In a meta-analysis of all candidate gene association studies in ischemic stroke, Casas and colleagues show that of 32 individual genes studied, 15 genes were identified for which at least 3 studies had been conducted that found significant associations. Factor V Leiden Arg506Gln, prothrombin G20210A, and angiotensin-converting enzyme insertion/deletion polymorphism showed significant associations with ischemic stroke. No single gene with a major effect was identified among those studied; rather, common variants in several genes, each exerting an effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies of predictive genetic testing for stroke.
Ptácek and Fu review episodic neurological phenotypes and their causal channelopathies in elegant detail. Since the molecular characterization of the first channelopathies less than 15 years ago, there has been an explosion of data implicating many different ion channel genes in the pathophysiology of a wide variety of human diseases. These advances underscore the power of human genetics in studying families segregating rare mendelian traits. Dr Ptácek has been a leader in this field, and his research as reviewed here will guide the search for complex genetic factors contributing to the risk of arrhythmia, headache, and seizures.
As reported by Tsai and colleagues, acute neuromuscular disease occurs with severe acute respiratory syndrome (SARS). Patients develop a syndrome compatible with critical illness myopathy and neuropathy, which is sometimes referred to as systemic inflammatory response syndrome. The case descriptions are compelling and will be of considerable value to clinicians caring for patients with SARS and acute neuromuscular disease. Editorial perspective is provided by Douglas W. Zochodne, MD, FRCPC.
Lyden and colleagues restudy the National Institutes of Health (NIH) Stroke Scale, which was originally created to detect treatment-related differences in clinical trials and was designed to measure right and left cerebral hemispheric function. They confirm prior results of cerebral localization in a new population of large hemispheric strokes. Left brain strokes score 4 more points on the NIH Stroke Scale compared with right brain strokes of larger volume.
Diffusion-weighted imaging, perfusion-weighted imaging, and magnetic resonance angiography are of value in assessing angiographic recanalization and clinical improvement in patients receiving thrombolytic therapy. Kwon and colleagues report successful angiographic recanalization and clinical improvement in 31 and 16 patients, with middle cerebral artery or internal carotid artery occlusion, respectively, who were treated with thrombolytics. Their experience and findings will be of value in evaluating patients with major artery occlusions and in treating them with thrombolytics.
McArthur and colleagues have investigated the relationships among plasma and cerebrospinal fluid human immunodeficiency virus (HIV) RNA levels, immune activation markers, and neurological status in HIV-seropositive subjects treated with combination antiretroviral therapy (CART). They report that, in contrast to observations in individuals not treated with CART, there was no relationship between cerebrospinal fluid markers and neurological status in their CART-using cohort with advanced HIV/AIDS. These negative findings for therapy response are discouraging but of importance in redefining future therapy clinical trials and emphasizing the need to treat early.
Cysique and colleagues studied the effect on neuropsychological function of highly active antiretroviral therapy (HAART) therapy in human immunodeficiency virus (HIV)-positive patients. Patient response was analyzed according to whether the patient’s regimen contained 3 or more neuroactive drugs (neuroHAART) or not (HAART). Treatment groups did not differ from one another on neuropsychological performance. Impaired patients in each treatment group were compared, and the neuroHAART group showed significantly better memory performance unrelated to plasma viral load, in comparison with the HAART group. The positive results are modest but of value in planning future clinical trials and evaluating the time of onset for treatment.
Thobois and colleagues have studied the issue of down-regulation of striatal dopamine D2 receptor expression as a consequence either of Parkinson disease itself or of dopaminergicdrug administration. In an elegant study using positronemission tomography and the ligand raclopride C 11, a dopamine D2 receptor ligand, they find that down-regulation of dopamine D2 receptors relates to the chronic and intermittent administration of dopaminergic therapy rather than to disease progression. Of note, they findup-regulation of putaminal D2 dopaminergic receptors in late-stage Parkinson disease after dopaminergic drug withdrawal. These data add interesting new insights into D2 receptor function in the natural history of Parkinson disease and dopaminergic therapy (Figure).
Mean raclopride C 11 binding in the putamen and caudate nucleus. In the putamen, no difference in raclopride C 11 binding was noted between control subjects and on-drug Parkinson disease (PD) patients, while raclopride C 11 binding was higher in off-drug PD patients compared with on-drug PD patients and controls (P=.03). In the caudate nucleus, on-drug PD patients had lower raclopride C 11 binding than did controls (P = .04) while no significant difference was noted between controls and off-drug PD patients (P = .3).
Rapoport and colleagues have studied the rate of delivery of homovanillic acid, a major dopamine metabolite, from brain to cerebrospinal fluid in young and older subjects. They find a 50% decline in the lower limit for the rate of homovanillic acid delivery from brain to cerebrospinal fluid in elderly subjects, which is consistent with other evidence that brain dopaminergic neurotransmission declines with age. These findings will be of importance in relating them to diseases of dopaminergic transmission as a diagnostic test or response to therapy.
Lanctôt and colleagues show that patients with Alzheimer disease and clinical aggression have regional hypoperfusion in the right medial temporal region, as studied with single-photon emission computed tomography. Their finding supports the hypothesis that pathological processes in this region are responsible for specific behavioral manifestations that accompany cognitive deficits of Alzheimer disease.
Godbolt and colleagues describe their findings in a large family with Alzheimer disease. Nineteen subjects with familial Alzheimer disease had clinical and neuropsychological assessments. The authors find that familial Alzheimer disease may have a long prodrome during which cognitive deficits are stable and may be initially limited to general intelligence and memory. Spelling was the most resilient cognitive domain. Naming and perception were also preserved to a late stage.
Kawai and colleagues have studied 16 patients with Machado-Joseph disease (MJD) for cognitive dysfunction. They find that MJD patients scored significantly lower than controls in verbal and visual memory, working memory, visuospatial/constructional ability, language, executive function, depression, and anxiety. These findings did not correlate to CAG repeat length. Thus, MJD patients, thought for many years to be unaffected by cognitive changes, do indeed show them and to a significant degree, as demonstrated by this careful and well-planned study. Early onset or asymptomatic carriers need to be studied to determine the motor or psychological issues that may interfere with cognitive testing.
This Month in Archives of Neurology. Arch Neurol. 2004;61(11):1644-1645. doi:10.1001/archneur.61.11.1644