Department of Neurology Faculty Papers Copyright (c) 2013 Thomas Jefferson University All rights reserved. http://jdc.jefferson.edu/neurologyfp Recent documents in Department of Neurology Faculty Papers en-us Fri, 22 Feb 2013 17:15:48 PST 3600 The Stigma of Migraine http://jdc.jefferson.edu/neurologyfp/49 http://jdc.jefferson.edu/neurologyfp/49 Thu, 17 Jan 2013 11:21:19 PST

Background

People who have a disease often experience stigma, a socially and culturally embedded process through which individuals experience stereotyping, devaluation, and discrimination. Stigma has great impact on quality of life, behavior, and life chances. We do not know whether or not migraine is stigmatizing.

Methods

We studied 123 episodic migraine patients, 123 chronic migraine patients, and 62 epilepsy patients in a clinical setting to investigate the extent to which stigma attaches to migraine, using epilepsy as a comparison. We used the stigma scale for chronic illness, a 24-item questionnaire suitable for studying chronic neurologic diseases, and various disease impact measures.

Results

Patients with chronic migraine had higher scores (54.0±20.2) on the stigma scale for chronic illness than either episodic migraine (41.7±14.8) or epilepsy patients (44.6±16.3) (p<0.001). Subjects with migraine reported greater inability to work than epilepsy subjects. Stigma correlated most strongly with the mental component score of the short form of the medical outcomes health survey (SF-12), then with ability to work and migraine disability score for chronic and episodic migraine and the Liverpool impact on epilepsy scale for epilepsy. Analysis of covariance showed adjusted scores for the stigma scale for chronic illness were similar for chronic migraine (49.3; 95% confidence interval, 46.2 to 52.4) and epilepsy (46.5; 95% confidence interval, 41.6 to 51.6), and lower for episodic migraine (43.7; 95% confidence interval, 40.9 to 46.6). Ability to work was the strongest predictor of stigma as measured by the stigma scale for chronic illness.

Conclusion

In our model, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine. Stigma correlated most strongly with inability to work, and was greater for chronic migraine than epilepsy or episodic migraine because chronic migraine patients had less ability to work.

]]> William B. Young et al. B-vitamin deficiency in patients treated with antiepileptic drugs. http://jdc.jefferson.edu/neurologyfp/48 http://jdc.jefferson.edu/neurologyfp/48 Wed, 07 Nov 2012 07:59:43 PST Enzyme-inducing antiepileptic drugs (AEDs) produce many alterations in metabolism, including vitamin levels. Whether they produce clinically relevant deficiency of B vitamins has rarely been assessed. We obtained B-vitamin levels in patients who were being converted from an inducing AED (phenytoin or carbamazepine) to a non-inducing AED (levetiracetam, lamotrigine, or topiramate), with measurements both before and ≥ 6 weeks after the switch. A group of normal subjects underwent the same studies. Neither folate nor B12 deficiency was seen in any patient. Vitamin B6 deficiency was found in 16/33 patients (48%) taking inducers, compared to 1/11 controls (9%; p=0.031). After switch to non-inducers, only 7 patients (21%) were B6 deficient (p=0.027). The incidence of deficiency was similar regardless of which inducing or non-inducing AED was being taken. Our findings demonstrate that treatment with inducing AEDs commonly causes pyridoxine deficiency, often severe. This could conceivably contribute to the polyneuropathy sometimes attributed to older AEDs, as well as other chronic heath difficulties.

]]> Scott Mintzer et al. Adolescent Adult Aged Aged, 80 and over Anticonvulsants Carbamazepine Epilepsy Female Humans Male Middle Aged Phenytoin Vitamin B Deficiency Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity. http://jdc.jefferson.edu/neurologyfp/47 http://jdc.jefferson.edu/neurologyfp/47 Fri, 03 Aug 2012 09:16:22 PDT The B cell-depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti-myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell-depleting therapies for autoimmune diseases.

]]> Michael A Maurer et al. Aged Antibodies, Monoclonal, Murine-Derived Autoantibodies Autoantigens Autoimmune Diseases of the Nervous System B-Lymphocyte Subsets Clinical Trials as Topic Clone Cells Double-Blind Method Female Humans Immunoglobulin M Immunologic Memory Lymphocyte Depletion Male Middle Aged Myelin-Associated Glycoprotein Severity of Illness Index Somatic Hypermutation, Immunoglobulin Treatment Outcome Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy http://jdc.jefferson.edu/neurologyfp/46 http://jdc.jefferson.edu/neurologyfp/46 Wed, 25 Apr 2012 11:33:54 PDT

PURPOSE:

Fluorodeoxyglucose positron emission computed tomography (FDG-PET) hypometabolism is important for surgical planning in patients with temporal lobe epilepsy (TLE), but its significance remains unclear in patients who do not have evidence of mesial temporal sclerosis (MTS) on magnetic resonance imaging (MRI). We examined surgical outcomes in a group of PET-positive, MRI-negative patients and compared them with those of patients with MTS.

METHODS:

We queried the Thomas Jefferson University Surgical Epilepsy Database for patients who underwent anterior temporal lobectomy (ATL) from 1991 to 2009 and who had unilateral temporal PET hypometabolism without an epileptogenic lesion on MRI (PET+/MRI-). We compared this group to the group of patients who underwent ATL and who had MTS on MRI. Patients with discordant ictal electroencephalography (EEG) were excluded. Surgical outcomes were compared using percentages of Engel class I outcomes at 2 and 5 years as well as Kaplan-Meier survival statistic, with time to seizure recurrence as survival time. A subgroup of PET+/MRI- patients who underwent surgical implantation prior to resection was compared to PET+/MRI- patients who went directly to resection without implantation. Key Findings:  There were 46 PET+/MRI- patients (of whom 36 had 2-year surgical outcome available) and 147 MTS patients. There was no difference between the two groups with regard to history of febrile convulsions, generalized tonic-clonic seizures, interictal spikes, depression, or family history. Mean age at first seizure was higher in PET+/MRI- patients (19 ± 13 vs.14 ± 13 years, Mann-Whitney test, p = 0.008) and disease duration was shorter (14 ± 10 vs. 22 ± 13 years, student's t-test, p = 0.0006). Class I surgical outcomes did not differ significantly between the PET+/MRI- patients and the MTS group (2 and 5 year outcomes were 76% and 75% for the PET+/MRI- group, and 71% and 78% for the MTS group); neither did outcomes of the PET+/MRI- patients who were implanted prior to resection versus those who went directly to surgery (implanted patients had 71% and 67% class I outcomes at 2 and 5 years, whereas. nonimplanted patients had 77% and 78% class I outcomes, p = 0.66 and 0.28). Kaplan-Meier survival statistics for both comparisons were nonsignificant at 5 years. Dentate gyrus and hilar cell counts obtained from pathology for a sample of patients also did not differ between groups.

SIGNIFICANCE:

PET-positive, MRI-negative TLE patients in our study had excellent surgical outcomes after ATL, very similar to those in patients with MTS, regardless of whether or not they undergo intracranial monitoring. These patients should be considered prime candidates for ATL, and intracranial monitoring is probably unnecessary in the absence of discordant data.

Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

]]> Carla LoPinto-Khoury et al. Acetate causes alcohol hangover headache in rats. http://jdc.jefferson.edu/neurologyfp/45 http://jdc.jefferson.edu/neurologyfp/45 Mon, 06 Feb 2012 13:25:45 PST BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity.

DISCUSSION: Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction.

]]> Christina R Maxwell et al. Acetaldehyde Acetates Alcohol Drinking Alcoholic Intoxication Analgesia Animals Chronic Disease Ethanol Headache Hypersensitivity Inflammation Male Nociceptors Rats Rats, Sprague-Dawley Touch Involvement of beta-chemokines in the development of inflammatory demyelination. http://jdc.jefferson.edu/neurologyfp/44 http://jdc.jefferson.edu/neurologyfp/44 Mon, 06 Feb 2012 13:07:55 PST The importance of beta-chemokines (or CC chemokine ligands - CCL) in the development of inflammatory lesions in the central nervous system of patients with multiple sclerosis and rodents with experimental allergic encephalomyelitis is strongly supported by descriptive studies and experimental models. Our recent genetic scans in families identified haplotypes in the genes of CCL2, CCL3 and CCL11-CCL8-CCL13 which showed association with multiple sclerosis. Complementing the genetic associations, we also detected a distinct regional expression regulation for CCL2, CCL7 and CCL8 in correlation with chronic inflammation in multiple sclerosis brains. These observations are in consensus with previous studies, and add new data to support the involvement of CCL2, CCL7, CCL8 and CCL3 in the development of inflammatory demyelination. Along with our own data, here we review the literature implicating CCLs and their receptors (CCRs) in multiple sclerosis and experimental allergic encephalomyelitis. The survey reflects that the field is in a rapid expansion, and highlights some of the pathways which might be suitable to pharmaceutical interventions.

]]> Ileana Banisor et al. MS4a4B, a CD20 homologue in T cells, inhibits T cell propagation by modulation of cell cycle. http://jdc.jefferson.edu/neurologyfp/43 http://jdc.jefferson.edu/neurologyfp/43 Mon, 06 Feb 2012 13:07:53 PST MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural killer cells (NK) and some T cell lines. But its expression in all malignant T cells, including thymoma and T hybridoma tested, was silenced. Interestingly, its expression was regulated during T cell activation. Viral vector-driven overexpression of MS4a4B in primary T cells and EL4 thymoma cells reduced cell proliferation. In contrast, knockdown of MS4a4B accelerated T cell proliferation. Cell cycle analysis showed that MS4a4B regulated T cell proliferation by inhibiting entry of the cells into S-G2/M phase. MS4a4B-mediated inhibition of cell cycle was correlated with upregulation of Cdk inhibitory proteins and decreased levels of Cdk2 activity, subsequently leading to inhibition of cell cycle progression. Our data indicate that MS4a4B negatively regulates T cell proliferation. MS4a4B, therefore, may serve as a modulator in the negative-feedback regulatory loop of activated T cells.

]]> Hui Xu et al. Animals Antigens, CD20 Blotting, Western Cell Cycle Cell Line Cell Line, Tumor Cell Proliferation Cells, Cultured Cyclin-Dependent Kinase 2 Green Fluorescent Proteins HEK293 Cells Humans Male Membrane Proteins Mice Mice, Inbred C57BL Microscopy, Confocal RNA Interference T-Lymphocytes Thymoma Conversion from enzyme-inducing antiepileptic drugs to topiramate: effects on lipids and C-reactive protein. http://jdc.jefferson.edu/neurologyfp/42 http://jdc.jefferson.edu/neurologyfp/42 Mon, 30 Jan 2012 11:37:25 PST PURPOSE: We previously demonstrated that converting patients from the enzyme-inducers phenytoin or carbamazepine to the non-inducers levetiracetam or lamotrigine reduces serum lipids and C-reactive protein (CRP). We sought to determine if the same changes would occur when patients were switched to topiramate, which has shown some evidence of enzyme induction at high doses. We also examined the effects of drug switch on low-density lipoprotein (LDL) particle concentration.

METHODS: We converted 13 patients from phenytoin or carbamazepine monotherapy to topiramate monotherapy (most at doses of 100-150 mg/day). Fasting lipids, including LDL particle concentration, and CRP were obtained before and ≥6 weeks after the switch. A group of normal subjects had the same serial serologic measurements to serve as controls.

RESULTS: Conversion from inducers to topiramate resulted in a -35 mg/dL decline in total cholesterol (p=0.033), with significant decreases in all cholesterol fractions, triglycerides, and LDL particle concentration (p≤0.03 for all), as well as a decrease of over 50% in serum CRP (p

CONCLUSIONS: Changes seen when inducer-treated patients are converted to TPM closely mimic those seen when inducer-treated patients are converted to lamotrigine or levetiracetam. These findings provide evidence that CYP450 induction elevates CRP and serum lipids, including LDL particles, and that these effects are reversible upon deinduction. Low-dose TPM appears not to induce the enzymes involved in cholesterol synthesis.

]]> Scott Mintzer et al. The Prevalence and Risk Factors of Acute Myocardial Infarction (AMI) After Acute Ischemic Stroke (AIS) in the United States http://jdc.jefferson.edu/neurologyfp/41 http://jdc.jefferson.edu/neurologyfp/41 Fri, 18 Nov 2011 08:12:45 PST Objectives: To determine the prevalence and risk factors for, and the association with in-hospital mortality of, AMI after AIS, and to study the effect of intravenous recombinant tissue plasminogen activator (r-tPA) in this setting. We hypothesized that AMI would be associated with lower survival rate at hospital discharge but that intravenous r-tPA would be associated with lower risk of AMI.

]]> Ali Seifi, MD et al. The Prevalence of Cervico-Arterial Dissection in Sub-Arachnoid Hemorrhage in the United States http://jdc.jefferson.edu/neurologyfp/40 http://jdc.jefferson.edu/neurologyfp/40 Thu, 17 Nov 2011 13:17:39 PST Objectives: In this study, we sought to determine the prevalence of cervico-arterial dissection in aubarachnoid hemorrhage (SAH) using a large administrative database.

]]> Ali Seifi, MD et al. Psychological and cognitive determinants of vision function in age-related macular degeneration. http://jdc.jefferson.edu/neurologyfp/39 http://jdc.jefferson.edu/neurologyfp/39 Thu, 18 Aug 2011 06:40:02 PDT OBJECTIVE: To investigate the effect of coping strategies, depression, physical health, and cognition on National Eye Institute Visual Function Questionnaire scores obtained at baseline in a sample of older patients with age-related macular degeneration (AMD) enrolled in the Improving Function in AMD Trial, a randomized controlled clinical trial that compares the efficacy of problem-solving therapy with that of supportive therapy to improve vision function in patients with AMD.

METHODS: Baseline evaluation of 241 older outpatients with advanced AMD who were enrolled in a clinical trial testing the efficacy of a behavioral intervention to improve vision function. Vision function was characterized as an interval-scaled, latent variable of visual ability based on the near-vision subscale of the National Eye Institute Vision Function Questionnaire-25 plus Supplement.

RESULTS: Visual ability was highly correlated with visual acuity. However, a multivariate model revealed that patient coping strategies and cognitive function contributed to their ability to perform near-vision activities independent of visual acuity.

CONCLUSIONS: Patients with AMD vary in their coping strategies and cognitive function and in their visual acuity, and that variability determines patients' self-report of vision function. Understanding patient coping mechanisms and cognition may help increase the precision of vision rating scales and suggest new interventions to improve vision function and quality of life in patients with AMD. Trial Registration clinicaltrials.gov Identifier: NCT00572039.

]]> Barry W. Rovner et al. Hormonal consequences of epilepsy and its treatment in men. http://jdc.jefferson.edu/neurologyfp/38 http://jdc.jefferson.edu/neurologyfp/38 Thu, 30 Jun 2011 08:01:37 PDT PURPOSE OF REVIEW: Epilepsy and anticonvulsant medications may substantially alter endocrine homeostasis, including the male reproductive hormonal system.

RECENT FINDINGS: Seizures in medial temporal lobe structures, through their connectivity to the hypothalamus, alter the secretion of gonadotropins. Levels of circulating bioavailable testosterone are affected by changes in the level of binding proteins, which in turn may be affected by seizure medications. The use of older generation medications that induce the cytochrome P450 system is associated with an increase in sex hormone-binding globulin and lower bioactive testosterone. Sexual dysfunction, including decreased libido and decreased potency, and infertility, is seen commonly in men with epilepsy. However, its relation to sex hormone levels remains unclear. Comorbid depression and anxiety may be important confounding factors. Testosterone and sexual function appear not to be affected by the newer generation (noninducing) anticonvulsants.

SUMMARY: Epilepsy and its drug treatments are associated with alterations in hormonal and sexual function in men. Further study is needed to clarify the precise mechanisms behind these alterations, as some of the data conflict. More attention should be paid to this issue in male patients with seizures; when appropriate, treatment for psychiatric comorbidity and switches in anticonvulsant therapy may be worth consideration.

]]> Kartik Sivaraaman et al. A test of the role of the medial temporal lobe in single-word decoding. http://jdc.jefferson.edu/neurologyfp/37 http://jdc.jefferson.edu/neurologyfp/37 Thu, 07 Apr 2011 09:43:56 PDT The degree to which the MTL system contributes to effective language skills is not well delineated. We sought to determine if the MTL plays a role in single-word decoding in healthy, normal skilled readers. The experiment follows from the implications of the dual-process model of single-word decoding, which provides distinct predictions about the nature of MTL involvement. The paradigm utilized word (regular and irregularly spelled words) and pseudoword (phonetically regular) stimuli that differed in their demand for non-lexical as opposed lexical decoding. The data clearly showed that the MTL system was not involved in single word decoding in skilled, native English readers. Neither the hippocampus nor the MTL system as a whole showed significant activation during lexical or non-lexical based decoding. The results provide evidence that lexical and non-lexical decoding are implemented by distinct but overlapping neuroanatomical networks. Non-lexical decoding appeared most uniquely associated with cuneus and fusiform gyrus activation biased toward the left hemisphere. In contrast, lexical decoding appeared associated with right middle frontal and supramarginal, and bilateral cerebellar activation. Both these decoding operations appeared in the context of a shared widespread network of activations including bilateral occipital cortex and superior frontal regions. These activations suggest that the absence of MTL involvement in either lexical or non-lexical decoding appears likely a function of the skilled reading ability of our sample such that whole-word recognition and retrieval processes do not utilize the declarative memory system, in the case of lexical decoding, and require only minimal analysis and recombination of the phonetic elements of a word, in the case of non-lexical decoding.

]]> Karol Osipowicz et al. Is phonophobia associated with cutaneous allodynia in migraine? http://jdc.jefferson.edu/neurologyfp/36 http://jdc.jefferson.edu/neurologyfp/36 Wed, 05 Jan 2011 11:16:13 PST ABSTRACT

Objective

To determine whether phonophobia and dynamic mechanical (brush) allodynia are associated in episodic migraine (EM).

Methods

Adult patients with EM were prospectively recruited. A structured questionnaire was used to obtain demographic and migraine related data. Phonophobia was tested quantitatively using a real time sound processor and psychoacoustic software. Sound stimuli were pure tones at frequencies of 1000 Hz, 4000 Hz and 8000 Hz, delivered to both ears at increasing intensities, until an aversive level was reached. Allodynia was assessed by brushing the patient’s skin with a gauze pad at different areas. Patients were tested both between and during acute attacks. Sound aversion thresholds (SATs) in allodynic and non-allodynic patients were compared.

Results

Between attacks, SATs were lower in allodynic compared with non-allodynic patients, with an average difference of 5.7 dB (p¼0.04). During acute attacks, the corresponding average SAT difference (allodynicenon-allodynic) was 15.7 dB (p¼0.0008). There was a significant negative correlation between allodynia scores and SATs, both within and between attacks.

Conclusions

The results support an association between phonophobia and cutaneous allodynia in migraine.

]]> Avi Ashkenazi et al. Acetate Causes Alcohol Hangover Headache in Rats http://jdc.jefferson.edu/neurologyfp/35 http://jdc.jefferson.edu/neurologyfp/35 Mon, 03 Jan 2011 11:26:32 PST Background

The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

Methods

We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

Results

Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity.

Discussion

Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction.

]]> Christina R. Maxwell et al. Clinical and Diagnostic Features of Patients with Compound Heterozygous A467T/W748S POLG1 Mutations: A Case Report and Review of Previous Cases http://jdc.jefferson.edu/neurologyfp/34 http://jdc.jefferson.edu/neurologyfp/34 Mon, 01 Nov 2010 09:10:04 PDT Introduction

Mutations in the POLG1 gene are considered to be the most common gene defect identified in autosomal recessive mitochondrial DNA depletion disorders. POLG1 is a gene encoding the 195kDa catalytic (alpha) subunit of the mitochondrial (gamma) DNA polymerase, located on chromosome 15q25 and is responsible for mtDNA replication. Mutations in POLG1 are associated with chronic progressive external ophthalmoplegia (CPEO). Other genes that have been implicated in causing syndromic and non-syndromic mitochondrial disorders have been found on both mtDNA (3243A>G, 8344A>G, 8993T>G, and 11778A>G) and nDNA (SURF1, POLG1, TWINKLE, and ANT1).

We report a patient with a rare type of POLG1 gene (A467T/W748S) mutation with a wide range of neurological manifestations, including, focal parieto-occipital lobe seizures, sensory axonal neuropathy, intestinal malabsorption, and impairement of visual perception and other cognitive domains. Mitochondrial disorders can have a very insidious clinical course, which can make the diagnosis difficult especially if genetic workup for routinely tested mitochondrial disorders is negative. Treatment of the epilepsy in patients with POLG1 gene mutations, specifically the compound heterozygous A457T/W748S, can be very challenging. While some conventionally used anti-seizure medications can turn out to be ineffective, others such as volproic acid can have deleterious effects on neurological function and make the seizures worse.

]]> David Roshal, D.O. et al. Combined effects of hyperglycemic conditions and HIV-1 Nef: a potential model for induced HIV neuropathogenesis. http://jdc.jefferson.edu/neurologyfp/33 http://jdc.jefferson.edu/neurologyfp/33 Sat, 03 Jul 2010 12:50:07 PDT Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our in vitro study. The results show that in vitro hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and the production of total nitrate and 8-iso-PGF2 alpha as reactive oxygen species (ROS) in human astrocytes leading to cell death in a dose-dependent manner. Delivery of purified recombinant HIV-1 Nef protein, or Nef expressed via HIV-1-based vectors in astrocytes showed similar results. The expression of Nef protein delivered via HIV-1 vectors in combination with hyperglycemia further augmented the production of ROS, C3, activation of caspase-3, modulation of filamentous protein (F-protein), depolarization of the mitochondria, and loss of astrocytes. To further verify the effects of hyperglycemia and HIV-1 Nef protein on CNS individually or in combination, in vivo studies were performed in streptozotocin (STZ) induced diabetic mice, by injecting HIV-1 Nef expressing viral particles into the sub-cortical region of the brain. Our in vivo results were similar to in vitro findings indicating an enhanced production of caspases-3, ROS (lipid oxidation and total nitrate), and C3 in the brain tissues of these animals. Interestingly, the delivery of HIV-1 Nef protein alone caused similar damage to CNS as augmented by hyperglycemia conditions. Taken together, the data suggests that HIV-1 infected individuals with hyperglycemia could potentially be at a higher risk of developing CNS related complications.

]]> Edward A Acheampong et al. Electronic Medical Records as a Research Tool: Evaluating Topiramate Use at a Headache Center. http://jdc.jefferson.edu/neurologyfp/32 http://jdc.jefferson.edu/neurologyfp/32 Tue, 08 Jun 2010 06:41:12 PDT Background.—Electronic medical records (EMRs) are used in large healthcare centers to increase efficiency and accuracy of documentation. These databases may be utilized for clinical research or to describe clinical practices such as medication usage.

Methods.—We conducted a retrospective analysis of EMR data from a headache clinic to evaluate clinician prescription use and dosing patterns of topiramate. The study cohort comprised 4833 unique de-identified records, which were used to determine topiramate dose and persistence of treatment.

Results.—Within the cohort, migraine was the most common headache diagnosis (n = 3753, 77.7%), followed by tension-type headache (n = 338, 7.0%) and cluster or trigeminal autonomic cephalalgias (n = 287, 5.9%). Physicians prescribed topiramate more often for subjects with migraine and idiopathic intracranial hypertension (P < .0001) than for those with other conditions, and more often for subjects with coexisting conditions including obesity, bipolar disorder, and depression. The most common maintenance dose of topiramate was 100 mg/day; however, approximately 15% of subjects received either less than 100 mg/day or more than 200 mg/day. More than a third of subjects were prescribed topiramate for more than 1 year, and subjects with a diagnosis of migraine were prescribed topiramate for a longer period of time than those without migraine.

Conclusions.—Findings from our study using EMR demonstrate that physicians use topiramate at many different doses and for many off-label indications. This analysis provided important insight into our patient populations and treatment patterns.

]]> Michael J. Marmura, MD et al. Valproate semisodium ER for migraine and cluster headache prophylaxis. http://jdc.jefferson.edu/neurologyfp/31 http://jdc.jefferson.edu/neurologyfp/31 Thu, 27 May 2010 09:44:54 PDT IMPORTANCE OF THE FIELD: Migraine and cluster headache (CH) are disabling syndromes that often require prophylactic treatment. Valproate semisodium ER (VPS ER) is FDA-approved for the treatment of epilepsy, acute mania in bipolar disorder and migraine prophylaxis.

AREAS COVERED IN THIS REVIEW: We reviewed literature regarding VPS ER pharmacokinetics and its use in migraine and CH prophylaxis.

WHAT THE READER WILL GAIN: VPS ER is well studied and effective in the preventive treatment of migraine and CH. This article reviews the evidence for its use, describes how to administer and dose this medication, and reviews important safety precautions.

TAKE HOME MESSAGE: VPS ER is effective in the prophylactic treatment of migraine and CH. This once-a-day dosing formulation may increase compliance.

]]> Brigitte V. Lovell et al. Metabolic consequences of antiepileptic drugs http://jdc.jefferson.edu/neurologyfp/30 http://jdc.jefferson.edu/neurologyfp/30 Wed, 21 Apr 2010 06:47:47 PDT Purpose of Review: Chemical properties of the widely used older generation antiepileptic drugs (AEDs) suggest that they might be responsible for a number of medical comorbidities. Recent Findings: AEDs which induce the cytochrome P450 system adversely affect bone, lipid, and gonadal steroid metabolism. Specifically, phenytoin causes loss of bone mass in women, and both phenytoin and carbamazepine produce increases in serum lipids and C-reactive protein, as well as decreases in bioactive testosterone in men. Patients treated with inducing AEDs are at increased risk of fracture. Some contradictory data raise the question of whether bone mass is truly related to enzyme induction, and analogously, of whether reductions in testosterone truly account for male sexual dysfunction. Data showing elevations of surrogate cardiovascular and cerebrovascular risk endpoints with epilepsy patients, mostly inducing AED treated, are consistent and concerning, however. Another older AED, valproate, is associated with the occurrence of polycystic ovary syndrome when used in young adulthood or adolescence. Summary: Older generation AEDs are associated with a panoply of metabolic abnormalities. Although more research is needed to see whether individual drugs are directly tied to specific clinical outcomes (e.g. risk of infarction), extant data are sufficiently concerning to suggest that these drugs may produce significant adverse health consequences. Newer generation AEDs may be preferable.

]]> Scott Mintzer