorsal root ganglia and spinal cord. In situ hybridization confirms that the changes are referable to neurons. These findings indicate that neuron-target interactions are important in APP gene regulation; that the APP695 and APPKPI transcripts are differentially regulated following neuronal injury; and that different neuronal populations regulate APP expression in a cell-type specific manner.