Andrew N. Wilner, MD, FAAN, FACP

　

Medscape Neurology & Neurosurgery.  2006;8(2) ©2006 Medscape

　

Introduction

The American Neurological Association held its 131st Annual Meeting in Chicago, October 8-11, 2006. In addition to multiple symposia including the neurobiology of dementia, emerging technologies, and the neuroscience of addictive and adversive behaviors, more than 350 posters displayed advances in basic neuroscience and clinical neurology (published in a special supplement of Annals of Neurology, Volume 60, Issue S10; registration required). This Medscape Conference Report highlights selected abstracts that revealed scientific advances of interest to clinical neurologists.

Atherosclerosis

Reducing the morbidity and mortality related to atherosclerosis, whether it be in the carotid and basilar arteries leading to transient ischemic attacks and stroke, the coronary arteries leading to angina and myocardial infarction, or in the iliac and femoral arteries leading to peripheral vascular disease, represents one of the greatest challenges of modern medicine. Two papers focused on cerebrovascular disease, one suggesting the importance of screening a high-risk population, and the other identifying a possible treatment to decrease the severity of ischemic stroke.

Seemant Chaturvedi, MD, Director of the Stroke Program, Wayne State University, Detroit, Michigan, and colleagues^[1] screened 101 (mean age, 59.6 years, 51% male) African Americans with existing ischemic heart disease with carotid duplex ultrasound. Thirty-six percent of the group had diabetes. Carotid stenosis (> 50%) was present in 22% of the diabetics compared with only 5% of the nondiabetics (P < .01). Among the diabetics, 37% of the patients 60 years and older had carotid stenosis, compared with only 6% of the patients younger than 60 years (P = .04). Only half of the patients were treated with statins (see below). Dr. Chaturvedi suggested that clinicians consider screening this high-risk group (African American patients with existing ischemic heart disease and diabetes, especially those older than 60 years) with carotid ultrasound.

Statins have been shown to reduce the risk for stroke in patients at risk for cardiovascular disease, and a preplanned secondary analysis from the SPARCL trial^[2] suggests that statin treatment may decrease stroke severity as well.^[3]

"This study shows that your stroke will be less severe, which may be due to effects of statins that go beyond their lipid-lowering effect," summarized Larry Goldstein, MD, Director of the Stroke Service at Duke University Medical Center, Durham, North Carolina, and one of the principal authors of SPARCL. Of 492 patients who had an ischemic stroke during the median follow-up of 4.9 years, 218 were treated with atorvastatin and 274 received placebo. Patients treated with atorvastatin 80 mg/day had fewer strokes in all severity categories (mild, moderate, severe, and fatal) as assessed by the Modified Rankin Index (P = .001). Treatment with statins was not without adverse events, however, as there was an increase in hemorrhagic strokes in the statin-treated group (55 patients vs 33, cause-specific adjusted hazard ratio 1.66).

"This is the first prospective study to demonstrate that a statin can decrease the severity of subsequent stroke in a population of patients with a history of stroke and no known coronary disease," observed Dr. Goldstein.

The studies by Amarenco and colleagues^[2] and Goldstein and colleagues^[3] provide us with direction to improve our care of patients with atherosclerotic vessel disease. The study by Chaturvedi and colleagues^[1] confirms the systemic nature of atherosclerosis, demonstrating that diabetic patients with ischemic cardiac disease are likely to have carotid disease as well. Screening at-risk patients with carotid ultrasound may lead to more aggressive medical or surgical therapy and improved patient outcomes. If the observation from SPARCL that statins may decrease the severity of ischemic stroke is confirmed, this represents a true breakthrough in the care of patients with cerebrovascular disease.

Autism

Autism affects approximately 3 in 1000 children who display repetitive, stereotyped behaviors with limitations in communication and social interactions to varying degrees. Parents are usually the first to notice these abnormities. The diagnosis is a clinical one, relying on observation of the child's behavior, screening instruments, and a comprehensive neurologic, genetic, and psychological evaluation. Immunologic abnormalities have been detected, which may play an etiologic role or simply represent a reaction to underlying cortical abnormalities.

Michael Chez, MD, a pediatric neurologist at Hawthorne Health Center, Libertyville, Illinois, and colleagues^[4] measured the titers of TNF-alpha, a proinflammatory cytokine, in 8 boys who developed autistic regression between 15 and 24 months of age. At the time of the CSF measurement, their ages ranged from 2.1 to 9.5 years. All 8 patients had elevated TNF-alpha levels in CSF compared with in serum (P = .049). The 4 patients who had not been treated with immunosuppressants had the highest CSF:serum TNF-alpha ratios (33:1) compared with ratios for the 4 patients who had received immunosuppressant therapy (6:1). Values of other CSF components, such as cell count, glucose, protein, immunoglobulin production, myelin basic protein, oligoclonal bands, and lactic acid levels were unremarkable. Dr. Chez observed, "Larger studies with a control group are needed to examine predictive markers of autism that may also be useful as indicators of response to treatment. Early intervention against heightened TNF-alpha in the CSF may prove to be protective."

This study provides provocative data that beg for confirmation and clarification of the role of TNF-alpha in the pathogenesis of autism. Research is also under way regarding the potential role of chemokines and growth factors. Specific CSF findings in children with autism may eventually lead to a diagnostic test, provide confirmatory evidence to support the diagnosis, or indicate response to treatment, as suggested by the findings described above. Definitive treatment will ultimately depend upon the discernment of etiologic and risk factors for the development of autism.

Multiple Sclerosis

The etiology of multiple sclerosis is presumed to be some combination of genetic susceptibility and environmental risk factors. Results from 2 studies have advanced our knowledge regarding the role of genetics in the susceptibility to develop multiple sclerosis^[5] and its severity.^[6]

Alberto Ascherio, MD, Associate Professor of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, and colleagues^[5] explored whether variations in the alleles coding for the envelope protein (env) of human endogenous retrovirus-K18 (HERV-K18) play a role in the susceptibility to multiple sclerosis. HERV-K18 can be induced by Epstein-Barr virus infection, which has been associated with the development of multiple sclerosis. In a nested case-control study, patients were identified from 2 cohorts, the Nurses Health Study (N = 121,700), which began in 1976, and the Nurses Health Study II (N = 116,671), which began in 1989. From these populations, 207 women with multiple sclerosis were identified, as were 403 controls. A significant association between HERV-K18 env genotype and the risk for multiple sclerosis was identified (P = .03). In particular, the K18.3 allele was associated with an 80% increased risk, compared with the K18.1 allele, which had a 28% increased risk compared with the K18.2 allele. The presence of human leukocyte antigen (HLA) DRB1*1501 was associated with 3 times the risk for multiple sclerosis, but adjusting for the presence of this and other covariates did not change the HERV-K18 association.

Dr. Ascherio commented, "We know that Epstein-Barr virus has a strong association with the risk for multiple sclerosis. One possible mechanism is that Epstein-Barr virus activates a retroviral sequence that encodes for superantigens, like HERV-K18. We don't know the mechanism of the increased risk for multiple sclerosis of K18.3, but we will attempt to determine this and await replication of these findings in another population."

Darin T. Okuda, MD, a specialist in multiple sclerosis at the University of California, San Francisco, and colleagues^[6] evaluated the impact of the presence of HLA-DRB1*1501 on MRI lesion load in 505 patients (aged 18-65 years) with early multiple sclerosis. Of the 505 patients, 232 (46%) were positive for HLA-DRB1*1501. Dr. Okuda used a semi-automated threshold with manual editing on a 3-Tesla MRI machine and counted lesions that were 3 mm or smaller. Patients positive for HLA-DRB1*1501 had a significantly higher lesion load (T2 volume increase of 1127 mm³) (P = .031). However, clinical status, as measured by the Expanded Disability Status Scale (EDSS), did not differ between the 2 groups.

Dr. Okuda commented, "The HLA-DRB1*1501 gene encodes a class II recognition molecule that has a propensity to bind peptide antigens of myelin and stimulate encephalitogenic T cells. Both binding and structural data support a peptide binding region that displays a high affinity for aromatic amino acids, including phenylalanine at amino acid 92 of myelin basic protein. Therefore, these data may explain the radiological differences between the cohorts studied. The lack of correlation with EDSS suggests that this scale may not detect subtle clinical differences." Dr. Okuda added that the number of copies of the gene may be important as well.

The well-performed epidemiologic studies by Ascherio and colleagues^[5] and Okuda and colleagues^[6] confirm the importance of genetic susceptibility in the development of multiple sclerosis and open the doors to further investigation of the importance of HERV-K18 and HLA DRB1*1501.

Epilepsy

The word "cure" is rarely heard in the neurology clinic, but it does apply to many patients with mesial temporal sclerosis successfully treated with temporal lobectomy. However, as with any surgical procedure, complications such as hemorrhage, infection, and death may occur. Gamma knife radiosurgery represents a potential new alternative to conventional epilepsy surgery. Mark Quigg, MD, MSc, Associate Professor of Neurology, University of Virginia, Charlottesville, and colleagues^[7] presented the 2-year outcomes of a prospective multicenter pilot study of gamma knife radiosurgery for 30 patients (12 males, 18 females; mean age, 34.1 years) with intractable mesial temporal lobe epilepsy. Seventeen patients received "low-dose" radiation (20 Gy at 50% isodose) and 13 patients received "high dose" radiation (24 Gy at 50% isodose). The radiation beams targeted the temporal portion of the amygdala and anterior 2 cm of the hippocampal gyrus and adjacent parahippocampal gyrus.

At 2-year follow-up, 85% of the high-dose-treated patients were seizure-free, compared with only 55% of those treated with low-dose radiation. Those who became seizure-free had a dramatic improvement in quality-of-life scores as measured by the QOLIE-10. Half of the patients required steroids for cerebral-edema-related headaches, and 1 patient with steroid-dependent scotoma and headache required "escape" surgical temporal lobectomy at 15 months.

Most patients who are good candidates for temporal lobectomy represent extremely low surgical risks. However, some patients refuse surgery because of fears of morbidity and mortality. Gamma knife radiosurgery may represent an alternative to traditional epilepsy surgery for some patients. One potential drawback to this procedure is that benefits from radiosurgery take time (1-3 years) to accrue, and patients may continue to have seizures with their attendant morbidity (and mortality) while waiting for the radiosurgery ablation to take effect. More data need to be collected regarding the advantages and disadvantages of gamma knife radiosurgery as a treatment for intractable focal epilepsy.

Conclusion

These studies illustrate important advances in screening and treatment of neurologic disease. The first paper characterizes a population at high risk for carotid stenosis, suggesting fertile ground for carotid ultrasound screening. Two epidemiologic genetic studies provide data to help us screen for susceptibility to multiple sclerosis and severity of multiple sclerosis. Dr. Chez's observation of elevated CSF TNF-alpha in boys with autistic regression may prove to be useful in confirming the diagnosis and/or monitoring response to treatment, but it is too early to say. Statins reduce the risk for stroke, and Dr. Goldstein's subanalysis of the SPARCL data argue that stroke severity is also reduced. Finally, the results of the first controlled trial of a new approach to epilepsy surgery, the gamma knife, suggest that this technology may provide an attractive alternative to conventional epilepsy surgery for some patients with intractable focal epilepsy.

Madhavan R, Norris G, Santhakumar S, et al. Diabetes is a predictor of carotid stenosis in African Americans with ischemic heart disease. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract T57. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. Goldstein LB, Amarenco P, Callahan A, et al, on behalf of the SPARCL investigators. The SPARCL trial: Effect of statins on stroke severity. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract T60. Chez MG, Chang M, Khana P, Dowling T. Clinical inflammatory markers in CSF of autistic children with regression. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract M143. Tai AK, O'Reilly EJ, Alroy KA, Munger KL, Huber BT, Ascherio A. Human endogenous retrovirus-K18 env as a potential risk factor in multiple sclerosis. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract M28. Okuda DT, Pelletier D, Cree BAC, et al. HLA-DRB1*1501 influences MRI lesion load in early multiple sclerosis. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract M22. Quigg M, Laxer K, Broshek D, Barbaro NM, and the Multicenter Radiosurgery Pilot Study Group. Two year outcomes of a multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure remission and secondary outcomes. Program and abstracts of the 131st Annual Meeting of the American Neurological Association; October 8-11, 2006; Chicago, Illinois. Abstract S95.