Neurology December 2008 Volume 71 Issue 24

Objective: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups.Methods: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)-binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [3H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1[beta], IL-6, interferon (IFN)-[gamma], and tumor necrosis factor (TNF)-[alpha] was evaluated using enzyme-linked immunosorbent spot assay.Results: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1[beta], IL-6, IFN-[gamma], or TNF-[alpha] production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1[beta]-, IL-6-, and TNF-[alpha]-secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN-[gamma]-secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS.Conclusions: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.(C)2008AAN Enterprises, Inc.

Background: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI).Objective: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS).Methods: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain 1H-MRS and 31P-MRS were evaluated in two patients.Results: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by 31P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex.Conclusion: Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.(C)2008AAN Enterprises, Inc.

Background: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG).Methods: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included.Results: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls.Conclusions: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant partial epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing.(C)2008AAN Enterprises, Inc.

Background: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD.Methods: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated.Results: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up.Conclusion: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.GLOSSARY: AD = Alzheimer disease; ADRDA = Alzheimer's Disease and Related Disorders Association; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; CDRSB = Clinical Dementia Rating Sum of Boxes; ERC = entorhinal cortex; FADRC-CC = Florida Alzheimer's Disease Research Center-Clinical Core; HPC = hippocampus; HR = hazard ratio; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MTA = medial temporal lobe atrophy; MTL = medial temporal lobe; NACC = National Alzheimer's Coordinating Center; naMCI = nonamnestic mild cognitive impairment; NCI = no cognitive impairment; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke; NS = not significant; PRC = perirhinal cortex; VRS = visual rating system.(C)2008AAN Enterprises, Inc.

Background: Expiratory muscle weakness due to cerebral infarction may contribute to reduced airway clearance in stroke patients.Methods: Transcranial magnetic stimulation (TMS) at the vertex and over each hemisphere and magnetic stimulation over the T10-11 spinal roots (Tw T10) and the phrenic nerves bilaterally (BAMPS) were performed in 15 acute ischemic stroke patients (age 68.9 +/- 9.8 years) and 16 matched controls. Surface electrodes recorded motor evoked potentials (MEPs) in the rectus abdominis (RA) and external oblique (EO) muscles bilaterally. Respiratory muscle function was assessed by measuring maximum static expiratory pressure (PEmax) and changes in intragastric (Pgas) and transdiaphragmatic (Pdi) pressure after voluntary cough, TMS, TwT10, and BAMPS. Regression models were used to assess determinants of peak voluntary cough flow rates (PCFR).Results: PCFR, cough Pgas, and vertex TMS Pgas were decreased in stroke patients compared with controls (203.6 +/- 151.1 vs 350.8 +/- 111.7 L/min, p = 0.004; 72.7 +/- 64.5 vs 163.4 +/- 55.8 cm H2O, p = 0.0003 and 8.7 +/- 3.3 vs 16.7 +/- 11.5 cm H2O, p = 0.023, respectively). There were no differences in TwT10 Pgas (25.2 +/- 7.8 vs 29.4 +/- 12.4 cm H2O, p = 0.153) or BAMPS Pdi (21.6 +/- 7.2 vs 19.2 +/- 3.4 cm H2O, p = 0.163). TMS Pgas was lower (4.1 +/- 2.8 vs 6.1 +/- 1.9 cm H2O, p = 0.023) following TMS of the injured compared with the uninjured hemisphere in stroke patients. Age and gender adjusted PCFR correlated with Pgas (r = 0.51, p = 0.009) and PEmax (r = 0.46, p = 0.024). Stroke was an independent determinant of PCFR after adjusting for Pgas and PEmax (p = 0.031).Conclusion: Ischemic cortical injury is associated with expiratory muscle weakness and may contribute to cough impairment in stroke patients.GLOSSARY: BAMPS = bilateral anterolateral magnetic phrenic stimulation; EO = external oblique; MEP = motor evoked potential; NIHSS = NIH Stroke Scale; Pdi = transdiaphragmatic pressure; Pes = esophageal pressure; Pgas = intragastric pressure; PCFR = peak voluntary cough flow rates; PEmax = maximum static expiratory pressure; POE = point of optimal excitability; RA = rectus abdominis; TMS = transcranial magnetic stimulation.(C)2008AAN Enterprises, Inc.