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

Copyright This 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 written permission of the NTWG. The NTWG reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. The National Technical Working Group on Blood and Blood Products makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

TABLE OF CONTENTS
Executive Summary ........................................................................................................................................ 4 Introduction ..................................................................................................................................................... 5 Methods .......................................................................................................................................................... 8 Acute Disseminated Encephalomyelitis .........................................................................................................11 Adrenoleukodystrophy ...................................................................................................................................14 Amyotrophic Lateral Sclerosis .......................................................................................................................15 Autism............................................................................................................................................................17 Chronic Inflammatory Demyelinating Polyneuropathy ...................................................................................19 Critical Illness Polyneuropathy.......................................................................................................................22 Dermatomyositis ............................................................................................................................................23 Diabetic Neuropathy ......................................................................................................................................26 Guillain-Barr Syndrome................................................................................................................................28 Inclusion Body Myositis..................................................................................................................................31 Intractable Childhood Epilepsy ......................................................................................................................33 Lambert-Eaton Myasthenic Syndrome...........................................................................................................35 Multifocal Motor Neuropathy ..........................................................................................................................37 Multiple Sclerosis ...........................................................................................................................................39 Myasthenia Gravis .........................................................................................................................................43 Opsoclonus-Myoclonus..................................................................................................................................47 Paraproteinemic Neuropathy (IgM variant) ....................................................................................................49 Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections .......................51 POEMS Syndrome.........................................................................................................................................53 Polymyositis...................................................................................................................................................55 Rasmussens Encephalitis .............................................................................................................................57 Stiff Person Syndrome ...................................................................................................................................59 External Review.............................................................................................................................................61 Summary of Recommendations for Use of IVIG for Adult and Pediatric Neurologic Conditions....................63 References ....................................................................................................................................................65

EXECUTIVE SUMMARY
Background: Canadas per capita utilization of intravenous immune globulin (IVIG) grew by approximately 71% between 1999 and 2004, making Canada one of the worlds highest per capita users of IVIG. It is believed that most of this growth is attributable to off-label usage. To help ensure IVIG utilization is in keeping with an evidence-based approach to the practice of medicine, the National Technical Working Group 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 neurologic conditions. Objective: The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditions and formulate recommendations on IVIG use for each. Methods: A panel of six clinical experts, one expert in practice guideline development and four representatives from the NTWG met to review the evidence and reach consensus on the recommendations for 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 in Canada for feedback. The results of this process were reviewed by the expert panel and modifications to the draft guideline were made where appropriate. This practice guideline will provide the NTWG with a basis for making recommendations to provincial and territorial health ministries regarding IVIG utilization management. Results: Recommendations for use of IVIG were made for 14 conditions. IVIG was not recommended for eight 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 to facilitate appropriate utilization of IVIG. 4

INTRODUCTION
Description of IVIG Intravenous immune globulin (IVIG) is a fractionated blood product consisting of concentrated immune globulin, primarily IgG, derived from human plasma in pools of 3,000 to 10,000 or more donors. IVIG was first 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, allogenic bone marrow transplantation, chronic B-cell lymphocytic leukemia, pediatric HIV-infection, Kawasaki disease 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. Health Canada has not evaluated the efficacy and risk of using a licensed IVIG product in the treatment of offlabel clinical indications. Nevertheless, some of these applications have a reasonably strong foundation in the 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 are risks 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. These reactions are typically self-limited, of mild to moderate severity and can often be avoided by reducing the rate of infusion during subsequent transfusions of IVIG. However, there is a paucity of published reports of prospectively collected data on the adverse event rate associated with IVIG. Moreover, each brand of IVIG may 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 serious adverse 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 data surrounding their frequency, the review concluded that clinicians should limit their prescription of IVIG to conditions 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 and transmissible disease testing of input plasma are stringent. In addition, the IVIG manufacturing process itself includes at least one and usually two steps of viral inactivation or removal to protect against infectious agents that might be present despite screening procedures. Hepatitis B virus and HIV have never been transmitted through IVIG. There has been no reported transmission of hepatitis C virus from any product used in Canada and there is no known case of Creutzfeldt-Jacob disease (CJD) or variant CJD transmission due to IVIG transfusion. Nevertheless, IVIG is a product made from large pools of human plasma and it is not 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 production and product withdrawals caused by the need for US-based plasma fractionators to comply with more stringent US Food and Drug Administration requirements. Although such a severe shortage has not recurred, the cost of IVIG has continued to rise. This has led to the adoption of various approaches to control IVIG use in several countries, in particular in Canada and Australia.

IVIG is an expensive therapeutic alternative in disease states where other interventions may be possible or where 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 approximately half of the CBS total budget. Since Canada is not self-sufficient in plasma, IVIG used in this country is manufactured 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 provide stability 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. There are 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 years with a less favourable US exchange rate the cost has been as high as $75-$80. The cost of one infusion of 1 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
Patient 20 kg child 70 kg adult Schedule 1 dose 1 x monthly for 1 yr 1 x 3 weeks for 1 yr 1 dose 1 x monthly for 1 yr 1 x 3 weeks for 1 yr 0.5g/kg $700 $8,400 $12,000 $2,500 $30,000 $42,500 Cost of IVIG* 1.0g/kg $1,400 $16,800 $24,000 $5,000 $60,000 $85,000 2.0g/kg $2,800 $33,600 $48,000 $10,000 $120,000 $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 Canada one of the highest per capita users of IVIG in the world. It is believed that most of the growth in use is attributable 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 appropriate and in keeping with an evidence-based approach to the practice of medicine. CBS convened a national consensus conference, entitled: Prescribing Intravenous Immune Globulin: Prioritizing Use and Optimizing Practice, in Toronto in October 2000. The recommendations of the panel of this conference can be found on the Canadian Blood Services website (www.bloodservices.ca). British Columbia implemented an IVIG utilization management program in 2002, which involved the division of medical conditions into those requiring either regular or special approval for IVIG use based on the evidence of benefit. The Atlantic provinces implemented a similar program in 2003, and individual facilities in other provinces undertook their own 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 utilization management issues, has been working on the development of an inter-provincial collaborative framework for IVIG utilization management. To facilitate this objective the NTWG and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditions and formulate recommendations on IVIG use for each condition. The practice guideline developed by this process will provide the NTWG with a basis for making recommendations to provincial and territorial health 6

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

METHODS
Expert Panel Letters of invitation were sent to a number of neurologists across Canada regarded by their peers as experts in their field. The panel consisted of six clinical experts, one expert in practice guideline development and four representatives from the NTWG. Table 2. Members of the Expert Panel
Clinical experts Dr. Brenda Banwell Dr. Timothy Benstead Dr. Vera Bril Dr. Tom Feasby Dr. Mark Freedman Dr. Angelika Hahn NTWG representatives Dr. Heather Hume (chair) Dr. John Freedman Dr. David Pi Dr. Louis Wadsworth Practice guidelines expert Dr. Melissa Brouwers Affiliation Director, Paediatric Multiple Sclerosis Clinic, Hospital for Sick Kids, Toronto Division of Neurology, QE II Health Sciences Centre, Halifax Division of Neurology, Toronto General Hospital, Toronto Division of Neurology, Department of Medicine, University of Alberta, Edmonton Division of Neurology, Ottawa General Hospital, Ottawa Clinical Neurological Sciences, London Health Sciences, London Affiliation Executive Medical Director, Transfusion Medicine, Canadian Blood Services, Ottawa Director, Transfusion Medicine, St. Michaels Hospital, Toronto Director, Provincial Blood Coordinating Office, St. Pauls Hospital, Vancouver Program Head, Hematopathology, Childrens & Womens Health Centre of BC, Vancouver Affiliation 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 any potential 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 further details. Table 3. Included clinical conditions
Clinical Conditions Acute disseminated encephalomyelitis Lambert-Eaton myasthenic syndrome Adrenoleukodystrophy Multifocal motor neuropathy Amyotrophic lateral sclerosis Multiple sclerosis Autism Myasthenia gravis Chronic inflammatory demyelinating polyradiculoneouropathy Opsoclonus-myoclonus Critical illness polyneuropathy Paraproteinemic neuropathy Dermatomyositis PANDAS* Diabetic neuropathy POEMS syndrome** Epilepsy (intractable childhood) Polymyositis Guillain-Barr syndrome Rasmussens encephalitis Inclusion 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:

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 of relevant journals, reference lists and unpublished sources. (b) Dates searched: 1966 to 2004 2) 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 reported Members of the expert panel were also encouraged to identify any additional studies relevant to the development of evidence-based recommendations. Refer to Table 4 for further information regarding sources used for each of the conditions considered by the expert panel. Table 4. Sources used in the development of the practice guideline
Clinical Condition Acute disseminated encephalomyelitis Adrenoleukodystrophy Amyotrophic lateral sclerosis Autism Chronic inflammatory demyelinating polyradiculoneuropathy Critical illness polyneuropathy Dermatomyositis Diabetic neuropathy Guillain-Barr syndrome Inclusion body myositis Intractable childhood epilepsy Lambert-Eaton myasthenic syndrome Multifocal motor neuropathy Multiple sclerosis Myasthenia gravis Opsoclonus-myoclonus PANDAS* Paraproteinemic neuropathy (IgM variant) POEMS syndrome** Polymyositis Rasmussens encephalitis Stiff person syndrome Appropriateness of IVIG review 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 Chalmers Institute SR of IVIG Literature Search by Expert Panel

9 9 9 9 9 9

9 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 system developed by Bob Phillips, Chris Ball, David Sackett, Brian Haynes, Sharon Straus and Finlay McAlister from 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 of factors influencing the decision-making process. The expert panel evaluated IVIG for a diverse range of neurologic conditions and the level of evidence required to recommend IVIG varied depending upon the condition for several reasons. For example, for rare diseases that have no effective alternative treatments the threshold was lower than for common diseases with established standard therapies. Refer to Table 6 for a list of some of the factors considered by the expert panel in their deliberations. While the members of the 9

panel are cognizant of the costs associated with IVIG, the role of costs and cost utility was not systematically factored into the discussions and the recommendations that emerged. Table 5. Levels of evidence
Level of Evidence 1a 1b 1c 2a 2b 2c 3a 3b 4 5 Whether a treatment is efficacious/effective/harmful Systematic Review (with homogeneity) of RCTs Individual RCT (with narrow confidence interval), including well-designed crossover trials All or none* Systematic Review (with homogeneity) of cohort studies Individual cohort study (including low quality RCTs) Outcomes research; ecological studies SR (with homogeneity) of case-control studies Individual case-control study Case-series (and poor quality cohort and case-control studies) Expert opinion without explicit critical appraisal, or based on physiology, bench research or first principles Whether a treatment is superior to another drug in same class Systematic Review (with homogeneity) of head-to-head RCTs Within a head-to-head RCT with clinically important outcomes N/A Within a head-to-head RCT with validated surrogate outcomes Across RCTs of different drugs vs. placebo in similar or different patients with clinically important or validated surrogate outcomes N/A Across subgroup analyses from RCTs of different drugs vs. placebo in similar or different patients, with clinically important or validated surrogate outcomes Across RCTs of different drugs vs. placebo in similar or different patients but with un-validated surrogate outcomes Between non-randomized studies (observational studies and administrative database research) with clinically important outcomes Expert opinion without explicit critical appraisal, or based on physiology, bench research or first principles; or non-randomized studies 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 before treatment 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 was informed by the Practitioner Feedback methodology used to create clinical practice guidelines on cancer care in Ontario (Browman et al., 1998). A draft of this practice guideline, along with an accompanying letter of 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 online through a Web-based survey tool. Written comments on the draft guideline were encouraged. Practitioners were 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 that predominantly 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 autoantigens share antigenic determinants with an infecting pathogen. Most patients show multiple characteristic lesions of demyelination in the deep and subcortical white matter on MRI. The differential diagnosis includes other inflammatory demyelinating disorders such as multiple sclerosis (MS), optic neuritis and transverse myelitis. Although most patients with ADEM experience a monophasic course, occasional patients may experience recurrence 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 to review the clinical features of ADEM and provide consensus clinical definitions for the various ADEM phenotypes (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 diagnosis of MS. Treatment at the time of acute symptomatology should be based on the clinical diagnosis at the time of illness, as most patients with ADEM (or an ADEM-like illness that is eventually determined to be the first manifestation of MS) are profoundly ill. High-dose corticosteroids are first-line treatment for ADEM. Plasmapheresis and IVIG have been used for patients who fail to respond to steroid therapy. Most patients with ADEM recover completely over a period of four 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 involved children with monophasic ADEM. Overall, 70% (14/20) of children with monophasic ADEM completely recovered 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 with relapsing 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 further details.

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Table 7. Pediatric acute disseminated encephalomyelitis IVIG studies

Study Monophasic ADEM Anderson (2003) Assa (1999) Balestri (2000) Jaing (2001) Kleiman (1995) Nishikawa (1999) Pradhan (1999) Shahar (2002) Design Case report Case reports Case report Case report Case report Case reports Case reports Case reports # of pts 1 2 1 1 1 3 4 16 Prior steroid treatment Yes No Yes No No No Yes Yes (1 case) No Yes Yes Yes Yes No Intervention IVIG+steroids IVIG IVIG IVIG IVIG IVIG IVIG IVIG or steroids or IVIG+steroids IVIG+steroids IVIG IVIG IVIG+steroids IVIG IVIG Response* Complete response Complete response: 1/2 (50%) Partial response: 1/2 (50%) Partial response Complete response Complete response Complete response: 3/3 (100%) Complete response: 3/4 (75%) Partial response: 1/4 (25%) IVIG: 1/1 (100%) complete response Steroids: 10/10 (100%) complete response IVIG+steroids: 2/5 (40%) complete response 3/5 (60%) partial or no response Complete response Partial response Complete response (maintained with monthly IVIG) Partial response (maintained with monthly IVIG) Partial response (no relapses after IVIG) Complete response

Straussberg (2001) RELAPSING ADEM Apak (1999) Hahn (1996) Mariotti (2003) Pittock (2001) Revel-Vilk (2000)

Case report Case report Case report Case report Case report Case report

1 1 1 1 1 1

*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 Monophasic ADEM Finsterer (1998) Fox (2000) Marchioni (2002) Nakamura (2003) Sahlas (2000) RELAPSING ADEM Marchioni (2002) Design Case report Case report Case reports Case report Case reports Case reports # of pts 1 1 3 1 2 2 Prior steroid treatment No No Yes Yes Yes Yes Intervention IVIG IVIG IVIG IVIG IVIG IVIG Response* No response Complete response Complete response: 1/3 (33%) Partial response: 2/3 (67%) Partial response Complete response: 2/2 (100%) 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, given the number of positive cases reported, it is the panels opinion that IVIG is a reasonable option as secondline therapy for monophasic ADEM in patients who do not respond to high-dose corticosteroids. The panel also agreed IVIG is a reasonable option for patients with monophasic ADEM who have contraindications to steroids. Sparse evidence is available on the use of IVIG for relapsing ADEM. The expert panel noted that clinical experience suggests some patients do respond to IVIG. Based on consensus, the panel agreed IVIG may be considered as an option to eliminate steroid dependency or for those patients who fail to respond, or have contraindications, to steroids. 12

Recommendations IVIG is recommended as an option for treatment of monophasic ADEM when first-line therapy with highdose 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 relapsing ADEM 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 and over two days for children is a reasonable option.

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ADRENOLEUKODYSTROPHY
Clinical Description Adrenoleukodystrophy (ALD) is an X-linked inherited disorder of peroxisomal metabolism that produces progressive 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 DNA analysis 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 and predominantly spinal cord involvement in the adult-onset variant. Childhood-onset ALD presents with symptoms in the first decade of life, with progressive cognitive, motor, visual and auditory decline and seizures, and is fatal within a few years. Adult-onset ALD presents with progressive involvement spinal cord degeneration 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 the management of ALD is based on studies suggesting that IVIG promotes remyelination in the central nervous system. (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 that examined the use of IVIG for ALD (level of evidence: 2b). Twelve patients with ALD were randomized to receive IVIG or not, in addition to being placed on a VLCFA-restricted diet with glycerol trioleate/erucic supplementation. All 12 patients showed normalization of VLCFA. At 12 months, there was no significant difference in the extent of neurological deterioration between patients in the IVIG group compared with controls. Table 9. Adrenoleukodystrophy IVIG studies
Study Cappa (1994) Design RCT Not blinded # of pts 12 Intervention IVIG + VLCFA restricted diet + GTOE vs. VLCFA restricted diet + GTOE Outcome No significant difference between IVIG group and controls in deterioration of neurological function as measured 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
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 unilateral assistance to walk 100 metres. EDSS of 7.0: walks less than five metres and essentially restricted to a wheelchair.

p value n.s.

n.s.

Interpretation and Consensus The available evidence is limited to one small, poor quality randomized trial. However, given that no benefit was observed for patients treated with IVIG, it is the expert panels opinion that IVIG should not be used for treatment of adrenoleukodystrophy. Recommendations IVIG is not recommended for the treatment of adrenoleukodystrophy.

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AMYOTROPHIC LATERAL SCLEROSIS

Clinical Description Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the upper and lower motor neurons leading to progressive weakness, disability and death. Sporadic ALS has an annual incidence of one to two per 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 an arm, 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 the disease progresses. Spasticity, extensor plantar responses and pseudobulbar palsy can be observed. Aspiration is life-threatening, and respiratory insufficiency is associated with a poor prognosis. Cognitive function, sensation, ocular movements and bowel/bladder control are spared. The differential diagnosis includes other motor neuronopathies (Kennedys disease, spinal muscular atrophy, 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 inflammatory demyelinating 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 and spinal cord result in progressive loss of motor function leading to death. This loss of motor units leads to weakness. Copper/zinc superoxide dismutase (SOD1) detoxifies superoxide anions which produce cell death, 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 underlying mechanism of neuronal death and loss in ALS. Furthermore, excess glutamate excitation causes increased calcium influx and this triggers enzymatic reactions that produce reactive oxygen species and promote cell death. There are no effective treatments for ALS. The average five year survival is 25% with a mean duration from onset of symptoms to death of 27 to 43 months. Riluzole prolongs survival and time to tracheostomy and may 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 for ALS (level of evidence: 4). No improvement in muscle strength or slowing of the rate of disease progression was observed in either case series. Table 10. Amyotrophic lateral sclerosis IVIG studies
Study Meucci (1996) Dalakas (1994) Design Case series Case series # of pts 7 9 Intervention IVIG + cyclophosphamide IVIG Outcome - 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 -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 or both). Modified Rankin scale: Range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention).

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Interpretation and Consensus The expert panel recognizes the available evidence is limited to case series data. Given that no benefit was observed either in slowing disease progression or improvement of symptoms, the panel agreed there is no role for IVIG in the treatment of ALS. Recommendations IVIG is not recommended for the treatment of amyotrophic lateral sclerosis.

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AUTISM
Clinical Description Autism is a neurodevelopmental disorder characterized by severe deficits in social and communicative skills, abnormal behaviours, and often global developmental delay. The term autism spectrum disorder is more 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 social development become apparent. The etiology of autism is unknown and neuroimaging studies are normal. A few small studies have suggested that circulating immune globulins of the IgA subclass are reduced in children with autism and that there exists a higher than normal prevalence of immunological disease in families of autistic children. These observations provided the impetus to explore the use of IVIG as a possible 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 parameters received IVIG monthly. After six months, 50% (5/10) of patients showed marked improvement in a number of autistic characteristics. The series by Plioplys et al. (1998) also included only patients with abnormal immune parameters. Only one of the 10 cases showed improvement in autistic symptoms after receiving IVIG. No improvement with IVIG treatment was observed in the third series. Table 11. Autism IVIG studies
Study Gupta (1996) Design and Participants Case series Included only patients with abnormal immune parameters Case series No immunological testing Case series Included only patients with abnormal immune parameters # of pts 10 Intervention IVIG Outcome After 6 months: - 5/10 (50%) had marked improvement in eye contact, calmer behaviour, speech, and echolalia - 5/10 (50%) showed minimal improvement After 6 months: - no significant change on any of the behavioural measures compared to baseline - 1/10 (10%) remarkable improvement in autistic symptoms - 4/10 (40%) parental reports of mild improvement in attention and hyperactivity that could not be confirmed by school reports or study authors. No improvement in autistic symptoms. - 5/10 (50%) no clinical improvement

DelGiudice-Asch (1999) Plioplys (1998)

7 10

IVIG IVIG

Interpretation and Consensus 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, such improvement can occur as part of the natural history of autism and in children receiving intensive psychological and developmental therapies. The panel noted the pathobiological rationale for use of IVIG in autism is very limited. Immunological studies have been performed largely from single centres on small cohorts and lack appropriate numbers of patients and healthy controls. The pathobiological rationale of IVIG use for autism should be further validated before the expense of a randomized controlled trial is contemplated.

17

Recommendations IVIG is not recommended for the treatment of autism.

18

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Clinical Description Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating peripheral neuropathy of presumed autoimmune etiology, which presents either as a chronically progressive or relapsing/remitting disorder. Patients experience progressive weakness in all four limbs accompanied by numbness, impaired proprioception and ataxia. Cranial nerves may be involved. Symptoms develop insidiously over weeks to months (arbitrarily defined minimum progression of eight weeks) and may lead to loss of ambulation and considerable morbidity. In children disease onset may be more rapid and the course relapsing. Prevalence in general is estimated as two per 100,000. CIDP occurs at all ages, but is more common in the fifth and sixth decades of life and males are preferentially affected. In the older age group, the disease course is often monophasic and progressive. Patients with relapsing/remitting CIDP tend to be younger and respond well to therapies. Criteria for the diagnosis of CIDP are based on the typical clinical presentation, supported by electrophysiological 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 longer mandatory for the diagnosis, since one can infer the demyelinating pathology from the electrophysiological examinations. At times, a trial of therapy may assist the diagnosis of CIDP, if documentation of quantitative clinical and functional assessments and follow-up electrodiagnostic studies show unequivocal improvements. Several treatments have proven beneficial for CIDP including prednisone and plasma exchange. Other immunosuppressive drugs e.g. azathioprine, cyclophosphamide, cyclosporin, mycophenoate mofetil, entarecept have occasionally been prescribed for refractory or unstable CIDP in open label treatment with variable 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-term management requires assessment on an individual basis. Evidence Summary The Appropriateness of IVIG Evidence Review identified a Cochrane systematic review with meta-analysis of IVIG use for CIDP (level of evidence: 1a). A systematic review by the Chalmers Research Institute on this topic included eight randomized controlled trials. Overall, five trials compared IVIG with placebo, two trials assessed IVIG versus either plasma exchange or prednisone, and one trial investigated different doses 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 the proportion of patients with significant improvement in disability scores. The results of the meta-analysis indicated that a significantly greater proportion of patients had significant improvement in disability within one month after treatment with IVIG versus placebo (RR: 3.17 [95% CI 1.74, 5.75; Fixed] p<0.0002; NNT 3). One additional trial, by Van Doorn (1990), compared IVIG with placebo. This trial was excluded from the Cochrane review due to selection bias as it studied only patients that had previously responded to IVIG. The trial reported significantly more patients improved one or more points on the Rankin disability scale by day eight with IVIG than placebo (p<0.02). 19

Table 12. Chronic inflammatory demyelinating polyneuropathy IVIG studies

Study Van Schaik (2002) Design SR with meta-analysis # of pts ---Intervention IVIG vs. placebo Outcome A significantly greater proportion of patients had significant improvement 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 on the modified Rankin scale by 1 month with IVIG vs. placebo RR: 2.47 [95% CI 1.02, 6.01; Fixed] At 6 weeks, IVIG and PLEX groups had significant improvement compared to baseline in: Mean NDS scores: IVIG (p=0.006) and PLEX (p<0.001) Mean CMAP scores: IVIG (p<0.001) and PLEX (p<0.001) No significant difference between IVIG and PLEX in mean change in NDS or summated CMAP scores at 6 weeks Mean change in NDS after 4 weeks (d 28): Significant improvement with IVIG vs. placebo Mean change in grip strength (p<0.001) and functional grade (p<0.002) at d 28 significantly improved with IVIG vs. placebo Mean change in nerve conduction tests at 4 weeks: Significant improvement in NCV with IVIG Significant improvement in summated proximal CMAP with IVIG Both IVIG (p=0.012) and prednisone (p=0.005) groups showed significant improvement in mean INCAT disability scores at 2 wks Mean change in INCAT scores (at 2 and 6 weeks): No significant difference between IVIG and oral prednisone Mean change in MRC sum score and modified Rankin score (6 wks): No significant difference between IVIG and oral prednisone Significant improvement in muscle strength (AMS) with IVIG at d 42: AMS mean difference(IVIG-placebo): 0.720.25 % of pts with improvement in disability scores at d 42: IVIG significantly higher than placebo Mean change in nerve conduction tests at d 42: Significant improvement in motor nerve conduction with IVIG Significant improvement in peroneal NCV Mean change in MRC sum scores at 2 weeks: No statistically significant difference between groups % of pts with improvement 1 point on Rankin scale by d 21: No significant difference between groups No significant difference in change in mean MRC sum score, CMAP, or nerve conduction velocity between groups % of pts with improvement 1 point on modified Rankin scale by d 8: IVIG significantly higher than placebo No significant difference between groups in mean CMAP or NCV % of pts with improvement 1 grade on disability scale (at 5 weeks): IVIG(0.4g/kg) significantly higher than IVIG(0.05g/kg) or IVIG(0.2g/kg) P value 0.0002 0.05 --n.s. 0.0001 ---0.0001 0.03 ---n.s. n.s. 0.006 0.019 0.003 0.03 n.s. n.s. n.s. 0.02 n.s. 0.004

Dyck (1994)

Crossover RCT

20

IVIG vs. PLEX

Hahn (1996)

Crossover RCT

30

IVIG vs. placebo

Hughes (2001)

Crossover RCT

32

IVIG vs. oral prednisone

Mendell (2001)

RCT

53

IVIG vs. placebo

Thompson (1996) Vermeulen (1993) Van Doorn (1990) Kubori (1999)

Crossover RCT RCT

7 28

IVIG vs. placebo IVIG vs. placebo IVIG vs. placebo IVIG (0.05 g/kg/d x5d) vs. IVIG (0.2 g/kg/d x5d) vs. IVIG (0.4 g/kg/d x5d)

Crossover RCT RCT

Van

7 62

Schaik (2002) converted different disability scale scores used in each trial to modified Rankin scores. Meta-analysis of disability scores used in RCTs included: Hahn (1996), Mendell (2001), Thompson (1996) and Vermeulen (1993); meta-analysis of modified Rankin scores included: Mendell (2001), Thompson (1996) and Vermeulen (1993). AMS Average muscle score. PLEX Plasma exchange. RR Relative risk. SR Systematic review. MRC Medical Research Council scale. NR Not reported. CMAP Compound muscle action potential. NCV Nerve conduction velocity. NDS Neuropathy disability score. NNT Number needed to treat. n.s. Not significant.

Two trials evaluated IVIG against other treatment options. One small, randomized crossover trial, by Dyck et al. (1994), compared IVIG with plasma exchange. At six weeks, both groups showed significant improvement compared to the baseline in mean Neuropathy Disability scores (IVIG: p=0.006; PLEX: 20

p<0.001) and mean summated Compound Muscle Action Potentials (IVIG: p<0.001; PLEX: p<0.001). No significant difference between IVIG and plasma exchange was identified. A randomized crossover trial by Hughes et al. (2001) assessed IVIG against oral prednisone. Both treatment groups had significant improvement in disability at two weeks, as measured by mean change on the INCAT disability scale (IVIG: p=0.012; prednisone: p=0.005). The two groups did not differ significantly in mean change in INCAT scores, Medical Research Council (MRC) sum scores, or modified Rankin scores at either two or six week followup. One trial by Kubori et al. (1999) investigated different doses of IVIG. Overall, 62 patients with CIDP were randomized to receive 0.05 g/kg, 0.2 g/kg, or 0.4 g/kg of IVIG daily for five days. A significantly higher percentage of patients in the IVIG 0.4 g/kg group improved at least one grade on the disability scale (scale not specified) compared to the other groups. Interpretation and Consensus High quality evidence is available to support the use of IVIG as an option for the short-term management of patients with CIDP. There is no evidence to support or refute the superiority of IVIG to plasma exchange or oral prednisone for the short-term treatment of CIDP. Nonetheless, IVIG is often chosen as the preferred initial therapy. No evidence is available to support or refute long-term (> 6 months) use of IVIG for CIDP. Although many panel members have experienced success with use of IVIG in this setting, there was considerable discussion on how best to frame the opinion of the expert panel regarding this clinical indication so as not to overstate the role of IVIG. Based on consensus of the expert panel, IVIG may be considered, in conjunction with other immunosuppressive therapies, for the long-term management of CIDP. IVIG is not recommended as monotherapy in this setting. If IVIG is to be used in the long-term management of CIDP, the patient should be under the care of a qualified expert with specialized knowledge of CIDP and a systematic approach should be taken to determine the minimal effective dose. The justification for continuation of IVIG therapy should be based on objective measures of the sustained effectiveness of IVIG and on a recurrence of symptoms or symptom worsening if IVIG is withdrawn. Recommendations IVIG is recommended as an option for the short-term management of new-onset CIDP or CIDP relapses. Based on consensus by the expert panel, IVIG may be considered as an option in combination with other immunosuppressive therapy for the long-term management of CIDP. If IVIG is to be used in the long-term management of CIDP, the patient should be under the care of a qualified expert with specialized knowledge of CIDP and a systematic approach should be taken to determine the minimal effective dose. 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 reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

21

CRITICAL ILLNESS POLYNEUROPATHY

Clinical Description Critical illness polyneuropathy (CIP) can develop in patients with multi-organ failure and sepsis. This is an axonal sensorimotor neuropathy associated with flaccid paralysis and respiratory weakness. Patients are often 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 and steroids may play a role. An underlying inflammatory process may be involved given the strong association of CIP with sepsis. Evidence Summary The Appropriateness of IVIG Evidence Review identified a retrospective chart review and one case series of IVIG for CIP (level of evidence: 4). The retrospective chart review of 16 patients who survived multi-organ failure and severe gram-negative sepsis found none of the patients (0/8) who received IVIG within 24 hours of sepsis being diagnosed developed CIP. Conversely, 88% (7/8) patients not treated with IVIG developed CIP. No benefit of IVIG for treatment of established CIP was observed in the case series. Table 13. Critical illness polyneuropathy IVIG studies
Study Mohr (1997) Wijdicks (1994) Design and participants Retrospective chart review Case series # of pts 16 3 Intervention IVIG IVIG Outcome 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 0/3 (0%) cases of established CIP improved with IVIG

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

Interpretation and Consensus The pathobiologic rationale for the use of IVIG in the treatment of CIP is not strong and the available evidence is limited to one very small case series that reported no improvement following IVIG therapy. The panel noted that the retrospective chart review did not assess IVIG for treatment of CIP, but rather its prevention. The expert panel does not recommend IVIG for the treatment of CIP. Recommendations IVIG is not recommended for the treatment of critical illness polyneuropathy.

22

DERMATOMYOSITIS
Clinical Description Dermatomyositis can occur in both adults and children. In children, dermatomyositis is the most common inflammatory myopathy. Skin rash is associated with muscle weakness and some patients will have the rash with 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 very mild to very severe. Serum creatine kinase (CK) is frequently elevated in dermatomyositis, but may be normal if the muscle weakness is mild. Electromyography changes are similar to those of polymyositis, with changes typical of a primary muscle disorder with active muscle fibre necrosis. Muscle and skin biopsies can confirm the diagnosis. The muscle pathology is typically perifascicular and perivascular inflammation can be seen in muscle and skin biopsies. In the adult with dermatomyositis, there is an increased risk of associated malignancy (lung, breast, ovary, GI tract) and this is greater in older individuals. Children with dermatomyositis are not at increased risk for malignancy. Dermatomyositis will usually respond to steroids or immune suppressing medication. Evidence Summary The Appropriateness of IVIG Evidence Review identified one randomized controlled trial, one nonrandomized controlled trial, one retrospective chart review and four case series of IVIG use for dermatomyositis (level of evidence: 1b). A broader systematic review by the Chalmers Research Institute of IVIG for myositis included the same randomized trial for dermatomyositis. A small randomized crossover trial, by Dalakas et al. (1993), compared IVIG plus prednisone to placebo plus prednisone for treatment of adult dermatomyositis. At three months, patients randomized to IVIG plus prednisone showed significant improvement as measured by mean scores on the neuromuscular symptom scale (p=0.035) and the modified medical research council scale (p=0.018) compared with placebo plus prednisone. One retrospective chart review and two case series assessed IVIG in addition to other therapies for juvenile dermatomyositis. Overall, 82% (28/34) of children showed clinical improvement with the addition of IVIG. In 70% (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. All three of these studies presented pooled data, so it was not possible to determine the outcome of IVIG treatment for only those patients with dermatomyositis. Refer to Table 14 for further details.

23

Table 14. Dermatomyositis IVIG studies

Study Design and Participants # of pts 18 Intervention IVIGsteroids other therapies IVIG+steroids vs. placebo+steroids IVIG+steroids other therapies IVIG+other therapies Outcome 12/18 (67%) Improved with IVIG, allowed steroid dose >50% 6/18 (33%) Remained steroid-dependent At 3 months, mean modified MRC* and NSS scores significantly higher in IVIG group vs. placebo. Mean modified MRC*: IVIG 84.64.6 vs. placebo 78.68.2 Mean NSS: IVIG 51.46.0 vs. placebo 45.711.3 Significant improvement in mean myometry score with IVIG 9/9 (100%) Clinical improvement with IVIG 6/8 (75%) patients on steroids were able to steroid dose 5/7 (72%) Clinical improvement with IVIG, steroid dose 1/7 (14%) Transient clinical improvement with IVIG 1/7 (14%) No improvement with IVIG No significant difference in CR between groups at 1 year At 4 years: - Significantly more patients given IVIG+steroids+CSA maintained complete remission compared with steroids+CSA - No significant difference between IVIG+steroids+CSA and IVIG+PLEX+steroids+CSA groups Significant improvement in muscle power: Mean muscle power*: Baseline 46.511.5; post-IVIG 67.115.4 Significant reduction in mean steroid dose (mg/d) Significant in creatine kinase levels No significant improvement in mean muscle power* from baseline - only 3/11 (27%) had significant clinical improvement Significant improvement in mean creatine kinase levels p value N/A

DERMATOMYOSITIS Al-Mayouf Retrospective (2000) review Dalakas (1993) Children Crossover RCT Adults Case series Children Case series

15

Sansome (1995) Tsai (1997)

9 7

0.018 0.035 NR in SR N/A

Children DERMATOMYOSITIS OR POLYMYOSITIS Danieli (2002) Non-RCT New onset, relapsed or Tx refractory Case series Tx refractory Cherin (1994b) Case series No previous tx
Other

20

Steroids+CSA or IVIG+Steroids+CSA or IVIG+PLEX+steroids+CSA

n.s. 0.001 n.s. 0.01 0.05 0.01 n.s. 0.01

Cherin (1994a)

35

IVIGsteroidsother tx

11

IVIG

therapies not specified in review. Azathioprine and/or cyclosporine. 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.

Interpretation and Consensus The available evidence suggests IVIG may be of benefit for patients with dermatomyositis. In the opinion of the expert panel IVIG may be considered as an adjunctive treatment option for patients who do not adequately respond to other immunosuppressant medications, such as corticosteroids, methotrexate or azathioprine. 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 a steroid-sparing measure for patients with dermatomyositis. Panel members also agreed, given IVIG can produce 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 expert in neuromuscular disease. The panel also agreed a muscle biopsy is required to diagnosis dermatomyositis and that the biopsy specimen should be examined by an expert in neuromuscular pathology.

24

Recommendations Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy is required 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 (including electron 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 dermatomyositis should 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 who have not adequately responded to other immunosuppressive therapies. IVIG is recommended, in combination with other agents, as a steroid-sparing option for patients with dermatomyositis. 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 and over two days for children is a reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

25

DIABETIC NEUROPATHY
Diabetic neuropathy affects 50% to 60% of patients with type 1 diabetes mellitus of more than 10 years duration and likely a similar number of type 2 diabetes mellitus patients. The majority of patients are either asymptomatic or mildly symptomatic. There are many sub-types of diabetic neuropathy with the most common being distal symmetrical diabetic polyneuropathy. Mononeuropathies (other than carpal tunnel syndrome) 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, diabetic lumbosacral plexopathy and other terms. It is likely that these are all similar disorders with variable responses to a common pathophysiological mechanism of nerve damage. These neuropathies are typically subacute in onset, very painful, often have disabling weakness and demonstrate a capacity to improve over long periods. Perivascular inflammation in the proximal lower limb neuropathies has led to investigation of the potential benefit of immune therapies in diabetic neuropathy. Rarely, a patient with diabetes also meets the criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). It is unclear whether this is a unique form of diabetic neuropathy or the cooccurrence of two independent disorders. Evidence Summary The Appropriateness of IVIG Evidence Review identified five case series that investigated the use of IVIG for various diabetic neuropathies (level of evidence: 4). Two series examined IVIG for chronic inflammatory demyelinating 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 as measured by the Neurologic Impairment Scale at four weeks (p<0.001). The series by Cocito et al. (2002) found no significant improvement in either motor or sensory deficits following IVIG. There was, however, significant improvement in both mean Rankin score (p=0.008) and indicators of demyelination on nerve conduction studies (p=0.03) at six month follow-up. One case series of 15 patients with rapidly progressing polyradiculoneuropathy examined the effect of IVIG or plasmapheresis with or without corticosteroids. All patients showed clinical improvement at one year and there was significant improvement in weakness as measured by the mean change in Neuropathy Disability Weakness Score (p<0.01). There was no significant difference between patients treated with IVIG compared to plasmapheresis. In the case series by Krendel et al. (1995), all 15 patients with progressive peripheral neuropathies given IVIG with or without additional anti-inflammatory or anti-immune treatment showed improvement in their condition. One small case series of three patients reported that treatment with IVIG neither prevented nor arrested progression of severe diabetic lumbosacral plexopathy. Refer to Table 15 for further details.

26

Table 15. Diabetic neuropathy IVIG studies

Study Sharma (2002) Design and Participants Case series # of pts 26 Intervention IVIG Outcome Significant improvement in lower limb motor function at 4 weeks Significant improvement in average NIS score: Baseline: 59.626.7 vs. At 4 week follow-up : 33.029.6 Significantly 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 Significant improvement in Rankin* score: Baseline: 2.40.7 vs. 6 month follow-up: 1.61.1 No improvement in motor or sensory deficits Significant in demyelinating sub-score on nerve conduction study at 6 months compared to baseline IVIG treatment did not prevent (1 case) or halt progression (2 cases) of severe diabetic lumbosacral plexopathy. 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) 15/15 (100%) of patients had improvement in symptoms after IVIG additional therapies. P value 0.01 0.001 0.03 N/A 0.008 n.s. 0.03 N/A

CIDP in DM Cocito (2002) Case series CIDP in DM Zochodne (2003) Case series Diabetic lumbosacral plexopathy Case series Rapidly progressing polyradiculoneuropathy Case series Progressive peripheral neuropathy 3 IVIG 9 IVIG

Jaradeh (1999)

15

IVIGsteroids or PLEXsteroids IVIGsteroids other tx

0.01 n.s.

Krendel (1995)

15

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.

Interpretation and Consensus The available evidence is quite limited and complicated by the fact that patients in the case series were clinically heterogeneous. In particular, it is unclear whether the CIDP subgroup involves two diseases in the same patient or a rare neuropathic phenotype in diabetes. Expert panel members also noted the need to consider the natural history of diabetic proximal neuropathy, which is gradual spontaneous improvement. A large randomized controlled trial would be required to separate any beneficial effect of IVIG from this natural improvement. In the opinion of the expert panel there is insufficient evidence to recommend the use of IVIG for diabetic polyneuropathy, mononeuropathy, or proximal lower limb neuropathy. The panel agreed IVIG use for patients with diabetes who have evidence of a CIDP phenotype should follow the recommendations as outlined in the CIDP section of this guideline. Recommendations IVIG is not recommended for treatment of diabetic polyneuropathy, mononeuropathy or proximal lower limb neuropathy. Based on consensus by the expert panel, IVIG use for patients with diabetes who have evidence of a chronic inflammatory demyelinating polyneuropathy (CIDP) phenotype should follow the recommendations outlined in the CIDP section of this guideline.

27

GUILLAIN-BARR SYNDROME
Clinical Description Guillain-Barr syndrome (GBS) is the most common cause of acute flaccid paralysis with an annual incidence of two per 100,000. This condition is characterized by rapidly evolving symmetrical limb weakness, 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 that requires ICU admission for assistive mechanical ventilation and for monitoring of autonomic and cardiovascular functions. The nadir, by arbitrary definition, is reached within four weeks, and is followed by a plateau 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 preceding bacterial or viral infection. Case-control studies confirm the clinical impression that both respiratory and gastrointestinal infections precede GBS more commonly than would be expected by chance. Campylobacter jejuni a leading cause of bacterial gastroenteritis is the most frequently identified antecedent pathogen. Infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-zoster virus, Mycoplasma pneumoniae 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 nerve fibres. Thus, molecular mimicry and cross-reactive immune responses are attractive pathogenetic mechanisms. 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 motor axonal neuropathy (AMAN), which often follows a C.jejuni infection, is particularly common in Asia and is associated with a characteristic panel of IgG antibodies against GM1 and GD1a gangliosides. Acute motor and sensory axonal neuropathy (AMSAN) is distinguished by severe sensory deficits, a fulminant onset and usually poorer prognosis. Miller-Fisher syndrome, characterized clinically by ophthalmoplegia, ataxia and areflexia, is triggered by C.jejuni and 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 are not yet known. Evidence Summary The Appropriateness of IVIG Evidence Review identified a Cochrane systematic review with meta-analysis of IVIG for GBS (level of evidence: 1a). Also, a systematic review by the Chalmers Research Institute on this topic included six randomized controlled trials and four non-randomized controlled trials. Most of the trials 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 der Meche et al. (1992)] that compared IVIG with plasma exchange were included in the Cochrane reviews meta-analysis, by Hughes et al. (2003). The meta-analysis found no significant difference between IVIG and plasma 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 IVIG with plasma exchange. One trial, by Hosokawa et al. (1998), found no significant difference between IVIG and 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 to plasma exchange (p<0.0012). 28

Table 16. Guillain-Barr syndrome IVIG studies

Study Hughes (2003) Bril (1996) Diener (2001) El Zunni (1997) Design and participants SR with meta-analysis* RCT Adults RCT Adults Non-RCT Adults Gurses (1995) RCT Children Haupt (1996) Non-RCT Adults Hosokawa (1998) Martinez Yelamos (1998) Nomura (2000) PSGBS group (1997) Raphael (2001) Non-RCT Adults Non-RCT Adults RCT Adults RCT Adults RCT Adults van der Meche (1992) RCT Adults+children 150 10 24 47 379 39 45 IAD+IVIG vs. IAD vs. PLEX IVIG vs. PLEX IVIG vs. PLEX IVIG vs. PLEX IVIG vs. PLEX vs. PLEX IVIG IVIG 0.4 g/kg/d x3d vs. IVIG 0.4 g/kg/d x6d IVIG vs. PLEX 18 # of pts 536 50 76 16 Intervention IVIG vs. PLEX IVIG vs. PLEX IVIG vs. PLEX vs. IAD IVIG vs. steroids vs. placebo IVIG vs. No treatment Outcome No significant difference between IVIG and PLEX in improvement in disability grade (DG) at 4 weeks: Weighted mean difference: -0.04 [95%CI -0.26, 0.19; Fixed] 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 No significant difference in mean time to improve 1 DG, % of pts who improved by 1 DG at 4 wks, mean time to reach DG-1, duration of intubation or hospitalization between the groups Mean time to improve 1 DG: IVIG significantly shorter than steroids or placebo No significant difference between groups in % of pts who improved by 1 DG at 1 month Time from maximum weakness to improvement and duration of hospitalization were significantly shorter with IVIG than no treatment No significant difference between groups in duration of mechanical ventilation 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 At 1 month, no significant difference between groups in % of pts with improvement in MRC sum scores or mean MRC sum scores Mean change in DG at 1 month: IVIG significantly better than PLEX Mean duration of hospitalization was significantly shorter with IVIG No significant difference between groups in % of patients who improved by 1 DG at 4 weeks, change in DG at 4 weeks, time to improve one DG, and time to improve two DG. No significant difference between IVIG, PLEX, and PLEX+ IVIG groups in mean improvement in DG at 4 weeks, time to walk unaided, duration of mechanical ventilation, or rate of recovery Time to regain ability to walk with aid (DG-3): Overall: No significant difference between groups Ventilated 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 % 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 IVIG P value n.s. n.s. n.s. NR n.s. 0.05 n.s. 0.02 n.s. n.s. 0.0012 0.0065 n.s. n.s. n.s. 0.04 n.s. 0.024 0.05

DG Disability grade: 0 - healthy, 1 - minor symptoms/signs but capable of manual work, 2 - able to walk without support but incapable 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 in patients with GBS. In this trial, 379 patients were randomized to receive IVIG, plasma exchange, or IVIG plus plasma exchange. No significant differences between the three groups were identified for any of the outcomes measured. Two trials evaluated IVIG against placebo or no therapy. A very small three-arm, non-randomized trial by El Zunni et al. (1997) reported the mean time to improve at least one disability grade was significantly shorter 29

with IVIG compared to either prednisone or placebo (p-value not reported). A small randomized trial by Gurses et al. (1995), that compared IVIG to no treatment in 18 children with GBS, found the interval from maximum weakness to improvement and the duration of hospitalization were both significantly shorter with IVIG compared to no treatment (p<0.05). One randomized trial evaluated different doses of IVIG. Raphael et al. (2001) compared administration of IVIG (0.4 g/kg) daily for three days versus six days. Overall, no significant differences between the two groups were identified. In the sub-group of patients who required mechanical ventilation, time to regain ability to walk with aid was significantly shorter in the group given IVIG for six days (p=0.04). Refer to Table 16 for further details. Interpretation and Consensus Evidence from several randomized controlled trials is available to support IVIG as an efficacious therapy for patients with severe GBS. Results of a meta-analysis from a Cochrane systematic review indicate IVIG and plasma exchange are equally effective for treatment of GBS. The expert panel noted that plasma exchange was the standard of care for treatment of GBS when the majority of the IVIG trials were conducted, thus IVIG was not compared to placebo. One large randomized trial reported no additional benefit from combined therapy with IVIG plus plasma exchange compared to either IVIG or plasma exchange alone for treatment of GBS. The panel discussed whether patients mildly affected with GBS should also be treated with IVIG. In the opinion of the expert panel, IVIG should be an option for mildly affected patients whose symptoms are progressing. In the opinion of the expert panel, re-treatment with IVIG is a reasonable option in the event of a relapse for patients who initially responded to IVIG. The expert panel also discussed and agreed that all of the recommendations also apply to patients with the Miller-Fisher and other variants of GBS. Recommendations IVIG is recommended as a treatment option for GBS within two weeks of symptom onset for: (i) Patients with symptoms of Grade 3 severity (able to walk with aid) or greater; or (ii) Patients with symptoms less than Grade 3 severity whose symptoms are progressing. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients who initially responded to IVIG and who are experiencing a relapse of symptoms. Based on consensus by the expert panel, the recommendations for use of IVIG for GBS also apply to patients with Miller-Fisher and other variants of GBS. Diagnosis of GBS variants should be made by a specialist with expertise in this area. 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 and over two days for children is a reasonable option.

30

INCLUSION BODY MYOSITIS

Clinical Description Inclusion body myositis (IBM) is very different from dermatomyositis and polymyositis. Inclusion body myositis is usually a disease of older adults and is likely the most common newly acquired inflammatory myopathy 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 to acquired IBM. Patients present with painless slowly progressive muscle weakness. Some muscle groups are particularly affected, including long finger flexors and knee extensors. The serum creatine kinase (CK) is normal or mildly elevated. Electromyography will demonstrate features of a myopathy with muscle fibre necrosis, 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 with granular inclusions. Making a pathological diagnosis, however, can be difficult and the muscle biopsy should be evaluated by an experienced neuropathologist to exclude the possibility of polymyositis. Unlike the other inflammatory 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 investigated IVIG for inclusion body myositis (level of evidence: 1b). A systematic review by the Chalmers Research Institute of IVIG for myositis included the same three randomized trials. Two small randomized crossover trials compared IVIG with placebo. No significant difference in muscle strength, as measured by mean change on the Medical Research Council (MRC) scale, was observed between IVIG and placebo groups. Walter et al. (2000) did report a small but significant improvement in neuromuscular symptom scale scores with IVIG versus placebo at six months (p<0.05). One randomized controlled trial evaluated IVIG plus prednisone against placebo plus prednisone. No significant differences in mean change in MRC scores or maximum voluntary isometric contraction measures between the two groups were identified. Table 17. Inclusion body myositis IVIG studies
Study Dalakas (1997) Design Crossover RCT Double blind RCT Double blind Crossover RCT Double blind # of pts 19 Intervention IVIG vs. placebo IVIG+steroids vs. placebo+steroids IVIG vs. placebo Outcome No significant difference between groups in mean change in MRC scores at 3 or 7 months No significant difference between groups in mean MVIC at 7 months Swallowing improved significantly with IVIG compared to placebo No significant difference between groups in mean change in MRC scores or % change in MVIC at 1, 2, or 3 months No significant difference between groups in mean change in modified MRC scores at 6 or 12 months Significant improvement in NSS with IVIG vs. placebo at 6 months Self-rated muscle weakness not significantly different between groups P value n.s. n.s. 0.05 n.s. n.s. 0.05 n.s.

Dalakas (2001) Walter (2000)

37 22

MVIC Maximum voluntary isometric contraction as measured by quantitative muscle testing. NSS Neuromuscular symptom score. MRC Medical Research Council Scale. n.s. Not significant.

Interpretation and Consensus The available evidence consists of three small randomized trials of moderate to high quality. The expert panel noted that although a small number of patients with inclusion body myositis showed some

31

improvement with IVIG, there was no evidence of sustained benefit. In the opinion of the expert panel, IVIG should 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 the biopsy 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 is required 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 neuromuscular pathology. IVIG is not recommended for the treatment of inclusion body myositis.

32

INTRACTABLE CHILDHOOD EPILEPSY

Clinical Description Epilepsies are characterized by recurrent, spontaneous and transient paroxysms of electrical discharges in the brain. Epileptic syndromes are defined on the basis of seizure type, electroencephalogram features, age of 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 not generally considered an immunological disorder, rare epileptic patients with low serum levels IgA, impaired or augmented humoral responses, and circulating antibodies to central nervous system (CNS) antigens have been reported. Large-scale immunological studies in patients with epilepsy and appropriate controls have not been performed. Evidence Summary The Appropriateness of IVIG Evidence Review identified two randomized controlled trials that examined the use of IVIG for intractable childhood epilepsy (level of evidence: 1b). In the larger trial, 61 patients were randomized to one of three different doses of IVIG (100 mg/kg, 250 mg/kg, and 400 mg/kg) or placebo. No significant 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 the combined IVIG groups compared with controls. A sub-group analysis found significantly more patients with partial 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 that were associated with improvements in EEG findings, cognitive performance and general well-being following IVIG. Table 18. Intractable childhood epilepsy IVIG studies
Study Van RaijckevorselHarmant (1994) Illum (1989) Design RCT # of pts 61 Intervention IVIG 100 mg/kg vs. IVIG 250 mg/kg vs. IVIG 400 mg/kg vs. placebo IVIG vs. placebo* Outcome 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%) - 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 on seizure frequency (None had high frequency, invariable seizures) P value n.s. n.s. 0.041 NR

Crossover RCT

10

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

Interpretation and Consensus 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 receive IVIG or placebo, in addition to their regular anti-epileptic medications, making it very difficult to evaluate the effect of IVIG. The panel discussed that although a sub-group analysis in one trial showed some benefit of IVIG for children with partial epilepsy, the number of patients studied was very small compared to the number of patients affected by this condition. Given the chronic nature of intractable epilepsy, use of IVIG would only be a temporizing measure or patients would require regular IVIG treatment for life. In the opinion of the expert panel, the available evidence does not support the use of IVIG for intractable childhood epilepsy. The panel also suggests further immunological studies in patients with epilepsy are required before additional clinical trials are warranted.

33

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

34

LAMBERT-EATON MYASTHENIC SYNDROME

Clinical Description The Lambert-Eaton myasthenic syndrome (LEMS) is a rare acquired autoimmune disorder with autoantibodies directed against voltage-gated calcium channels (VGCC) on the presynaptic nerve terminal of the neuromuscular junction and of autonomic synapses. Patients have weakness and autonomic symptoms. The differential diagnosis includes myasthenia gravis, other disorders of neuromuscular transmission, myopathies, and peripheral neuropathies. The diagnosis of LEMS can be made with single-fibre electromyography studies that show elevated jitter and blocking, and by repetitive nerve stimulation studies that show an incremental response. Post-exercise facilitation 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 have proximal weakness of the extremities, depressed reflexes and dry mouth and eyes. Men have erectile dysfunction. Distal sensory neuropathy may be present. Bulbar and ocular symptoms are mild and rare. The weakness may improve transiently and the reflexes may be obtained after brief maximal voluntary contraction (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 of patients with SCLC have LEMS. Neurologic symptoms may precede the detection of the malignancy by years. 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 release and normal neuromuscular transmission. Antibodies to VGCC are found in 95% of patients with paraneoplastic LEMS and 90% of patients with sporadic LEMS. These antibodies downregulate the VGCC and interfere with release of acetylcholine at the neuromuscular junction and at autonomic ganglia resulting in the clinical features of LEMS. Some patients have an associated paraneoplastic cerebellar ataxia and positive anti-neuronal antibodies such as anti-Hu. Paraneoplastic LEMS may improve with appropriate therapy of the underlying malignancy. Surveillance for malignancy 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 achieved with 3,4-diaminopyridine which inhibits the neuronal voltage-gated K+ ion channel, resulting in increased calcium ion entry and thus, increased ACh release. Immunosuppression with corticosteroids, azathioprine and/or other immunosuppressant drugs can be used to achieve remission. Immunomodulation with plasma exchange or intravenous immune globulin produces temporary improvement and may be useful adjunctive therapy in difficult cases of LEMS, especially when steroids are not effective or cause intolerable side effects. The prognosis of SCLC in patients with LEMS is better than for patients without LEMS. Drugs such as aminoglycoside 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 the use 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), respiratory muscle strength (p=0.028) and bulbar muscle strength (p=0.017) following IVIG compared with placebo.

35

Table 19. Lambert-Eaton myasthenic syndrome IVIG studies

Study Bain (1996) Design Crossover RCT # of pts 9 Intervention IVIG vs. placebo* Outcome Significant improvement in limb strength with IVIG vs. placebo Significant improvement in vital lung capacity with IVIG vs. placebo Significant improvement in bulbar muscle strength (as measured by drinking time) with IVIG vs. placebo p value 0.038 0.028 0.017

*Crossover after eight week washout period.

Interpretation and Consensus Given the positive results from the randomized trial, the severity of this condition and its underlying pathogenesis which is similar to myasthenia gravis, the panel agreed it is reasonable to consider IVIG as an option for treatment of LEMS. While the available evidence is limited to one small crossover trial, a larger trial is unlikely given the rarity of this condition. The expert panel agreed objective evidence of clinical improvement is required for sustained use of IVIG. Recommendations IVIG is recommended as an option for treatment of Lambert-Eaton myasthenic syndrome. Objective evidence 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 reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

36

MULTIFOCAL MOTOR NEUROPATHY

Clinical Description Multifocal motor neuropathy (MMN) presents as slowly progressive muscle weakness and wasting within the territory of individual motor nerves and with a predilection for the distal upper limbs. Focal cramps and fasciculations are common, particularly following exercise. Sensory symptoms and signs are notably absent on both clinical and electrophysiological examination. The electrodiagnostic hallmark of MMN is finding focal conduction blocks (CB) in motor nerves outside regions normally prone to nerve entrapments. The CB corresponds to focal areas of chronic demyelination. MMN is an uncommon neuropathy. However, due to the generally slow progression of MMN, its prevalence is higher than expected and has been estimated at two per 100,000. Generally MMN begins between the ages 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 of inflammation and vasculitis. Cerebrospinal fluid examination usually reveals normal or only slightly raised protein content. MRI imaging may show focal areas of high signal on T2-weighted images pre- and postcontrast, 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 of IgM anti-GM1 antibodies in the pathogenesis of MMN remains controversial. However, elevated anti-GM1 antibodies serve as a marker for positive response to treatment with high dose IVIG. MMN is thought to be an 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 a patients condition. Other immunosuppressive drugs such as mycophenoate, azathioprine, methotrexate, or cyclophosphamide may be considered. However, toxicity and long-term side-effects from these agents are problematic 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 that investigated the use of IVIG for multifocal motor neuropathy. A recently published Cochrane systematic review of IVIG for multifocal motor neuropathy, identified by an update literature search, included the same four 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 the trials for muscle strength, disability, resolution of conduction blocks and side-effects. Significantly more patients showed significant improvement in muscle strength following IVIG compared with placebo (Relative Risk: 11.00 [95% CI 2.86, 42.25; Fixed], p=0.0005). There was no significant difference between IVIG and placebo in the proportion of patients with significant improvement in disability scores or resolution of one or more conduction blocks. Significantly more patients experienced side-effects with IVIG compared to placebo (Relative Risk: 10.33 [95% CI 2.15, 49.77; Fixed], p=0.004). Tests for heterogeneity were not statistically significant. Refer to Table 20 for further details.

37

Table 20. Multifocal motor neuropathy IVIG studies

Study van Schaik (2005) Design and Participants SR with meta-analysis Meta-analysis included: - 3 trials for disability - 3 trials for muscle strength - all 4 for conduction blocks - 2 trials* for side-effects # of pts ---Intervention IVIG vs. placebo Outcome No significant difference in proportion of pts with significant improvement in disability scores between IVIG and placebo: RR: 3.00 [95% CI 0.89, 10.12; Fixed] Significantly greater proportion of patients had significant improvement in muscle strength with IVIG vs. placebo: RR: 11.00 [95% CI 2.86, 42.25; Fixed] No significant difference in proportion of pts with resolution of 1 conduction blocks between IVIG and placebo: RR: 7.00 [95% CI 0.95, 51.70; Fixed] Significantly greater proportion of pts had side-effects with IVIG: RR: 10.33 [95% CI 2.15, 49.77; Fixed], p=0.004 Significant in isometric strength with IVIG at day 28 No significant difference in % in strength at 2 month follow up Significant improvement in NDS scores with IVIG at day 28 Significant in grip strength with IVIG at day 28 Significant improvement in conduction blocks with IVIG At 4 months, no significant difference between groups in change in MRC scores or severity of conduction blocks Self-evaluation scores improved significantly with IVIG 5/6 (83%) responded to IVIG with muscle strength, but not placebo p value n.s. 0.0005 n.s. 0.004 0.05 n.s. 0.038 0.0021 0.037 n.s. 0.05 N/A

Azulay (1994) Federico (2000) Leger (2001) Van den Berg (1995)

Crossover RCT Crossover RCT Crossover RCT Crossover RCT

5 16 19 6

IVIG vs. placebo IVIG vs. placebo IVIG vs. placebo IVIG vs. placebo

meta-analysis included Azulay (1994), Leger (2001), and van den Berg (1995). Muscle strength meta-analysis included Azulay (1994), Federico (2000), van den Berg (1995). *Side-effects meta-analysis included Azulay (1994) and Federico (2000). SR Systematic review. RR Relative risk. MRC Medical Research Council Scale. n.s.Not significant. NDS Neurologic Disability Scale. Patients rated ability to perform five motor activities of daily life. N/A Not applicable.

Disability

Interpretation and Consensus The expert panel agreed IVIG is the only treatment demonstrated by clinical trial to be effective for multifocal motor neuropathy and it is widely accepted as first-line therapy for this condition. Patients with multifocal motor neuropathy who do not respond to IVIG should not be retreated with IVIG. Based on clinical experience, members of the panel noted that the effect of IVIG is variable and over time the interval between treatments may shorten as the therapeutic benefit of IVIG declines. The panel emphasized the importance of continuing regular IVIG maintenance therapy to avoid secondary axonal degeneration. The panel also highlighted that objective measurement of improvement is difficult as physiological change does not correlate well with clinical outcome. Quantitative muscle strength testing will help to ascertain responsiveness. Recommendations IVIG is recommended as first-line treatment for multifocal motor neuropathy. Based on consensus by the expert panel, diagnosis of multifocal motor neuropathy should be made by a neuromuscular specialist, as the diagnosis requires very specific electro-diagnostic expertise. 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 reasonable initial treatment option. For patients requiring repeated treatment, IVIG maintenance therapy should be tailored to the lowest dose that maintains clinical efficacy, usually 1 g/kg or less per treatment course. The frequency of IVIG treatment will vary and may shorten over time. 38

MULTIPLE SCLEROSIS
Clinical Description Multiple sclerosis (MS) is the most common neurological disability in young adults with a prevalence of one in 500 to 1,000 in Canada. Most patients first present with clinical symptoms between 20 and 40 years of age, although the disease may have its onset in childhood or late adulthood. The majority of patients (approximately 85%) initially have a relapsing-remitting course that typically evolves into a secondary progressive course over 20 or more years. About 10% of patients experience a predominantly progressive course from the outset. The pathobiology of multiple sclerosis is thought to represent a complex interplay of immune system reactivity to environmental triggers (e.g. viruses) set upon a background of genetic susceptibility that leads to immune mediated demyelination, axon loss and neurodegeneration. Putative environmental triggers, such as vitamin D homeostasis, early dietary exposures, seasonality of birth, and the timing and sequence of viral exposures during childhood are being explored. The main differential diagnoses include monophasic demyelination diseases (e.g. acute disseminated encephalomyelitis), vasculopathies, connective tissue diseases such as systemic lupus erythematous, mitochondrial disease (e.g. CADASIL), non-specific granulomatous disease such as sarcoidosis and certain infections (e.g. Borreliosis). As discussed in the acute disseminated encephalomyelitis (ADEM) section, some patients who are ultimately diagnosed with MS may manifest with an initial demyelinating event indistinguishable from ADEM. Acute management should reflect the clinical phenotype, and the guidelines for the use of IVIG in these patients should follow those described for ADEM. Current proven therapy for multiple sclerosis involves the immunomodulatory agents: beta-interferon and glatiramer acetate with immunosuppressive medications (e.g. mitoxantrone) reserved for more advanced cases. Plasma exchange has been used in addition to pulse steroids for acute attacks. New therapeutic options under investigation include other immunomodulatory agents, chemokine receptor antagonists, monoclonal antibodies to cytokines and cytokine receptors and in the extreme, immunoablation in the form of autologous bone marrow transplantation with stem cell rescue. Novel concepts of neuroprotection, and aspects of myelin repair and oligodendroglial regeneration are all active areas of research. Evidence Summary The Appropriateness of IVIG Evidence Review identified one systematic review with meta-analysis and six randomized controlled trials of IVIG use for MS (level of evidence: 1a). A systematic review with quantitative synthesis by the Chalmers Research Institute on this topic included the same six trials plus four additional randomized controlled trials that reported outcome data. Two recent randomized trials, one of which has not yet been published, were identified by a member of the expert panel. Overall, 11 randomized trials compared IVIG with placebo and one trial assessed IVIG versus no treatment. Two trials had three arms and also evaluated different doses of IVIG. None of the trials compared IVIG against other therapies for MS. Seven randomized trials evaluated IVIG for relapsing-remitting MS. Six of these trials were placebocontrolled. A systematic review by Sorenson et al. (2002) and the Chalmers review conducted metaanalyses of the trials that compared IVIG against placebo in patients with relapsing-remitting MS. Both reviews reported significant improvement in mean change on the Expanded Disability Status Scale (EDSS) with IVIG versus placebo (Chalmers: weighted mean difference -0.39 [95% CI -0.55, -0.23; Random], p<0.001; Sorenson: effect size -0.24 [95% CI -0.46, -0.01], p=0.042). The randomized trials included in the meta-analyses differed slightly between the systematic reviews. The Chalmers meta-analysis included Achiron (1998), Fazekas (1997), Lewanska (2002), and Oztekin (1998), while the meta-analysis by Sorenson et al. (2002) included Achiron (1998), Fazekas (1997), Lewanska (2002), and Sorensen (1998). 39

Table 21. Multiple sclerosis IVIG studies

Study Design # of pts ------Intervention IVIG vs. placebo IVIG vs. placebo Outcome Significant improvement in mean EDSS with IVIG vs. placebo: Weighted mean difference: -0.39 [95% CI -0.55, -0.23; Random] Significant improvement in mean EDSS with IVIG vs. placebo: Effect size: -0.24 [95% CI -0.46, -0.01]; NNT: 4 Annual relapse rate significantly lower with IVIG vs. placebo: Effect size: -0.50 [95% CI -0.73, -0.27]; NNT: 2 Proportion of relapse-free pts significantly with IVIG vs. placebo: Effect size: 0.29 [95%CI 0.18, 0.39]; NNT: 3 Mean annual relapse rate, % of pts with relapses, % of severe relapses significantly lower with IVIG vs. no treatment No significant difference between groups in mean change in EDSS score or % of pts who improved 1 EDSS grade Mean annual relapse rate significantly lower with IVIG than placebo % of relapse-free pts at 2 years (p=0.001) and mean time to 1st relapse (p=0.003) significantly with IVIG No significant difference between groups in mean in EDSS at 2 years Mean annual relapse rate significantly lower with IVIG than placebo % of relapse-free pts significantly higher with IVIG vs. placebo Significant improvement in mean EDSS with IVIG vs. placebo No significant difference between groups in mean time to first relapse Mean annual relapse rate at 1 year: No significant difference between IVIG groups Combined IVIG groups significantly lower than placebo Mean change in EDSS score at 1 year: No significant difference between IVIG groups Combined IVIG groups significant improvement compared with placebo No significant difference between groups in mean annual relapse rate or mean change in EDSS scores at 22 months No between group comparisons reported. No significant differences between any of the groups in the primary outcome measure, the proportion relapse-free at 48 months. No significant difference between groups in terms of any secondary outcome measure, either other relapse-related outcomes or MRI. No significant difference between groups in time to EDSS progression, annual relapse rate, or change in T2-lesion load. At 3 and 6 months, no significant difference between groups in mean change in % of normal strength of TND muscles nor mean EDSS No significant difference between groups in mean change in visual acuity or mean change in EDSS scores at 6 or 12 months % of relapse-free pts significantly higher with IVIG than placebo No significant difference between groups in # of relapses or mean change in EDSS scores at 15 months No significant difference between the groups in mean change in isometric muscle strength of TND muscles Sub-group analysis of patients with relapsing-progressive MS: IVIG group had significantly fewer relapses at 1 year than placebo P value 0.001 0.042 0.00003 2.1x10-8 0.001 n.s. 0.0002 ---n.s. 0.03 0.008 n.s. n.s. 0.01 n.s. 0.003 n.s. N/A n.s. n.s. n.s. n.s. n.s. 0.02 n.s. n.s. NR

RELAPSING REMITTING MS Chalmers group SR with (in progress) meta-analysis Sorensen (2002) SR with meta-analyses

Achiron (1996)

RCT

36

IVIG vs. no treatment IVIG vs. placebo IVIG vs. placebo IVIG 0.4 g/kg vs. IVIG 0.2 g/kg vs. placebo

Achiron (1998)

RCT

40

Fazekas (1997)

RCT

148

Lewanska (2002)

RCT

49

Ostekin (1998) [abstract} Teksam (2000) PRIVIG (2006)

RCT RCT RCT

36 13 127

IVIG vs. placebo IVIG vs. placebo IVIG-C 0.2 g/kg vs. IVIG-C 0.4 g/kg vs. placebo

SECONDARY PROGRESSIVE MS Hommes (2004) RCT

IVIG vs. placebo RELAPSING REMITTING OR SECONDARY PROGRESSIVE MS Noseworthy RCT 67 IVIG vs. (2000) placebo Noseworthy RCT 55 IVIG vs. (2001) placebo Sorensen (1998) Crossover 21 IVIG vs. RCT placebo RELAPSING PROGRESSIVE OR SECONDARY PROGRESSIVE MS Poehlau (1996) RCT 40 IVIG vs. [abstract] placebo

318

SR Systematic review. N/A Not applicable. n.s. Not significant. TND Targeted neurological deficit muscles. NR Not reported. EDSS Expanded Disability Status Scale: range 0 (normal neurologic exam) to 10 (death). NNT Number needed to treat. Included pts with episodes of optic neuritis. Chalmers meta-analysis included: Achiron (1998), Fazekas (1997), Oztekin (1998), and Lewanska (2002).Sorensen meta-analyses included: Achiron (1998), Fazekas (1997), Sorensen (1998), and Lewanska (2002).

40

Sorenson et al. (2002) also performed meta-analyses for relapse rate and the proportion of relapse-free patients. The conclusion from these quantitative syntheses was IVIG significantly decreased annual relapse rate compared with placebo (effect size: -0.50 [95% CI -0.73, -0.27] and the proportion of patients with relapsing-remitting MS who remained relapse-free was significantly greater with IVIG than placebo (effect size: 0.29 [95%CI 0.18, 0.39], p=2.1x10-8). Recently, a large randomized, double-blind, placebo-controlled trial was performed (called PRIVIG), though the results have not yet been published. An abstract, to be presented at the European Neurological Society conference in June 2006, has been shared with the authors of this guideline. The PRIVIG trial has been included in the guideline at this point for several reasons: the trial is large, placebo-controlled and it evaluated two doses of a newer IVIG product prepared by chromatography. The overall results from the PRIVIG trial were negative. There was no significant difference between any of the groups on any of the relapse or MRI outcome measures. One large randomized placebo-controlled trial evaluated IVIG for patients with secondary progressive MS. Hommes et al. (2004) reported no significant difference in time to EDSS progression or annual relapse rate between IVIG and placebo. Four randomized placebo-controlled trials included a mix of patients with different MS subtypes. Only one of these trials reported a significant difference between IVIG and placebo for any of the primary outcomes measured. In this crossover trial by Sorensen et al. (1998) the proportion of relapse-free patients was significantly higher with IVIG compared to placebo (p<0.02). One randomized controlled trial evaluated different doses of IVIG. No significant difference between IVIG treatment arms was identified. Interpretation and Consensus Evidence from two meta-analyses and several randomized controlled trials is available to support IVIG as superior to placebo for treatment of patients with relapsing-remitting MS. However, the outcome of the recently completed PRIVG trial raises doubt about the efficacy of IVIG in the routine treatment of RRMS. The expert panel agreed that the current and appropriate first-line treatment for patients with relapsingremitting MS consists of the proven effective disease modifying agents, beta-interferon and glatiramer acetate. No randomized trials have compared IVIG against standard therapy. In the opinion of the panel, IVIG should be reserved as an option for patients with relapsing-remitting MS who fail, decline or are not able to take standard immunomodulatory therapies. If IVIG is to be used for long-term management of relapsing-remitting MS, the patient should be under the care of a qualified expert with specialized knowledge of MS. The optimal dose of IVIG is uncertain. Dosages used in the randomized trials ranged between 0.15 g/kg to 2 g/kg once a month. The panel agreed that 1 g/kg monthly with or without a five day induction of 0.4 g/kg daily is a reasonable starting option for treatment of patients with relapsing-remitting MS, but emphasized that a systematic approach should be taken to determine the minimum effective dose of IVIG required. The expert panel does not recommend IVIG for treatment of primary or secondary progressive MS. Based on consensus by the expert panel, IVIG is not recommended for treatment of acute exacerbations of MS, except in patients with severe, refractory, optic neuritis who have had no recovery of vision after three months of standard therapy. Preliminary evidence suggests IVIG might be of benefit in this latter group. The panel also discussed several specific circumstances where little, if any, evidence exists and made recommendations for IVIG use based on expert consensus. For women with relapsing-remitting MS who are pregnant or breastfeeding, the panel agreed it is reasonable to consider IVIG as a treatment option. For neuromyelitis optica (i.e. Devics syndrome) and Marburg disease, which are likely variants of MS, the panel 41

agreed other therapies have greater validity. For Marburg disease, which is an acute and often fatal, demyelinating phenotype, characterized by fulminant demyelinatination and necrosis, the panel agreed IVIG may be considered among the treatment options given the life-threatening nature of this condition. The panel also discussed the recent discovery of a circulatory antibody to aquaporin-4 in many patients with neuromyelitis optica. The ability to screen patients for the presence of this antibody may lead to new evidence for a role for IVIG in antibody-positive patients. Thus, although the current level of evidence does not support the use of IVIG in patients with neuromyelitis optica, future studies in this area are needed. The expert panel identified several other areas that would benefit from further clinical research. These include a randomized controlled trial of IVIG for acute exacerbations of MS (in particular for patients with severe, refractory, optic neuritis) and randomized trials that compare IVIG with current immunomodulatory therapies for relapsing-remitting MS. Randomized controlled trials are also needed to evaluate IVIG for treatment of primary and secondary progressive MS, as well as trials to determine the optimal dose of IVIG. Recommendations IVIG is recommended as an option for treatment of patients with relapsing-remitting MS who fail, decline or are not able to take standard immunomodulatory drug therapies. For those patients with rapidly advancing relapsing-remitting MS, consideration should first be given to immunosuppression therapy. IVIG is not recommended for the treatment of primary or secondary progressive MS. Based on consensus by the expert panel, IVIG is not recommended for treatment of acute exacerbations of MS, except in patients with severe, refractory, optic neuritis who have had no recovery of vision after three months of standard steroid therapy, or patients for whom corticosteroid therapy is contraindicated. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients with relapsing-remitting MS who are pregnant or breastfeeding or in the immediate post-partum period for women whose exacerbation rate was high prior to pregnancy and who were on disease modifying agents prior to pregnancy with plans to re-commence therapy following birth or breastfeeding. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients with Marburg disease, given the life-threatening nature of this disease. Dose and Duration Based on consensus by the expert panel, 1 g/kg monthly with or without a five day induction of 0.4 g/kg daily is a reasonable starting option for treatment of patients with relapsing-remitting MS. The panel emphasized that a systematic approach should be taken to determine the minimum effective dose of IVIG required.

42

MYASTHENIA GRAVIS
Clinical Description Myasthenia gravis is an acquired autoimmune disease characterized by the formation of autoantibodies to the acetylcholine receptor (AChR) and fatigable weakness. The incidence of myasthenia gravis is seven per 1,000,000 and the prevalence is 75 to 125 per million. Women are affected 1.4 times more frequently than men, particularly those under 40 years of age. The differential diagnosis includes psychogenic weakness, chronic fatigue, myopathies and cranial nerve compression syndromes. Patients with myasthenia gravis have fatigable and variable muscle weakness that worsens with activity and during the course of the day, and improves with rest. In about 15% of patients, weakness is limited to the extraocular muscles (ocular myasthenia gravis). For the remaining 85% of patients, the disease becomes generalized reaching maximum severity within three years. Weakness starts in the ocular muscles with symptoms of ptosis, diplopia, and blurred vision in half the patients. Those patients with bulbar and respiratory muscle weakness are at risk for aspiration pneumonia and myasthenic crisis. Exertion, exposure to heat or hot weather, infections, or emotional upsets can precipitate weakness. Myasthenia gravis does not involve cardiac or smooth muscle, cognitive skills, coordination, sensation, or tendon reflexes. Modulating or blocking AChR antibodies are present in approximately 70% of patients with generalized myasthenia gravis and in about 50% with ocular myasthenia gravis. Antibodies against the muscle-specific receptor tyrosine kinase (MuSK) are present in 70% of AChR antibody-negative myasthenia gravis patients. The antibodies prevent normal neuromuscular transmission by reducing the number of available AChR with consequent weakness. Correlations between AChR antibody levels and clinical weakness are poor. Thymic hyperplasia has been reported to occur in 65% of myasthenic patients and thymoma in up to 15%. Treatment for myasthenia gravis includes anticholinesterase drugs, thymectomy, immunosuppressive therapy, and immunomodulation (e.g. plasmapheresis, IVIG). Anticholinesterase medication reduces symptoms, but does not alter the course of the disease. Thymectomy is advised in most patients with thymoma and in patients up to age 60 with generalized myasthenia gravis to increase the probability of remission or improvement. Immunosuppression with corticosteroids is prescribed for most patients who have significant weakness and the response is observed in two to four weeks. Other immunosuppressive medications used for myasthenia gravis are: azathioprine, cyclosporine, cyclophosphamide, and mycophenolate mofetil. Immunomodulation with plasma exchange or IVIG removes AChR antibodies or modulates antibody effects temporarily. Plasma exchange is the standard treatment for myasthenic crisis, acute deterioration, or pre-thymectomy in patients with respiratory or bulbar involvement. Some drugs such as aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, and betablockers exacerbate myasthenia gravis and should be avoided. Transient neonatal myasthenia gravis develops in approximately 12% of infants born to myasthenic mothers and persists for several weeks. Evidence Summary The Appropriateness of IVIG Evidence Review identified a Cochrane systematic review of IVIG use for myasthenia gravis (level of evidence: 1b). A systematic review by the Chalmers Research Institute on this topic included three randomized controlled trials and seven non-comparative case series. The Cochrane systematic review by Gajdos et al. (2003) included four randomized controlled trials of IVIG use for myasthenia gravis. No meta-analysis was conducted due to the heterogeneity of patient populations, interventions and outcomes. The authors of the Cochrane review concluded that further randomized trials are needed to investigate the effectiveness of IVIG compared to plasma exchange for the treatment of

43

myasthenia gravis exacerbations or crises and to determine the indications for IVIG in moderate and severe myasthenia gravis. Table 22. Myasthenia gravis IVIG studies
Study Design and Participants # of pts 147 87 Intervention IVIG vs. other tx or placebo IVIG(0.4 g/kg/d x3d) vs. IVIG(0.4 g/kg/d x5d) vs. PLEX Outcome No meta-analysis was performed due to heterogeneity of interventions and outcomes assessed. Mean change in MMS at d15: No significant difference between IVIG(3d) vs. IVIG(5d) No significant difference between IVIG(combined) and PLEX All groups improved significantly from baseline at d2 No significant difference between groups in median time to response or change in anti-AchR antibody titer at d15 QMGS at 1 or 4 wks not significantly different between groups Both groups had significant improvement in QMGS at 4 weeks % change in anti-AchR antibody titer: PLEX: week 1 (p<0.05), no significant at week 4, 8, or 16 IVIG: no significant at week 1, 4, 8, or 16 No significant difference between groups in QMGS of two most affected criteria at d14 or time to maximum improvement No significant difference between groups at d42 in QMGS, mean consecutive difference on single fiber EMG, % decrement on repetitive nerve stimulation, or MG-ADL Significant improvement in mean severity of disease as measured by the Osserman scale at 1year At d60, 57% of pts improved 1 grade on the OGCCMS scale. No significant difference in response between patients in acute phase and patients with chronic stable MG Significant mean improvement on OGCCMS scale (p<0.00005) All pts showed improvement on the OGCCMS scale Significant mean improvement on functional scale All pts showed improvement on the OGCCMS scale Significant mean improvement on functional scale All pts showed improvement on the OGCCMS scale Reported adverse events only. One case of hemolytic anemia IVIG temporarily stabilized all 3 cases and allowed thymectomy to be performed 8/10 (80%) pts improved 1 grade in functional status on the Osserman scale with median duration of improvement 25 days No improvement with IVIG plus neostigmine Improved with IVIG plus neostigmine p value N/A n.s. n.s. 0.02 n.s. n.s. 0.05 ---n.s. n.s. n.s. 0.001 NR n.s. ---NR NR N/A N/A NR N/A N/A

ADULT MYASTHENIA GRAVIS Gajdos (2003) Systematic review Gajdos (1997) RCT MG acute exacerbation

Ronager (2001)

Crossover RCT Moderate to severe MG

12

IVIG vs. PLEX

Schuchardt [Unpublished]* Wolfe (2002) Achiron (2000) Cosi (1991) Hilkevich (2001)

RCT MG exacerbation RCT Mild-moderate MG or chronic MG Case series MG acute exacerbation Case series Acute-relapsing MG

33 15 10 37 11 6 6 38 3 10 1 1

IVIG vs. oral MP IVIG vs. placebo IVIG IVIG IVIG IVIG IVIG IVIG IVIG IVIG IVIG + neostigmine IVIG + neostigmine

Case series Chronic, severe MG Huang (2003) Case series Chronic, moderate MG Wegner (2002) Case series Chronic MG Wilson (1997) Case series JUVENILE MYASTHENIA GRAVIS Herman (1998) Case reports Selcen (2000) Case series

NEONATAL MYASTHENIA GRAVIS Tagher (1999) Case report Bassan (1998) Case report

SR Systematic review. PLEX Plasma exchange. n.s. Not significant. MMS Myasthenic muscle score. Change. Tx Treatment. QMGS Quantified MG clinical score. ADL Activities of daily living. N/A Not applicable. *As of August (2005). NR Not reported. SR included 4 trials: Gajdos (1997), Wolfe (2002), Ronager (2001) and Schuchardt (unpublished). Defined as an increase in MMS score of 20 points. MP Methylprednisolone. OGCCMS Oosterhuis Global Clinical Classification of Myasthenic Severity.

Two small randomized trials compared IVIG with plasma exchange. The trial by Gajdos (1997) included patients with acute exacerbations of myasthenia gravis, while the crossover trial by Ronager (2001) evaluated IVIG in patients with moderate to severe, but stable, myasthenia gravis. Neither trial identified a significant difference between IVIG and plasma exchange for any of the outcomes assessed. Both trials reported significant improvement from baseline following treatment with IVIG or plasma exchange as measured by mean change in Myasthenic Muscle Score or Quantified Myasthenia Gravis Clinical Score. 44

The randomized trial by Gajdos et al. (1997) also evaluated different doses of IVIG. No significant difference between IVIG treatment arms was identified. One very small, under-powered trial by Wolfe et al. (2002) compared IVIG against placebo. No significant difference between groups was observed for any of the outcomes evaluated. One unpublished trial randomized 33 patients with moderate exacerbations of myasthenia gravis to receive IVIG or oral methylprednisolone. No significant difference between the groups was identified for any of the outcomes measured. Almost all of the case series and case reports identified reported significant improvement with IVIG. Please refer to Table 22 for further details. Interpretation and Consensus The expert panel acknowledged there is a strong immunological rationale for the use of IVIG in the treatment of myasthenia gravis. However, the panel raised several concerns about the quality of the available evidence. Problems with the randomized controlled trials include the patient populations studied, endpoints measured, and methodological issues such as lack of blinding and early termination. In the opinion of the panel, mild to moderate myasthenia gravis can be successfully managed with symptomatic and immunosuppressive medications. The panel agreed IVIG should be reserved for treatment of severe exacerbations or myasthenic crises. The panel noted IVIG and plasma exchange are currently used in clinical practice as short-term measures until more effective long-term immunosuppression can be achieved for patients with severe myasthenic exacerbations or in preparation for surgery. The available evidence does not suggest a significant difference between plasma exchange and IVIG. A definitive randomized controlled trial is needed, however, to establish whether IVIG or plasma exchange is superior for treatment of severe myasthenic exacerbations. Given the limited evidence available, the expert panel agreed IVIG should not be used as maintenance therapy for chronic myasthenia gravis. Extremely limited evidence is available for use of IVIG for myasthenia gravis in the pediatric setting. Based on consensus by the expert panel, use of IVIG for juvenile myasthenia gravis should follow the recommendations outlined for adults. The panel also agreed IVIG should be an option for treatment of neonates severely affected by myasthenia gravis. Recommendations Adult and Juvenile Myasthenia Gravis IVIG is recommended as a treatment option for patients with severe exacerbations of myasthenia gravis or myasthenic crises. Based on consensus by the expert panel, IVIG may be considered as an option to stabilize patients with myasthenia gravis prior to surgery. IVIG is not recommended as maintenance therapy for patients with chronic myasthenia gravis. Neonatal Myasthenia Gravis Based on consensus by the expert panel, IVIG may be considered among the treatment options for neonates severely affected with myasthenia gravis. 45

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 reasonable option. If additional therapy is required, the dose should be adjusted depending upon response and titrated to the minimum effective dose.

46

OPSOCLONUS-MYOCLONUS
Clinical Description Opsoclonus-myoclonus syndrome is a rare neurological disorder characterized by an unsteady, trembling gait, myoclonus (brief, shock-like muscle spasms) and opsoclonus (irregular, rapid eye movements). Other symptoms may include difficulty speaking, poorly articulated speech, or an inability to speak. A decrease in muscle tone, lethargy, irritability and malaise may also be present. The underlying basis of this disorder is thought to be immune-mediated. Opsoclonus-myoclonus typically presents either following a childhood viral infection or as a paraneoplastic syndrome. The paraneoplastic syndrome is most frequently associated with neural crest tumours, in particular, neuroblastoma. Evidence Summary The Appropriateness of IVIG Evidence Review identified one retrospective chart review and nine case reports that assessed the use of IVIG for opsoclonus-myoclonus (level of evidence: 4). Overall, the complete response rate to IVIG with or without additional therapies was 33% (6/18) and the partial response rate was 44% (8/18). Table 23. Adult opsoclonus-myoclonus IVIG studies
Study IDIOPATHIC OM Bataller (2001) Pless (1996) Pranzatelli (2002) PARANEOPLASTIC OM Bataller (2001) Design Retrospective chart review Case report Case report Retrospective chart review # of pts 5 1 1 4 Intervention IVIGsteroids ACTH IVIG ACTH+ steroids IVIG IVIG Response Monophasic course: 2/3 complete recovery; 1/3 partial recovery Relapsing course: 2/2 remission with IVIG (mild ataxia remained) Monophasic course, complete recovery with IVIG Relapsing course, partial recovery with monthly IVIG 1/4 partial recovery (IVIG at same time as antineoplastic therapy) 3/4 no response to IVIG

Table 24. Pediatric opsoclonus-myoclonus IVIG studies

Study IDIOPATHIC OM Suige (1992) Yiu (2001) Design Case report Case report # of pts 1 1 1 1 1 1 1 Intervention Steroids IVIG ACTH+azathioprine + IVIG Steroids IVIG IVIG ACTH IVIG IVIG + ACTH Steroids IVIG Response Monophasic course: Complete recovery Monophasic course: Transient partial recovery Relapsing course: No response to IVIG Complete recovery Complete recovery Partial recovery Partial recovery

Penzien (1993) Case report NEUROBLASTOMA-ASSOCIATED OM Petruzzi (1995) Case report Eiris (1996) Case report Borgna-Pignatti (1996) Case report Fisher (1994) Case report

Interpretation and Consensus Extremely sparse evidence is available for use of IVIG for opsoclonus-myoclonus. Stronger evidence is unlikely, however, given the rarity of this condition. In the opinion of the expert panel, it is reasonable to consider IVIG as a treatment option for opsoclonus-myoclonus given the seriousness of this disorder. The panel stressed that objective evidence of clinical improvement would be required for sustained use of IVIG. 47

The panel suggested development of a registry to document the use of IVIG and other therapies for patients with opsoclonus-myoclonus. Recommendations Based on consensus by the expert panel, IVIG may be considered as an option for treatment of opsoclonusmyoclonus. 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 and over two days for children is a reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

48

PARAPROTEINEMIC NEUROPATHY (IgM VARIANT)

Clinical Description Most patients with IgM paraproteinemic demyelinating neuropathy present with a chronic, slowly progressive, distal and predominantly sensory neuropathy. Patients usually experience prominent gait ataxia, paraesthesias and numbness in the hands with impaired dexterity and coarse tremors. While vibration sense and position sense are severely impaired, there is no or relatively little distal weakness. The disease progresses very slowly over months to years. Males are more commonly affected than females. Electrophysiological examinations demonstrate all features of a CIDP-like demyelinating polyneuropathy with markedly slowed nerve conduction velocity without conduction block. Distal latencies are characteristically very prolonged. Despite the predominance of sensory symptoms, demyelination similarly affects motor and sensory fibers. Paraprotein may be detected by standard serum protein electrophoresis; however, both serum immunoelectrophoresis (SIEP) and serum immunofixation electrophoresis (SIFE) are more sensitive techniques to detect lower paraprotein concentrations. Heavy (IgM) and light chain (kappa or lambda) class should be identified. Almost 50% of IgM-associated demyelinating polyneuropathy have high titers of antibodies cross-reacting with myelin-associated glycoprotein (MAG), which are more likely to be of kappa light chain type. There is considerable evidence that these anti-MAG antibodies are involved in the pathogenesis of the demyelinating neuropathy. Full proof is still lacking. Deposition of the paraprotein on the myelin sheaths of primarily large fibers in nerve biopsies, shown by immunohistochemical techniques, is strongly supportive of this concept. This correlates with widely spaced outer myelin lamellae demonstrated by electronmicroscopic examination of the nerve biopsy. Cerebrospinal fluid protein is elevated in approximately 85% of cases. Regular blood cell counts and bone marrow investigations are usually normal. Bence Jones protein is negative. Monitoring monoclonal protein peak and the bone marrow at regular intervals of three to five years to search for malignant transformation is recommended. IgM anti-MAG positive or anti-MAG negative paraproteinemic neuropathy does not need to be treated if symptoms are mild. Given the role anti-MAG antibodies are thought to play in the pathogenesis of the neuropathy, treatments have focused on decreasing circulating IgM by removal (e.g. plasma exchange), inhibition (e.g. IVIG) or reduction of synthesis (e.g. corticosteroids, immunosuppressive drugs, interferon alpha or rituximab). To date, none of these treatments have yielded particularly promising results. Evidence Summary The Appropriateness of IVIG Evidence Review identified one Cochrane systematic review and three randomized controlled trials of IVIG use for IgM paraproteinemic neuropathy (level of evidence: 1b). The Cochrane systematic review examined whether any form of immunotherapy decreased disability or impairment associated with IgM anti-MAG positive paraproteinemic neuropathy. Three of the five randomized controlled trials included in the Cochrane review assessed the efficacy of IVIG. Two trials compared IVIG with placebo and one trial assessed IVIG versus interferon alpha. The Cochrane review did not perform a meta-analysis of the effect of IVIG treatment versus placebo because of differences in outcomes assessed. A small crossover trial by Comi et al. (2002) examined the short-term effect of IVIG treatment. At two weeks, significant improvement in modified Rankin scores was observed with IVIG compared to placebo (p=0.008). At four weeks, change in mean overall disability score was significantly improved with IVIG versus placebo (p<0.05). Another small crossover trial that evaluated IVIG against placebo found no significant difference between groups in change in mean Rankin scores at three months. 49

One non-blinded, crossover trial that evaluated IVIG versus interferon alpha reported significant improvement in mean clinical neuropathy disability scores with interferon alpha compared to IVIG at six month follow-up (p=0.02). Table 25. Paraproteinemic neuropathy (IgM variant) IVIG studies
Study Lunn (2003) Comi (2002) Design Systematic review Included 3 RCTs below Crossover RCT # of pts --22 Intervention IVIG vs. placebo or INF- IVIG vs. placebo Outcome Meta-analysis for overall treatment effect of IVIG vs. placebo was not performed due to heterogeneity of outcomes. At 2 weeks: - significant improvement in modified Rankin scores with IVIG vs. placebo - no significant difference between groups in change in mean disability score At 4 weeks: - change in mean overall disability score significantly with IVIG vs. placebo - significant improvement in handgrip with IVIG vs. placebo Mean change in modified Rankin score: IVIG: 912.7 vs. placebo: -1.18.3 At 6 months: - Significant improvement in mean CNDS with INF- vs. IVIG - CNDS improved >20%: IVIG 1/10 (10%) vs. INF- 8/10 (80%) p value N/A 0.008 n.s. 0.05 0.05 n.s. 0.02 0.005

Dalakas (1996) Mariette (1997)

Crossover RCT Crossover RCT (Not blinded)

11 20

IVIG vs. placebo IVIG vs. INF-

n.s. Not significant. N/A Not applicable. CNDS Clinical neuropathy disability score. INF- Interferon alpha. Modified Rankin scale: Range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention).

Interpretation and Consensus The available evidence is limited to three small trials of variable quality and mixed results. While one placebo-controlled trial by Comi et al. (2002) reported benefit of IVIG for IgM paraproteinemic neuropathy, the expert panel questioned the clinical significance of the results given the extremely short duration of the trial. As IgM paraproteinemic neuropathy is a chronic condition, if there is a benefit of IVIG, it is likely too transient. The panel noted that no significant difference between IVIG and placebo was detected in the longer-term randomized trial by Dalakas et al. (1996). The expert panel does not recommend IVIG for the treatment of IgM paraproteinemic neuropathy. Recommendations IVIG is not recommended for the treatment of IgM paraproteinemic neuropathy.

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PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH STREPTOCOCCAL INFECTIONS

Clinical Description Simple motor tics are common, affecting up to 1-2% of school-age children. The association of rapid-onset tics associated with obsessive-compulsive disorder (OCD) in the context of recovery from streptococcal infection (PANDAS) was first reported in 1994. Molecular mimicry between streptococcal antigens and the central nervous system (CNS) have been hypothesized to underlie Sydenhams chorea, a well-recognized post-streptococcal disorder, and by analogy have been implicated in PANDAS. Treatment to interrupt the autoimmune process in PANDAS led to trials of IVIG and plasma exchange in affected children. Similar trials in children with non-streptococcal associated OCD or tics were uniformly negative. Evidence Summary The Appropriateness of IVIG Evidence Review identified one randomized controlled trial that examined the use of IVIG for PANDAS (level of evidence: 1b). In this trial, 29 children who had new onset or severe exacerbations of obsessive-compulsive or tic disorders following streptococcal infections were randomly assigned to receive IVIG, plasma exchange, or placebo. At one month, there was no significant difference between the IVIG and plasma exchange groups. Patients who received treatment with either IVIG or plasma exchange showed significant improvement in obsessive-compulsive symptoms (p=0.006), anxiety (p=0.001), depression (p=0.002), emotional lability (p=0.001) and overall functioning (p=0.0009) compared with placebo. The improvement in symptoms was still evident at one year follow-up. Table 26. PANDAS IVIG studies
Study Perlmutter (1999) Design RCT # of pts 29 Intervention IVIG vs. PLEX vs. placebo Outcome At 1 month: No significant difference between IVIG and PLEX groups Significant improvement in the following with IVIG or PLEX vs. placebo: obsessive-compulsive symptoms anxiety depression emotional lability overall functioning At 1 year: Symptoms remained improved from baseline on all measures for patients who received IVIG or PLEX p value n.s. 0.006 0.001 0.002 0.001 0.0009 NR

PLEX Plasma exchange. NR Not reported. n.s. Not significant.

Interpretation and Consensus While the evidence is limited to one small placebo-controlled trial, the results are compelling. In the opinion of the expert panel, it is reasonable to consider IVIG among the options for treatment of PANDAS. The panel emphasized that this syndrome is not well understood and diagnosis of PANDAS requires expert consultation. The optimum dose and duration of IVIG for treatment of PANDAS is uncertain. The randomized trial used 1 g/kg daily for two days and there was agreement that this is a reasonable option. Recommendations IVIG is recommended as an option for treatment of patients with PANDAS. Based on consensus by the expert panel, diagnosis of PANDAS requires expert consultation. 51

Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over two days is recommended as a reasonable option.

52

POEMS SYNDROME
Clinical Description A chronic progressive and predominantly motor neuropathy resembling CIDP is the major clinical manifestation of POEMS syndrome. Peak incidence is in the fifth and sixth decades of life and it predominantly occurs in males. Many patients are initially thought to suffer from idiopathic CIDP, until an IgG or IgA paraprotein is detected by a careful search with protein electrophoresis or immuno fixation electrophoresis. Most patients have a lambda light chain containing M protein peak that is usually small. In addition they often harbour a solitary sclerotic plasmacytoma bone lesion detected in a diligent search by skeletal survey which should include the long bones of the extremities. Alternatively, patients may have Castlemans disease along with typical features of POEMS. In either case, bone marrow examination reveals only 5% or less of plasma cells. The acronym POEMS stands for polyneuropathy, organomegaly (hepatosplenomegaly or lymphadenopathy), endocrinopathy, M protein, skin changes (hypertrichiosis, hyperpigmentation, diffuse skin thickening, finger clubbing, haemangiomas, white nail beds). Papilloedema, ascitis, pleural effusions and generalized edema are frequent, caused by the massive secretion of vascular endothelial growth factor (VEGF). VEGF targets the endothelial cell and induces a rapid, reversible increase in vascular permeability as well as angiogenesis. Thrombocytosis is a constant feature of POEMS syndrome and VEGF has been shown to be secreted from platelets. Patients also show high levels in serum of tumour necrosis factor and interleukins (IL-1and IL-6). Electrophysiological studies show a mixed picture of demyelination and axonal degeneration with a generalized slowing of nerve conduction velocities without conduction block, and a reduction in compound motor action potential amplitudes. Nerve biopsies show a mixture of demyelination with uncompacted myelin lamellae and axonal degeneration. The diagnosis of POEMS syndrome is made on clinical grounds. If the condition is suspected the following investigations should be considered: endocrine blood tests (TSH, FSH, LH, glucose), abdominal ultrasound or CT abdomen (organomegaly), CBC (thrombocytosis), measurement of VEGF levels in serum, and a nerve biopsy. There are no controlled clinical trials of treatments for the neuropathy in POEMS syndrome. A recent retrospective review of 99 patients with POEMS reported approximately 75% of patients had some response to therapy [Dispenzieri et al. (2003)]. Patients with solitary plasmacytomas benefited from local radiation or surgical excision. A combination of melphalan and corticosteroids were effective in approximately 55% of patients. Autologous peripheral blood stem cell transplantation led to neurological improvement or stabilization in 88% (14/16) patients, but was associated with significant morbidity. Evidence Summary The Appropriateness of IVIG Evidence Review identified four cases of IVIG use for POEMS (level of evidence: 4). Two patients showed improvement following IVIG plus dexamethasone or radiotherapy. No improvement with IVIG was observed for two patients with Castlemans disease and POEMS.

53

Table 27. POEMS syndrome IVIG studies

Study Benito-Leon (1998) Henze (1995) Huang (1995) Design and participants Case report Variant of POEMS Case report Severe POEMS Case report POEMS and Castlemans disease # of pts 1 1 2 Intervention IVIG + radiotherapy IVIG IVIG + steroids IVIG Outcome At 1 month: marked improvement in numbness, dyspnea, impotence At 1 year: independent ambulation, improved nerve conduction IVIG alone: partial response ( paresthesias, no change in paresis) IVIG+steroids: independent ambulation, improved muscle power No improvement with IVIG in either case.

Interpretation and Consensus Extremely sparse evidence is available for the use of IVIG in POEMS. The expert panel discussed that recently other treatments such as radiotherapy and autologous peripheral blood stem cell transplantation have shown benefit for patients with POEMS. In the opinion of the panel there is no role for IVIG in the treatment of POEMS syndrome. Recommendations IVIG is not recommended for the treatment of POEMS syndrome.

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POLYMYOSITIS
Clinical Description Polymyositis usually presents in adults, with slowly progressive proximal muscle weakness, particularly affecting the hip and shoulder girdles. Some patients will have associated muscle pain. The disorder can occur as an isolated autoimmune muscle disease or as part of a specific connective tissue disease, such as systemic lupus erythematosis or mixed connective tissue disease. Serum creatine kinase (CK) is usually elevated and is often extremely high. Electromyography abnormalities are present in most patients and indicate a primary muscle disease with associated muscle fibre necrosis, but a specific diagnosis requires muscle biopsy. Making a pathological diagnosis can be difficult and the muscle biopsy should be evaluated by an experienced neuropathologist to exclude the possibility of inclusion body myositis. Some patients will have a fulminant muscle fibre necrosis, with severe weakness and dysphagia from esophageal and oralpharyngeal weakness. Several auto-antibodies have been identified as being associated in some patients with polymyositis. There is a mild increase in risk of malignancy in adult patients with polymyositis. Most patients will have improvement in their muscle weakness with steroids or immune suppression. Evidence Summary The Appropriateness of IVIG Evidence Review identified one non-randomized controlled trial and three case series of IVIG use for polymyositis (level of evidence: 4). A systematic review by the Chalmers Research Institute of IVIG use for myositis included the same non-randomized trial. Only one case series explored the use of IVIG exclusively in patients with polymyositis. The other studies included patients with either polymyositis or dermatomyositis. Table 28. Polymyositis IVIG studies
Study POLYMYOSITIS Cherin (2002) Design and Participants Case series Tx refractory POLYMYOSITIS OR DERMATOMYOSITIS Danieli (2002) Non-RCT New onset, relapsed or Tx refractory Case series Tx refractory Cherin (1994b) Case series No previous tx 11 IVIG # of pts 35 IVIG Intervention Outcome Clinical improvement with IVIG: 25/35 (71%) patients Significant improvement in muscle power and MDS: Mean muscle power*: Baseline 47.811.1; post-IVIG 67.412.7 Mean MDS score: Baseline 22.38.0; post-IVIG 10.96.1 Significant reduction in mean steroid dose (mg/d) Significant in creatine kinase levels No significant difference in CR between groups at 1 year At 4 years: - Significantly more patients given IVIG+steroids+CSA maintained complete remission compared with steroids+CSA - No significant difference between IVIG+steroids+CSA and IVIG+PLEX+steroids+CSA groups Significant improvement in muscle power: Mean muscle power*: Baseline 46.511.5; post-IVIG 67.115.4 Significant reduction in mean steroid dose (mg/d) Significant in creatine kinase levels No significant improvement in mean muscle power* from baseline - only 3/11 (27%) had significant clinical improvement Significant improvement in mean creatine kinase levels P value

0.01 0.01 0.05 0.01 n.s. 0.001 n.s. 0.01 0.05 0.01 n.s. 0.01

20

Steroids+CSA or IVIG+Steroids+CSA or IVIG+PLEX+steroids+CSA

Cherin (1994a)

35

IVIGsteroidsother tx

*Muscle power score: used a modified MRC scale; treatment classified as successful if score increase by 18 points. MDS Muscle Disability Scale: range 0 (no disability) to 75 (maximum disability). CSA cyclosporine A. PLEX Plasma exchange. CR Complete remission, defined as increase in strength of 3 affected muscles with normal creatine kinase levels. For patients with normal baseline creatine kinase levels, absence of pathological EMG spontaneous activity was required to be classified as CR. Other treatments included methotrexate, azathoprine, or plasma exchange. Tx Treatment. n.s. Not significant.

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The only case series, by Cherin (2002), that investigated IVIG exclusively in patients with polymyositis observed clinical improvement in 71% (25/35) of patients and reported significant improvement in muscle power, muscle disability scores and creatine kinase levels (p<0.01) after IVIG. There was also a significant reduction in mean steroid dose following treatment with IVIG (p<0.05). All three studies that included patients with polymyositis or dermatomyositis presented pooled data and it was not possible to determine the outcome of IVIG treatment for only those patients with polymyositis. Refer to Table 28 for further details. Interpretation and Consensus Many patients with polymyositis will respond to first-line therapies (e.g. steroids). The expert panel discussed and agreed that it is reasonable to include IVIG among the options for those patients with polymyositis who fail to respond to first-line therapies. The panel also agreed a skeletal muscle biopsy is required to diagnosis polymyositis and that the biopsy 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 is required for the diagnosis of polymyositis. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens and that the final interpretation be made by an expert in neuromuscular pathology. Based on consensus by the expert panel, IVIG may be considered among the treatment options for patients with polymyositis who fail to respond to first-line therapies (e.g. steroids). 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 reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

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RASMUSSENS ENCEPHALITIS
Clinical Description Rasmussens encephalitis is a rare progressive form of epilepsy with onset in the first decade of life. The disorder is associated with severe focal epilepsy, lateralized brain atrophy, and progressive central nervous system (CNS) impairment. Outcome is uniformly poor. Surgical resection of the affected hemisphere is viewed as the mainstay of therapy, but has significant morbidity. Evidence that Rasmussens encephalitis has an autoimmune basis stems from pathological evidence of inflammation in resected brain tissue. However, inflammatory reactions can be seen in patients with refractory epilepsy due to other etiologies not specific to Rasmussens. Circulating antibodies directed against the glutamate receptor 2 in Rasmussens syndrome have also been reported, although their pathological significance is debated. Evidence Summary The Appropriateness of IVIG Evidence Review identified one case series and four case reports of IVIG use for Rasmussens encephalitis. Overall, 31% (5/16) of patients showed marked improvement in symptoms following IVIG alone or in combination with additional therapies. Table 29. Rasmussens encephalitis IVIG studies
Study Granata (2003) Design Case series # of pts 11 Intervention IVIGsteroidsPLEX other therapies* Outcome Effect of IVIG: 1/11(9%) transient seizure frequency >50%, improved neurologic condition 2/11(18%) transient seizure frequency up to 50% 5/11 (46%) no effect 3/11(27%) not assessable Mild improvement in symptoms Marked improvement in hyperkinetic movements Marked improvement (>75% seizure frequency, improved cognition) 2/2 (100%) Marked improvement in seizure frequency, hemiparesis, cognition

Korn-Lubetzki (2004) Frucht (2001) Villani (2001) Leach (1999)

Case report Case report Case report Case report

1 1 1 2

IVIG IVIG+ganciclovir IVIG IVIG

*Other therapies included cyclophosamide and protein A immunoadsorption

Interpretation and Consensus The rationale for use of IVIG is based on the premise of an infectious or peri-infectious etiology for Rasmussens encephalitis and the possibility of circulating GLUR3 antibodies. The expert panel agreed that while the available evidence is quite limited it does suggest IVIG may be of transient benefit for some patients with Rasmussens encephalitis. The expert panel agreed the accepted and appropriate standard of care for this condition is hemispherectomy. In the opinion of the expert panel, it is reasonable to consider IVIG among the options for short-term, temporizing measures in the management of patients with Rasmussens encephalitis. Given that surgical management is the preferred treatment strategy, the expert panel does not recommend long-term use of IVIG for this condition. Recommendations IVIG may be an option as a short-term, temporizing measure for patients with Rasmussens encephalitis. IVIG is not recommended for long-term therapy for Rasmussens encephalitis as surgical treatment is the current standard of care.

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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 and over two days for children is a reasonable option.

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STIFF PERSON SYNDROME

Clinical Description Stiff person syndrome is an uncommon acquired disorder that produces severe disabling muscle spasms and rigidity. Approximately 50% of patients have anti-glutamic acid decarboxylase (GAD65) antibodies. Stiff person syndrome is thought to have an autoimmune etiology and is associated with other autoimmune disorders, most frequently diabetes. The disorder can affect children or adults. Axial muscles and limbs are usually affected, however, there is a variant with restricted limb involvement. Drugs that have been beneficial for some patients include diazepam, baclofen and valproate. Plasma exchange has also been reported to be of benefit for some patients. Evidence Summary The Appropriateness of IVIG Evidence Review identified one randomized controlled trial that assessed use of IVIG for stiff person syndrome (level of evidence: 1b). This small crossover trial of 14 patients reported a significant direct effect of treatment with IVIG compared to placebo on improvements in both mean stiffness scores (p=0.01) and mean sensitivity scores (p=0.03). A carry over treatment effect of IVIG was identified with patients who received IVIG first maintaining improvements in stiffness during the one-month washout period and into the placebo phase (p<0.001). Table 30. Stiff person syndrome IVIG studies
Study Dalakas (2001) Design and Participants Crossover RCT All pts had anti-GAD65 antibodies # of pts 14 Intervention IVIG vs. placebo* Outcome Stiffness scores: Significant direct treatment effect of IVIG vs. placebo on improvement in mean stiffness scores Significant first-order carry over effect of IVIG on stiffness scores Sensitivity scores: Significant direct treatment effect of IVIG vs. placebo on improvement in mean heightened-sensitivity scores p value 0.01 0.001

0.03

*IVIG or placebo once per month for three months, followed by a one-month washout period then crossed to other treatment. Distribution of stiffness index: one point each for stiffness of lower trunk, upper trunk, legs, arms, face, abdomen (Range: 0 to 6). Scores range from 1 to 7, one point for each source of or type of spasm.

Interpretation and Consensus The available evidence, while limited to one small randomized controlled trial, suggests IVIG could play a role in the treatment of stiff person syndrome. In the opinion of the panel, gabaergic medications should remain first-line treatment for this disorder. Based on consensus by the expert panel, IVIG is a reasonable treatment option if gabaergic medications fail or for patients who have contraindications to gabaergic medications. Recommendations IVIG is recommended as an option for treatment of stiff person syndrome, if gabaergic medications fail or for patients who have contraindications to gabaergic medications. 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 and over two days for children is a reasonable initial treatment option. For patients requiring IVIG maintenance therapy, a systematic approach should be taken to determine the minimum effective dose and continued 59

use of IVIG should be based on objective measures of its sustained effectiveness. The maximum dose of IVIG per treatment course should be 2 g/kg.

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EXTERNAL REVIEW
Process Feedback on this practice guideline was obtained from neurologists in Canada. The process was informed by the Practitioner Feedback methodology used to create clinical practice guidelines on cancer care in Ontario (Browman et al., 1998). A draft of this practice guideline, along with an accompanying letter of 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 online through a Web-based survey tool. Written comments on the draft guideline were encouraged. Practitioners were asked to provide feedback within three weeks. Results Feedback on the draft practice guideline was received from 27 neurologists. The greatest number of respondents were from Ontario (9/27 [33%]), followed by Alberta (6/27 [22%] and Quebec (5/27 [19%]). Table 31. External review survey results
Clinical Condition Acute disseminated encephalomyelitis Adrenoleukodystrophy Amyotrophic lateral sclerosis Autism Chronic inflammatory demyelinating polyradiculoneuropathy Critical illness polyneuropathy Dermatomyositis Diabetic neuropathy Guillain-Barr syndrome Inclusion body myositis Intractable childhood epilepsy Lambert-Eaton myasthenic syndrome Multifocal motor neuropathy Multiple sclerosis Myasthenia gravis Opsoclonus-myoclonus PANDAS Paraproteinemic neuropathy (IgM variant) POEMS syndrome Polymyositis Rasmussens encephalitis Stiff person syndrome Overall Questions The guidelines will be useful in optimizing practice I will use the guidelines in my practice Respondent agreement with draft recommendations for use of IVIG Strongly agree Disagree or Average level of Neutral or agree strongly disagree agreement* 12 (100%) 0 (0%) 0 (0%) 4.25 10 (83%) 0 (0%) 2 (17%) 4.08 10 (83%) 0 (0%) 2 (17%) 4.33 10 (83%) 0 (0%) 2 (17%) 4.17 11 (92%) 1 (8%) 0 (0%) 4.33 9 (75%) 2 (17%) 1 (8%) 4.08 10 (83%) 2 (17%) 0 (0%) 4.39 9 (75%) 2 (17%) 1 (8%) 3.83 12 (100%) 0 (0%) 0 (0%) 4.75 9 (75%) 3 (25%) 0 (0%) 4.17 9 (75%) 2 (17%) 1 (8%) 4.08 9 (75%) 2 (17%) 1 (8%) 3.92 11 (92%) 1 (8%) 0 (0%) 4.42 6 (50%) 3 (25%) 3 (25%) 3.25 11 (92%) 0 (0%) 1 (8%) 4.17 8 (67%) 4 (33%) 0 (0%) 3.92 9 (75%) 3 (25%) 0 (0%) 4.00 9 (75%) 2 (17%) 1 (8%) 4.00 8 (67%) 4 (33%) 0 (0%) 3.92 8 (73%) 3 (27%) 0 (0%) 3.91 8 (67%) 2 (17%) 2 (17%) 3.58 10 (83%) 2 (17%) 0 (0%) 4.25 Respondent agreement with overall statements Strongly agree Disagree or Average level of Neutral or agree strongly disagree agreement* 11 (92%) 1 (8%) 0 (0%) 4.58 10 (83%) 2 (17%) 0 (0%) 4.33

*Measured on a 5-point scale: 1=strongly disagree, 2=disagree, 3=neutral, 4=agree, and 5=strongly agree.

A total of 10 respondents completed the entire external review survey, 16 respondents completed some items on the survey and one respondent provided written comments only. For all of the conditions surveyed, the majority of respondents either agreed or strongly agreed with the draft guidelines recommendations for use of IVIG. Approximately 90% (11/12) of respondents indicated that the guidelines 61

would be useful in optimizing practice and 83% (10/12) of respondents agreed that they would use the guidelines in their practice. Overall, 33% (9/27) of respondents provided written comments on the draft practice guideline. Discussion and Guideline Modifications The expert panel discussed the external review results at a teleconference in November, 2005. The number of responses received was quite low. However, given the length and breadth of the guideline, the panel recognizes that the time required to review and provide feedback on the entire document was likely a considerable deterrent. Overall, the feedback received was positive, with the majority of respondents in agreement with the draft recommendations. One external review respondent expressed disappointment that the draft guideline did not address IVIG use for pediatric neurologic conditions. The expert panel disagrees with this comment. The guideline addresses several conditions affecting children, such as autism, Guillain-Barr syndrome, acute disseminated encephalomyelitis, PANDAS, adrenoleukodystrophy and Rasmussens encephalitis. The guideline also provides recommendations for dose and duration of IVIG use for both adults and children, where applicable. A few respondents commented that there is insufficient data available to support the use of IVIG for Rasmussens encephalitis. While the expert panel acknowledges that there is very limited evidence available, given the rarity and severity of this condition the panel feels it is reasonable to consider IVIG among the options for short-term, temporizing measures in the management of patients with Rasmussens encephalitis. The panel emphasized that the accepted and appropriate standard of care for this condition is hemispherectomy. After the external review process was completed, the expert panel was informed of the results of a large randomized, double-blind trial (referred to as the PRIVIG trial). An abstract of the results from the trial will be presented at the European Neurological Society conference in June, 2006. The expert panel discussed and agreed that although the results are not yet published the PRIVIG trial should be included in the guideline at this point as this is the largest trial that has examined IVIG for the treatment of relapsing-remitting MS. The placebo-controlled trial evaluated two doses of a new chromatographed version of IVIG. The trial found no significant difference between any of the groups on any of the relapse or MRI outcome measures.

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SUMMARY OF RECOMMENDATIONS FOR USE OF IVIG FOR ADULT AND PEDIATRIC NEUROLOGIC CONDITIONS
Summary of Recommendations by Condition [For Further Information Please Refer to the Specific Condition in the Practice Guideline] Acute disseminated encephalomyelitis 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 relapsing ADEM to eliminate steroid dependency or for those patients who fail to respond, or have contraindications, to steroids. Adrenoleukodystrophy IVIG is not recommended for the treatment of adrenoleukodystrophy. Amyotrophic lateral sclerosis IVIG is not recommended for the treatment of amyotrophic lateral sclerosis. Autism IVIG is not recommended for the treatment of autism. Chronic inflammatory demyelinating polyneuropathy IVIG is recommended as an option for the short-term management of new-onset CIDP or CIDP relapses. Based on consensus by the expert panel, IVIG may be considered as an option in combination with other immunosuppressive therapy for the long-term management of CIDP. If IVIG is to be used in the long-term management of CIDP, the patient should be under the care of a qualified expert with specialized knowledge of CIDP and a systematic approach should be taken to determine the minimal effective dose. Critical illness polyneuropathy IVIG is not recommended for the treatment of critical illness polyneuropathy. Dermatomyositis Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy is required 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 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 dermatomyositis should 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 who have not adequately responded to other immunosuppressive therapies. IVIG is recommended, in combination with other agents, as a steroid-sparing option for patients with dermatomyositis. Diabetic neuropathy IVIG is not recommended for treatment of diabetic polyneuropathy, mononeuropathy or proximal lower limb neuropathy. Based on consensus by the expert panel, IVIG use for patients with diabetes who have evidence of a chronic inflammatory demyelinating polyneuropathy (CIDP) phenotype should follow the recommendations outlined in the CIDP section of this guideline. Guillain-Barr syndrome IVIG is recommended as a treatment option for GBS within two weeks of symptom onset for: (i) Patients with symptoms of Grade 3 severity (able to walk with aid) or greater; or (ii) Patients with symptoms less than Grade 3 severity whose symptoms are progressing. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients who initially responded to IVIG and who are experiencing a relapse of symptoms. Based on consensus by the expert panel, the recommendations for use of IVIG for GBS also apply to patients with Miller-Fisher and other variants of GBS. Diagnosis of GBS variants should be made by a specialist with expertise in this area. Inclusion body myositis Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy is required 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 and that the final interpretation be made by an expert in neuromuscular pathology. IVIG is not recommended for the treatment of inclusion body myositis. Intractable childhood epilepsy IVIG is not recommended for the treatment of intractable childhood epilepsy. Lambert-Eaton myasthenic syndrome IVIG is recommended as an option for treatment of Lambert-Eaton myasthenic syndrome. Objective evidence of clinical improvement is needed for sustained use of IVIG.

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Summary of Recommendations by Condition [For Further Information Please Refer to the Specific Condition in the Practice Guideline] Multifocal motor neuropathy IVIG is recommended as first-line treatment for multifocal motor neuropathy. Based on consensus by the expert panel, diagnosis of multifocal motor neuropathy should be made by a neuromuscular specialist, as the diagnosis requires very specific electro-diagnostic expertise. Multiple sclerosis IVIG is recommended as an option for treatment of patients with relapsing-remitting MS who fail, decline or are not able to take standard immunomodulatory drug therapies. For those patients with rapidly advancing relapsing-remitting MS, consideration should first be given to immunosuppression therapy. IVIG is not recommended for the treatment of primary or secondary progressive MS. Based on consensus by the expert panel, IVIG is not recommended for treatment of acute exacerbations of MS, except in patients with severe, refractory, optic neuritis who have had no recovery of vision after three months of standard steroid therapy or patients for whom corticosteroid therapy is contraindicated. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients with relapsing-remitting MS who are pregnant or breastfeeding or in the immediate post-partum period for women whose exacerbation rate was high prior to pregnancy and who were on disease modifying agents prior to pregnancy with plans to re-commence therapy following birth or breastfeeding. Based on consensus by the expert panel, IVIG may be considered as a treatment option for patients with Marburg disease, given the lifethreatening nature of this disease. Myasthenia gravis Adult and Juvenile myasthenia gravis IVIG is recommended as a treatment option for patients with severe exacerbations of myasthenia gravis or myasthenic crises. Based on consensus by the expert panel, IVIG may be considered as an option to stabilize patients with myasthenia gravis prior to surgery. IVIG is not recommended as maintenance therapy for patients with chronic myasthenia gravis. Neonatal myasthenia gravis Based on consensus by the expert panel, IVIG may be considered among the treatment options for neonates severely affected with myasthenia gravis. Opsoclonus-myoclonus Based on consensus by the expert panel, IVIG may be considered as an option for treatment of opsoclonus-myoclonus. Paraproteinemic neuropathy (IgM variant) IVIG is not recommended for the treatment of IgM paraproteinemic neuropathy. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections IVIG is recommended as an option for treatment of patients with PANDAS. Based on consensus by the expert panel, diagnosis of PANDAS requires expert consultation. POEMS syndrome IVIG is not recommended for the treatment of POEMS syndrome. Polymyositis Based on consensus by the expert panel, pathological confirmation by means of a skeletal muscle biopsy is required for the diagnosis of polymyositis. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens and that the final interpretation be made by an expert in neuromuscular pathology. Based on consensus by the expert panel, IVIG may be considered among the treatment options for patients with polymyositis who fail to respond to first-line therapies (e.g. steroids). Rasmussens encephalitis IVIG may be an option as a short-term, temporizing measure for patients with Rasmussens encephalitis. IVIG is not recommended for long-term therapy for Rasmussens encephalitis as surgical treatment is the current standard of care. Stiff person syndrome IVIG is recommended as an option for treatment of stiff person syndrome, if gabaergic medications fail or for patients who have contraindications to gabaergic medications.

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Autism DelGiudice-Asch G, Simon L, Schmeidler J, Cunningham-Rundles C, Hollander E. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord. 1999;29(2):157-60. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996;26(4):439-52. Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. 1998;13(2):7982. Chronic Inflammatory Demyelinating Polyneuropathy Dyck PJ, Litchy WJ, Kratz KM, Suarez GA, Low PA, Pineda AA, Windebank AJ, Karnes JL, O'Brien PC. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 1994;36(6):838-45. Hahn AF, Bolton CF, Zochodne D, Feasby TE. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain. 1996;119(Pt 4):1067-77. Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, Nobile-Orazio E, van Doorn P, Dalakas M, Bojar M, Swan A. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001;50(2):195-201. Kubori T, Mezaki T, Kaji R, Kimura J, Hamaguchi K, Hirayama K et al. [The clinical usefulness of high-dose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy]. [Japanese]. No to Shinkei - Brain & Nerve. 1999;51(2):127-35. Mendell JR, Barohn RJ, Freimer ML, Kissel JT, King W, Nagaraja HN et al. Randomized controlled trial of IVIG in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 2001;56(4):445-9. Thompson N, Choudhary P, Hughes RA, Quinlivan RM. A novel trial design to study the effect of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol. 1996;243(3):280-5. Van Doorn PA, Brand A, Strengers PF, Meulstee J, Vermeulen M. High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study. Neurology. 1990;40(2):209-12. Van Schaik IN, Winer JB, De Haan R, Vermeulen M. 1. Cochrane Review: Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. (Download in two parts) Cochrane Database Syst Rev. 2002;(2):CD001797. Vermeulen M, van Doorn PA, Brand A, Strengers PF, Jennekens FG, Busch HF. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry. 1993;56(1):36-9.

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Critical Illness Polyneuropathy Mohr M, Englisch L, Roth A, Burchardi H, Zielmann S. Effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure and gram-negative sepsis. Intensive Care Med. 1997; 23(11):1144-9. Wijdicks EF, Fulgham JR. Failure of high dose intravenous immunoglobulins to alter the clinical course of critical illness polyneuropathy. Muscle Nerve. 1994; 17(12):1494-5. Dermatomyositis Al-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis efficacy and safety. J Rheumatol. 2000 Oct; 27(10):2498-503. Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S. Results and long-term follow up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002 Feb; 46(2):467-74. Cherin P, Herson Serge. Indications for intravenous gammaglobulin therapy in inflammatory myopathies. J. Neurol Neurosurg Psychiatry. 1994a; 57 Suppl 50-54. Cherin P, Piette JC, Wechsler B, Bletry O, Ziza JM, Laraki R, Godeau P, Herson S. Intravenous gamma globulin as first line therapy in polymyositis and dermatomyositis: an open study in 11 adult patients. J Rheumatol. 1994b Jun; 21(6):1092-7. Dalakas MC, Illa I, Dambrosia JM, Soveidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993 Dec 30;329(27):1993-2000. Danieli MG, Malcangi G, Palmieri C, Logullo F, Salvi A, Piani M et al. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis. Ann Rheum Dis. 2002; 61(1):37-41. Sansome A, Dubowitz V. Intravenous immunoglobulin in juvenile dermatomyositis four year review of nine cases. Arch Dis Child. 1995 Jan; 72(1):25-8. Tsai MJ, Lai CC, Lin SC, Chiang BL, Chou CC, Hsieh KH. Intravenous immunoglobulin therapy in juvenile dermatomyositis. 1997 Mar-Apr;38(2):111-5. Diabetic Neuropathy Cocito D, Ciaramitaro P, Isoardo G, Barbero P, Migliaretti G, Pipieri A, Proto G, Quadri R, Bergamasco B, Durelli L. Intravenous immunoglobulin as first treatment in diabetics with concomitant distal symmetric axonal polyneuropathy and CIDP. J Neurol. 2002 Jun;249(6);719-22. Jaradeh SS, Prieto TE, Lobeck LJ. Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy. J Neurol Neurosurg Psychiatry. 1999;67(5):607-12. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995;52(11):1053-61. Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol. 2002 May;59(5):758-65. 68

Zochodne DW, Isaac D, Jones C. Failure of immunotherapy to prevent, arrest or reverse diabetic lumbosacral plexopathy. Acta Neurol Scand. 2003;107(4):299-301. Guillain-Barr Syndrome Bril V, Ilse WK, Pearce R, Dhanani A, Sutton D, Kong K. Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barr syndrome. Neurology. 1996;46(1):100-3. Diener HC, Haupt WF, Kloss TM, Rosenow F, Philipp T, Koeppen S et al. A preliminary, randomized, multicenter study comparing intravenous immunoglobulin, plasma exchange, and immune adsorption in Guillain-Barr syndrome. Eur Neurol. 2001;46(2):107-9. El Zunni S, Prakash PS, Saiti KM, Busnaina IA. Guillain Barr syndrome (GBS): An appraisal. Cent Afr. J Med. 1997; 43(4):99-103. Gurses N, Uysal S, Cetinkaya F, Islek I, Kalayci AG. Intravenous immunoglobulin treatment in children with Guillain-Barr syndrome. Scand J Infect Dis. 1995;27(3):241-3. Haupt WF, Rosenow F, van der Ven C, Borberg H, Pawlik G. Sequential treatment of Guillain-Barr syndrome with extracorporeal elimination and intravenous immunoglobulin. J Neurol Sci. 1996;137(2):145-9. Hosokawa T, Hamaguchi K, Tomioka R, Tsuji T, Nomura K, Ohno R et al. Comparative study of efficacy of plasma exchange versus intravenous gammaglobulin treatment on acute postinfectious polyradiculoneuropathy: a preliminary report. Ther Apher. 1998;2(4):288-91. Hughes RAC, Raphael JC, Swan AV, van Doorn PA. Systematic Review: Intravenous immunoglobulin for Guillain-Barr syndrome. Cochrane Database Syst Rev. Neurol. 2003 Sep 16;(2):CD002063. Martinez YA, Huerta VM, Olive PM, Montero HJ, Serra CJ, Martinez-Matos JA. [Treatment of Guillain-barr syndrome: immunoglobulins or plasmapheresis?]. [Spanish]. Neurologia. 1998;13(4):166-9. Plasma Exchange/Sandoglobulin Guillain-Barr Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barr syndrome. 1997 Jan 25;349(9047):225-30. Raphael JC, Chevret S, Hughes RA, Annane D. 1. Systematic Review: Plasma exchange for Guillain-Barr syndrome. (In 2 parts) Cochrane Database Syst Rev. 2001;(2):CD001798. van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barr syndrome. Dutch Guillain-Barr Study Group. N Engl J Med. 1992;326(17):11239. Inclusion Body Myositis Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiffperson syndrome. N Engl J Med. 2001;345(26):1870-6. Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with IVIG: a double-blind, placebo-controlled study. Neurology. 1997;48(3):712-6.

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Walter MC, Lochmuller H, Toepfer M, Schlotter B, Reilich P, Schroder M et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. 2000;247(1):22-8. Intractable Childhood Epilepsy Illum N, Taudorf K, Heilmann C, Smith T, Wulff K, Mansa B, Platz P. Intravenous immunoglobulin: a single blind trial in children with Lennox-Gastaut syndrome. Neuropediatrics. 1990 May;21(2):87-90. van Rijckevorsel-Harmant K, Delire M, Schmitz-Moorman W, Wieser HG. Treatment of refractory epilepsy with intravenous immunoglobulins. Results of the first double-blind/dose finding clinical study. Int J Clin Lab Res. 1994;24(3):162-6. Lambert-Eaton Myasthenic Syndrome Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47(3):678-83. Multifocal Motor Neuropathy Azulay JP, Blin O, Pouget J, Boucraut J, Bille-Turc F, Carles G, Serratrice G. Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology. 1994;44(3 Pt 1):429-32. Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology. 2000;55(9):1256-62. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain. 2001;124(Pt 1):14553. Van den Berg LH, Kerkhoff H, Oey PL, Franssen H, Mollee I, Vermeulen M, Jennekens FG, Wokke JH. Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry. 1995 Sep;59(3):248-52. van Schaik IN, van den Berg LH, de Haan R. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD004429. Multiple Sclerosis Achiron A, Gabbay U, Gilad R, Hassin-Baer S, Barak Y, Gornish M, Elizur A, Goldhammer Y, SarovaPinhas I. RRMS: Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology. 1998; 50(2):398-402. Achiron A, Barak Y, Goren M, Gabbay U, Miron S, Rotstein Z, Noy S, Sarova-Pinhas I. Intravenous immune globulin in multiple sclerosis: clinical and neuroradiological results and implications for possible mechanisms of action. Clin Exp Immunol. 1996 May; 104 Suppl 1:67-70. Chalmers Research Institute. IVIG Systematic Reviews. Forthcoming 2006. 70

Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. RRMS: Randomised placebocontrolled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet 1997; 349(9052):589-93. Hommes OT, Sorensen PS, Fazekas F, Maas Enriquez M, Koelmel HW, Fernandez O, Pozzilli C, OConnor P, for the European Study on Immunoglobulin in Multiple Sclerosis trialists. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Mult Scler. 2003; 364:114956. Lewanska M, Siger-Zajdel M, Selmaj K. RRMS: No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. European Journal of Neurology. 2002; 9(6):565-72. Noseworthy JH, O'Brien PC, Petterson TM, Weis J, Stevens L, Peterson WK et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. 2001; 56(11):1514-22. Noseworthy JH, O'Brien PC, Weinshenker BG, Weis JA, Petterson TM, Erickson BJ, Windebank AJ, Whisnant JP, Stolp-Smith KA, Harper CM Jr, Low PA, Romme LJ, Johnson M, An KN, Rodriguez M. IV immunoglobulin does not reverse established weakness in MS. Neurology. 2000; 55(8):1135-43. Oztekin NaO. Intravenous immunoglobulin treatment in relapsing-remitting multiple sclerosis: a double blind cross over study. Mult Scler. 1998; 4:391. Poehlau D. Treatment of chronic progressive multiple sclerosis with intravenous immunoglobulins--interim results on drug safety of an ongoing study. IVIG study group. Mult Scler. 2000;6 Suppl 2:S21-S23. Poehlau D. Results of double-blind, randomised, placebo-controlled pilot study on the treatment of multiple sclerosis with intravenous immunoglobulin. Eur J Neurol. 1996; 3 Suppl 4. Sorensen PS, Fazekas F, Lee M. 1. Meta Analysis: Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 2002; 9(6):557-63. Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, Kirsmeier H, Larsen VA, Lee ML. RRMS: Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology. 1998; 50(5):1273-81. Teksam M, Tali T, Kocer B, Isik S. RRMS: Qualitative and quantitative volumetric evaluation of the efficacy of intravenous immunoglobulin in multiple sclerosis: preliminary report. Neuroradiology. 2000; 42(12):885-9. Myasthenia Gravis Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle & Nerve. 2000;23(4):551-5. Bassan H, Muhlbaur B, Tomer A, Spirer Z. High-dose intravenous immunoglobulin in transient neonatal myasthenia gravis. Pediatr Neurol. 1998;18(2):181-3. Cosi V, Lombardi M, Piccolo G, Erbetta A. Treatment of myasthenia gravis with high-dose intravenous immunoglobulin. Acta Neurol Scand. 1991;84(2):81-4. Gajdos P, Chevret S, Toyka K. 1. Systematic Review: Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2003;(2):CD002277. 71

Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol. 1997;41(6):789-96. Herrmann DN, Carney PR, Wald JJ. Juvenile myasthenia gravis: treatment with immune globulin and thymectomy. Pediatr Neurol. 1998;18(1):63-6. Hilkevich O, Drory VE, Chapman J, Korczyn AD. The use of intravenous immunoglobulin as maintenance therapy in myasthenia gravis. Clin Neuropharmacol. 2001;24(3):173-6. Huang CS, Hsu HS, Kao KP, Huang MH, Huang BS, bshuang@vghtpe.gov.tw et al. Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis. Acta Neurol Scand. 2003;108(2):136-8. Ronager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs. 2001;25(12):967-73. Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol. 2000;22(1):40-3. Tagher RJ, Baumann R, Desai N. Failure of intravenously administered immunoglobulin in the treatment of neonatal myasthenia gravis. J Pediatr.1999;134(2):233-5. Wegner B, Ahmed I. Intravenous immunoglobulin monotherapy in long-term treatment of myasthenia gravis. Clinical Neurology & Neurosurgery. 2002;105(1):3-8. Wilson JR, Bhoopalam H, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve. 1997;20(9):1142-5. Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, Thornton CA, Nations SP, Bryan WW, Amato AA, Freimer ML, Parry GJ. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve. 2002;26(4):549-52. Opsoclonus-Myoclonus Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain. 2001;124(Pt 2):437-43. Borgna-Pignatti C, Balter R, Marradi P, Colamaria V. Treatment with intravenously administered immunoglobulins of the neuroblastoma-associated opsoclonus-myoclonus. J Pediatr. 1996;129(1):179-80. Eiris J, del Rio M, Castro-Gago M. Immune globulin G for treatment of opsoclonus-polymyoclonus syndrome. J Pediatr. 1996;129(1):175. Fisher PG, Wechsler DS, Singer HS. Anti-Hu antibody in a neuroblastoma-associated paraneoplastic syndrome. Pediatr Neurol. 1994;10(4):309-12. Penzien JM, Speck S, Vassella F. Opsoclonus polymyoclonia syndrome. Acta Paediatr. 1993;82(3):319-20. Petruzzi MJ, de Alarcon PA. Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G. J Pediatr. 1995;127(2):328-9. 72

Pless M, Ronthal M. Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin. Neurology. 1996;46(2):583-4. Pranzatelli MR, Tate ED, Kinsbourne M, Caviness VS Jr, Mishra B. Forty-one year follow-up of childhoodonset opsoclonus-myoclonus-ataxia: cerebellar atrophy, multiphasic relapses, and response to IVIG. Mov Disord. 2002;17(6):1387-90. Sugie H, Sugie Y, Akimoto H, Endo K, Shirai M, Ito M. High-dose i.v. human immunoglobulin in a case with infantile opsoclonus polymyoclonia syndrome. Acta Paediatr. 1992 Apr;81(4):371-2. Yiu VW, Kovithavongs T, McGonigle LF, Ferreira P. Plasmapheresis as an effective treatment for opsoclonus-myoclonus syndrome. Pediatr Neurol. 2001;24(1):72-4. Paraproteinemic Neuropathy (IgM Variant) Comi G, Roveri L, Swan A, Willison H, Bojar M, Illa I, Karageorgiou C, Nobile-Orazio E, van den Bergh P, Swan T, Hughes R, Aubry J, Baumann N, Hadden R, Lunn M, Knapp M, Leger JM, Bouche P, Mazanec R, Meucci N, van der Meche F, Toyka K. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol. 2002;249(10):1370-7. Dalakas MC, Quarles RH, Farrer RG, Dambrosia J, Soueidan S, Stein DP, Cupler E, Sekul EA, Otero C. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. 1996;40(5):792-5. Lunn MP, Nobile-Orazio E. 1. Cochrane Review: Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev. 2003;(1):CD002827. Mariette X, Chastang C, Clavelou P, Louboutin JP, Leger JM, Brouet JC. A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM. The IgM-associated Polyneuropathy Study Group. J Neurol Neurosurg Psychiatry. 1997;63(1):28-34. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999;354(9185):1153-8. POEMS Syndrome Benito-Leon J, Lopez-Rios F, Rodriguez-Martin FJ, Madero S, Ruiz J. Rapidly deteriorating polyneuropathy associated with osteosclerotic myeloma responsive to intravenous immunoglobulin and radiotherapy. Journal of the Neurological Sciences.1998;158(1):113-7. Dispenzieri A. POEMS syndrome. Hematology (Am Soc Hematology Educ Program). 2005: 360-7. Henze T, Krieger G. Combined high-dose 7S-IgG and dexamethasone is effective in severe polyneuropathy of the POEMS syndrome. J Neurol. 1995;242(7):482-3. Huang CC, Chu CC. Poor response to intravenous immunoglobulin therapy in patients with Castlemans disease and the POEMS syndrome. J Neurol. 1996 Oct;243(10):726-7. 73

Polymyositis Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S. Results and long-term follow up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002 Feb;46(2):467-74. Cherin P, Piette JC, Wechsler B, Bletry O, Ziza JM, Laraki R, Godeau P, Herson S. Intravenous gamma globulin as first line therapy in polymyositis and dermatomyositis: an open study in 11 adult patients. J Rheumatol. 1994 Jun;21(6):1092-7. Danieli MG, Malcangi G, Palmieri C, Logullo F, Salvi A, Piani M et al. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis. Ann Rheum Dis. 2002;61(1):37-41. Rasmussens Encephalitis Frucht S. Dystonia, athetosis, and epilepsia partialis continua in a patient with late-onset Rasmussen's encephalitis. Mov Disord. 2002;17(3):609-12. Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G, Vigevano F, Bernardina BD, Spreafico R, Antozzi C. Experience with immunomodulatory treatments in Rasmussen's encephalitis. Neurology. 2003;61(12):1807-10. Korn-Lubetzki I, Bien CG, Bauer J, Gomori M, Wiendl H, Trajo L, Ovadia H, Wilken B, Hans VH, Elger CE, Hurvitz H, Steiner I. Rasmussen encephalitis with active inflammation and delayed seizures onset. Neurology. 2004;62(6):984-6. Leach JP, Chadwick DW, Miles JB, Hart IK. Improvement in adult-onset Rasmussen's encephalitis with long-term immunomodulatory therapy. Neurology. 1999;52(4):738-42. Villani F, Spreafico R, Farina L, Giovagnoli AR, Bernasconi P, Granata T, Avanzini G. Positive response to immunomodulatory therapy in an adult patient with Rasmussen's encephalitis. Neurology. 2001;56(2):24850. Stiff Person Syndrome Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiffperson syndrome. N Engl J Med. 2001;345(26):1870-6.

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