Ivig Neurology Guideline

7/28/2019 Ivig Neurology Guideline

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Guidelines on the Use of Intravenous ImmuneGlobulin (IVIG) for Neurologic Conditions


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CopyrightThis guideline is copyrighted by the National Technical Working Group on Blood and Blood Products(NTWG). The guideline and the illustrations herein may not be reproduced without the express writtenpermission of the NTWG. The NTWG reserves the right at any time, and at its sole discretion, to change orrevoke this authorization.

Disclaimer

Care has been taken in the preparation of the information contained in this document. Nonetheless, anyperson seeking to apply or consult these guidelines is expected to use independent medical judgment in thecontext of individual clinical circumstances or seek out the supervision of a qualified clinician. The NationalTechnical Working Group on Blood and Blood Products makes no representation or warranties of any kindwhatsoever regarding their content or use or application and disclaims any responsibility for their applicationor use in any way.


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TABLE OF CONTENTS

Executive Summary........................................................................................................................................ 4Introduction ..................................................................................................................................................... 5Methods .......................................................................................................................................................... 8

Acute Disseminated Encephalomyelitis .........................................................................................................11Adrenoleukodystrophy ...................................................................................................................................14Amyotrophic Lateral Sclerosis .......................................................................................................................15Autism............................................................................................................................................................17Chronic Inflammatory Demyelinating Polyneuropathy ...................................................................................19Critical Illness Polyneuropathy.......................................................................................................................22Dermatomyositis ............................................................................................................................................23Diabetic Neuropathy ......................................................................................................................................26Guillain-Barr Syndrome................................................................................................................................28Inclusion Body Myositis..................................................................................................................................31Intractable Childhood Epilepsy ......................................................................................................................33Lambert-Eaton Myasthenic Syndrome...........................................................................................................35Multifocal Motor Neuropathy ..........................................................................................................................37Multiple Sclerosis ...........................................................................................................................................39Myasthenia Gravis .........................................................................................................................................43Opsoclonus-Myoclonus..................................................................................................................................47Paraproteinemic Neuropathy (IgM variant) ....................................................................................................49Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections .......................51POEMS Syndrome.........................................................................................................................................53Polymyositis...................................................................................................................................................55Rasmussens Encephalitis .............................................................................................................................57Stiff Person Syndrome...................................................................................................................................59External Review.............................................................................................................................................61Summary of Recommendations for Use of IVIG for Adult and Pediatric Neurologic Conditions....................63References ....................................................................................................................................................65


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EXECUTIVE SUMMARY

Background: Canadas per capita utilization of intravenous immune globulin (IVIG) grew by approximately71% between 1999 and 2004, making Canada one of the worlds highest per capita users of IVIG. It isbelieved that most of this growth is attributable to off-label usage. To help ensure IVIG utilization is inkeeping with an evidence-based approach to the practice of medicine, the National Technical WorkingGroup on Blood and Blood Products (NTWG) and Canadian Blood Services (CBS) convened a panel of

national experts to develop an evidence-based practice guideline on the use of IVIG for neurologicconditions.

Objective: The mandate of the expert panel was to review evidence regarding use of IVIG for 22neurologic conditions and formulate recommendations on IVIG use for each.

Methods: A panel of six clinical experts, one expert in practice guideline development and fourrepresentatives from the NTWG met to review the evidence and reach consensus on the recommendationsfor the use of IVIG. The primary sources used by the panel were two recent evidence-based reviews.Recommendations were based on interpretation of the available evidence, and where evidence was lacking,consensus of expert clinical opinion. A draft of the practice guideline was circulated to neurologists inCanada for feedback. The results of this process were reviewed by the expert panel and modifications tothe draft guideline were made where appropriate. This practice guideline will provide the NTWG with abasis for making recommendations to provincial and territorial health ministries regarding IVIG utilizationmanagement.

Results: Recommendations for use of IVIG were made for 14 conditions. IVIG was not recommended foreight conditions.

Specific recommendations for use of IVIG were developed for: Acute disseminated encephalomyelitis Chronic inflammatory demyelinating polyneuropathy Dermatomyositis Diabetic neuropathy Guillain-Barr syndrome

Lambert-Eaton myasthenic syndrome Multifocal motor neuropathy Multiple sclerosis Myasthenia gravis Opsoclonus-myoclonus Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections Polymyositis Rasmussens encephalitis Stiff person syndrome

IVIG was not recommended for: Adrenoleukodystrophy

Amyotropic lateral sclerosis Autism Critical illness polyneuropathy Inclusion body myositis Intractable childhood epilepsy Paraproteinemic neuropathy (IgM variant) POEMS syndrome

Conclusions: Development and dissemination of evidence-based clinical practice guidelines may help tofacilitate appropriate utilization of IVIG.


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INTRODUCTION

Description of IVIG

Intravenous immune globulin (IVIG) is a fractionated blood product consisting of concentrated immuneglobulin, primarily IgG, derived from human plasma in pools of 3,000 to 10,000 or more donors. IVIG wasfirst introduced in the early 1980s for the treatment of primary humoral immunodeficiencies and is currently

licensed by Health Canada for treatment of primary and secondary immunodeficiency diseases, allogenicbone marrow transplantation, chronic B-cell lymphocytic leukemia, pediatric HIV-infection, Kawasakidisease and idiopathic thrombocytopenic purpura.

In addition to its licensed indications, IVIG is used to treat a growing range of off-label indications,including a variety of immunological disorders, hematological conditions and neurological diseases. HealthCanada has not evaluated the efficacy and risk of using a licensed IVIG product in the treatment of off-label clinical indications. Nevertheless, some of these applications have a reasonably strong foundation inthe medical literature while others have a less conclusive or even no basis in evidence.

In appropriately selected patients and clinical settings, IVIG therapy can be lifesaving. However, there arerisks and significant costs associated with IVIG. This provides a strong incentive to ensure that IVIG is

prescribed only for appropriate clinical indications for which there is a known benefit.

Risks Associated with IVIG

The rate of systemic reactions to IVIG infusion is usually reported to be in the three to 15% range. Thesereactions are typically self-limited, of mild to moderate severity and can often be avoided by reducing therate of infusion during subsequent transfusions of IVIG. However, there is a paucity of published reports ofprospectively collected data on the adverse event rate associated with IVIG. Moreover, each brand of IVIGmay have unique tolerability and safety profiles due to proprietary differences in the manufacturing methods.

A recent review by Pierce and Jain (2003) found that a significant number of IVIG-associated seriousadverse events affecting renal, cardiovascular, central nervous, integumentary, and hematologic systems

have been reported. In view of the seriousness of potential adverse events and current lack of datasurrounding their frequency, the review concluded that clinicians should limit their prescription of IVIG toconditions for which efficacy is supported by adequate and well-controlled clinical trials.

The risk of infectious complications from IVIG is extremely low. The requirements for donor screening andtransmissible disease testing of input plasma are stringent. In addition, the IVIG manufacturing processitself includes at least one and usually two steps of viral inactivation or removal to protect against infectiousagents that might be present despite screening procedures. Hepatitis B virus and HIV have never beentransmitted through IVIG. There has been no reported transmission of hepatitis C virus from any productused in Canada and there is no known case of Creutzfeldt-Jacob disease (CJD) or variant CJD transmissiondue to IVIG transfusion. Nevertheless, IVIG is a product made from large pools of human plasma and it isnot possible to claim with certainty that there is no risk of infectious disease transmission.

Costs of IVIG

In 1997 there was a worldwide IVIG shortage. The shortage was due primarily to disruption of productionand product withdrawals caused by the need for US-based plasma fractionators to comply with morestringent US Food and Drug Administration requirements. Although such a severe shortage has notrecurred, the cost of IVIG has continued to rise. This has led to the adoption of various approaches tocontrol IVIG use in several countries, in particular in Canada and Australia.


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IVIG is an expensive therapeutic alternative in disease states where other interventions may be possible orwhere its efficacy is questionable. IVIG represents the single largest component (approximately one-third)of Canadian Blood Services (CBS) plasma protein products budget, which, in turn, represents approximatelyhalf of the CBS total budget. Since Canada is not self-sufficient in plasma, IVIG used in this country ismanufactured from plasma donated either voluntarily in Canada or by paid donors in the United States.CBS ensures a supply of IVIG for Canada through multi-year agreements with manufacturers, which providestability in pricing and purchase volumes. Funding for IVIG comes from provincial and territorial health

budgets as part of their payment to CBS, thus this charge is not directly visible to either patient or provider.Provinces and territories are charged for the actual amount of product used in their province/territory. Thereare also direct hospital costs as IVIG must be administered intravenously over several hours.

IVIG currently costs between $55 and $70 per gram (all estimates in Canadian dollars), but in past yearswith a less favourable US exchange rate the cost has been as high as $75-$80. The cost of one infusion of1 g/kg of IVIG for a 70 kg adult is approximately $5,000. Refer to Table 1.

Table 1. Examples of the cost of IVIG

Cost of IVIG*Patient Schedule

0.5g/kg 1.0g/kg 2.0g/kg1 dose $700 $1,400 $2,8001 x monthly for 1 yr $8,400 $16,800 $33,600

20 kg child

1 x 3 weeks for 1 yr $12,000 $24,000 $48,0001 dose $2,500 $5,000 $10,0001 x monthly for 1 yr $30,000 $60,000 $120,000

70 kg adult

1 x 3 weeks for 1 yr $42,500 $85,000 $170,000*Cost of IVIG alone, does not include costs associated with administration of IVIG. All prices are in Canadian dollars.

Canadas per capita utilization of IVIG grew by approximately 71% between 1999 and 2004, making Canadaone of the highest per capita users of IVIG in the world. It is believed that most of the growth in use isattributable to off-label usage.

Impetus and Mandate to Develop an IVIG Practice Guideline

In view of the escalating costs, potential for shortages and growing off-label usage associated with IVIG,there have been several initiatives in Canada aimed at ensuring that IVIG utilization remains appropriateand in keeping with an evidence-based approach to the practice of medicine. CBS convened a nationalconsensus conference, entitled: Prescribing Intravenous Immune Globulin: Prioritizing Use and OptimizingPractice, in Toronto in October 2000. The recommendations of the panel of this conference can be foundon the Canadian Blood Services website (www.bloodservices.ca). British Columbia implemented an IVIGutilization management program in 2002, which involved the division of medical conditions into thoserequiring either regular or special approval for IVIG use based on the evidence of benefit. The Atlanticprovinces implemented a similar program in 2003, and individual facilities in other provinces undertook theirown utilization management initiatives.

To help strengthen these efforts, the National Technical Working Group on Blood and Blood Products(NTWG), an advisory group to provincial and territorial Deputy Ministers of Health regarding blood utilizationmanagement issues, has been working on the development of an inter-provincial collaborative frameworkfor IVIG utilization management. To facilitate this objective the NTWG and Canadian Blood Servicesconvened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG forneurologic conditions.

The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditionsand formulate recommendations on IVIG use for each condition. The practice guideline developed by thisprocess will provide the NTWG with a basis for making recommendations to provincial and territorial health
http://www.bloodservices.ca/http://www.bloodservices.ca/


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ministries regarding IVIG utilization management. The practice guideline will also be widely circulated toclinicians in Canada.


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METHODS

Expert Panel

Letters of invitation were sent to a number of neurologists across Canada regarded by their peers asexperts in their field. The panel consisted of six clinical experts, one expert in practice guidelinedevelopment and four representatives from the NTWG.

Table 2. Members of the Expert Panel

Clinical experts AffiliationDr. Brenda Banwell Director, Paediatric Multiple Sclerosis Clinic, Hospital for Sick Kids, TorontoDr. Timothy Benstead Division of Neurology, QE II Health Sciences Centre, HalifaxDr. Vera Bril Division of Neurology, Toronto General Hospital, TorontoDr. Tom Feasby Division of Neurology, Department of Medicine, University of Alberta, EdmontonDr. Mark Freedman Division of Neurology, Ottawa General Hospital, OttawaDr. Angelika Hahn Clinical Neurological Sciences, London Health Sciences, London

NTWG representatives AffiliationDr. Heather Hume (chair) Executive Medical Director, Transfusion Medicine, Canadian Blood Services, Ottawa

Dr. John Freedman Director, Transfusion Medicine, St. Michaels Hospital, TorontoDr. David Pi Director, Provincial Blood Coordinating Office, St. Pauls Hospital, VancouverDr. Louis Wadsworth Program Head, Hematopathology, Childrens & Womens Health Centre of BC, VancouverPractice guidelines expert AffiliationDr. Melissa Brouwers Director, Program in Evidence-based Care, CCO. Assistant Professor, McMaster University, Hamilton

The panel met in Toronto on September 9 and 10, 2004. Panel members were asked to declare anypotential conflicts of interest. Conflicts were declared and noted by the Chair.

Clinical Conditions

The expert panel evaluated the use of IVIG for 22 neurologic conditions. Please refer to Table 3 for furtherdetails.

Table 3. Included clinical conditions

Clinical ConditionsAcute disseminated encephalomyelitis Lambert-Eaton myasthenic syndromeAdrenoleukodystrophy Multifocal motor neuropathyAmyotrophic lateral sclerosis Multiple sclerosisAutism Myasthenia gravisChronic inflammatory demyelinating polyradiculoneouropathy Opsoclonus-myoclonusCritical illness polyneuropathy Paraproteinemic neuropathyDermatomyositis PANDAS*Diabetic neuropathy POEMS syndrome**

Epilepsy (intractable childhood) PolymyositisGuillain-Barr syndrome Rasmussens encephalitisInclusion body myositis Stiff person syndrome

*Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections**Polyneuropathy, organomegaly, endrocrinopathy, M protein and skin changes

Evidence-base for Practice Guideline

The expert panel was provided with recent evidence-based reviews of IVIG use from two sources:


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1) Systematic reviews by the Chalmers Research Institute, University of Ottawa.(a) Sources searched: Medline, Embase, Current Contents, PreMedline, Dissertation Abstracts,

CENTRAL (Cochrane Librarys controlled clinical trials registry) plus manual searching ofrelevant journals, reference lists and unpublished sources.

(b) Dates searched: 1966 to 20042) The Appropriateness of IVIG Evidence Review conducted by Dr. Feasby and colleagues as part of

CIHR -funded research, University of Alberta.

(a) Sources searched: PubMed, the Cochrane Library and reference lists of relevant publications.(b) Publication dates searched: Not reportedMembers of the expert panel were also encouraged to identify any additional studies relevant to thedevelopment of evidence-based recommendations. Refer to Table 4 for further information regardingsources used for each of the conditions considered by the expert panel.

Table 4. Sources used in the development of the practice guideline

Clinical ConditionAppropriateness of

IVIG reviewChalmers Institute

SR of IVIGLiterature Search by

Expert PanelAcute disseminated encephalomyelitis 9Adrenoleukodystrophy 9Amyotrophic lateral sclerosis 9

Autism 9Chronic inflammatory demyelinating polyradiculoneuropathy 9 9Critical illness polyneuropathy 9Dermatomyositis 9 9Diabetic neuropathy 9Guillain-Barr syndrome 9 9Inclusion body myositis 9 9Intractable childhood epilepsy 9Lambert-Eaton myasthenic syndrome 9Multifocal motor neuropathy 9 9Multiple sclerosis 9 9 9Myasthenia gravis 9 9Opsoclonus-myoclonus 9PANDAS* 9Paraproteinemic neuropathy (IgM variant) 9POEMS syndrome** 9Polymyositis 9 9Rasmussens encephalitis 9Stiff person syndrome 9

SR Systematic review. * Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections**Polyneuropathy, organomegaly, endrocrinopathy, M protein, skin changes

The level of evidence available to inform recommendations for each condition was assessed using a systemdeveloped by Bob Phillips, Chris Ball, David Sackett, Brian Haynes, Sharon Straus and Finlay McAlisterfrom the NHS Centre for Evidence-Based Medicine. Refer to Table 5 for further details.

Development of Recommendations for Use of IVIG

Recommendations were based on interpretation of the available evidence, and where evidence was lacking,consensus of expert clinical opinion. Interpretation of the evidence involved recognition and discussion offactors influencing the decision-making process. The expert panel evaluated IVIG for a diverse range ofneurologic conditions and the level of evidence required to recommend IVIG varied depending upon thecondition for several reasons. For example, for rare diseases that have no effective alternative treatmentsthe threshold was lower than for common diseases with established standard therapies. Refer to Table 6 fora list of some of the factors considered by the expert panel in their deliberations. While the members of the


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panel are cognizant of the costs associated with IVIG, the role of costs and cost utility was notsystematically factored into the discussions and the recommendations that emerged.

Table 5. Levels of evidence

Level ofEvidence

Whether a treatment is efficacious/effective/harmful Whether a treatment is superior to another drug in same class

1a Systematic Review (with homogeneity) of RCTs Systematic Review (with homogeneity) of head-to-head RCTs

1bIndividual RCT (with narrow confidence interval),including well-designed crossover trials

Within a head-to-head RCT with clinically important outcomes

1c All or none* N/A2a Systematic Review (with homogeneity) of cohort studies Within a head-to-head RCT with validated surrogate outcomes

2b Individual cohort study (including low quality RCTs)Across RCTs of different drugs vs. placebo in similar or differentpatients with clinically important or validated surrogate outcomes

2c Outcomes research; ecological studies N/A

3a SR (with homogeneity) of case-control studiesAcross subgroup analyses from RCTs of different drugs vs. placeboin similar or different patients, with clinically important or validatedsurrogate outcomes

3b Individual case-control studyAcross RCTs of different drugs vs. placebo in similar or differentpatients but with un-validated surrogate outcomes

4 Case-series (and poor quality cohort and case-controlstudies) Between non-randomized studies (observational studies andadministrative database research) with clinically important outcomes

5Expert opinion without explicit critical appraisal, orbased on physiology, bench research or first principles

Expert opinion without explicit critical appraisal, or based onphysiology, bench research or first principles; or non-randomizedstudies with un-validated surrogate outcomes

Developed by B. Phillips, C. Ball, D. Sackett, B. Haynes, S. Straus, F. McAlister from the NHS Centre for Evidence-Based Medicine.*Met when all patients died before the treatment became available, but some now survive on it; or when some patients died beforetreatment became available, but none now die of it. RCT=Randomized Control Trial. SR=Systematic Review. N/A Not applicable.

Table 6. Contextual and methodological factors

Common Factors Considered by Expert Panel For rare conditions, small sample size and study design used will not likely improve

The severity of the condition and the availability of alternative treatment options Juxtaposing the level of evidence (e.g. case series) against the natural history of the disease

The presence of clinical heterogeneity of the study sample and/or in presentation of the disorder

The appropriateness of the comparison group (e.g. placebo-controlled or appropriate standard therapy)

The appropriateness of outcomes measured and whether the most important outcomes were evaluated

The consistency of findings across different studies for the same condition

The clinical significance of improvement versus statistical significance

External Review

Feedback on this practice guideline was obtained from neurologists throughout Canada. The process wasinformed by the Practitioner Feedbackmethodology used to create clinical practice guidelines on cancercare in Ontario (Browman et al., 1998). A draft of this practice guideline, along with an accompanying letterof explanation and feedback survey, was e-mailed to members of the Canadian Neurological Society.Practitioners were given the option of faxing their completed survey or providing their responses onlinethrough a Web-based survey tool. Written comments on the draft guideline were encouraged. Practitionerswere asked to provide feedback within three weeks.


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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Clinical Description

Acute disseminated encephalomyelitis (ADEM) is an uncommon, usually self-limited, disease thatpredominantly occurs in children and young adults. ADEM often follows a viral infection or immunization.Patients typically present with fever, meningeal signs, myelopathy and acute encephalopathy. The most

common neurologic signs are motor deficits (e.g. ataxia, hemiparesis) and impaired consciousness.

ADEM is thought to be an autoimmune disorder of the central nervous system in which myelin autoantigensshare antigenic determinants with an infecting pathogen. Most patients show multiple characteristic lesionsof demyelination in the deep and subcortical white matter on MRI. The differential diagnosis includes otherinflammatory demyelinating disorders such as multiple sclerosis (MS), optic neuritis and transverse myelitis.

Although most patients with ADEM experience a monophasic course, occasional patients may experiencerecurrence of the initial symptoms (relapsing ADEM), or may experience a second episode of ADEM(multiphasic ADEM). The National Multiple Sclerosis Society has recently convened a panel of experts toreview the clinical features of ADEM and provide consensus clinical definitions for the various ADEMphenotypes (in press). Even with clinical definitions for relapsing and multiphasic ADEM, distinction from MS

remains very difficult and some children and adults with ADEM will eventually meet criteria for the diagnosisof MS. Treatment at the time of acute symptomatology should be based on the clinical diagnosis at the timeof illness, as most patients with ADEM (or an ADEM-like illness that is eventually determined to be the firstmanifestation of MS) are profoundly ill.

High-dose corticosteroids are first-line treatment for ADEM. Plasmapheresis and IVIG have been used forpatients who fail to respond to steroid therapy. Most patients with ADEM recover completely over a period offour to six weeks from onset of symptoms.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified 25 cases of IVIG use for pediatric ADEM and eight

cases of IVIG use for adult ADEM (level of evidence: 4). The majority of pediatric case reports involvedchildren with monophasic ADEM. Overall, 70% (14/20) of children with monophasic ADEM completelyrecovered following administration of IVIG or IVIG plus corticosteroids. Of the five cases of relapsing ADEM,two children completely recovered after IVIG and the three others showed improvement. Two children withrelapsing ADEM required monthly IVIG to maintain their response. Refer to Table 7 for further details.

Overall, 50% (4/8) of adults with monophasic ADEM completely recovered following treatment with IVIG.Both adults with relapsing ADEM showed marked improvement following IVIG. Refer to Table 8 for furtherdetails.


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Table 7. Pediatric acute disseminated encephalomyelitis IVIG studies

Study Design# ofpts

Prior steroidtreatment

Intervention Response*

Monophasic ADEM

Anderson (2003) Case report 1 Yes IVIG+steroids Complete responseAssa (1999) Case reports 2 No IVIG Complete response: 1/2 (50%)

Partial response: 1/2 (50%)

Balestri (2000) Case report 1 Yes IVIG Partial responseJaing (2001) Case report 1 No IVIG Complete responseKleiman (1995) Case report 1 No IVIG Complete responseNishikawa (1999) Case reports 3 No IVIG Complete response: 3/3 (100%)Pradhan (1999) Case reports 4 Yes IVIG Complete response: 3/4 (75%)

Partial response: 1/4 (25%)Shahar (2002) Case reports 16 Yes

(1 case)IVIG orsteroids orIVIG+steroids

IVIG: 1/1 (100%) complete responseSteroids: 10/10 (100%) complete responseIVIG+steroids: 2/5 (40%) complete response

3/5 (60%) partial or no responseStraussberg (2001) Case report 1 No IVIG+steroids Complete responseRELAPSINGADEM

Apak (1999) Case report 1 Yes IVIG Partial response

Hahn (1996) Case report 1 Yes IVIG Complete response (maintained with monthly IVIG)Mariotti (2003) Case report 1 Yes IVIG+steroids Partial response (maintained with monthly IVIG)Pittock (2001) Case report 1 Yes IVIG Partial response (no relapses after IVIG)Revel-Vilk (2000) Case report 1 No IVIG Complete response

*Complete response: normal (baseline) neurological function. Partial response: improved, but not normal, neurological function.Most severe cases treated with IVIG plus high-dose methylprednisolone. N/A Not applicable.

Table 8. Adult acute disseminated encephalomyelitis IVIG studies

Study Design# ofpts

Prior steroidtreatment

Intervention Response*

Monophasic ADEM

Finsterer (1998) Case report 1 No IVIG No response

Fox (2000) Case report 1 No IVIG Complete responseMarchioni (2002) Case reports 3 Yes IVIG Complete response: 1/3 (33%)

Partial response: 2/3 (67%)Nakamura (2003) Case report 1 Yes IVIG Partial responseSahlas (2000) Case reports 2 Yes IVIG Complete response: 2/2 (100%)RELAPSINGADEM

Marchioni (2002) Case reports 2 Yes IVIG Partial response: 2/2 (100%)*Complete response: normal (baseline) neurological function. Partial response: improved, but not normal, neurological function.Patient diagnosed with Bickerstaffs brainstem encephalitis.

Interpretation and Consensus

The expert panel acknowledges the evidence for IVIG in the treatment of ADEM is limited. However, giventhe number of positive cases reported, it is the panels opinion that IVIG is a reasonable option as second-line therapy for monophasic ADEM in patients who do not respond to high-dose corticosteroids. The panelalso agreed IVIG is a reasonable option for patients with monophasic ADEM who have contraindications tosteroids.

Sparse evidence is available on the use of IVIG for relapsing ADEM. The expert panel noted that clinicalexperience suggests some patients do respond to IVIG. Based on consensus, the panel agreed IVIG maybe considered as an option to eliminate steroid dependency or for those patients who fail to respond, orhave contraindications, to steroids.


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Recommendations

IVIG is recommended as an option for treatment of monophasic ADEM when first-line therapy with high-dose corticosteroids fails or when there are contraindications to steroid use.

Based on consensus by the expert panel, IVIG may be considered as an option for treatment of relapsingADEM to eliminate steroid dependency or for those patients who fail to respond, or have contraindications,

to steroids.

Dose and Duration

Based on consensus by the expert panel, a total dose of 2 g/kg given over two to five days for adults andover two days for children is a reasonable option.


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ADRENOLEUKODYSTROPHY


Adrenoleukodystrophy (ALD) is an X-linked inherited disorder of peroxisomal metabolism that producesprogressive central nervous system degeneration associated with central nervous system demyelination.The abnormality in peroxisomal metabolism results in accumulation of very long chain fatty acids (VLCFA)

and the disease can be diagnosed by measurement of VLCFA in serum. Some patients require DNAanalysis for diagnosis. ALD affects both the cerebral and spinal cord white matter (adrenomyeloneuropathy)with much more extensive involvement of the cerebral white matter in the childhood-onset form andpredominantly spinal cord involvement in the adult-onset variant. Childhood-onset ALD presents withsymptoms in the first decade of life, with progressive cognitive, motor, visual and auditory decline andseizures, and is fatal within a few years. Adult-onset ALD presents with progressive involvement spinal corddegeneration leading to paraplegia. About 80% of ALD patients have associated adrenal insufficiency.

There is currently no effective treatment for ALD. The rationale for the application of IVIG in themanagement of ALD is based on studies suggesting that IVIG promotes remyelination in the central nervoussystem. (Rodriguez M, Lennon VA. Immune globulins promote remyelination in the central nervous system.

Ann Neurol 1990;27:12-17).

Evidence Summary

The Appropriateness of IVIG Evidence Review identified one small randomized controlled trial thatexamined the use of IVIG for ALD (level of evidence: 2b). Twelve patients with ALD were randomized toreceive IVIG or not, in addition to being placed on a VLCFA-restricted diet with glycerol trioleate/erucicsupplementation. All 12 patients showed normalization of VLCFA. At 12 months, there was no significantdifference in the extent of neurological deterioration between patients in the IVIG group compared withcontrols.

Table 9. Adrenoleukodystrophy IVIG studies

Study Design # ofpts Intervention Outcome pvaluCappa (1994) RCT

Not blinded12 IVIG + VLCFA restricted diet + GTOE vs.

VLCFA restricted diet + GTOENo significant difference between IVIG group andcontrols in deterioration of neurological function asmeasured by the EDSS* scale at 12 months.

EDSS scores (Mean SD):Baseline: IVIG 2.31.0 vs. Controls 3.31.6

At 12 months: IVIG 6.72.9 vs. Controls 6.03.6

n.s.

n.s.VLCFA Very long chain fatty acid. GTOE Glycerol trioleate/erucic. SD Standard deviation.EDSS (Expanded Disability Status Scale): Range 3.0 (mild disability) to 9.0 (vegetative state). EDSS of 6.0: requires unilateralassistance to walk 100 metres. EDSS of 7.0: walks less than five metres and essentially restricted to a wheelchair.


The available evidence is limited to one small, poor quality randomized trial. However, given that no benefitwas observed for patients treated with IVIG, it is the expert panels opinion that IVIG should not be used fortreatment of adrenoleukodystrophy.

Recommendations

IVIG is not recommended for the treatment of adrenoleukodystrophy.


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AMYOTROPHIC LATERAL SCLEROSIS


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the upper and lower motor neuronsleading to progressive weakness, disability and death. Sporadic ALS has an annual incidence of one to twoper 100,000 population and peaks between ages 55 and 75. In 5% to 10% of cases the disorder is

autosomal dominant. Familial ALS starts about 10 years earlier than the sporadic form of the disorder.

Sixty percent of patients present with painless, progressive, focal and asymmetric weakness beginning in anarm, leg, or the bulbar muscles. Other presenting symptoms include muscle cramps, weight loss,fasciculations, neck and truncal weakness, and respiratory distress. All these symptoms are common as thedisease progresses. Spasticity, extensor plantar responses and pseudobulbar palsy can be observed.

Aspiration is life-threatening, and respiratory insufficiency is associated with a poor prognosis. Cognitivefunction, sensation, ocular movements and bowel/bladder control are spared.

The differential diagnosis includes other motor neuronopathies (Kennedys disease, spinal muscularatrophy, lymphoma-related motor neuronopathy, progressive postpolio muscular atrophy), myelopathies(foramen magnum tumours, cervical spondylitic myelopathy, syringomyelia, multiple sclerosis),

radiculopathies, neuropathies (multifocal motor neuropathy with conduction block, chronic inflammatorydemyelinating polyneuropathy), myopathies (inflammatory myopathy, isolated neck extensor weakness,oculopharyngeal dystrophy), and endocrinopathies (hyperparathyroidism, hyperthyroidism).

Progressive degeneration and loss of motor neurons in the cerebral cortex, limbic system, brain stem andspinal cord result in progressive loss of motor function leading to death. This loss of motor units leads toweakness. Copper/zinc superoxide dismutase (SOD1) detoxifies superoxide anions which produce celldeath, and an SOD1 gene mutation has been identified in about 15% to 20% of patients with familial ALS.Since familial ALS is identical to sporadic ALS, oxidative damage to neurons may be the underlyingmechanism of neuronal death and loss in ALS. Furthermore, excess glutamate excitation causes increasedcalcium influx and this triggers enzymatic reactions that produce reactive oxygen species and promote celldeath.

There are no effective treatments for ALS. The average five year survival is 25% with a mean duration fromonset of symptoms to death of 27 to 43 months. Riluzole prolongs survival and time to tracheostomy andmay slow progression of ALS by blocking glutamate.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified two case series that examined the use of IVIG forALS (level of evidence: 4). No improvement in muscle strength or slowing of the rate of disease progressionwas observed in either case series.

Table 10. Amyotrophic lateral sclerosis IVIG studies

Study Design# ofpts

Intervention Outcome

Meucci (1996) Case series 7 IVIG +cyclophosphamide

- muscle strength in all cases as measured by the MRC scale- Rankin and/or bulbar function scores worsened in all patients- no improvement in rate of disease progression

Dalakas (1994) Case series 9 IVIG -at 3 months, muscle strength (MVIC* mega scores) in all cases- mean vital lung capacity at 3 months by 0.3L from baseline

*MVIC Maximum voluntary isometric contraction mega scores: sum of MVIC scores from five individual muscle groups in two limbs.MRC scale: Muscle strength on 10 muscles/limb. Bulbar function scale: Range 1 (normal) to 5 (tube feeding or unable to speak orboth). Modified Rankin scale: Range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention).


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The expert panel recognizes the available evidence is limited to case series data. Given that no benefit wasobserved either in slowing disease progression or improvement of symptoms, the panel agreed there is norole for IVIG in the treatment of ALS.

Recommendations

IVIG is not recommended for the treatment of amyotrophic lateral sclerosis.


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AUTISM


Autism is a neurodevelopmental disorder characterized by severe deficits in social and communicativeskills, abnormal behaviours, and often global developmental delay. The term autism spectrum disorder ismore commonly used, as the clinical features and severity of impairment in social and communicative skills

can be highly variable. The incidence of autism spectrum disorder is approximately five per 10,000 children.

Most children are diagnosed between ages one to three years when their deficits in language and socialdevelopment become apparent. The etiology of autism is unknown and neuroimaging studies are normal. Afew small studies have suggested that circulating immune globulins of the IgA subclass are reduced inchildren with autism and that there exists a higher than normal prevalence of immunological disease infamilies of autistic children. These observations provided the impetus to explore the use of IVIG as apossible treatment option.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified three case series of IVIG use for autism (level of

evidence: 4). In the case series by Gupta et al. (1996) 10 patients with abnormal immune parametersreceived IVIG monthly. After six months, 50% (5/10) of patients showed marked improvement in a numberof autistic characteristics. The series by Plioplys et al. (1998) also included only patients with abnormalimmune parameters. Only one of the 10 cases showed improvement in autistic symptoms after receivingIVIG. No improvement with IVIG treatment was observed in the third series.

Table 11. Autism IVIG studies

Study Design and Participants# ofpts


Gupta (1996) Case series

Included only patients withabnormal immune parameters

10 IVIG After 6 months:- 5/10 (50%) had marked improvement in eye contact, calmerbehaviour, speech, and echolalia- 5/10 (50%) showed minimal improvement

DelGiudice-Asch (1999) Case series

No immunological testing

7 IVIG After 6 months:- no significant change on any of the behavioural measurescompared to baseline

Plioplys (1998) Case series

Included only patients withabnormal immune parameters

10 IVIG - 1/10 (10%) remarkable improvement in autistic symptoms- 4/10 (40%) parental reports of mild improvement in attentionand hyperactivity that could not be confirmed by school reportsor study authors. No improvement in autistic symptoms.- 5/10 (50%) no clinical improvement


The expert panel agreed the available evidence does not support the use of IVIG for treatment of autism.While there are a few children who appeared to improve dramatically following IVIG infusion, suchimprovement can occur as part of the natural history of autism and in children receiving intensivepsychological and developmental therapies. The panel noted the pathobiological rationale for use of IVIG inautism is very limited. Immunological studies have been performed largely from single centres on smallcohorts and lack appropriate numbers of patients and healthy controls. The pathobiological rationale of IVIGuse for autism should be further validated before the expense of a randomized controlled trial iscontemplated.


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Recommendations

IVIG is not recommended for the treatment of autism.


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CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY


Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating peripheralneuropathy of presumed autoimmune etiology, which presents either as a chronically progressive orrelapsing/remitting disorder. Patients experience progressive weakness in all four limbs accompanied by

numbness, impaired proprioception and ataxia. Cranial nerves may be involved. Symptoms developinsidiously over weeks to months (arbitrarily defined minimum progression of eight weeks) and may lead toloss of ambulation and considerable morbidity. In children disease onset may be more rapid and the courserelapsing.

Prevalence in general is estimated as two per 100,000. CIDP occurs at all ages, but is more common in thefifth andsixth decades of life and males are preferentially affected. In the older age group, the diseasecourse is often monophasic and progressive. Patients with relapsing/remitting CIDP tend to be younger andrespond well to therapies.

Criteria for the diagnosis of CIDP are based on the typical clinical presentation, supported byelectrophysiological findings of unequivocal demyelination, as well as the characteristic increase in

cerebrospinal fluid protein and a lymphocyte count of less than 10/mm3. A nerve biopsy is no longermandatory for the diagnosis, since one can infer the demyelinating pathology from the electrophysiologicalexaminations. At times, a trial of therapy may assist the diagnosis of CIDP, if documentation of quantitativeclinical and functional assessments and follow-up electrodiagnostic studies show unequivocalimprovements.

Several treatments have proven beneficial for CIDP including prednisone and plasma exchange. Otherimmunosuppressive drugs e.g. azathioprine, cyclophosphamide, cyclosporin, mycophenoate mofetil,entarecept have occasionally been prescribed for refractory or unstable CIDP in open label treatment withvariable results.

For patients with very mild symptoms and signs initial management may be close monitoring without

treatment. More severely affected patients should be treated without delay with either IVIG or prednisone.Plasma exchange, although a very effective therapy, is used as second-line treatment. Long-termmanagement requires assessment on an individual basis.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified a Cochrane systematic review with meta-analysisof IVIG use for CIDP (level of evidence: 1a). A systematic review by the Chalmers Research Institute onthis topic included eight randomized controlled trials. Overall, five trials compared IVIG with placebo, twotrials assessed IVIG versus either plasma exchange or prednisone, and one trial investigated differentdoses of IVIG. All of the trials evaluated IVIG for the short-term management of CIDP.

The Cochrane review by Van Schaik et al. (2002) included four randomized trials of IVIG versus placebo[Hahn (1996), Mendell (2001), Thompson (1996) and Vermeulen (1993)] in a meta-analysis of theproportion of patients with significant improvement in disability scores. The results of the meta-analysisindicated that a significantly greater proportion of patients had significant improvement in disability withinone month after treatment with IVIG versus placebo (RR: 3.17 [95% CI 1.74, 5.75; Fixed] p


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Table 12. Chronic inflammatory demyelinating polyneuropathy IVIG studies

Study Design# ofpts

Intervention Outcomeva

Van Schaik(2002)

SR withmeta-analysis ----

IVIG vs.placebo

A significantly greater proportion of patients had significantimprovement in disability by 1 month with IVIG vs. placebo:

RR: 3.17 [95% CI 1.74, 5.75; Fixed]; NNT: 3

A significantly greater proportion of patients improved 1 point onthe modified Rankin scale by 1 month with IVIG vs. placebo

RR: 2.47 [95% CI 1.02, 6.01; Fixed]

0.0

0Dyck (1994) Crossover

RCT20 IVIG vs.

PLEXAt 6 weeks, IVIG and PLEX groups had significant improvementcompared to baseline in:

Mean NDS scores: IVIG (p=0.006) and PLEX (p


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p


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CRITICAL ILLNESS POLYNEUROPATHY


Critical illness polyneuropathy (CIP) can develop in patients with multi-organ failure and sepsis. This is anaxonal sensorimotor neuropathy associated with flaccid paralysis and respiratory weakness. Patients areoften identified as it becomes apparent that they are having difficulty weaning from the ventilator. The

precise etiology of CIP is not known; however, medications such as neuromuscular blocking agents andsteroids may play a role. An underlying inflammatory process may be involved given the strong associationof CIP with sepsis.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified a retrospective chart review and one case series ofIVIG for CIP (level of evidence: 4). The retrospective chart review of 16 patients who survived multi-organfailure and severe gram-negative sepsis found none of the patients (0/8) who received IVIG within 24 hoursof sepsis being diagnosed developed CIP. Conversely, 88% (7/8) patients not treated with IVIG developedCIP. No benefit of IVIG for treatment of established CIP was observed in the case series.

Table 13. Critical illness polyneuropathy IVIG studies

StudyDesign andparticipants

# ofpts


Mohr (1997) Retrospective chartreview

16 IVIG Of 16 patients who survived MOF and severe sepsis*:- 0/8 (0%) pts given IVIG within 24 hrs of sepsis dx developed CIP- 7/8 (88%) pts not given IVIG developed CIP

Wijdicks (1994) Case series 3 IVIG 0/3 (0%) cases of established CIP improved with IVIG

MOF Multi-organ failure. Dx Diagnosis. *Sepsis caused by gram-negative bacteria.


The pathobiologic rationale for the use of IVIG in the treatment of CIP is not strong and the availableevidence is limited to one very small case series that reported no improvement following IVIG therapy. Thepanel noted that the retrospective chart review did not assess IVIG for treatment of CIP, but rather itsprevention. The expert panel does not recommend IVIG for the treatment of CIP.

Recommendations

IVIG is not recommended for the treatment of critical illness polyneuropathy.


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DERMATOMYOSITIS


Dermatomyositis can occur in both adults and children. In children, dermatomyositis is the most commoninflammatory myopathy. Skin rash is associated with muscle weakness and some patients will have the rashwith very little evidence of muscle involvement. The skin rash is heliotrope in colour and commonly presents

on the face, extensor surfaces of extremities and sun exposed areas. The weakness can range from verymild to very severe.

Serum creatine kinase (CK) is frequently elevated in dermatomyositis, but may be normal if the muscleweakness is mild. Electromyography changes are similar to those of polymyositis, with changes typical of aprimary muscle disorder with active muscle fibre necrosis. Muscle and skin biopsies can confirm thediagnosis. The muscle pathology is typically perifascicular and perivascular inflammation can be seen inmuscle and skin biopsies. In the adult with dermatomyositis, there is an increased risk of associatedmalignancy (lung, breast, ovary, GI tract) and this is greater in older individuals. Children withdermatomyositis are not at increased risk for malignancy. Dermatomyositis will usually respond to steroidsor immune suppressing medication.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified one randomized controlled trial, one non-randomized controlled trial, one retrospective chart review and four case series of IVIG use fordermatomyositis (level of evidence: 1b). A broader systematic review by the Chalmers Research Institute ofIVIG for myositis included the same randomized trial for dermatomyositis.

A small randomized crossover trial, by Dalakas et al. (1993), compared IVIG plus prednisone to placeboplus prednisone for treatment of adult dermatomyositis. At three months, patients randomized to IVIG plusprednisone showed significant improvement as measured by mean scores on the neuromuscular symptomscale (p=0.035) and the modified medical research council scale (p=0.018) compared with placebo plusprednisone.

One retrospective chart review and two case series assessed IVIG in addition to other therapies for juveniledermatomyositis. Overall, 82% (28/34) of children showed clinical improvement with the addition of IVIG. In70% (23/33) of cases, IVIG allowed for reduction of steroid dose without clinical deterioration.

One non-randomized trial and two case series included patients with dermatomyositis or polymyositis. Allthree of these studies presented pooled data, so it was not possible to determine the outcome of IVIGtreatment for only those patients with dermatomyositis. Refer to Table 14 for further details.


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Table 14. Dermatomyositis IVIG studies

StudyDesign andParticipants

# ofpts


DERMATOMYOSITISAl-Mayouf(2000)

Retrospectivereview

Children

18 IVIGsteroidsother therapies

12/18 (67%) Improved with IVIG, allowed steroid dose >50%6/18 (33%) Remained steroid-dependent

N

Dalakas (1993) CrossoverRCT

Adults

15 IVIG+steroids vs.placebo+steroids

At 3 months, mean modified MRC* and NSS scoressignificantly higher in IVIG group vs. placebo.Mean modified MRC*: IVIG 84.64.6 vs. placebo 78.68.2Mean NSS: IVIG 51.46.0 vs. placebo 45.711.3

0.0.

Sansome (1995) Case series

Children

9 IVIG+steroidsother therapies

Significant improvement in mean myometry score with IVIG9/9 (100%) Clinical improvement with IVIG6/8 (75%) patients on steroids were able to steroid dose

NRS

Tsai (1997) Case series

Children

7 IVIG+other therapies 5/7 (72%) Clinical improvement with IVIG, steroid dose1/7 (14%) Transient clinical improvement with IVIG1/7 (14%) No improvement with IVIG

N

DERMATOMYOSITIS ORPOLYMYOSITISDanieli (2002) Non-RCT

New onset,relapsed orTx refractory

20 Steroids+CSA or

IVIG+Steroids+CSA orIVIG+PLEX+steroids+CSA

No significant difference in CR between groups at 1 year

At 4 years:- Significantly more patients given IVIG+steroids+CSAmaintained complete remission compared with steroids+CSA- No significant difference between IVIG+steroids+CSA andIVIG+PLEX+steroids+CSA groups

n

0.

n

Cherin (1994a) Case series

Tx refractory

35 IVIGsteroidsother tx Significant improvement in muscle power:Mean muscle power*: Baseline 46.511.5; post-IVIG

67.115.4Significant reduction in mean steroid dose (mg/d)Significant in creatine kinase levels

000

Cherin (1994b) Case series

No previous tx

11 IVIG No significant improvement in mean muscle power* frombaseline- only 3/11 (27%) had significant clinical improvement

Significant improvement in mean creatine kinase levels

n

0

Other therapies not specified in review. Azathioprine and/or cyclospor ine. N/A Not applicable. NR Not reported.NSS Neuromuscular symptom scale, maximum score of 60 indicates normal function. SR Systematic review.*Modified Medical research council scale: maximum score 90. n.s. Not significant.


The available evidence suggests IVIG may be of benefit for patients with dermatomyositis. In the opinion ofthe expert panel IVIG may be considered as an adjunctive treatment option for patients who do notadequately respond to other immunosuppressant medications, such as corticosteroids, methotrexate orazathioprine. The panel emphasized that IVIG should not be given as monotherapy for dermatomyositis.

In the opinion of the expert panel, it is reasonable to consider IVIG in combination with other treatments as asteroid-sparing measure for patients with dermatomyositis. Panel members also agreed, given IVIG canproduce improvement rapidly, that IVIG may be considered in conjunction with other treatments (e.g.corticosteroids) in the rare situation when a patient is critically ill from dermatomyositis.

The decision to use IVIG for the treatment of dermatomyositis should be made in consultation with an expertin neuromuscular disease. The panel also agreed a muscle biopsy is required to diagnosis dermatomyositisand that the biopsy specimen should be examined by an expert in neuromuscular pathology.


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Recommendations

Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy isrequired for the diagnosis of dermatomyositis. It is critical that the muscle specimen be procured, processed,and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens (includingelectron microscopy) and that the final interpretation be made by an expert in neuromuscular pathology.

Based on consensus by the expert panel, use of IVIG for the treatment of patients with dermatomyositisshould be made in consultation with an expert in neuromuscular disease.

IVIG is not recommended as monotherapy for dermatomyositis.

IVIG is recommended as an option, in combination with other agents, for patients with dermatomyositis whohave not adequately responded to other immunosuppressive therapies.

IVIG is recommended, in combination with other agents, as a steroid-sparing option for patients withdermatomyositis.

Based on consensus by the expert panel, IVIG may be considered in conjunction with other agents for

treatment of severe, life-threatening dermatomyositis.

Dose and Duration

Based on consensus by the expert panel, a total dose of 2 g/kg given over two to five days for adults andover two days for children is a reasonable initial treatment option. For patients requiring IVIG maintenancetherapy, a systematic approach should be taken to determine the minimum effective dose and continueduse of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose ofIVIG per treatment course should be 2 g/kg.


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DIABETIC NEUROPATHY

Diabetic neuropathy affects 50% to 60% of patients with type 1 diabetes mellitus of more than 10 yearsduration and likely a similar number of type 2 diabetes mellitus patients. The majority of patients are eitherasymptomatic or mildly symptomatic. There are many sub-types of diabetic neuropathy with the mostcommon being distal symmetrical diabetic polyneuropathy. Mononeuropathies (other than carpal tunnelsyndrome) and asymmetrical regional neuropathies are less common.

Proximal asymmetrical lower limb neuropathies have been variously labeled as diabetic amyotrophy,diabetic proximal neuropathy, diabetic polyradiculoneuropathy, diabetic radiculoplexus neuropathy, diabeticlumbosacral plexopathy and other terms. It is likely that these are all similar disorders with variableresponses to a common pathophysiological mechanism of nerve damage. These neuropathies are typicallysubacute in onset, very painful, often have disabling weakness and demonstrate a capacity to improve overlong periods. Perivascular inflammation in the proximal lower limb neuropathies has led to investigation ofthe potential benefit of immune therapies in diabetic neuropathy.

Rarely, a patient with diabetes also meets the criteria for diagnosis of chronic inflammatory demyelinatingpolyneuropathy (CIDP). It is unclear whether this is a unique form of diabetic neuropathy or the co-occurrence of two independent disorders.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified five case series that investigated the use of IVIGfor various diabetic neuropathies (level of evidence: 4). Two series examined IVIG for chronic inflammatorydemyelinating polyneuropathy in patients with diabetes. In the largest series, by Sharma et al. (2002), 81%(21/26) of patients treated with IVIG showed clinically significant improvement in neurologic function asmeasured by the Neurologic Impairment Scale at four weeks (p


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Table 15. Diabetic neuropathy IVIG studies

StudyDesign andParticipants

# ofpts


Sharma (2002) Case series

CIDP in DM

26 IVIG Significant improvement in lower limb motor function at 4 weeksSignificant improvement in average NIS score:

Baseline: 59.626.7 vs. At 4 week follow-up : 33.029.6Significantly more pts with conduction blocks had improved NIS

scores with IVIG (11/11) vs. pts without conduction blocks (10/15)Of IVIG responders: 6/21(29%) relapsed; 2nd course of IVIG: 3/4(75%) pts had good response and 1/4 (25%) poor response

0

0.

0

NCocito (2002) Case series

CIDP in DM

9 IVIG Significant improvement in Rankin* score:Baseline: 2.40.7 vs. 6 month follow-up: 1.61.1

No improvement in motor or sensory deficitsSignificant in demyelinating sub-score on nerve conductionstudy at 6 months compared to baseline

0.n

0

Zochodne (2003) Case series

Diabetic lumbosacralplexopathy

3 IVIG IVIG treatment did not prevent (1 case) or halt progression(2 cases) of severe diabetic lumbosacral plexopathy. N/A

Jaradeh (1999) Case series

Rapidly progressingpolyradiculoneuropathy

15 IVIGsteroids or

PLEXsteroids

At 1year, all pts showed clinical improvement and the mean

change in weakness NDSW scores of 29.19.3 was significant.

No significant difference between IVIG (6 pts) vs. PLEX (9 pts)

0

nKrendel (1995) Case series

Progressive peripheralneuropathy

15 IVIGsteroidsother tx

15/15 (100%) of patients had improvement in symptoms afterIVIG additional therapies.

CIDP Chronic inflammatory demyelinating polyneuropathy. DM Diabetes mellitus. PLEX Plasmapheresis. N/A Not applicable.NDSW Weakness sub-scale of the Neuropathy Disability Scale. NIS Neurologic Impairment Score. Tx Treatment.*Modified Rankin scale: Range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention).Other therapies included plasma exchange, cyclophosphamide, and azathioprine.


The available evidence is quite limited and complicated by the fact that patients in the case series wereclinically heterogeneous. In particular, it is unclear whether the CIDP subgroup involves two diseases in thesame patient or a rare neuropathic phenotype in diabetes. Expert panel members also noted the need toconsider the natural history of diabetic proximal neuropathy, which is gradual spontaneous improvement. Alarge randomized controlled trial would be required to separate any beneficial effect of IVIG from this naturalimprovement.

In the opinion of the expert panel there is insufficient evidence to recommend the use of IVIG for diabeticpolyneuropathy, mononeuropathy, or proximal lower limb neuropathy. The panel agreed IVIG use forpatients with diabetes who have evidence of a CIDP phenotype should follow the recommendations asoutlined in the CIDP section of this guideline.

Recommendations

IVIG is not recommended for treatment of diabetic polyneuropathy, mononeuropathy or proximal lower limbneuropathy.

Based on consensus by the expert panel, IVIG use for patients with diabetes who have evidence of achronic inflammatory demyelinating polyneuropathy (CIDP) phenotype should follow the recommendationsoutlined in the CIDP section of this guideline.


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GUILLAIN-BARR SYNDROME


Guillain-Barr syndrome (GBS) is the most common cause of acute flaccid paralysis with an annualincidence of two per 100,000. This condition is characterized by rapidly evolving symmetrical limbweakness, facial and bulbar paralysis, loss of tendon reflexes, and absence of or mild sensory signs. Nearly

50% of patients become bedridden within a few days and 25% of cases develop respiratory failure thatrequires ICU admission for assistive mechanical ventilation and for monitoring of autonomic andcardiovascular functions. The nadir, by arbitrary definition, is reached within four weeks, and is followed by aplateau phase of variable duration and then gradual recovery. Despite frequently prolonged hospitalization,the prognosis of GBS is favourable with a return to almost normal function in about 85% of patients.

GBS, the prototype of a post-infectious autoimmune disease, is commonly triggered by a precedingbacterial or viral infection. Case-control studies confirm the clinical impression that both respiratory andgastrointestinal infections precede GBS more commonly than would be expected by chance. Campylobacterjejunia leading cause of bacterial gastroenteritis is the most frequently identified antecedent pathogen.Infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-zoster virus, Mycoplasmapneumoniae and Haemophilus influenzae are also associated with GBS. These infectious agents express

ganglioside-like epitopes in their lipopolysaccharide capsules which are identical to those on normal nervefibres. Thus, molecular mimicry and cross-reactive immune responses are attractive pathogeneticmechanisms.

In recent years it has been recognized that GBS comprises several subtypes with specific clinical,electrophysiological and pathological features. The classic acute inflammatory demyelinating neuropathy(AIDP) is the most common form in North America and Europe (approximately 85% of cases). Acute motoraxonal neuropathy (AMAN), which often follows a C.jejuniinfection, is particularly common in Asia and isassociated with a characteristic panel of IgG antibodies against GM1 and GD1a gangliosides. Acute motorand sensory axonal neuropathy (AMSAN) is distinguished by severe sensory deficits, a fulminant onset andusually poorer prognosis. Miller-Fisher syndrome, characterized clinically by ophthalmoplegia, ataxia andareflexia, is triggered by C.jejuniand is associated with anti-GQ1b IgG antibody. In the various forms of

GBS the primary immune responses are directed towards epitopes contained in either the myelin or axons.

Although considerable progress has been made in our understanding of the immunopathogenesis of GBS,host factors that determine susceptibility to GBS and those that down-regulate the immune responses arenot yet known.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified a Cochrane systematic review with meta-analysisof IVIG for GBS (level of evidence: 1a). Also, a systematic review by the Chalmers Research Institute onthis topic included six randomized controlled trials and four non-randomized controlled trials. Most of thetrials evaluated IVIG against plasma exchange, an established treatment for GBS.

Five trials [Bril et al. (1996), Diener et al. (2001), Nomura et al. (2000), PSGBS group (1997) and Van derMeche et al. (1992)] that compared IVIG with plasma exchange were included in the Cochrane reviewsmeta-analysis, by Hughes et al. (2003). The meta-analysis found no significant difference between IVIG andplasma exchange in improvement in disability grade at four weeks (weighted mean difference: -0.04 [95%CI-0.26, 0.19; Fixed], p-value: not significant). Two additional small, non-randomized trials also compared IVIGwith plasma exchange. One trial, by Hosokawa et al. (1998), found no significant difference between IVIGand plasma exchange on any of the outcomes measured. The other trial, by Martinez Yelamos et al. (1998),reported significant improvement in mean change in disability grade at one month with IVIG compared toplasma exchange (p


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Table 16. Guillain-Barr syndrome IVIG studies

StudyDesign andparticipants

# ofpts


Hughes (2003) SR withmeta-analysis*

536 IVIG vs.PLEX

No significant difference between IVIG and PLEX in improvement indisability grade (DG) at 4 weeks:

Weighted mean difference: -0.04 [95%CI -0.26, 0.19; Fixed] nBril (1996) RCT

Adults

50 IVIG vs.

PLEX

No significant difference between IVIG and PLEX in % of patients

who improved by 1 DG at 4 weeks, mean time to improve 1 DG,mean time to reach DG-1 or mean DG at 4 weeks n

Diener (2001) RCT

Adults

76 IVIG vs.PLEX vs.IAD

No significant difference in mean time to improve 1 DG, % of ptswho improved by 1 DG at 4 wks, mean time to reach DG-1,duration of intubation or hospitalization between the groups n

El Zunni (1997) Non-RCT

Adults

16 IVIG vs.steroids vs.placebo

Mean time to improve 1 DG:IVIG significantly shorter than steroids or placebo

No significant difference between groups in % of pts who improvedby 1 DG at 1 month

N

nGurses (1995) RCT

Children

18 IVIG vs.No treatment

Time from maximum weakness to improvement and duration ofhospitalization were significantly shorter with IVIG than no treatmentNo significant difference between groups in duration of mechanicalventilation

0

n

Haupt (1996) Non-RCT

Adults

45 IAD+IVIG vs.IAD vs.PLEX

Mean change in DG at 4 weeks:IAD+IVIG significantly better than combined IAD and PLEX groups

Mean change in DG at 6 and 12 month follow-up:IAD+IVIG vs. combined IAD+ PLEX not significantly different

0

nHosokawa (1998) Non-RCT

Adults10 IVIG vs.

PLEXAt 1 month, no significant difference between groups in % of pts withimprovement in MRC sum scores or mean MRC sum scores n

Martinez Yelamos(1998)

Non-RCT

Adults

24 IVIG vs.PLEX

Mean change in DG at 1 month:IVIG significantly better than PLEX

Mean duration of hospitalization was significantly shorter with IVIG0.00.0

Nomura (2000) RCT

Adults

47 IVIG vs.PLEX

No significant difference between groups in % of patients whoimproved by 1 DG at 4 weeks, change in DG at 4 weeks, time toimprove one DG, and time to improve two DG. n

PSGBS group (1997) RCT

Adults

379 IVIG vs.

PLEX vs.PLEX IVIG

No significant difference between IVIG, PLEX, and PLEX+ IVIG

groups in mean improvement in DG at 4 weeks, time to walkunaided, duration of mechanical ventilation, or rate of recovery n

Raphael (2001) RCT

Adults

39 IVIG 0.4 g/kg/d x3dvs.IVIG 0.4 g/kg/d x6d

Time to regain ability to walk with aid (DG-3):Overall: No significant difference between groupsVentilated pts: IVIG(6 days) significantly shorter than IVIG(3 days)

No significant difference in % pts who improved by 1 DG at 4 wks,duration of intubation, or mortality rate at 1 yr between groups

n0

nvan der Meche (1992) RCT

Adults+children

150 IVIG vs.PLEX

% of patients who improved by 1 DG at 4 weeks:IVIG significantly higher than PLEX

Mean time to improve by 1 DG significantly shorter with IVIG0.0

DG Disability grade: 0 - healthy, 1 - minor symptoms/signs but capable of manual work, 2 - able to walk without support butincapable of manual work, 3 - walks with support, 4 - confined to bed or chair bound, 5 - requires assisted ventilation, 6 - dead.*Meta-analysis included Bril (1996), Diener (2001), Nomura (2000), PSGBS group (1997) and Van der Meche (1992)Haupt (1996) combined results from IAD and PLEX groups after finding no significant differences between the two groups.PSGBS Plasma exchange/Sandoglobulin Guillain-Barr syndrome trial group. PLEX Plasma exchange. IAD Immune adsorption.SR Systematic review. MRC Medical Research Council scale.

A large trial by the PSGBS group (1997) investigated the combined effect of IVIG and plasma exchange inpatients with GBS. In this trial, 379 patients were randomized to receive IVIG, plasma exchange, or IVIGplus plasma exchange. No significant differences between the three groups were identified for any of theoutcomes measured.

Two trials evaluated IVIG against placebo or no therapy. A very small three-arm, non-randomized trial by ElZunni et al. (1997) reported the mean time to improve at least one disability grade was significantly shorter


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with IVIG compared to either prednisone or placebo (p-value not reported). A small randomized trial byGurses et al. (1995), that compared IVIG to no treatment in 18 children with GBS, found the interval frommaximum weakness to improvement and the duration of hospitalization were both significantly shorter withIVIG compared to no treatment (p


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INCLUSION BODY MYOSITIS


Inclusion body myositis (IBM) is very different from dermatomyositis and polymyositis. Inclusion bodymyositis is usually a disease of older adults and is likely the most common newly acquired inflammatorymyopathy in patients over the age of 65. Inclusion body myositis can be seen in younger patients, but is

rarely seen in those under the age of 50. There is a very rare inherited disorder that has similar pathology toacquired IBM. Patients present with painless slowly progressive muscle weakness. Some muscle groupsare particularly affected, including long finger flexors and knee extensors. The serum creatine kinase (CK) isnormal or mildly elevated. Electromyography will demonstrate features of a myopathy with muscle fibrenecrosis, but there is a characteristic mixture of large and small motor unit potentials that typify the disorder.The muscle biopsy will show muscle fibre necrosis, inflammatory infiltrates and rimmed vacuoles withgranular inclusions. Making a pathological diagnosis, however, can be difficult and the muscle biopsy shouldbe evaluated by an experienced neuropathologist to exclude the possibility of polymyositis. Unlike the otherinflammatory myopathies, patients with inclusion body myositis do not usually respond to immune therapies.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified three randomized controlled trials that investigatedIVIG for inclusion body myositis (level of evidence: 1b). A systematic review by the Chalmers ResearchInstitute of IVIG for myositis included the same three randomized trials.

Two small randomized crossover trials compared IVIG with placebo. No significant difference in musclestrength, as measured by mean change on the Medical Research Council (MRC) scale, was observedbetween IVIG and placebo groups. Walter et al. (2000) did report a small but significant improvement inneuromuscular symptom scale scores with IVIG versus placebo at six months (p


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improvement with IVIG, there was no evidence of sustained benefit. In the opinion of the expert panel, IVIGshould not be used for the treatment of inclusion body myositis.

The panel agreed that a skeletal muscle biopsy is required to diagnosis inclusion body myositis and that thebiopsy specimen should be examined by an expert in neuromuscular pathology.

Recommendations

Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy isrequired for the diagnosis of inclusion body myositis. It is critical that the muscle specimen be procured,processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens(including electron microscopy) and that the final interpretation be made by an expert in neuromuscularpathology.

IVIG is not recommended for the treatment of inclusion body myositis.


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INTRACTABLE CHILDHOOD EPILEPSY


Epilepsies are characterized by recurrent, spontaneous and transient paroxysms of electrical discharges inthe brain. Epileptic syndromes are defined on the basis of seizure type, electroencephalogram features, ageof onset, and clinical course. At least 10%-20% of childhood epilepsies are intractable, defined as failure to

control seizures after an adequate trial of first-line anti-epileptic medications. Although epilepsy is notgenerally considered an immunological disorder, rare epileptic patients with low serum levels IgA, impairedor augmented humoral responses, and circulating antibodies to central nervous system (CNS) antigenshave been reported. Large-scale immunological studies in patients with epilepsy and appropriate controlshave not been performed.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified two randomized controlled trials that examined theuse of IVIG for intractable childhood epilepsy (level of evidence: 1b). In the larger trial, 61 patients wererandomized to one of three different doses of IVIG (100 mg/kg, 250 mg/kg, and 400 mg/kg) or placebo. Nosignificant differences between IVIG groups were identified. At six months, there was no significant

difference in the number of patients with a 50% or greater reduction in seizure frequency between thecombined IVIG groups compared with controls. A sub-group analysis found significantly more patients withpartial epilepsy who received IVIG versus placebo had a 50% or greater reduction in seizure frequency(p=0.041). A small crossover trial reported 20% (2/10) of patients had reductions in seizure frequency thatwere associated with improvements in EEG findings, cognitive performance and general well-beingfollowing IVIG.

Table 18. Intractable childhood epilepsy IVIG studies

Study Design# ofpts

Intervention OutcomeP

valuVan Raijckevorsel-Harmant (1994)

RCT 61 IVIG 100 mg/kg vs.IVIG 250 mg/kg vs.IVIG 400 mg/kg vs.placebo

No significant difference between IVIG groups

# of pts with

50%

in seizure frequency at 6 months:All patients: IVIG(all groups) 21/40 (53%) vs. placebo 5/18 (28%)Partial epilepsy: IVIG(all groups) 19/34 (56%) vs. placebo 2/12 (17%)

n.s

n.s0.04

Illum (1989) CrossoverRCT

10 IVIG vs.placebo*

- 2/10 (20%) seizure frequency, improved EEG and general condition(Both patients had high frequency, invariable seizures)- 8/10 (80%) no change in EEG or general condition, variable effect onseizure frequency (None had high frequency, invariable seizures)

NR

*Crossover after four week washout period. Sub-group analysis of patients with partial epilepsy. n.s. Not significant. NR Notreported.


The available evidence is limited to two small, randomized trials that had broad inclusion criteria and

allowed entry of children with varied epileptic syndromes. In both trials, children were randomized to receiveIVIG or placebo, in addition to their regular anti-epileptic medications, making it very difficult to evaluate theeffect of IVIG. The panel discussed that although a sub-group analysis in one trial showed some benefit ofIVIG for children with partial epilepsy, the number of patients studied was very small compared tothe number of patients affected by this condition. Given the chronic nature of intractable epilepsy, use ofIVIG would only be a temporizing measure or patients would require regular IVIG treatment for life. In theopinion of the expert panel, the available evidence does not support the use of IVIG for intractable childhoodepilepsy. The panel also suggests further immunological studies in patients with epilepsy are requiredbefore additional clinical trials are warranted.


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Recommendations

IVIG is not recommended for the treatment of intractable childhood epilepsy.


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LAMBERT-EATON MYASTHENIC SYNDROME


The Lambert-Eaton myasthenic syndrome (LEMS) is a rare acquired autoimmune disorder withautoantibodies directed against voltage-gated calcium channels (VGCC) on the presynaptic nerve terminalof the neuromuscular junction and of autonomic synapses. Patients have weakness and autonomic

symptoms. The differential diagnosis includes myasthenia gravis, other disorders of neuromusculartransmission, myopathies, and peripheral neuropathies.

The diagnosis of LEMS can be made with single-fibre electromyography studies that show elevated jitterand blocking, and by repetitive nerve stimulation studies that show an incremental response. Post-exercisefacilitation and exhaustion are common findings following brief maximal exercise.

The median age of onset is in the sixth decade and more men than women are affected. The patients haveproximal weakness of the extremities, depressed reflexes and dry mouth and eyes. Men have erectiledysfunction. Distal sensory neuropathy may be present. Bulbar and ocular symptoms are mild and rare. Theweakness may improve transiently and the reflexes may be obtained after brief maximal voluntarycontraction (facilitation). About half of the patients have an underlying neoplasm. Small cell lung cancer

(SCLC) is the most frequent, accounting for approximately 80% of paraneoplastic cases. Three percent ofpatients with SCLC have LEMS. Neurologic symptoms may precede the detection of the malignancy byyears. Other autoimmune disorders such as hypothyroidism, rheumatoid arthritis, juvenile diabetes mellitus,and MG have been associated with the nonmalignant form of LEMS.

VGCC on the presynaptic membrane of the nerve terminal are essential for calcium-evoked ACh releaseand normal neuromuscular transmission. Antibodies to VGCC are found in 95% of patients withparaneoplastic LEMS and 90% of patients with sporadic LEMS. These antibodies downregulate the VGCCand interfere with release of acetylcholine at the neuromuscular junction and at autonomic ganglia resultingin the clinical features of LEMS. Some patients have an associated paraneoplastic cerebellar ataxia andpositive anti-neuronal antibodies such as anti-Hu.

Paraneoplastic LEMS may improve with appropriate therapy of the underlying malignancy. Surveillance formalignancy should be maintained for a minimum of three years following diagnosis of sporadic LEMS.Therapy for LEMS is symptomatic and/or immunomodulatory. Symptomatic improvement can be achievedwith 3,4-diaminopyridine which inhibits the neuronal voltage-gated K+ ion channel, resulting in increasedcalcium ion entry and thus, increased ACh release. Immunosuppression with corticosteroids, azathioprineand/or other immunosuppressant drugs can be used to achieve remission. Immunomodulation with plasmaexchange or intravenous immune globulin produces temporary improvement and may be useful adjunctivetherapy in difficult cases of LEMS, especially when steroids are not effective or cause intolerable sideeffects.

The prognosis of SCLC in patients with LEMS is better than for patients without LEMS. Drugs such asaminoglycoside antibiotics, procainamide, quinidine, adrenergic blocking agents, and lithium should be used

cautiously in patients with LEMS due to adverse effects on neuromuscular transmission.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified one randomized controlled trial that evaluated theuse of IVIG for Lambert-Eaton myasthenic syndrome (level of evidence: 1b). This small, placebo-controlled,crossover trial of nine patients reported significant improvement in limb strength (p=0.038), respiratorymuscle strength (p=0.028) and bulbar muscle strength (p=0.017) following IVIG compared with placebo.


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Table 19. Lambert-Eaton myasthenic syndrome IVIG studies

Study Design# ofpts

Intervention Outcomep

valueBain (1996) Crossover

RCT9 IVIG vs.

placebo*Significant improvement in limb strength with IVIG vs. placeboSignificant improvement in vital lung capacity with IVIG vs. placeboSignificant improvement in bulbar muscle strength (as measured bydrinking time) with IVIG vs. placebo

0.0380.028

0.017

*Crossover after eight week washout period.


Given the positive results from the randomized trial, the severity of this condition and its underlyingpathogenesis which is similar to myasthenia gravis, the panel agreed it is reasonable to consider IVIG as anoption for treatment of LEMS. While the available evidence is limited to one small crossover trial, a largertrial is unlikely given the rarity of this condition. The expert panel agreed objective evidence of clinicalimprovement is required for sustained use of IVIG.

Recommendations

IVIG is recommended as an option for treatment of Lambert-Eaton myasthenic syndrome. Objectiveevidence of clinical improvement is needed for sustained use of IVIG.

Dose and Duration

Based on consensus by the expert panel, a total dose of 2 g/kg given over two to five days is a reasonableinitial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should betaken to determine the minimum effective dose and continued use of IVIG should be based on objectivemeasures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.


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MULTIFOCAL MOTOR NEUROPATHY


Multifocal motor neuropathy (MMN) presents as slowly progressive muscle weakness and wasting within theterritory of individual motor nerves and with a predilection for the distal upper limbs. Focal cramps andfasciculations are common, particularly following exercise. Sensory symptoms and signs are notably absent

on both clinical and electrophysiological examination. The electrodiagnostic hallmark of MMN is findingfocal conduction blocks (CB) in motor nerves outside regions normally prone to nerve entrapments. The CBcorresponds to focal areas of chronic demyelination.

MMN is an uncommon neuropathy. However, due to the generally slow progression of MMN, its prevalenceis higher than expected and has been estimated at two per 100,000. Generally MMN begins between theages of 20 to 40 years and affects men far more frequently than women.

Patients with MMN typically have normal parameters on all standard blood tests, including markers ofinflammation and vasculitis. Cerebrospinal fluid examination usually reveals normal or only slightly raisedprotein content. MRI imaging may show focal areas of high signal on T2-weighted images pre- and post-contrast, which on biopsy showed very chronic demyelination.

High titers of IgM anti-GM1 antibodies are found in approximately 50% of patients with MMN. The role ofIgM anti-GM1 antibodies in the pathogenesis of MMN remains controversial. However, elevated anti-GM1antibodies serve as a marker for positive response to treatment with high dose IVIG. MMN is thought to bean autoimmune disorder, yet neither its etiology nor pathogenesis is fully understood.

Plasma exchange and corticosteroids are not effective for treatment of MMN and, in fact, may worsen apatients condition. Other immunosuppressive drugs such as mycophenoate, azathioprine, methotrexate, orcyclophosphamide may be considered. However, toxicity and long-term side-effects from these agents areproblematic and a lack of firm evidence of benefit with these drugs should discourage their use.

Evidence Summary

The Appropriateness of IVIG Evidence Review identified four small randomized controlled trials thatinvestigated the use of IVIG for multifocal motor neuropathy. A recently published Cochrane systematicreview of IVIG for multifocal motor neuropathy, identified by an update literature search, included the samefour trials (level of evidence: 1a). All of the trials used a crossover design and compared IVIG with placebo.

The Cochrane systematic review, by van Schaik et al. (2005), quantitatively synthesized the results from thetrials for muscle strength, disability, resolution of conduction blocks and side-effects. Significantly morepatients showed significant improvement in muscle strength following IVIG compared with placebo (RelativeRisk: 11.00 [95% CI 2.86, 42.25; Fixed], p=0.0005). There was no significant difference between IVIG andplacebo in the proportion of patients with significant improvement

Documents

Ivig Neurology Guideline