guidelines on the use of intravenous immune globulin for ......polyneuropathy, inclusion body,...

Guidelines on the Use of Intravenous Immune Globulin forNeurologic 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 con-

vened 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 recom-

mendations 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 recommenda-

tions 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 neurolo-

gists in Canada for feedback. The results of this

Transfusion Medicine Reviews, Vol 21, No 2, Suppl 1 (April), 2007:

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 inflammato-

ry demyelinating polyneuropathy, dermatomyositis,

diabetic neuropathy, Guillain-Barre syndrome, Lam-

bert-Eaton myasthenic syndrome, multifocal motor

neuropathy, multiple sclerosis, myasthenia gravis,

opsoclonus-myoclonus, pediatric autoimmune neuro-

psychiatric disorders associated with streptococcal

infections, polymyositis, Rasmussen’s encephalitis,

and stiff person syndrome; IVIG was not recommen-

ded 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.

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. E-mail: [email protected]

0887-7963/07/$ - see front matter

n 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.tmrv.2007.01.002

DESCRIPTION OF INTRAVENOUS IMMUNEGLOBULIN

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

10000 or more donors. Intravenous immune

globulin was first introduced in the early 1980s

for the treatment of primary humoral immunode-

ficiencies and is currently licensed by Health

Canada for treatment of primary and secondary

immunodeficiency diseases, allogenic bone mar-

row 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-labelQindications, 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 applica-

tions 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

pp S57-S107 S57

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 $2200

1 � monthly for 1 y $6600 $13200 $26400

1 � 3 wk for 1 y $9350 $18700 $37400

70-kg adult 1 dose $2000 $4000 $8000

1 � monthly for 1 y $24000 $48000 $96000

1 � 3 wk for 1 y $34000 $68000 $136000

4Cost of IVIG alone does not include costs associated with administration of IVIG. All costs are in Canadian dollars.

FEASBY ET ALS58

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 proprie-

tary differences in the manufacturing methods.

A recent review by Pierce and Jain1 found that a

significant number of IVIG-associated serious

adverse events affecting renal, cardiovascular,

central nervous, integumentary, and hematologic

systems have been reported. In view of the

seriousness of potential adverse events and current

lack of data surrounding their frequency, the

review concluded that clinicians should limit their

prescription of IVIG to conditions for which

efficacy is supported by adequate and well-

controlled clinical trials.

The risk of infectious complications from IVIG

is extremely low. The requirements for donor

screening and transmissible disease testing of

input plasma are stringent. In addition, the IVIG

manufacturing process itself includes at least 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 transfu-

sion. 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 repre-

sents the single largest component (approximate-

ly 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 manufac-

tured 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 manufac-

turers, 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 prov-

ince/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).

Table 2. Members of the Expert Panel

Clinical experts

Dr Brenda Banwell Director, Paediatric Multiple Sclerosis Clinic, Hospital for Sick Children, Toronto

Dr Timothy Benstead Division of Neurology, Queen Elizabeth II Health Sciences Centre, Halifax

Dr Vera Bril Division of Neurology, Toronto General Hospital, Toronto

Dr Tom Feasby Division of Neurology, Department of Medicine, University of Alberta, Edmonton

Dr Mark Freedman Division of Neurology, Ottawa General Hospital, Ottawa

Dr Angelika Hahn Clinical Neurological Sciences, London Health Sciences, London

NAC representatives

Dr Heather Hume Executive Medical Director, Transfusion Medicine, Canadian Blood Services, Ottawa

Dr John Freedman Director, Transfusion Medicine, St Michael’s Hospital, Toronto

Dr David Pi Director, Provincial Blood Coordinating Office, St Paul’s Hospital, Vancouver

Dr Louis Wadsworth Program Head, Hematopathology, Children’s & Women’s Health Centre of BC, Vancouver

Practice guidelines expert

Dr Melissa Brouwers Director, Program in Evidence-Based Care, Cancer Care Ontario, Assistant Professor, McMaster

University, Hamilton

USE OF IVIG FOR NEUROLOGIC CONDITIONS S59

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

Clinical conditions

Acute disseminated

encephalomyelitis

Lambert-Eaton myosthenic

syndrome

Adrenoleukodystrophy Multiple motor neuropathy

Amyotrophic lateral sclerosis Multiple sclerosis

Autism Myasthenia gravis

Chronic inflammatory

demyelinating

polyradiculoneouropathy

Opsoclonus-myoclonus

Critical illness polyneuropathy

Paraproteinemic neuropathy

Dermatomyositis

PANDAS

Diabetic neuropathy

POEMS syndrome

Polymyositis

Guillain-Barre syndrome

Rasmussen’s encephalitis

Inclusion body myositis

Stiff person syndrome

Intractable childhood epilepsy

Abbreviations: PANDAS, pediatric autoimmune neuropsychi-

atric disorders associated with streptococcal infections;

POEMS, polyneuropathy, organomegaly, endocrinopathy,

M protein, skin changes.

evidence-based approach to the practice of medi-

cine. Canadian Blood Services convened a national

consensus conference, entitled: bPrescribing Intra-

venous Immune Globulin: Prioritizing Use and

Optimizing Practice,Q in Toronto in October 2000.

British Columbia implemented an IVIG use man-

agement 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 under-

took 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 guide-

line developed by this process will provide the

NAC with a basis for making recommendations to

provincial and territorial health ministries regard-

ing IVIG utilization management. The practice

guideline will also be widely circulated to

clinicians in Canada.

Table 5. Levels of Evidence

Level 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

FEASBY ET ALS60

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, 2004. 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

encephalomyelitis

U

Adrenoleukodystrophy U

Amyotrophic lateral

sclerosis

U

Autism U


demyelinating

polyradiculoneuropathy

U U

Critical illness

polyneuropathy

U

Dermatomyositis U U

Diabetic neuropathy U

Guillain-Barre syndrome U U

Inclusion body myositis U U

Intractable

childhood epilepsy

U

Lambert-Eaton

myasthenic syndrome

U

Multiple motor

neuropathy

U U

Multiple sclerosis U U U

Myasthenia gravis U U

Opsoclonus-myoclonus U

PANDAS U

Paraproteinemic

neuropathy

(IgM variant)

U

POEMS syndrome U

Polymyositis U U

Rasmussen’s

encephalitis

U

Stiff person

syndrome

U

Abbreviations: SR, systematic review; PANDAS, pediatric

autoimmune neuropsychiatric disorders associated with strep-

tococcal infections; POEMS, polyneuropathy, organomegaly,

endocrinopathy, M protein, skin changes.

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.

Clinical Conditions

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 Re-

search Institute, University of Ottawa2

a. Sources searched: Medline; Embase;

current contents; PreMedline; disserta-

tion abstracts; CENTRAL (Cochrane

Library’s controlled clinical trials regis-

try); plus manual searching of relevant

journals, reference lists, and unpub-

lished sources.

b. Dates searched: 1966 to 2004

2. The bAppropriateness of IVIGQ evidence

review conducted by Feasby3 as part of

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 Co-

chrane Library, and reference lists of

relevant publications.

b. Publication dates searched: not reported

Members of the expert panel were also encour-

aged to identify any additional studies relevant to

the development of evidence-based recommenda-

tions. 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 recogni-

tion and discussion of factors influencing the

decision-making process. The expert panel eval-

uated 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 ther-

apies. 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 systemati-

cally factored into the discussions and the recom-

mendations 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 e-mailed to members of the Canadian

Neurological Society. Practitioners were given the

option of faxing their completed survey or provid-

ing 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 (CNS) 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 diagno-

sis includes other inflammatory demyelinating

disorders such as multiple sclerosis (MS), optic

neuritis, and transverse myelitis.

Although most patients with ADEM experi-

ence a monophasic course, occasional patients

may experience recurrence of the initial symp-

toms (relapsing ADEM) or may experience a

second episode of ADEM (multiphasic ADEM).

Table 7. Pediatric Acute Disseminated Encephalomyelitis (ADEM) IVIG Studies

Study Design No. of patients

Prior steroid

treatment Intervention Response4

Monophasic ADEM

Anderson et al6 Case report 1 Yes IVIG + steroids Complete response

Assa et al7 Case reports 2 No IVIG Complete response:

50% (1/2)

Partial response:

50% (1/2)

Balestri et al8 Case report 1 Yes IVIG Partial response

Jaing et al9 Case report 1 No IVIG Complete response

Kleiman and Brunquell10 Case report 1 No IVIG Complete response

Nishikawa et al11 Case reports 3 No IVIG Complete response:

100% (3/3)

Pradhan et al12 Case reports 4 Yes IVIG Complete response:

75% (3/4)

Partial response:

25% (1/4)

Shahar et al13 Case reports 16 Yes (1 case) IVIG or steroids or

IVIG + steroidsyIVIG: 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 al14 Case report 1 No IVIG + steroids Complete response

Relapsing ADEM

Apak et al15 Case report 1 Yes IVIG Partial response

Hahn et al16 Case report 1 Yes IVIG Complete response

(maintained with

monthly IVIG)

Mariotti et al17 Case report 1 Yes IVIG + steroids Partial response

(maintained with

monthly IVIG)

Pittock et al18 Case report 1 Yes IVIG Partial response

(no relapses after IVIG)

Revel-Vilk et al19 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.

FEASBY ET ALS62

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 deter-

mined 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 com-

pletely over a period of 4 to 6 weeks from onset of

symptoms.

Evidence Summary

The bAppropriateness of IVIGQ evidence reviewidentified 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%

Table 8. Adult Acute Disseminated Encephalomyelitis (ADEM) IVIG Studies

Study Design No. of patients Prior steroid treatment Intervention Response4

Monophasic ADEM

Finsterer et al20 Case report 1 No IVIG No response

Fox et al21y Case report 1 No IVIG Complete response

Marchioni et al22 Case reports 3 Yes IVIG Complete response: 33% (1/3)

Partial response: 67% (2/3)

Nakamura et al23 Case report 1 Yes IVIG Partial response

Sahlas et al24 Case reports 2 Yes IVIG Complete response: 100% (2/2)

Relapsing ADEM

Marchioni et al22 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


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 re-

ported, 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 contra-

indications, to steroids.

Recommendations

Intravenous immune globulin is recommended

as an option for treatment of monophasic ADEM

when first-line therapy with high-dose cortico-

steroids 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


Adrenoleukodystrophy (ALD) is an X-linked

inherited disorder of peroxisomal metabolism that

produces progressive CNS degeneration associat-

ed with CNS 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, predom-

inantly, 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

Table 9. Adrenoleukodystrophy IVIG Studies

Study Design No. of patients Intervention Outcome P

Cappa et al26 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

NS

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

NS

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.

FEASBY ET ALS64

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 CNS.25

Evidence Summary

bThe Appropriateness of IVIGQ evidence reviewidentified 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

Table 10. Amyotrophic Latera

Study Design No. of patients

Meucci et al27 Case series 7 IVIG +

Dalakas et al28 Case series 9

Abbreviation: MVIC, maximum voluntary isometric contraction.

4MRC scale: Muscle strength on 10 muscles per limb.

yModified Rankin scale: range 0 (asymptomatic) to 5 (severely disab

zBulbar function scale: range 1 (normal) to 5 (tube feeding or unabl

§MVIC mega scores: sum of MVIC scores from 5 individual muscle

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).


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.

l Sclerosis IVIG Studies

Intervention Outcome

cyclophosphamide Muscle strength A in all cases

as measured by the MRC4 scale

Rankiny and/or bulbarfunctionz scoresworsened in all patients

No improvement in

rate of disease progression

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

led, totally dependent, requiring constant attention).

e to speak or both).

groups in 2 limbs.

Table 11. Autism IVIG Studies

Study Design and participants No. of patients Intervention Outcome

Gupta et al29 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

et al30Case series 7 IVIG After 6 mo:

No immunologic testing No significant change on any of the

behavioral measures compared with baseline

Plioplys31 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 recommen-

ded for the treatment of ALD.

AMYOTROPHIC LATERAL SCLEROSIS


Amyotrophic lateral sclerosis (ALS) is a neuro-

degenerative disorder of the upper and lower motor

neurons leading to progressive weakness, disabil-

ity, and death. Sporadic ALS has an annual

incidence of 1 to 2 per 100000 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 be-

ginning in an arm, leg, or the bulbar muscles. Other

presenting symptoms include muscle cramps,

weight loss, fasciculations, neck and truncal weak-

ness, 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-threaten-

ing, 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 muscu-

lar atrophy, lymphoma-related motor neuronop-

athy, progressive postpolio muscular atrophy),

myelopathies (foramen magnum tumors, cervical

spondylitic myelopathy, syringomyelia, multiple

sclerosis), radiculopathies, neuropathies (multifo-

cal motor neuropathy with conduction block,

chronic inflammatory demyelinating polyneurop-

athy), myopathies (inflammatory myopathy, isolat-

ed neck extensor weakness, oculopharyngeal

dystrophy), and endocrinopathies (hyperparathy-

roidism, 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 superox-

ide 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.

Table 12. Chronic Inflammatory Demyelinating Polyneuropathy IVIG Studies

Study Design

No. of

patients Intervention Outcome P

Van Schaik et al32 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, 1.74-5.75; fixed); NNT: 3 .0002

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, 1.02-6.01; fixed) .05

Dyck et al33 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

NS

Hahn et al33 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 al39 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

NS

Mean change in MRC sum

score and modified Rankin score (6 wk):


between IVIG and oral prednisone

NS

Mendell et al34 RCT 53 IVIG vs placebo Significant improvement in

muscle strength (AMS) with IVIG at d 42:

AMS mean difference

(IVIG � placebo): 0.72 F 0.25

.006

% 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

conduction with IVIG

.003

Significant improvement in peroneal NCV .03

Thompson et al35 Crossover RCT 7 IVIG vs placebo Mean change in MRC sum scores at 2 wk:

No statistically significant

difference between groups

NS

FEASBY ET ALS66

Vermeulen et al36 RCT 28 IVIG vs placebo % of Patients with improvement

z1 point on Rankin scale by d 21:

No significant difference between groups NS

No significant difference in change

in mean MRC sum score, CMAP,

or nerve conduction velocity

between groups

NS

Van Doorn et al37 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


groups in Dmean CMAP or NCV

NS

Kubori et al40 RCT 62 IVIG (0.05 g/kg per

d � 5 d) vs IVIG

(0.2 g/kg per

d � 5 d) vs IVIG

(0.4 g/kg

per d � 5 d)

% of patients with improvement

z1 grade on disability scale (at 5 wk):

IVIG(0.4 g/kg) significantly higher than

IVIG(0.05 g/kg) or IVIG(0.2 g/kg)

.004

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 al35 and Vermeulen et al36;

meta-analysis of modified Rankin scores included: Mendell et al,34 Thompson et al35 and Vermeulen et al.36

yVan Schaik et al32 converted different disability scale scores used in each trial to modified Rankin scores.

Table 12 (continued)

Study Design

No. of



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 reviewidentified 2 case series that examined the use of

IVIG for ALS (level of evidence: 4). No improve-

ment in muscle strength or slowing of the rate of

disease progression was observed in either case

series (Table 10).


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


ded for the treatment of ALS.

AUTISM


Autism is a neurodevelopmental disorder char-

acterized by severe deficits in social and commu-

nicative 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 disor-

der is approximately 5 per 10000 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

FEASBY ET ALS68

and that there exists a higher-than-normal preva-

lence 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 reviewidentified 3 case series of IVIG use for autism (level

of evidence: 4).29-31 In the case series by Gupta

et al,29 10 patients with abnormal immune param-

eters received IVIG monthly. After 6 months, 50%

(5/10) of patients showed marked improvement in

several autistic characteristics. The series by Plio-

plys31 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).


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 infu-

sion, such improvement can occur as part of the

natural history of autism and in children receiving

intensive psychological and developmental thera-

pies. The panel noted the pathobiologic rationale

for use of IVIG in autism is very limited. Immuno-

logic 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


ded for the treatment of autism.

CHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY


Chronic inflammatory demyelinating poly-

neuropathy (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 propriocep-

tion, 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

100000. Chronic inflammatory demyelinating pol-

yneuropathy 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 progres-

sive. 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 demy-

elination, as well as the characteristic increase in

cerebrospinal fluid protein and a lymphocyte count

of less than 10/mm3. A nerve biopsy is no longer

mandatory for the diagnosis because one can infer

the demyelinating pathology from the electrophys-

iologic 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, cyclo-

sporin, mycophenoate mofetil, entarecept, have

occasionally been prescribed for refractory or

unstable CIDP in open-label treatment with vari-

able 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 reviewidentified a Cochrane systematic review with meta-

analysis of IVIG use for CIDP (level of evidence:

1a). A systematic review by the Chalmers Research

Institute on this topic included 8 randomized

Table 13. Critical Illness Polyneuropathy IVIG Studies


Mohr et al41 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 al42 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 al32

included 4 randomized trials of IVIG vs pla-

cebo33-36 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}, 1.74-5.75; 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 treat-

ment 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 al39 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 al40 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.


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 short-

term treatment of CIDP. Nonetheless, IVIG is often

chosen as the preferred initial therapy.

No evidence is available to support or refute

long-term (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 globu-

lin 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

Table 14. Dermatomyositis IVIG Studies

Study

Design and

participants No. of patients Intervention Outcome P

Dermatomyositis

Al-Mayouf et al44 Retrospective

review

18 IVIG F steroids F

other therapies4

67% (12/18) Improved

with IVIG, allowed

steroid dose A N50%

N/A

Children 33% (6/18) Remained

steroid-dependent

Dalakas et al43 Crossover RCT 15 IVIG + steroids vs

placebo + steroids

At 3 mo, mean modified

MRCy and NSS scores

significantly higher in

IVIG group vs placebo.

Adults Mean modified MRCy:IVIG, 84.6 F 4.6 vs

placebo, 78.6 F 8.2

.018

Mean NSS: IVIG,

51.4 F 6.0 vs

placebo, 45.7 F 11.3

.035

Sansome and

Dubowitz45Case series 9 IVIG + steroids F

other therapieszSignificant improvement

in mean myometry

score with IVIG

NR in SR

Children 100% (9/9) Clinical

improvement with IVIG

75% (6/8) of patients

on steroids were able

to A steroid dose

Tsai et al46 Case series 7 IVIG + other

therapies4

72% (5/7) Clinical

improvement with

IVIG, A steroid dose

N/A

Children 14% (1/7) Transient

clinical improvement

with IVIG

14% (1/7) No improvement

with IVIG

Dermatomyositis or polymyositis

Danieli et al47 Non-RCT 20 Steroids + CSA or

IVIG + Steroids +

CSA or IVIG +

PLEX +

steroids + CSA


in CR4 between

groups at 1 y

NS

New onset,

relapsed or

tx refractory

At 4 y:

Significantly more patients

given IVIG + steroids +

CSA maintained complete

remission compared with

steroids + CSA.

.001


between IVIG + steroids +

CSA and IVIG + PLEX +

steroids + CSA groups

NS

Cherin and

Herson48Case series 35 IVIG F steroids F

other txzSignificant improvement

in muscle power:

tx refractory Mean muscle power4:

baseline 46.5 F 11.5;

post IVIG 67.1 F 15.4

.01

Significant reduction in

mean steroid dose (mg/d)

.05

Significant A in CK levels .01

FEASBY ET ALS70

Study

Design and

participants No. of patients Intervention Outcome P

Cherin et al49 Case series 11 IVIG No significant

improvement in

mean muscle

powery frombaseline

NS

No previous tx Only 27% (3/11) had

significant clinical

improvement

.01

Significant improvement

in mean CK levels

Abbreviations: CSA, cyclosporine A; tx, treatment; NSS, 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


as an option for the short-term management of

new-onset CIDP or CIDP relapses.


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


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 mini-

mum 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


Critical illness polyneuropathy (CIP) can devel-

op in patients with multiorgan failure and sepsis.

This is an axonal sensorimotor neuropathy associ-

ated with flaccid paralysis and respiratory weak-

ness. 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 neuro-

muscular 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 reviewidentified 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 Gram-

negative sepsis found none of the patients (0/8)

who received IVIG within 24 hours of sepsis being

diagnosed developed CIP. Conversely, 88% (7/8)

patients not treated with IVIG developed CIP.41 No

benefit of IVIG for treatment of established CIP

was observed in the case series42 (Table 13).


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.

Table 15. Diabetic Neuropathy IVIG Studies

Study Design and participants No. of patients Intervention Outcome P

Sharma et al50 Case series 26 IVIG Significant improvement

in lower limb motor

function at 4 wk

.01

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

.001


with Canadian Blood Services had improved

NIS scores with IVIG

(11/11) vs patients

without Canadian Blood Services (10/15).

.03

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

N/A

Cocito et al51 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

.008

No improvement in

motor or sensory deficits

NS

Significant A in demyelinating

subscore on nerve

conduction study at

6 mo compared

with baseline

.03

Zochodne et al54 Case series 3 IVIG IVIG treatment did

not prevent (1 case) or

halt progression (2 cases)

of severe diabetic

lumbosacral plexopathy.

N/A

Diabetic

lumbosacral

plexopathy

Jaradeh et al52 Case series 15 IVIG F steroids or

PLEX F steroids

At 1 y, all patients showed

clinical improvement,

and the mean change

in weakness NDSW

scores of 29.1 F 9.3

was significant.

.01

Rapidly progressing

polyradiculo-

neuropathy


between IVIG

(6 patients) vs

PLEX (9 patients)

NS

Krendel et al53 Case series 15 IVIG F steroids F

other txy100% (15/15) of patients

had improvement

in symptoms after

IVIG F additional therapies.

Progressive

peripheral

neuropathy

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.

FEASBY ET ALS72


Recommendation


ded for the treatment of CIP.

DERMATOMYOSITIS


Dermatomyositis can occur in both adults and

children. In children, dermatomyositis is the most

common inflammatory myopathy. Rash is associ-

ated 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 weak-

ness can range from very mild to very severe.

Serum creatine kinase (CK) is frequently elevat-

ed 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 perivas-

cular 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 derma-

tomyositis are not at increased risk for malignancy.

Dermatomyositis will usually respond to steroids

or immune suppressing medication.

Evidence Summary

The bAppropriateness of IVIGQ evidence reviewidentified 1 randomized controlled trial, 1 non-

randomized 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 al43 compared IVIG plus prednisone to placebo

plus prednisone for treatment of adult dermato-

myositis. At 3 months, patients randomized to

IVIG plus prednisone showed significant improve-

ment, 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.44-46 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 poly-

myositis.47-49 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.


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 cortico-

steroids, 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 conjunc-

tion 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, patho-

logic confirmation by means of a skeletal muscle

biopsy is required for the diagnosis of dermato-

myositis. It is critical that the muscle specimen be

procured, processed, and interpreted in a laboratory

familiar with the correct handling of muscle biopsy

specimens (including electron microscopy) and that

Table 16. Guillain-Barre Syndrome IVIG Studies

Study

Design and

participants

No. of


Hughes et al59 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, �0.26to 0.19; fixed)

NS

Bril et al55 RCT 50 IVIG vs PLEX No significant difference

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

NS

Adults

Diener et al56 RCT 76 IVIG vs

PLEX vs IAD


in mean time to improve

z1 DG, % of patients who


mean time to reach DG-1,

duration of intubation or

hospitalization between the groups

NS

Adults

El Zunni et al63 Non-RCT 16 IVIG vs steroids vs

placebo

Mean time to improve z1 DG:

Adults IVIG significantly shorter

than steroids or placebo

NR


groups in % of patients who

improved by z1 DG at 1 mo

NS

Gurses et al64 RCT

Children

18 IVIG vs

No treatment

Time from maximum weakness

to improvement and duration of

hospitalization were significantly

shorter with IVIG than no treatment.

.05


groups in duration of

mechanical ventilation

NS

Haupt et al66 Non-RCT 45 IAD + IVIG vs

IAD vs PLEX

Mean change in DG at 4 wk:

Adults IAD + IVIG significantly better

than combined IAD

and PLEXy groups

.02

Mean change in DG at 6

and 12-mo follow-up:

IAD + IVIG vs combined

IAD + PLEX not

significantly different

NS

Hosokawa et al61 Non-RCT 10 IVIG vs PLEX At 1 mo, no significant


in % of patients with

improvement in MRC sum

scores or mean DMRC sum scores

NS

Adults

Martinez et al62 Non-RCT 24 IVIG vs PLEX Mean change in DG at 1 mo:

Adults IVIG significantly better than PLEX .0012

Mean duration of hospitalization

was significantly shorter with IVIG

.0065

Nomura et al59 RCT 47 IVIG vs PLEX No significant difference between

groups in % of patients who


change in DG at 4 wk, time to

improve 1 DG, and time to

improve 2 DG.

NS

Adults

FEASBY ET ALS74


Study

Design and

participants

No. of


PSGBS group68 RCT 379 IVIG vs PLEX vs

PLEX Y IVIG


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

NS

Adults

Raphael et al68a RCT 39 IVIG 0.4 g/kg

per d � 3d vs

IVIG 0.4 g/kg

per d � 6 d

Time to regain ability to

walk with aid (DG-3):

Adults Overall: No significant


NS

Ventilated patients:

IVIG(6 d) significantly

shorter than IVIG(3 d)

.04


in % of patients

who improved by

z1 DG at 4 wk,

duration of intubation,

or mortality rate

at 1 y between groups

NS

van der Meche

and Schmitz67RCT 150 IVIG vs PLEX % of patients who improved

by z1 DG at 4 wk:

Adults + children IVIG significantly

higher than PLEX

.024

Mean time to improve by

z1 DG significantly

shorter with IVIG

.05

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 al59 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


Based on consensus by the expert panel, use of

IVIG for the treatment for patients with dermato-

myositis should be made in consultation with an

expert in neuromuscular disease.


ded as monotherapy for dermatomyositis.


as an option, in combination with other agents,

for patients with dermatomyositis who have not

adequately responded to other immunosuppres-

sive therapies.

Intravenous immune globulin is recommended,

in combination with other agents, as a steroid-

sparing option for patients with dermatomyositis.

Based on consensus by the expert panel, IVIGmay

be considered in conjunction with other agents for

treatment of severe, life-threatening dermatomyositis.

Dose and Duration


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

Table 17. Inclusion Body Myositis IVIG Studies


Dalakas et al68 Crossover, RCT,

double blind

19 IVIG vs placebo No significant difference

between groups in mean

change in MRC

scores at 3 or 7 mo

NS



MVIC at 7 mo

NS

Swallowing improved

significantly with

IVIG compared

with placebo

.05

Dalakas et al68a 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

NS

Walter et al67 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

NS

Significant

improvement in

NSS with IVIG vs

placebo at 6 mo

.05

Self-rated muscle

weakness not


between groups

NS

FEASBY ET ALS76

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 polyradicu-

loneuropathy, 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 capac-

ity to improve over long periods. Perivascular

inflammation in the proximal lower limb neuropa-

thies 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 reviewidentified 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 improve-

ment in neurologic function as measured by

the Neurologic Impairment Scale at 4 weeks

(P b .001). The series by Cocito et al51 found no

significant improvement in either motor or sensory

deficits after IVIG. There was, however, signifi-

cant improvement in both mean Rankin score

(P = .008) and indicators of demyelination on

nerve conduction studies (P = .03) at 6-month

follow-up.

Table 18. Intractable Childhood Epilepsy IVIG Studies


Van Rijckevorsel-

Harmant et al69RCT 61 IVIG 100 mg/kg vs

IVIG 250 mg/kg vs

IVIG 400 mg/kg vs

placebo


between IVIG groups

NS

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)

NS

Partial epilepsy4: IVIG(all groups),

56% (19/34) vs placebo, 17% (2/12)

.041

Illum et al70 Crossover, RCT 10 IVIG vs placeboy 20% (2/10) A seizure frequency,

improved EEG and general

condition (both patients had

high frequency, invariable seizures)

NR

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.


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 neuropa-

thies given IVIG with or without additional anti-

inflammatory 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



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 re-

quired 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, mononeurop-

athy, 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


ded for treatment of diabetic polyneuropathy, mono-

neuropathy, or proximal lower limb neuropathy.


use for patients with diabetes who have evidence

of a CIDP phenotype should follow the recom-

mendations outlined in the CIDP section of

this guideline.

GUILLAIN-BARRE SYNDROME


Guillain-Barre syndrome (GBS) is the most

common cause of acute flaccid paralysis, with an

annual incidence of 2 per 100000. 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

Table 19. Lambert-Eaton Myasthenic Syndrome IVIG Studies


Bain et al71 Crossover, RCT 9 IVIG vs placebo4 Significant improvement

in limb strength with

IVIG vs placebo

.038


in vital lung capacity

with IVIG vs placebo

.028


in bulbar muscle strength

(as measured by drinking

time) with IVIG vs placebo

.017

4Crossover after 8-week washout period.

FEASBY ET ALS78

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 hospitali-

zation, the prognosis of GBS is favorable, with a

return to almost normal function in about 85%

of patients.

Guillain-Barre syndrome, the prototype of a

postinfectious autoimmune disease, is commonly

triggered by a preceding bacterial or viral infection.

Case-control studies confirm the clinical impres-

sion 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 path-

ogen. Infections caused by cytomegalovirus,

Epstein-Barr virus, Varicella-zoster virus, Myco-

plasma 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 neurop-

athy 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 fulmi-

nant onset and usually poorer prognosis. Miller-

Fisher syndrome, characterized clinically by oph-

thalmoplegia, 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 reviewidentified a Cochrane systematic review with meta-

analysis of IVIG for GBS (level of evidence: 1a).

In addition, a systematic review by the Chalmers

Research Institute on this topic included 6 ran-

domized controlled trials and 4 nonrandomized

controlled trials. Most of the trials evaluated IVIG

against PLEX, an established treatment of GBS.

Five trials55-59 that compared IVIG with PLEX

were included in the Cochrane review’s meta-

analysis by Hughes et al60 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

[NS]). 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

Table 20. Multifocal Motor Neuropathy IVIG Studies

Study Design and participants

No. of


van Schaik et al72 Systematic review

with meta-analysis

IVIG vs placebo No significant

difference in

proportion of patients with


in disability scores

between IVIG and placebo:

Meta-analysis included: – RR, 3.00 (95% CI,

0.89-10.12; fixed)

NS

3 trials4 for disability

Significantly greater

proportion of patients

had significant improvement in

muscle strength

with IVIG vs placebo:

3 trialsy for muscle strength

RR, 11.00 (95% CI,

2.86-42.25; fixed)

.0005

All 4 for conduction blocks

2 trialsz for side effects


in proportion of patients

with resolution of

z1 Canadian Blood Services

between IVIG and placebo:

RR, 7.00 (95% CI,

0.95-51.70; fixed)

NS

Significantly greater

proportion of patients

had side effects with IVIG:

RR, 10.33 (95% CI,

2.15-49.77; fixed],

P = .004

.004

Azulay et al73 Crossover, RCT 5 IVIG vs placebo Significant z in

isometric strength

with IVIG at d 28

.05


in % D in strength at

2 mo follow-up

NS

Federico et al74 Crossover, RCT 16 IVIG vs placebo Significant improvement

in NDS scores

with IVIG at d 28

.038

Significant z in grip

strength with IVIG at d 28

.0021


in Canadian Blood Services

with IVIG

.037

Leger et al75 Crossover, RCT 19 IVIG vs placebo At 4 mo, no significant


in change in MRC scores

or severity of Canadian

Blood Services

NS

Self-evaluation scores§ improved

significantly with IVIG

.05

Van den

Berg et al76Crossover RCT 6 IVIG vs placebo 83% (5/6) responded to IVIG

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 al73 and Federico et al.74

§Patients rated ability to perform 5 motor activities of daily life.


Table 21. Multiple Sclerosis IVIG Studies


Relapsing-remitting MS

Chalmers group

(unpublished)

Systematic review

with meta-analysis4

– IVIG vs placebo Significant improvement in mean

DEDSS with IVIG vs placebo:

Weighted mean difference: �0.39(95% CI, -0.55 to 0.23; random)

.001

Sorensen et al78 Systematic review

with meta-analysesy– IVIG vs placebo Significant improvement in mean

DEDSS with IVIG vs placebo:

Effect size: �0.24 (95% CI,

�0.46 to �0.01); NNT: 4.042

Annual relapse rate significantly

lower with IVIG vs placebo:

Effect size: �0.50 (95% CI,

-0.73 to -0.27); NNT: 2

.00003

Proportion of relapse-free

patients significantly

z with IVIG vs placebo:

Effect size: 0.29 (95% CI,

0.18- 0.39); NNT: 3

2.1 �10�8

Achiron et al84 RCT 36 IVIG vs

no treatment

Mean annual relapse rate, % of

patients with relapses, % of

severe relapses significantly lower

with IVIG vs no treatment

.001


groups in mean change in EDSS

score or % of patients who

improved z1 EDSS grade

NS

Achiron et al79 RCT 40 IVIG vs placebo Mean annual relapse rate significantly

lower with IVIG than placebo

.0002

% of relapse-free patients at 2 y

( P = .001) and mean time to

first relapse ( P = .003)

significantly z with IVIG

–


between groups in mean D

in EDSS at 2 y

NS

Fazekas et al80 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

.03

Significant improvement in

mean DEDSS with

IVIG vs placebo

.008



time to first relapse

NS

Lewanska et al81 RCT 49 IVIG 0.4 g/kg vs

IVIG 0.2 g/kg vs

placebo

Mean annual relapse rate at 1 y:


between IVIG groups

NS

Combined IVIG groups

significantly lower than placebo

.01

Mean change in EDSS score at 1 y:


between IVIG groups

NS

Combined IVIG groups


compared with placebo

.003

FEASBY ET ALS80



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

NS

Teksam et al85 RCT 13 IVIG vs placebo No between group

comparisons reported

N/A

PRIVIG (2006) RCT 127 IVIG-C 0.2 g/kg vs

IVIG-C 0.4 g/kg vs

placebo

No significant differences

between any of the groups

in the primary outcome

measure, the proportion

relapse-free at 48 mo

NS


groups in terms of any

secondary outcome measure,

either other relapse-related

outcomes or MRI

NS

Secondary progressive MS

Hommes et al86 RCT 318 IVIG vs placebo No significant difference

between groups in time

to EDSS progression,

annual relapse rate,

or change in T2-lesion load

NS

Relapsing-remitting or secondary progressive MS

Noseworthy et al87 RCT 67 IVIG vs placebo At 3 and 6 mo, no significant


in mean change in % of

Normal strength of TND

muscles nor mean DEDSS

NS

Noseworthy et al88z RCT 55 IVIG vs placebo No significant difference


change in visual acuity

or mean change in

EDSS scores at 6 or 12 mo

NS

Sorensen et al83 Crossover, RCT 21 IVIG vs placebo % of Relapse-free patients

significantly higher with

IVIG than placebo

.02


between groups in

no. of relapses or

mean change in

EDSS scores at 15 mo

NS

Relapsing progressive or secondary progressive MS

Poehlau89

[abstract]

RCT 40 IVIG vs placebo No significant difference between

the groups in mean change

in isometric muscle strength

of TND muscles

NS

Subgroup analysis of patients with

relapsing-progressive MS:

IVIG group had significantly fewer

relapses at 1 y than placebo

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 al81

ySorensen meta-analyses included: Achiron et al,77 Fazekas, Sorensen et al,88 and Lewanska et al81

zIncluded patients with episodes of optic neuritis.


Table 22. Myasthenia Gravis IVIG Studies


Adult myasthenia gravis

Gajdos et al90 Systematic review4 147 IVIG vs other

tx or placebo

No meta-analysis

was performed due

to heterogeneity of

interventions and

outcomes assessed.

N/A

Gajdos et al91 RCT 87 IVIG(0.4 g/kg per

d � 3 d) vs IVIG

(0.4 g/kg per

d � 5 d) vs PLEX

Mean change in

MMS at d 15:

MG acute

exacerbation


between IVIG(3 d) vs IVIG(5 d)

NS


between IVIG(combined)

and PLEX

NS

All groups improved

significantly from

baseline at d 2

.02


between groups in median

time to responsey or changein anti- AChR antibody

titer at d 15

NS

Ronager et al92 Crossover RCT 12 IVIG vs PLEX DQMGS at 1

or 4 wk not


between groups

NS

Moderate to

severe MG

Both groups had


in QMGS at 4 wk

.05

% 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

NS

Schuchardt

(unpublished)zRCT 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

NS

MG exacerbation

Wolfe et al93 RCT 15 IVIG vs placebo No significant

difference between

groups at

d 42 in DQMGS,

mean consecutive

difference on single

fiber EMG, % decrement

on repetitive nerve

stimulation, or MG-ADL

NS

Mild-moderate

MG or chronic MG

Achiron et al94 Case series 10 IVIG Significant

improvement in

mean severity of

disease as measured

by the Osserman

scale at 1 y

.001

MG acute

exacerbation

FEASBY ET ALS82



Adult myasthenia gravis

Cosi et al93 Case series

Acute-relapsing MG

37 IVIG At d 60, 57% of patients

improved z1 grade

on the OGCCMS scale.

NR


in response between

patients in acute phase

and patients with

chronic stable MG

NS

Hilkevich et al96 Case series

Chronic, severe MG

11 IVIG Significant mean

improvement on

OGCCMS scale

( P b .00005)

–

All patients showed

improvement on the

OGCCMS scale

Huang et al97 Case series

Chronic, moderate MG


improvement on

functional scale

NR

All patients showed

improvement on the

OGCCMS scale

Wegner and

Ahmed98Case series

Chronic MG


improvement on

functional scale

NR

All patients showed

improvement on the

OGCCMS scale.

Wilson et al99 Case series 38 IVIG Reported adverse

events only; 1 case

of hemolytic anemia

N/A

Juvenile myasthenia gravis

Herman100 Case reports 3 IVIG IVIG temporarily stabilized

all 3 cases

and allowed

thymectomy to

be performed.

N/A

Selcen et al101 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.

NR

Neonatal myasthenia gravis

Tagher et al102 Case report 1 IVIG + neostigmine No improvement with

IVIG plus neostigmine

N/A

Bassan et al103 Case report 1 IVIG + neostigmine Improved with IVIG

plus neostigmine

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 al98 and Schuchardt (unpublished).

yDefined as an increase in MMS score of z20 points.

zAs of August (2005).


FEASBY ET ALS84

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/Sando-

globulin Guillain-Barre 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 differ-

ences 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 al63 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 com-

pared 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, com-

pared with no treatment (P b .05).

One randomized trial evaluated different doses

of IVIG. Raphael et al65 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



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 addi-

tional 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


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.


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



over 2 days for children is a reasonable option.

INCLUSION BODY MYOSITIS


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


serum CK is normal or mildly elevated. Electro-

myography will demonstrate features of a myop-

athy 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, inflam-

matory infiltrates, and rimmed vacuoles with

granular inclusions. Making a pathologic diagno-

sis, 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 reviewidentified 3 randomized controlled trials that

investigated IVIG for IBM (level of evidence:

1b). A systematic review by the Chalmers Re-

search Institute of IVIG for myositis included the

same 3 randomized trials.

Two small randomized crossover trials com-

pared 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 al67

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 contrac-

tion measures between the 2 groups were identified

(Table 17).


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


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 speci-

mens (including electron microscopy) and that the

final interpretation be made by an expert in



ded for the treatment of IBM.

INTRACTABLE CHILDHOOD EPILEPSY


Epilepsies are characterized by recurrent, spon-

taneous and transient paroxysms of electrical

discharges in the brain. Epileptic syndromes are

defined based on seizure type, electroencephalo-

gram (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 CNS 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 reviewidentified 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

Table 23. Adult Opsoclonus-Myoclonus IVIG Studies

Study Design No. of patients Intervention Response

Idiopathic opsoclonus-myoclonus

Bataller et al104 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 Ronthal105 Case report 1 ACTH Y IVIG Monophasic course,

complete recovery

with IVIG

Pranzatelli et al106 Case report 1 ACTH +

steroidsY IVIG

Relapsing course,

partial recovery

with monthly IVIG

Paraneoplastic opsoclonus-myoclonus

Bataller et al104 Retrospective

chart review

4 IVIG 1/4 partial recovery

(IVIG at same time as

antineoplastic therapy)

3/4 no response

to IVIG

Abbreviation: ACTH, adrenocortico trophic hormone.

FEASBY ET ALS86

frequency that were associated with improvements

in EEG findings, cognitive performance, and

general well-being after IVIG70 (Table 18).


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 random-

ized 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

Table 24. Pediatric Opsoclonus

Study Design No. of patients Inte

Idiopathic opsoclonus-myoclonus

Sugie et al107 Case report 1 Steroi

Yiu et al108 Case report 1 ACTH + aza

Penzien et al109 Case report 1 Steroi

Neuroblastoma-associated opsoclonus-myoclonus

Petruzzi and de Alarcon110 Case report 1

Eiris et al111 Case report 1 ACTH

Borgna-Pignatti et al112 Case report 1 IVIG

Fisher et al113 Case report 1 Steroi

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 recom-

mended for the treatment of intractable child-

hood epilepsy.

-Myoclonus IVIG Studies

rvention Response

ds Y IVIG Monophasic course: complete recovery

thioprine + IVIG Monophasic course: transient partial recovery

ds Y IVIG Relapsing course: no response to IVIG

IVIG Complete recovery

Y IVIG Complete recovery

+ ACTH Partial recovery

ds Y IVIG Partial recovery


LAMBERT-EATON MYASTHENIC SYNDROME


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 diagno-

sis includes myasthenia gravis, other disorders of

neuromuscular transmission, myopathies, and pe-

ripheral 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 neuropa-

thy may be present. Bulbar and ocular symptoms are

mild and rare. The weakness may improve tran-

siently 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 paraneo-

plastic cases. Three percent of patients with SCLC

have LEMS. Neurologic symptomsmay 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 presyn-

aptic 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 acetylcho-

line at the neuromuscular junction and at auto-

nomic ganglia resulting in the clinical features of

LEMS. Some patients have an associated paraneo-

plastic cerebellar ataxia and positive antineuronal

antibodies such as anti-Hu.

Paraneoplastic LEMS may improve with appro-

priate 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 symptom-

atic and/or immunomodulatory. Symptomatic

improvement can be achieved with 3,4-diamino-

pyridine, which inhibits the neuronal voltage-gated

K+ ion channel, resulting in increased calcium ion

entry and thus, increased acetylcholine release.

Immunosuppression with corticosteroids, azathio-

prine 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, procai-

namide, quinidine, adrenergic blocking agents,

and lithium should be used cautiously in patients

with LEMS due to adverse effects on neuromuscu-

lar transmission.

Evidence Summary

The bAppropriateness of IVIGQ evidence reviewidentified 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), respira-

tory muscle strength (P = .028), and bulbar muscle

strength (P = .017) after IVIG, compared with

placebo (Table 19).


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 reason-

able 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.

Table 25. Paraproteinemic neuropathy (IgM variant) IVIG Studies

Study Design

No. of


Lunn and

Nobile-Orazio114Systematic 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.

N/A

Comi et al115 Crossover 22 IVIG vs placebo At 2 wk:

RCT Significant improvement

in modified Rankin

scores with IVIG vs placebo

.008


between groups in change in mean

disability score

NS

At 4 wk:

Change in mean overall disability

score significantly A with IVIG vs placebo

.05

Significant improvement in handgrip with

IVIG vs placebo

.05

Dalakas et al116 Crossover RCT 11 IVIG vs placebo Mean change in

modified Rankin score:

NS

IVIG: 9 F 12.7 vs placebo: �1.1 F 8.3

Mariette et al117 Crossover 20 IVIG vs INF-a At 6 mo:

RCT (not blinded) Significant improvement

in mean CNDS with INF-a vs IVIG

.02

CNDS improved N20%:

IVIG 10% (1/10) vs

INF-a 80% (8/10)

.005

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).

FEASBY ET ALS88

Recommendation


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


requiring IVIG maintenance therapy, a system-

atic 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


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 electrophysio-

logic examination. The electrodiagnostic hallmark

of MMN is finding focal conduction blocks in

motor nerves outside regions normally prone to

nerve entrapments. The conduction block corre-

sponds 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 100000. 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. Cerebro-

spinal fluid examination usually reveals normal or

only slightly raised protein content. Magnetic

resonance imaging may show focal areas of high

Table 26. PANDAS IVIG Studies


Perlmutter et al118 RCT 29 IVIG vs PLEX vs

placebo

At 1 mo:


between IVIG and PLEX groups

NS

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

on all measures for patients who

received IVIG or PLEX

NR


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 immunosup-

pressive drugs such as mycophenoate, azathio-

prine, methotrexate, or cyclophosphamide may be

considered. However, toxicity and long-term side-

effects from these agents are problematic, and a

lack of firm evidence of benefit with these drugs

should discourage their use.

Evidence Summary

The bAppropriateness of IVIGQ evidence reviewidentified 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. Significant-

ly more patients showed significant improve-

ment in muscle strength after IVIG compared

with placebo (RR, 11.00 [95% CI, 2.86-42.25;

fixed]; P = .0005). There was no significant

difference between IVIG and placebo in the

proportion of patients with significant improve-

ment in disability scores or resolution of 1 or more

conduction blocks. Significantly more patients

experienced side-effects with IVIG compared with

placebo (RR, 10.33 [95% CI, 2.15-49.77; fixed],

P = .004). Tests for heterogeneity were not

statistically significant. Refer to Table 20 for

further details.


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 continu-

ing regular IVIG maintenance therapy to avoid

secondary axonal degeneration. The panel also

highlighted that objective measurement of im-

provement is difficult as physiological change

does not correlate well with clinical outcome.

Quantitative muscle strength testing will help to

ascertain responsiveness.

Table 27. POEMS Syndrome IVIG studies


Benito-Leon et al120 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 Krieger121 Case report 1 IVIG Y IVIG +

steroids

IVIG alone:

partial response

(A paresthesias,

no change in paresis)

Severe POEMS IVIG + steroids:

independent ambulation,

improved muscle power

Huang and Chu122 Case report 2 IVIG qNo improvement with

IVIG in either case.POEMS and

Castleman’s disease

FEASBY ET ALS90

Recommendations


as first-line treatment of for MMN.

Based on consensus by the expert panel,

diagnosis of MMN should be made by a neuro-

muscular specialist, as the diagnosis requires very

specific electrodiagnostic expertise.

Dose and Duration




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


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 trig-

gers, 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 dis-

eases such as systemic lupus erythematous;

mitochondrial disease (eg, cerebral autosomal

dominant arteriopathy with subcortical infarcts

and leukoencephalopathy [CADASIL]), nonspe-

cific granulomatous disease such as sarcoidosis,

and certain infections (eg, borreliosis). As dis-

cussed in the ADEM section, some patients who

are ultimately diagnosed with MS may manifest

with an initial demyelinating event indistinguish-

able 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 gla-

tiramer acetate with immunosuppressive medica-

tions (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-

Table 28. Polymyositis IVIG Studies


Polymyositis

Cherin et al123 Case series

Tx refractory

35 IVIG Clinical improvement

with IVIG: 71%

(25/35)

of patients


in muscle power and MDS:

Mean muscle power4:

baseline, 47.8 F 11.1;

post-IVIG, 67.4 F 12.7

.01

Mean MDS score:



.01



.05


Polymyositis or dermatomyositis

Danieli et al47 Non-RCT

New onset,

relapsed or

Tx refractory

20 Steroids + CSA or

IVIG + steroids +

CSA or IVIG +

PLEX + steroids + CSA

No significant

difference in

CRy between

groups at 1 y

NS

At 4 y:


given IVIG + steroids +

CSA maintained complete

remission compared with

steroids + CSA

.001


between IVIG + steroids +

CSA and IVIG + PLEX +

steroids + CSA groups

NS

Cherin and Herson48 Case series

Tx refractory

35 IVIG F steroids F

other txzSignificant

improvement

in muscle power:

Mean muscle power4:



.01



.05


Cherin et al49 Case series

No previous tx

11 IVIG No significant

improvement

in mean muscle

power4 from baseline

NS

Only 27% (3/11) had

significant clinical

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.


Table 29. Rasmussen’s Encephalitis IVIG Studies

Study Design No. of patients Intervention Outcome

Granata et al124 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 al125Case report 1 IVIG Mild improvement

in symptoms

Frucht126 Case report 1 IVIG + ganciclovir Marked improvement

in hyperkinetic

movements

Villani et al127 Case report 1 IVIG Marked improvement

(N75% A seizure

frequency, improved cognition)

Leach et al128 Case report 2 IVIG 100% (2/2) Marked improvement

in seizure frequency,

hemiparesis, cognition

4Other therapies included cyclophosamide and protein A immunoadsorption.

FEASBY ET ALS92

kine receptor antagonists, monoclonal antibodies to

cytokines and cytokine receptors, and in the

extreme, immunoablation in the form of autolo-

gous 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 re-

view identified one systematic review with meta-

analysis 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 al78 and the Chalmers review (unpub-

lished) 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 al78 included Achiron et al,79 Fazekas et al,80

Lewanska et al,81 and Sorensen et al83 (Table 21).

Sorensen et al78 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, 0.18-0.39], P = 2.1 � 10�8).

Table 30. Stiff Person Syndrome IVIG Studies


Dalakas et al129 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

.01

Significant first-order

carry over effect of

IVIG on stiffness scores

.001

Sensitivity scores:

Significant direct treatment

effect of IVIG vs placebo

on improvement in mean

heightened sensitivity scoresz

.03

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 Immu-

noglobulin [PRIVIG]) and presented in abstract

form at the European Neurological Society

conference in June 2006.77a 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, placebo-

controlled, 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 pro-

gressive MS. Hommes et al86 reported no signif-

icant difference in time to EDSS progression or

annual relapse rate between IVIG and placebo.

Four randomized placebo-controlled trials in-

cluded 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 al83, the proportion

of relapse-free patients was significantly higher

with IVIG compared with placebo (P b .02).

One randomized controlled trial evaluated dif-

ferent doses of IVIG. No significant difference

between IVIG treatment arms was identified.


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 relapsing-

remitting MS consists of the proven effective

disease modifying agents, b-interferon, and glatir-

amer 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 immuno-

modulatory 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.

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


demyelinating

polyradiculoneuropathy

11 (92%) 1 (8%) 0 (0%) 4.33

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-Barre 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

neuropathy (IgM variant)

9 (75%) 2 (17%) 1 (8%) 4.00

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.

11 (92%) 1 (8%) 0 (0%) 4.58

I will use the guidelines

in my practice.

10 (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.

FEASBY ET ALS94

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 exacer-

bations 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 circum-

stances 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 syn-

drome) 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-threat-

ening nature of this condition. The panel also

discussed the recent discovery of a circulatory

antibody to aquaporin-4 in many patients with

neuromyelitis optica. The ability to screen patients

for the presence of this antibody may lead to new


evidence for a role for IVIG in antibody-positive

patients. Thus, although the current level of

evidence does not support the use of IVIG in

patients with neuromyelitis optica, future studies

in this area are needed.

The expert panel identified several other areas

that would benefit from further clinical research.

These include a randomized controlled trial of

IVIG for acute exacerbations of MS (in particular,

for patients with severe, refractory, optic neuritis)

and randomized trials that compare IVIG with

current immunomodulatory therapies for relapsing-

remitting MS. Randomized controlled trials are

also needed to evaluate IVIG for treatment of

primary and secondary progressive MS, as well as

trials to determine the optimal dose of IVIG.

Recommendations


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 advanc-

ing relapsing-remitting MS, consideration should

first be given to immunosuppression therapy.


ded for the treatment of primary or secondary

progressive MS.

Based on consensus by the expert panel, IVIG is

not recommended for treatment of acute exacer-

bations 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.


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.


may be considered as a treatment option for

patients with Marburg disease, given the life-

threatening nature of this disease.

Dose and Duration

Based on consensus by the expert panel, 1 g/kg

monthly with or without a 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


Myasthenia gravis is an acquired autoimmune

disease characterized by the formation of autoanti-

bodies to the acetylcholine receptor (AChR) and

fatigable weakness. The incidence of myasthenia

gravis is 7 per 1000000, 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, myopa-

thies, 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 reach-

ing 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 pneu-

monia 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 anti-

cholinesterase drugs, thymectomy, immunosup-

pressive therapy, and immunomodulation (eg,

FEASBY ET ALS96

plasmapheresis, IVIG). Anticholinesterase medica-

tion 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 improve-

ment. 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, cyclospor-

ine, cyclophosphamide, and mycophenolate mofe-

til. Immunomodulation with PLEX or IVIG

removes AChR antibodies or modulates antibody

effects temporarily. Plasma exchange is the stan-

dard treatment of myasthenic crisis, acute deterio-

ration, or prethymectomy in patients with

respiratory or bulbar involvement.

Some drugs such as aminoglycosides, ciproflox-

acin, 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 reviewidentified 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 al90 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 Gajdos91 included patients

with acute exacerbations of myasthenia gravis,

whereas the crossover trial by Ronager92 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 al91 also evaluated

different doses of IVIG. No significant difference

between IVIG treatment arms was identified.

One very small, underpowered trial by Wolfe

et al93 compared IVIG against placebo. No

significant difference between groups was ob-

served 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.94-99 Please refer to Table 22 for further

details.


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 medi-

cations. The panel agreed IVIG should be reserved

for treatment of severe exacerbations or myasthen-

ic crises. The panel noted IVIG and PLEX are

currently used in clinical practice as short-term

measures until more effective long-term immuno-

suppression 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 myas-

thenic exacerbations.


Given the limited evidence available, the expert

panel agreed IVIG should not be used as mainte-

nance therapy for chronic myasthenia gravis.

Extremely limited evidence is available for use of

IVIG for myasthenia gravis in the pediatric set-

ting.100-103 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 myas-

thenia gravis.

Recommendations

Adult and Juvenile Myasthenia Gravis. Intra-

venous immune globulin is recommended as a

treatment option for patients with severe exacer-

bations of myasthenia gravis or myasthenic crises.


may be considered as an option to stabilize patients

with myasthenia gravis before surgery.


ded as maintenance therapy for patients with

chronic myasthenia gravis.

Neonatal Myasthenia Gravis. Based on con-

sensus by the expert panel, IVIG may be consid-

ered 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


Opsoclonus-myoclonus syndrome is a rare neu-

rologic disorder characterized by an unsteady,

trembling gait, myoclonus (brief, shock-like muscle

spasms), and opsoclonus (irregular, rapid eye move-

ments). 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 typical-

ly 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 reviewidentified one retrospective chart review and 9 case

reports that assessed the use of IVIG for opsoclo-

nus-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).


Extremely sparse evidence is available for use of

IVIG for opsoclonus-myoclonus. Stronger evi-

dence 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 re-

quired 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


may be considered as an option for treatment of

opsoclonus-myoclonus.

Dose and Duration










should be 2 g/kg.

PARAPROTEINEMIC NEUROPATHY(IGM VARIANT)


Most patients with IgM paraproteinemic demy-

elinating neuropathy present with a chronic, slowly

progressive, distal, and predominantly sensory

FEASBY ET ALS98

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 polyneur-

opathy with markedly slowed nerve conduction

velocity without conduction block. Distal latencies

are characteristically very prolonged. Despite the

predominance of sensory symptoms, demyelin-

ation similarly affects motor and sensory fibers.

Paraprotein may be detected by standard serum

protein electrophoresis; however, both serum im-

munoelectrophoresis 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 de-

myelinating 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 evi-

dence that these anti-MAG antibodies are involved

in the pathogenesis of the demyelinating neuropa-

thy. Full proof is still lacking. Deposition of the

paraprotein on the myelin sheaths of primarily large

fibers in nerve biopsies, shown by immunohisto-

chemical techniques, is strongly supportive of this

concept. This correlates with widely spaced outer

myelin lamellae demonstrated by electron micro-

scopic examination of the nerve biopsy.

Cerebrospinal fluid protein is elevated in ap-

proximately 85% of cases. Regular blood cell

counts and bone marrow investigations are usually

normal. Bence Jones protein is negative. Monitor-

ing 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 promis-

ing results.

Evidence Summary

The bAppropriateness of IVIGQ Evidence Re-

view identified one Cochrane systematic review

and 3 randomized controlled trials of IVIG use for

IgM paraproteinemic neuropathy (level of evi-

dence: 1b). The Cochrane systematic review

examined whether any form of immunotherapy

decreased disability or impairment associated with

IgM anti-MAG positive paraproteinemic neuropa-

thy.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 meta-

analysis of the effect of IVIG treatment vs placebo

because of differences in outcomes assessed.

A small crossover trial by Comi et al115 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 improve-

ment in mean clinical neuropathy disability scores

with interferon-a compared with IVIG at 6-month

follow-up (P = .02)117 (Table 25).


The available evidence is limited to 3 small

trials of variable quality and mixed results.

Although one placebo-controlled trial by Comi

et al115 reported benefit of IVIG for IgM para-

proteinemic neuropathy, the expert panel ques-

tioned 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 recom-

mend IVIG for the treatment of IgM paraproteine-

mic neuropathy.


Recommendation


ded for the treatment of IgM paraproteine-

mic neuropathy.

PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRICDISORDERS ASSOCIATED WITHSTREPTOCOCCAL INFECTIONS


Simple motor tics are common, affecting up to

1% to 2% of school-age children. The association

of rapid-onset tics associated with obsessive-

compulsive disorder (OCD) in the context of

recovery from streptococcal infection (pediatric

autoimmune neuropsychiatric disorders associated

with streptococcal infections [PANDAS]) was first

reported in 1994. Molecular mimicry between

streptococcal antigens and the CNS 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


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-com-

pulsive 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).


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


as an option for treatment of patients with

PANDAS.

Based on consensus by the expert panel, diag-

nosis of PANDAS requires expert consultation.

Dose and Duration


dose of 2 g/kg given over 2 days is recommended

as a reasonable option.

POEMS SYNDROME


A chronic progressive and predominantly motor

neuropathy resembling CIDP is the major clinical

manifestation of POEMS syndrome. Peak inci-

dence 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 Cas-

tleman’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 polyneurop-

athy, organomegaly (hepatosplenomegaly or

lymphadenopathy), endocrinopathy, M protein,

skin changes (hypertrichiosis, hyperpigmentation,

diffuse skin thickening, finger clubbing, haeman-

giomas, white nail beds). Papilloedema, ascites,

pleural effusions, and generalized edema are

frequent, caused by the massive secretion of

vascular endothelial growth factor (VEGF). Vas-

cular endothelial growth factor targets the endo-

FEASBY ET ALS100

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 hor-

mone, follicle-stimulating hormone, luteinizing

hormone, glucose), abdominal ultrasound or com-

puted tomography (organomegaly), complete

blood count (thrombocytosis), measurement of

VEGF levels in serum, and a nerve biopsy.

There are no controlled clinical trials of treat-

ments 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 radi-

ation or surgical excision. A combination of

melphalan and corticosteroids were effective in

approximately 55% of patients. Autologous pe-

ripheral 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 reviewidentified 4 cases of IVIG use for POEMS (level

of evidence: 4). Two patients showed improve-

ment after IVIG plus dexamethasone or radiother-

apy.120,121 No improvement with IVIG was

observed for 2 patients with Castleman’s disease

and POEMS122 (Table 27).


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


ded for the treatment of POEMS syndrome.

POLYMYOSITIS


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 erythema-

tosus 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 pos-

sibility 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 autoanti-

bodies 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 im-

provement in their muscle weakness with steroids

or immune suppression.

Evidence Summary

The bAppropriateness of IVIGQ Evidence Re-

view 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 poly-

myositis or dermatomyositis.


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.47-49 Refer to Table 28 for

further details.


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 neuromus-

cular pathology.

Recommendations

Based on consensus by the expert panel, patho-

logic 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 speci-

mens and that the final interpretation be made by an

expert in neuromuscular pathology.


may be considered among the treatment options for

patients with polymyositis who fail to respond to

first-line therapies (eg, steroids).

Dose and Duration




requiring IVIG maintenance therapy, a systematic

approach should be taken to determine the mini-

mum 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


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 epilep-

sy, lateralized brain atrophy, and progressive CNS

impairment. Outcome is uniformly poor. Surgical

resection of the affected hemisphere is viewed as the

mainstay of therapy but has significant morbidity.

Evidence that 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 improve-

ment in symptoms after IVIG alone or in combi-

nation with additional therapies (Table 29).


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 Rasmus-

sen’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.

FEASBY ET ALS102


ded for long-term therapy for Rasmussen’s en-

cephalitis as surgical treatment is the current

standard of care.

Dose and Duration



over 2 days for children is a reasonable option.

STIFF PERSON SYNDROME


Stiff person syndrome is an uncommon ac-

quired 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 chil-

dren 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


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).


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


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










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 meth-

odology 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 e-mailed to

members of the Canadian Neurological Society.

Practitioners were given the option of faxing their

completed survey or providing their responses

online through a Web-based survey tool. Written

comments on the draft guideline were encouraged.

Practitioners were asked to provide feedback

within 3 weeks.

Results

Feedback on the draft practice guideline was

received from 27 neurologists. The greatest num-

ber 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


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 com-

ments on the draft practice guideline.

Discussion and Guideline Modifications

The expert panel discussed the external review

results at a teleconference in November 2005. The

number of responses received was quite low.

However, given the length and breadth of the

guideline, the panel recognizes that the time

required to review and provide feedback on the

entire document was likely a considerable deter-

rent. Overall, the feedback received was positive,

with most respondents in agreement with the

draft recommendations.

One external review respondent expressed dis-

appointment 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 manage-

ment 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 complet-

ed, 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. Nonethe-

less, 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 represen-

tation 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.

REFE

1. Pierce LR, Jain N: Risks associated with the use of

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guidelines on the use of intravenous immune globulin for ......polyneuropathy, inclusion body,...

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