OBJECTIVE:

To study the immune response against varicella-zoster virus (VZV) in patients with multiple sclerosis before and during fingolimod therapy.

METHODS:

The VZV-specific immune response was studied using interferon (IFN)-γ enzyme-linked immunosorbent spot assay, proliferation assays, and upregulation of T-cell activation markers in patients before (n = 38) and after 3 months of fingolimod therapy (n = 34), in untreated (n = 33) and IFN-β-treated (n = 25) patients with multiple sclerosis, and in healthy controls (n = 22). Viral replication was analyzed by using real-time PCR in 76 peripheral blood mononuclear cell samples and 146 saliva samples.

RESULTS:

Treatment with fingolimod led to a marked reduction of CD3(+) T cells with a relative decrease of naive and central memory T cells and an increase of effector memory T cells. Expression of the activation markers CD137 and CD69 upon VZV stimulation was unaltered by fingolimod. However, the absolute number of cells proliferating upon VZV stimulation was reduced in the blood of patients treated with fingolimod. Also, VZV-specific and Epstein-Barr virus (EBV)-specific IFN-γ-producing cells were reduced after fingolimod therapy. Seven of the 35 patients treated with fingolimod showed signs of VZV or EBV reactivation in saliva compared with 3 of the 111 controls. None of the 76 tested samples showed signs of viral reactivation in the peripheral blood mononuclear cells.

CONCLUSION:

Patients treated with fingolimod show a slightly reduced antiviral T-cell response. This reduced response is accompanied by a subclinical reactivation of VZV or EBV in the saliva of 20% of patients treated with fingolimod.

OBJECTIVE:

To examine the joint association of migraine headache and major depressive disorder on brain volume in older persons without dementia.

METHODS:

Participants (n = 4,296, 58% women) from the population-based Age, Gene/Environment Susceptibility-Reykjavik Study were assessed for migraine headache in 1967-1991 (age 51 years [range 33-65]) according to modified International Classification of Headache Disorders-II criteria. In 2002-2006 (age 76 years [range 66-96]), lifetime history of major depressive disorder (depression) was diagnosed according to DSM-IV criteria, and full-brain MRI was acquired, which was computer postprocessed into total brain volume (TBV) (gray matter [GM], white matter [WM], white matter hyperintensities) and CSF volume for each study subject. We compared brain tissue volumes by headache categories with or without depression using linear regression, adjusting for intracranial volume and other factors.

RESULTS:

Compared with the reference group (no headache, no depression) TBV and WM and GM volumes were smaller in those with both migraine and depression (TBV -19.2 mL, 95% confidence interval [CI] -35.3, -3.1, p = 0.02; WM -12.8 mL, CI -21.3, -4.3, p = 0.003; GM -13.0 mL, CI -26.0, 0.1, p = 0.05) but not for those with migraine alone (TBV 0.4 mL, WM 0.2 mL, GM 0.6 mL) or depression alone (TBV -3.9 mL, WM -0.9 mL, GM -2.9 mL).

CONCLUSIONS:

Reporting both migraine and major depressive disorder was associated with smaller brain tissue volumes than having one or neither of these conditions. Migraineurs with depression may represent a distinct clinical phenotype with different long-term sequelae. Nonetheless, the number of subjects in the current study is relatively small and these findings need to be confirmed in future studies.

OBJECTIVES:

We sought to document the prevalence and nature of sleep-disordered breathing (SDB) in individuals with Friedreich ataxia (FRDA) as well as establish the relationship, if any, between SDB and clinical parameters of FRDA.

METHODS:

Eighty-two individuals with FRDA were administered the Epworth Sleepiness Scale on an annual basis for up to 3 years. Individuals were referred for a sleep study if they had an Epworth Sleepiness Scale score >8 or had clinical symptoms suggestive of SDB.

RESULTS:

From this cohort, 21 individuals underwent a sleep study and 17 were diagnosed with obstructive sleep apnea syndrome, giving a minimum prevalence of 21%, which is greater than that found in the general population (3%-7%). Moreover, the presence of obstructive sleep apnea was significantly correlated with the duration of disease and clinical severity of FRDA.

CONCLUSION:

It is recommended that individuals with FRDA undergo regular screening for obstructive sleep apnea to identify the need for a sleep study and subsequent treatment if SDB is diagnosed.

OBJECTIVE:

Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials.

METHODS:

We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain.

RESULTS:

There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant.

CONCLUSIONS:

Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.

OBJECTIVE:

To characterize the rate of cognitive decline during the premotor phase of essential tremor (ET) in comparison to prevalent ET cases and controls.

METHODS:

In this population-based, prospective study of people aged 65 years and older (Neurological Disorders in Central Spain), a 37-item version of the Mini-Mental State Examination was administered at 2 visits (baseline and follow-up, approximately 3 years later). We compared the rate of cognitive decline in 3 groups: prevalent ET cases (i.e., participants diagnosed with ET at baseline and at follow-up), "premotor" ET cases (i.e., participants diagnosed with incident ET at follow-up, but not at baseline), and controls (i.e., participants not diagnosed with ET at baseline or follow-up).

RESULTS:

The 2,375 participants included 135 prevalent ET cases, 56 premotor ET cases, and 2,184 controls. During the follow-up period of 3.4 ± 0.5 years (mean ± SD), the 37-item version of the Mini-Mental State Examination declined by 0.7 ± 3.3 points (0.2 ± 1.0 points/year) in prevalent ET cases, 1.1 ± 3.5 points (0.3 ± 1.0 points/year) in premotor ET cases, and 0.1 ± 3.9 points (0.0 ± 1.2 points/year) in controls (p = 0.014). The difference between premotor ET cases and controls was significant (p = 0.046), as was the difference between prevalent ET cases and controls (p = 0.027).

CONCLUSIONS:

In this prospective cohort, cognitive test scores in premotor and prevalent ET cases declined at a faster rate than in elders without this disease. A decline in global cognitive function may occur in a premotor phase of ET.

BACKGROUND:

This study attempts to explore the clinical features, possible mechanisms and prognosis of the neurologic complications in patients with acute aortic dissection (AD).

METHODS:

Medical records of 278 consecutive patients with AD (165 with type A and 113 with type B dissection) over 11.5 years were retrospectively analyzed for clinical history, CT findings, neurologic complications and outcome. Neurologic complications were classified into early-onset or delayed-onset complications. Independent t-test or Chi-square test (or Fisher exact test) was used for comparing the different groups. Multivariable logistic regression analysis was performed to determine the independent association between variables.

RESULTS:

The mean age of the included patients (145 male and 133 female) was 59.4 years (range 19--91 years). 41 patients (14.7%) had a neurologic complication, which included 21 with early-onset complication and 23 with delayed-onset complication, including 3 with both. Advanced age and classic type of dissection were independently associated with the neurologic complication in patients with type A dissection. The most frequent manifestation was ischemic stroke (26 patients, 9.4%), followed by hypoxic encephalopathy (9, 3.2%), ischemic neuropathy (5, 1.8%), spinal cord ischemia (5, 1.8%), seizure (2, 0.7%), hoarseness (1, 0.4%) and septic encephalopathy (1, 0.4%). Overall in-hospital mortality was 10.1%, whereas the complicated group had a mortality rate of 43.9%. Renal impairment, pulse deficit, neurologic complication and nonsurgical treatment were independent variables for determining in-hospital mortality in patients with type A dissection.

CONCLUSIONS:

The dominance of neurologic symptom in the early stage of AD may make its early diagnosis difficult. Besides chest pain and widened mediastinum in chest x-ray, variable neurologic symptoms including left hemiparesis with asymmetric pulse and hypotension may suggest underlying AD.

BACKGROUND:

The aetiology of multiple sclerosis (MS) remains unknown. This hampers molecular diagnosis and the discovery of bio-molecular markers. Consequently, MS diagnostic procedures are complex and criteria for assessing therapeutic efficacy are controversial, suggesting that a pathophysiological rather than an aetiological approach to the disease would be more appropriate. In this regard, blood-proteomics represents a still-unexplored tool. We investigated the potential of proteomics as applied to peripheral blood mononuclear cells (PBMCs) for differentiating treatment-naive RR-MS patients from healthy controls and from IFN-treated RR-MS patients.

METHODS:

A comparative analysis of PBMC proteins isolated from 13 unselected IFN-treated RR-MS patients, 6 IFN-untreated RR-MS patients and 14 matched healthy controls was performed using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. We considered the volume of each spot, expressed as a percentage of the total volume of all spots in the gel. Heuristic clustering was applied to a composite population made up of a random sequence of gels from the different groups in comparison. For the differentially expressed proteins, we applied the Student's t-test to identify only those down- or up-regulated at least 2.5-fold [Ratio(R) >= 2.5] with respect to the homologous spots of the compared groups.

RESULTS:

Rho-GDI2, Rab2 and Cofilin1 were found to be associated with down-regulated and naive group phenotypes; Cortactin and Fibrinogen beta-Chain Precursor were found to be associated with down-regulated and group-related IFN-treated RR-MS phenotypes. Thus, by means of similarity analysis, the proteomes were homogeneously segregated into three distinct groups corresponding to naive, IFN-treated and healthy control subjects. Interestingly, no separation was found between IFN-treated and healthy controls. Moreover, the molecular phenotypes were consistent with disease pathogenesis.

CONCLUSIONS:

We demonstrated for the first time, albeit only with preliminary data, the aprioristic possibility of distinguishing naive and IFN-treated MS groups from controls, and naive from IFN-treated MS patients using a blood sample-based methodology (i.e. proteomics) alone. The functional profile of the identified molecules provides new pathophysiological insight into MS. Future development of these techniques could open up novel applications in terms of molecular diagnosis and therapy monitoring in MS patients.

A 41-year-old man developed progressive bilateral hand weakness and spastic paraparesis. MRI demonstrated cord edema and "pancake-like" gadolinium enhancement (figure). Inflammatory/neoplastic causes were investigated and not found. He continued to deteriorate despite empiric corticosteroid treatment. One year later, cervical decompression stabilized his clinical condition but intramedullary T2 signal worsened. Persistent enhancement raised concern about alternative diagnoses.

A 61-year-old man with factor V Leiden thrombophilia presented with hemorrhage and transverse sinus thrombosis (figure, A). Four years later, he developed worsening aphasia, new hemorrhage, and hemispheric edema (figure, B). Susceptibility-weighted imaging (SWI) showed bright signal in the straight sinus (figure, C). A dural arteriovenous fistula (DAVF) was diagnosed (figure, D). The brain edema improved (figure, E) and SWI sinus hyperintensity resolved after endovascular disconnection of the fistula (figure, F).