Featured Articles from the European Neurological Journal

A Systematic Review of Human Neural Stem Cell Transplantation in Animal Stroke Models

Matthew B. Jensen, Abdullah Al Sawaf and Su-Chun Zhang

Affiliation: Department of Neurology, University of Wisconsin, Madison, WI, USA

Transplantation of cultured animal neural stem cells (NSCs) has shown benefit for improving recovery after stroke in animal models, which led to investigation of cultured human NSCscells for the same purpose.To assess the currently available evidence of human neural stem cell transplantation in animal stroke models,we searched PubMed, Science Citation Index, and Biological Abstracts for full articles published prior to January 1, 2010, which matched our inclusion criteria. Experiments transplanting cultured human cells expressing NSC markers in vitro prior to transplantation into an animal stroke model of focal cerebral ischemia, intracerebral hemorrhage, or subarachnoid hemorrhage were included. Two reviewers assessed articles for inclusion, extracted data, and graded the level of evidence.We evaluated 510 articles and found 42 matching our inclusion criteria. The most common model was focal cerebral ischemia by transient intraluminal filament middle cerebral artery occlusion in the rat. The most common origin of the transplanted NSCswas the fetal brain tissue. Most studies used genetically modified cells prior to transplantation, most commonly with forms of a myc transgene. The most frequent time point for transplantation was one week after stroke, and the most common route of cell delivery was intracerebral injection. With one exception, all of the studies found transplanted cells in the brain with histology, and the grafted cells expressed markers of neurons more often than other cell types. Most studies did not find stroke volume reduction, but all studies that reported behavioral testing found behavioral rescue with grafting on at least one test. No cell-related adverse events were reported, and data were reported suggesting multiple potential mechanisms of benefit.This review found wide disparities in most of the key variables of NSCtransplantation in animal stroke models, but despite this, the currently published studies nearly unanimously reported graft cell survival in the brain and behavioral rescue, without cell-related adverse events. These data not only support the promise and need for further development of this strategy as a future treatment for stroke patients, but also suggest the possibility of publication bias.

Keywords: Stroke, stroke model, neural stem cells, cell therapy, systematic review

Correspondence: Matthew B. Jensen, MD, 1685 Highland Ave, room 7273 Madison, WI 53705-2281, USA. Tel: 608-263-5448; Fax: 608-263- 0412; e-mail: jensen@neurology.wisc.edu

A case of recurrent transverse myelopathy

Cristina D Ghinda¹ and Linh-Khue Bui²

Affiliations: ¹Université de Montréal, Montréal and ²Pierre Boucher Hospital, Longueil, QC, Canada

ABSTRACT

OBJECTIVES

To report a case of recurrent transverse myelopathy associated with hematological and immunological abnormalities suggesting a diagnosis of connective tissue disease.

DESIGN

Case report.

PATIENT

A previously healthy 34-year-old woman presented three recurring acute transverse myelitis episodes of paraplegia, urinary retention, and a thoracic sensory level in the absence of other neurological or systemic signs.

RESULTS

The results of magnetic resonance imaging and cerebrospinal fluid electrophoresis countered a diagnosis of multiple sclerosis. After two episodes of exacerbation and remission consistent with the clinical diagnosis of recurrent idiopathic transverse myelitis, during the course of the third attack we found hematological and immunological abnormalities consisting of positive antinuclear antibodies (ANA), markedly reduced serum complement, and persistent proteinuria. These findings suggested a diagnosis of connective tissue disease. During each episode, the patient responded favorably to a course of corticosteroids showing complete remission.

CONCLUSION

Recurrent transverse myelitis (RTM) can occur as an isolated manifestation of a connective disease and may respond favorably to immunosuppressive therapy. Although there was no other clinical evidence of a collagen disease, RTM has already been reported as an isolated manifestation of systemic lupus erythematosus, which can be considered in the differential diagnosis of acute transverse myelitis.

Keywords: recurrent transverse myelitis, multiple sclerosis, systemic lupus erythematosus

Correspondence: Linh-Khue Bui, Pierre Boucher Hospital, 1333, bv Jacques-Cartier Est, Longueil, Quebec, J4M 2A5, Canada. Tel: +1-450 468 8111; Fax: +1-450 468 8274; e-mail: cristina.diana.ghinda@umontreal.ca

Diagnostic Approach for Dopa-Responsive Dystonia (Segawa Syndrome)

Eduardo López-Laso

Affiliation: Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofia, University of Córdoba, Córdoba, Spain

Correspondence: Eduardo López-Laso, Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofia, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain. Tel: +34-957-011-908; Fax: +34-957-010-017; e-mail: elolaso@gmail.com

ABSTRACT

Autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, also called dopa-responsive dystonia (DRD) or Segawa disease, is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations or deletions in the GCH1 gene. Most mutations and deletions in GCH1 are unique and up to 40% of patients do not have identifiable mutations in the coding region or the splice sites. Clinical features and response to levodopa have remained the diagnostic gold standard until recently. However, the adGTPCH deficiency causes a wide phenotypic spectrum of clinical variability including dystonia, parkinsonism, and spasticity, and further, this phenotype is in continuous expansion. Therefore, there is a need to confirm the clinical diagnosis of this treatable disorder through biochemical and/or molecular investigations. In recent years, important progress has been made in biochemical and molecular testing in this disease. The phenylalanine loading test is a useful tool for the diagnosis of adGTPCH deficiency; however, false-positive and false-negative results are possible. The analysis of pterins and biogenic amines in CSF is highly specific for DRD but has the inconvenience of being invasive. The measurement of the activity of GTPCH in cytokine-stimulated fibroblasts provides absolute confirmation in the diagnosis. Recently, the yield of molecular studies has improved with the implementation of two techniques to detect heterozygous GCH1 exon deletions, undetectable by sequencing, the quantitative PCR analyses and multiplex ligation-dependent probe amplification. This article provides a diagnostic approach for adGTPCH deficiency in patients with unexplained dystonia, parkinsonism, and/or spasticity.

Critical Care Monitoring and Management of Aneurysmal Subarachnoid Hemorrhage

Monisha A Kumar and Joshua M Levine

Affiliation: Departments of Neurology, Neurosurgery, and Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: Joshua M. Levine, Department of Neurology, University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. Tel: (1)-215-662-3368; Fax: (1)-215-614-1927; joshua.levine@uphs.upenn.edu

ABSTRACT

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with nearly one-third of patients requiring life-long care. The worldwide incidence of this disease has remained stable, but mortality rates are improving likely due to early diagnosis, endovascular treatments, novel therapies for delayed cerebral ischemia (DCI), and dedicated neurointensive care units. The most consistently identified independent risk factors for aneurysmal SAH include female gender, hypertension, tobacco use, and heavy alcohol consumption. Large aneurysm size and posterior location increase the risk of rupture. Successful management requires a prompt and accurate diagnosis, anticipation of the natural history and complications of the disease, and prevention of further neurological injury. This article reviews the acute, early, and late strategies for critical care management of SAH including the use of new imaging modalities and modern multimodality monitoring tools. Aneurysmal rebleeding, hydrocephalus, seizures, vasospasm, and delayed neurological ischemic deficits represent major threats. Systemic complications, such as hypotension, hyponatremia, and cardiac dysfunction, can exacerbate neurological deficits and cause further damage. Early identification and treatment of these disturbances improves outcome.

Metabolic Network Modulation by Bilateral Subthalamic Nucleus Stimulation in the Treatment of Advanced Parkinson's Disease

Zhemin Huang, Chuantao Zuo and Yihui Guan

Affiliation: PET Center, Huashan Hospital, Fudan University, Shanghai, China

Correspondence: Chuantao Zuo, PET Center, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China. Tel: (86)-21-64285263; Fax: (86)-21-64283265; e-mail: skywalkerhuang@gmail.com

ABSTRACT

Parkinson's disease (PD) in the advanced stage may require surgical interventions. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) was proposed to improve the symptoms of PD. Five patients (age 61.6±3.9 years) in advanced stage of PD were scanned using FDG-PET during both “ON” and “OFF” conditions of stimulation. Statistical parametric mapping (SPM) was used to assess the effect of the stimulation. Network analysis was also used to assess the effect of stimulation on the expression of an abnormal PD-related spatial covariance pattern (PDRP). Our study indicated that bilateral STN DBS increased the metabolism of the midbrain and decreased the metabolism of the parietal lobe, the cerebellum, lentiform nucleus, and the thalamus; it also reduced PDRP network activity that correlated significantly with the clinical improvement in advanced PD patients. All five patients who used levodopa as the only medication for PD reduced their daily dosage by approximately 30.7% (range 8.3–51.5%) after the surgery. These findings suggest that DBS is more likely to function by regulating the entire neuronetwork rather than merely exciting or inhibiting certain nucleus.

Folic acid: when to supplement and by how much

Ged O’Connor¹ and Colin P. Doherty^2–4

Affiliations: ¹Department of Neurology, Beaumont Hospital, Dublin 9, Ireland; ²Department of Neurology, St James’s Hospital, Dublin 8, Ireland; ³Department of Clinical Neurological Sciences, RCSI, Dublin, Ireland and ⁴Lecturer in Clinical Medicine, Trinity College, School of Medicine, Dublin, Ireland

Correspondence: Ged O’Connor, MRCPI, Department of Neurology, Beaumont Hospital, Dublin 9, Ireland. Tel: + 00353 (0)1 8092053; Fax: + 00353 (0)1 8092302; e-mail: ged.oconnor@oceanfree.net

ABSTRACT

INTRODUCTION

Folate is a water-soluble B vitamin, found particularly in such foods as leafy green vegetables and citrus fruits. Folic acid is the synthetic form of the vitamin. The value of pre-conceptual dietary supplementation with folic acid in women of child bearing age in reducing major congenital malformations (MCMs) and neural tube defects (NTDs) has been demonstrated in a number of large studies. However, the role and dosing of folic acid in women with epilepsy (WWE) who are taking anti-epileptic medication (AEDs) is less clear.

OBJECTIVE

To review the role of folate in the development of the neural tube and the evidence underlying the recommendations for folic acid supplementation in women of child bearing age and in WWE.

METHODS

We performed a formal literature search and from the results we reviewed the available studies and guidelines on the use of folic acid in the general population and in WWE.

CONCLUSION

Standard dose (0.4mg) of folic acid use should be encouraged in all women of childbearing potential, but the evidence to support the use of high-dose (ie, 5mg) folic acid in women who do not have a personal or family history of NTD/MCM occurrence is not strong. The evidence that folic acid supplementation will protect WWE from MCMs and NTDs is poor. However, given the potential interference in the metabolism of folate by some AEDs, high dose folic acid (5mg) should be prescribed in WWE but only in those without a personal history of malignancy.

Callosal Disconnection Syndrome in Transient Splenial Lesion of the Corpus Callosum

Viktoria Kapina¹, Maria Isabelle Vargas² and Judit Horvath¹

Affiliations: ¹Department of Neurology, University Hospitals of Geneva, Geneva, Switzerland and ²Department of Neuroradiology, University Hospitals of Geneva, Geneva, Switzerland

Correspondence: Kapina Viktoria, Department of Neurology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel: 0041795533794; Fax: +41223728299; e-mail: Viktoria.Kapina@hcuge.ch

ABSTRACT

A 64-year-old male patient presented with fever, agitation, and flu-like symptoms as well as difficulty in using his hands simultaneously. The brain magnetic resonance imaging (MRI) showed a solitary lesion in the splenium of the corpus callosum (SCC). The detailed neuropsychological examination revealed signs of disturbed interhemispheric transfer. The diagnosis of encephalitis was supported by the acute onset of brain dysfunction and the inflammatory changes of the cerebrospinal fluid (CSF). The clinical and MRI abnormalities completely recovered within one week without any treatment. In previously published reports of reversible focal lesions of the SCC, neuropsychological symptoms have rarely been reported. Our case underlines the importance of targeted neuropsychological examination in detecting callosal dysfunction and exemplifies the spontaneously benign prognosis of SCC.

Intracranial Hypotension Mimicking Cervical Radiculopathy

Enrico Ferrante¹, Dante Facchetti¹, Ines Arpino², Pietro Tiraboschi¹, and Alberto Citterio¹

Affiliations: ¹Neurosciences and Anaesthesiology Departments, Niguarda Ca’ Granda Hospital, Milan, Italy and ²Anaesthesiology Departments, Niguarda Ca’Granda Hospital, Milan, Italy

Correspondence: Enrico Ferrante, Divisione di Neurologia Ospedale Niguarda Cà Granda, Piazza Ospedale Maggiore, 3-20162 Milan, Italy. e-mail: enricoferrante@libero.it

ABSTRACT

Intracranial hypotension typically presents with an orthostatic headache, often with one or more of the following symptoms: nausea, vomiting, change in hearing, diplopia, blurred vision, and neck pain. Rarely it presents with upper limb numbness, paresthesias, and aches. We report the case of a 35-year-old man who—after a polytrauma car accident—had an orthostatic headache, diplopia, and bilateral muffled hearing. After 7 months he started presenting progressive weakness of the right upper limb and atrophy mainly of the right deltoid, biceps and triceps muscles, and milder weakness of the right forearm and left arm muscles without pain or loss of sensation. A neurophysiological examination showed marked neurogenic impairment in muscles of C5–C6 and C7 bilaterally suggestive of motor cervical radiculopathy. A spine MRI revealed an epidural CSF collection at the cervico-thoracic junction and a CT myelography revealed an extravasation of contrast medium at the same level. The man was diagnosed with an intracranial hypotension form of cervical CSF leakage by dural tear and a lumbar autologous epidural blood patch was performed with a progressive, albeit partial, improvement of the motor impairment during the following 24 months. Pure motor cervical radiculopathy with spinal amyotrophy is yet another mode of the still broadening clinical presentation of intracranial hypotension syndrome.

Gender Differences in Risk Factors, Mortality, and Length of Stay of Patients Discharged From a Pakistani Stroke Unit: A Comparative Cross-Sectional Study

Farzin Majeed¹, Bilal Ahmed², Maria Khan³, Shaista Anwar Siddiqi⁴ and Ayeesha Kamran Kamal⁵

Affiliations: ¹Department of Medicine, Section of Neurology, International Cerebrovascular Translational Clinical Research Training Program, Stroke Service, Aga Khan University, Karachi, Pakistan; ²Department of Medicine, Epidemiology and Biostatistics, Aga Khan University, Karachi, Pakistan; ³Department of Medicine, International Cerebrovascular Translational Clinical Research Training Program, Aga Khan University, Karachi, Pakistan; ⁴Department of Medicine, Section of Neurology, Stroke Service, Aga Khan University, Karachi, Pakistan and ⁵Program Director, Stroke Services and Neurovascular Research and Clinical Training Programs, Aga Khan University, Karachi, Pakistan

Correspondence: Ayeesha Kamran Kamal, MD, Department of Medicine, Section of Neurology, Stroke Service, Neurovascular Fellowship Program, International Cerebrovascular Translational Clinical Research Training Program, Aga Khan University, Karachi, Pakistan. Tel: +(9221) 34930051-4559; Fax: +(9221) 4934294; e-mail: ayeesha.kamal@aku.edu

ABSTRACT

BACKGROUND

Differences between women and men in relation to stroke are increasingly being recognized. There is a scarcity of data on gender-based differences in stroke risk factors and outcomes from Pakistan.

METHODS

We enrolled 231 consecutive patients diagnosed with acute stroke. All patients received care along a standardized stroke pathway in a single stroke unit. We analyzed demographic and medical factors, NIHSS scores, and outcomes.

RESULTS

Of 213 consecutive hospitalized patients, 135 patients were men and 76 were women. The male to female ratio was 1.84. The mean age of males was 62.3±13.56, as compared to females 61.15±11.60 years. Hypertension, smoking, and dyslipidemia were more commonly found in men whereas ischemic heart disease, atrial fibrillation, and history of prior stroke were more frequently encountered in women. However, after adjustment for age and gender smoking in men (P=.059) and atrial fibrillation (P=.054) and prior stroke (P=.017) in women, these were found to be independent predictors of stroke. Diabetes was equally distributed between the two genders. Women were more likely to be dependent prestroke (P=.524), have more severe strokes (P=.142), and more likely to have a longer hospital stay (P=.942). In-hospital mortality was higher in women than in men (6.7% vs 5%; P=.524) and they had poorer discharge modified Rankin Scale scores (mRS 5; 8.5% vs 5%; P=.775); however, these differences were not statistically significant.

CONCLUSION

There appear to be gender-based differences in the risk factor profile and perhaps outcome in Pakistani patients despite standardized care in a dedicated stroke unit.

Wasp Stings-Related Cerebral Infarction in a Toddy Tapper With Multiple Previous Stings.

Kamatchi Sundaramoorthy¹, Stalin Viswanathan², and Jayanthi Arulneyam³

Affiliations: ¹Pondicherry Institute of Medical Sciences, Kalapet, Pondicherry, India; ²Department of Internal Medicine, Pondicherry Institute of Medical Sciences, Kalapet, Pondicherry, India and ³Department of Neurology, Pondicherry Institute of Medical Sciences, Kalapet, Pondicherry, India

Correspondence: Stalin Viswanathan MD, Department of Internal Medicine, Pondicherry Institute of Medical Sciences, Kalapet, Pondicherry-605014, India. Tel: +91 0413 3051111; Fax: +91-0413-2656273; e-mail: stalinviswanathan@ymail.com

ABSTRACT

Local reactions such as redness, edema, pain, and urticaria are commonly seen in patients with bee or wasp stings. Systemic reactions such as anaphylaxis, angioedema, and respiratory distress are often encountered in clinical practice. Some of the unusual reactions reported include stroke, acute renal failure, and Guillain-Barre syndrome. Here, we report a case of wasp sting-associated stroke in a toddy tapper who had history of multiple wasp stings in the past, who subsequently recovered after 4 days

SOD1 Mutations in Amyotrophic Lateral Sclerosis

Stefania Battistini¹, Michele Benigni¹, Claudia Ricci¹ and Alessandro Rossi²

Affiliations: ¹Department of Neuroscience, Neurology Section and ²Department of Neurological, Neurosurgical, Behavioural Sciences, Neurophysiology Clinic Section, University of Siena, Siena, Italy

Correspondence: Stefania Battistini, Department of Neuroscience, University of Siena, Viale Bracci, 2, 53100 Siena, Italy. Tel: +39-(0577)-233142; Fax: +39-(0577)-270260; e-mail: battistinis@unisi.it

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder characterized by degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases of ALS appear sporadically but about 1–13.5% of patients have a family history of ALS. Although the precise cause for the majority of cases is still unknown, mutations in the gene encoding for copper–zinc superoxide dismutase (SOD1) have been found in 12–23% of familial cases of the disease. Currently, more than 150 different SOD1 gene mutations have been identified in ALS patients most of which with autosomal dominant transmission. Occasionally, specific mutations are associated with a particular phenotype. Some SOD1 mutations occur as recurrent or founder mutations with a different geographic distribution. The discovery of mutations in the SOD1 gene has marked a change in ALS research and enabled the development of novel experimental rodent models to investigate the pathogenesis of familial ALS. However, the mechanism by which mutant SOD1 causes neural death remains elusive. Several lines of evidence suggest that ALS is a protein-folding disease and the increased propensity of mutant SOD1 to form aggregates may confer toxicity in motor neurons. Despite the apparent selectivity for motor neurons, recent data indicate that non-neuronal cell types contribute to pathogenesis and disease progression.

Amyloid Imaging in Alzheimer's Disease: Relationships to Memory Deficits, Brain Atrophy, and Hypometabolism

Gaël Chételat^1,2, Christopher Rowe^1,3 and Victor Villemagne^1,3,4

Affiliations: ¹Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia; ²Inserm-EPHE-Université de Caen/Basse-Normandie, Caen, France; ³Department of Medicine, Austin Health and ⁴The Mental Health Research Institute, The University of Melbourne, Heidelberg, VIC, Australia

Correspondence: Gaël Chételat, Department of Nuclear Medicine and Centre for PET, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia. Tel: +61-3-9496 3324; Fax: +61-3-9458 5023; e-mail: chetelat@cyceron.fr

ABSTRACT

Amyloid neuroimaging has made it possible to visualize in vivo one of the main hallmarks of Alzheimer's disease (AD), creating the opportunity to better diagnose, monitor, and understand this neurodegenerative condition. This review focuses on the relationships between amyloid deposition as assessed with [11C]Pittsburgh compound B (PiB) positron emission tomography (PET), and memory deficits, atrophy, and hypometabolism in different stages of AD. The presence of β -amyloid (Aβ) at a presymptomatic stage supports the hypothesis that the abnormal processing of Aβ, leading to β -amyloid deposition, is an upstream process. However, the link between global neocortical Aβ deposition and memory appears to be weak, early, and probably indirect though there may be a direct effect in specific brain regions. Studies assessing the relationships between PiB binding and atrophy or metabolism show that PiB (i) correlated to local atrophy only in the early stage and in regions of highest amyloid deposition (anterior and posterior cingulate and temporo-parietal areas), whereas hippocampal atrophy is related to distant deposition; (ii) shows only weak negative relationships with metabolism, essentially in the parietal cortex in AD; and (iii) can be observed in the non-expected direction (i.e., increased volume or metabolism with increased PiB), especially in the early stages. This suggests that atrophy and hypometabolism in AD-typical brain regions are not directly caused by the degree of local amyloid deposition. As a whole, neuroimaging studies suggest that, while Aβ dysregulation and deposition is necessary for the development of AD, the way this leads to neurodegeneration and dementia is complex, indirect, and not dose-dependant.

Association of Cardinal Motor Symptoms with Region-Specific Dopamine Transporter Activity in Mild to Moderate Parkinson's Disease

Martijn L.T.M. Müller¹, Roger L. Albin^2–4 and Nicolaas I. Bohnen^1–4

Affiliations: ¹Department of Radiology; ²Department of Neurology, University of Michigan, Ann Arbor; ³Neurology Service and ⁴GRECC, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA

Correspondence: Martijn L.T.M. Müller, Functional Neuroimaging, Cognitive, and Mobility Laboratory, Domino’s Farms, Suite B1000, Box No. 362, 24 Frank Lloyd Wright Drive, Ann Arbor, MI, 48106 USA. Tel: +1.734.998.8400; Fax: +1.734.998.8403; e-mail: mtmuller@umich.edu

ABSTRACT

Objective

To investigate the relationship between measures of the cardinal motor features and the degree of nigrostriatal dopaminergic denervation in patients with mild to moderate Parkinson's disease (PD).

Methods

PD patients (Hoehn and Yahr stages I–III, n=27) underwent C-β-CFT dopamine transporter (DAT) positron emission tomography. Clinical examination included the Unified PD Rating Scale (UPDRS) motor examination with sub-scores for the cardinal motor features of PD, grooved pegboard, and finger- and foot-tapping scores. Postural sway was also assessed. Patients on dopaminergic drugs were studied in the “off” state.

Results

Lower total striatal DAT binding was associated with higher UPDRS motor scores, slower performance on the grooved pegboard, and higher variability of postural sway. UPDRS subscale scores for rigidity and tremor, and footand finger tapping did not significantly correlate with striatal DAT binding. Thalamic DAT binding correlated with finger-tapping (r=0.532, p=0.005) and foot-tapping scores (r=0.474, p=0.017). Regional striatal analysis showed that ventral striatal DAT binding robustly correlated with UPDRS total motor (r=−0.507, p=0.007) and grooved pegboard (r=−0.567, p=0.002) performance. Posturography analysis showed increased sway variability with decreased posterior putamen DAT activity (r=−0.475, p=0.019).

Conclusion

These findings indicate that the nigrostriatal dopaminergic model of PD has limited correlations with the motor features of this disorder. Although nigrostriatal patterns of denervation may explain some of these findings, a more comprehensive model of parkinsonian motor impairments likely involves extra-striatal dopaminergic and non-dopaminergic mechanisms.

Spinal Muscular Atrophy in the Chinese

Vivian Chan and Virginia CN Wong

Affiliation: Department of Medicine and Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong

Correspondence: Vivian Chan, University Department of Medicine, Queen Mary Hospital, Hong Kong. Tel: +852-2255-4249; Fax: +852-2816-2863; e-mail: vnychana@hkucc.hku.hk

ABSTRACT

Spinal muscular atrophy (SMA) is one of the common neuromuscular disorders in children. In this review, the classification, phenotype, genetics, and management strategy for Chinese SMA patients are discussed, together with insights on new treatment modalities and prospective trials. SMA is an autosomal-recessive disorder with progressive muscle weakness and fatal outcome in many severely affected cases. Thus, identification of the otherwise healthy and asymptomatic carriers is of paramount importance toward prevention of the disease by prenatal diagnosis. Carrier testing among family members and even population screening should be advocated. Different methods of carrier testing to detect heterozygous deletion of the SMN1 gene, gene mutation, the 2+0 SMN1 genotype, and assessment of relative gene dosage of SMN1 and SMN2 are considered.

Mills Syndrome with Dementia

Andrew J Larner¹ and Christopher Gardner-Thorpe²

Affiliations: ¹Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ and Apothecaries Lecturer at the University of Liverpool; United Kingdom and ²Consultant Neurologist, Exeter; Apothecaries Lecturer at the Peninsula College of Medicine and Dentistry; United Kingdom

Correspondence: AJ Larner, Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ, UK. Tel: (+44) 151 529 5727; Fax: (+44) 151-529-8552; e-mail: a.larner@thewaltoncentre.nhs.uk

ABSTRACT

In the first decade of the twentieth century, the American neurologist Charles Karsner Mills described a syndrome of slowly progressive ascending or descending hemiplegia without significant sensory involvement, which now bears his name. The nosology and etiology of this rare syndrome has remained uncertain, but certainly some cases result from a localized form of amyotrophic lateral sclerosis (ALS). Since cognitive impairments, sometimes amounting to a dementia, are increasingly recognized to be a feature of ALS, it might be expected that Mills syndrome might also be attended with cognitive impairments, as first reported in 2005. This review article examines the original publication of Mills, the nosology of his syndrome, its relation to ALS, and the cognitive phenotype seen in this condition, as well as suggesting how to classify this disorder within the current nomenclature for frontotemporal lobar degenerations.

Cerebral Microbleeds: Are They Indicative of a Hemorrhage-Prone Brain?

Seung-Hoon Lee and Jae Kyu Roh

Affiliation: Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea

Correspondence: JK Roh, 28 Yeongeon-dong, Chongro-gu, 110-744 Seoul, Republic of Korea. Tel: (+822)-2072-3265; Fax: (+822)-3672-7553; e-mail: rohjk@snu.ac.kr

ABSTRACT

Cerebral microbleeds (CMBs) are tiny, round, dark signal lesions that are usually detected on gradient-echo MR images. CMBs consist of extravasations of blood components through fragile microvascular walls with lipohyalinosis and surrounding macrophages. The prevalence of CMBs in elderly subjects without a history of cerebrovascular disease is around 5%, but it is much higher in ischemic or hemorrhagic stroke patients. The development of CMBs is closely related to various vascular risk factors, and in particular, lobar CMBs are considered to be associated with cerebral amyloid angiopathy. Because CMBs are tiny spots, their presence has been hypothesized to reflect a cerebral hemorrhage-prone status in patients with a hypertensive status or amyloid microangiopathy. Furthermore, it has been consistently documented that stroke survivors with CMBs have an elevated risk of subsequent hemorrhagic stroke or an antithrombotic-related hemorrhagic complication. However, previous studies have failed to establish a link between hemorrhagic transformation after thrombolytic treatment and CMBs. Therefore, the authors considered that a larger prospective study was required to conclude the clinical significance of CMBs and their applicability as a decision-making index.

Plural Information Processing and a Large Neural Network Are Necessary for Numerical Processing

Masayo Urano¹, Sachiko Anamizu² and Masaru Mimura³

Affiliations: ¹Department of Rehabilitation Medicine, Yokohama Stroke and Brain Center, Kanagawa, Japan and ²Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan and ³Department of Neuropsychiatry, Showa University School of Medicine, Tokyo, Japan

Correspondence: Masayo Urano, Department of Rehabilitation Medicine, Yokohama Stroke and Brain Center, 1-2-1 Takigashira, Isogo-ku, Yokohama, Kanagawa 235-0012, Japan. Tel: 81-45-753-2500; e-mail: masayo@ad.cyberhome.ne.jp

ABSTRACT

Calculation is not a unitary cognitive function. Instead, it is supported by multiple and interrelated neurocognitive components subserved by functional brain networks. In this review, we first address the roles of particular cognitive components in supporting number processing that have been highlighted by previous neuropsychological case reports of isolated acalculia or dissociable calculation deficits. Second, the clinical importance of dissociation of exact/approximate calculation is emphasized. Our patient with global aphasia caused by a large left-hemisphere lesion [1] presented with well-preserved approximate calculation, despite severely impaired exact calculation, thereby indicating that dissociable neurocognitive mechanisms may underlie different calculation abilities. Lastly, based on recent functional neuroimaging studies, we propose that calculation is subserved by a wide range of brain networks, including the left parietal lobe and left frontal lobe, as well as the right cerebral hemisphere

Genome-Wide Association Studies in Alzheimer's Disease

Christiane Reitz^1,2,3, Sandra Barral^2,3, and Richard Mayeux^1,2,3,4,5

Affiliations: ¹Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, USA; ²Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, USA; ³Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, USA; ⁴Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University, New York, USA and ⁵Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, USA

Correspondence: Richard Mayeux, Gertrude H. Sergievsky Center, 630 West 168th Street, Columbia University, New York, NY 10032, USA. Tel: +1 212 305 3192; Fax: +1 212 305 2518; e-mail: rpm2@columbia.edu

ABSTRACT

INTRODUCTION

Late-onset Alzheimer's disease (LOAD) is among the most common diseases in aging societies but the genetic factors contributing to the disease are largely unknown.

OBJECTIVE

To summarize the current knowledge on the genetic causes underlying LOAD and specifically review the recent discoveries, strengths, and pitfalls of genome-wide association studies.

METHODS

The primary sources of the studies addressed in this review article were the AlzGene database updated May 2010, and full-text articles and abstracts published in English in the PUBMED database between 1980 and October 2010.

RESULTS

Despite remarkable technological advances in gene mapping in recent years, to date only five genes—amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), apolipoprotein E (APOE), and the neuronal sortilin-related receptor gene (SORL1)—have been firmly implicated in the cause. Among the additional genes reported, in particular CLU, CR1, PICALM, and BIN1 are promising candidates as they are biologically plausible and have been identified by the largest GWAS data sets available to date.

CONCLUSION

High-throughput whole-genome association studies have gained considerable momentum for the identification of novel disease genetic variants for LOAD risk genes, but no single functional risk variant was identified. For the promising candidate genes reported, both replication and validation by a sufficient number of independent data sets and functional approaches are still lacking but crucial.

Gender Differences in Risk Factors, Mortality, and Length of Stay of Patients Discharged From a Pakistani Stroke Unit: A Comparative Cross-Sectional Study

Farzin Majeed¹, Bilal Ahmed², Maria Khan³, Shaista Anwar Siddiqi⁴ and Ayeesha Kamran Kamal^5*

Affiliations: ¹Department of Medicine, Section of Neurology, International Cerebrovascular Translational Clinical Research Training Program, Stroke Service, Aga Khan University, Karachi, Pakistan; ²Department of Medicine, Epidemiology and Biostatistics, Aga Khan University, Karachi, Pakistan; ³Department of Medicine, International Cerebrovascular Translational Clinical Research Training Program, Aga Khan University, Karachi, Pakistan; ⁴Department of Medicine, Section of Neurology, Stroke Service, Aga Khan University, Karachi, Pakistan and ⁵Program Director, Stroke Services and Neurovascular Research and Clinical Training Programs, Aga Khan University, Karachi, Pakistan

Correspondence: Ayeesha Kamran Kamal, MD, Department of Medicine, Section of Neurology, Stroke Service, Neurovascular Fellowship Program, International Cerebrovascular Translational Clinical Research Training Program, Aga Khan University, Karachi, Pakistan. Tel: +(9221) 34930051-4559; Fax: +(9221) 4934294; e-mail: ayeesha.kamal@aku.edu

ABSTRACT

BACKGROUND

Differences between women and men in relation to stroke are increasingly being recognized. There is a scarcity of data on gender-based differences in stroke risk factors and outcomes from Pakistan.

METHODS

We enrolled 231 consecutive patients diagnosed with acute stroke. All patients received care along a standardized stroke pathway in a single stroke unit. We analyzed demographic and medical factors, NIHSS scores, and outcomes.

RESULTS

Of 213 consecutive hospitalized patients, 135 patients were men and 76 were women. The male to female ratio was 1.84. The mean age of males was 62.3±13.56, as compared to females 61.15±11.60 years. Hypertension, smoking, and dyslipidemia were more commonly found in men whereas ischemic heart disease, atrial fibrillation, and history of prior stroke were more frequently encountered in women. However, after adjustment for age and gender smoking in men (P=.059) and atrial fibrillation (P=.054) and prior stroke (P=.017) in women, these were found to be independent predictors of stroke. Diabetes was equally distributed between the two genders. Women were more likely to be dependent prestroke (P=.524), have more severe strokes (P=.142), and more likely to have a longer hospital stay (P=.942). In-hospital mortality was higher in women than in men (6.7% vs 5%; P=.524) and they had poorer discharge modified Rankin Scale scores (mRS 5; 8.5% vs 5%; P=.775); however, these differences were not statistically significant.

CONCLUSION

There appear to be gender-based differences in the risk factor profile and perhaps outcome in Pakistani patients despite standardized care in a dedicated stroke unit.

Neurological Manifestations Related to Blast Injury

N Awad¹ and LC Doering²

Affiliations: ¹School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada and ²Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

Correspondence: Awad N, School of Biomedical Engineering, McMaster University, 1280 Main St. W., Hamilton, ON, Canada. Tel: (905) 525-9140 ext: 23486; Fax: (905) 529-9688; e-mail: awadn@mcmaster.ca

ABSTRACT

Blast-induced neurotrauma, a consequence of military conflict or domestic explosions, becomes a major focus of health care around the world. In general, the most important medical concern of neurotrauma is the potential long-term manifestations of mild traumatic brain injury. Blast overpressure can induce hidden mild neurotrauma that is considered to be a critical health and socioeconomic problem. Increased research efforts to understand the mechanisms of blast-induced neurotrauma and the subsequent neuropathophysiological responses are required to address these problems. The objectives of this review are to highlight a range of neurochemical and pathological reactions as well as the clinical manifestations of patients with blast-related neurotrauma.

Pharmacological Management of Central Neuropathic Pain

ABSTRACT

Central neuropathic pain (central pain) may be a serious consequence of injuries or diseases affecting the central nervous system, occurring in up to 50% of patients following spinal cord injury, 25% with multiple sclerosis, and 10% following stroke. Central pain should be suspected if the pain: (1) arises at or within months following a lesion in the central nervous system with no other obvious cause, (2) is distributed within an area of sensory abnormality corresponding to the lesion, (3) is diffuse, (4) is described in terms such as burning, freezing, pins and needles, shooting, or squeezing, or (5) is unrelated to movements or specific positions of the pain-affected area. It is important to exclude nociceptive types of pain for which there may be a curative treatment. Randomized controlled trials support a pharmacological treatment similar to that used in peripheral neuropathic pain. Tricyclic antidepressants, pregabalin, and gabapentin are usually recommended as first-line treatment for central pain, while serotonin–noradrenaline reuptake inhibitors may be used if tricyclic antidepressants are contraindicated. Tramadol and opioids may be used as second-line treatment or escape medication. Central pain patients may be particularly prone to side effects, and an individual treatment approach is necessary.

Strengths and Limitations of Systematic Reviews of Drug Trials: The Biostatistical Perspective

Some thousands of randomized controlled trials are published each year. But clinicians are pinched for time to study the literature. Hence, systematic reviews are important to combine the results for a specific medical question. Meta-analysis is only a statistical method that was used in systematic reviews to combine the results of individual studies. Our aim is to discuss the strengths and potential pitfalls of systematic reviews on the basis of five examples from the literature. We focus on aspects limiting the strength of systematic reviews, such as publication bias, imputation of missing data, and the use of inappropriate statistical methods. Although systematic reviews are key to summarizing evidence, meta-analyses of drug trials should be read with a healthy portion of scepticism.

Topiramate in Migraine Prophylaxis

Review Article

Mark Obermann , Steffen Naegel, Charly Gaul, and Hans-Christoph Diener

Affiliation : Department of Neurology and Headache Center, University of Duisburg-Essen, Essen, Germany

ABSTRACT

The prevalence of migraine in the global adult population is approximately 10%. Migraine has a serious socioeconomic impact on society in general and is associated with considerable medical disability for individual patients. Migraine is characterized by the combination of typical headache with associated autonomic symptoms and/or the presence of aura. Within the past years, considerable advances were made in understanding the pathophysiology of migraine. This has led to improved treatment options for the acute migraine attack as well as migraine prophylaxis. Topiramate is an antiepileptic drug (AED) with a complex mode of action, which has proven its efficacy and safety in the prophylactic treatment of episodic migraine in a number of randomized controlled clinical trials. Topiramate is also effective in treating patients with chronic migraine with and without medication overuse headache. In clinical trials, it was generally considered to be well tolerated by patients, but in everyday clinical practice, side effects can be therapy-limiting in some patients. Treatment benefits and potential adverse events have to be considered carefully for each individual patient to assure optimal treatment success with topiramate. This is a revised and updated version of a previous review by Naegel and Obermann (2010).


Keywords: topiramate, migraine, migraine prophylaxis, chronic migraine, migraine treatment

Correspondence: Mark Obermann, Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Tel: (+49)-201-723-84385; Fax: (+49)-201-723-5542; e-mail: mark.obermann@uni-due.de

Recent Developments in the Management of Posttraumatic Neuropathic Pain

Review Article

Kurien Koshy and Cory Toth

Affiliation : Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

ABSTRACT

Injury to the nervous system may lead to posttraumatic neuropathic pain (NeP), an often refractory condition associated with pain, sensory disturbance, and potential weakness and autonomic dysfunction (such as with complex regional pain syndrome). In addition, NeP is often associated with insomnia, difficulties with mood or anxiety, and impaired quality of life. This review will review the causes and nature of NeP with a discussion on the recent breakthroughs in understanding its pathophysiology. Management of this condition is often difficult and requires a multidisciplinary approach consisting of both pharmacological and nonpharmacological treatment. Recent studies identifying gabapentinoids as effective in posttraumatic forms of NeP will be reviewed. Posttraumatic NeP is a complicated and complex disease process that requires ongoing research to understand and manage the needs of its patient population.

Keywords: neuropathic pain, posttraumatic neuropathic pain, complex regional pain syndrome, neuropathy, pharmacotherapy, pregabalin,antidepressants

Correspondence: Cory Toth, Department of Clinical Neurosciences, University of Calgary, HMRB Room 155, 3330 Hospital Drive NW,
Calgary, Alberta, Canada T2N 4N1. Tel: +1-(403)-220-8831; Fax: +1-(403)-283-8731; e-mail: corytoth@shaw.ca

Differential Diagnosis of Longitudinally Extensive Transverse Myelitis in Adults

Review Article


Christopher Eckstein, Stephanie Syc and Shiv Saidha

Affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

ABSTRACT

Longitudinally extensive transverse myelitis (LETM), characterized by spinal cord inflammation extending three or more vertebral segments in length, may be caused by a multitude of disorders. LETM is most commonly associated with neuromyelitis optica (NMO). Such is the frequent association between these two entities that there is a growing tendency amongst physicians to regard them as being practically synonymous with each other. The objective of this review is to highlight the wide range of disorders that may cause LETM and to emphasize the need to carefully consider all potential etiologies in the assessment of LETM. In particular, we focus on the salient clinical, laboratory, and radiographic features of these various disorders, which help them to be differentiated from one another.

Keywords: Longitudinally Extensive Transverse Myelitis, LETM, NMO, neuromyelitis optica, myelopathy

Correspondence: Dr Shiv Saidha, Department of Neurology, Johns Hopkins University School of Medicine, Pathology 627, 600 North Wolfe Street, Baltimore, MD 21287, USA. Tel: +1-4106141653; Fax: +1-4105026736; e-mail: ssaidha2@jhmi.edu

Clinical Data on the Prolonged Release Formulation of Ropinirole

Review Article

Wolfgang H. Jost¹ and Lars Bergmann²

Affiliations: ¹Deutsche Klinik für Diagnostik, Wiesbaden and ²GlaxoSmithKline GmbH, Munich, Germany

ABSTRACT

In the treatment of Parkinson's disease (PD), non-ergoline dopamine agonists are considered the first-choice therapy. Ropinirole has been an internationally established therapy used to treat the signs and symptoms of idiopathic PD for more than 10 years. Because of its moderate elimination half-life, the immediate release (IR) formulation is administered three times daily. Now a prolonged release (PR) form is available, and despite administration once-daily in the morning, plasma level fluctuations are reduced over 24 hours, versus IR, allowing for symptomatic treatment during day and night time with once-daily dosing. The PR formulation can be up-titrated more rapidly and simply, reaching clinical efficacy as early as the second week of therapy. In clinical studies, higher doses of ropinirole were achieved with the PR formulation compared with the IR formulation. The results of a randomized double-blind head-to-head study of both formulations in patients with advanced PD demonstrated significantly greater efficacy and a larger l-dopa dose reduction. A positive effect on nighttime motor symptoms and quality of sleep has already been established. Because of once-daily administration, compliance and adherence may also be improved.

Keywords: ropinirole, Parkinson’s disease, dopamine agonist, prolonged release

Correspondence: Prof. Dr.Wolfgang Jost, Deutsche Klinik für Diagnostik, Aukammallee 33, 65191 Wiesbaden/Germany. Tel: 0049-611-577430;Fax: 0049-611-577311; e-mail: jost.neuro@dkd-wiesbaden.de

Neurological Manifestations of Celiac Disease in Children and Adults

Review Article

Aaron Lerner^1, Badira F. Makhoul² and Rami Eliakim³

Affiliation : ¹Pediatric Gastroenterology and nutrition Unit, Carmel Medical Center and ²Department of Gastroenterology, Rambam Health Care Campus and ^1,2Bruce Rappaport School of Medicine, Technion-Israel institute of Technology, Haifa, Israel

ABSTRACT

Celiac disease (CD) is a common, life-long, autoimmune condition, affecting the small intestine of genetically susceptible individuals. The classical clinical picture is disappearing as awareness progresses and the extra-intestinal presentation is emerging. Skin, endocrine, hepatic, skeletal, hematological, gynecological, infertility, dental, and behavioral abnormalities are emerging. Among the new growing domains is the extra-intestinal presentation of CD affecting the peripheral and central neurological systems. This review highlights neurological presentations in these patients, focusing on the clinical signs/symptoms in the pediatric and the adult age group, separately.

Keywords: Celiac disease, neurology, children, adults

Correspondence: Rami Eliakim, Department of Gastroenterology, Rambam Health Care Campus, Bat Galim, Haifa, Israel, 31096. Tel: +972-4-854-3784; Fax: +972-4-854-3058; e-mail: r_eliakim@rambam.health.gov.il

Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage

REVIEW ARTICLE

Jade W Wei, Hisatomi Arima and Craig S Anderson

Affiliation : The George Institute for Global Health and Department of Neurology, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia

ABSTRACT

Intracerebral hemorrhage (ICH) is the most serious form of stroke, with more than two-thirds of the patients either dying or left permanently disabled from the condition. Despite considerable research effort, there is still no treatment of proven efficacy for ICH and the chances of surviving an ICH has failed to improve in recent decades. The brain damage from the initial hematoma is considered largely irreversible, which is because of the early time window of opportunity for treatment benefit and the modest potential effects of any medical therapy that limits hematoma growth. Knowledge has accumulated regarding the nature of secondary effects of the perihematomal edema in ICH, making it an attractive therapeutic target. The pathophysiology of ICH-related perihematomal edema is complex: a number of different mechanisms are involved from the initial hydrostatic pressure of the hematoma to the subsequent toxic effects of breakdown products resulting from coagulation cascade activation and erythrocyte lysis as part of the natural process of hematoma resolution. Although perihematomal edema and hematoma volumes are strongly correlated, there is less and conclusive evidence regarding the independent prognostic role of perihematomal edema per se. Patient management is primarily supportive and aimed at reducing resulting increases in intracranial pressure. No therapies have been shown to definitely influence outcome, and all are associated with some hazard. Further studies are required to clarify the relationship between perihematomal edema and outcome in ICH, and to translate the positive results of therapies identified in the laboratory into the clinical domain.

Keywords: perihematomal edema, intracerebral hemorrhage, stroke, treatment

Correspondence: Craig S Anderson, The George Institute for Global Health, P.O. BoxM201,Missenden Rd, Camperdown,NSW2050, Australia.
Tel: +61-2-9993-4521; Fax: +61-2-9993-4502; e-mail: canderson@george.org.au

A Complete Literature Survey: Vitamin D and Multiple Sclerosis – What is Clearly Evident?

REVIEW ARTICLE


Irfan Rafique and Jette Lautrup Frederiksen

Affiliation: Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark

ABSTRACT

An increase in the number of multiple sclerosis (MS) cases is seen with increasing distance from the equator. This has directed attention toward vitamin D, which is synthesized in our skin with the help of sunlight. Thus the following questions are raised: Is the level of serum vitamin D associated to MS? Is there any difference in the risk of MS depending on whether vitamin D is formed by sun exposure or consumed through diet? Is the impact of vitamin D on MS genetically correlated? Is it possible to treat MS with vitamin D? Fifty-two articles found on the Internet by peer-reviewed databases, primarily PubMed, form the basis of this complete literature survey. Eight of nine examinations showed significant connection of low concentrations of vitamin D in the serum and MS. Exposure to sun during both childhood and puberty is of significance to the development of MS, whereas vitamin D consumed in diet is not decisive. The fact that there is coherence between vitamin D receptor gene polymorphism and MS is not unambiguous, since several investigations have showed conflicting results. As a result of limitations in trials we are not able to conclude whether vitamin D should be used as treatment.

Keywords: multiple sclerosis, 25 (OH)D, vitamin D 1,25 (OH)D, vitamin D receptor genes, vitamin supplements, sunlight
Correspondence: Irfan Rafique, Medical Student;. Tel: + 45 43 233 041; Fax: + 45 43 233 92; e-mail: xlz855@alumni.ku.dk