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This Month in Archives of Neurology
May 2010

This Month in Archives of Neurology

Arch Neurol. 2010;67(5):531-533. doi:10.1001/archneurol.2010.77

TOMM40 Gene for Late-Onset Alzheimer Disease

Roses (Article) reviews the impressive new findings that a variable length, poly-T polymorphism in the TOMM40 (translocase of the outer mitochondrial membrane 40 homologue [yeast]) gene, which lies adjacent to APOE on chromosome 19, accounts for the age at onset distribution of late-onset Alzheimer disease. These new data explain the average age at disease onset for patients with the APOE4/4 genotype and differentiate the 2 forms of TOMM40 poly-T polymorphisms linked to APOE, with each form associated with a different age at disease onset distribution. When linked to APOE3, the longer TOMM40 poly-T repeats (19-39 nucleotides) at the rs10524523 locus are associated with earlier age at onset and shorter TOMM40 alleles (11-16 nucleotides) with later onset.

LRRK2 and Parkinson Disease

Dächsel and FarrerArticle review the molecular genetics and functional biology of leucine-rich repeat kinase 2 (LRRK2) in parkinsonism. They show that both affected and asymptomatic LRRK2 carriers now provide the opportunity to define the natural history of Parkinson disease. This includes the frequency, penetrance, and rate of motor symptoms, nonmotor comorbidities, and their associated biomarkers.

Attitudes and Performance of Third- vs Fourth-Year Neurology Clerkship Students

Dewey and AgostiniArticle compared student performance, attitudes, and career plans based on whether the neurology clerkship was taken in the third or fourth year. During the 1-year transition from the fourth to the third year at their institution, students took the identical clinical clerkship and were mixed together at each clinical site, where faculty were blinded to students' year. Performance, enthusiasm, and match results were analyzed by year of medical school for differences. Students' enthusiasm for neurologic learning was significantly higher in third-year compared with fourth-year students (P = .004). The probability that students would choose a career in neurology was higher for third- than fourth-year students (P < .001) but there was no correlation between year and matching for a neurology residency (P = .17). The findings support the belief among academic neurologists that students who take the neurology clerkship in the third year have greater enthusiasm for the field and look more favorably on neurology as a possible career than those who take neurology in their fourth year. Nevertheless, their findings do not support the notion that third-year placement results in superior achievement.

HIV-Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy: the CHARTER Study

Ellis and colleaguesArticle provide updated estimates of the prevalence and clinical effect of HIV sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy era. A total of 881 subjects had HIV-SN. Of these, 38.4% described neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.8-2.5 per 10 years), lower CD4 nadir (OR, 1.2; 95% CI, 1.1-1.2 per 100-cell decrease), current antiretroviral use (OR, 1.6; 95% CI, 1.3-2.8), and past “d-drug” use (OR, 2.0; 95% CI, 1.3-2.6). Risk factors for neuropathic pain were prior d-drug use and higher CD4 nadir. They find that HIV-SN and neuropathic pain remain prevalent, causing substantial disability and reduced quality of life even when receiving successful combination antiretroviral therapy. Dennis L. Kolson, MD, PhD, and Francisco González-Scarano, MD, provide editorial perspective.Article

Intracerebral Hemorrhage Among Eligible Warfarin-Treated Patients Receiving Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke

Prabhakaran et alArticle determined whether warfarin-treated patients with an international normalized ratio (INR) less than 1.7 who receive intravenous tissue plasminogen activator for acute ischemic stroke are at increased risk of symptomatic intracerebral hemorrhage (sICH). The overall rate of sICH was 6.5%, but it was nearly 10-fold higher among patients who took warfarin compared with those who did not take warfarin at baseline (30.8% vs 3.2%; P = .004). Baseline warfarin use remained strongly associated with sICH (P = .004) after adjusting for relevant covariates including age, atrial fibrillation, National Institutes of Health Stroke Scale score, and INR. Thus, they conclude that, despite an INR less than 1.7, warfarin-treated patients are more likely than those not taking warfarin to experience sICH following treatment with intravenous tissue plasminogen activator.

Long-term Blood Pressure Fluctuation and Cerebrovascular Disease in an Elderly Cohort

Brickman and colleaguesArticle determined the association of blood pressure (BP) level and long-term fluctuation in BP with cerebrovascular disease. White matter hyperintensity volume increased across the 4 study groups in a linear fashion, with the lowest white matter hyperintensity volume in the lowest mean/lowest SD group and the highest in the highest mean/highest SD group (F3,610 = 27.43; P = .002). Frequency of infarction also increased monotonically across groups (from 22% to 41%; P = .004 for trend). They conclude that, compared with individuals with low BP with low fluctuations in BP, the risk of cerebrovascular disease increases with increasing BP and BP fluctuation. Given that cerebrovascular disease is associated with disability, these findings suggest that interventions should focus on long-term fluctuating BP as well as elevated BP.

Effect of Systolic Blood Pressure Reduction on Hematoma Expansion

Qureshi et alArticle explored the relationship between various parameters of systolic blood pressure (SBP) reduction and hematoma expansion, perihematomal edema, and 3-month outcomes of patients with intracerebral hemorrhage. The median SBP reduction was 54 mm Hg and 62 mm Hg at 2 hours and 6 hours, respectively, from treatment initiation. The frequency of intracerebral hemorrhage growth was 23% vs 29%; relative edema growth, 38% vs 61%; and death or severe disability, 38% vs 44% (all P > .05) in subjects with greater than median SBP reduction at 2 hours compared with those with lesser magnitude of SBP reduction. They found no significant relationship between SBP reduction and any of the outcomes measured in this trial.

Racial Disparities in the Surgical Management of Intractable Temporal Lobe Epilepsy in the United States

McClelland et alArticle indicate that anterior temporal lobectomy (ATL) has emerged as the most effective modality for the treatment of intractable temporal lobe epilepsy (TLE), having been proven far superior to continued medical management. Previous reports from single hospitals indicate that the proportion of ATL performed on African American patients with TLE may be far less than on those who are not African American. This study was performed to determine whether, over a long time span, race and/or other predictive factors for patients with TLE who received ATL exist on a national level. They find that less than 10% of the TLE patient population receives ATL. Younger age and private insurance are independent predictors of receiving ATL, and African American race independently predicts decreased likelihood of receiving ATL. Despite recent attempts to bridge racial health disparities, the gap between African American individuals and other races in optimal TLE management has remained relatively unchanged on a nationwide level.

Plot of adjusted odds ratios (ORs) for African American race for 3 time periods. The adjusted OR of receiving anterior temporal lobectomy (ATL) comparing African American individuals with those of other races from the multiple logistic regression for the time periods 1988 through 1992, 1993 through 1996, and 1997 through 2003 are 0.25 (95% confidence interval [CI], 0.04-1.59), 0.70 (95% CI, 0.40-1.20), and 0.51 (95% CI, 0.32-0.83), respectively.

Plot of adjusted odds ratios (ORs) for African American race for 3 time periods. The adjusted OR of receiving anterior temporal lobectomy (ATL) comparing African American individuals with those of other races from the multiple logistic regression for the time periods 1988 through 1992, 1993 through 1996, and 1997 through 2003 are 0.25 (95% confidence interval [CI], 0.04-1.59), 0.70 (95% CI, 0.40-1.20), and 0.51 (95% CI, 0.32-0.83), respectively.

Gamma Knife Thalamotomy for Disabling Tremor

Lim et alArticle evaluated clinical outcomes after gamma knife thalamotomy (GKT) for disabling tremor with blinded assessments. Consecutive patients had unilateral GKT for essential tremor and Parkinson disease tremor. Overall, they found that GKT provided only modest antitremor efficacy. Of the 2 patients with essential tremor who experienced marked improvement in tremor, 1 subsequently experienced a serious adverse event. Further prospective studies with careful neurologic evaluation of outcomes are necessary before GKT can be recommended for disabling tremor on a routine clinical basis.

Impulse Control Disorders in Parkinson Disease

Weintraub and colleaguesArticle studied the association between dopamine-replacement therapies and impulse control disorders (ICDs) in Parkinson disease. A total of 3090 patients with treated idiopathic Parkinson disease at 46 movement disorders centers in the United States and Canada who received routine clinical care were included. They report that an ICD was identified in 13.6% of patients (gambling, 5.0%; sexual behavior, 3.5%; buying, 5.7%; and binge-eating disorder, 4.3%), and 3.9% had 2 or more ICDs. Impulse control disorders were more common in dopamine agonist (DA)–treated patients than in patients not taking a DA (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08; 3.54; P < .001). The frequency of ICD was similar for pramipexole and ropinirole (17.7% vs 15.5%; OR, 1.22; 95% CI, 0.94; 1.57; P = .14). Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems. They conclude that DA treatment in Parkinson disease is associated with a 2- to 3½-fold increased in the odds of having an ICD. This association represents a drug class relationship across ICDs.

FDG-PET in Progressive Apraxia of Speech and Primary Progressive Aphasia Variants

Josephs et alArticle determined patterns of hypometabolism on fluorodeoxyglucose F18 positron emission tomography (FDG-PET) in patients with progressive apraxia of speech and primary progressive aphasia variants and used these patterns to further refine current classification. They find that patterns of FDG-PET hypometabolism support the clinical categorizations of fluency, the distinction of apraxia of speech from progressive nonfluent aphasia, and the designation of a progressive fluent aphasia category.

Identification of 2 Loci at Chromosomes 9 and 14 in a Genome-wide Linkage Study of a Multiplex Family With FTLD-ALS

Gijselinck and colleaguesArticle conducted a genome-wide linkage study in a multiplex family with frontotemporal lobar degeneration–amyotrophic lateral sclerosis (FTLD-ALS) with subsequent fine mapping and mutation analyses. The index patient with clinical FTLD showed typical FTLD pathology with neuronal ubiquitin immunoreactive inclusions that were transactivation response DNA-binding protein 43 positive.

They report significant linkage to chromosome 9p23-q21 (multipoint logarithm of odds [LOD] score = 3.38) overlapping with a known FTLD-ALS locus (ALSFTD2) and nearly significant linkage to a second locus at chromosome 14q31-q32 (multipoint LOD score = 2.79). Obligate meiotic recombinants defined candidate regions of 74.7 megabase pairs (Mb) at chromosome 9 and 14.6 Mb near the telomere of chromosome 14q. In both loci, the disease haplotype segregated in all patients in the family. Mutation analysis of selected genes and copy number variation analysis in both loci did not reveal segregating pathogenic mutations. This family (DR14) provides additional significant evidence of the importance of the chromosome 9 gene to FTLD-ALS and unravels a possible novel locus for FTLD-ALS at chromosome 14.

Family Study of Restless Legs Syndrome in Quebec

Xiong et alArticle have ascertained the familial aggregation of restless legs syndrome (RLS) and characterized the clinical features of familial RLS (fRLS) cases. Their data showed that RLS aggregates in families with a familial rate of 77%, a sibling relative risk (λs) of 3.6 (95% confidence interval [CI], 2.8-4.4), and an offspring relative risk (λo) of 1.8 (95% CI, 1.0-2.7). Familial RLS is a chronic disorder with a mean (SD) disease duration of 24 (16) years and a wide range of age at onset (28 [15] years), with most family members presenting early-onset but mild to moderate RLS symptoms. Their clinical data also indicated that fRLS is more prominent in women, who also present increased incidence of anemia/iron deficiency, arthritis, and number of pregnancies. Pregnancy-related RLS seems to be a characteristic feature of fRLS, and these women tend to have much younger age at onset. They conclude that RLS is significantly aggregated in families with variable phenotypic expressivity, and the siblings of severely affected individuals have an increased risk of developing the disease.