Chinnock P, Roberts I This record should be cited as: Chinnock P, Roberts I. Gangliosides for acute spinal cord injury. (Protocol) The Cochrane Databa

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1 T A B L E O F C O N T E N T S ABSTRACT BACKGROUND OBJECTIVES CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES METHODS OF THE REVIEW POTENTIAL CONFLICT OF INTEREST SOURCES OF SUPPORT REFERENCES COVER SHEET Copyright 005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd i

2 Chinnock P, Roberts I This record should be cited as: Chinnock P, Roberts I. Gangliosides for acute spinal cord injury. (Protocol) The Cochrane Database of Systematic Reviews, Issue. Art. No.: CD DOI: 0.00/ CD This version first published online: July 00 in Issue,. Date of most recent substantive amendment: 8 February 00 A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: To quantify the evidence for the effectiveness and safety of gangliosides when used to treat acute spinal cord injury. B A C K G R O U N D Acute spinal cord injury Acute spinal cord injury (SCI) is damage to the spinal cord that results in loss of feeling and movement. The consequences can be devastating for the patient and his or her carers. There is no accepted figure for the number of new cases of acute SCI globally; estimates range from 5 to 40 cases per million annually (Sekhon 00). The Japanese Society of Paraplegia has estimated the annual incidence nationally to be 9.4 per million (Shingu 994). In the USA, it has been estimated that the number of cases admitted to hospitals will increase from,500 in 994 to,400 in 00, and that the number of people living with the consequences of an acute SCI will increase from 07,000 to 47,00 over the same period (Lasfargues 995). Those injured are often young; a US study found that average age at injury was (Kirshblum 00). Leading causes of acute SCI are road traffic injury, violence, and injuries sustained in sports and other recreational activities (particularly diving and certain forms of football). The picture varies considerably between and within countries; thus traffic injury is the biggest cause in most developed countries (44.9% in Japan (Shingu 994) but in south-eastern Turkey the leading causes were falls (7.%), gunshot wounds (9.%) and traffic injury (5.%) (Karamehmetoglu 997). Care for people with acute SCI has improved, leading to an increase in survival rates. Attempts to improve patients feeling and movement have involved the use of a wide range of drugs. Gangliosides Gangliosides are compounds that occur naturally in cell membranes. They are particularly abundant in the membranes of the central nervous system. In vitro studies with gangliosides, dating back to the 970s, suggested that gangliosides could promote axon growth (Roisen 98). Animal studies have suggested that gangliosides may have protective effects on nerves and, in the longerterm, help them to re-grow (Ledeen 984). The mechanisms of ganglioside action remain unclear (Blight 00) but those proposed include anti-excitotoxic activity, apoptosis prevention, and potentiation of neuritic sprouting and the effects of nerve growth factors (Geisler 00). Clinical trials have taken place using gangliosides for a number of neurological conditions, most notably stroke (for which use there has been a Cochrane systematic review (Candelise 00) and Parkinson s disease (Schneider 998). No major problem with adverse effects has been detected, although sporadic cases of Guillain- Barré syndrome have been noted in stroke patients receiving gangliosides (Candelise 00). The potential use of gangliosides for patients with SCI has attracted considerable attention within the medical community and, in the USA, more widely (Torg 995). Researchers have focused on one ganglioside - GM ganglioside (monosialotetrahexosylganglioside GM; Sygen ). Other gangliosides include GM, GM, GDa and GDb. O B J E C T I V E S To quantify the evidence for the effectiveness and safety of gangliosides when used to treat acute spinal cord injury. Copyright 005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

3 C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W Types of studies All randomised controlled trials (including quasi-randomised), where controls may receive standard treatment, no treatment, or a placebo. Types of participants All patients with a diagnosis of acute spinal cord injury. The acute period will be taken as within one week of the injury. Types of intervention All treatment with gangliosides (independently of duration, dosage and route of administration), with and without the use of other drug treatment (including steroids which are now given as standard treatment in many US hospitals). Types of outcome measures The following outcome measures will be included, as recorded after one year of follow-up (or the nearest date possible): recovery of motor function improvement in sensory measures (e.g. pinprick and light touch sensation) measures of functional activity / activities of daily living (ADL) infections and any other adverse effects recorded in the study, including Guillain-Barré syndrome all-cause mortality GI bleeding, pneumonia, atelectasis and other problems specific to acute spinal cord injury. S E A R C H S T R A T E G Y F O R I D E N T I F I C A T I O N O F S T U D I E S See: search strategy We will search the following databases to identify trials for inclusion: CENTRAL, MEDLINE, EMBASE, and the National Research Register. We will also search web-based trials registers such as Current Controlled Trials. We will use the following keywords, with appropriate thesaurus terms and truncation as appropriate for each database: (SCI OR spinal cord injury), (paraplegia), (quadriplegia), (tetraplagia), (*paresis) AND (gangliosides OR GM- OR GM- or Sygen) It is also hoped to search the files of the US National Acute Spinal Cord Injury Study. Fidia Pharmaceuticals, who manufacture GM ganglioside as Sygen, have been contacted to enquire whether they have any unpublished data on clinical studies with this drug that they are willing to have included in this systematic review. There will be no language restrictions. M E T H O D S O F T H E R E V I E W Abstracts of all studies identified will be scanned by both reviewers and the full text of relevant articles will be retrieved. The two reviewers will independently assess the identified studies for eligibility. Any disagreement will be resolved by discussion. The quality of trials will be assessed using methodology developed by Schultz and Chalmers (Schulz 995).This considers whether the intervention was blinded, whether people evaluating outcome are blinded, how many subjects were followed up, and the quality of the randomisation process. Allocation concealment will be rated: A - adequate, B - unclear and C - inadequate. The reviewers will ascertain whether intention-to-treat analysis has been undertaken in the trials. Clinical data will be reported from each trial. Where appropriate, authors will be contacted for additional information. Data will be extracted from each study using an appropriate data extraction form. A fixed effects model will be assumed in the analysis. For dichotomous outcomes, odds ratios with 95% confidence intervals (95%CI) will be calculated. For continuous data, weighted mean differences (WMD) will be used. A standard heterogeneity test will be used to assist in decisions whether or not to produce typical estimates of effect. Sub-group analysis will be conducted as follows: according to the quality of allocation concealment in trials, type of ganglioside, whether administration is early (within eight hours) or late, and whether spinal injury is considered complete or incomplete. If there is heterogeneity in the length of follow-up, then a sensitivity analysis will be considered, data allowing. P O T E N T I A L I N T E R E S T None known. C O N F L I C T O F S O U R C E S O F S U P P O R T External sources of support National Health Service UK Internal sources of support No sources of support supplied Copyright 005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

4 Additional references Blight 00 Blight A. Miracles and molecules - progress in spinal cord repair. Nature Neuroscience Supplement 00;5: Candelise 00 Candelise L, Ciccone A. Gangliosides for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library,, 00.Oxford: Update Software.0.00/ CD Geisler 00 Geisler FH, Coleman WP, Grieco G, Poonian D (Collective Name - the Sygen Study Group). The Sygen multicenter acute spinal cord injury study. Spine 00;6(4 Suppl):S Karamehmetoglu 997 Karamehmetoglu SS, Nas K, Karacan I, Sarac AJ, Koyuncu H, Ataoglu S, Erdogan F. Traumatic spinal cord injuries in southeast Turkey: an epidemiological study. Spinal Cord 997;5(8):5-55. Kirshblum 00 Kirshblum SC, Groah SL, McKinley WO, Gittler MS, Stiens SA. Spinal cord injury medicine.. Etiology, classification, and acute medical management. Archives of Physical Medicine & Rehabilitation 00;8( Suppl ):S50-7, S Lasfargues 995 Lasfargues JE, Custis D, Morrone F, Carswell J, Nguyen T. A model for estimating spinal cord injury prevalence in the United States. Paraplegia 995;():6-68. R E F E R E N C E S Ledeen 984 Ledeen RW. Biology of gangliosides: neuritogenic and neuronotrophic properties. Journal of Neuroscience Research 984;(- ): Roisen 98 Roisen F, Bartfield H, Nagele R, Yorke G. Ganglioside stimulation of axonal sprouting in vitro. Science 98;4(450): Schneider 998 Schneider JS. GM ganglioside in the treatment of Parkinson s disease. Annals of the New York Academy of Science 998;845(Jun):6-7. Schulz 995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 995; 7(5): Sekhon 00 Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 00;6(4):Suppl S-. Shingu 994 Shingu H, Ikata T, Katoh S, Akatsu. Spinal cord injuries in Japan: a nationwide epidemiological survey in 990. Paraplegia 994;(): -8. Torg 995 Torg JS, Currier B, Douglas R, Hershman E, O Leary PF. Symposium: spinal cord resuscitation. Contemporary Orthopaedics 995;0 (6): , Title Authors Contribution of author(s) Issue protocol first published 00/4 C O V E R S H E E T Gangliosides for acute spinal cord injury Chinnock P, Roberts I Date of most recent amendment 6 August 00 Date of most recent SUBSTANTIVE amendment Information not supplied by author 8 February 00 Review expected to be published in Issue, 004 What s New DOI Cochrane Library number Editorial group Editorial group code Information not supplied by author 0.00/ CD CD Cochrane Injuries Group HM-INJ Copyright 005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd