Ron Dabby

Minocycline treatment in acute stroke: an open-label, evaluator-blinded study.

Background: Ischemic animal model studies have shown a neuroprotective effect of minocycline. Objective: To analyze the effect of minocycline treatment in human acute ischemic stroke. Methods: We performed an open-label, evaluator-blinded study. Minocycline at a dosage of 200 mg was administered orally for 5 days. The therapeutic window of time was 6 to 24 hours after onset of stroke. Data from NIH Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Barthel Index (BI) were evaluated. The primary objective was to compare changes from baseline to day 90 in NIHSS in the minocycline group vs placebo. Results: One hundred fifty-two patients were included in the study. Seventy-four patients received minocycline treatment, and 77 received placebo. NIHSS and mRS were significantly lower and BI scores were significantly higher in minocycline-treated patients. This pattern was already apparent on day 7 and day 30 of follow-up. Deaths, myocardial infarctions, recurrent strokes, and hemorrhagic transformations during follow-up did not differ by treatment group. Conclusions: Patients with acute stroke had significantly better outcome with minocycline treatment compared with placebo. The findings suggest a potential benefit of minocycline in acute ischemic stroke. GLOSSARY: ACE = angiotensin-converting enzyme; ACEI = angiotensin-converting enzyme inhibitor; BI = Barthel Index; mRS = modified Rankin Scale; NIHSS = NIH Stroke Scale; PUD = peptic ulcer disease; SU = sulfonylurea.

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.

Objective –  To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment.

Skin biopsy for assessment of autonomic denervation in Parkinson’s disease

Summary.Autonomic dysfunction in Parkinson’s disease (PD) is considered a late complication of the disease or an adverse effect of anti-parkinsonian medications. Morphological changes are demonstrated only by postmortem examination. The study objective was to evaluate peripheral autonomic neural involvement in PD using punch skin biopsy. The study sample included 22 patients (mean age 50 ± 7.7 years, mean disease duration 5.3 ± 3.8 years) and 19 controls. Four-millimeter skin biopsies were immunohistochemically stained with anti-PGP 9.5 antibody. Autonomic innervation of the blood vessels, sweat glands, and erector pili muscles was assessed and rated from 0 (normal) to 2 (severe). Cutaneous autonomic innervation was decreased in patients compared to controls. Semi quantitative analysis demonstrated reduced autonomic innervation of the blood vessels (1.0 ± 0.8 vs. 0.42 ± 0.8 in controls; p < 0.02), of sweat glands (0.95 ± 0.67 vs. 0.47 ± 0.61; p < 0.02) and of the erector pili muscles (1.06 ± 0.55 vs 0.21 ± 0.42; p < 0.001). This method demonstrates that the peripheral autonomic system is affected in PD at early stage of the disease and that autonomic involvement in PD may be more prevalent than previously thought.

The effect of duloxetine on primary pain symptoms in Parkinson disease.

Objectives: To study the effect of duloxetine (Cymbalta), a selective serotonin and norepinephrine reuptake inhibitor, on pain symptoms in Parkinson Disease (PD). Methods/Patients: Twenty-three patients with PD with painful phenomena were treated with duloxetine for 6 weeks in an open-label design. Assessments were performed before and at treatment completion and consisted of a Visual Analogue Scale, the Brief Pain Inventory, Short-Form McGill Pain Questionnaire, Parkinson Disease Quality of Life Questionnaire-39-item version, and motor part of the Unified Parkinson Disease Rating Scale. Pain threshold was assessed by quantitative sensory tests. Results: Thirteen of the 20 patients who completed the study reported varying degrees of pain relief. The mean Visual Analogue Scale, Brief Pain Inventory, and Short-Form McGill Pain Questionnaire scores decreased significantly. There was no change in pain threshold after treatment. Conclusions: Duloxetine seems to be effective for the treatment of central pain in PD.

Clinical and radiologic correlates of frontal intermittent rhythmic delta activity.

To assess the clinical and radiologic correlates of frontal intermittent rhythmic &dgr; activity (FIRDA), the authors reviewed the hospital charts of patients whose EEGs depicted this EEG finding, and recorded their past medical and neurologic history, the reason for hospital admission, and their neurologic status both on admission and during EEG recordings. Laboratory results on admission and concomitant to the EEG recording, computed tomography, or MRI findings during hospital admission were also reviewed. Sixty-eight patients were assessed. The gender ratio was 1:1; mean age was 56 years. Chronic disease occurred in 78% of patients, including hypertension (34%), diabetes (32%), and renal failure (18%). On admission, renal failure (n = 34) and hyperglycemia (n = 22) were most prominent. The majority of patients had at least one abnormal laboratory result. Thirty-eight of 51 patients in whom the level of consciousness was stated during EEG were described as awake. More than half of 58 patients whose EEG background activity was stipulated demonstrated diffuse slowing, mostly in the &thgr; range. MRI was abnormal in 15 of 17 patients. Intrahemispheric lesions, particularly ischemic and hemorrhagic, were most common (n = 10), followed by basal ganglia lacunae (n = 4). Computed tomography was abnormal in 29 of 44 patients. Hemispheric pathology, diffuse or localized, occurred in 22 patients. Frontal intermittent rhythmic &dgr; activity is associated with mild to moderate encephalopathy and is detected principally in awake patients. Most patients in this series had chronic systemic illness. Old ischemic structural brain lesions may predispose some patients to develop FIRDA during acute metabolic derangement, such as uremia and hyperglycemia. Frontal intermittent rhythmic &dgr; activity was not associated with EEG epileptiform activity. Deep midline lesions, posterior fossa tumors, and hydrocephalus were not detected in this series of patients with FIRDA.

Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure.

Objectives: The incidence of seizures is known to be high in the elderly. The most common cause of an unprovoked seizure in the elderly population is stroke. These patients require effective and well-tolerated antiepileptic treatment because they frequently experience other medical conditions and use other medications that can interact with the antiepileptic treatment. The aim of the study was to analyze the tolerability and efficacy of lamotrigine (LTG) versus sustained-release carbamazepine (CBZ) treatment in newly diagnosed symptomatic poststroke seizure. Methods: Sixty-four patients with a first post episode of seizures were randomized in a 1:1 ratio to either LTG or CBZ treatment and were followed up prospectively for up to 12 months for efficacy and tolerability of the drugs. Results: More patients in the LTG group were seizure-free (72%) versus those in the CBZ group (44%; P = 0.06), but the numbers did not reach statistical significance because of a relative small number of study patients. The number of patients who withdraw from the study because of adverse events was statistically significantly less in the LTG group (3%) compared with the CBZ group (31%; P = 0.02). Conclusions: The LTG treatment in poststroke seizures versus CBZ treatment is a relatively better-tolerated drug and can be acceptable as initial treatment in this specific group of patients.

Are post intracerebral hemorrhage seizures prevented by anti-epileptic treatment?

Prophylactic antiepileptic treatment in patients with non-traumatic, non-aneurysmatic spontaneous intracerebral hemorrhage (SICH) is controversial. The purpose of our study was to assess the occurrence of seizures and neurologic outcome in SICH patients who were treated with valproic acid or a placebo for a period of one month and follow-up of one year in a hospital inpatient neurologic department and ambulatory clinic settings. The study is a prospective randomized, double-blind, placebo-controlled clinical trial. The patients were treated for one month with either valproic acid (VPA) or placebo immediately after a SICH and were followed-up for one year to evaluate seizure rate and neurologic function as measured by the National Institutes of Health Stroke Scale (NIHSS). Seventy-two patients participated in the study--36 were treated with VPA and 36 with placebo. During follow-up, 21% of the patients developed seizures. A by-treatment difference in incident seizures was not detected. However, a difference between reduction in early seizures and late one was observed in the VPA group. VPA-treated patients exhibited improved neurological outcome as measured by NIHSS. Early prophylaxis with VPA in SICH patients did not prevent the occurrence of seizures post intracerebral hemorrhage, but was found to reduce early seizures. VPA-treated patients had improved NIHSS scores, suggesting that this treatment may confer some neuroprotective effect. Further studies with a larger number of patients and with other antiepileptic drugs are needed to properly clarify this finding.

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

Acute steroid responsive small-fiber sensory neuropathy: a new entity?

Abstract  Small‐fiber neuropathy is often idiopathic and commonly follows a chronic course. Treatment is often effective in treating the core symptom of pain, but it has no effect on the pathologic process. We describe four patients with acute small‐fiber neuropathy who responded dramatically to steroid therapy. All patients had acute onset neuropathic pain, normal nerve conduction studies, and evidence of small‐fiber dysfunction in quantitative sensory testing and skin biopsy. Symptoms were distal and symmetrical in three patients and generalized in one patient. In two cases, the neuropathy presented as an erythromelalgia‐like syndrome. Marked clinical improvement occurred 1–2 weeks after oral prednisone therapy was initiated. Three patients remained symptom free, and one patient experienced recurrence of neuropathy after prednisone was tapered.

The Proteomic Profile of Hereditary Inclusion Body Myopathy

Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. The goal of this study was to unravel new clues on the biological pathways leading to HIBM by proteomic comparison. Muscle cultures and biopsies were analyzed by two dimensional gel electrophoresis (2-DE) and the same biopsy extracts by isobaric tag for relative and absolute quantitation (iTRAQ). Proteins that were differentially expressed in all HIBM specimens versus all controls in each analysis were identified by mass spectrometry. The muscle cultures 2-DE analysis yielded 41 such proteins, while the biopsies 2-DE analysis showed 26 differentially expressed proteins. Out of the 400 proteins identified in biopsies by iTRAQ, 41 showed altered expression. In spite of the different nature of specimens (muscle primary cultures versus muscle biopsies) and of the different methods applied (2D gels versus iTRAQ) the differentially expressed proteins identified in each of the three analyses where related mainly to the same pathways, ubiquitination, stress response and mitochondrial processes, but the most robust cluster (30%) was assigned to cytoskeleton and sarcomere organization. Taken together, these findings indicate a possible novel function of GNE in the muscle filamentous apparatus that could be involved in the pathogenesis of HIBM.