Neurology January 2009 Volume 72 Issue 2

Objective: To establish phenotype-genotype correlations in early-onset Parkinson disease (EOPD), we performed neurologic, neuropsychological, and psychiatric evaluations in a series of patients with and without parkin mutations.Background: Parkin (PARK2) gene mutations are the major cause of autosomal recessive parkinsonism. The usual clinical features are early-onset typical PD with a slow clinical course, an excellent response to low doses of levodopa, frequent treatment-induced dyskinesias, and the absence of dementia.Methods: A total of 44 patients with EOPD (21 with and 23 without parkin mutations) and 9 unaffected single heterozygous carriers of parkin mutations underwent extensive clinical, neuropsychological, and psychiatric examinations.Results: The neurologic, neuropsychological, and psychiatric features were similar in all patients, except for significantly lower daily doses of dopaminergic treatment and greater delay in the development of levodopa-related fluctuations (p < 0.05) in parkin mutation carriers compared to noncarriers. There was no major difference between the two groups in terms of general cognitive efficiency. Psychiatric manifestations (depression) were more frequent in patients than in healthy single heterozygous parkin carriers but did not differ between the two groups of patients.Conclusion: Carriers of parkin mutations are clinically indistinguishable from other patients with young-onset Parkinson disease (PD) on an individual basis. Severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta in these patients is associated with an excellent response to low doses of dopa-equivalent and delayed fluctuations, but cognitive impairment and special behavioral or psychiatric symptoms were not more severe than in other patients with early-onset PD.(C)2009AAN Enterprises, Inc.

Objective: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS.Methods: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of [alpha] = 0.05 was used.Results: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo.Conclusions: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.(C)2009AAN Enterprises, Inc.

Background: Cognitive decline is one of the clinical hallmarks of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebrovascular disease caused by NOTCH3 mutations. In this 7-year follow-up study, we aimed to determine whether there are associations between the different radiologic hallmarks in CADASIL and decline in specific cognitive domains.Methods: Twenty-five NOTCH3 mutation carriers and 13 controls had standardized neuropsychological testing and MRI examinations at baseline and after a follow-up of 7 years. To identify longitudinal associations between MRI abnormalities and cognitive decline, correlation analysis was used.Results: At follow-up, mutation carriers showed a decline in global cognitive function (CAMCOG, p < 0.01) and in the cognitive domains language, memory, and executive function, compared to controls. Cognitive decline, especially executive dysfunction, was associated with increase in lacunar infarcts, microbleeds, and ventricular volume. In contrast, WMHs and brain atrophy were not associated with cognitive decline.Conclusion: Increase in lacunar infarcts, microbleeds, and ventricular volume, but not white matter lesions or atrophy, are associated with cognitive decline in the process of CADASIL in younger-aged, mildly affected patients with CADASIL.(C)2009AAN Enterprises, Inc.

Background: [alpha]-Internexin (INA) is a proneural gene encoding a neurofilament interacting protein that is upregulated in some gliomas, particularly oligodendrogliomas.Methods: INA expression was evaluated by immunohistochemistry in a series of 122 gliomas, and correlated to the 1p19q codeletion, a favorable prognostic marker of oligodendroglial tumors.Results: INA expression was strong (>10% positive cells) in 22 cases (22 oligodendroglial tumors and 0 astrocytic tumors), weak (<10% cells) in 14 cases (12 oligodendroglial tumors, 2 glioblastoma with an oligodendroglial component, and 0 astrocytic tumors), and negative in 86 cases (49 oligodendroglial tumors, 9 glioblastoma with an oligodendroglial component, and 28 astrocytic tumors). Among the 27 tumors exhibiting the 1p19q codeletion (all with an oligodendroglial phenotype), INA was detected in 96% (26/27, 18 strong, 8 weak) as compared to 11% (10/95, 4 strong, 6 weak) in the tumors without 1p19q codeletion (with an oligodendroglial or an astrocytic phenotype) (p < 0.001). In oligodendroglial tumors, INA expression specificity for 1p19q codeletion was 86%, sensitivity 96%, positive predictive value 76%, and negative predictive value was 98%. The prognostic impact of INA expression could be evaluated in grade III oligodendroglial tumors. Similar to 1p19q deletion, positive INA expression was correlated with better progression-free survival (52.6 vs 8.7 months [p = 0.001]) and overall survival (121.1 vs 31.4 months [p = 0.0001]).Conclusion: [alpha]-Internexin (INA) expression appears to be a simple, reliable prognostic marker and a surrogate marker of 1p19q codeletion.(C)2009AAN Enterprises, Inc.

Background: The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa.Objective: To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV- individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined.Methods: At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV- individuals received identical clinical assessments and were followed up for 6 months.Results: In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV- individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART.Conclusions: After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.(C)2009AAN Enterprises, Inc.

Background: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy.Methods: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence.Results and Recommendations: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.GLOSSARY: AAN = American Academy of Neurology; AANEM = American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R = American Academy of Physical Medicine and Rehabilitation; ART = autonomic reflex testing; BRSI = baroreflex sensitivity index; CASS = composite autonomic scoring scale; CIDP = chronic inflammatory demyelinating polyneuropathy; DSFN = distal small fiber neuropathy; DSP = distal symmetric polyneuropathy; EDx = electrodiagnosis; EFNS = European Federation of Neurological Societies; HRV = heart rate variability; IAN = idiopathic autonomic neuropathy; IENF = intraepidermal nerve fibers; MSNA = muscle sympathetic nerve activity; NCSs = nerve conduction studies; PGP 9.5 = protein-gene-product 9.5; PN = peripheral neuropathy; PRT = blood pressure recovery time; QAE = quantitative autonomic examination; QSART = quantitative sudomotor axon reflex test; QSS = Quality Standards Subcommittee; QST = quantitative sensory testing; SFSN = small fiber sensory polyneuropathy; TST = thermoregulatory sweat testing.(C)2009AAN Enterprises, Inc.