Guidelines on the Use of Intravenous Immune Globulin for Neurologic Conditions

Transcription

1 Guidelines on the Use of Intravenous Immune Globulin for Neurologic Conditions Tom Feasby, Brenda Banwell, Timothy Benstead, Vera Bril, Melissa Brouwers, Mark Freedman, Angelika Hahn, Heather Hume, John Freedman, David Pi, and Louis Wadsworth Canada s per capita use of intravenous immune globulin (IVIG) grew by approximately 115% between 1998 and 2006, making Canada one of the world s highest per capita users of IVIG. It is believed that most of this growth is attributable to off-label usage. To help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products (NAC) 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. A panel of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC met to review the evidence and reach consensus on the recommendations for the use of IVIG. The primary sources used by the panel were 2 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 NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management. Recommendations for use of IVIG were made for 14 conditions, including acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, diabetic neuropathy, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, polymyositis, Rasmussen s encephalitis, and stiff person syndrome; IVIG was not recommended for 8 conditions including adrenoleukodystrophy, amyotropic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body, myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and POEMS syndrome. Development and dissemination of evidence-based clinical practice guidelines may help to facilitate appropriate use of IVIG. A 2007 Elsevier Inc. All rights reserved. DESCRIPTION OF INTRAVENOUS IMMUNE GLOBULIN INTRAVENOUS IMMUNE GLOBULIN (IVIG) is a fractionated blood product consisting of concentrated immune globulin, primarily IgG, derived from human plasma in pools of 3000 to or more donors. Intravenous immune globulin 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, and idiopathic thrombocytopenic purpura. In addition to its licensed indications, IVIG is used to treat a growing range of boff-labelq indications, including a variety of immunologic disorders, hematologic conditions, and neurologic diseases. Health Canada has not evaluated the efficacy and safety of using a licensed IVIG product in the treatment of boff-labelq clinical indications. Nevertheless, some of these applications have a reasonably strong foundation in the medical literature, whereas others have a less conclusive or even no basis in evidence. In appropriately selected patients and clinical settings, IVIG therapy can be life-saving. 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 range of 3% to 15%. 1 These reactions are typically self-limited, of mild to moderate severity, and can often be avoided by From the IVIG Hematology and Neurology Expert Panels. Address reprint requests to Heather Hume, MD, FRCPC, Executive Medical Director, Transfusion Medicine, Canadian Blood Services, 1800 Alta Vista Drive, Ottawa, ON Canada K1G 4J5. [email protected] /07/$ - see front matter n 2007 Elsevier Inc. All rights reserved. doi: /j.tmrv Transfusion Medicine Reviews, Vol 21, No 2, Suppl 1 (April), 2007: pp S57-S107 S57

2 S58 FEASBY ET AL Table 1. Examples of the Cost of IVIG Cost of IVIG4 Patient Schedule 0.5 g/kg 1.0 g/kg 2.0 g/kg 20-kg child 1 dose $550 $1100 $ monthly for 1 y $6600 $13200 $ wkfor1y $9350 $18700 $ kg adult 1 dose $2000 $4000 $ monthly for 1 y $24000 $48000 $ wkfor1y $34000 $68000 $ Cost of IVIG alone does not include costs associated with administration of IVIG. All costs are in Canadian dollars. 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 because of proprietary differences in the manufacturing methods. A recent review by Pierce and Jain 1 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 wellcontrolled 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 1 and usually 2 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 or variant Creutzfeldt- Jacob disease 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. Intravenous immune globulin is a relatively 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. Because 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 multiyear 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. Intravenous immune globulin currently costs between $51 and $64 per gram (all estimates in Canadian dollars), but in past years, with a less favorable US exchange rate, the cost has been as high as $75 to $80. The cost of 1 infusion of 1 g/kg of IVIG for a 70-kg adult is approximately $4000 (Table 1).

3 USE OF IVIG FOR NEUROLOGIC CONDITIO S59 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 NAC representatives Dr Heather Hume Dr John Freedman Dr David Pi Dr Louis Wadsworth Practice guidelines expert Dr Melissa Brouwers Director, Paediatric Multiple Sclerosis Clinic, Hospital for Sick Children, Toronto Division of Neurology, Queen Elizabeth 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 Executive Medical Director, Transfusion Medicine, Canadian Blood Services, Ottawa Director, Transfusion Medicine, St Michael s Hospital, Toronto Director, Provincial Blood Coordinating Office, St Paul s Hospital, Vancouver Program Head, Hematopathology, Children s & Women s Health Centre of BC, Vancouver Director, Program in Evidence-Based Care, Cancer Care Ontario, Assistant Professor, McMaster University, Hamilton Canada s per capita use of IVIG grew by approximately 83% between 1998 and 2004 (and another 18% between 2004 and 2006), 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 use remains appropriate and in keeping with an Table 3. Included Clinical Conditions Acute disseminated encephalomyelitis Adrenoleukodystrophy Amyotrophic lateral sclerosis Autism Chronic inflammatory demyelinating polyradiculoneouropathy Critical illness polyneuropathy Dermatomyositis Diabetic neuropathy Guillain-Barré syndrome Inclusion body myositis Intractable childhood epilepsy Clinical conditions Lambert-Eaton myosthenic syndrome Multiple motor neuropathy Multiple sclerosis Myasthenia gravis Opsoclonus-myoclonus Paraproteinemic neuropathy PANDAS POEMS syndrome Polymyositis Rasmussen s encephalitis Stiff person syndrome Abbreviations: PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. evidence-based approach to the practice of medicine. Canadian Blood Services convened a national consensus conference, entitled: bprescribing Intravenous Immune Globulin: Prioritizing Use and Optimizing Practice,Q in Toronto in October British Columbia implemented an IVIG use management program in 2002, which involved the division of medical conditions into those requiring either bregularq or bspecialq 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 Advisory Committee on Blood and Blood Products (NAC), an advisory group to Canadian Blood Services and provincial and territorial Deputy Ministers of Health regarding blood utilization management issues, has been working on the development of an interprovincial collaborative framework for IVIG utilization management. To facilitate this objective, the NAC 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 NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG utilization management. The practice guideline will also be widely circulated to clinicians in Canada.

4 S60 FEASBY ET AL METHODS Expert Panel Letters of invitation were sent to several neurologists across Canada, regarded by their peers as experts in their field. The panel consisted of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC (Table 2). The panel met in Toronto on September 9 and 10, Panel members were asked to declare any potential conflicts of interest. Conflicts were declared and noted by the Chair. Table 4. Sources Used in the Development of the Practice Guideline Clinical condition Appropriateness of IVIG review Chalmers Institute SR of IVIG Literature search by expert panel Acute disseminated U encephalomyelitis Adrenoleukodystrophy U Amyotrophic lateral U sclerosis Autism U Chronic inflammatory U U demyelinating polyradiculoneuropathy Critical illness U polyneuropathy Dermatomyositis U U Diabetic neuropathy U Guillain-Barré syndrome U U Inclusion body myositis U U Intractable U childhood epilepsy Lambert-Eaton U myasthenic syndrome Multiple motor U U neuropathy Multiple sclerosis U U U Myasthenia gravis U U Opsoclonus-myoclonus U PANDAS U Paraproteinemic U neuropathy (IgM variant) POEMS syndrome U Polymyositis U U Rasmussen s U encephalitis Stiff person syndrome U Abbreviations: SR, systematic review; PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. Level of evidence Clinical Conditions Table 5. Levels of Evidence Whether a treatment is efficacious/effective/harmful 1a Systematic review (with homogeneity) of RCTs 1b Individual RCT (with narrow CI), including well-designed crossover trials 1c All or none4 2a Systematic review (with homogeneity) of cohort studies 2b Individual cohort study (including low-quality RCTs) 2c boutcomesq research; ecological studies 3a Systematic review (with homogeneity) of case-control studies 3b Individual case-control study 4 Case-series (and poor quality cohort and case-control studies) 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or bfirst principlesq NOTE. Developed by B Phillips, C Ball, D Sackett, B Haynes, S Straus, and F McAlister from the National Health Service Centre for Evidence-Based Medicine. 4 Abbreviation: RCT, randomized controlled trial. 4Met 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. The expert panel evaluated the use of IVIG for 22 neurologic conditions. Please refer to Table 3 for details. Evidence base for Practice Guideline The expert panel was provided with recent evidence-based reviews of IVIG use from 2 sources: 1. Systematic reviews by the Chalmers Research Institute, University of Ottawa 2 a. Sources searched: Medline; Embase; current contents; PreMedline; dissertation abstracts; CENTRAL (Cochrane Library s controlled clinical trials registry); plus manual searching of relevant journals, reference lists, and unpublished sources. b. Dates searched: 1966 to The bappropriateness of IVIGQ evidence review conducted by Feasby 3 as part of

5 USE OF IVIG FOR NEUROLOGIC CONDITIO S61 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 (eg, 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 (eg, placebo-controlled or appropriate bstandardq 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 vs statistical significance Canadian Institute for Health Research 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. 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. 4 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. Although the members of the panel are cognizant of the costs associated with IVIG, the role of costs and cost use was not systematically factored into the discussions and the recommendations that emerged. 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. 5 A draft of this practice guideline, along with an accompanying letter of explanation and feedback survey, was ed 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 3 weeks. 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 (eg, ataxia, hemiparesis) and impaired consciousness. ADEM is thought to be an autoimmune disorder of the central nervous system (C) 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 magnetic resonance imaging (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).

6 S62 FEASBY ET AL Table 7. Pediatric Acute Disseminated Encephalomyelitis (ADEM) IVIG Studies Study Design No. of patients Prior steroid treatment Intervention Response4 Monophasic ADEM Anderson et al 6 Case report 1 Yes IVIG + steroids Complete response Assa et al 7 Case reports 2 No IVIG Complete response: 50% (1/2) Partial response: 50% (1/2) Balestri et al 8 Case report 1 Yes IVIG Partial response Jaing et al 9 Case report 1 No IVIG Complete response Kleiman and Brunquell 10 Case report 1 No IVIG Complete response Nishikawa et al 11 Case reports 3 No IVIG Complete response: 100% (3/3) Pradhan et al 12 Case reports 4 Yes IVIG Complete response: 75% (3/4) Partial response: 25% (1/4) Shahar et al 13 Case reports 16 Yes (1 case) IVIG or steroids or IVIG + steroidsy IVIG: 100% (1/1) complete response Steroids: 100% (10/10) complete response IVIG + steroids: 40% (2/5) complete response 60% (3/5) partial or no response Straussberg et al 14 Case report 1 No IVIG + steroids Complete response Relapsing ADEM Apak et al 15 Case report 1 Yes IVIG Partial response Hahn et al 16 Case report 1 Yes IVIG Complete response (maintained with monthly IVIG) Mariotti et al 17 Case report 1 Yes IVIG + steroids Partial response (maintained with monthly IVIG) Pittock et al 18 Case report 1 Yes IVIG Partial response (no relapses after IVIG) Revel-Vilk et al 19 Case report 1 No IVIG Complete response Abbreviation: N/A, not applicable. 4Complete response: normal (baseline) neurologic function. Partial response: improved, but not normal, neurologic function. ymost severe cases treated with IVIG plus high-dose methylprednisolone. Distinction from MS is often very difficult, and some children and adults with ADEM will eventually meet criteria for the diagnosis of MS. Treatment at the time of acute symptoms 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 of 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 4 to 6 weeks from onset of symptoms. Evidence Summary The bappropriateness of IVIGQ evidence review identified 25 cases of IVIG use for pediatric ADEM and 8 cases of IVIG use for adult ADEM (level of evidence: 4). Most pediatric case reports involved children with monophasic ADEM. Overall, 70%

7 USE OF IVIG FOR NEUROLOGIC CONDITIO S63 Table 8. Adult Acute Disseminated Encephalomyelitis (ADEM) IVIG Studies Study Design No. of patients Prior steroid treatment Intervention Response4 Monophasic ADEM Finsterer et al 20 Case report 1 No IVIG No response Fox et al 21 y Case report 1 No IVIG Complete response Marchioni et al 22 Case reports 3 Yes IVIG Complete response: 33% (1/3) Partial response: 67% (2/3) Nakamura et al 23 Case report 1 Yes IVIG Partial response Sahlas et al 24 Case reports 2 Yes IVIG Complete response: 100% (2/2) Relapsing ADEM Marchioni et al 22 Case reports 2 Yes IVIG Partial response: 100% (2/2) 4Complete response: normal (baseline) neurologic function. Partial response: improved, but not normal, neurologic function. ypatient diagnosed with Bickerstaff s brainstem encephalitis. (14/20) of children with monophasic ADEM completely recovered after administration of IVIG or IVIG plus corticosteroids. Of the 5 cases of relapsing ADEM, 2 children completely recovered after IVIG, and the 3 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 after treatment with IVIG. Both adults with relapsing ADEM showed marked improvement after IVIG. Refer to Table 8 for further details. 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 panel s opinion that IVIG is a reasonable option as second-line therapy for monophasic ADEM in patients who do not respond to high-dose corticosteroids. The 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 that IVIG may be considered as an option to eliminate steroid dependency or for those patients who fail to respond, or have contraindications, to steroids. Recommendations Intravenous immune globulin is recommended as an option for treatment of monophasic ADEM when first-line therapy with high-dose corticosteroids fail 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 2 to 5 days for adults and over 2 days for children is a reasonable option. ADRENOLEUKODYSTROPHY Clinical Description Adrenoleukodystrophy (ALD) is an X-linked inherited disorder of peroxisomal metabolism that produces progressive C degeneration associated with C 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. Adrenoleukodystrophy 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

8 S64 FEASBY ET AL Table 9. Adrenoleukodystrophy IVIG Studies Study Design No. of patients Intervention Outcome P Cappa et al 26 RCT; not blinded 12 IVIG + VLCFA restricted diet + GTOE vs VLCFA restricted diet + GTOE No significant difference between IVIG group and controls in deterioration of neurologic function as measured by the EDSS* scale at 12 mo EDSS scores (mean F SD): Baseline: IVIG, 2.3 F 1.0 vs controls, 3.3 F 1.6 At 12 mo: IVIG, 6.7 F 2.9 vs controls, 6.0 F 3.6 Abbreviations: VLCFA, very long chain fatty acids; GTOE, glycerol tricleate/erucic supplementation. * EDSS: range 3.0 (mild disability) to 9.0 (vegetative state). EDSS of 6.0 requires unilateral assistance to walk 100 m. EDSS of 7.0: walks less than 5 m and essentially restricted to a wheelchair. paraplegia. About 80% of ALD patients have associated adrenal insufficiency. There is currently no effective treatment of ALD. The rationale for the application of IVIG in the management of ALD is based on studies suggesting that IVIG promotes remyelination in the C. 25 Evidence Summary bthe Appropriateness of IVIGQ 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 neurologic deterioration between patients in the IVIG group compared with controls (Table 9). Interpretation and Consensus The available evidence is limited to 1 small, poor-quality randomized trial. However, given that no benefit was observed for patients treated with IVIG, it is the expert panel s opinion that IVIG should not be used for treatment of ALD. Table 10. Amyotrophic Lateral Sclerosis IVIG Studies Study Design No. of patients Intervention Outcome Meucci et al 27 Case series 7 IVIG + cyclophosphamide Muscle strength A in all cases as measured by the MRC4 scale Rankiny and/or bulbar functionz scores worsened in all patients No improvement in rate of disease progression Dalakas et al 28 Case series 9 IVIG At 3 mo, muscle strength (MVIC mega scores) A in all cases Mean vital lung capacity at 3 mo A by 0.3 L from baseline Abbreviation: MVIC, maximum voluntary isometric contraction. 4MRC scale: Muscle strength on 10 muscles per limb. ymodified Rankin scale: range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention). zbulbar function scale: range 1 (normal) to 5 (tube feeding or unable to speak or both). MVIC mega scores: sum of MVIC scores from 5 individual muscle groups in 2 limbs.

9 USE OF IVIG FOR NEUROLOGIC CONDITIO S65 Table 11. Autism IVIG Studies Study Design and participants No. of patients Intervention Outcome Gupta et al 29 Case series 10 IVIG After 6 mo: Included only patients with abnormal immune parameters 50% (5/10) had marked improvement in eye contact, calmer behavior, speech, and echolalia 50% (5/10) showed minimal improvement DelGiudice-Asch Case series 7 IVIG After 6 mo: et al 30 No immunologic testing No significant change on any of the behavioral measures compared with baseline Plioplys 31 Case series 10 IVIG 10% (1/10) remarkable improvement in autistic symptoms Included only patients with abnormal immune parameters 40% (4/10) 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 50% (5/10) no clinical improvement Recommendations Intravenous immune globulin is not recommended for the treatment of ALD. 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 1 to 2 per population and peaks between ages 55 and 75 years. 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 (Kennedy s disease, spinal muscular atrophy, lymphoma-related motor neuronopathy, progressive postpolio muscular atrophy), myelopathies (foramen magnum tumors, 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. 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. Because familial ALS is clinically 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.

10 S66 FEASBY ET AL Table 12. Chronic Inflammatory Demyelinating Polyneuropathy IVIG Studies Study Design No. of patients Intervention Outcome P Van Schaik et al 32 Systematic review with meta-analysis4 IVIG vs placebo A significantly greater proportion of patients had significant improvement in disability by 1 mo with IVIG vs placebo: RR, 3.17 (95% CI, ; fixed); NNT: A significantly greater proportion of patients improved z1 point on the modified Rankin scaley by 1 mo with IVIG vs placebo. RR, 2.47 (95% CI, ; fixed).05 Dyck et al 33 Crossover RCT 20 IVIG vs PLEX At 6 wk, IVIG and PLEX groups had significant improvement compared with baseline in: Mean NDS scores: IVIG (P =.006) and PLEX (P b.001) Mean CMAP scores: IVIG (P b.001) and PLEX (P b.001) No significant difference between IVIG and PLEX in mean change in NDS or summated CMAP scores at 6 wk Hahn et al 33 Crossover RCT 30 IVIG vs placebo Mean change in NDS after 4 wk (d 28): Significant improvement with IVIG vs placebo.0001 Mean change in grip strength (P b.001) and functional grade (P b.002) at d 28 significantly improved with IVIG vs placebo Mean change in nerve conduction tests at 4 wk: Significant improvement in NCV with IVIG.0001 Significant improvement in summated proximal CMAP with IVIG.03 Hughes et al 39 Crossover RCT 32 IVIG vs oral prednisone Both IVIG (P =.012) and prednisone (P =.005) groups showed significant improvement in mean INCAT disability scores at 2 wk Mean change in INCAT scores (at 2 and 6 wk): No significant difference between IVIG and oral prednisone Mean change in MRC sum score and modified Rankin score (6 wk): No significant difference between IVIG and oral prednisone Mendell et al 34 RCT 53 IVIG vs placebo Significant improvement in muscle strength (AMS) with IVIG at d 42: AMS mean difference.006 (IVIG placebo): 0.72 F 0.25 % of Patients with improvement in disability scores at d 42: IVIG significantly higher than placebo.019 Mean change in nerve conduction tests at d 42: Significant improvement in motor nerve.003 conduction with IVIG Significant improvement in peroneal NCV.03 Thompson et al 35 Crossover RCT 7 IVIG vs placebo Mean change in MRC sum scores at 2 wk: No statistically significant difference between groups

11 USE OF IVIG FOR NEUROLOGIC CONDITIO S67 Table 12 (continued) Study Design No. of patients Intervention Outcome P Vermeulen et al 36 RCT 28 IVIG vs placebo % of Patients with improvement z1 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 Van Doorn et al 37 Crossover RCT 7 IVIG vs placebo % of Patients with improvement z1 point on modified Rankin scale by d 8: IVIG significantly higher than placebo.02 No significant difference between groups in Dmean CMAP or NCV Kubori et al 40 RCT 62 IVIG (0.05 g/kg per d 5d)vsIVIG (0.2 g/kg per % of patients with improvement z1 grade on disability scale (at 5 wk): IVIG (0.4 g/kg) significantly higher than d 5d)vsIVIG (0.4 g/kg per d 5d) IVIG (0.05 g/kg) or IVIG (0.2 g/kg) Abbreviations: AMS, average muscle score; D, change; NR, not reported; CMAP, compound muscle action potential; NCV, nerve conduction velocity; NDS, Neuropathy Disability Scale. 4Meta-analysis of disability scores used in RCTs included: Hahn, 33 Mendell et al, 34 Thompson et al 35 and Vermeulen et al 36 ; meta-analysis of modified Rankin scores included: Mendell et al, 34 Thompson et al 35 and Vermeulen et al. 36 yvan Schaik et al 32 converted different disability scale scores used in each trial to modified Rankin scores. There are no effective treatments for ALS. The average 5-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 bappropriateness of IVIGQ evidence review identified 2 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). 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. Recommendation Intravenous immune globulin is not recommended for the treatment of ALS. AUTISM Clinical Description Autism is a neurodevelopmental disorder characterized by severe deficits in social and communicative skills, abnormal behaviors, 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 5 per children. Most children are diagnosed between ages 1 and 3 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

12 S68 FEASBY ET AL and that there exists a higher-than-normal prevalence of immunologic 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 bappropriateness of IVIGQ evidence review identified 3 case series of IVIG use for autism (level of evidence: 4) In the case series by Gupta et al, patients with abnormal immune parameters received IVIG monthly. After 6 months, 50% (5/10) of patients showed marked improvement in several autistic characteristics. The series by Plioplys 31 also included only patients with abnormal immune parameters. Only 1 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). Interpretation and Consensus The expert panel agreed the available evidence does not support the use of IVIG for treatment of autism. Although there are a few children who appeared to improve dramatically after 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 pathobiologic rationale for use of IVIG in autism is very limited. Immunologic studies have been performed largely from single centers on small cohorts and lack appropriate numbers of patients and healthy controls. The pathobiologic rationale of IVIG use for autism should be further validated before the expense of a randomized controlled trial is contemplated. Recommendation Intravenous immune globulin is not recommended for the treatment of autism. 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 4 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 8 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 2 per Chronic inflammatory demyelinating polyneuropathy occurs at all ages but is more common in the fifth and sixth decades of life, and men 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 electrophysiologic findings of unequivocal demyelination, as well as the characteristic increase in cerebrospinal fluid protein and a lymphocyte count of less than 10/mm 3. A nerve biopsy is no longer mandatory for the diagnosis because one can infer the demyelinating pathology from the electrophysiologic 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 (PLEX). Other immunosuppressive drugs, for example, 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 bappropriateness of IVIGQ evidence review identified a Cochrane systematic review with metaanalysis of IVIG use for CIDP (level of evidence: 1a). A systematic review by the Chalmers Research Institute on this topic included 8 randomized

13 USE OF IVIG FOR NEUROLOGIC CONDITIO S69 Table 13. Critical Illness Polyneuropathy IVIG Studies Study Design and participants No. of patients Intervention Outcome Mohr et al 41 Retrospective chart review 16 IVIG Of 16 patients who survived MOF and severe sepsis4: 0% (0/8) of Patients given IVIG within 24 hours of sepsis dx developed CIP. 88% (7/8) of Patients not given IVIG developed CIP Wijdicks et al 42 Case series 3 IVIG 0% (0/3) of Cases of established CIP improved with IVIG Abbreviations: MOF, multiorgan failure; dx, diagnosis. 4Sepsis caused by gram-negative bacteria. controlled trials. Overall, 5 trials compared IVIG with placebo, 2 trials assessed IVIG vs either PLEX or prednisone, and 1 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 32 included 4 randomized trials of IVIG vs placebo 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 1 month after treatment with IVIG vs placebo (relative risk [RR], 3.17 [95% confidence interval {CI}, ; fixed] P b.0002; number needed to treat [NNT] 3). One additional trial, by Van Doorn et al, 37 compared IVIG with placebo. This trial was excluded from the Cochrane review because of selection bias, as it studied only patients who had previously responded to IVIG. The trial reported significantly more patients improved 1 or more points on the Rankin disability scale by day 8 with IVIG than placebo ( P b.02) (Table 12). Two trials evaluated IVIG against other treatment options. One small, randomized crossover trial by Dyck et al, 38 compared IVIG with PLEX. At 6 weeks, both groups showed significant improvement, compared with the baseline in mean neuropathy disability scores (IVIG, P =.006; PLEX, P b.001) and mean summated Compound Muscle Action Potentials (IVIG, P b.001; PLEX, P b.001). No significant difference between IVIG and PLEX was identified. A randomized crossover trial by Hughes et al 39 assessed IVIG against oral prednisone. Both treatment groups had significant improvement in disability at 2 weeks, as measured by mean change on the INCAT disability scale (IVIG: P =.012; prednisone: P =.005). The 2 groups did not differ significantly in mean change in Inflammatory Neuropathy Cause and Treatment Group (INCAT) scores, or modified Rankin scores at either 2- or 6- week follow-up. One trial by Kubori et al 40 investigated different doses of IVIG. Overall, 62 patients with CIDP were randomized to receive 0.05, 0.2, or 0.4 g/kg of IVIG daily for 5 days. A significantly higher percentage of patients in the IVIG 0.4 g/kg group improved at least 1 grade on the disability scale (scale not specified), compared with 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 PLEX or oral prednisone for the shortterm treatment of CIDP. Nonetheless, IVIG is often chosen as the preferred initial therapy. No evidence is available to support or refute long-term (N6 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. Intravenous immune globulin 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

14 S70 FEASBY ET AL Table 14. Dermatomyositis IVIG Studies Study Design and participants No. of patients Intervention Outcome P Dermatomyositis Al-Mayouf et al 44 Retrospective review Children 18 IVIG F steroids F other therapies4 Dalakas et al 43 Crossover RCT 15 IVIG + steroids vs placebo + steroids Adults Sansome and Case series 9 IVIG + steroids F Dubowitz 45 other therapiesz Children Tsai et al 46 Case series 7 IVIG + other therapies4 Children Dermatomyositis or polymyositis Danieli et al 47 Non-RCT 20 Steroids + CSA or IVIG + Steroids + CSA or IVIG + New onset, relapsed or tx refractory PLEX + steroids + CSA Cherin and Case series 35 IVIG F steroids F Herson 48 other txz tx refractory 67% (12/18) Improved with IVIG, allowed steroid dose AN50% 33% (6/18) Remained steroid-dependent At 3 mo, mean modified MRC y and S scores significantly higher in IVIG group vs placebo. Mean modified MRCy: IVIG, 84.6 F 4.6 vs placebo, 78.6 F 8.2 Mean S: IVIG, 51.4 F 6.0 vs placebo, 45.7 F 11.3 Significant improvement in mean myometry score with IVIG 100% (9/9) Clinical improvement with IVIG 75% (6/8) of patients on steroids were able to A steroid dose 72% (5/7) Clinical improvement with IVIG, A steroid dose 14% (1/7) Transient clinical improvement with IVIG 14% (1/7) No improvement with IVIG N/A NR in SR N/A No significant difference in CR4 between groups at 1 y At 4 y: Significantly more patients.001 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 power4:.01 baseline 46.5 F 11.5; post IVIG 67.1 F 15.4 Significant reduction in.05 mean steroid dose (mg/d) Significant A in CK levels.01

15 USE OF IVIG FOR NEUROLOGIC CONDITIO S71 Table 14 (continued) Study Design and participants No. of patients Intervention Outcome P Cherin et al 49 Case series 11 IVIG No significant improvement in mean muscle powery from baseline No previous tx Only 27% (3/11) had.01 significant clinical improvement Significant improvement in mean CK levels Abbreviations: CSA, cyclosporine A; tx, treatment; S, Neuromuscular Symptom Scale (maximum score of 60 indicates normal function). 4Other therapies not specified in review. ymaximum score, 90. zazathioprine and/or cyclosporine. 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 Intravenous immune globulin 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 2 to 5 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. CRITICAL ILLNESS POLYNEUROPATHY Clinical Description Critical illness polyneuropathy (CIP) can develop in patients with multiorgan 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 bappropriateness of IVIGQ 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 multiorgan failure and severe Gramnegative 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. 41 No benefit of IVIG for treatment of established CIP was observed in the case series 42 (Table 13). 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 after 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.

16 S72 FEASBY ET AL Table 15. Diabetic Neuropathy IVIG Studies Study Design and participants No. of patients Intervention Outcome P Sharma et al 50 Case series 26 IVIG Significant improvement in lower limb motor function at 4 wk CIDP in DM Significant improvement in average NIS score: Baseline: 59.6 F 26.7 vs at 4-wk follow-up: 33.0 F 29.6 Significantly more patients with Canadian Blood Services had improved NIS scores with IVIG (11/11) vs patients without Canadian Blood Services (10/15). Of IVIG responders: 29% (6/21) relapsed; 2nd course of IVIG; 75% (3/4) of patients had good response and 25% (1/4) poor response Cocito et al 51 Case series 9 IVIG Significant improvement in Rankin4 score: CIDP in DM Baseline: 2.4 F 0.7 vs 6-mo follow-up: 1.6 F 1.1 No improvement in motor or sensory deficits Significant A in demyelinating subscore on nerve conduction study at 6 mo compared with baseline Zochodne et al 54 Case series 3 IVIG IVIG treatment did Diabetic lumbosacral plexopathy Jaradeh et al 52 Case series 15 IVIG F steroids or PLEX F steroids Rapidly progressing polyradiculoneuropathy Krendel et al 53 Case series Progressive 15 IVIG F steroids F other txy peripheral neuropathy not prevent (1 case) or halt progression (2 cases) of severe diabetic lumbosacral plexopathy. At 1 y, all patients showed clinical improvement, and the mean change in weakness NDSW scores of 29.1 F 9.3 was significant. No significant difference between IVIG (6 patients) vs PLEX (9 patients) 100% (15/15) of patients had improvement in symptoms after IVIG F additional therapies N/A N/A.01 Abbreviations: DM, diabetes mellitus; NDSW, Weakness Subscale of the Neuropathy Disability Scale; NIS, Neurologic Impairment Score; tx, treatment. 4Modified Rankin scale: range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention). yother therapies included PLEX, cyclophosphamide, and azathioprine.

17 USE OF IVIG FOR NEUROLOGIC CONDITIO S73 Recommendation Intravenous immune globulin is not recommended for the treatment of CIP. DERMATOMYOSITIS Clinical Description Dermatomyositis can occur in both adults and children. In children, dermatomyositis is the most common inflammatory myopathy. Rash is associated with muscle weakness, and some patients will have the rash with very little evidence of muscle involvement. The rash is heliotrope in color 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 fiber 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, gastrointestinal 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 bappropriateness of IVIGQ evidence review identified 1 randomized controlled trial, 1 nonrandomized controlled trial, 1 retrospective chart review, and 4 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 43 compared IVIG plus prednisone to placebo plus prednisone for treatment of adult dermatomyositis. At 3 months, patients randomized to IVIG plus prednisone showed significant improvement, as measured by mean scores on the neuromuscular symptom scale ( P =.035) and the modified MRC scale ( P =.018), compared with placebo plus prednisone. One retrospective chart review and 2 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 nonrandomized trial and 2 case series included patients with dermatomyositis or polymyositis All 3 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. 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 (eg, 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. Recommendations Based on consensus by the expert panel, pathologic 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

18 S74 FEASBY ET AL Table 16. Guillain-Barré Syndrome IVIG Studies Study Design and participants No. of patients Intervention Outcome P Hughes et al 59 Systematic review with meta-analysis4 536 IVIG vs PLEX No significant difference between IVIG and PLEX in improvement in DG at 4 wk: Weighted mean difference: 0.04 ([95% CI, 0.26 to 0.19; fixed) Bril et al 55 RCT 50 IVIG vs PLEX No significant difference Adults between IVIG and PLEX in % of patients who improved by z1 DG at 4 wk, mean time to improve z1 DG, mean time to reach DG-1 or mean DDG at 4 wk Diener et al 56 RCT 76 IVIG vs No significant difference Adults PLEX vs IAD in mean time to improve z1 DG, % of patients who improved by z1 DG at 4 wk, mean time to reach DG-1, duration of intubation or hospitalization between the groups El Zunni et al 63 Non-RCT 16 IVIG vs steroids vs Mean time to improve z1 DG: Adults placebo IVIG significantly shorter NR than steroids or placebo No significant difference between groups in % of patients who improved by z1 DGat1mo Gurses et al 64 RCT 18 IVIG vs Time from maximum weakness.05 Children No treatment to improvement and duration of hospitalization were significantly shorter with IVIG than no treatment. No significant difference between groups in duration of mechanical ventilation Haupt et al 66 Non-RCT 45 IAD + IVIG vs Mean change in DG at 4 wk: Adults IAD vs PLEX IAD + IVIG significantly better.02 than combined IAD and PLEXy groups Mean change in DG at 6 and 12-mo follow-up: IAD + IVIG vs combined IAD + PLEX not significantly different Hosokawa et al 61 Non-RCT 10 IVIG vs PLEX At 1 mo, no significant Adults difference between groups in % of patients with improvement in MRC sum scores or mean DMRC sum scores Martinez et al 62 Non-RCT 24 IVIG vs PLEX Mean change in DG at 1 mo: Adults IVIG significantly better than PLEX.0012 Mean duration of hospitalization.0065 was significantly shorter with IVIG Nomura et al 59 RCT 47 IVIG vs PLEX No significant difference between Adults groups in % of patients who improved by z1 DG at 4 wk, change in DG at 4 wk, time to improve 1 DG, and time to improve 2 DG.

19 USE OF IVIG FOR NEUROLOGIC CONDITIO S75 Study Design and participants Table 16 (continued) No. of patients Intervention Outcome P PSGBS group 68 RCT 379 IVIG vs PLEX vs Adults PLEX Y IVIG Raphael et al 68a RCT Adults 39 IVIG 0.4 g/kg per d 3d vs IVIG 0.4 g/kg per d 6d Ventilated patients: IVIG (6 d) significantly shorter than IVIG (3 d) No significant difference in % of patients who improved by z1 DG at 4 wk, duration of intubation, or mortality rate at 1 y between groups No significant difference between IVIG, PLEX, and PLEX + IVIG groups in mean improvement in DG at 4, 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 van der Meche and Schmitz 67 RCT 150 IVIG vs PLEX % of patients who improved by z1 DG at 4 wk: Adults + children IVIG significantly higher than PLEX Mean time to improve by z1 DG significantly shorter with IVIG Abbreviations: IAD, immune adsorption; 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. 4Meta-analysis included Bril et al, 55 Diener et al, 56 Nomura et al, 59 PSGBS group, 57 and van der Meche and Schmitz. 58 yhaupt et al 59 combined results from IAD and PLEX groups after finding no significant differences between the 2 groups the final interpretation be made by an expert in neuromuscular pathology. Based on consensus by the expert panel, use of IVIG for the treatment for patients with dermatomyositis should be made in consultation with an expert in neuromuscular disease. Intravenous immune globulin is not recommended as monotherapy for dermatomyositis. Intravenous immune globulin is recommended as an option, in combination with other agents, for patients with dermatomyositis who have not adequately responded to other immunosuppressive therapies. Intravenous immune globulin is recommended, in combination with other agents, as a steroidsparing 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 2 to 5 days for adults and over 2 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. DIABETIC NEUROPATHY Diabetic neuropathy affects 50% to 60% of patients with type 1 diabetes mellitus of more than 10 years in duration and, likely, a similar number of type 2 diabetes mellitus patients. Most patients are either asymptomatic or mildly symptomatic. There are many subtypes of diabetic neuropathy

20 S76 FEASBY ET AL Table 17. Inclusion Body Myositis IVIG Studies Study Design No. of patients Intervention Outcome P Dalakas et al 68 Crossover, RCT, double blind 19 IVIG vs placebo No significant difference between groups in mean change in MRC scores at 3 or 7 mo No significant difference between groups in mean MVIC at 7 mo Swallowing improved significantly with IVIG compared with placebo.05 Dalakas et al 68a RCT, double blind 37 IVIG + steroids vs placebo + steroids No significant difference between groups in mean change in MRC scores or % change in MVIC at 1, 2, or 3 mo Walter et al 67 Crossover, RCT, double blind 22 IVIG vs placebo No significant difference between groups in mean change in modified MRC scores at 6 or 12 mo Significant improvement in S with IVIG vs placebo at 6 mo Self-rated muscle weakness not significantly different between groups.05 with the most common being distal symmetrical diabetic polyneuropathy. Mononeuropathies (other than carpal tunnel syndrome) and asymmetric regional neuropathies are less common. Proximal asymmetric 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 pathophysiologic 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 CIDP. It is unclear whether this is a unique form of diabetic neuropathy or the co-occurrence of 2 independent disorders. Evidence Summary The bappropriateness of IVIGQ evidence review identified 5 case series that investigated the use of IVIG for various diabetic neuropathies (level of evidence: 4). Two series examined IVIG for CIDP in patients with diabetes. In the largest series by Sharma et al, 50 81% (21/26) of patients treated with IVIG showed clinically significant improvement in neurologic function as measured by the Neurologic Impairment Scale at 4 weeks ( P b.001). The series by Cocito et al 51 found no significant improvement in either motor or sensory deficits after IVIG. There was, however, significant improvement in both mean Rankin score ( P =.008) and indicators of demyelination on nerve conduction studies ( P =.03) at 6-month follow-up.

21 USE OF IVIG FOR NEUROLOGIC CONDITIO S77 Table 18. Intractable Childhood Epilepsy IVIG Studies Study Design No. of patients Intervention Outcome P Van Rijckevorsel- Harmant et al 69 RCT 61 IVIG 100 mg/kg vs IVIG 250 mg/kg vs IVIG 400 mg/kg vs placebo No significant difference between IVIG groups No. of patients with z50% A in seizure frequency at 6 mo: All patients: IVIG (all groups), 53% (21/40) vs placebo, 28% (5/18) Partial epilepsy4: IVIG (all groups), 56% (19/34) vs placebo, 17% (2/12) Illum et al 70 Crossover, RCT 10 IVIG vs placeboy 20% (2/10) A seizure frequency, improved EEG and general condition (both patients had high frequency, invariable seizures) 80% (8/10) no change in EEG or general condition, variable effect on seizure frequency (none had high frequency, invariable seizures) 4Subgroup analysis of patients with partial epilepsy. ycrossover after 4-week washout period..041 NR One case series of 15 patients with rapidly progressing polyradiculoneuropathy examined the effect of IVIG or plasmapheresis with or without corticosteroids. 52 All patients showed clinical improvement at 1 year, and there was significant improvement in weakness as measured by the mean change in Neuropathy Disability Weakness Score ( P b.01). There was no significant difference between patients treated with IVIG compared with plasmapheresis. In the case series by Krendel et al, 53 all 15 patients with progressive peripheral neuropathies given IVIG with or without additional antiinflammatory or anti-immune treatment showed improvement in their condition. One small case series of 3 patients reported that treatment with IVIG neither prevented nor arrested progression of severe diabetic lumbosacral plexopathy. 54 Refer to Table 15 for further details. 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 2 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 Intravenous immune globulin 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 CIDP phenotype should follow the recommendations outlined in the CIDP section of this guideline. GUILLAIN-BARRÉ SYNDROME Clinical Description Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis, with an annual incidence of 2 per 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

22 S78 FEASBY ET AL Table 19. Lambert-Eaton Myasthenic Syndrome IVIG Studies Study Design No. of patients Intervention Outcome P Bain et al 71 Crossover, RCT 9 IVIG vs placebo4 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 4Crossover after 8-week washout period within a few days, and 25% of cases develop respiratory failure that requires intensive care unit admission for assistive mechanical ventilation and for monitoring of autonomic and cardiovascular functions. The nadir, by arbitrary definition, is reached within 4 weeks and is followed by a plateau phase of variable duration and then gradual recovery. Despite frequently prolonged hospitalization, the prognosis of GBS is favorable, with a return to almost normal function in about 85% of patients. Guillain-Barré syndrome, the prototype of a postinfectious autoimmune disease, is commonly triggered by a preceding bacterial or viral infection. Case-control studies confirm the clinical impression that both respiratory and gastrointestinal tract 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, Epstein-Barr virus, 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 fibers. Thus, bmolecular mimicryq and cross-reactive immune responses are attractive pathogenetic mechanisms. In recent years it has been recognized that GBS comprises several subtypes with specific clinical, electrophysiologic, and pathologic features. The classic acute inflammatory demyelinating neuropathy is the most common form in North America and Europe (approximately 85% of cases). Acute motor axonal neuropathy, 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 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 toward 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 bappropriateness of IVIGQ evidence review identified a Cochrane systematic review with metaanalysis of IVIG for GBS (level of evidence: 1a). In addition, a systematic review by the Chalmers Research Institute on this topic included 6 randomized controlled trials and 4 nonrandomized controlled trials. Most of the trials evaluated IVIG against PLEX, an established treatment of GBS. Five trials that compared IVIG with PLEX were included in the Cochrane review s metaanalysis by Hughes et al 60 The meta-analysis found no significant difference between IVIG and PLEX in improvement in disability grade at 4 weeks (weighted mean difference, 0.04 [95% CI, 0.26 to 0.19; fixed]; P = nonsignificant []). Two additional small nonrandomized trials also compared IVIG with PLEX. One trial, by Hosokawa et al, 61 found no significant difference between IVIG and PLEX on any of the outcomes

23 USE OF IVIG FOR NEUROLOGIC CONDITIO S79 Table 20. Multifocal Motor Neuropathy IVIG Studies Study Design and participants No. of patients Intervention Outcome P van Schaik et al 72 Systematic review with meta-analysis IVIG vs placebo No significant difference in proportion of patients with significant improvement in disability scores between IVIG and placebo: Meta-analysis included: RR, 3.00 (95% CI, 3 trials4 for disability ; fixed) 3 trialsy for muscle strength All 4 for conduction blocks 2 trialsz for side effects Significantly greater proportion of patients had significant improvement in muscle strength with IVIG vs placebo: RR, (95% CI, ; fixed) No significant difference in proportion of patients with resolution of z1 Canadian Blood Services between IVIG and placebo: RR, 7.00 (95% CI, ; fixed) Significantly greater proportion of patients had side effects with IVIG: RR, (95% CI, ; fixed], P =.004 Azulay et al 73 Crossover, RCT 5 IVIG vs placebo Significant z in isometric strength with IVIG at d 28 No significant difference in % D in strength at 2 mo follow-up Federico et al 74 Crossover, RCT 16 IVIG vs placebo Significant improvement in NDS scores with IVIG at d 28 Significant z in grip strength with IVIG at d 28 Significant improvement in Canadian Blood Services with IVIG Leger et al 75 Crossover, RCT 19 IVIG vs placebo At 4 mo, no significant difference between groups in change in MRC scores or severity of Canadian Blood Services Self-evaluation scores improved significantly with IVIG Van den Crossover RCT 6 IVIG vs placebo 83% (5/6) responded to IVIG Berg et al 76 with z muscle strength, but not placebo N/A Abbreviation: NA, not applicable. 4Disability meta-analysis included Azulay et al, 73 Leger et al, 75 and Van den Berg et al. 76 ymuscle strength meta-analysis included Azulay et al, 73 Federico et al, 74 Van den Berg et al. 76 zside-effects meta-analysis included Azulay et al 73 and Federico et al. 74 Patients rated ability to perform 5 motor activities of daily life.

24 S80 FEASBY ET AL Table 21. Multiple Sclerosis IVIG Studies Study Design No. of patients Intervention Outcome P Relapsing-remitting MS Chalmers group (unpublished) Sorensen et al 78 Systematic review with meta-analysis4 Systematic review with meta-analysesy Achiron et al 84 RCT 36 IVIG vs no treatment IVIG vs placebo Significant improvement in mean DEDSS with IVIG vs placebo: Weighted mean difference: 0.39 (95% CI, to 0.23; random) IVIG vs placebo Significant improvement in mean DEDSS with IVIG vs placebo: Effect size: 0.24 (95% CI, 0.46 to 0.01); NNT: 4 Annual relapse rate significantly lower with IVIG vs placebo: Effect size: 0.50 (95% CI, to -0.27); NNT: 2 Proportion of relapse-free patients significantly z with IVIG vs placebo: Effect size: 0.29 (95% CI, ); NNT: 3 Mean annual relapse rate, % of patients 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 patients who improved z1 EDSS grade Achiron et al 79 RCT 40 IVIG vs placebo Mean annual relapse rate significantly lower with IVIG than placebo % of relapse-free patients at 2 y ( P =.001) and mean time to first relapse ( P =.003) significantly z with IVIG No significant difference between groups in mean D in EDSS at 2 y Fazekas et al 80 RCT 148 IVIG vs placebo Mean annual relapse rate significantly lower with IVIG than placebo % of Relapse-free patients significantly higher with IVIG vs placebo Significant improvement in mean DEDSS with IVIG vs placebo No significant difference between groups in mean time to first relapse Lewanska et al 81 RCT 49 IVIG 0.4 g/kg vs IVIG 0.2 g/kg vs placebo Mean annual relapse rate at 1 y: No significant difference between IVIG groups Combined IVIG groups significantly lower than placebo Mean change in EDSS score at 1 y: No significant difference between IVIG groups Combined IVIG groups significant improvement compared with placebo

25 USE OF IVIG FOR NEUROLOGIC CONDITIO S81 Table 21 (continued) Study Design No. of patients Intervention Outcome P Ostekin (1998) [abstract] RCT 36 IVIG vs placebo No significant difference between groups in mean annual relapse rate or mean change in EDSS scores at 22 mo Teksam et al 85 RCT 13 IVIG vs placebo No between group comparisons reported PRIVIG (2006) RCT 127 IVIG-C 0.2 g/kg vs No significant differences IVIG-C 0.4 g/kg vs between any of the groups placebo in the primary outcome measure, the proportion relapse-free at 48 mo No significant difference between groups in terms of any secondary outcome measure, either other relapse-related outcomes or MRI Secondary progressive MS Hommes et al 86 RCT 318 IVIG vs placebo No significant difference between groups in time to EDSS progression, annual relapse rate, or change in T2-lesion load Relapsing-remitting or secondary progressive MS Noseworthy et al 87 RCT 67 IVIG vs placebo At 3 and 6 mo, no significant difference between groups in mean change in % of Normal strength of TND muscles nor mean DEDSS Noseworthy et al 88 z RCT 55 IVIG vs placebo No significant difference between groups in mean change in visual acuity or mean change in EDSS scores at 6 or 12 mo Sorensen et al 83 Crossover, RCT 21 IVIG vs placebo % of Relapse-free patients significantly higher with IVIG than placebo No significant difference between groups in no. of relapses or mean change in EDSS scores at 15 mo Relapsing progressive or secondary progressive MS Poehlau 89 [abstract] RCT 40 IVIG vs placebo No significant difference between the groups in mean change in isometric muscle strength of TND muscles Subgroup analysis of patients with relapsing-progressive MS: IVIG group had significantly fewer relapses at 1 y than placebo N/A.02 NR Abbreviation: TND, targeted neurologic deficit. NOTE. EDSS: range 0 (normal neurologic exam) to 10 (death). 4Chalmers meta-analysis included: Achiron et al, 77 Fazekas et al, 79 Oztekin, 84 and Lewanska et al 81 ysorensen meta-analyses included: Achiron et al, 77 Fazekas, Sorensen et al, 88 and Lewanska et al 81 zincluded patients with episodes of optic neuritis.

26 S82 FEASBY ET AL Table 22. Myasthenia Gravis IVIG Studies Study Design and participants No. of patients Intervention Outcome P Adult myasthenia gravis Gajdos et al 90 Systematic review4 147 IVIG vs other tx or placebo Gajdos et al 91 RCT 87 IVIG(0.4 g/kg per d 3d)vsIVIG MG acute exacerbation (0.4 g/kg per d 5 d) vs PLEX No meta-analysis was performed due to heterogeneity of interventions and outcomes assessed. Mean change in MMS at d 15: No significant difference between IVIG (3 d) vs IVIG (5 d) No significant difference between IVIG (combined) and PLEX All groups improved significantly from baseline at d 2 No significant difference between groups in median time to responsey or change in anti- AChR antibody titer at d 15 Ronager et al 92 Crossover RCT 12 IVIG vs PLEX DQMGS at 1 or 4 wk not significantly different between groups Moderate to severe MG Both groups had significant improvement in QMGS at 4 wk % Change in anti- AChR antibody titer: PLEX: A wk 1 ( P b.05), no significant D at wk 4, 8, or 16 IVIG: no significant D at wk 1, 4, 8, or 16 Schuchardt (unpublished)z RCT MG exacerbation 33 IVIG vs oral MP No significant difference between groups in DQMGS of 2 most affected criteria at d 14 or time to maximum improvement Wolfe et al 93 RCT 15 IVIG vs placebo No significant Mild-moderate MG or chronic MG Achiron et al 94 Case series 10 IVIG Significant MG acute exacerbation difference between groups at d42indqmgs, mean consecutive difference on single fiber EMG, % decrement on repetitive nerve stimulation, or MG-ADL improvement in mean severity of disease as measured by the Osserman scale at 1 y N/A

27 USE OF IVIG FOR NEUROLOGIC CONDITIO S83 Table 22 (continued) Study Design and participants No. of patients Intervention Outcome P Adult myasthenia gravis Cosi et al 93 Case series Acute-relapsing MG Hilkevich et al 96 Huang et al 97 Wegner and Ahmed 98 Case series Chronic, severe MG Case series Chronic, moderate MG Case series Chronic MG 37 IVIG At d 60, 57% of patients improved z1 grade on the OGCCMS scale. No significant difference in response between patients in acute phase and patients with chronic stable MG 11 IVIG Significant mean improvement on OGCCMS scale ( P b.00005) All patients showed improvement on the OGCCMS scale 6 IVIG Significant mean improvement on functional scale All patients showed improvement on the OGCCMS scale 6 IVIG Significant mean improvement on functional scale All patients showed improvement on the OGCCMS scale. Wilson et al 99 Case series 38 IVIG Reported adverse events only; 1 case of hemolytic anemia Juvenile myasthenia gravis Herman 100 Case reports 3 IVIG IVIG temporarily stabilized all 3 cases and allowed thymectomy to be performed. Selcen et al 101 Case series 10 IVIG 80% (8/10) of patients improved z1 grade in functional status on the Osserman scale with median duration of improvement 25 d. Neonatal myasthenia gravis Tagher et al 102 Case report 1 IVIG + neostigmine No improvement with IVIG plus neostigmine Bassan et al 103 Case report 1 IVIG + neostigmine Improved with IVIG plus neostigmine NR NR NR N/A N/A NR N/A N/A Abbreviations: MMS, Myasthenic muscle score; QMGS, quantified MG clinical score; ADL, activities of daily living; MP, methylprednisolone; OGCCMS, Oosterhuis Global Clinical Classification of Myasthenic Severity. 4SR included 4 trials: Gajdos, 94 Wolfe et al, 103 Ronager et al 98 and Schuchardt (unpublished). ydefined as an increase in MMS score of z20 points. zas of August (2005).

28 S84 FEASBY ET AL measured. The other trial, by Martinez et al, 62 reported significant improvement in mean change in disability grade at 1 month with IVIG compared with PLEX ( P b.0012). A large trial by the Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group (PSGBS) 57 investigated the combined effect of IVIG and PLEX in patients with GBS. In this trial, 379 patients were randomized to receive IVIG, PLEX, or IVIG plus PLEX. No significant differences between the 3 groups were identified for any of the outcomes measured. Two trials evaluated IVIG against placebo or no therapy. A very small 3-arm, nonrandomized trial by El Zunni et al 63 reported the mean time to improve at least 1 disability grade was significantly shorter with IVIG compared with either prednisone or placebo ( P value not reported). A small randomized trial by Gurses et al, 64 which 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 with no treatment ( P b.05). One randomized trial evaluated different doses of IVIG. Raphael et al 65 compared administration of IVIG (0.4 g/kg) daily for 3 vs 6 days. Overall, no significant differences between the 2 groups were identified. In the subgroup of patients who required mechanical ventilation, time to regain ability to walk with aid was significantly shorter in the group given IVIG for 6 days ( P =.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 PLEX are equally effective for treatment of GBS. The expert panel noted that PLEX was the standard of care for treatment of GBS when most IVIG trials were conducted; thus, IVIG was not compared with placebo. One large randomized trial reported no additional benefit from combined therapy with IVIG plus PLEX compared with either IVIG or PLEX 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, retreatment 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 Intravenous immune globulin is recommended as a treatment option for GBS within 2 weeks of symptom onset for: 1. Patients with symptoms of grade 3 severity (able to walk with aid) or greater; or 2. 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 2 to 5 days for adults and over 2 days for children is a reasonable option. 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 older than 65 years. Inclusion body myositis can be seen in younger patients but is rarely seen in those younger than 50 years. 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

29 USE OF IVIG FOR NEUROLOGIC CONDITIO S85 serum CK is normal or mildly elevated. Electromyography will demonstrate features of a myopathy with muscle fiber necrosis, but there is a characteristic mixture of large and small motor unit potentials that typify the disorder. The muscle biopsy will show muscle fiber necrosis, inflammatory infiltrates, and rimmed vacuoles with granular inclusions. Making a pathologic 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 IBM do not usually respond to immune therapies. Evidence Summary The bappropriateness of IVIGQ evidence review identified 3 randomized controlled trials that investigated IVIG for IBM (level of evidence: 1b). A systematic review by the Chalmers Research Institute of IVIG for myositis included the same 3 randomized trials. Two small randomized crossover trials compared IVIG with placebo. 67,68 No significant difference in muscle strength, as measured by mean change on the MRC scale, was observed between IVIG and placebo groups. Walter et al 67 did report a small but significant improvement in neuromuscular symptom scale scores with IVIG vs placebo at 6 months ( P b.05). One randomized controlled trial evaluated IVIG plus prednisone against placebo plus prednisone. 68a No significant differences in mean change in MRC scores or maximum voluntary isometric contraction measures between the 2 groups were identified (Table 17). Interpretation and Consensus The available evidence consists of 3 small randomized trials of moderate to high quality. The expert panel noted that although a small number of patients with IBM showed some 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 IBM. The panel agreed that a skeletal muscle biopsy is required to diagnosis IBM and that the biopsy specimen should be examined by an expert in neuromuscular pathology. RECOMMENDATION Based on consensus by the expert panel, pathologic confirmation by means of a skeletal muscle biopsy is required for the diagnosis of IBM. 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. Intravenous immune globulin is not recommended for the treatment of IBM. INTRACTABLE CHILDHOOD EPILEPSY Clinical Description Epilepsies are characterized by recurrent, spontaneous and transient paroxysms of electrical discharges in the brain. Epileptic syndromes are defined based on seizure type, electroencephalogram (EEG) features, age of onset, and clinical course. At least 10% to 20% of childhood epilepsies are intractable, defined as failure to control seizures after an adequate trial of first-line antiepileptic medications. Although epilepsy is not generally considered an immunologic disorder, rare epileptic patients with low serum levels IgA, impaired or augmented humoral responses, and circulating antibodies to C antigens have been reported. Large-scale immunologic studies in patients with epilepsy and appropriate controls have not been performed. Evidence Summary The bappropriateness of IVIGQ evidence review identified 2 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 1 of 3 different doses of IVIG (100, 250, and 400 mg/kg) or placebo. 69 No significant differences between IVIG groups were identified. At 6 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 subgroup analysis found significantly more patients with partial epilepsy who received IVIG vs placebo had a 50% or greater reduction in seizure frequency ( P =.041). A small crossover trial reported 20% (2/10) of patients had reductions in seizure

30 S86 FEASBY ET AL Table 23. Adult Opsoclonus-Myoclonus IVIG Studies Study Design No. of patients Intervention Response Idiopathic opsoclonus-myoclonus Bataller et al 104 Retrospective chart review 5 IVIG F steroids Monophasic course: 2/3 complete recovery; 1/3 partial recovery Relapsing course: 2/2 remission with IVIG (mild ataxia remained) Pless and Ronthal 105 Case report 1 ACTH Y IVIG Monophasic course, complete recovery with IVIG Pranzatelli et al 106 Case report 1 ACTH + steroidsy IVIG Paraneoplastic opsoclonus-myoclonus Bataller et al 104 Retrospective chart review Abbreviation: ACTH, adrenocortico trophic hormone. Relapsing course, partial recovery with monthly IVIG 4 IVIG 1/4 partial recovery (IVIG at same time as antineoplastic therapy) 3/4 no response to IVIG frequency that were associated with improvements in EEG findings, cognitive performance, and general well-being after IVIG 70 (Table 18). Interpretation and Consensus The available evidence is limited to 2 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 antiepileptic medications, making it very difficult to evaluate the effect of IVIG. The panel discussed that although a subgroup analysis in one trial showed some benefit of IVIG for children with partial epilepsy, the number of patients studied was very small, compared with 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 immunologic studies in patients with epilepsy are required before additional clinical trials are warranted. RECOMMENDATION Intravenous immune globulin is not recommended for the treatment of intractable childhood epilepsy. Table 24. Pediatric Opsoclonus-Myoclonus IVIG Studies Study Design No. of patients Intervention Response Idiopathic opsoclonus-myoclonus Sugie et al 107 Case report 1 Steroids Y IVIG Monophasic course: complete recovery Yiu et al 108 Case report 1 ACTH + azathioprine + IVIG Monophasic course: transient partial recovery Penzien et al 109 Case report 1 Steroids Y IVIG Relapsing course: no response to IVIG Neuroblastoma-associated opsoclonus-myoclonus Petruzzi and de Alarcon 110 Case report 1 IVIG Complete recovery Eiris et al 111 Case report 1 ACTH Y IVIG Complete recovery Borgna-Pignatti et al 112 Case report 1 IVIG + ACTH Partial recovery Fisher et al 113 Case report 1 Steroids Y IVIG Partial recovery

31 USE OF IVIG FOR NEUROLOGIC CONDITIO S87 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-fiber electromyography studies that show elevated jitter and blocking, and by repetitive nerve stimulation studies that show an incremental response. Postexercise facilitation and exhaustion are common findings after 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, type 1 diabetes mellitus, and myasthenia gravis have been associated with the nonmalignant form of LEMS. Voltage-gated calcium channels on the presynaptic membrane of the nerve terminal are essential for calcium-evoked acetylcholine 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 down-regulate 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 antineuronal antibodies such as anti-hu. Paraneoplastic LEMS may improve with appropriate therapy for the underlying malignancy. Surveillance for malignancy should be maintained for a minimum of 3 years after 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 acetylcholine release. Immunosuppression with corticosteroids, azathioprine and/or other immunosuppressant drugs can be used to achieve remission. Immunomodulation with PLEX 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 bappropriateness of IVIGQ evidence review identified one randomized controlled trial that evaluated the use of IVIG for LEMS (level of evidence: 1b). 71 This small, placebo-controlled, crossover trial of 9 patients reported significant improvement in limb strength ( P =.038), respiratory muscle strength ( P =.028), and bulbar muscle strength ( P =.017) after IVIG, compared with placebo (Table 19). 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. Although 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.

32 S88 FEASBY ET AL Table 25. Paraproteinemic neuropathy (IgM variant) IVIG Studies Study Design No. of patients Intervention Outcome P Lunn and Nobile-Orazio 114 Systematic review included 3 RCTs below IVIG vs placebo or INF-a Meta-analysis for overall treatment effect of IVIG vs placebo was not performed due to heterogeneity of outcomes. Comi et al 115 Crossover 22 IVIG vs placebo At 2 wk: RCT Significant improvement in modified Rankin scores with IVIG vs placebo No significant difference between groups in change in mean disability score At 4 wk: Change in mean overall disability score significantly A with IVIG vs placebo Significant improvement in handgrip with IVIG vs placebo Dalakas et al 116 Crossover RCT 11 IVIG vs placebo Mean change in modified Rankin score: IVIG: 9 F 12.7 vs placebo: 1.1 F 8.3 Mariette et al 117 Crossover 20 IVIG vs INF-a At 6 mo: RCT (not blinded) Significant improvement in mean CNDS with INF-a vs IVIG CNDS improved N20%: IVIG 10% (1/10) vs INF-a 80% (8/10) N/A Abbreviations: CNDS, Clinical Neuropathy Disability Score. INF-a, interferon a. NOTE. Modified Rankin scale: range 0 (asymptomatic) to 5 (severely disabled, totally dependent, requiring constant attention). Recommendation Intravenous immune globulin is recommended as an option for treatment of LEMS. 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 2 to 5 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. 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 after exercise. Sensory symptoms and signs are notably absent on both clinical and electrophysiologic examination. The electrodiagnostic hallmark of MMN is finding focal conduction blocks in motor nerves outside regions normally prone to nerve entrapments. The conduction block corresponds to focal areas of chronic demyelination. MMN is an uncommon neuropathy. However, because of the generally slow progression of MMN, its prevalence is higher than expected and has been estimated at 2 per Generally, MMN begins between the ages of 20 and 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. Magnetic resonance imaging may show focal areas of high

33 USE OF IVIG FOR NEUROLOGIC CONDITIO S89 Table 26. PANDAS IVIG Studies Study Design No. of patients Intervention Outcome P Perlmutter et al 118 RCT 29 IVIG vs PLEX vs placebo At 1 mo: No significant difference between IVIG and PLEX groups Significant improvement in the following with IVIG or PLEX vs placebo: Obsessive-compulsive symptoms.006 Anxiety.001 Depression.002 Emotional lability.001 Overall functioning.0009 At 1 y: Symptoms remained improved from baseline NR on all measures for patients who received IVIG or PLEX signal on T2-weighted images pre and post contrast, which, on biopsy, showed very chronic demyelination. High titers of IgM anti-gm1 antibodies are found in approximately 50% of patients with MMN. The role 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 patient s condition. Other immunosuppressive drugs such as mycophenoate, azathioprine, methotrexate, or cyclophosphamide may be considered. However, toxicity and long-term sideeffects from these agents are problematic, and a lack of firm evidence of benefit with these drugs should discourage their use. Evidence Summary The bappropriateness of IVIGQ evidence review identified 4 small randomized controlled trials that investigated the use of IVIG for MMN. A recently published Cochrane systematic review of IVIG for MMN, identified by an update literature search, included the same 4 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, 72 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 after IVIG compared with placebo (RR, [95% CI, ; fixed]; P =.0005). There was no significant difference between IVIG and placebo in the proportion of patients with significant improvement in disability scores or resolution of 1 or more conduction blocks. Significantly more patients experienced side-effects with IVIG compared with placebo (RR, [95% CI, ; fixed], P =.004). Tests for heterogeneity were not statistically significant. Refer to Table 20 for further details. Interpretation and Consensus The expert panel agreed IVIG is the only treatment demonstrated by clinical trial to be effective for MMN, and it is widely accepted as first-line therapy for this condition. Patients with MMN 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.

34 S90 FEASBY ET AL Table 27. POEMS Syndrome IVIG studies Study Design and participants No. of patients Intervention Outcome Benito-Leon et al 120 Case report 1 IVIG + radiotherapy At 1 mo: marked improvement in numbness, dyspnea, impotence Variant of POEMS At 1 y: independent ambulation, improved nerve conduction Henze and Krieger 121 Case report 1 IVIG Y IVIG + steroids Severe POEMS IVIG alone: partial response (A paresthesias, no change in paresis) IVIG + steroids: independent ambulation, improved muscle power Huang and Chu 122 Case report 2 IVIG qno improvement with POEMS and IVIG in either case. Castleman s disease Recommendations Intravenous immune globulin is recommended as first-line treatment of for MMN. Based on consensus by the expert panel, diagnosis of MMN should be made by a neuromuscular specialist, as the diagnosis requires very specific electrodiagnostic expertise. Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 to 5 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. MULTIPLE SCLEROSIS Clinical Description Multiple sclerosis (MS) is the most common neurologic disability in young adults with a prevalence of one in 500 to 1000 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. Most 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 MS is thought to represent a complex interplay of immune system reactivity to environmental triggers (eg, 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 (eg, ADEM), vasculopathies, connective tissue diseases such as systemic lupus erythematous; mitochondrial disease (eg, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), nonspecific granulomatous disease such as sarcoidosis, and certain infections (eg, borreliosis). As discussed in the 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 MS involves the immunomodulatory agents: b-interferon and glatiramer acetate with immunosuppressive medications (eg, 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, chemo-

35 USE OF IVIG FOR NEUROLOGIC CONDITIO S91 Table 28. Polymyositis IVIG Studies Study Design and participants No. of patients Intervention Outcome P Polymyositis Cherin et al 123 Case series Tx refractory Polymyositis or dermatomyositis Danieli et al 47 Non-RCT New onset, relapsed or Tx refractory Cherin and Herson 48 Cherin et al 49 Case series Tx refractory Case series No previous tx 35 IVIG Clinical improvement with IVIG: 71% (25/35) of patients Significant improvement in muscle power and MDS: Mean muscle power4:.01 baseline, 47.8 F 11.1; post-ivig, 67.4 F 12.7 Mean MDS score:.01 baseline, 22.3 F 8.0; post-ivig, 10.9 F 6.1 Significant reduction in.05 mean steroid dose (mg/d) Significant A in CK levels Steroids + CSA or IVIG + steroids + CSA or IVIG + PLEX + steroids + CSA 35 IVIG F steroids F other txz No significant difference in CRy between groups at 1 y At 4 y: Significantly more patients.001 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 power4:.01 baseline, 46.5 F 11.5; post-ivig, 67.1 F 15.4 Significant reduction in.05 mean steroid dose (mg/d) Significant A in CK levels IVIG No significant improvement in mean muscle power4 from baseline Only 27% (3/11) had significant clinical improvement. Significant improvement in mean CK levels.01 Abbreviations: MDS, Muscle Disability Scale: range 0 (no disability) to 75 (maximum disability); CR, complete remission. 4Muscle power score: used a modified MRC scale; treatment classified as successful if score increase by z18 points. ydefined as increase in strength of z3 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. zother treatments included methotrexale, azathoprine, or plasma exchange.

36 S92 FEASBY ET AL Table 29. Rasmussen s Encephalitis IVIG Studies Study Design No. of patients Intervention Outcome Granata et al 124 Case series 11 IVIG F steroids F PLEX F other therapies4 Effect of IVIG: 9% (1/11) transient A seizure frequency N50%, improved neurologic condition 18% (2/11) transient A seizure frequency up to 50% 46% (5/11) no effect 27% (3/11) not assessable Korn-Lubetzki et al 125 Case report 1 IVIG Mild improvement in symptoms Frucht 126 Case report 1 IVIG + ganciclovir Marked improvement in hyperkinetic movements Villani et al 127 Case report 1 IVIG Marked improvement (N75% A seizure frequency, improved cognition) Leach et al 128 Case report 2 IVIG 100% (2/2) Marked improvement in seizure frequency, hemiparesis, cognition 4Other therapies included cyclophosamide and protein A immunoadsorption. kine 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 bappropriateness of IVIGQ evidence review identified one systematic review with metaanalysis and 6 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 6 trials plus 4 additional randomized controlled trials that reported outcome data. Two recent randomized trials were identified by a member of the expert panel. 77,77a Overall, 11 randomized trials compared IVIG with placebo and one trial assessed IVIG vs no treatment. Two trials had 3 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 placebo-controlled. A systematic review by Sorensen et al 78 and the Chalmers review (unpublished) conducted meta-analyses 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 vs placebo (Chalmers: weighted mean difference 0.39 [95% CI, 0.55 to 0.23; random], P b.001; Sorensen: effect size, 0.24 [95% CI, 0.46 to 0.01]; P =.042). The randomized trials included in the meta-analyses differed slightly between the systematic reviews. The Chalmers meta-analysis included Achiron et al, 79 Fazekas et al, 80 Lewanska et al, 81 and Oztekin, 82 whereas the meta-analysis by Sorensen et al 78 included Achiron et al, 79 Fazekas et al, 80 Lewanska et al, 81 and Sorensen et al 83 (Table 21). Sorensen et al 78 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 to 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, ], P = ).

37 USE OF IVIG FOR NEUROLOGIC CONDITIO S93 Table 30. Stiff Person Syndrome IVIG Studies Study Design and participants No. of patients Intervention Outcome P Dalakas et al 129 Crossover RCT 14 IVIG vs placebo4 Stiffness scores: All patients had anti-gad65 antibodies Significant direct treatment effect of IVIG vs placebo on improvement in mean stiffness scoresy 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 scoresz 4IVIG or placebo once per month for 3 months, followed by a 1-month washout period then crossed to other treatment. ydistribution of stiffness index: one point each for stiffness of lower trunk, upper trunk, legs, arms, face, abdomen (range, 0-6). zscores range from 1 to 7, one point for each source of or type of spasm Recently, a large randomized, double-blind, placebo-controlled trial was performed (called Prevention of Relapse With Intravenous Immunoglobulin [PRIVIG]) and presented in abstract form at the European Neurological Society conference in June a Although published only in abstract form to date, the PRIVIG trial has been included in the guideline at this point for several reasons: the trial is large, placebocontrolled, and it evaluated 2 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 86 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 83, the proportion of relapse-free patients was significantly higher with IVIG compared with placebo (P b.02). One randomized controlled trial evaluated different doses of IVIG. No significant difference between IVIG treatment arms was identified. Interpretation and Consensus Evidence from 2 meta-analyses and several randomized controlled trials is available to support IVIG as superior to placebo for treatment for patients with relapsing-remitting MS. However, the outcome of the recently completed PRIVIG trial raises doubt about the efficacy of IVIG in the routine treatment of relapsing-remitting MS. 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, b-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 and 2 g/kg once a month. The panel agreed that 1 g/kg monthly with or without a 5-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.

38 S94 FEASBY ET AL Table 31. External Review Survey Results Respondent agreement with draft recommendations for use of IVIG Clinical condition Strongly agree or agree Neutral Disagree or strongly disagree Average level of agreement4 Acute disseminated encephalomyelitis 12 (100%) 0 (0%) 0 (0%) 4.25 Adrenoleukodystrophy 10 (83%) 0 (0%) 2 (17%) 4.08 Amyotrophic lateral sclerosis 10 (83%) 0 (0%) 2 (17%) 4.33 Autism 10 (83%) 0 (0%) 2 (17%) 4.17 Chronic inflammatory 11 (92%) 1 (8%) 0 (0%) 4.33 demyelinating polyradiculoneuropathy Critical illness polyneuropathy 9 (75%) 2 (17%) 1 (8%) 4.08 Dermatomyositis 10 (83%) 2 (17%) 0 (0%) 4.39 Diabetic neuropathy 9 (75%) 2 (17%) 1 (8%) 3.83 Guillan-Barré syndrome 12 (100%) 0 (0%) 0 (0%) 4.75 Inclusion body myositis 9 (75%) 3 (25%) 0 (0%) 4.17 Intractable childhood epilepsy 9 (75%) 2 (17%) 1 (8%) 4.08 Lambert-Eaton myasthenic syndrome 9 (75%) 2 (17%) 1 (8%) 3.92 Multiple motor neuropathy 11 (92%) 1 (8%) 0 (0%) 4.42 Multiple sclerosis 6 (50%) 3 (25%) 3 (25%) 3.25 Myasthenia gravis 11 (92%) 0 (0%) 1 (8%) 4.17 Opsoclonus-myoclonus 8 (67%) 4 (33%) 0 (0%) 3.92 PANDAS 9 (75%) 3 (25%) 0 (0%) 4.00 Paraproteinemic 9 (75%) 2 (17%) 1 (8%) 4.00 neuropathy (IgM variant) POEMS syndrome 8 (67%) 4 (33%) 0 (0%) 3.92 Polymyositis 8 (73%) 3 (27%) 0 (0%) 3.91 Rasmussen s encephalitis 8 (67%) 2 (17%) 2 (17%) 3.58 Stiff person syndrome 10 (83%) 2 (17%) 0 (0%) 4.25 Respondent agreement with overall statements Overall questions Strongly agree or agree Neutral Disagree or strongly disagree Average level of agreement4 The guidelines will be useful in optimizing practice. I will use the guidelines in my practice. 11 (92%) 1 (8%) 0 (0%) (83%) 2 (17%) 0 (0%) 4.33 Abbreviations: PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. 4Measured on a 5-point scale: 1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, and 5 = strongly agree. 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 3 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 (ie, Devic s syndrome) and Marburg disease, which are likely variants of MS, the panel 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

39 USE OF IVIG FOR NEUROLOGIC CONDITIO S95 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 relapsingremitting 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 Intravenous immune globulin 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. Intravenous immune globulin 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 3 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 postpartum period for women whose exacerbation rate was high before pregnancy and who were on disease modifying agents before pregnancy with plans to recommence therapy after 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. Dose and Duration Based on consensus by the expert panel, 1 g/kg monthly with or without a 5 day induction of 0.4 g/kg daily is a reasonable starting option for treatment for patients with relapsing-remitting MS. The panel emphasized that a systematic approach should be taken to determine the minimum effective dose of IVIG required. 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 7 per , and the prevalence is 75 to 125 per million. Women are affected 1.4 times more frequently than men, particularly those younger than 40 years. 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 3 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 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 of myasthenia gravis includes anticholinesterase drugs, thymectomy, immunosuppressive therapy, and immunomodulation (eg,

40 S96 FEASBY ET AL 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 60 years of age 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 2 to 4 weeks. Other immunosuppressive medications used for myasthenia gravis are azathioprine, cyclosporine, cyclophosphamide, and mycophenolate mofetil. Immunomodulation with PLEX or IVIG removes AChR antibodies or modulates antibody effects temporarily. Plasma exchange is the standard treatment of myasthenic crisis, acute deterioration, or prethymectomy in patients with respiratory or bulbar involvement. Some drugs such as aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, and b-blockers 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 bappropriateness of IVIGQ 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 3 randomized controlled trials and 7 noncomparative case series. The Cochrane systematic review by Gajdos et al 90 included 4 randomized controlled trials of IVIG use for myasthenia gravis. No meta-analysis was conducted because of 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 with PLEX for the treatment of myasthenia gravis exacerbations or crises and to determine the indications for IVIG in moderate and severe myasthenia gravis. Two small randomized trials compared IVIG with PLEX. The trial by Gajdos 91 included patients with acute exacerbations of myasthenia gravis, whereas the crossover trial by Ronager 92 evaluated IVIG in patients with moderate-to-severe, but stable, myasthenia gravis. Neither trial identified a significant difference between IVIG and PLEX for any of the outcomes assessed. Both trials reported significant improvement from baseline after treatment with IVIG or PLEX, as measured by mean change in Myasthenic Muscle Score or Quantified Myasthenia Gravis Clinical Score. The randomized trial by Gajdos et al 91 also evaluated different doses of IVIG. No significant difference between IVIG treatment arms was identified. One very small, underpowered trial by Wolfe et al 93 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 immunologic 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, end points 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 PLEX 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 PLEX and IVIG. A definitive randomized controlled trial is needed, however, to establish whether IVIG or PLEX is superior for treatment of severe myasthenic exacerbations.

41 USE OF IVIG FOR NEUROLOGIC CONDITIO S97 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. Intravenous immune globulin 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 before surgery. Intravenous immune globulin 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. Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 to 5 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. OPSOCLONUS-MYOCLONUS Clinical Description Opsoclonus-myoclonus syndrome is a rare neurologic 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 after a childhood viral infection or as a paraneoplastic syndrome. The paraneoplastic syndrome is most frequently associated with neural crest tumors, in particular, neuroblastoma. Evidence Summary The bappropriateness of IVIGQ evidence review identified one retrospective chart review and 9 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) (Tables 23 and 24). 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. 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 opsoclonus-myoclonus. Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 to 5 days for adults and over 2 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. PARAPROTEINEMIC NEUROPATHY (IGM VARIANT) Clinical Description Most patients with IgM paraproteinemic demyelinating neuropathy present with a chronic, slowly progressive, distal, and predominantly sensory

42 S98 FEASBY ET AL neuropathy. Patients usually experience prominent gait ataxia, paraesthesias, and numbness in the hands with impaired dexterity and coarse tremors. Although 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. Men are more commonly affected than women. Electrophysiologic 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 and serum immunofixation electrophoresis are more sensitive techniques to detect lower paraprotein concentrations. Heavy- (IgM) and light-chain (j or k) class should be identified. Almost 50% of IgM-associated demyelinating polyneuropathy have high titers of antibodies cross-reacting with myelin-associate glycoprotein (MAG), which are more likely to be of j 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 electron microscopic 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 3 to 5 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 (eg, PLEX), inhibition (eg, IVIG) or reduction of synthesis (eg, corticosteroids, immunosuppressive drugs, interferon-a or rituximab). To date, none of these treatments have yielded particularly promising results. Evidence Summary The bappropriateness of IVIGQ Evidence Review identified one Cochrane systematic review and 3 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. 114 Of the 5 randomized controlled trials included in the Cochrane review, 3 assessed the efficacy of IVIG. Two trials compared IVIG with placebo, and 1 trial assessed IVIG vs interferon a. The Cochrane review did not perform a metaanalysis of the effect of IVIG treatment vs placebo because of differences in outcomes assessed. A small crossover trial by Comi et al 115 examined the short-term effect of IVIG treatment. At 2 weeks, significant improvement in modified Rankin scores was observed with IVIG compared with placebo ( P =.008). At 4 weeks, change in mean overall disability score was significantly improved with IVIG vs placebo ( P b.05). Another small crossover trial that evaluated IVIG against placebo found no significant difference between groups in change in mean Rankin scores at 3 months. 116 One nonblinded, crossover trial that evaluated IVIG vs interferon-a reported significant improvement in mean clinical neuropathy disability scores with interferon-a compared with IVIG at 6-month follow-up ( P =.02) 117 (Table 25). Interpretation and Consensus The available evidence is limited to 3 small trials of variable quality and mixed results. Although one placebo-controlled trial by Comi et al 115 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. 116,118,119 The expert panel does not recommend IVIG for the treatment of IgM paraproteinemic neuropathy.

43 USE OF IVIG FOR NEUROLOGIC CONDITIO S99 Recommendation Intravenous immune globulin is not recommended for the treatment of IgM paraproteinemic neuropathy. PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH STREPTOCOCCAL INFECTIO Clinical Description Simple motor tics are common, affecting up to 1% to 2% of school-age children. The association of rapid-onset tics associated with obsessivecompulsive disorder (OCD) in the context of recovery from streptococcal infection (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections [PANDAS]) was first reported in Molecular mimicry between streptococcal antigens and the C have been hypothesized to underlie Sydenham s chorea, a well-recognized poststreptococcal disorder and, by analogy, have been implicated in PANDAS. Treatment to interrupt the autoimmune process in PANDAS led to trials of IVIG and PLEX in affected children. Similar trials in children with nonstreptococcal associated OCD or tics were uniformly negative. Evidence Summary The bappropriateness of IVIGQ 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 OCD or tic disorder after streptococcal infections were randomly assigned to receive IVIG, PLEX, or placebo. 118 At 1 month, there was no significant difference between the IVIG and PLEX groups. Patients who received treatment with either IVIG or PLEX showed significant improvement in obsessive-compulsive symptoms ( P =.006), anxiety ( P =.001), depression ( P =.002), emotional lability ( P =.001), and overall functioning ( P =.0009) compared with placebo. The improvement in symptoms was still evident at 1-year follow-up (Table 26). Interpretation and Consensus Although 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 2 days and there was agreement that this is a reasonable option. Recommendations Intravenous immune globulin is recommended as an option for treatment of patients with PANDAS. Based on consensus by the expert panel, diagnosis of PANDAS requires expert consultation. Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 days is recommended as a reasonable option. 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 men. 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 immunofixation electrophoresis. Most patients have a k light chain containing M protein peak that is usually small. In addition they often harbor 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 Castleman s 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, ascites, pleural effusions, and generalized edema are frequent, caused by the massive secretion of vascular endothelial growth factor (VEGF). Vascular endothelial growth factor targets the endo-

44 S100 FEASBY ET AL thelial 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 tumor necrosis factor a and interleukins (IL-1 and IL-6). Electrophysiologic 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 (thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, glucose), abdominal ultrasound or computed tomography (organomegaly), complete blood count (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. 119 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 neurologic improvement or stabilization in 88% (14/16) patients but was associated with significant morbidity. Evidence Summary The bappropriateness of IVIGQ evidence review identified 4 cases of IVIG use for POEMS (level of evidence: 4). Two patients showed improvement after IVIG plus dexamethasone or radiotherapy. 120,121 No improvement with IVIG was observed for 2 patients with Castleman s disease and POEMS 122 (Table 27). 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. Recommendation Intravenous immune globulin is not recommended for the treatment of POEMS syndrome. 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 erythematosus or mixed connective tissue disease. Serum 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 fiber necrosis, but a specific diagnosis requires muscle biopsy. Making a pathologic 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 fiber necrosis, with severe weakness and dysphagia from esophageal and oral-pharyngeal weakness. Several autoantibodies 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 bappropriateness of IVIGQ Evidence Review identified one nonrandomized controlled trial and 3 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 nonrandomized 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.

45 USE OF IVIG FOR NEUROLOGIC CONDITIO S101 The only case series, by Cherin et al, 123 which 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 CK levels ( P b.01) after IVIG. There was also a significant reduction in mean steroid dose after treatment with IVIG ( P b.05). All 3 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 (eg, 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, pathologic 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 (eg, steroids). Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 to 5 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. RASMUSSEN S ENCEPHALITIS Clinical Description Rasmussen s 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 C impairment. Outcome is uniformly poor. Surgical resection of the affected hemisphere is viewed as the mainstay of therapy but has significant morbidity. Evidence that Rasmussen s encephalitis has an autoimmune basis stems from pathologic 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 Rasmussen s. Circulating antibodies directed against the glutamate receptor 2 (GLUR2) in Rasmussen s syndrome have also been reported, although their pathologic significance is debated. Evidence Summary The bappropriateness of IVIGQ Evidence Review identified 1 case series and 4 case reports of IVIG use for Rasmussen s encephalitis. Overall, 31% (5/16) of patients showed marked improvement in symptoms after IVIG alone or in combination with additional therapies (Table 29). Interpretation and Consensus The rationale for use of IVIG is based on the premise of an infectious or peri-infectious etiology for Rasmussen s encephalitis and the possibility of circulating GLUR2 antibodies. The expert panel agreed that, although the available evidence is quite limited, it does suggest IVIG may be of transient benefit for some patients with Rasmussen s 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 Rasmussen s 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 Intravenous immune globulin may be an option as a short-term, temporizing measure for patients with Rasmussen s encephalitis.

46 S102 FEASBY ET AL Intravenous immune globulin is not recommended for long-term therapy for Rasmussen s encephalitis as surgical treatment is the current standard of care. Dose and Duration Based on consensus by the expert panel, a total dose of 2 g/kg given over 2 to 5 days for adults and over 2 days for children is a reasonable option. 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 antiglutamic 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 bappropriateness of IVIGQ 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 with placebo on improvements in both mean stiffness scores ( P =.01) and mean sensitivity scores ( P =.03). A carryover treatment effect of IVIG was identified with patients who received IVIG first maintaining improvements in stiffness during the 1-month washout period and into the placebo phase ( P b.001) (Table 30). Interpretation and Consensus The available evidence, although limited to 1 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 of 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. Recommendation Intravenous immune globulin 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 2 to 5 days for adults and over 2 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. 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. 5 A draft of this practice guideline, along with an accompanying letter of explanation and feedback survey, was ed 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 3 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). A total of 10 respondents completed the entire external review survey, 16 respondents completed some items on the survey, and 1 respondent provided written comments only. For all of the conditions surveyed, most respondents either

47 USE OF IVIG FOR NEUROLOGIC CONDITIO S103 agreed or strongly agreed with the draft guideline s recommendations for use of IVIG. Approximately 90% (11/12) of respondents indicated that the guidelines 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 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 most 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, GBS, ADEM, PANDAS, ALD, and Rasmussen s 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 are insufficient data available to support the use of IVIG for Rasmussen s encephalitis. Although 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 Rasmussen s 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). As discussed above, the expert panel discussed and agreed that although the results had not been published and this information was not available at the time of external review of the guidelines, the PRIVIG trial was included in the guideline at this point as this is the largest trial that has examined IVIG for the treatment of relapsing-remitting MS. 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 NAC 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. REFERENCES 1. Pierce LR, Jain N: Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 17: , Chalmers Research Institute. IVIG systematic reviews. Unpublished 3. Feasby TE. Appropriateness of IVIG Hematology summaries. Unpublished 4. Phillips B, Ball C, Sackett D, et al: Levels of evidence Browman GP, Newman TE, Mohide EA, et al: Progress of clinical oncology guidelines development using the practice guidelines development cycle: The role of practitioner feedback. J Clin Oncol 16: , Andersen JB, Rasmussen LH, Herning M, et al: Dramatic improvement of severe acute disseminated encephalomyelitis after treatment with intravenous immunoglobulin in a three-year-old boy. Dev Med Child Neurol 43: , Assa A, Watemberg N, Bujanover Y, et al: Demyelinative brainstem encephalitis responsive to intravenous immunoglobulin therapy. Pediatrics 104: , Balestri P, Grosso S, Acquaviva A, et al: Plasmapheresis in a child affected by acute disseminated encephalomyelitis. Brain Dev 22: , Jaing TH, Lin KL, Chiu CH, et al: Acute disseminated encephalomyelitis in autoimmune hemolytic anemia. Pediatric Neurology 24: , Kleiman M, Brunquell P: Acute disseminated encephalomyelitis: Response to intravenous immunoglobulin. J Child Neurol 10: , 1995

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