PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES by FRIDAY SPECIAL MAGZINE

PAKISTAN JOURNAL OF

VOLUME 10, NUMBER 2, JAN - MARCH 2015

NEUROLOGICAL SCIENCES

PSYCHIATRIC DIAGNOSIS AND HUMAN EMOTIONS DETERMINATION OF THE FACTORS LEADING TO NONCOMPLIANCE WITH ANTIEPILEPTIC DRUG UNDER RECOGNIZED ENTITY: CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY WITH LUPUS SPECTRUM OF NEUROMUSCULAR INJURIES IN VICTIMS OF BOMB BLASTS AN ODE TO NEUROLOGY THE LAND OF OPPORTUNITIES FOR RESEARCH ON RARE GENETIC NEUROLOGICAL DISORDERS NATIONAL GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF PARKINSON’S DISEASES IN PAKISTAN

(PSN) (PASN) (PINS)

Recognized by: Eastern Mediterranean Regional Office of the World Health Organitation (EMRO-WHO) Pakistan Medical & Dental Council (PMDC) ISSN 1990-6269 Higher Education Commission (HEC)

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES VOLUME 10, NUMBER 1, JAN - MARCH 2015

CONTENTS

EDITORIAL PSYCHIATRIC DIAGNOSIS AND HUMAN EMOTIONS Riffat Moazam Zaman JOURNEY OVER FOUR DECADES TO DISCOVER NEW DEFINITIONS OF STROKE AND TIA FOR 21ST CENTURY: ARE WE READY FOR THE CHANGE? Muhammad Athar Javed

EIGHT -AND-HALF SYNDROME: A RARE NEURO-OPHTHALMIC SYNDROME “POSSIBLE NINE SYNDROME” Dr. Muslim Ali Lakhiar, Dr. Shaheen Ahmed Mughal A 2 ½ YEARS OLD BOY WITH SQUINT AND SPEECH LOSS Shaila Ali, Zia ur Rehman, Tipu Sultan

CASE SERIES

ORIGINAL ARTICLE

SPECTRUM OF NEUROMUSCULAR INJURIES IN VICTIMS OF BOMB BLASTS Dureshahwar Kanwar, Ambreen Iqrar, Zaitoon Shivji and Sara Khan

DETERMINATION OF THE FACTORS LEADING TO NONCOMPLIANCE WITH ANTIEPILEPTIC DRUG Abdul Hafiz, Naila Naeem Shahbaz, Jai perkash, Muslim Ali Lakhiar EFFICACY OF MEMANTINE ON COGNITIVE FUNCTIONS OF PATIENTS WITH MODERATE VASCULAR DEMENTIA. Dr Saima Nazish, Dr Bashir A Soomro, Dr Shafaq Alvi POST STROKE DEMENTIA AND ITS PUTATIVE RISK FACTORS: A HOSPITAL-BASED STUDY Iranmanesh, Sheykholeslami, Rahimdel, Gadari, Vazirinajad, Syedyazdi

POETRY AN ODE TO NEUROLOGY Dr. Marina Wazir,

COMMENTARY THE LAND OF OPPORTUNITIES FOR RESEARCH ON RARE GENETIC NEUROLOGICAL DISORDERS Muhammad Ulusyar Khan, Fazal M. Arain

RESTLESS LEGS SYNDROME IN PATIENTS WITH TYPE 2 DIABETES MELLITUS Shaista A. Siddiqi, Javeria Rauf, Anita Haroon, Bilal Ahmed, Saera Suhail Kidwai, Lubna Nazir

GUIDELINES

CASE REPORT UNDER RECOGNIZED ENTITY: CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY WITH LUPUS Ali Zohair Nomani,Haris Majid Rajput, Rao Sohail Yasin Khan, Mansoor Iqbal, Zakir Jan, Uzma Jamil, Mazhar Badshah, Muhammad Irshad

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NATIONAL GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF PARKINSON’S DISEASES IN PAKISTAN Nadir A Syed, Farwa Ali, Khalid Sher, Amer Ikram, Bashir Soomro, Naila Shahbaz, Mughis Sheerani, Sarwar Jamil, Ahsan Numan, ManzoorLakhair, Irshad Awan, Saleem Barech, Haroon Basheer

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES VOLUME 10, NUMBER 1, JAN - MARCH 2015

EDITOR

PREVIOUS EDITORS

Mohammad Wasay, AKU, Karachi

Mohammad Nasrullah, KEMU, Lahore (2001-2006) Saad Shafqat, AKU, Karachi (2006-2011)

DEPUTY EDITOR

EDITORIAL BOARD

Akhter Sherin, Peshawar

Steve Roach, USA Richard Barohn, USA Sardar Alam, Pakistan Imran Ali, USA Sten Frederikson, Sweden Shahnaz Ibrahim, Pakistan MM Mehndiratta, India Mazhar Mannan, Bangladesh Padma Gunaratne, Sri Lanka Shubash Kaul, India Mohammad Saadatnia, Iran Naeem Kasuri, Pakistan Ehsanullah Syed, USA Rasheed Jooma, Pakistan Naweed Syed, Canada Mohammad Nizam, Canada Amir Arain, USA NV Ramani, Singapore Rohit Bakshi, USA Mubeen Rafay, Canada Saadat Kamran, Qatar J Stam, Netherlands Fayyaz Ahmed, UK Nirmal Suriya, India Bashir Soomro, Karachi

SECTION EDITOR Farooq Rathore, FCPS CMH Lahore Section of Neurorehabilitation

ASSOCIATE EDITORS lsmail Khatri, Saudi Arabia Sarwar Siddiqi, AKU, Karachi Abdul Malik, NCFC, Karachi Murad Moosa, AKU, Karachi Zafar Sajjad, AKU, Karachi Shahzad Shamim, AKU, Karachi

ADVISORY BOARD Ashfaq Shuaib, Alberta, Canada Adnan Qureshi, Minnesota, USA Shaukat Ali, NMI, Karachi Mohammad Tariq, Islamabad Ather Enam, AKU, Karachi

MANAGING EDITOR Abdul Rasheed Dal

ASSISTANT EDITORS Mohammed Bilal Shayan Ali

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E D I T O R I A L

PSYCHIATRIC DIAGNOSIS AND HUMAN EMOTIONS

Riffat Moazam Zaman,

Professor, Department of Psychiatry, Aga Khan University, Karachi. Email: riffat.moazam-zaman@aku.edu Date of Submission: December 10, 2014, Date of Revision: December 21, 2014, Date of Acceptance: December 28, 2014

Psychiatry is a human science and its subject matter is the individual’s psychic reality which defies the degree of certainty and validity required of the discourse in natural sciences. However, modern psychiatry, as we know it, in the 21st century has moved from understanding the psychogenic cause of a symptom to a medical model of controlling and manipulating symptoms. An important reason for this shift was the increasing awareness that some medications (lithium carbonate, antipsychotics, antidepressants, anxiolytics) were of benefit to certain kinds of disorders, and the ongoing research in this area held a promise for better and more effective medications that could target many other mental disorders. Equally important was the dissatisfaction and conflict within the profession, as well as the attacks, in the 1950’s, from the antipsychiatry movement that challenged the arbitrariness of psychiatric diagnosis which lacked a pathophysiologic explanation for the illness. An indication of the American Psychiatric Association’s (APA) struggle to develop a credible classification system of psychiatric disorders is best reflected in the history of the Diagnostic Statistical Manual (DSM). This manual was first published in 1952, with subsequent revisions, the latest being the publication of DSM-5, in 2013. Until the 1970’s the manuals (DSM-I and DSM-II) were conceived on a biopsychosocial model with a psychodynamic tilt influenced by Freud’s theory of personality development and intrapsychic conflict, as well as Meyer’s psychosocial model, which downplayed psychiatric disorders as discrete, specific pathological entities. This model had a significant impact in teaching and clinical practice with individual psychotherapy becoming an essential feature of psychiatry. However the shortcoming of this approach was that it lacked a clear demarcation between the mentally healthy and sick; this lead to questions about the status and legitimacy of psychiatry as a medical science. Added to the grave doubts about the validity and reliability of psychiatric diagnosis was the embarrassment when in the early 1970’s the gay rights movement lobbied against homosexuality being labeled as a disorder in DSM-II, which was later excluded from DSM III published in 1980. So the removal of a disorder was based on political pressure, rather than scientific research. DSM-III (followed by DSM-III- R, 1989) which was a significant turning point in the history of psychiatry in USA, adopted a descriptive, nosological approach which could be supported by research findings that lent greater reliability and validity to psychiatric constructs. Assessment through description of symptoms which were publicly visible was stressed over psychological etiology which by its very nature was private and invisible. This bold and creditable step by the APA was not free from criticisms, many of which were warranted. A most vocal critic of DSM-III-R, Dr. Paula Caplan a clinical and research psychologist, and a human rights advocate, forwarded a trenchant argument against the inclusion of diagnostic labels, such as Self-Defeating Personality Disorder (SDPD) and Premenstrual Dysphoric Disorder (PMDD). Both these disorders were applicable to a majority of women. The former (SDPD), facetiously referred to as “good wife syndrome”, included characteristics such a putting needs of others ahead of one’s own, feeling unappreciated etc. Interestingly, this “portrait” of SDPD is most germane to the accepted and desirable gender role for Pakistani women as well. The latter’s (PMDD) diagnostic features consist of “bloating” breast tenderness coupled with irritability, fatigue, being “on edge” etc. Dr. Caplan questioned the scientific basis of inclusion of PMDD in a psychiatric manual, pointing out that it is just a fancy name for PMS. In lieu of the scathing criticism from feminists, the two diagnoses were not included in the main text of DSM-III-R and DSM-IV-TM (2004) but were instead placed in an appendix titled “Diagnostic Categories Needing Further Study.” The publication of DSM-5 in 2013, nine years after DSM-IV-TM was awaited with much anticipation. Surprisingly, mental health professionals expressed concerns while DSM-5 was in the making. Most of these concerns were around newly introduced categories and the lowering of thresholds for many disorders which would invariably lead to over diagnosis of the existing disorders. Allen Frances, who chaired the task force of DSM-IV was the most forceful and potent critic of DSM-5. In his high profile articles he argued that many changes were arbitrary and scientifically untenable and with the expansiveness of diagnostic categories and diagnosis based on checklists of symptoms, would be more beneficial to drug companies than to the client themselves. He also bemoaned the fact that DSM’s descriptive and atheoretical approach was biased in favor of medication and downplayed the role of psychotherapy and counseling. While it is not possible to address all the contentious changes in DSM-5, the elimination of bereavement exclusion from Major Depressive Disorder (MDD), increases

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the probability of diagnosing normal grief reaction as MDD. To be diagnosed with MDD if a person has 5 out of the 9 symptoms (such as sadness, insomnia, difficulty in concentration and engaging in everyday activities etc.) which have persisted for more than 2 months, criteria of MDD has been met. The checklist of symptoms for MDD are similar to the anguish felt and observed in a person who has lost a loved one. In conclusion there is no denying that the DSM has provided psychiatrists with a common, agreed upon language which is indispensable if research has to keep pace with modern medicine. In lending clarity to the diagnosis of some major disorders the DSM has provided guidance to the diligent use of psychotropic medication. However, DSM with its ever- expanding list and confusing rearrangement of diagnostic categories has medicalized normal human emotions. In its quest to be scientific, it seems to have lost sight of the nature of psychological suffering, a construct that is fundamentally non-empirical.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

American Psychiatric Association (1987), DSMIII-R. APA Washington, DC. American Psychiatric Association (2005), DSMIV-TM. APA Washington, DC. American Psychiatric Association (2012). DSM. History of the Manual Retrieved. July 12. American Psychiatric Association (2013), DSMV-TM. APA Washington, DC. Caplan, P.J. (1995). They Say Youâ&#x20AC;&#x2122;re Crazy. Addison-Wesley Publishing Co. Mass. Choices, N. H. S. (2013). Controversy over DSM-5: new mental health guide-Health NewsNHS Choices Frances, A. (2014). DSM. Psychotherapy,

10. 11.

Counselling and Medicalization of Mental Illness. T Professional Counselor, 4, 282-284. Frances, A. J. (2012). DSM 5 is guide not bibleâ&#x20AC;&#x201D;Ignore its ten worst changes. Psychology Today. Pilgrim, D. (2013). The Failure of Diagnostic Psychiatry and Some Prospects of Scientific Progress Offered by Critical Realism. Journal of Critical Realism, 12 (3), 336-358. Wakefield, J. (2013). An overview of Changes and Controversies. Clinical Social Work Journal, 41 (2), 139-154. Wilson, M. (1993). DSM-III and the Transformation of American Psychiatry: A History. American Journal of Psychiatry. 150: 3, 399-410.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil

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JOURNEY OVER FOUR DECADES TO DISCOVER NEW DEFINITIONS OF STROKE AND TIA FOR 21ST CENTURY: ARE WE READY FOR THE CHANGE? Muhammad Athar Javed

FRCP, Associate Professor Neurology, King Edward Medical University,Lahore Correspondence to: Muhammad Athar Javed, FRCP, Associate Professor Neurology, King Edward Medical University,Lahore. Email.dratharjaved59@gmail.com Date of Submission: October 30, 2014, Date of Revision: November 25, 2014, Date of Acceptance: November 28, 2014

Stroke was the second most frequent cause of death worldwide in 2012, accounting for 6.7 million deaths.(1) Approximately 17 million people had a stroke in 2010 and 33 million people have previously had a stroke and were still alive making total population of 50 million with stroke in the world.(2) Stroke is the number one preventable cause of permanent disability.(3)Projections show that by 2030, stroke prevalence will increase by more than 20% over 2012. (3) The World Health Organization (WHO) definition (1970) of stroke“rapidly developing clinical signs of focal (or global) disturbance of cerebral function,lasting more than 24 hours or leading to death, with noapparent cause other than that of vascular origin” is still frequently used.(4) This definition has been accepted by neurology community for more than 40 years despite many pitfalls. Firstly, this definition stresses on focal or global cerebral dysfunction and did not include stroke caused bybrainsten, retinal or spinal cord vascular events. Secondly, few vascular events may present with headache without causing focal or global cerebral dysfunction such as mild cases of cerebral venous thrombosis and subarachnoid hemorrhage and would not fulfill this WHO definition. Thirdly, old definition also did not address silent infarction and silent cerebral hemorrhage found on neuroimaging or neuropathological examination.Fourthly, another component of this definition i.e. “global cerebral dysfunction” occurs only in special setting such as severe hypotension and after a period of cardiac arrest causing global cerebral ischemia and, in strict sense, is not a stroke syndrome. As a result oldest WHO definition of stroke has become outdated, obsolete and needed reformulation. First definition of transient ischemic attacks “TIAs” was proposed in 1964 by J. Marshall and defined such attacks as “a disturbance of neurological function of less than 24 hours’ duration occurring in the territory of supply of the carotid or vertebrobasilar arteries.”(5) In 1975, an Ad Hoc Committee on Cerebrovascular Disease published the following definition: “Transient ischemic attacks are episodes of temporary and focal dysfunction of vascular origin, which are variable in duration, commonly lasting from 2 to 15 minutes, but occasionally lasting as long as a day (24 hours). They leave no persistent neurological deficit”.(6) When this definition was formulated, diagnostic techniques were unavailable that could determine the presence of brain infarction. The definition of TIA that was used in the 1975 report was universally cited until the beginning of the 21st century. There were two pitfalls in old definition of TIAs: duration of TIAs and lack of imagingfindings. As neurological deficit may recover completely clinicallywith in24 hours but imaging may show evidence of infarction. Frequency of DWI abnormality in patients withtransient neurological episodes of different durations was found between 30-51% in a pooled analysis from 10 MRI Studies enrolling 818 patients.(7) During the last 40 years, lot of development and progress has been made in understanding stroke and therapeutic approaches to stroke.New techniques in imaging have been developed with better understanding of stroke syndrome that has prompted attempts at new redefinition of “Stroke” and “TIAs”.The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. In this editorial I would highlight some of these new definitions of stroke related syndromes as formulated by expert panel and has already been published in journal of “Stroke”.(8) The updated definition of stroke incorporates clinical and tissue criteria especially imaging. The term “Stroke” is broadly applicable to include all cases of CNS infarction, intracerebral hemorrhage, and subarachnoid hemorrhage. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury (i.e symptoms persisting ≥24 hours or until death, and other etiologies excluded). CNS infarction also includes hemorrhagic infarctions, types I and II. Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms. Almost 50 years ago, Fisher first described the presence of cerebral infarction in the absence of any clinically apparent stroke or transient ischemic attack. (9) It is only in recent years with major advances in imaging technology, however, that ‘silent’ brain infarcts (SBI) have been studied in any detail. Silent CNS infarction is defined as imaging or neuropathological evidence of CNS infarction, without a history of acute neurological dysfunction attributable to the lesion.The prevalence of SBI ranges from 5% to 62% in populationbased cohorts, most estimates falling in the 10% to 20% range. Longitudinal studies suggest an annual incidence between 2% and 4%. (10) Silent

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brain infarcts increase the risk of clinical infarction by 2 to 4 times in population-based studies.(11) This led to incorporation of brain infarction into the ABCD system (ABCD2I score) which improved prediction of stroke in the acute phase after transient ischemic attack.(12) The presence of hemorrhage in ischemic infarction has forced many treating physicians to stop ischemic treatment till hemorrhage is resolved. This hemorrhagic transformation of ischemic infarction has also been more clearly defined in two categories i.e. hemorrhagic infarction and parenchymal hemorrhage with clear guidelines regarding continuation or discontinuation of anti thrombotic treatment. “Hemorrhagic infarction” is defined as hemorrhage that may occur after infarction, either spontaneously or caused by antithrombotic or thrombolytic therapy. Hemorrhagic infarction is characterized by its lack of mass effect. Hemorrhagic infarction type I is defined by petechiae of blood along the margins of the infarction, whereas type II has confluent petechiae within the infarction but without a space occupying effect. Despite presence of hemorrhage these patients are treated according to ischemic protocol and are considered cerebral infarctions.In contrast, parenchymal hemorrhage is defined by the presence of mass effect, similar to the ICH definition of a focal collection of blood. Parenchymal hemorrhage type-I is a confluent hemorrhage limited to ≤30% of the infarcted area with only mild space-occupying effect, and type II is >30% of the infarcted area and/or exerts a significant space-occupying effect. These parenchymal hemorrhages parenchymal hemorrhages should be considered ICHs and may require reversal of antithrombotic therapy, aggressive antihypertensive therapy, and/or anti-edema therapy’.Similary stroke due to intracerebralhemoorhage, Subarachnoid hemorrhage, Cerebral venous thrombosis and Stroke, not otherwise specified has been redfined by the expert panel.(8) At the end I would like to highlight recent definitions of TIA. In 2002, an expert committee proposed a new definition: “A TIA is a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction”.(13) In 2009, an expert committee of the American Heart Association/American Stroke Association published a scientific statement defining TIA and recommending evaluation. The definitionof transient ischemic attack (TIA) proposed was: “a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction”.(14) Because of the variability of duration ; there is now general agreement that a fixed time designation should not be the primary distinguishing factor between stroke and TIA. Time should be a secondary consideration when adequate imaging is unavailable. Future implications of new definitions for physicians in Pakistan. The new definitions rely more on imaging techniques especially DWI and / or PWI MRI which can detect infarction within few minutesafter the arterial occlusion and even in patients who had transient vascular event on clinical ground. In Pakistan, neurological services are available only in main teaching hospitals and MRI facilities are limited to major cities. More over the use of thrombolytic therapy for acute stroke is even rare in the country. Under these circumstances treating physician would have no choice to adhere to the older definitions which are more clinical than imaging or tissue based. How we need to develop the neurological services in the country and update the knowledge of physicians with new trends and development in the world. REFERENCES 1. 2.

3. 4.

cerebrovascular attacks. Q J Med 1964;33:309–324 A classification and outline of cerebrovascular diseases, II. Stroke. 1975; 6:564–616. 7. Shah SH, Saver JL, Kidwell CS, Albers GW, Rothwell PM, Ay H, Koroshetz WJ, Inatomi Y, Uchino M, Demchuk AM, Coutts SB, Purroy F, Alvarez-Sabin JS, Sander D, Sander K, Restrepo L, Wityk RJ, Marx JJ, Easton JD. A multicenter pooled, patient-level data analysis of diffusion-weighted MRI in TIA patients. Stroke. 2007;38:463. 8. Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:2064. 9. Fisher CM: Lacunes: small, deep cerebral infarcts. Neurology 1965, 15:774–784 10. Fanning JP, Wong AA, and Fraser JF. The epidemiology of silent brain infarction: a systematic review of population-based cohorts. BMC Medicine 2014, 12:119 6.

“ The top 10 causes of death”. WHO Fact sheet no 310, May 2014. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T, O'Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shino hara Y, Witt E, Ezzati M, Naghavi M, Murray C (2014). "Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010". Lancet 383(9913): 245–54ournals Heart disease and stroke statistics 2014 update: http://circ.ahajournals.org/content/early/2013/12/18 /01. cir.0000441139.02102.80 Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. Cerebrovascular disease in the community: results of a WHO collaborative study. Bull World Health Organ. 1980;58:113–130 Marshall J. The natural history of transient ischaemic

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11. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34:1126–1129 12. Giles MF, Albers GW, Amarenco P, et.al. Addition of Brain Infarction to the ABCD2 Score (ABCD2I) A Collaborative Analysis of Unpublished Data on 4574 Patients. Stroke. 2010;41: 1907-1913. 13. Albers GW, Caplan LR, Easton JD, Fayad PB, Mohr JP, Saver JL, Sherman DG; TIA Working Group. Transient ischemic attack: proposalfor a new definition. N Engl J Med. 2002;347: 1713–1716

14. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, Miller E, Sacco RL. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. Stroke. 2009; 40:2276–2293.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil

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DETERMINATION OF THE FACTORS LEADING TO NONCOMPLIANCE WITH ANTIEPILEPTIC DRUG Abdul Hafiz, Naila Naeem Shahbaz, Jai perkash, Muslim Ali Lakhair Dow University of Health Sciences, Karachi.

Correspondence to: Naila Naeem shahbaz FCPS, Associate Professor, DUHS, Karachi. naila.shahbaz@gmail.com Date of Submission: January 30, 2015, Date of Revision: March 15, 2015, Date of Acceptance: March 31, 2015

ABSTRACT Background: Epilepsy is a chronic disorder or group of chronic disorder in which the indispensable feature is recurrence of seizures that are typically unprovoked and usually unpredictable. It is well established that non-adherence to antiepileptic drugs may lead to a loss of seizure control. Negative outcomes that may be associated with a loss of seizure control include: injury, increase hospitalizations, and decrease in productivity. All of these contribute to increased direct and indirect healthcare costs related to epilepsy. Objective: To determine factors leading to noncompliance with antiepileptic drugs in patients attending a tertiary care hospital. Methods & Results: In the crosssectional study design, total 203 patients, attending neurology outpatient clinic at Department of Neurology Civil Hospital Karachi, Pakistan, from August, 2010 to February, 2011, with epilepsy were included in the study. Non probability, purposive sampling technique was applied. Detailed history was taken from each patient. A structured proforma was filled for each patient at the time of visit and note was made of the factors that were responsible for non-compliance. Overall mean (ÂąSD) age was 29.1 Âą16.9 years (ranging from 6 to 60 years) with Male: Female = 1.9: 1. Most common reason for non compliance was high cost of antiepileptic drugs 126 (62.1%) followed by unemployment in 58 (28.6%) patients, more than one antiepileptic drug in 35 (17.2%) patients, side effects of antiepileptic drugs 19 (9.4%), freedom free periods from fits 18 (8.9%), deviation from prescription 13 (6.4%) and Non Availability of drugs 12 (5.9%). Conclusion: In this study, high cost of antiepileptic drugs was the most common reason for non compliance and non-availability of drugs was the least common reason. While unemployment was the second common reason for non-compliance Key Words: Epilepsy, AED, non-compliance, epileptic seizure INTRODUCTION

and perceptions and beliefs), illness-related factors (e.g., severity of illness and frequency of symptoms), medication-related factors (e.g., number of daily doses, efficacy, and side effects), and physician-related factors (e.g., patient-physician relationship).3 Research regarding patient adherence to AEDs has focused largely on the impact of the patient physician relationship on adherence and potential education programs intended to improve adherence. Findings suggest that patients tend to be more adherent when physicians have open dialogue regarding epilepsy and its treatments and when patients are comfortable speaking with their physician.4 Due to the paucity of published studies on non adherence among patients with epilepsy, this study investigates the factors associated with non-adherence to AEDs and help in taking possible measures to improve antiepileptic drug compliance and prevent consequences of uncontrolled seizures. The prevalence of epilepsy in Pakistan is about 9.99/1000. Highest prevalence is seen in people younger than 30 years of age. Higher prevalence is observed in rural population. Only 27.5% epileptic persons in urban areas and 1.9%

In medicine, by the word compliance we mean how much a patient behaves in accordance with medical advice regarding medication usage, modification of lifestyle and follow up visits to the attending physician. With respect to drug therapy, compliance is defined as the degree of correspondence of the actual dosing history with the prescribed drug regimen.1 Epilepsy is one those chronic conditions where failure to comply with treatment regimen leads to two major consequences: an unfavorable and unwanted health outcome for the patient and an increase in health care costs. Negative health outcomes include loss of seizure control with resultant injury, increased morbidity and even death. An increase in health care cost is attributed to an increase in physician office visits, emergency room care and/or hospitalizations, and a decrease in productivity (e.g., missing school and work).2 Studies regarding adherence have found four primary factors associated with medication non-adherence: patientrelated factors (e.g., socio-economic characteristics,

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taking other medicines). Mean and standard deviation was computed for quantitative variables like age. Stratification was done on age, gender and education status to see the effects on outcome.

in the rural areas were treated with antiepileptic drugs.3 When treating epilepsy, the ideal is to achieve complete seizure control if compliant; up to 70 per cent of people with epilepsy can expect to become seizure free with optimal AED therapy.5

Results

Methods

A total of 203 diagnosed cases of epilepsy were included in this study. Of 203 cases of epilepsy, 133 (65.5%) patients were male and 70 (34.5%) female (Male: Female = 1.9: 1). (Table-1)

This was a cross-sectional study carried out at the Department of Neurology, Dow University of Health Sciences and Civil Hospital Karachi. All the patients with epilepsy attending Neurology outpatient Clinic between a period of six months extending from February 2010 to August 2010 were analyzed and study group was selected according to the predetermined inclusion and exclusion criteria. In addition to demographic data, factors responsible for non compliance were assessed with the help of a structured proforma designed specifically for this purpose. In this cross-sectional study, a total of 203 patients with epilepsy, attending Neurology Outpatient Clinic at Civil Hospital Karachi during a period of six months extending from August 2010 to February 2011 were included. Non probability, purposive sampling technique was applied. Detailed history was taken from each patient. A structured proformas was filled for each patient at the time of visit to note the factors that were responsible for non-compliance. Following is Patient Inclusion Criteria •

• • •

Gender n Gender % Male 133 Male 65.5 Female 70 Female 34.5

•

Diagnosis of idiopathic epilepsy irrespective of the duration of disease and have been prescribed antiepileptic drug by a physician with a proper prescription Patients skipping at least one dose of antiepileptic drug in a week. Or missing the dose infrequently but missing resulting in seizure. Age: 06 to 60 years either male or female.

65.5 34.5

Education level of participants was also noted .The majority of patients were illiterate 101(49.8%), 82 (40.4%) participants were educated up to matric, 18 (8.9%) were intermediate and only 2 (1%) patients were graduate. (Table-2) Education Level n Level% Education Illiterate 101 49.8% Illiterate MatricMatric 82 40.4% Intermediate 8.9% Intermediate18 Graduation 1.0% Graduation 2

Patients with symptomatic epilepsy Diagnosed case of chronic renal or hepatic failure or any other metabolic disorder that would have impaired the concentration of AED. Patients who were given inadequate dosage or inadequate instructions by their physicians.

101 82 18 2

49.8% 40.4% 8.9% 1.0%

Most common reason for non compliance was high cost of antiepileptic drugs 126 (62.1%). Fifty eight (28.6%) patients had poor drug compliance because they were not employed consequently do not have enough money to buy medicine, 35 (17.2%) patients skipped from timely dose because they were prescribed more than one antiepileptic drug followed by side effects of antiepileptic drugs 19 (9.4%), freedom from fits 18 (8.9%), deviation from prescription 13 (6.4%) and Non Availability of drugs 12 (5.9%) (Table-3)

Data was analyzed on SPSS version 14.0. Frequencies and percentages were computed for qualitative variables, gender, age group, educational status and factors leading to non-compliance (e.g high cost, unemployment, kept on more than on drug, side effects, freedom from fits, deviation from prescription, non availability of drugs, personal belief-taboos and

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The mean age of patients attended Department of Neurology, Civil Hospital Karachi was 29.1 ±16.9 years and their age ranged from 6 years to 60 years. Majority 83 (40.9%) of cases had age between 5 – 20 years. (Figure-1)

Patients with following criteria were excluded • •

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Factors n (%) Gender High CostFactors 126 (62.1) Male Female Unemployment 58 (28.6) n(%) n(%) Kept on more than on drug 90 35 (17.2) 36 Side 19 (9.4) HighEffects Cost (71.4) (28.6) Freedom from fits 18 (8.9) Non Availability of 6 6 Deviation 13 (6.4) (50) drugs from Prescription (50.0) Non Availability of drugs 12 (5.9) 4 7 Personal Personalbelief-taboos belief-taboos 11 (5.4) (36.4) (63.6) Taking other medicines 5 (2.5) 12 6 Freedom from fits (66.7) (33.3) 57 1 Unemployment (98.3) (1.7) 11 8 Side Effects (57.9) (42.1) 2 3 Taking other medicines (40.0) (60) Kept on more than on 17 18 drug (48.6) (51.4) Deviation from 5 8 Prescription (38.5) (61.5)

When reasons for noncompliance were cross tabulated against different age groups, Unemployment (44.8%) was found most prominent reason of poor drug compliance in age groups 21-40 and 41-60. Personal belieftaboos (45.4%) was associated with younger age group 5-20. (Table-5) Factors Age Group (Years) Age Group (Years) Factors 05-20 41-60 05-20 21-40 41-60 21-40 51 High Cost 51 (40.47%) 3636 (28.5%) 39 3 9 High Cost (40.47%) (28.5%) (30.9%) (30.9%) Non Non Availability of drugs 44 (33.3%) 5 5 (41.6%) of 3 (25%) 3Availability (25%) (33.3%) (41.6%) drugs Personal belief-taboos 5 (45.4%) 2 (18.1%) 5 2 4 4Personal (36.3%) belief-taboos (45.4%) (18.1%) (36.3%) Freedom from fits 5 (27.7%) 7 (38.8%) 5 7 6 6Freedom (33.3%) from fits (27.7%) (38.8%) (33.3%) Unemployment 6 (10.3%) 26 (44.8%) 2 6 6 26 26 (44.8%) Unemployment (10.3%) (44.8%) (44.8%) Side Effects 15 (78.9%) 2 (10.5%) 2 15 2 2 (10.5%) Side Effects (78.9%) (10.5%) (10.5%) Taking other medicines 0.0% 0.0% 100.0% Taking other 0.0% Kept on more than on 0.0% drug 20 (57.1%)100.0% 6 medicines (17.1%) 9 (25.7%) Kept on more 20 6 9 Deviation 6 (46.1%) (25.7%) 5 than on from drug Prescription (57.1%) (17.1%) (38.4%) 2 (15.3%) Deviation from 6 5 2

In male patients most dominant reason for poor drug compliance was unemployment 57 (98.3%), followed by high cost 90 (71.4%), freedom from fits 12(66.7%), side effects 11 (57.9%) and non availability of drugs 6 (50%). (Table-4)

Prescription

Whereas in female patients the most prominent reason for poor drug compliance was personal belief â&#x20AC;&#x201C;taboos 7 (63.6%), followed by taking other medicines for other illness 3 (60%), deviation from prescription 8 (61.5%) and kept on more than one antiepileptic drug 18 (51.4%). (Table-4) Factors High Cost Non Availability of drugs Personal belief-taboos Freedom from fits Unemployment Side Effects Taking other medicines Kept on more than on drug Deviation from Prescription

Male n(%) 90 (71.4) 6 (50.0) 4 (36.4) 12 (66.7) 57 (98.3) 11 (57.9) 2 (40.0) 17 (48.6) 5 (38.5)

(46.1%)

(38.4%)

(15.3%)

Factors associated to noncompliance were also analyzed against education level of patients. Non availability of antiepileptic drug 9 (75%) was the major cause of poor compliance in illiterate patients. Unemployment 30 (51.7%) and high cost 61 (48.4%) were the main causes of non compliance in matriculate patients. (Table-6)

Gender Female n(%) 36 (28.6) 6 (50) 7 (63.6) 6 (33.3) 1 (1.7) 8 (42.1) 3 (60) 18 (51.4) 8 (61.5)

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Factors

High Cost Non Availabilit y of drugs Personal belieftaboos Freedom from fits Unemplo yment Side Effects Taking other medicine s Kept on more than on drug Deviation from Prescripti on

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No Educat ion 50 (39.7 %)

Interme diate

Grad uate

61 (48.4 %)

13 (1.6%)

2 (1.6 %)

9 (75% )

3 (25%)

0 (0%)

8 (72.7 %) 12 (66.7 %) 23 (39.7 %) 11 (57.9 %)

3 (27.3 %) 4 (22.2 %) 30 (51.7 %) 6 (31.6 %)

0 (0%)

2 (11.1%)

0 (0%)

5 (8.6%)

0 (0%)

1 (5.3%)

1(5.3 %)

2 (40% )

2 (40%)

1 (20%)

0 (0%)

19 (54.3 )

13 (37.1 %)

2 (5.7%)

1 (2.9 %)

6 (46.2 %)

5 (38.5 %)

2 (15.4%)

0 (0%)

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Discussion

from prescription (6.4%) and Non Availability of drugs (5.9%). A survey undertaken by Neurologists (n=661) in the USA10 revealed that 71% of patients with epilepsy forgot to take their AED (anti-epileptic drug) at least once per month and it was evident that the chance of a patient missing a dose increased with the number of tablets prescribed. Of patients that missed a dose 45% reported a seizure. Patients taking a larger number of tablets/capsules increased their odds of having a seizure after a missed dose by 43%. Similar results were reported in a recent UK study 12 which revealed that 59% of epilepsy patients had poor compliance and that this was related to an increased frequency of seizures. A study in Germany13 measured post-ictal serum levels of anti-epileptic medications and confirmed that in at least 44% of cases the seizure was related to poor compliance. A review of 10,892 epilepsy patients in a USA managed care system 14 revealed that poor adherence was associated with a 11% increase in hospitalization and a 47% increase in emergency admissions and as a consequence there was significantly increased healthcare costs. It is evident that if patientsâ&#x20AC;&#x2122; seizures are not controlled by one AED there may be no point changing to another if the reason for lack of efficacy is noncompliance. Studies have investigated a range of interventions, but improving compliance in chronic conditions such as epilepsy is a complex task.15 Clinical guidelines provide detailed recommendations about the importance of ongoing counseling, education and support for people with epilepsy16, and it is also essential to ask about practical problems that may reduce compliance, including any difficulties in taking the medicine, side-effects or inconvenient AED dosing. The number of daily doses is the most consistent predictor of noncompliance with AED treatment and an increased risk of seizure.10 The aim should be to move towards an easy-to-take once daily medication whenever possible. Opportunities to simplify the dosage of an AED are limited since the majority of these drugs must be taken twice or three times daily and the licensed indications of some once-daily drugs are limited.

Compliance with a prescribed medicine regimen is a ubiquitous problem not confined to the treatment of asymptomatic conditions. Despite this, the poor compliance in patients with epilepsy is somewhat surprising given that patients are aware of the serious consequences in terms of seizures and even death. In this context it is important that we look for ways to improve epilepsy patientsâ&#x20AC;&#x2122; adherence to the prescribed medication as a way of improving outcome. There are many factors that influence compliance in people with epilepsy but the frequency, type and severity of seizures do not in themselves appear to influence compliance rates.6 Irregular requests for repeat AED prescriptions, lack of response to appropriate therapy and an increase in seizure frequency may indicate non-compliance. It is, however, difficult to identify all patients who do not comply with their AED therapy. Health professionals should therefore be alert to the potential for noncompliance in all patients with epilepsy, enquiring nonjudgementally about medicine taking at each consultation and being prepared to support patients in complying with their treatment. In addition to the diagnosis of epilepsy in a considerable number of patients depressive mood changes exist. In those patients rates of adherence is reduced and requires special strategies for continuous treatment.7 The patients can have poor compliance if they do not understand the importance of taking their medication, if they experience side effects, feel stigmatized by their condition, have difficulty in swallowing their medication or have multiple doses.8 These issues can be multiplied if the patient is on multiple medications for concomitant conditions. Age can also be a factor with compliance being particularly poor in teenagers.9 Although non-compliance in epilepsy may be unintentional, most non-compliance with AEDs is intentional and results from conscious choices by patients.10 These decisions are based on patientsâ&#x20AC;&#x2122; beliefs about medicines in general that are affected by the experience of family and friends, culture, education, social circumstances, fears and anxieties and may be the result of an incomplete understanding of epilepsy and the proposed treatment. The result may be that patients are unsure that the benefits of AED treatment outweigh the perceived risks of taking medication. 11 In this study most common reason for non compliance was high cost of antiepileptic drugs (62.1%). (28.6%) patients had poor drug compliance because they were not employed consequently do not have enough money to buy medicine, 35 (17.2%) patients skipped from timely dose because they were prescribed more than one antiepileptic drug followed by side effects of antiepileptic drugs (9.4%), freedom from fits (8.9%), deviation

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Conclusion In this study, high cost of antiepileptic drugs was the most common reason for non compliance and nonavailability of drugs was the least common reason. While unemployment was the second common reason for non-compliance. These findings underscore the factors associated with and the impact of nonadherence in adult patients with epilepsy. Targeted epilepsy management programs and communication strategies are necessary to improve adherence and to avoid the clinical consequences of poor adherence.

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References 1. 2. 3. 4. 5. 6. 7. 8.

Urquhardt J. Role of patient compliance in clinical pharmacokinetics: review of recent research. Clin Pharmacokinet1994; 27: 202–215 Wirrell EC. Epilepsy-related injuries. Epilepsia 2006;47:79–86. Greenhouse WJ, Meyer B, Johnson SL. Coping and medication adherence in bipolar disorder. J Affect Disord 2000;59:237–41 Schachter SC. Epilepsy: quality of life and cost of care. Epilepsy Behav 2000;1:120–7. Harden CL, Goldstein MA. Mood disorders in patients with epilepsy: epidemiology and management. CNS Drugs 2002;16:291-302. Buck D, Jacoby A, Baker GA, Chadwick DW. Factors influencing non-compliance with antiepileptic drug regimes. Seizure 1997;6:87-93. Vergouwen AC, van Hout HP, Bakker A. Methods to improve patient compliance in the use of antidepressants. Ned Tijdschr Geneeskd, 2002;146:204-7 Carter S, Taylor D, Levenson R. A question of choice compliance in medicine taking. A preliminary review (2nd edition). London: Medicines Partnership 2003. Kerr M. Epilepsy and learning disability. In: Sander JW, Walker MC. Smalls JE (Eds). Epilepsy 2007: From Cell to Community, a Practical Guide to

10. 11. 12.

13. 14. 15.

16.

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Epilepsy. Eleventh edition. International League Against Epilepsy (UK Chapter) and the National Society for Epilepsy, London. Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy & Behavior 2002;3:338-42. WHO (World Health Organisation). Adherence to Long-Term Therapies: Evidence for Action. World Health Organisation, Geneva. 2003 Jones RM, Butler JA, Thomas VA. Adherence to treatment in patients with epilepsy: associations with seizure conrol and illness beliefs. Seizure 2006;15:504-8. Specht U. Postictal serum levels of antiepileptic drugs for detection of non-compliance. Epilepsy & Behavior 2003;4:487-95. Davis KL. Prevalence and cost of nonadherence with antiepileptic drugs in an adult managed care population Epilepsia. 2005;49:446-54. Haynes RB, Ackloo E, Sahota N. Interventions for enhancing medication adherence. Cochrane Database of Systematic Reviews 2008;2: CD000011 Stokes T, Shaw EJ, Juarez-Garcia A. Clinical guidelines and evidence review for the epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of Physicians, 2004.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Author’s contribution: Dr. Abdul Hafiz: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Naila N Shhabaz: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Jai Perkash: Data collection, data analysis, manuscript writing, manuscript review Dr. Muslim Lakhair: Data collection, data analysis, manuscript writing, manuscript review

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EFFICACY OF MEMANTINE ON COGNITIVE FUNCTIONS OF PATIENTS WITH MODERATE VASCULAR DEMENTIA Dr Saima Nazish,Dr Bashir A Soomro,Dr Shafaq Alvi

Neurology section, Department of Medicine. Ziauddin university hospital Karachi. Correspondence to: Dr Saima Nazish, Flat no G3 Fareed Terrace, sec 15A/5,Buffer Zone Karachi. Email:saima_nzsh@yahoo.com Date of Submission: September 05, 2014, Date of Revision: December 22, 2014, Date of Acceptance: December 29, 2014

ABSTRACT Introduction: Vascular dementia is a common condition for which there is no effective approved pharmacological treatment available. Absence of effective treatment creates a difficult situation for those suffering from the disease, their caregivers, and healthcare providers. The objective of this study is todetermine the Efficacy of Memantine on cognitive functions in patients with Moderate vascular dementia. Material and methods: This Case series study was carried out inthe Neurology Section of department of Medicine Ziauddin University and Hospitals North Nazimabad campus, Karachifrom 12th March 2010 to 11th March 2011.90 patients were included, who fulfilled the inclusion criteria after taking an informed consent. The SPSS version 11 was applied to the data. Results: There were 55 (59.1%) males and 38 (40.9%) females. Mean ± standard deviation age 69.7 ± 6.6 years, mean duration of symptoms was 1.76 ± 1.1 years. Baseline minimental examination score was 15.14 ± 3.1. Minimental score after 24 weeks of drug therapy was 17.14 ± 4.1. Efficiency was found in 62 (66.7%) patients. Conclusion: Memantine produced only a small benefit in cognition (of uncertain clinical significance) in patients with moderate vascular dementia. Data is insufficient to support widespread use of this drug in vascular dementia. Individual patient analysis is needed to identify subgroups of patients with vascular dementia who might benefit. Key words: Vascular Dementia, Treatment, Memantine, INTRODUCTION

daily life activity an behavioral symptoms(7). Further moreSeveral previous studies have shown that Anticholinesterase can benefit patients with vascular dementia or concurrent Alzheimers disease and cerebrovascular disease. A 28 weeks,randomized placebo controlled trial on efficacy and tolerability of memantine in the treatment of mild to moderate vascular dementia has shown, improvement of 1.8 plus minus 3.51 points in cognition scale over base line score in 60% with memantine compared with 52% with placebo group, p=0.227(4). As vascular dementia acounts for 15 to 20 percent of dementia cases worldwide and no effective treatment is available for it so, the aim of this study is to determine the effects of Memantine on cognitive functions of patients with vascular dementia. By knowing this we can prescribe drug to improve cognition in patients of vascular dementia. Therefore, our study will open new horizons in the era where dementia is considered untreatable . It will also be a positive addition to the available local data (9, 10) . So that it could be used in future, as there are only limited studies done on this topic.

Anticholinesterase and Memantine are Drugs, which specifically treat Alzheimers disease. Although these drugs do not halt the disease or reverse existing brain damage, they can improve symptoms and slow the progression of the disease(1). Many researchers are also examining whether these drugs may be useful for treating other types of dementia (1-3).Improvement of dementia symptoms in clinical trials are assessed in 3 domains. 1. Cognitive end point, cognition is measured by objective test. 2. Functional end point, that is activity of daily living 3. Global end point, overall clinical response is measured by Global assessment. Minimental state examination (MMSE) is an objective Tool that is used for screening and measuring out come in cognition enhancing drug trials. It has a good sensitivity and specificity in detecting cognitive impairment with different dementia syndromes along with good concurrent validity when compared to verbal and performance intellectual quocient of the adult intelligence scale(5). Some studies have confirmed the reliability and capacity of MMSE to measure cognitive improvement following treatment of depression(6) pooled trials of cholinesterase inhibitors identified an improvement of 1.4 point on MMSE over 6 months with simaltanous small but statistically significant improvements in

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MATERIAL AND METHODS This Case series study was conducted inout patient department of Neurology Section, Department of Medi-

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cine Ziauddin University and Hospital North Nazimabad campus, Karachi from 12th March 2010 to 11th March 2011. Sample size was calculated on the basis of proportion of previous studies, by using formula which includesp=60%,d=10%,1-alpha=95%,n=93 patients. Total 120 patients were enrolled, in order to compensate for dropouts,non probability purposive sampling technique was used. Inclusion criteria included patients of either gender of age being greater than 60 years, who fulfilled the DSMIV diagnostic criteria ofvascular dementia,and were graded as moderate vascular dementia on the basis of MMSE score ranging between 10-19 and with the duration of symptoms of more than 6 months.Patients with psychiatric illness ,history of stroke within prior 28 days or history of myocardial infarction were excluded from study. As these patients were deemed unable to make independent decision due to their decliningcognition, an informed consent was taken from their first kins and caregivers detailed explanation of the purpose of study, effects, side effects of the drug was provided. Patients were given Tab Memantine 10mg/day.then followed in out patient department by researcher herself for 6 months, at week 6, 12, 18 and 24. The dose was stepwise escalated to 20 mg/day according to patients response ( in terms of improvement in symptoms ) till maximum tolerable gastrointestinal side effectsoccured. Minimental scoring was done after completion of 6 months of drug therapy and this information was entered in performa by the researcher. Improvement of >1 point from the baseline minimental score was labeled as efficacy positive. The data feeding and analysis was done on computer package SPSS (Statistical Package for Social Science) version 11.0. The results were

computed as frequency and percentage for gender and efficacy, Mean and SD were used for age and duration of disease. Stratification was done with regared to age, gender and duration of disease to see the effect of these on the out come. RESULTS Ninety three patients fulfilling the inclusion criteria were included in this study. There were 55 (59.1%) males and 38 (40.9%) females (Figure I). Mean± standard deviation age 69.7 ± 6.6 years, mean duration of symptoms was 1.76 ± 1.1 years (Table I). Base line mini mental examination score was 15.14 ± 3.1 (Table I). Mini mental score after 24 weeks of drug therapy was 17.14 ± 4.1 (Table I). Symptomatic improvement was found in 62 (66.7 %) patients (Figure II). Mean age of male patients was 69 ± 6.3 years and mean age of female patients was 70.61 ± 7.0 years (Table II). Mean duration of male patients was 1.61 ± 0.99 years and mean duration of female patients was 1.97 ± 1.26 years. (Table II). Mean base line mini mental examination score of males was 15.33 ± 3.1 and mean base line mini mental of females was 4.87 ± 3.1 (Table II). Mini mental examination score after 24 weeks of drug therapy of males was 17.3 ± 4.2 and mini mental examination score after 24 weeks of drug therapy of females was 16.95 ± 3.94 ( Table II). Mean age of patient in whom drug was effective was 69.7 ± 6.8 years, mean duration of symptoms 1.7 ± 1.1 years, mean base line mini mental examination score was 15.6 ± 3 and mini mental examination score after 24 weeks of drug therapy was 17.13 ± 4.09 (Table III).

TABLE I ANALYSIS OF DESCRIPTIVE STATISTICS Variable Age/years Duration of symptoms Baseline minimental examination score Minimental examination score after 24 weeks of drug therapy

Minimum 61 1 9

Maximum 87 6 19

Mean 69.7 1.8 15.1

Std. Deviation 6.6 1.1 3.1

17.1

4.1

TABLE II ANALYSIS OF DESCRIPTIVE STATISTICS AMONG THE GENDER Gender Male Female p value

Age Mean SD Mean SD

69 6.3 70.6 7 0.483

Duration of symptoms 1.6 1 2 1.3 0.040

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Baseline minimental examination score 15.3 3.1 14.9 3.1 0.266

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TABLE III ANALYSIS OF DESCRIPTIVE STATISTICS AMONG THE EFFICACY Symptomatic improvement Yes Mean SD No Mean SD p value

Age 69.7 6.8 69.7 6.4 0.808

Duration of symptoms 1.7 1.1 1.8 1.2 0.775

Baseline minimental examination score 15.6 3 14.2 4 0.002

DISCUSSION

Minimental examination score after 24 weeks of drug therapy 18.1 3.7 15.3 4.2 0.057

analysis showed significant improvement in cognitive functions from baseline over placebo with no change inclinical global scale (16). An other pooled analysis of 6 months clinical trial showed cognitive improvement (using the ADAD-cog). patientswho receivedMemantine, had statistically significant better outcome and mild adverse effects.(17). A study of Memantine/chEI combination therapy had similar results and Conclusion(18). On basis of these studies one can conclude that memantine has a potential to treat vascular dementia but at the same time they also indicate that there is inadequate data available in this regard and further studies are needed to consider.

Vascular dementia is the second most common cause of dementia after Alzheimers disease in aging population (9). It is a heterogenous condition including single large infarct,multiple small infarcts along with diffuse whitematter ischemic lesions (12). It is evident that stroke risk factors such as Hypertension, Diabetesmelitis, Myocardialinfarction and Smoking have a contributory effect on Alzheimers disease and there is also an overlap in pathphysiology of both Alzheimers and vascular dementia (13, 14). Memantine produces its effect by being aN methyl D Aspartate receptor antagonist. Since NMDA Receptor mediated excitotoxic nerve cell death, is considered to be of paramount importance in ischemic cell death. It is alsoneuroprotectiveand consider potentialy therapeutic in many neuropsychiatric diseases as well(15).

FIGURE II ANALYSIS OF SYMPTOMATIC IMPROVEMENT SYMPTOMATIC IMPROVEMENT

FIGURE I ANALYSIS OF GENDER

In our study we did not find statistically significant improvement in cognitive function of patients with moderate vascular dementia. On further review of literature it has been observed that there are relatively few studies on the treatment of vascular dementia with several compounds of different mechanism of actions that showed mild efficiency in cognitive functions of these patients.So probably its not only cytotoxic cell death, but a number of other different mechanisms which play role in etiopathgenesis of vascular dementia.Micro array analysis of messenger RNA for monitoring of behavior of large number of genes may also reveal complex cascade of reactions for regulation of nerve cell susceptibility to injury(19). In future otherneuroprotective drugs with simultaneous targeting effects on multiple events related to cell death and

It has been approved by FDA as monotherpy and in combination with anticholinesterase for moderate to severe Alzeimers disease. On the basis of overlap in pathophsiology of Alzheimers disease and vascular dementia,its considered quite promising to use Memantinefor later. A 28 weeks placebo based triall tested Memantinein dose of 20 mg/day dose.Data

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certain transcription related genes are expected to be very effective in treatment of vascular dementia.

CONCLUSION 10.

Memantine produces small benefits in cognition of uncertain clinical significance in patients with mild to moderate vascular dementia. Data is insufficient to support widespread use of this drugs in vascular dementia. Individual patient analysis is needed to identify subgroups of patients with vascular dementia who might benefit from it.

11. 12.

REFERENCES 1.

4. 5.

6. 7. 8.

13. Raschetti1R, Emiliano Albanese1, Nicola Vanacore1, Marina Maggini1. Cholinesterase in hibitors in mild cognitive impairment: a systematic review of randomized trials. PLoS Medi Nov 2007;4(11):338. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomized controlled trials. Lancet Neurol 2007 Sep;6(9):7 82-92. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, Rivastigmine for dementia associated with parkinson’s disease N Eng J Med Dec9,2004 ;351:2509-18. Zekry D. Is it possible to treat vascular dementia? Front NeurolNeurosci. 2009;24:95-106. FolsteinMF, Folstein SE,MC HughPR. Minimental state A practical mthod for grading the cognitive state of patients for clinician. JPychiat Res 1975 ;12(3): 189-98 Nelson A, FogelBS, FaustD. Bedsie cognitive screening instrument, A critical Assessment. J NervMent Dis 1986;74(2):73-85. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006. Orgogozo JM, Rigaud AS, StöfflerA. Efficacy and safety of memantine in patients with mild tomoderate

14. 15.

16. 17. 18.

19.

vascular dementia. Stroke 2002;33:1834-9. Kaiser F. Frontal temporal dementia (FTD) in a charsada family.Pak J Med Res Oct - Dec 2004; 43(4):211-2. Numan A, Nasrullah M.Efficacy and safety of ivastigmine - an acetylcholinesterase inhibitor for the treatment of patients with Alzheimer's Disease. Pak J Neurol Dec 2000;6(1-2):3-7. Román GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci. 2002 Nov 15;203-204:7-10. Catherine McVeigh and Peter Passmore. Vascular dementia: prevention and treatment. ClinInterv-Aging. Sep 2006;1 (3): 229–235. Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors; a review.Int J Stroke. 2012; Jan;7(1):61-73. Korczyn AD. Is Alzheimer's disease a homogeneous disease entity? J Neural Transm. 2013 Oct;120 (10):1475-7. Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. ClinInterv Aging. 2009;4:367-77. Areosa SA, Sherriff F, McShane R. 2005. Memantine for dementia.Cochrane Database Syst Rev, C Info: CD003154 Mobius HJ, Stoffler A. Memantine in vascular dementia. Intpsychogeriatr 2003; 15Suppl 1:207–213. H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascu lar dementia: a metaanalysis of randomized controll ed trials. Lancet neurol. 2007;6(9):782–792. Baskys A, Blaabjerg M. 2005. Understanding regulation of nerve cell death by mGluRs as a method for development of successful neuroprotective strategies. J NeurolSci, 229-230:201-9.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Author’s contribution: Dr. Saima Nazish: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Bashir A Soomro: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Shafaqalvi: Data collection, data analysis, manuscript writing, manuscript review

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POST STROKE DEMENTIA AND ITS PUTATIVE RISK FACTORS: A HOSPITAL-BASED STUDY Iranmanesh F1, Sheykholeslami NZ2, Rahimdel A3, Gadari F4, Vazirinajad, R5, Syedyazdi F5,

Professor of Neurology, Neurology Research Center, Kerman University of Medical Sciences, Kerman, Iran. Associate Professor of Infection Disease, Qum University of Medical Sciences, Qum, Iran. 3 Assistant Professor of Neurology, Yazd University of Medical Sciences, Yazd Iran. 4 Kerman University of Medical Sciences, Kerman, Iran. 5 Associate professor of Epidemiology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 6 Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 1 2

Correspondence to: E- mail fpp_farhad@yahoo.com Date of Submission: July 17, 2014, Date of Revision: October 29, 2014, Date of Acceptance: November 5, 2015

ABSTRACT Introduction: Dementia is common after stroke and has a considerable impact on mortality, rehabilitation and quality of life. There are some published articles regarding post stroke dementia but there are many controversies surrounding this topic. Our aim was to identify the prevalence of post stroke dementia 3 months after stroke and evaluation of some its putative risk factors in Iranian population. Method: In this cross-sectional study, 151 patients with acute stroke were evaluated. The diagnosis was confirmed by physical examination and neuroimaging. Three months after the stroke, all patients were visited again. The diagnosis of post stroke dementia was made according to the criteria in the DSM-IV. Demographic data were collected using a questionnaire and data about lesion location and kind of stroke were obtained according to neuroimaging. To analyze the data, descriptive statistics, and chi-square test were used. Results: In our study, 47% patients were male and the rest were female. Thirty five (23.2%) of patients had post stroke dementia(PSD) after 3 months. 70.6 % of patients were 60 years old or more. 88.7% of patients had ischemic infarction and the rest had hemorrhagic stroke . The most frequent lesion locations were temporal, frontal and parietal lobes respectively., There was no significant statistical difference between PSD and sex, age, educational status, lesion location and kind of stroke. Conclusion: Our results show that a significant portion of patients with stroke are prone to PSD. The risk of dementia occurring after a stroke does not seem to be influenced by the stroke type. Key words: Dementia, Stroke, Risk factor INTRODUCTION

factors. Some demographic, genetic and lesion-related radiological factors have been reported to predict dementia in stroke patients, but there has not been a consensus about them (10, 11). Realizing the importance of research in this filed and lack of any published studies about PSD from Iran , we decided to evaluate the prevalence of PSD and some of its putative risk factors. To our knowledge, this is the first hospitalbased study among Iranian population about PSD.

Stroke is one of the most leading causes of mortality and disability in the world. (1) Many patients are left with residual cognitive deficits such as personality disorders, depression and memory loss after acute phase of stroke (2, 3). Post stroke dementia (PSD) is the second most common cause of dementia (4) and one of the main causes of dependency in survivors and includes any dementia after a stroke, irrespective of its cause (5). In Europe and North America, Alzheimer's disease predominates over PSD in a 2:1 ratio; in contrast, in some Asian countries PSD accounts for almost 50% of all dementias (6). Its prevalence ranges from 6 to 32% (7) and it has been found to be higher than previously expected, and a stroke increases the risk of dementia 4 to 12 times (8). The diagnosis of PSD is based on the patient history, the clinical evaluation and neuroimaging (9) , and it is associated with high rates morbidity and mortality (2). Then, it is important to determine its risk

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METHODS 1. Subjects This cross-sectional study was conducted on 151 patients with first-ever stroke in Rafsanjan (south of Iran). Patients with a clinical suspicion of stroke underwent neuroimaging (CT scan and MRI) and the diagnosis was confirmed by them. All patients with history of any underling disease especially dementia and mild cognitive

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CONCLUSION

impairment were excluded from the study except patients with ischemic heart disease (IHD), diabetes (DM), hypertension (HTN) and hyperlipidemia (HLP). Other exclusion criteria were history of opium or other substance addiction, inadequate vision and hearing, aphasia any drug consumption (except drugs were used for treatment of IHD, DM, HTN, HLP) such as antipsychotic and anti depressant. The ethics committee of Yazd branch of Islamic Azad University had confirmed the research.

In our hospital-based study prevalence of PSD was 23.2 % . This finding shows that a significant portion of patients with stroke are prone to PSD. We did not find any published article about PSD concerning the Iranian population; it seems that in Iranian population, our study is the first in this field but many studies have been conducted in other countries. Prevalence of PSD is reported to be between 7% and 41%, (10). Some studies show the same frequency of PSD as our study, such as those conducted in Italy (24.6%) and America (26.3%) (12,13 ) where as others show lower prevalence such as Portugal( 5.9% ) and Taiwan( 9.2%) (14, 15) or higher in Finland (31.8%) (16). In a systematic review ,the prevalence of post stroke memory dysfunction varied from 23% to 55% 3 months post stroke, which declined from 11% to 31% 1 year post stroke.(17 ). The prevalence of dementia among people with a history of stroke is similar to that observed in subjects 10 years older without a history of stroke (18). Also, several studies have confirmed that stroke doubles the probability of developing dementia and that risk is higher in the first 6-12 months and in a community based study done over 25 years, the cumulative incidence of PSD was 7% after 1 year, 10% after 3 years, 15% after 5 years, 23% after 10 years, and 48% after 25 years (19 ) These discrepancies may be related to different population studies, different criteria used for the diagnosis of dementia and different time interval between stroke and the neuropsychological assessment (20). Although, stroke was recognized as an important cause of dementia more than a century ago (21) , many aspects of PSD pathophysiology are not clear. The causes of PSD are multifactorial and involve neuronal networks needed for memory (22). Disturbance in some neurotransmitters (6), genetic factors (23), direct neuronal damage and impaired vascular autoregulatory mechanisms are some factors involved in PSD patophysiology. (2, 24, 25) Our results showed that PSD can be seen in both ischemic and hemorrhagic lesions. The risk and severity of cognitive disturbances occurring after a stroke do not seem to be influenced by type of stroke (ischemic or hemorrhagic) (8, 13, 14). In most studies such as ours, no gender specifity was observed (15,21) . Similarly, many studies did not find any relationship between location of the vascular lesion and PSD (14,15,21) . Higher educational attainment has been found to be a protective factor for PSD (5) however, we could not ascertain this effect in our study and neither could the research performed in Spain (21). Although we did not find a relationship between age and dementia, some have studies suggested an association between the two (11, 21). It should be mentioned that controversies about age, sex, location of lesion and educational

2. Clinical characteristics Following information was collected for each patient: baseline demographics (age, gender and educational status), stroke type according to Oxfordshire Community Stroke Project Classification. The subjects were screened for PSD using the DSM-IV at three months. 3. Statistical analysis To analyze the data, descriptive statistics, and chi-square test were used and pâ&#x2030;¤0.05 was considered statistically significant. RESULTS In our study, 71(47%) patients were male and the rest were80 (53%) female. Mean age of men and women were 65.5 and 66.5 years, respectively. 35 (23.2%) patients had PSD after three months. 70.6 % of patients were 60 years old or more. 88.7% of patients had ischemic infarction and the others had hemorrhagic stroke. The most frequent lesion locations were temporal, frontal and parietal lobes respectively. There was no significant statistical difference between PSD and sex, age, educational status, lesion location and kind of stroke. (Table 1) PSD Variable Sex

Yes N( % ) 18(25.35) 17(21.25) 10(22.73) 14(13.9 ) 13(30.23) 8(26.66) 4(16) 3(27.27) 1(5) 6(27.27)

M F Age 59 or less 60 or more Lesion location Temporal Frontal Parietal Occipital Infratentorial More than one location Educational status Illiterate 7(25) Elementary 10(23.25) Diploma 7(20) Associates degree 5(22.72) Bachelor 5(23.80) Master or higher 1(50 ) Kind of stroke Ischemic 29(21.64) Hemorrhagic 6(35.29)

No N( % ) 53(74.64) 63(78.75) 34(77.27 ) 93(86.91 ) 30(69.76) 22(73.33) 21(84) 8(72.73) 19(95) 16(72.72)

P value 0.355 0.511 0.292

21(75) 0.957 33(76.74) 28(80) 17(77.27) 16(76.19) 1(50 ) 105( 78.58) 0.209 11(64.70)

Table1: Frequency of risk factors in patients

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status are frequent(7 ,11), and some factors such as dysphasia, hemiparesis, hemianopia (10), silent infarcts, cortical cerebral atrophy (26) medial temporal lobe atrophy and white matter changes , have been associated with an increased risk to develop PSD in some studies(19). Our study had some limitations. First, our study was a cross-sectional study. Second; we fallowed the patients only three months. Third, patients with aphasia were excluded from our study. These limitations may have some effects on the results. In conclusion, our study showed high prevalence of PSD in Iranian population. Both ischemic and hemorrhagic lesions have a similar effect on PSD and early recognition and treatment of PSD risk factors will definitely improve the quality of life of the patients.

11- Klimkowicz-Mrowiec A, Dziedzic T, Słowik A, Szczudlik A. Predictors of poststroke dementia: results of a hospital-based study in poland. Dement Geriatr Cogn Disord. 2006;21(5-6): 328-34. 12- Lindén T, Skoog I, Fagerberg B, Steen B, Blomstrand C. Cognitive impairment and dementia 20 months after stroke. Neuroepidemiology. 2004 ;23 (1-2):45-52. 13- Desmond DW, Moroney JT, Paik MC, Sano M, Mohr JP, Aboumatar S, Tseng CL, Chan S, Williams JB, Remien RH, Hauser WA, Stern Y. Frequency and clinical determinants of dementia after ischemic stroke. Neurology. 2000;14;54(5):1124-31. 14- Madureira S, Guerreiro M, Ferro JM: Dementia and cognitive impairment three months af ter stroke. Eur J Neurol 2001; 8: 621–627. 15- Lin JH, Lin RT, Tai CT, Hsieh CL, Hsiao SF,Liu CK: Prediction of poststroke dementia. Neurology 2003;61: 343–348. 16- Pohjasvaara T, Erkinjuntti T, Ylikoski R, Hietanen M, Vataja R, Kaste M: Clinical determinants of poststroke dementia. Stroke 1998;29:75–81. 17- Snaphaan L, de Leeuw FE. Poststroke memory function in nondemented patients: a systematic review on frequency and neuroimaging correlates. Stroke. 2007 ;38(1):198-203 18- De Ronchi D, Palmer K, Pioggiosi P, Atti AR, Berardi D, Ferrari B, Dalmonte E, Fratiglioni L: The combined effect of age, education, and stroke on dementia and cognitive impairment no dementia in the elderly. Dement Geriatr Cogn Disor 2007; 24:266-273 19- Pasi M, Poggesi A, Salvadori E, Pantoni L. Post stroke dementia and cognitive impairment. Front Neurol Neurosci. 2012;30:65-9. 20- Desmond DW, Bagiella E, Moroney JT, Stern Y: The effect of patient attrition on estimates of the frequency of dementia following stroke. Arch Neuro 1998;55:390-394 21- Pendlebury ST. Stroke-related dementia: Rates, risk factors and implications for future research. Maturitas. 2009 ;20;64(3):165-71 22- Igoumenou A, Ebmeier KP. Diagnosing and managing vascular dementia. Practitioner. 2012 ;256 (1747):13-6, 2. 23- Wagle J, Farner L, Flekkøy K, Wyller TB, Sandvik L, Eiklid KL, Fure B, Stensrød B, Engedal K. Association between ApoE epsilon4 and cognitive impairment after stroke. Dement Geriatr Cogn Disord. 2009;27(6):525-33. 24- Makin SD, Turpin S, Dennis MS, Wardlaw JM. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence

Acknowledgment: Authors thank the Yazd branch of Islamic Azad University for supporting this project. REFERENCES 1-

Delbari A, Salman Roghani R, et al. Stroke epidemiology and one-month fatality among an urban population in Iran. Int J Stroke 2011;6(3):195-200. 2- Ankolekar S, Geeganage C, Anderton P, Hogg C, Bath PM. Clinical trials for preventing post stroke cognitive impairment. J Neurol Sci. 2010 15;299 (1-2):168-74. 3- Stephens S, Kenny RA, Rowan E, Allan L, Kalaria RN, Bradbury M, Ballard CG. Neuropsychological characteristics of mild vascular cognitive impairment and dementia after stroke. Int J Geriatr Psychiatry. 2004 Nov;19(11):1053-7. 4- Erkinjuntti T. Diagnosis and management of vascular cognitive impairment and dementia. J Neural Transm Suppl. 2002;(63):91-109. 5- Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol. 2005 Nov;4(11):752-9. 6- Román GC. Facts, myths, and controversies in vascular dementia. J Neurol Sci. 2004 Nov 15; 226(1-2):49-52. 7- Hénon H, Pasquier F, Leys D: Poststroke dementia. Cerebrovasc Di 2006;22:61-70. 8- Barba R, Martinez-Espinoza S, Rodriguez Garcia E, Pondal M, Vivancos J, Del Ser T: Poststroke dementia: clinical features and risk factors. Stroke 2000; 31: 1494–1501. 9- Peters N, Dichgans M. Vascular dementia. Nervenarzt. 2010 Oct;81(10):1245-53; quiz 1254-5. 10- Pendlebury ST, Rothwell PM: Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neuro 2009;8:1006-1018.

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and comparison with other stroke subtypes. J Neurol Neurosurg Psychiatry. 2013 ;84 (8):893-900 25- Cumming TB, Brodtmann A. Can stroke cause neurodegenerative dementia? Int J Stroke. 2011 ;6 (5):416-24. 26- Desmond DW, Moroney JT, Paik MC, Sano M, Mohr JP, Aboumatar S, Tseng CL, Chan S, Williams JB, Remien RH, Hauser WA, Stern Y: Frequency and clinical determinants of dementia after ischemic stroke. Neurolog 2000;54:1124-1131 Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Authorâ&#x20AC;&#x2122;s Contribution: Dr. Iranmanesh F: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Sheykholeslami NZ: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Rahimdel A: Protocol writing, data collection, data analysis, manuscript writing, manuscript reviewmanuscript writing, manuscript review Dr. Gadari F: Data collection, data analysis, manuscript writing, manuscript review Dr.Vazirinajad R: Data collection, data analysis, manuscript writing, manuscript review Dr.SyedYazdi F: Data collection, data analysis, manuscript writing, manuscript review

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O R I G I N A L

A R T I C L E

RESTLESS LEGS SYNDROME IN PATIENTS WITH TYPE 2 DIABETES MELLITUS Shaista A. Siddiqi1, Javeria Rauf2, Anita Haroon3, Bilal Ahmed2, Saera Suhail Kidwai1 and Lubna Nazir1, Department of Medicine, Jinnah Medical College Hospital, Karachi, Pakistan Department of Medicine, Aga Khan University Hospital, Karachi 3 Department of Medicine, Jinnah Post Graduate Medical Centre, Karachi 1 2

Correspondence to: Shaista Anwar Siddiqi. Email-: ghaniasiddiqi@yahoo.com Date of Submission: September 16, 2014, Date of Revision: December 9, 2014, Date of Acceptance: December 28, 2014

ABSTRACT Objective: To determine the frequency of restless legs syndrome (RLS) and its associated factors in patients with type 2 diabetes mellitus. Design and Methods: It was single centered, cross-sectional study done with convenient sampling. The study population comprised 174 subjects (120 diabetics and 54 non-diabetics). Participants were recruited from the Diabetes clinic of Jinnah Medical College Hospital, Karachi. The relevant clinical and laboratory parameters were obtained by clinical history and chart review. Multivariable logistic regression was done to identify the factors of RLS among diabetics. Results: Using the International RLS Study Group (IRLSSG) criteria, RLS was identified only in 67(55.8%) subjects from the diabetic group. The mean age of RLS subjects was 56Âą8 years as compared to 46Âą8 years in the non-RLS subjects. Forty percent (26/67) of the diabetic/RLS+ subjects had diabetes for >10 years and had significantly deranged glycemic indices. Periodic limb movements during sleep (PLMS) as reported by the bed partner or close family member were reported by 32(26.7%) of the diabetic subjects only; of which 21(65.6%) subjects had RLS. Sleep disturbances were more frequent among patients with RLS as compared to non-RLS (61.2% versus 21.5%). According to Semmes-Weinstein filament test, 61% of diabetics and 67% of diabetic/RLS subjects had peripheral neuropathy. Interestingly, none of our subjects who were diagnosed as RLS was ever asked by their physician for symptoms of RLS prior to this study. Conclusion: RLS is a common problem among patients with type 2 diabetes mellitus and is associated with increasing age, peripheral neuropathy and impaired day time functioning. Poor recognition by physicians result in delayed diagnosis. Keywords: Restless leg syndrome (RLS), diabetes mellitus, polyneuropathy INTRODUCTION

and is found to be higher in women than in men. The intensity of sensory and motor symptoms generally tends to increase with advancing age. Alcoholics, smokers and selective serotonin reuptake inhibitor (SSRI) users as well as patients suffering from neuropathy are more likely to have RLS [2, 13-16]. Diabetes mellitus is a lifelong disease and a common cause of sensorimotor polyneuropathy [13]. However, previous studies on RLS in diabetic neuropathy yielded conflicting results with a prevalence rate ranging from 8.8 to 27%, not significantly different even from controls in some studies [11, 17-18]. Poor glycemic control with RLS may also impact the associated consequences of diabetes mellitus including sleep quality, sleep cycle alterations, fatigue, and depression [19]. Norma G et al reported that diabetic people at risk for RLS were at increased risk for obstructive sleep apnea and insomnia-sleep problems often reported in diabetes [19]. Montplasir et al reported significant association between RLS and Periodic Limb Movements during Sleep (PLMS) during sleep or while

Restless legs syndrome (RLS) is a chronic sensorimotor disorder [1-4]. RLS can either be primary or secondary. Primary or idiopathic RLS, diagnosed when clinical conditions responsible for secondary forms are excluded by laboratory and clinical examinations, accounts for about 70 -80% of all RLS cases [1,5]. Among secondary or symptomatic forms, several conditions such as iron deficiency anemia, uremia, pregnancy, polyneuropathy and type 2 diabetes mellitus have been implicated in association with RLS [6-11]. RLS has recently been characterized by The International Restless Legs Syndrome Study Group (IRLSSG) as a clinical syndrome presenting as a combination of intense desire to move the limbs associated with paresthesias/dysesthesias; motor restlessness; exacerbation of symptoms with inactivity and relief by activity; and a nocturnal worsening in the symptom [12]. According to the Western data, it affects approximately 7-11.5% of the adult population

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awake [20]. However, there is paucity of local data in this regard. We hypothesized that patients with type 2 diabetes mellitus will show a high frequency of RLS. Therefore, we sought to determine the frequency of RLS in subjects with type 2 diabetes mellitus and its associated factors especially sleep disturbances, daytime time functioning and PLMS. with non-adherence to AEDs and help in taking possible measures to improve antiepileptic drug compliance and prevent consequences of uncontrolled seizures. The prevalence of epilepsy in Pakistan is about 9.99/1000.

disturbance was defined as difficulty in falling asleep and awakening. Daytime sleepiness was assessed by Epworth Sleepiness Scale (ESS) which is a validated tool. A score of >10 was indicative of excessive daytime sleepiness. [13] Patients were considered to have daytime dysfunctioning when they have a subjective complain about it. Presence of PLMS as reported by the bed partner or close family member was ascertained as described in the literature i.e. periodic jerky movements causing flexion of the ankle, knee, or hip; occasionally accompanied by arousals from sleep, leading to sleep fragmentation and excessive daytime sleepiness [18].

METHODS Patient selection For this study, 120 consecutive subjects with type 2 diabetes mellitus who attended the diabetes clinic of Jinnah Medical Dental College Hospital, Karachi from July 2009 to July 2010 were recruited. Ethical approval for the study was taken from local ethics review committee of the hospital. The non-diabetic group consisted of 54 consecutive patients who attended the medical outpatient clinics for some seasonal illness during the study period with no sign/symptom of any chronic disease. We included all the subjects who were 30 years old or above, irrespective of the gender. We excluded all the patients who were known to have (or were being treated for) anemia, chronic liver disease, thyroid dysfunction, uremia and non-diabetic polyneuropathy. Similarly, pregnant women were excluded from the study as RLS is already expected to be more prevalent in this set of population. Patients who had a language barrier were also excluded to minimize the biases in clinical findings and ensure the authenticity of information. All the participants provided an informed consent. General Protocol Records were reviewed and patients were interviewed using a closed ended questionnaire regarding their demographic aspects, past medical history, family history and use of medications. In particular, we inquired about the clinical conditions which support RLS (such as iron-deficiency anemia, hypothyroidism, uremia, and rheumatoid arthritis) and about the drugs which could possibly worsen RLS symptoms (antidepressants or antipsychotics) or rather improve RLS symptoms (dopaminergic agents, benzodiazepines, and anticonvulsants such as gabapentin, carbamazepine, oxcarbazepine, and valproic acid). Moreover, both diabetic and non-diabetic subjects were specifically asked for: (1) disturbance of sleep (2) daytime sleepiness (3) daytime dysfunction; and (4) presence of PLMS. Sleep

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RLS Protocol In all the study subjects, a neurologist confirmed the presence of RLS using the criteria defined by the International Restless Legs Syndrome Study Group (IRLSSG) [12] . Only the patients who fulfilled all 4 criteria were considered affected by RLS and were further asked about the frequency, duration and intensity of the symptoms. Presence of RLS symptoms in first-degree relatives was established in both diabetic and nondiabetic subjects. Laboratory Data Laboratory data was obtained at the time of interview

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for complete blood count, creatinine, random and fasting blood glucose in all subjects and for serum ferritin and glycosylated hemoglobin (HbA1c) in 79 and 152 subjects respectively.

population along with 80 percent power, 0.05 significance level, 5 percent bond on error, and 5% adjustment for non-response rate. As previously reported by Rozina S et al, RLS was seen in around 10% of the general population.[7] Data was entered and analyzed using Statistical Package Social Sciences (SPSS) version 19.0. Initially descriptive statistics and frequencies and proportions were generated. Continuous variables were analyzed by t– test and categorical by chi-square or Fisher exact, where appropriate. Later stepwise multivariable logistic regression was done to identify factors related with RLS among diabetics.

Evaluation of polyneuropathy Distal sensory function was examined bilaterally using Semmes-Weinstein (SW) filaments as recommended by the World Health Organization and International Diabetes Federation for screening peripheral neuropathy in diabetic subjects [21]. The dorsal surface of the foot and the heel was tested in a random manner on 10 predetermined sites [21-22] with the filament pressed perpendicularly, for 1 second, and pressure enough to bend the filament. Patient’s response was noted on the basis of yes/no option. Those patients who were able to perceive at less than 6 points were considered to have neuropathy [21].

RESULTS General characteristics of the diabetic and non-diabetic subjects are presented in Table 1. Diabetic subjects were comparably elder as compared to the non-diabetic subjects. Also, there was a slight preponderance of male gender in the diabetic subjects. Presence of sleep disorders, PLMS and RLS, family history of diabetes mellitus and RLS, and higher glycemic indices were significantly frequent among diabetic subjects. Only 34% of the diabetic subjects had a value of HbA1c < 7%. Most of the patients (94%) were taking oral hypoglycemic agents, the rest were on insulin therapy. PLMS were reported by 32 (26.7%) diabetics’ subjects only; of whom 21(65%) subjects had RLS. Sixty seven of the 120 subjects with type 2 diabetes mellitus (55.8%) were diagnosed as having RLS (p < 0.05). Among these subjects, 28/67 (41.8%) had diabetes for < 5years, 26/67 (38.8%) for >10 years, while the rest of them (13/67; 19.4%) had diabetes for 5-10 years. The laboratory parameters of RLS subjects revealed higher values for the glycemic indices including random and fasting blood sugar; and HbA1c level (Table 2). Among RLS subjects, none reported a positive family history of any sleep disorder which was in contrast to 4 (3.7%) of the non-RLS subjects. Among the subjects who did not fulfill the RLS criteria (n;53) the individual RLS like complains were evaluated. Unpleasant sensation in the legs with urge to move them was reported in 42.8%, worsening during inactivity or rest in 25.6%, relieved by activity in 18.1% while nocturnal worsening was reported by 22.4% of non- RLS subjects. Among RLS subjects, the majority of the subjects were using overthe-counter analgesics (59/67; 88%). In univariate analysis, female gender, increasing age, clinical evidence of neuropathy, disturbance of sleep, daytime sleepiness, and impaired daytime functioning appeared as predictors of presence of RLS (Table 3). However, only advancing age, impaired daytime functioning and clinical evidence of neuropathy appeared as the predictors of RLS in multivariate analysis (Table 4). The multivariable

Statistical Analysis Sample size estimation: A sample size of at least 175 was required to estimate the proportion of RLS among diabetics, however there is no literature available in our region assuming 10-15% prevalence in the regional

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analysis showed that having impaired daytime functioning due to sleep disorder was 47 times more associated with RLS adjusting for other covariates (adjusted Odds Ratio (OR) 47; 95% CI 10.3-217). Likewise, odds of having RLS among those with an evidence of neuropathy were 15 times more than those without neuropathy (adjusted OR= 15, 95% CI = 3.8-58). Every one year increase in age showed a 20% increase in risk of having RLS after adjusting other variables (Adjusted OR= 1.2, 95% CI = 1.1-1.3). Interestingly, despite the high prevalence reported from the subcontinent, none of the non-diabetic subject suffered from either RLS or PLMS. To our surprise, none of the subjects who were diagnosed as RLS was ever asked by their physician for symptoms or diagnosis of RLS prior to this study.

those with an evidence of neuropathy were 15 times more than those without neuropathy (adjusted OR= 15, 95% CI = 3.8-58). Diabetic subjects who were affected by RLS described their symptoms as an urge to move their limbs while those who had clinical evidence of neuropathy described their symptoms as pain, electric, or burning (pricking) sensations. This is in accordance with previous results shown by Winkelmann et al and Merlino et al [4, 35] A part from neuropathy, iron deficiency anemia is a well known contributor towards symptomatic form of RLS.[10] Our iron studies have shown insignificant association between RLS/diabetic+ subjects and iron studies which was in accordance with results demonstrated by previous studies [4, 11] thus further pointing towards a lack of association. However, more clinic-pathological studies are needed to further verify this hypothesis. Significant number of RLS patients in our study reported sleep disturbance with daytime sleepiness and impaired daytime functioning which was consistent with results from previous studies on diabetic subjects. We found sleep disturbance to be associated with polyneuropathy and RLS. Similar correlation has been demonstrated by previous other studies [11, 14, 36-37] . Our study has shown a significant association between RLS and PLMS as the majority of the PLMS patients were suffering from RLS too. In addition to diabetes, studies have also reported a significant association of RLS with diseases such as hypertension which could be due to concomitant sleep disturbances in such patients [38-41]. Advancing age and polyneuropathy have been shown to be associated with an increased prevalence of RLS [18,28]. The multivariate analysis established this association in our subjects as well (Table 2). A large number of our non-RLS subjects were those who suffered from a combination of symptoms included in the IRLSSG diagnostic criteria but they however, failed to meet all 4 criteria to be defined as RLS. We assume that these patients might be a potential case of RLS and may be defined as possible or probable RLS later. We propose that this criterion might be revised to take into account these large number of potential RLS patients so that early diagnosis and thus early identification of risk factors and their treatment might help them to enjoy a better quality of life. Interestingly, none of the non-diabetic subject suffered from either RLS or PLMS. Most importantly, none of our RLS subjects were ever asked by their physician for symptoms or diagnosis of RLS prior to this study. This may be because of the poor awareness of RLS among physicians as well.

DISCUSSION The reported prevalence of RLS in general population by Western countries ranges between 5-15% [23] whereas data from Asian countries has reported a lower prevalence (1.5% in Japan [24], 1% in Singapore [25], 3.19% in Turkey [26]). Recently, higher prevalence rate i.e. 9.71% [27] has been reported by a Turkish study but their study population included subjects aged 40 years and above. Population based studies have found higher prevalence rates of RLS among subjects with advanced age, increased body mass index, smoking and diabetes mellitus [28,29]. Such varied differences in ranges might be due to the reason that some have heterogeneity in study design, study population and sample size. With no local data in this regard from Pakistan, this is the first Pakistani study confirming significant association between RLS and type 2 diabetes mellitus. The frequency of RLS in our diabetic subjects (55.8%) is significantly higher than compared to the international literature. Merlino et al diagnosed the RLS on the basis of International RLS Study Group criteria and reported a prevalence of 17.7% in their study population of diabetic subjects [4]. Lopes et al reported a comparatively higher frequency of RLS in 27% of the diabetic subjects [18] , which is still lower than the frequency we found in our cohort. Peripheral neuropathy has been postulated to be associated with the pathogenesis of RLS. Qu S and Jensen et al have hypothesized that RLS in diabetic subjects could be due to the concurrence of decreased inhibitory dopaminergic control on the dorsal horns of the spinal gray matter [30-31] with the excitatory nociceptive inputs due to the peripheral neuropathy [32]. Various clinical studies have reported a significant association between RLS and polyneuropathy [8,33,34]. However, Skomro et al reported an insignificant association between RLS and diabetic polyneuropathy (p-value: 0.78) [11]. In our study, odds of having RLS among

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LIMITATIONS Our study was a single centered study so results cannot be generalized over the whole population. Ideally the

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patients who are suspected to have neuropathy by SW monofilament testing should undergo a standard nerve conduction study â&#x20AC;&#x201C;the gold standard for the confirmation of neuropathy. Also, PLMS needs to be diagnosed with standard polysomnography.

Hence, nerve conduction study (NCS/EMG) is not an economically pliable tool for the diagnosis of sensory neuropathy in our general community. So, SW filament utility has again come up in our study as a useful tool. CONCLUSION RLS is a common problem among patients with type 2 diabetes mellitus and is associated with increasing age, peripheral neuropathy and impaired day time functioning. Its diagnosis is often delayed because of poor recognition by the physicians. Early diagnosis may result in improved quality of life of these patients. Considering a substantial number of subjects with one or more symptoms suggestive of RLS in the non-RLS group, further studies with larger sample size are needed to establish the importance of individual symptoms to guide the investigation and the therapy in this sub-set of patients. REFERENCES 1.

2. STRENGTHS

This will be the first study from Pakistan which has addressed the frequency of RLS and its association with diabetes mellitus. Therefore, the results of this study are important as they provide the insight into this important and potentially treatable medical disorder in the local perspective. In addition to results shown above, our study has also shown the utility of SW monofilament in screening for the presence of sensory neuropathy. This is important in view of World Health Organization (WHO) report which has stated that 32% of the Pakistani population lives below poverty line.

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Bosco D, Plastino M, Fava A, Ettore M, Bosco F, Ermio C, Tallarigo F, Pirritano D, Consoli D. Role of the Oral Glucose Tolerance Test (OGTT) in the idiopathic restless legs syndrome. J Neurol Sci. 2009;287(1-2):60-63. Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev. 2006;10(3): 153-167. Pascale VS, Damien C, Karine D, Christine B, Philippe B and Richard T. Is restless legs syndrome under recognized? Current management. Joint Bone Spine. 2006;73(4);369-373. Merlino G, Fratticci L, Valente M, Del Giudice A, Noacco C, Dolso P, Cancelli I, Scalise A, Gigli GL. Association of restless legs syndrome in type 2 diabetes: a case-control study. Sleep. 2007;30 (7):866-871. Merlino G, Valente M, Serafini A, Fratticci L, Del Giudice A, Piani A, Noacco C, Gigli GL. Effects of restless legs syndrome on quality of life and psychological status in patients with type 2 diabetes. Diabetes Educ. 2010;36(1):79-87. Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-Strambi L, Granieri E. Restless legs syndrome and pregnancy. Neurology. 2004;63(6):1065-1069. Sikandar R, Khealani BA, Wasay M. Predictors of restless legs syndrome in pregnancy: a hospital based cross sectional survey from Pakistan. Sleep Med. 2009;10(6):676-678. Nineb A, Rosso C, Dumurgier J, Nordine T, Lefaucheur JP, CreÂ´ange A. Restless legs syndrome is

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frequently overlooked in patients being evaluated for polyneuropathies. Eur J Neurol. 2007; 14(7) : 788â&#x20AC;&#x201C;792. Gigli GL, Adorati M, Dolso P, Piani A, Valente M, Brotini S, Budai R: Restless legs syndrome in end-stage renal disease. Sleep Med. 2004; 5 (3) : 309-315. O'Keeffe ST, Gavin K, Lavan JN: Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23(3):200-203. Skomro RP, Ludwig S, Salamon E, Kryger MH. Sleep complaints and restless legs syndrome in adult type 2 diabetics. Sleep Med. 2001;2(5) : 417-422. Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4 (2):121-132. Lopes LA, Lins Cde M, Adeodato VG, Quental DP, de Bruin PF, Montenegro RM, Jr., de Bruin VM. Restless legs syndrome and quality of sleep in type 2 diabetes. Diabetes Care. 2005;28(11):2633-2636. Cuellar NG, Ratcliffe SJ. Restless legs syndrome in type 2 diabetes: implications to diabetes educators. Diabetes Educ. 2008;34(2):218-234. Ohayon MM, Roth T. Prevalence of restless leg syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002; 53 (1) :547-554. Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. Chest. 2006;130(5):1596-1604. Gemignani F, Brindani F, Vitetta F, Marbini A, Calzetti S. Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy. J Peripher Nerv Syst. 2007;12 (1) : 50-53. Cuellar NG, Ratcliffe SJ. A Comparison of Glycemic Control, Sleep, Fatigue, and Depression in Type 2 Diabetes with and without Restless Legs Syndrome. J Clin Sleep Med. 2008;4(1):50-56. Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997; 12(1) : 6 1-65. Lee S, Kim H, Choi S, Park Y, Kim Y, Cho B. Clinical Usefulness of the Two-site Semmes-Weinstein Monofilament Test for Detecting Diabetic Peripheral Neuropathy. J Korean Med Sci. 2003; 18(1) : 1 03-7. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG: Choosing a Practical Screening Instrument

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of 300 patients. Sleep. 2000;23(5):597-602. 35. Kawakami N, Takatsuka N, Shimizu H. Sleep disturbance and onset of type 2 diabetes. Diabetes Care. 2004;27(1):282-283. 36. Resnick HE, Redline S, Shahar E, Gilpin A, Newman A, Walter R, Ewy GA, Howard BV, Punjabi NM. Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. Diabetes Care. 2003;26(3):702-709. 37. Gangwisch JE, Heymsfield SB, Boden-Albala B et al Gangwisch JE, Heymsfield SB, Boden-Albala B, Buijs RM, Kreier F, Pickering TG, Rundle AG, Zammit GK, Malaspina D. Short sleep duration as a risk factor for hypertension: analyses of the first National Health and Nutrition Examination Survey. Hypertension. 2006;47(5):833-839.

38. Gottlieb DJ, Redline S, Nieto FJ, Baldwin CM, Newman AB, Resnick HE, Punjabi NM. Association of usual sleep duration with hypertension: the Sleep Heart Health Study. Sleep. 2006 ; 29 (8) : 1009-1 014. 39. Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E: Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol. 2005;99(5):2008-2019. 40. Nilsson PM, Roost M, Engstrom G, Hedblad B, Berglund G. Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care. 2004;27(10):2464-2469.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Authorâ&#x20AC;&#x2122;s Contribution: Dr. Shaista A Siddiqi: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Javeria Rauf: Protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Anita Haroon: Data collection, data analysis, manuscript writing, manuscript review Dr. Bilal Ahmed: Protocol writing,data analysis, manuscript writing, manuscript review Dr. Saera Suhail Kidwai: Data collection, data analysis, manuscript writing, manuscript review Dr. Lubna Nazir: Data collection, data analysis, manuscript writing, manuscript review

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UNDER RECOGNIZED ENTITY: CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY WITH LUPUS Ali Zohair Nomani,Haris Majid Rajput, Rao Sohail Yasin Khan, Mansoor Iqbal, Zakir Jan, Uzma Jamil, Mazhar Badshah, Muhammad Irshad Department of Neurology, Pakistan Institute of Medical Sciences, Pakistan

Correspondence to: Ali ZohairNomani, Department of Neurology, Pakistan Institute of Medical Sciences, 44000, Islamabad, Pakistan. Email: alin9432@gmail.com. Telephone: +92-3365295351 Date of Submission: 17 January, 2015, Date of Revision: 20 March, 2015, Date of Acceptance: 21 March, 2015

ABSTRACT Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired, autoimmune peripheral neuropathy. It has an insidious disease progression resulting in a debilitating illness. It is a well known neurological disorder. The causative factors are elucidating and it is generally considered idiopathic. However, its’ associations with various systemic disorders is well established albeit under recognized, especially with lupus as evident by few of the case reports/ series published in the recent past. The aim of this report is to highlight this neglected but important aspect of clinical neurology in common practice. Key words: Chronic inflammatory demyelinating polyneuropathy: lupus; Intravenous immunoglobulin; pulse therapy; plasma exchange; steroids; immunosuppressant. INTRODUCTION

the autoimmune work-up was negative. (Table 1) Nerve conduction studies (NCS) revealed markedly prolonged distal latencies with markedly reduced velocities and amplitudes of both the median motor nerves. There was no response in both peroneal and tibial nerves. Median and ulnar nerves did not show any F wave responses. The sensory median and ulnar nerves also showed no responses. NCS was clearly suggestive of demyelinating polyneuropathy and electromyography was therefore not conducted. (Table 2)CSF showed albuminocytological dissociation. Considering insidious onset and gradual progression of symmetrical proximal and distal weakness and sensory dysfunction of all extremities over a course of more than 8 weeks; clinically absent tendon reflexes in all extremities and NCS showing motor distal latency prolongation ≥ 50% above upper limit of normal in two nerves plus reduction of motor conduction velocity ≥ 30% below lower limit of normal in two nerves; with all the exclusion criteria fulfilled; the patient was labeled as CIDP. (Table 2) Autoimmune workup confirmed SLE with lupus nephritis. (Table 1) Table 1: Lab parameters of our patient shown serially with time

While chronic inflammatory demyelinating polyneuropathy (CIDP) has been exclusively studied, the tempospatial relationship between CIDP and connective tissue diseases especially systemic lupus erythematosis (SLE) is still an active research subject emphasizing the importance of its identification as a possible cause of CIDP. SLE is a multisystemic, autoimmune disease that can affect the peripheral nervous system(1,2). The term “CIDP with lupus” has been used in the category of “CIDP with systemic diseases” but only a handful of case reports/ series have been published so far (2,3). By this report, we aim to share our own experience of a patient of CIDP with lupus in order to highlight this neglected but important aspect of clinical neurology in common practice. CASE PRESENTATION A 17 years old girl presented to us with numbness and progressive weakness of both the arms and legs for the last 6 months in January 2011. She had generalized edema for the last 2 months as well. Her motor power in upper limbs was 2/5 while that in the lower was 1/5 with absent reflexes and flexor plantar responses. She had microscopic hematuria and proteinuria with low C3 and C4. In the light of she having urinary findings with hypocomplimentemia, her ANA and anti-dsDNA were done, both of which turned out to be positive. Rest of

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Year

Lab parameters ANA

Anti Sm Anti-RNP Anti SSA Anti SSB Anti Jo 1 Anti Sc 70 c-ANCA p-ANCA Anti GBM AMA ASMA Proteinuria WBC Hb Platelets Bilirubin ALT Alkaline phosphatase Urea Creatinine

Value 13.31 IU/l (normal < 1.5 IU/l) 56 mm/ 1sthr (normal < 20 mm) 72 IU/l (normal < 20 IU/ml) 0.69 g/l (normal 0.83-1.93g/l) 0.07 g/l (normal 0.15-0.57 g/l) 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 0.0 g/l 3.12 g/l (normal < 0.3 g/l) 7900/ ul 12.2g/dl 214000/ul 0.30 mg/dl 17 U/l 39 U/l 20 mg/dl 0.30 mg/dl

U/S abdomen

ANA Anti ds DNA ESR C3 level C4 level

9.12 IU/l 61.6 IU/l 36 mm/ 1sthr 0.29 g/l 0.13 g/l

ESR Anti ds DNA C3 level C4 level

Jan. 2011

Jun. 2011

Jun. 2014

Table 2: Nerve conduction studies in 2011: NR = No response; N.= Normal; Amp = Amplitude; Neg. = Negative; Dur. = Duration; O = Onset; P = Peak; Dist = distance; Vel = Velocity; APB = Abductor PolicisBrevis; ADM = Abductor DigitiMinimi; EDB = Extensor DigitorumBrevis; AHB = Abductor HallucisBrevis.

Inference +ve High +ve Low Low -ve -ve -ve -ve -ve -ve -ve -ve -ve -ve -ve Nephrotic range Normal Normal Normal Normal Normal Normal Normal Normal Ascitis + pleural effusion +ve +ve High Low Low Subnephrotic range Normal Normal Unremarkable study +ve +ve -ve

8.98 20.1 6

< 4.2

5.55 11.5 6

< 4.2

< 5.5

> 2.5

> 40

< 6.0

> 3.0

> 41

< 6.0

> 3.0

> 41

10.5 5 22.5 8

< 4.2

ElbowWrist

12.0 3

19.9 5

> 50.0

Thus, consolidated diagnosis was that of CIDP with lupus. She was given 1g methylprednisolone for 3 days. Her limb power gradually improved and proteinuria markedly decreased until she was able to walk without any functional disability as estimated using modified Rankin Scale (mRS) over a period of 4 weeks. She was discharged on maintenance dose of oral prednisone (1mg/kg/day) and 500 mg of cyclosporine three times daily. On follow-up visits after 3 months, the patient showed well controlled lupus with no renal or neurological impairment. Dose of prednisone was tapered down to 10 mg per day and cyclosporin continued with well controlled symptoms for both CIDP and SLE on 3 monthly follow-ups. After 30 months from initial diagnosis, the patient again presented with progressive weakness and numbness of all four limbs for the last 45 days, following a lower respiratory type infection. Her motor power in upper limbs was 4/5 while that in the lower was 2/5 with absent reflexes and flexor plantar responses. She, however, did not show any symptoms, signs or lab abnormalities suggesting renal compromise this time. (Table 1) Repeat NCS showed markedly prolonged distal latencies with reduced voltage and markedly reduced velocities in both median nerves and ulnar nerves. Peroneal and tibial nerves showed no response and median and ulnar nerves did not show any F wave responses. There was a conduction block from right median motor nerve; an electrophysiological hallmark of acquired demyelination. The sensory median and ulnar nerves also showed no responses. (Table 3) CSF showed albuminocytological dissociation. Her plasma exchange was done (200-250 ml/kg) with gradual improvement of symptoms until she was able to walk without support. She was discharged and put on maintenance dose of prednisone 1mg/kg/day plus 1g methyprednisolone once monthly. On routine followups, patient showed marked recovery with resolution of neurological symptoms and regain of full functional status over the next 6 months.

Peak (ms)

N. Peak (ms)

PTAmp (ÂľV)

Segment Name

Delt a-P (ms)

Dist (cm)

Vel (m/s 2 )

N. Vel (m/s )

Table 3: Nerve conduction studies of our patient revealing features of CIDP in 2014

< 3.7

Proteinuria

1.56 g/l

Urea Creatinine

20 mg/dl 0.30 mg/dl

U/S abdomen

ANA Anti ds DNA Proteinuria

10.30 IU/l 54.8 IU/l Nil

Table 1: Lab parameters of our patient shown serially with time: starting from January 2011 to June 2014. Table 2: Nerve conduction studies of our patient revealing features of CIDP in 2011 NCS of June 2011 Motor Nerves Site

Right Median (APB) Wrist Elbow

Right Ulnar (ADM) Wrist B Elbow

Right Peroneal (EDB) Ankle NR B Fib NR P-TA NR Right Tibial (AHB) Ankle NR Knee NR Left Tibial (AHB) Ankle NR Knee NR Left Median (APB) Wrist

Elbow

Sensory Nerves Site

N. Onse onse t t (ms) (ms)

O-P (mV) 0.88 0.22 1.80 1.47

0.31 0.18

Right Median Anti (2nd digit) Wrist

Right Ulnar Anti NR (5th digit) Left Median Anti (2nd digit) Wrist

Left Ulnar Anti (5th digit) Wrist

N.A mp (mV)

> 5.0

> 3.0

> 5.0

N. Amp (ÂľV) >15. 0 > 15.0

Neg. Dur (ms) 6.72 8.20 7.66 9.45

6.41 7.27

Segment Name

Delt a-O (ms)

Dist (cm)

Vel (m/s 2 )

N. Vel (m/s 2 )

ElbowWrist

11.1 7

22.3 8

> 50.0

B Elbow6.02 Wrist

39.8 7

> 53.0

> 39

> 50

> 15.0

> 39

> 15.0

> 50

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NCS of April 2014 Motor Nerves Site

Right Median (APB) Wrist Elbow

Right Ulnar (ADM) Wrist B Elbow

Right Peroneal (EDB) Ankle NR B Fib NR P-TA NR Right Tibial (AHB) Ankle NR Knee NR Left Median (APB) Wrist Elbow

Left Ulnar (ADM) Wrist B Elbow

Sensory Nerves NR

N. Onse onse t t (ms) (ms)

O-P (mV)

NR NR

24.7 6

> 50.0

B Elbow7.27 Wrist

30.2 6

> 53.0

ElbowWrist

8.28

< 5.5

> 2.5

> 40

< 6.0

> 3.0

> 41

ElbowWrist

7.89

20.5

25.9 8

> 50.0

B Elbow7.89 Wrist

22.5

28.5 2

> 53.0

Segment Name

Delt a-P (ms)

Dist (cm)

Vel (m/s 2 )

> 39

> 50

< 4.2

5.23 13.1 3

< 4.2

Peak (ms)

N. Peak (ms)

4.04 3.27

1.82 1.69 4.42 4.16 PTAmp (µV)

> 5.0

> 3.0

> 5.0

> 3.0

N. Amp (µV) > 15.0 > 15.0

7.73 7.89 9.38

4.53 5.47 6.56 7.19

< 3.7

> 15.0

> 39

> 15.0

> 50

< 3.7

presents with back pain and rarely with symptoms of lumbar canal stenosis and caudaequina syndrome suggestive of nerve root hypertrophy and requires neurosurgical intervention. Autonomic involvement in CIDP is generally mild and limited. Impaired bowel and bladder control usually are not the presenting symptoms and rather appear late in severe cases. (4, 8, 9, 10) Most patients with CIDP exhibit a slowly progressive course, but a relapsing-remitting course, relapsing/ recurrent AIDP like episodes exist in at least one-third of patients. Such an observation is more common in younger patients. The accession of early treatment for CIDP has made the temporal progression of the disease more difficult to characterize and categorize, since remissions may be related to therapy rather than to the natural course of the disease. This is why it’s almost always impossible for neurophysicians to differentiate between the two on first visit. (7, 8) The treatment of CIDP requires a systemic approach including the prevention of further demyelination and recovery of functional disability using exercise, occupational and physical therapy. In general, it includes an induction phase, long term management plan and supportive care. (9, 10) It is only in recent past that physicians have been able to appreciate association of the disease with lupus.The combination can present either way; diagnosed SLE followed or complicated by CIDP or vice versa. That is why it is extremely important for physicians to be aware of this association as general weakness due to multisystem involvement in SLE as a part of chronic ailment is often blamed to be the cause behind motor weakness whereas the real problem lies undiagnosed. This is said so because it is a potentially treatable disease that can greatly improve the quality of life for such patients and reduce morbidity associated with functional disability. (9, 10) As such cases can pose difficulty in diagnosis at times, whenever in doubt, physicians should have a low threshold of suspicion and timely refer such cases for specialist care.

N. Vel (m/s )

< 3.7

Left Ulnar Anti (5th digit) Wrist

20.5

Segment Name

< 4.2

Right Ulnar Anti NR (5th digit) Left Median Anti (2nd digit) Wrist

N. Vel( m/s2 )

3.67 10.9 4

0.85

7.73

Dist (cm)

Vel (m/s 2 )

Delt a-O (ms)

< 4.2

Right Median Anti (2nd digit) Wrist

Neg. Dur( ms)

9.38 17.6 6

8.52 16.4 1

1.90

N.A mp( mV)

Table 3: Nerve conduction studies in 2014: NR = No response; N.= Normal; Amp = Amplitude; Neg. = Negative; Dur. = Duration; O = Onset; P = Peak; Dist = distance; Vel= Velocity; APB = Abductor PolicisBrevis; ADM = Abductor DigitiMinimi; EDB = Extensor DigitorumBrevis; AHB = Abductor HallucisBrevis. DISCUSSION Chronic inflammatory demyelinating polyneuropathy is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. CIDP is at times considered the chronic subset of acute inflammatory demyelinating polyneuropathy (AIDP), most common form of which is GuillainBarré syndrome (GBS). (4, 5, 6) CIDP is under-recognized and under-treated due to its heterogeneous presentation (both clinical and electrophysiological) and the limitations of clinical, serologic, and electrophysiologic diagnostic criteria. (15) While difficult to diagnose earlier in its course, timely treatment is important in preventing irreversible axonal loss and improving functional recovery. (7, 8, 9) The pathologic hallmark of the disease is loss of the myelin sheath of peripheral nerves. (3,6) As a result of immune action, affected nerves demyelinate and fail to respond or respond only weakly to stimuli causing numbness, tingling, pain, progressive muscle weakness and loss of deep tendon reflexes. Weakness in CIDP is both proximal and distal; a hallmark of acquired demyelinating polyneuropathy. Cranial nerve and bulbar involvement occurs in 10-20% of patients only. Sometimes, CIDP

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CONCLUSIONS Successful management of CIDP with lupus requires high degree of suspicion to correctly diagnose and thereafter manage such cases. This may at times require the expertise of a trained neurologist and therefore physicians should not hesitate to timely refer such cases for specialist care. REFERENCES 1.

Jasmin R, Sockalingam S, Shahrizaila N, Cheah TE, Zain AA, Goh KJ. Successful treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in systemic lupus erythematosus (SLE) with oral

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cyclophosphamide. Lupus. 2012;21(10):1119-23. Zoilo MA, Eduardo B, Enrique F, delRocio MV. Chronic inflammatory demyelinating polyradiculo neuropathy in a boy with systemic lupus erythema tosus. Rheumatol Int. 2010;30(7):965-8. Hatano T, Fukuda M, Shiotsuki H, Miwa H, Urabe T, Mizuno Y. Chronic inflammatory demyelinating polyneuropathy followed by systemic lupus erythematosus and Sjögren syndrome: a case report. RinshoShinkeigaku. 2006;46(3):203-9. Vina ER, Fang AJ, Wallace DJ, Weisman MH. Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: prognosis and outcome. Semin Arthritis Rheum. 2005; 35(3):175-84. Sindern E, Stark E, Haas J, Steck AJ. Serum antibodies to GM1 and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy. Acta Neurol Scand. 1991;83(6):399-402. Sanz PG, García Méndez CV, Cueto AL, Silva VB, Walther JC, Diez RA, Martins S, Giannaula RJ. Chronic inflammatory demyelinating polyradiculoneuropathy in a patient with systemic lupus erythematosus

and good outcome with rituximab treatment. Rheumatol Int. 2012; 32 (12):4061-3 7. Rhee WI, Lee JA, Shin CH, Lee JY. Chronic Inflammatory Demyelinating Polyradiculoneuropathy in Patient with Systemic Lupus Erythematosus: A case report. J Korean AcadRehabil Med. 2008; 3 2(1):112-115. 8. D J Feeney, J D Pollard, J G McLeod, G J Stewart, T J Doran. HLA antigens in chronic inflammatorydemyelinating polyneuropathy. Journal of Neurology, Neurosurgery, and Psychiatry. 1990;53:170-172. 9. Nageen Hussain, GhazalaJaffery. Distribution of Human Leukocyte Antigen allelesinSystemic Lupus Erythematosus patients with AngiotensinConverting Enzyme Insertion/Deletion Polymorphism. Bosn J Basic Med Sci 2013; 13 (1): 57-62. 10. Andreas Jönsen, Anders A Bengtsson, Gunnar Sturfelt and LennartTruedsson. Analysis of HLA DR, HLA DQ, C4A, FcyRIIa, FcyRIIIa, MBL, andIL-1Ra allelic variants in Caucasian systemic lupus erythematosuspatients suggests an effect of the combined FcyRIIa R/R andIL-1Ra 2/2 genotypes on disease susceptibility. Arthritis Res Ther2004, 6:R557-R562.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Author’s Contribution: All authors contributed equally to this work. They performed the literature search, did data collection, analyzed the data and wrote the paper. All the authors meet the criteria for authorship as established by ICMJE. Research Funding: This work has been carried out without any grants or funds. It has been completed without external financial support and the expenses whatsoever for the purpose of this study have been contributed solely by the author’s themselves and no one else

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EIGHT -AND-HALF SYNDROME: A RARE NEURO-OPHTHALMIC SYNDROME “POSSIBLE NINE SYNDROME” Dr. Muslim Ali Lakhiar, Dr. Shaheen Ahmed Mughal

Correspondence to: Dr. Muslim Ali Lakhiar, Assistant Professor Neurology. PUMHS Nawabshah-SBA. Email: drmuslimali@yahoo.com Date of Submission: November 29, 2014, Date of Revision: December 28, 2014, Date of Acceptance: January 3, 2015

ABSTRACT “Eight-and-half” syndrome is “one-and-a-half” syndrome characterized by conjugated horizontal gaze palsy and internuclearopthalmoplegia plus ipsilateral fascicular seventh nerve palsy. We report a case of 50 year old woman who presented with right eight and half syndrome together with contralateral hemiparesis and hemihypesthesia. Non contrast CT scan brain showed hyperdensesignal on right pontine region. MRI brain plain revealed hemorrhagicpontinetegmentuminfarction as well as corticospinal tract and medial meniscus. This spectrum of presentation suggests a possible “Nine syndrome” as a novel neuropthalmicpontine syndrome. The first of its kind ever reported from Pakistan Key words: infarction, hemorrhage, eight-and-halfSyndrome, nine syndrome. INTRODUCTION

episodes of non projectile vomiting. At the time of presentation her blood pressure was 200/100mmHg, Pulse 90 b/min, respiratory rate 17 breaths/min and Tem.98F. On neurologic examination she had a Glasgow coma scale 11/15, Pupils 4mm and reactive bilaterally, fundoscopy normal, oculomotor examination revealed conjugated horizontal gaze paresis. Corneal reflex showed blink response on left side only, she had a right seventh nerve palsy which was lower motor neuron type and rest of cranial nerve were normal. On motor system examination bulk was normal, tone decreased on left side in upper and lower limb, power was 0/5 in upper limb and 3/5 in lower limb on left side while reflexes were 3+ and left planter was upgoing. The Respiratory system, cardiovascular and abdomen were all normal ABC was maintained & patient was started on i/v 3rd generation cephalosporin, tablet enalapril 10mg and regular insulin according to sliding scale while RBS done at presentation was 234mg/dl, meanwhile baseline investigations sent. On second day of admission her blood pressure dropped to 160/90mmgh and GCS became 15/15. However oculomotor examination revealed conjugated horizontal gaze paresis except left sided nystagmus on abduction while from primary position vertical eye movements were normal, power was same. Cerebellar signs normal. Pinprick, temperature, vibration &joint position sense were diminished on left side. Laboratory investigations showed a raised WBC count 13000/mm3 with platelet count of 373000, while blood urea, creatinine, HbsAg, Anti HCV, LFTs, electrolytes, APPT, PT-INR, Bleeding time and clotting time were normal. Urine detailed report showed pus

The “one and ahalf ” syndrome, first reported and named byMiller Fisher in 1967[1], is a clinical syndrome of horizontal gazepalsy to one side along with ipsilateral inter-nuclearopthalmoplegia (INO) resulting in loss of allhorizontal movements in the ipsilateral eye, exceptabduction of the contralateral eye. This syndrome is due to a unilateral lesion in the lower part of the dorsal pontinetegmentum, affecting the ipsilateralparamedianpontine reticular formation (PPRF)which serves as the conjugate gaze center for horizontal eye movements, abducensnucleus and internuclear fibers of the ispsilateral medial longitudinal fasciculus (MLF). It is caused by circumscribed lesions of the pontinetegmentum as a result of infarction, hemorrhage, demyelination (Multiple Sclerosis), gliomas, and cystic lesions.It is one of the most localizing brainstem syndromes. Involvement of facial nervewith “one and a half” syndrome has been termed as “eight and a half” syndrome by Eggen-Berger [2] whofirst reported three such cases. Keeping this in view we report another rare case of “Eight and a half” syndromewith additional features of contralateral hemiparesis & hemihypoesthesia as a possible “NINE Syndrome”. CASE PRESENTATION A 50 year old female, right handed, known case of Hypertension and Diabetes mellitus admitted through casualty in Medical ward with sudden onset altered level of consciousness, left sided weakness, facial asymmetry, diplopia in horizontal gaze and two

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cells. ECG was unremarkable and Hemoglobin A1c was 7.3% (4.0-7.0%). Non contrast CT scan brain showed hyperdensesignal on right pontine tegmental region. Computed Tomographic Angiography did not reveal any aneurysm or vascular malformation, MRI brain plain done one week later revealed hyperintense signals over right pontinetegmentum on T1,T2 and flair imaging suggesting subacute hemorrhagic pontine infarction involvingcorticospinal tract and medial meniscus as well. MRA was unremarkable. Over a period of 1 week the condition of patient gradually improved in terms of power which became 1/5 in upper limb and 4/5 in lower limbbut her diplopia in horizontal gaze remained same. Patient was discharge on antihypertensive and oral hypoglycemic agents to follow up in Neurology OPD.

Figure-02 Non contrast CT scan showing hyperdense signal at right pontinetegmentum extending to 4th Ventricle&MRI Brain Plain showing Hyperintense signals on T1WI, T2WI and Flair imaging.

Figure -01 showing eye movement abnormality.

Figure-03 Magnetic Resonance Angiography (MRA) & CT Angiography Normal

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DISCUSSION

CONCLUSION

One-and-a-half syndrome (OHS) refers to horizontal gaze palsy (one) with intranuclearopthalmoplegia (half) due to a lesion of the paramedianpontine reticular formation (PPRF) and medial longitudinal fasciculus. [1]. When one-and-a-half syndrome is associated with other cranial nerve involvement, the number of the cranial nerve is added to one-and-a-half to describe the clinical syndrome like eight and half syndrome [2,3,4], Nine syndrome [5], thirteen and half syndrome[6], Fifteen and half syndrome [7], sixteen and half syndrome [8,9] . Hence, “Eight-and-a-half” syndrome is “one-anda-half” syndrome (conjugated horizontal gaze palsy and internuclearopthalmoplegia) plus ipsilateral fascicular cranial nerve seventh palsy.Eight-and-a-half syndrome is caused by a lesion in the dorsal tegmentum of the caudal pons involving the PPRF or abducens nucleus and the medial longitudinal fasciculus (MLF), as well as the nucleus and fasciculus of the facial nerve [3]. The facial nucleus lies adjacent to the PPRF and gives rise to cranial nerve VII (CN7) which courses through the PPRF before circling the abducens nucleus and exiting the brainstem. This rare condition, particularly when isolated, is caused by circumscribed lesions of the pontinetegmentumas a result of infarction, hemorrhage, demyelination (Multiple Sclerosis), gliomas, and cystic lesions. Our case presented with eight and a half syndrome associated with contralateral hemiparesis and hemihypesthesia, Almost similar clinicalentity has been termed as “Nine syndrome” previously reported by Rosni at al [5] resulting from lacunar pontine infarction. Our patient was younger who developedhemorrhagic pontinetegmentum infarction as a result of high blood pressure. Pons is one of the most common sites for hemorrhagic stroke apart from putamen, thalamus and cerebellum.No such clinical entity has been reported yet in Pakistan.This is an addition in the spectrum of brainstem syndromes which not only have clinical importance but also help anatomic localization from student’s point of view as well in order to have appropriate imaging.

Recognition of one-and-a-half plus syndrome at the bedside is of importance for precise localization and also for planning appropriate investigations to determine the possible cause. REFERENCES 1. 2. 3. 4. 5.

7. 8. 9.

Fisher CM. Some neuro-ophthalmological observations. J NeurolNeurosurg Psychiatry. 196 7;30:38 3-92. Eggenberger E. Eight-and-a-Half Syndrome: Oneand-a-Half Syndrome plus Cranial Nerve VII Palsy. J Neuro-ophthalmology. 1998;18:114-116. SarwalA, Garewal M, Sahota S, Sivaraman M. Eight-and-a-half syndrome. Journal of Neuroimaging. July 2009;19(3):288-90. Nandhagopal R Krishnamoorthy SG. Eight‐and‐a‐half syndrome. J NeurolNeurosurg Psychiatr y. April 2006;77(4): 463. Rosini F, Pretegiani E, Guideri F, Cerase A, Rufa A, Eight and a Half Syndrome with Hemiparesis and Hemihypesthesia: The Nine Syndrome? J StrokeCerebrovas Dis. November 2013;22(8):637–638. Rath A, Jawatkar J, Guruprasd H, Saxena A. B, Murthy J. M. K.One-and-a-half Plus Syndromes: Report of Three Cases .Annals of Indian Academy of Neurology; 2007 Supplement 2, Vol. 10, p6 Bae JS, Song HK.One-and-a-Half Syndrome with Facial Diplegia: The 15 1/2 Syndrome?. Journal of Neuro-opthmology. March 2005;25(1)55-53 Cummins G, O’Hare A, Dunne R, et al. "Sixteen and a half": a novel pontineneuroophthalmological syndrome. J Neurol. July 2011;258(7):1347-8. Singh et al / “Sixteen and a half”: a rare neurological syndrome. Internet Journal of Medical Update. July 2012;7(2):51-53

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Author’s contribution: Dr. Muslim Lakhiar: Study concept and design, protocol writing, data collection, data analysis, manuscript anuscriwriting, mpt review Dr. Shaheen Mughal: Study concept and design, data collection, data collection, data analysis, manuscript writing, manuscript review.

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A 2 ½ YEARS OLD BOY WITH SQUINT AND SPEECH LOSS

Shaila Ali, Zia ur Rehman, Tipu Sultan

The Children Hospital & Institute of Child Health, Lahore. Correspondence Author: Dr Tipu Sultan, The Children Hospital & Institute of Child Health, Lahore. Email: tipusultanmalik@hotmail.com Date of Submission: October 25, 2014, Date of Revision: December 9, 2014, Date of Acceptance: December 20, 2014

ABSTRACT Tuberculosis of central nervous system is not uncommon in children of developing countries. Tuberculomaswere initially misdiagnosed due to lack of radiological expertise, un availability of CT scans and MRI. For early diagnosis and treatment, they should be kept in differential of space occupying lesions.We had a 2 ½ years old patient had fever, squint, aphasia and loss of motor milestones. On examination he was a malnourished child with right sided hypertonia and involvement of 9th and 10th cranial nerves with hepatospleenomegaly. His CRP was raised and CXRshowed B/L milliary shadowing which helped us to find out the primary focus leading to tuberculoma. His PCR test of blood was positive for Mycobacterium tuberculosis while CSF examination was normal. His work up led us to the diagnosis of a space occupying lesion i.etuberculoma, fungal infection of brain or metastasis. He was managed conservatively as he responded well to antituberculous therapy along with steroids. This concludes that early and prompt treatment of this deadliest disease is the key for favorable outcome. Key Words: Tuberculomas, space occupying lesion, primary Focus, Antituberculomastherapy. INTRODUCTION

granulomas are usually hypo-intense on T1 W1, hyperintense on T2 W1 and appear nodular or ring enhancement on post-contrast studies. These findings are nonspecific and they have to be differentiated from other cases of space-occupying lesions such as high grade gliomas, pyogenic abscess, metastases, toxoplasmosis, cysticercosis and lymphoma (4).

Tuberculosis is one of the world’s deadliest diseases. It affects 1/3rd of world’s population. The world health organization estimates that every year; childhood TB accounts for 6% to 10% of the TB cases worldwide(1). Pakistan stands fifteen among countries with highest prevalence rate of TB. CNS tuberculosis accounts for only 10% of all cases of TB. Children younger than 4 years of age are prone to most severe form of TB including extrapulmonaryTB e.g. CNS Tuberculomas(2). It develops either due to hematogenous dissemination from a primary foci or spinal infection. Tuberculomas are firm, vascular, spherical masses, with size varying form 2cm to 10 cm. They have tubercle bacilli in them. They may be unilateral or multiple.

CASE REPORT A 2 ½ years old boy presented with history of recurrent fever, squint of right eye and speech loss for last 2 months. His fever was high grade, intermittent associated with rigors, chills and vomiting.Vomiting was non-bilious, non-projectile, containing food particles. It was associated with squint of right eye and slurring of speech. There was also history of difficulty in walking, which increased with time and within 2 months period and on presentation he was unable to walk, stand and sit. He could only holdhis neck partially. There was no history of fits, altered state of consciousness, nasal regurgitations, cough, respiratory distress, urinary or bowel complaints. He was diagnosed to have megaloblastic anemia 4 months back and was discharged on injectable Vit B12 + Folic acid therapy. His birth history was uneventful. He was vaccinated according to EPI schedule. He achieved all developmental milestones at appropriate age. He belonged to a low socioeconomic status. His

On CT Scan brain: Typical imaging findings of tuberculomas include solitary or multiple, round “nodules” showing ring enhancement after contrast. It has a target sign with ring enhancing lesion having an additional central area of enhancement as calcification (3) On MRI The initial tuberculomas consisting of non-caseating

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general physical examination showed that he had stable vital signs with pallor. BCG scar was present on his right upper arm.His anthroprometric measures were low for his age and sex. His weight was 10 kg (5th centile) and height was 90 cm (50th centile) and OFC : 48.5 cm (50thcentile) His neurological examination revealed Glasgow coma scale of 12/15, normal fundus examination and a right sided 6th cranial nerve palsy, signs of meningeal irritation were also +ve, while sensory and cerebellar systems were intact. He was unable to walk and stand but could sit with support and holds neck partially for short time.

Investigation CBC Hb MCV WBC ESR CRP Immunoglobulin IgA Antibodies IgM Antibodies IgG Antibodies Torch Profile Blood C/S CSF WBC Sugar Protein C/S S/Ceruloplasmia Abd. USG Echo Cardiography Bone Marrow

On motor examination He had generalized reduced muscle bulk with right sided hypertonia, power of 3/5 and hyper-reflexia in all limbs and right sided upgoing planters. There was involvement 9th& 10th cranial nerve in the form of drooling of saliva and weak gag reflex

Results 10 mg/dl 65 2.9 05 12 Normal

Normal Negative

PCR of Blood for mycobacterium TB

On Systemic examination:

Picture # 2

There was hepatosplenomegaly with liver of 6cm palpable below right costal margin having total span of 10cm, firm in consistency, regular margins and non-tender, spleen was 4 cm palpable below left costal margin. For publication of pictures consent was taken from the parents.

Patients chest X-ray:

10 60 40 Negative Normal Hepatospleenomegaly Normal Myeloid hyperplasia, Megaloblastic Anemia Positive

Showed B/L milliary Patients CT scanbrain reveals: Picture 3 A:

Picture 3 A: CT scan done on 09-12-2013 showing cerebral hypodensities Picture 3 B:

Picture 1: child with weak gag reflex and nasogastric tube in place

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Picture # 6

Picture 3 B: CT scan done on 09-12-2013 showing cerebellar hypodensities CT brain with contrast

Picture # 7

Non-enhancing patchy hypodensities in both cerebral and cerebellar hemispheres Suggestive of encephalitis Patients MRI BrainReveals: Picture 4: (17-12-2013) MRI brain with contrast:

Picture # 8

Picture # 5 Picture 4, 5 & 8 shows: Innumerable ,marginally enhancing round to oval lesions involving cerebral and cerebellar hemispheres Picture 6 & 7 shows: Predominant involvement of deep and juxtacortical white matter Impression: acute disseminated encephlomyelitis or infective process

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Picture: 9 (08-01-2014)

enhancing lesions along cerebral hemispheres. In our index case the differential diagnosis includes ---disseminated tuberculosis, Tuberculoma, Fungal infections of brain and metastasis. Our patient remained sick initially for 3-4 weeks and was kept in neurocritical care in high dependency unit. He was treated with antipyretics, antibiotics, antifungal therapy (initially for 3 days). He was also given treatment of raised intracranial pressure. In between when he deteriorated, during his stay he developed fits which were controlled by anticonvulsants. He was given four drugs ATT along with steroids i.e. isoniazid, Rifampicin, Pyrazinamide, streptomycin and vit B6. DISCUSSION

Picture # 10

Intracranial tuberculomasare least common type of CNS TB. Due to its rarity and varied radiological findings they remain a clinical challenge. However, they must always be included in differential diagnosis of space occupying lesions. Our patient was difficult to diagnose as he had history of CNS symptoms, viseromegalyand regression of motor mile stones. He was vaccinated against TB (BCG scar was present). He had no contact with any tuberculous patient. His ESR was 5 and montouxtest was negative, while his CT scan and MRI opened several differential diagnosis among physicians, surgeons and radiologists. Most of them had highest suspicion of fungoma ortuberculoma. His CXR was done showing B/L milliary shadows and his PCR was done which was +ve for mycobacterium, tuberculosis, mean while antifungal treatment was stopped after 3 days and ATT continued after detailed discussion with radiologists and neurosurgeons. In children differential diagnosis of tuberculoma includes neurocysticercosis, brain abscess, fungal infection of brain, Brain tumors and metastasis. In a study in India carried out by Patel NHet all, out of 50 patients of space â&#x20AC;&#x201C; occupying lesion in children 13 had tuberculomas(5). Therefore, it is essential to look for primary focus of TB infection when ever you are suspecting tuberculoma, as it is a treatable disease and if early diagnosed, leads to favourable outcome. Studies showed that usually the primary focus lies in lungs (6) but sometimes rare organs and locations can also have primary focus. A 10 year old child from Reunion Island had mesenteric adenopathy, only picked up due to thorough and vigilant systemic examination and paying attention to CNS as well as to other presenting complaints (7). Anti-tuberculosis therapy with steroids shows favorable outcome regarding mortality although a distressing level of neurological morbidity is still present (8). On CT scan brain and MRI brain variety of findings can be seen in addition to tuberculomas. These include hydrocephalus, basal

Picture # 11

Picture 9 & 10 shows: MR features of multiple variables nodular and ring enhancing lesions along both cerebral and cerebellar hemispheres with involvement of brainstem and thala mi suggest Tuberculomas. Picture 11 shows: MR features of multiple variable nodular and ring

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meningeal enhancement (9) and multiple ring enhancing lesions (10). Tuberculomas can be present in frontal, parietal, temporal and occipital lobes as well as cerebellum, pituitary areas (9), sellar and suprasellar areas (11). Our patient showed improvement after 3 weeks of antituberclosis therapy along with steroids. His fever subsided; he was off NG feed and started taking orally. His motor milestones improved, he was able to hold neck and started sitting with support. He remained fit free after 2 weeks of ATT treatment.

Picture 12: After 3 months of treatment child improved. He was able to hold his neck and he could eat and drink independently.

Picture # 12

Pakistan is a developing country with limited health resources. There is lack of adequate knowledge regarding severity of tuberculosis among general population. According to WHO more than 74,000 people die from TB each year (1). It can only be eliminated by educating our people regarding, nutrition, proper vaccination, early consultation with local general practitioner, diagnosis and proper dosage and duration of treatment. This case shows that tuberculomas are difficult to diagnose but if kept in differential diagnosis of space occupying lesion, then can be early picked up and managedconservatively.

After 3 months of treatment

REFERENCES

Picture # 13

Picture 13 & 14: After 6 months of treatment child started sitting with support. CONCLUSION

2. 3. 4. 5.

After 6 months of treatment Picture # 14

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World health organization website – childhood Tuberculous page. -2010 (www.cdc.gov/tb/topic/population/tb in children/global.htm) Newton SM, Brent AJ, Andreson S, Whittaker E, Kampmann B. Paediatric tuberculosis Lancet Infect Dis 2008 Aug; 8: 498-510 A Helmy, NM Antoun, PJ Hutchinson CerebralTuberculoma and Magnetic Resonance imaging. J R Soc Med July 2011; 104 (7): 299-3 01. YAN H, HAN T, Wang JH, cerebral tuberculoma located in left frontal lobe. Chin med j 2013 Feb; 126 (3): 600. Patel NH, Jain AR, Lyer VK, shah AG, Jain DA, Shah AA. Clinico diagnostic and therapeutic relevance of computed tomography scan of brain in children with partial seizures. Ann Indian Acadneurol 2013 Jul; 16 (3): 352-356. Azam M, Bhatti N. Intracranial, Tuberculomas and caries spine: an experience from children’s Hospital Islamabad. J Ayub Med collabbottabad 2004 Oct – Dec ; 16 (4): 7-11. Vernaz A, Enaud L, Blanc S, stoven C, Tasset C, Losi S, Andriolo E, piyaraly S, Flodrops H. Brain uberculoma in a 10 years old child : the diagnosis is in the belly. Arch pediatr. 2012 Aug; 19 (8): 832-6. Buonsenso D,Serranti D, Valentini P. Dept of Peads catholic University of sacred heart, Rome (Italy), Management of CNS TB in Children; light and

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shade. Eur Rev Med pharmacolSci 2010; 14 (10) :845-853. Tinsa F, Essadan L, Fitouri Z et al. Department of Paediatrics, Children’s hospital of Tunis, Tunisia, CNS TB In infants, J child Nerol January 2010; 25 (1) : 102-106. 10. Krygowski JD, Brennen, DF, Counselman FL. Intracranial Tuberculomas an unusual cause of altered mental status In a pediatric patient. J Emerg Med 2010 Apr; 38 (3): 323-7. 11. Nayil K, Singh S, Makhdooni R, Ramzan A, Wani A. (PediatrNeurol 2011 Jun; 44 (6): 463-6. Sellarsuprasellartuberculomas in children: 2 cases. 9.

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Author’s Contribution: Dr. Shaila Ali: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Zia Ur Rehman: Data collection, data analysis, manuscript writing, manuscript review Dr. Tipu Sultan: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review

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SPECTRUM OF NEUROMUSCULAR INJURIES IN VICTIMS OF BOMB BLASTS Dureshahwar Kanwar, Ambreen Iqrar, Zaitoon Shivji and Sara Khan

Department of Neurology, The Aga Khan University Hospital, Karachi, Pakistan Correspondence to: : Sara Khan M.D, Assistant Professor, Department of Neurology, Aga Khan University Hospital, Stadium Road, Karachi, Pakistan. Email: sara.khan@aku.edu Phone No: 011-92-34864654 Date of Submission: September 23, 2014, Date of Revision: January 05, 2015, Date of Acceptance: January 12, 2015

ABSTRACT Introduction: Bomb blast (BB) injuries outside war zones were a rare phenomenon until recently. With the spreading wave of terrorism across the globe, BB related trauma is resurfacing. Explosions can produce unique patterns of neuromuscular injury. No recent data exists categorizing such injuries. Methods: Medical records and electrodiagnostic findings of 20 patients with BB related neuromuscular injuries (NMI) were reviewed retrospectively. Results: Most common site of injury was the lower extremities (55%) with majority presenting clinically with foot drop (40%) or weakness (30%). 9/17 patients (45%) had associated shrapnel or penetrating trauma. 6/20 patients had associated fractures. The most common finding was of mononeuropathies. Discussion: As we re-enter an era of war, we need to recreate awareness of the possible spectrum of NMI. Awareness of such injuries will lead to early identification of nerve trauma and the possibility of reduction in overall disability if treated appropriately soon after the injury. Key words: Bomb blasts, neuromuscular injuries, mononeuropathies, plexopathies, electromyography/nerve conduction studies

INTRODUCTION

RESULTS

Bomb blast (BB) injuries were a rare phenomenon until recently. It is now becoming a common cause of trauma with the spreading wave of terrorism and war across the globe. Blast injuries in various regions of Pakistan and Afghanistan are an everyday norm and these frequently occur outside war zones. They have the potential to inflict multi-system life threatening injuries on many people simultaneously. The current available data for neuromuscular injuries (NMI) sustained by victims of bomb blasts is next to negligible. We conducted this study to see the spectrum of NMI in such patients, as this type of affliction will increasingly be seen across the world and with proper management the long term effects of these can be minimized.

For the 20 BB victims with NMI, the age ranged from 13 to 70 years (33.9 Âą 15.7) and 18 (90%) were men. Majority hailed from Pakistan 16/19 with 3 victims from Afghanistan.75 % (15/17) victims had onset of their symptoms within one month of the inciting event, while such data was missing for 3 patients. The most common site of injury was the lower extremities (11/20; 55%) with majority presenting clinically with foot drop (8/20; 40%) or lower extremity weakness (6/20; 30%). 9/17 patients (45%) had associated shrapnel or penetrating trauma, while 6/20 patients had associated fractures all involving the lower extremity. On electromyography/nerve conduction studies (EMG/NC S), the most common finding was of mononeuropathies either in the upper or lower extremities (Table 1). Other injuries identified included brachial or lumbosacral plexopathy and cervical or lumbosacral radiculopathy (Table 1). 5 (25%) had multiple mononeuropathies, while only 1 (5%) had a normal study. As expected, no evidence of a muscle or neuromuscular junction disorder was identified in these patients, secondary to the inciting event. Of patients who underwent intervention for their injury, 5 had nerve exploration with repair, 2 had nerve grafting with tendon transfer and 1 had

MATERIALS AND METHODS We reviewed all the patients who were evaluated in the electromyography laboratory at The Aga Khan University Hospital for BB related injuries; between 2009 and 2014. A cohort of 20 patients was identified. We retrospectively reviewed and analyzed their clinical and electrodiagnostic data. There were no exclusions. This study was approved by the Ethics review committee of the Aga Khan University Hospital.

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tendon release surgery. Five patients underwent orthopedic intervention (internal or external fixation) prior to identification of nerve injury. Unfortunately most patients were lost to follow-up. Of 3/20 patients who did follow-up post procedure, 1 showed recovery while 2 had no change in their weakness.

limb salvage or amputation in the traumatized lower extremity continues to be a difficult problem in the military and civilian sectors (7). Although symptoms of nerve trauma were identified within a month of the inciting event in most of our patients, evaluation in a tertiary care hospital was delayed by an average of 11.7 months Âą 22.09. There is a bias in selection of our patients as our hospital is a private, self paid tertiary care center and patients seeking care here do not represent the general population. In all likelihood, there are victims out there who suffer from far worse nerve injuries then those represented in our sample. Follow-up care was poor, as most patients came from remote areas for a short stay and had difficulty in access to a tertiary care center. As we re-enter an era of war, we need to recreate awareness of the possible spectrum of nerve injuries, affecting civilians and armed forces personnel which will lead to early identification of nerve trauma and the possibility of reduction in overall disability if treated appropriately soon after injury.

DISCUSSION Wars have been fought since the beginning of recorded history. Throughout time, the casualties of war have transcended all geographical, ethnic and cultural boundaries. Although the methods of warfare have changed, the injuries that result have remained constant over time.(1) Bomb blasts related injuries have become a threat for populations all over the world. The management of casualties by blasts once mainly came under the domain of military doctors, but given the present state of world dynamics any doctor may be called on to manage patients injured in BB. (2) Healthcare providers are increasingly faced with the possibility of needing to care for people injured in explosions, but can often, however, feel undertrained for the unique aspects of the patient's presentation and management .8 BB can cause a spectrum of NMI. Primary blast injuries most commonly involve airâ&#x20AC;&#x201C;fluid interfaces including the ear, lung, and gut. Secondary injuries are penetrating injuries from fragments that are part of the weapon or those that result from explosion and are the leading cause of death and injury. Tertiary blast injuries also result from people being thrown into fixed objects by the wind of explosion. Any body part may be affected, and fractures, traumatic amputations, and open or closed brain injuries occur.(3) In our study, the most common nerve related injury was mononeuropathies. Majority of the patients (13/20; 65%) had associated penetrating shrapnel trauma and/or limb fractures, similar to reports in other studies (4). While penetrating trauma was directly responsible for nerve injury, we were unable to establish if bone fragments due to fractures or treatment of these fractures (external or internal fixation) were responsible for subsequently identified nerve injury. Most patients were male (90%) in the productive age group (Mean age: 33.9 yrs) since BB tend to occur in crowded areas (markets, educational institutions); ultimately impacting the economic structure of society due to significant disability secondary to nerve injuries. Disability in such patients can be significantly reduced by early identification and intervention of nerve damage (5) . Also a basic education in the mechanisms of blast damage, a methodical approach to resuscitation, and mangled extremity treatment, likely can improve surgical success (6). However determining whether to perform

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ABBREVIATIONS BB: Bomb blasts EMG/NCS: Electromyography, Nerve Conduction Studies. NMI: Neuromuscular injuries REFERENCES 1.

2. 3. 4.

5. 6.

Cohen SP, Griffith S, Larkin TM, Villena F, Larkin R. Presentation, diagnoses, mechanisms of injury, and treatment of soldiers injured in Operation Iraqi Freedom: an epidemiological study conducted at two military pain management centers. Anesth Analg. 2005 Oct;101(4):1098-103, Chaloner E. Blast injury in enclosed spaces. BMJ. 2005 Jul 16;331(7509):119-20 DePalma RG, Burris DG, Champion HR, Hodgson MJ. Blast injuries. N Engl J Med. 2005 Mar 31;35 2(13):1335-42. Adhikari S1, Bandyopadhyay T, Sarkar T, Saha JK. last injuries to the hand: Pathomechanics, patterns and treatment. J Emerg Trauma Shock. 2013 Jan;6(1):29-36 Griffin JW, Hogan MV, Chhabra AB, Deal DN. Peripheral nerve repair and reconstruction. J Bone Joint Surg Am. 2013 Dec 4;95(23):2144-51. Langworthy MJ1, Smith JM, Gould M. Treatment of the mangled lower extremity after a terrorist blast injury. Clin Orthop Relat Res. 2004 May; (422 ):8 8-96. Shawen SB1, Keeling JJ, Branstetter J, Kirk KL, Ficke JR. The mangled foot and leg: salvage versus

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amputation. Foot Ankle Clin. 2010 Mar;15(1):63-75. Wolf SJ1, Bebarta VS, Bonnett CJ, Pons PT, Cantrill SV. Blast injuries. Lancet. 2009 Aug 1;374 (9687):405-15.

Table 1: Spectrum and frequency of nerve injuries sustained by bomb blast victims Nerve injury (n=20) Brachial plexopathy Lumbosacral plexopathy Median Ulnar Radial Axillary Sciatic Tibial Peroneal Facial Cervical radiculopathy Lumbosacral radiculopathy

Frequency 2 1 4 2 2 1 4 3 4 1 2 2

Percentage (%) 10 5 20 10 10 5 20 15 20 5 10 10

Conflict of Interest: Author declares no conflict of interest. Funding Disclosure: Nil Authorâ&#x20AC;&#x2122;s Contribution: Dr. Dureshahwar Kanwar: Study concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review Dr. Ambreen Iqrar: Study concept and design, data collection, data analysis, manuscript writing, manuscript review Zaitoon Shivji: Data collection, data analysis, manuscript review Dr.Sara Khan: Concept and design, protocol writing, data collection, data analysis, manuscript writing, manuscript review

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P O E T R Y

AN ODE TO NEUROLOGY

Dr. Marina Wazir,

Postgraduate Trainee General Medicine, Shifa International Hospital, H-8/4, Islamabad.

The functional organization of the human brain does enthrall us indeed, For such great lengths take place at great speeds. The reticular activating system does keep us awake, Control of the motor system is one job the basal ganglia won’t easily forsake. Some disorders we will discuss next, Differentiating between them may be complex. Parkinsonism is characterized by tremors rigidity and bradykinesia, Alzheimer’s disease as we do know leads to amnesia. When both upper and lower motor neuron signs are simultaneously seen, Motor neuron disease among your differentials ought to have been. Sodium valproate for generalized tonic clonic seizures is considered first line, Carbamazipine or lamotrigine may be added some point in time. With parietal lobe lesions Gerstmann’s syndrome may be seen, In which alexia, acalculia and finger agnosia ought to have been. The triad for NPH is ataxia, urinary incontinence and dementia, With myotonic dystrophy there may be frontal alopecia. In Wilson’s disease, tremor and chorea are some neurological signs, Alongwith which hepatic function may decline. Wernicke’s encephalopathy has the triad of ataxia, confusion and ophthalmoplegia, A lesion of the contralateral parietal lobe could show agraphesthesia. In cases of myasthenia gravis anticholinesterase antibodies ought to be checked, With ring enhancing lesions in neurocysticercosis; the MRI will be decked. Demyelinating lesions we often see in multiple sclerosis, With low grade fever, weight loss and night sweats one would suspect CNS tuberculosis. Vitamin B12 deficiency can lead to subacute degeneration of the spinal cord, Natalizumab in the treatment of MS would be a double edged sword. In friedreichs ataxia pes cavus is often found on examination, Patients with HSV encephalitis can have confabulation. A lesion of the lateral medulla can cause Wallenberg’s syndrome, Prion disease may have an underlying palindrome. There is a wide variety of neurological disorders you will encounter, An understanding of the basic anatomy and physiology will make you smarter. So with patients you would be able to extend a helping hand, Which is a feeling that is truly grand.

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THE LAND OF OPPORTUNITIES FOR RESEARCH ON RARE GENETIC NEUROLOGICAL DISORDERS Muhammad Ulusyar Khan, Fazal M. Arain

Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi, Pakistan

Date of Submission: November 17, 2014, Date of Revision: December 15, 2014, Date of Acceptance: January 5, 2015

Our knowledge about rare genetic neurological disorders is fairly limited, which translates into poor treatment options for them. The very fact the we do not know the prevalence of many such diseases is a testament that we do not invest as much time and funding in research on such diseases as we should. We also ignore the fact that the findings from any study conducted on these rare genetic diseases are not restricted to those particular diseases but rather applies to more common diseases as well. The disease Hereditary Sensory Autonomic Neuropathy II (HSAN II) is an example. Cardinal symptoms of this autosomal recessive neurological disorder include severe loss of pain, temperature and touch sensation since birth(1). The loss of sensations in these patients can leave even severe injuries, including fractures of bones, unnoticed until they develop severe infections which might lead to amputation of digits and even limbs(1). The incidence of this disease is not known and there is only symptomatic treatment available for it. Although a few candidate genes have been associated with this disease, the exact gene responsible for HSAN II remains unknown. Few studies have been published on HSAN II, even though research conducted on this disease will not only lead to development of treatment options for this disease but also for other diseases. For example, if we can completely understand the reason for the lack of pain sensation in these patients, we can use this knowledge to develop pain management treatment options for other painful diseases like end stage cancers. Another example of note is simple Autosomal Recessive Optic Atrophy(2). Patients diagnosed with this disease are normal in every aspect except being completely blind since birth or soon afterwards. The reason for their optic nerve atrophy is not understood and there is also no confirmed mutation associated with this disease. As expected, there is also no available treatment option for it. If more research is conducted on this disease, we can not only develop treatment options for this disease but also for other diseases that require optic nerve regeneration for their cure. The apparent lack of enthusiasm by the scientific community could be due to oversight of rare genetic neurological disorders.However, it is more likely to

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identify such rare genetic neurological disorders in populations where intra-family marriages are common and chances of passing on a “faulty gene” to the next generation is high. Pakistan is a country where intrafamily arranged marriages are very common and much more socially preferred compared to “out of family” marriages, making the genetic pool of this country much denser compared to western countries. Because of this dense genetic pool it is fair to assume that what is ‘rare’ in western countries is ‘not so rare’ in Pakistan. Good quality population studies can identify large families in which rare genetic neurological disorders exists. Data collected from them will allow further high impact studies not only on these disorders but also provide evidence for generating new hypothesis that can reshape the very foundations of basic biological sciences. An interesting example of this comes from Uner Tan syndrome. This, probably autosomal recessive disorder, was recently described in a large family belonging to a small village in Turkey. Six out of nineteen siblingsbelonging to this family have quadrupedal gait, dysarthric speech, mental retardation, epilepsy and cerebrocerebellar hypoplasia(3). Genetic mutations and their mechanism of action for the manifestation of this disorder are being actively investigated. Although extremely controversial, this disorder has been proposed as an example of a novel hypothesis, ‘reverse evolution’. The transformation from quadrupedal to bipedalism is believed to be the very foundation of the evolution from ape to human(4). The findings from this and four other families diagnosed with Uner Tan syndrome has not only introduced a new disorder, but also shaken the very foundations of evolutionary biology and attracted a lot of attention from the scientific community. Hence, identification of families with novel rare genetic neurological disorders not only helps in research of that particular disorder but they can also lead to ground breaking discoveries that have impact on other fields of biological sciences. The high incidence of intra-family marriages in Pakistan makes it a ‘land of opportunities’ to study rare genetic neurological disorders. In order to seize these opportunities we need to conduct epidemiological studies to identify large families with high

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researchers to grab our extended hand. We also need to remove any senseless restrictions on research and make Pakistan, â&#x20AC;&#x2DC;the land of opportunities for research on rare genetic diseasesâ&#x20AC;&#x2122;, a productive place to conduct research on rare genetic neurological disorders.

prevalence of rare genetic neurological disorders followed by research to identify the genes responsible for these disorders and the mechanism of action of their faulty or absent proteins. Further research can help us to not only develop treatment options for these diseases but also provide findings that may have ground breaking consequences in other aspects of biological sciences. However, it must be realized that Pakistan is a country with poor socio-economic conditions and understandably large investments are not made in the field of scientific research. But the opportunity to study rare genetic disorders in Pakistan should not be wasted. The way to counter this issue is to develop more collaboration with researchers in other countries where funding to support research is not a big problem. We can share knowledge and biological samples and through these collaborations perform high impact research. Therefore, we need to better advertise these opportunities and make it more conducive for other

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REFERENCES 1. 2. 3. 4.

Axelrod FB et.al. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet Journal of Rare Diseases 2007, 2:39. Vaphiades M, Brodsky MC. Pediatric optic atrophy. IntOphthalmolClin. 2012; 52: 17-28. Tan U. Uner Tan syndrome: history, clinical evaluations, genetics and the dynamics of human quadrupedalism. Open Neurol J. 2010; 4: 78-89. Harcourt-Smith WE, Ajello LC. Fossils, feet and the evolution of human bipedal locomotion. J Anat. 2004; 204(5): 403-16.

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G U I D E L I N E S

NATIONAL GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF PARKINSON’S DISEASE IN PAKISTAN Nadir A Syed (South City,Karachi), Farwa Ali (South City Hospital, Karachi), Khalid Sher (JPMC, Karachi) Amer Ikram (Doctors Hospital, Lahore), Bashir Soomro (Ziauddin, Karachi), Naila Shahbaz (DUHS, Karachi) Mughis Sheerani (AKU, Karachi), Sarwar Jamil (AKU, Karachi), Ahsan Numan (services Hospital, Lahore) Manzoor Lakhair (LUMS, Jamshoro), Irshad Awan (PIMS, Islamabad), Saleem Barech (BMC, Quetta) Haroon Basheer (Pakistan Parkinson's Society) ADVISOR’S: Ronald Pfieffer (USA), Zeba Vanek (USA), Jawwad Bajwa (KSA), Mustafa Saad Siddiqui (USA), Daniel Truong (USA) Correspondence to: Dr. Nadir A Syed, South City Hospital, Clifton, Karachi. Email: nadiralisyed@gmail.com Date of Submission: December 28, 2014, Date of Revision: January 30, 2015, Date of Acceptance: February 1, 2015

INTRODUCTION TO PARKINSON’S DISEASE Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s disease. Prevalence in people older than age 60 is approximately 1.4%.[1, 2] PD is characterized by many motor and non-motor symptoms. It presents with a range of motor symptoms usually consisting of asymmetric bradykinesia, resting tremor, and rigidity; postural instability may develop later in the course of the disease.[3, 4] However 'pre-motor' PD-a range of nonmotor symptoms, particularly sleep disorders, mood disorders, impaired sense of smell, and constipation may occur up to 20 years before the onset of motor symptoms.[5] The clinical paradigm has shifted from PD being considered a pure motor or movement disorder to being recognized as a systemic synucleinopathy with many motor and non-motor symptoms and signs. The etiology of PD is largely unknown, but a combination of genetic and environmental factors is postulated. Several genes have been associated with inherited and early onset form of PD (LRK1, PINK1, Parkin, and DJ-1) but these represent only a small subset (10-15%) of all PD cases.[6] It is now known that PD can present with changes in mood, sleep, behavior, cognition and autonomic function this can initiate referrals to psychiatric, general medicine, geriatric, orthopedic and even rheumatology clinics, before neurological referral is considered. Etiology is multifactorial and is thought to be related to multiple mechanisms. Factors associated with development or Parkinsonism include exposure to oxidant toxins (e.g. pesticides, MPTP), head trauma, manganese exposure, head trauma. General Approach to Parkinson’s disease

Diagnosis of Parkinson’s disease

tion combined with clinicopathological correlation. In subsequent studies it has been demonstrated to have up to 90 % accuracy in diagnosing PD when diagnosed by an experienced neurologist. This is a three step recommended strategy for diagnosis of Parkinson’s disease.

The diagnosis of PD remains primarily clinical. In 1988, Gibb and Lees developed the Queen Square Brain Bank (QSBB) criteria for PD, based on careful clinical observa-

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UK Queen Square Brain Bank Criteria for the diagnosis of Parkinson's disease[7] Step 1: Diagnosis of a Parkinsonian Syndrome

• •

Bradykinesia (slow to initiate voluntary movement with progressively reduced speed and amplitude of repetitive actions) and at least one of the following: • Muscular rigidity • Postural instability unrelated to primary visual, cerebellar, vestibular or proprioceptive dysfunction • Resting tremor

palsy, cerebellar signs, early severe autonomic involvement, Babinski's sign, early severe dementia with disturbance of language, memory or praxis Exposure to Neurotoxin Presence of cerebral tumour or communicating hydrocephalus on neuroimaging

Step 3: Supportive Criteria for Parkinson's Disease Three or more of the following are required for the diagnosis of definite Parkinson's disease • Unilateral onset • Rest tremor present • Progressive disorder • Persistent asymmetry primarily affecting the side of initial onset • Excellent response to levodopa (70%–100%) • Severe levodopa-induced chorea • Levodopa response for more than 5 years • Clinical course of over 10 years

Step 2: Exclusion Criteria for Parkinson's Disease History of: • Repeated strokes with stepwise progression • Repeated head injury • Antipsychotics or dopamine-depleting drugs • Definite encephalitis and/or oculogyric crisis on no drug treatment More than one affected relative (Note: this exclusion • criteria is usually ignored) • Sustained Remission • Negative response to large doses of levodopa (if malabsorption excluded) • Strictly unilateral features after 3 years • Other neurological features: supranuclear gaze

Work up of Parkinsonism at Initial Presentation In patients with a clear clinical diagnosis and no atypical signs the physician may decide not to order blood tests or neuroimaging studies. There is no definitive diagnostic test for PD. These tests are performed to diagnose other conditions that may present like Parkinson’s disease.

[9-11] Parkinson’s disease Mimics Once structural, infectious, toxic and metabolic causes of Parkinsonism have been excluded, the evaluating physician must consider features of the patient’s history and physical examination that may suggest an alternative cause for the symptoms. A diagnosis of idiopathic PD should be assumed only after ruling out PD mimics such as other tremor disorders, drug-induced Parkinsonism, vascular parkinsonism, normal pressure hydrocephalus and parkinsonism-plus conditions. The following table outlines features that may help in the differential diagnosis of these conditions:[3]

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Parkinson’s disease more likely

Alternative diagnosis more likely

Slow onset and progression of symptoms over months and years For example a 55 year old man presenting with slowly progressive difficulty using left hand with a mild tremor at rest over the past year

Sudden onset or rapid progression over days and weeks should suggest an alternative diagnosis such as a stroke, brain tumour or TB meningitis

Unilateral disease or significant asymmetry on signs and symptoms in the beginning of the disease

Symmetrical onset more commonly is associated with other Parkinsoniansyndromes such as Diffuse Lewy Body disease, Multisystem Atrophy, Progressive Supranuclear Palsy etc.

Tremor: Tremor usually involves extremities and, less commonly the jaw. Head tremor is almost never present in idiopathic PD. 25% of Parkinson’s patients may never manifest a tremor. The classic tremor in Parkinson’s disease is a slow resting (low frequency) pill-rolling tremor best seen when the hands are at rest or while the patient is walking.It decreases with activity and can be suppressed temporarily by the patient. Re-emergent tremor: Tremor tends to diminish at least temporarily once the patient is asked to stretch out the arms and may return as this becomes the new rest position. Onset of tremor is generally unilateral and over time may involve the other side

Tremor: Enhanced physiologic tremor: Tremor related to anxiety is present in outstretched hands and throughout the range of motion. Benign essential tremor is more prominent when the patient stretches out his hands as it is predominantly a postural tremor. Benign essential tremor often involves the head causing a side-to-side or up/down tremor (a 'no-no' or ‘yes-yes’ tremor). ). It can affect the voice, is worsened with activity and is often familial. Parkinson’s plus syndromes are less likely to have a tremor at presentation.

Responsive to Levodopa

Lack of robust response to Levodopa

Autonomic symptoms include urinary urgency, orthostasis

Early onset of multiple autonomic symptoms suggest MSA

Bulbar involvement is possible

Predominant early bulbar signs suggest a Parkinson’s Plus syndrome like PSP

Falls occur late after significant rigidity or bradykinesia develop

Frequent falls early in the course of disease suggests a Parkinson’s Plus syndrome like PSP

Non motor symptoms may include constipation, anosmia, insomnia and depression. Lack of eye movement restriction except there may be some impairment of conjugate upgaze and convergence

Vertical gaze palsy in which initial abnormality is impairment of downgaze with intact oculocephalic maneuver suggests PSP

Lack of early respiratory muscle compromise

Stridor/strangulated dysarthria suggests MSA Chronic history of neuroleptic use or antiemetic use suggests a medication induced parkinsonism

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Table 1 Neuroimaging in Parkinson’s disease and Parkinson’s Plus Syndromes

tant for the physician to partner with the patient and the family to treat PD. It is important that the patient understands that the treatment will allow for many years of very adequate function but that the disease is progressive and incurable. Any patient with social or functional impairment should be initiated on treatment. Almost all patients that present to a physician require some form of treatment. The most obvious motor symptom for many patients is tremor, which is socially distressing; however the tremor often does not impair function if it is not severe. Rigidity, bradykinesia and in later stages postural instability are frequently greater sources of functional impairment. [13]

In a patient with classic features of Parkinson’s disease, and absence of red flags for atypical Parkinsonism, neuroimaging is not indicated initially. If the patient subsequently develops any atypical features, then brain MRI without contrast can be considered [10, 12] Treatment of Motor Symptoms in Parkinson’s disease PD is the only common neurodegenerative condition in which effective long-term treatment is readily available. Special care needs to be exercised in treating PD as both under treatment and over treatment can worsen a patient's condition and may even accelerate the progression to disability. The key is to treat the patient appropriately and not to under or over treat. This implies a level of treatment that relieves symptoms to the point that the patient has a fairly good quality of life. The physician needs to explain to the patient early on that PD is an incurable but treatable disease that will require a lifelong patient-physician partnership. The objectives of optimal treatment should be clearly explained. The objectives should be to treatment to a point that the patient is adequately functional and has a good quality of life. The first step in managing PD is to determine whether treatment is needed or not. It is important for the physician to partner with the patient and the family to treat PD. The treatment usually results in many years of a productive and functional life. In many patients the disease does progress and the symptoms become refractory to the treatments. Patients with social or functional impairment should be initiated on treatment and almost all patients that present to a physician require some form of treatment. The most obvious motor symptom for many patients is tremor, which is socially distressing; however the tremor often does not impair function if it is not severe. Rigidity, bradykinesia and in later stages postural instability are frequently greater sources of functional impairment. [30] The first step in managing a diagnosed case of PD is to determine whether treatment is needed or not. It is impor-

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Overview of Pharmacologic Therapy for Motor Symptoms in Parkinson’s disease [9, 13-17] Pharmacologic treatment options include: Carbidopa/ levodopa; sooner or later virtually all patients with PD will require carbidopa/levodopa. Dopamine agonists (although not as effective ascarbidopa/ levodopa, carry an advantage of delaying motor fluctuations and dyskinesias, especially in younger patients) [35]. Monoamine oxidase type B inhibitors (symptomatic improvement is modest with these); these are rasagiline and selegiline)[36]. Anticholinergics (eg procyclidine and trihexyphenidyl). These predominantly improve the tremor, drooling and urinary frequency. These are associated with many adverse effects, which may be particularly severe in the elderly and include urinary retention, constipation, blurred vision, dry mouth, confusion, and orthostatic hypotension)[34,37]. Amantadine [38] may reduce dyskinesias very effectively and can also help tremor and fatigue. COMT inhibitors (entacapone, tolcapone)[39]; prolong the half-life of carbidopa/levodopa and make it last longer and make it more effective.

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Carbidopa/ levodop

bromocriptine, are still used in Pakistan but should be avoided due to the associated high frequency of cardiac valvular, peritoneal and pleural fibrosis. Common adverse effects of dopamine agonists include: Sedation (may be severe and cause sleep attacks that may be sudden and severe enough to cause car accidents). Confusion, disorientation, hallucinations, delusions, psychosis and hallucinations. Postural hypotension and nausea. Impulse control disorder; this can consist of pathological gambling, hypersexuality, compulsive eating, compulsive shopping, compulsive hobbying.

A variety of pharmacologic and non-pharmacologic treatments are effective in treating PD. The cheapest and the most effective medication is still carbidopa/levodopa. Common adverse effects include nausea and light headedness. In the past there was concern about potential neurotoxicity and acceleration of underlying disease associated with use of carbidopa/levodopa but this concern has been laid to rest. Recent studies reveal earlier use of carbidopa/levodopa does not accelerate progression of PD. Peak-dose dyskinesia (involuntary-dance like movements) may develop after several years of using carbidopa/levodopa in younger patients and patients on high doses. This is one reason why many neurologists would prefer to avoid carbidopa/levodopa as first line treatment in the younger (<60 years age) patient and initiate treatment with a dopamine agonist and rasagiline instead. In individuals already on carbidopa/ levodopa, shortening the interdose interval and reducing individual doses may reduce the severity and even postpone development of motor fluctuations and complications [40]. In Pakistan the available formulation of levodopa contains 250 mg levodopa in combination with 25 mg of carbidopa. This may not be the optimal formulation to be given in the earlier stages of PD. Using a 25 carbidopa/100 levodopa formulation (available as imported medicine) or quarter or half of the 25/250 pill may be better.

Response to Treatment as Parkinson’s disease Progresses As PD progresses the response to treatment varies. Early Parkinson's disease; The early stage of PD is also called the “honeymoon period” when symptoms respond well to a variety of treatments and there is a sustained response to single doses of medications. [41] Late Parkinson's disease; As PD progresses, the response to dopamine therapy becomes less sustained, probably as a consequence of the loss of dopaminergic neurons. Motor fluctuations develop and the addition of MAO-B inhibitors or COMT-inhibitors may then be considered. These agents increase the potency of levodopa and prolong its effect by inhibiting the metabolic breakdown of levodopa and increasing its bio-availability. If given in combination with Carbidopa/ levodopa they help to decrease off-time and prolong the on-time. MAO-B inhibitors include selegiline and rasagiline. This class of drug produces modest symptomatic benefit but has not been shown to delay motor complications. A rare adverse effect of selegiline but not rasagiline is precipitation of a hypertensive crisis if consumed with tyramine containing foods. COMTinhibitors includeentacapone and tolcapone. COMTinhibitors produce moderate improvement in motor symptoms. Entacapone in combination with levodopa shows minimal delay in onset of motor complications (dyskinesia). Tolcapone comes with a black box warning for fulminant liver failure, which may be fatal.

Dopamine Agonists Dihydroergocryptine, pergolide, pramipexole, ropinirole, piribedil, rotigotine, bromocriptine, cabergoline and lisuride are the dopamine agonists used in PD. Ropinirole is the most widely available and frequently used dopamine agonist in Pakistan. There is no particular difference in efficacy between different dopamine agonists, so physicians should familiarize themselves with the dosage titration and potential adverse effect of one of them. Ergot-based dopamine agonists, such as Treatment of Parkinson’s disease based on Patient’s Age

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In patients older than 60 years of age who present with symptoms, consider starting with carbidopa/levodopa as it is more effective and generally better tolerated. In younger patients (<60 years) it may be better to start with one of the dopamine agonists in order to delay the

dyskinesias that may occur with Carbidopa/levodopa therapy, particularly in the young PD patients. Eventually even the younger patients may require Carbidopa/ levodopa as the disease progresses and a more potent medication is needed.

Table 1; Characteristics of commonly used medications for motor symptoms in PD [19] Drug Class Levodopa Dopamine Agonists

Indication First line therapy in patients over 60 years of age First line therapy in younger patients or add on to carbidopa/levodopa

Impact on Motor symptoms Excellent Moderate

MAO-B Inhibitors

First line for mild disease with depression. Add on therapy for motor fluctuationsto carbidopa/levodopa

Limited

COMT inhibitors Anticholinergics

Add on therapy for motor fluctuations Limited use. Only improves PD tremor

Improves wearing off of Carbidopa/levodopa Limited

Amantadine

Reduces dyskinesias and can improve wearing off symptoms

Limited

Important Adverse Effects Motor fluctuations Dyskinesia Sedation/sleep attacks Impulse control disorder Pedal edema, Weight gain Serotonin syndrome and hypertensive crises may rarely occur Narrow therapeutic window Diarrhea Confusion, Dry eyes/mouth Urinary retention, Constipation Confusion Lividoreticularis Pedal edema

Table 2 [3] Relative Efficacy Profile Factors affecting treatment choices

Levodopa

Dopamine Agonists

MAO-B Inhibitors

COMT Inhibitors

Efficacy on motor symptoms Ease of Use Risk of inducing motor complications

High Low High

Moderate Moderate Low

Low Moderate Low

Moderate Low- Moderate Low

Table 3 Relative Cost of Different Medications (as listed in Pharma guide 2014, electronic version) Carbidopa/ levodopa 25/250 mg Aptidopa Dopasel Meddopa Neudopa Sinedopa Sinemet

Name of company

Price in PKR /tablet

Rasagiline 1 mg

Name of company

Price in PKR /tablet

Ropinirole 1 mg

Name of company

Price in PKR/tablet

aptcure kurative medera Platinum Valor/Al-Hameed OBS

8 8 8 8 9 14.61

Alzilo Rasagin

Searle HiranisPharma

19.20 11.40

Amantadine 100 mg Amantin PK-Merz Viofral

Name of company Gene-Tech Brookes Biocare

Price in PKR /tablet 11.35 15.60 13.25

Propinol Reol Requip Ronirol Ropinol XMG

Shrooq Genome GSK Hilton Amarant Atco

9.50 16,66 34.28 21.19 24,33 12

Table 4 Titration Template for Commonly Used Medications for Motor Symptoms in Parkinsonâ&#x20AC;&#x2122;s disease [19, 20]

Medication Carbidopa/levodopa Pramipexole

Start of titration 50 mg AM 3x0.088 mg

Weekly up-titration 50 mg Q3day 2nd week 3x0.18mg 3rd week 3x0.35mg Then weekly 3x0.18 mg 2nd week 0.52 mg 3rd week 1.05 mg 4th week 2.1 mg 5th week 3.15 mg Weekly 1mg 2 mg 2mg/24 hr 50 mg every 2 weeks

Pramipexole ER

0.25 mg AM

Ropinirole Ropinirole ER Rotigotine Patch Piribedil Selegiline Rasagiline Entacapone Tolcapone

1 mg AM 2 mg AM 2mg/24h 50 mg HS 50 mg AM 100 mg AM

50 mg every 3 days

Amantadine

100 mg AM

100 mg q3days

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Maintenance dose 3-4 x 100 mg

Daily dose 300-800 mg

3x0.35-0.7 mg 1x 1.05-2.1 mg

1.05-3.3 mg 1.05-3.15 mg

3x 3-8 mg 6-24 mg 4-8 mg/24h 2-3 x 50 mg 5-10 mg 1 mg 3-4 x 100 mg 2-3 x 100 mg at 6-12 hour intervals 1-3 x 100 mg

6-24 mg 6-24 mg 8-16 mg/24h 150-250 mg 5-10 mg 1 mg 600 mg 600 mg

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100-400 mg

Deep Brain Stimulation in Parkinson’s disease

dopamine or underlying anxiety/ depression. Nocturia may disturb the normal sleep pattern and may be due to an over active bladder or an underlying sub-clinical urinary tract infection.. Dopaminergic drug-wearing-off may contribute to poor sleep and this may require a bedtime dose of a long acting dopaminergic agent. Restless legs syndrome is commonly associated with Parkinson's disease and can be readily diagnosed and treated. RLS presents with restlessness, pain, cramps or vague discomfort in the legs upon rest, particularly after laying down to sleep at night. The symptoms improve upon movement, such as moving the legs or getting up and walking, but symptoms often return once the patient is recumbent again. RLS is associated with involuntary leg movements as well, which can occur during wakefulness or sleep. RLS symptoms should trigger a search for underlying iron deficiency, which should then be treated with iron replacement and Vitamin C which may facilitate its absorption. If iron deficiency is not present, RLS responds well to dopaminergic agonists such as ropinirole, typically administered 2 hours before bedtime. Gabapentin, pregabalin and tramadol also are effective REM sleep behavior disorder includes a variety of presentations wherein patients may seem to be acting out dreams. Questioning the family members may reveal the patient has been talking in their sleep or even thrashing around and acting out physical fights while asleep (which may result in injuries). Always screen for REM sleep behavior disorder as it is a treatable condition.[22-25] It is usually responsive to a low dose of clonazepam.

[21]

Deep brain stimulation of the sub thalamic nucleus or globus pallidus internum is used in the treatment of motor symptoms of PD. There are multiple theories to suggest the mechanism of action including a micro-lesioning effect, resetting of aberrant pathways and circuits and modulating excito-toxicity. Deep brain stimulation of the subthalamic nucleus or globus pallidum may be considered in the following situations. • • • • •

Medication refractory disabling tremor. Carbidopa/Levodopa responsive disease. Motor fluctuations (on-off fluctuating motor symptoms that require high doses of medications that need to be given very frequently. Disabling dyskinesias. Patient does not have dementia or severe depression.

Axial and autonomic symptoms and freezing of the gait usually does not get better with this surgery. The surgery should only be done by high trained and experienced Parkinson’s disease surgeons and after the surgery the medications and the stimulator needs to be adjusted by experienced Parkinson’s disease neurologists. It requires life-long management by these teams and if not done and managed properly can often make the condition of the patient worse after the surgery. Treatment of Non-Motor Symptoms in Parkinson’s Disease

Depression And Anxiety:

Non-motor symptoms are a major contributor to impaired quality of life of patients suffering from PD. [5] However, these symptoms are often neglected during evaluation and treatment. Non-motor symptoms are often easily treatable, but lack of attention to them may make treatment of motor symptoms more difficult.[12] Non-motor symptoms include behavioral symptoms like depression, anxiety and psychosis, sleep disorders, dementia, dysautonomia (dysphagia, drooling, constipation, urinary urgency and frequency, orthostatic hypotension) and sensory symptoms (pain, Restless Legs Syndrome, numbness, joint stiffness in the limbs affected by the symptoms, etc). Non-motor symptoms can precede motor symptoms by years.

Mood disorders are common in Parkinson's disease and are frequently under-recognized and under-treated. PD patients with depression may be difficult to motivate to engage in regular exercise and in rehabilitation programs. They also are more likely to be noncompliant with treatment. Serotonin specific reuptake inhibitors (SSRI's) often are effective in usual doses and can greatly improve the quality of life of the patients. Episodic shortness of breath and sweating are often seen with advancing Parkinson's disease and may or may not respond to dopaminergic medication. These resemble panic attacks.[17,18]. Anxiety can be a nonmotor component of PD and although it perhaps most often appears as a wearing off phenomenon, it also can present as a more pervasive sense of anxiety in some patients. It can often be treated by giving the dopaminergic medications more frequently at lower doses.

Sleep Disorders: These include rapid eye movement (REM) sleep behavi or disorder (acting out dreams), insomnia, restless legs syndrome (RLS), and poor sleep maintenance. Usually the history provides the diagnostic clues needed to address sleep issues. Insomnia can be related to lack of

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Dementia: PD dementia may develop in people after several years

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and correlates with the presence of subcortical and cortical Lewy bodies. Environmental modifications are the best tolerated interventions. Try to minimize changes to routine, provide familiar things and memory cues to minimize agitation.

may be helpful. Speech therapy is important along with assessment of swallowing and advice regarding the prevention of aspiration. Enteral feeding options (short-term nasogastric tube or percutaneous endoscopic gastrostomy) may be needed in advanced cases. [24] . Eating pureed and soft foods with the head slightly bent may be better and extra care with thin fluids like water and tough foods like meat that are more likely to cause dysphagia is important. Pills can be also be crushed and administered with yogurt to facilitate swallowing.

Discontinue potential aggravators: Anticholinergics, amantadine, tricyclic antidepressants, tolterodine and oxybutynin, benzodiazepines. If treatment becomes necessary, the addition of a cholinesterase inhibitor, such as rivastigmine, donepezil or galantamine may be considered. Memantine also may be tried.[26, 27]

Orthostatic hypotension: This is very important to recognize, prevent and treat as it can cause dizziness, fainting spells and falls. This is aggravated by volume depletion, diuretics, antihypertensive drugs, tricyclic antidepressants, nitrates and alphablockers used to treat prostatic hypertrophy. Dopaminergic drugs also may induce orthostatic hypotension. It improves with increased salt intake. Elevating the headend of the bed at night (30–40°) may be helpful, as may wearing of waist-high elastic-pressure stockings and/or abdominal binders (if weather allows). Changing positions slowly and exercises of the legs (leg crossing, toe raising, and thigh contraction) before sitting up and standing can help. If all of these are unsuccessful, medications, such as midodrine or fludrocortisone, may be necessary. [25,26]. Domperidone can block the peripheral effect of the dopaminergic medications and can help as well.

Psychosis: Symptoms of psychosis, such as hallucinations, delusions, and illusions, are complications of therapy and also may arise from the progression of the disease process. When they occur, it is important to first correct any metabolic abnormalities or fluid imbalance and to treat any infection. It is important to minimize polypharmacy. Decreasing or stopping non-levodopa medications and optimizing levodopa can improve psychosis. Antipsychotics may be needed, but those that are potent dopamine depleting drugs can worsen Parkinsonism, especially the typical antipsychotics. Quetiapine is a sedating antipsychotic that does not appear to worsen the motor symptoms of Parkinson's disease. However as with other atypical antipsychotics, there may be a small risk of cardiac complications and therefore its use requires considering the risks and benefits for each individual patient.

Constipation: Constipation is a manifestation of general bradykinesia and autonomic dysfunction in Parkinson’s disease. This is a common problem aggravated by poor oral intake of water/fiber. Bowel dysfunction has two components decreased bowel movement frequency and difficulty with the act of defecation. Decreased bowel movement frequency results from slow colon transit and the difficulty with the act of defecation is due to impaired coordination and relaxation of the anorectal muscles. Slow transit constipation often responds to increasing water intake, fiber (ispaghula husk) and regular use of Milk of Magnesia or lactulose. Defecatory dysfunction usually does not respond to these interventions.

Urinary Urgency, Frequency and Nocturia: These are common autonomic symptoms in PD. Recognizing and treating sub-clinical urinary tract infection is very important. Initial treatment may involve reduced intake of fluids after 6 pm and no caffeinated drinks after 12 noon. If that is not sufficient, then anticholinergic medications may help. Anticholinergics that do not cross the blood brain barrier are better, since these do not worsen cognition. Tolterodine (2 mg twice daily) can be considered for these symptoms. Botulinum toxin type A injected in the detrusor muscle can also help but is a very expensive form of treatment that should be given only by trained physicians.[22,23]. For patients who cannot tolerate medications, diapers and bedside urinals should be available for patients.

Drooling: Drooling is another common and distressing symptom. Drooling is typically due to impairment of the swallowing mechanism rather than overproduction of saliva and may improve with chewing gum or sucking on honey or ice. Drooling may require use of anticholinergic agents or botulinum toxin injections into the salivary glands [19].

Dysphagia: Multiple factors contribute to dysphagia in PD. Optimization of motor control with dopamine replacement therapy

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However anticholinergics should generally be avoided in the elderly patients and those with cognitive impairment as they can result in confusion, hallucinations, blurring of vision, constipation and urinary retention.

of motor and non-motor symptoms but also addressing multiple areas of rehabilitation and improving the quality of life of the individual as a whole. There is a significant role for speech therapy, swallow evaluations, physical therapy, exercise and gait training from the time of diagnosis. Counseling patients and discussing possible modifications to their life style and home set-up in anticipation of expected disease progressionalsoare important. There is increasing data to suggest that exercise is neuroprotective for Parkinson’s disease, may improve executive function and slow progression of motor symptoms. SPARX trial and other smaller studies show that exercise improves motor scores in patients with Parkinson’s disease hence reducing falls and improves quality of life.[31-44] Levodopa therapy is related to increase homocystine due to its metabolism by COMT enzyme. This theoretically increases the risk of stroke in patients suffering from Parkinson’s treated with levodopa. It might be reasonable to treat prophylactically with Vitamin B 12, folate, Vitamin B6.[45] Rehabilitation measures are focused towards improving mobility and preventing fall-related morbidity. The team caring for a PD patient should ideally be a combination of a physician, speech therapist, occupational therapist and physical therapist.[13, 46, 47]

Pain and Dystonia: Patients with PD suffer from pain related to multiple pathogenic mechanisms, including central and peripherally mediated pain. Some of this may be related to immobilization from bradykinesia or dystonia. Exercise, physical therapy, pain management and botulinum toxin injections for dystonia may improve the quality of life of the patient.[28-30] When to Refer to a Neurologist Primary care providers can diagnose and treat Parkinsons however consider referring to a neurologist if diagnosis is not clear; difficulty in managing or complications with management; suboptimal response with management options Importance of Multidisciplinary Care in the Management of Parkinson’s disease Effective management of PD not only includes management Fall prevention in Parkinson’s Disease.

Gait Training: Take larger steps and make larger truns Home modifications; - Imporve lighting. - Remove rugs and minimize clutter. - Avoid slippery surfaces Careful selection of gait aid: Usually walker better than cane Most Falls occur during Freezing: Use Laser pointers or visual cues to help re-initiate gait Always consider an early referral to Physical medicine Work closely with the family and care takers [48, 49] Resources and Support for Patients with Parkinson’s disease There are many global patient education and advocacy forums where patients may be referred for information and counseling. Pakistan Parkinson's Society American Parkinson’s Disease Association www.apdaparkinson.org National Parkinson Foundation. www.parkinson.org The Michael J. Fox Foundation for Parkinson's Research www.michaeljfox.org World Parkinson Congress. www.pdf.org/world_parkinson_congress

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