Guidelines on the Use of Intravenous Immune Globulin for ......polyneuropathy, inclusion body, myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and
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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: heather.hume@blood.ca
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
Chronic inflammatory
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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S61
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S63
(14/20) of children with monophasic ADEM
completely recovered after administration of IVIG
or IVIG plus corticosteroids. Of the 5 cases of
relapsing ADEM, 2 children completely recovered
after IVIG, and the 3 others showed improvement.
Two children with relapsing ADEM required
monthly IVIG to maintain their response. Refer to
Table 7 for further details.
Overall, 50% (4/8) of adults with monophasic
ADEM completely recovered after treatment
with IVIG. Both adults with relapsing ADEM
showed marked improvement after IVIG. Refer to
Table 8 for further details.
Interpretation and Consensus
The expert panel acknowledges the evidence
for IVIG in the treatment of ADEM is limited.
However, given the number of positive cases 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
Clinical Description
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).
Interpretation and Consensus
The available evidence is limited to 1 small,
poor-quality randomized trial. However, given that
no benefit was observed for patients treated with
IVIG, it is the expert panel’s opinion that IVIG
should not be used for treatment of ALD.
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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S65
Recommendations
Intravenous immune globulin is not recommen-
ded for the treatment of ALD.
AMYOTROPHIC LATERAL SCLEROSIS
Clinical Description
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):
No significant difference
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
No significant difference between
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
patients Intervention Outcome P
USE OF IVIG FOR NEUROLOGIC CONDITIONS S67
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).
Interpretation and Consensus
The expert panel recognizes the available
evidence is limited to case series data. Given that
no benefit was observed either in slowing disease
progression or improvement of symptoms, the
panel agreed there is no role for IVIG in the
treatment of ALS.
Recommendation
Intravenous immune globulin is not recommen-
ded for the treatment of ALS.
AUTISM
Clinical Description
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).
Interpretation and Consensus
The expert panel agreed the available evidence
does not support the use of IVIG for treatment of
autism. Although there are a few children who
appeared to improve dramatically after IVIG 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
Intravenous immune globulin is not recommen-
ded for the treatment of autism.
CHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY
Clinical Description
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
Study Design and participants No. of patients Intervention Outcome
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S69
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.
Interpretation and Consensus
High-quality evidence is available to support the
use of IVIG as an option for the short-term
management of patients with CIDP. There is no
evidence to support or refute the superiority of
IVIG to PLEX or oral prednisone for the 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
No significant difference
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
No significant difference
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.
Table 14 (continued)
USE OF IVIG FOR NEUROLOGIC CONDITIONS S71
therapy should be based on objective measures of
the sustained effectiveness of IVIG and on a
recurrence of symptoms or symptom worsening if
IVIG is withdrawn.
Recommendations
Intravenous immune globulin is recommended
as an option for the short-term management of
new-onset CIDP or CIDP relapses.
Based on consensus by the expert panel, IVIG
may be considered as an option in combination
with other immunosuppressive therapy for the
long-term management of CIDP. If IVIG is to be
used in the long-term management of CIDP, the
patient should be under the care of a qualified
expert with specialized knowledge of CIDP and a
systematic approach should be taken to determine
the minimal effective dose.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days is a
reasonable initial treatment option. For patients
requiring IVIG maintenance therapy, a systematic
approach should be taken to determine the 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
Clinical Description
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).
Interpretation and Consensus
The pathobiologic rationale for the use of
IVIG in the treatment of CIP is not strong, and
the available evidence is limited to one very
small case series that reported no improvement
after IVIG therapy. The panel noted that the
retrospective chart review did not assess IVIG for
treatment of CIP but, rather, its prevention. The
expert panel does not recommend IVIG for the
treatment of CIP.
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
Significantly more patients
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
No significant difference
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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S73
Recommendation
Intravenous immune globulin is not recommen-
ded for the treatment of CIP.
DERMATOMYOSITIS
Clinical Description
Dermatomyositis can occur in both adults and
children. In children, dermatomyositis is the most
common inflammatory myopathy. Rash is 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.
Interpretation and Consensus
The available evidence suggests IVIG may be of
benefit for patients with dermatomyositis. In the
opinion of the expert panel, IVIG may be
considered as an adjunctive treatment option for
patients who do not adequately respond to other
immunosuppressant medications, such as 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
patients Intervention Outcome P
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
No significant difference
in mean time to improve
z1 DG, % of patients who
improved by z1 DG at 4 wk,
mean time to reach DG-1,
duration of intubation or
hospitalization between the groups
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
No significant difference between
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
No significant difference between
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
difference between groups
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
improved by z1 DG at 4 wk,
change in DG at 4 wk, time to
improve 1 DG, and time to
improve 2 DG.
NS
Adults
FEASBY ET ALS74
Table 16 (continued)
Study
Design and
participants
No. of
patients Intervention Outcome P
PSGBS group68 RCT 379 IVIG vs PLEX vs
PLEX Y IVIG
No significant difference between
IVIG, PLEX, and PLEX + IVIG
groups in mean improvement
in DG at 4, time to walk unaided,
duration of mechanical ventilation,
or rate of recovery
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
difference between groups
NS
Ventilated patients:
IVIG(6 d) significantly
shorter than IVIG(3 d)
.04
No significant difference
in % of patients
who improved by
z1 DG at 4 wk,
duration of intubation,
or mortality rate
at 1 y between groups
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S75
the final interpretation be made by an expert in
neuromuscular pathology.
Based on consensus by the expert panel, use of
IVIG for the treatment for patients with dermato-
myositis should be made in consultation with an
expert in neuromuscular disease.
Intravenous immune globulin is not recommen-
ded as monotherapy for dermatomyositis.
Intravenous immune globulin is recommended
as an option, in combination with other agents,
for patients with dermatomyositis who have not
adequately responded to other 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
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days for adults and
over 2 days for children is a reasonable initial
treatment option. For patients requiring IVIG
maintenance therapy, a systematic approach should
be taken to determine the minimum effective dose,
and continued use of IVIG should be based on
objective measures of its sustained effectiveness.
The maximum dose of IVIG per treatment course
should be 2 g/kg.
DIABETIC NEUROPATHY
Diabetic neuropathy affects 50% to 60% of
patients with type 1 diabetes mellitus of more than
10 years in duration and, likely, a similar number
of type 2 diabetes mellitus patients. Most patients
are either asymptomatic or mildly symptomatic.
There are many subtypes of diabetic neuropathy
Table 17. Inclusion Body Myositis IVIG Studies
Study Design No. of patients Intervention Outcome P
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
No significant difference
between groups in mean
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
significantly different
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
Study Design No. of patients Intervention Outcome P
Van Rijckevorsel-
Harmant et al69RCT 61 IVIG 100 mg/kg vs
IVIG 250 mg/kg vs
IVIG 400 mg/kg vs
placebo
No significant difference
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S77
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
Table 15 for further details.
Interpretation and Consensus
The available evidence is quite limited and
complicated by the fact that patients in the
case series were clinically heterogeneous. In
particular, it is unclear whether the CIDP subgroup
involves 2 diseases in the same patient or a rare
neuropathic phenotype in diabetes. Expert panel
members also noted the need to consider the
natural history of diabetic proximal neuropathy,
which is gradual spontaneous improvement. A
large randomized controlled trial would be 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
Intravenous immune globulin is not recommen-
ded for treatment of diabetic polyneuropathy, mono-
neuropathy, or proximal lower limb neuropathy.
Based on consensus by the expert panel, IVIG
use for patients with diabetes who have evidence
of a CIDP phenotype should follow the recom-
mendations outlined in the CIDP section of
this guideline.
GUILLAIN-BARRE SYNDROME
Clinical Description
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
Study Design No. of patients Intervention Outcome P
Bain et al71 Crossover, RCT 9 IVIG vs placebo4 Significant improvement
in limb strength with
IVIG vs placebo
.038
Significant improvement
in vital lung capacity
with IVIG vs placebo
.028
Significant improvement
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
patients Intervention Outcome P
van Schaik et al72 Systematic review
with meta-analysis
IVIG vs placebo No significant
difference in
proportion of patients with
significant improvement
in disability scores
between IVIG and placebo:
Meta-analysis included: – RR, 3.00 (95% CI,
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
No significant difference
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
No significant difference
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
Significant improvement
in Canadian Blood Services
with IVIG
.037
Leger et al75 Crossover, RCT 19 IVIG vs placebo At 4 mo, no significant
difference between groups
in change in MRC scores
or severity of Canadian
Blood Services
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S79
Table 21. Multiple Sclerosis IVIG Studies
Study Design No. of patients Intervention Outcome P
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
No significant difference between
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
–
No significant difference
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
No significant difference
between groups in mean
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:
No significant difference
between IVIG groups
NS
Combined IVIG groups
significantly lower than placebo
.01
Mean change in EDSS score at 1 y:
No significant difference
between IVIG groups
NS
Combined IVIG groups
significant improvement
compared with placebo
.003
FEASBY ET ALS80
Table 21 (continued)
Study Design No. of patients Intervention Outcome P
Ostekin (1998)
[abstract]
RCT 36 IVIG vs placebo No significant difference between
groups in mean annual relapse
rate or mean change in EDSS
scores at 22 mo
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
No significant difference between
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
difference between groups
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
between groups in mean
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
No significant difference
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S81
Table 22. Myasthenia Gravis IVIG Studies
Study Design and participants No. of patients Intervention Outcome P
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
No significant difference
between IVIG(3 d) vs IVIG(5 d)
NS
No significant difference
between IVIG(combined)
and PLEX
NS
All groups improved
significantly from
baseline at d 2
.02
No significant difference
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
significantly different
between groups
NS
Moderate to
severe MG
Both groups had
significant improvement
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
Table 22 (continued)
Study Design and participants No. of patients Intervention Outcome P
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
No significant difference
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
6 IVIG Significant mean
improvement on
functional scale
NR
All patients showed
improvement on the
OGCCMS scale
Wegner and
Ahmed98Case series
Chronic MG
6 IVIG Significant mean
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).
USE OF IVIG FOR NEUROLOGIC CONDITIONS S83
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
Table 16 for further details.
Interpretation and Consensus
Evidence from several randomized controlled
trials is available to support IVIG as an efficacious
therapy for patients with severe GBS. Results of a
meta-analysis from a Cochrane systematic review
indicate IVIG and PLEX are equally effective for
treatment of GBS. The expert panel noted that
PLEX was the standard of care for treatment of
GBS when most IVIG trials were conducted; thus,
IVIG was not compared with placebo.
One large randomized trial reported no 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
Intravenous immune globulin is recommended
as a treatment option for GBS within 2 weeks of
symptom onset for:
1. Patients with symptoms of grade 3 severity
(able to walk with aid) or greater; or
2. Patients with symptoms less than grade 3
severity whose symptoms are progressing.
Based on consensus by the expert panel, IVIG
may be considered as a treatment option for
patients who initially responded to IVIG and who
are experiencing a relapse of symptoms.
Based on consensus by the expert panel, the
recommendations for use of IVIG for GBS also
apply to patients with Miller-Fisher and other
variants of GBS. Diagnosis of GBS variants should
be made by a specialist with expertise in this area.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days for adults and
over 2 days for children is a reasonable option.
INCLUSION BODY MYOSITIS
Clinical Description
Inclusion body myositis (IBM) is very different
from dermatomyositis and polymyositis. Inclusion
body myositis is usually a disease of older adults
and is likely the most common newly acquired
inflammatory myopathy in patients older than
65 years. Inclusion body myositis can be seen in
younger patients but is rarely seen in those
younger than 50 years. There is a very rare
inherited disorder that has similar pathology to
acquired IBM. Patients present with painless
slowly progressive muscle weakness. Some
muscle groups are particularly affected, including
long finger flexors and knee extensors. The
USE OF IVIG FOR NEUROLOGIC CONDITIONS S85
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).
Interpretation and Consensus
The available evidence consists of 3 small
randomized trials of moderate to high quality.
The expert panel noted that although a small
number of patients with IBM showed some
improvement with IVIG, there was no evidence
of sustained benefit. In the opinion of the expert
panel, IVIG should not be used for the treatment
of IBM.
The panel agreed that a skeletal muscle biopsy is
required to diagnosis IBM and that the biopsy
specimen should be examined by an expert in
neuromuscular pathology.
RECOMMENDATION
Based on consensus by the expert panel,
pathologic confirmation by means of a skeletal
muscle biopsy is required for the diagnosis of IBM.
It is critical that the muscle specimen be procured,
processed, and interpreted in a laboratory familiar
with the correct handling of muscle biopsy speci-
mens (including electron microscopy) and that the
final interpretation be made by an expert in
neuromuscular pathology.
Intravenous immune globulin is not recommen-
ded for the treatment of IBM.
INTRACTABLE CHILDHOOD EPILEPSY
Clinical Description
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).
Interpretation and Consensus
The available evidence is limited to 2 small,
randomized trials that had broad inclusion criteria
and allowed entry of children with varied epileptic
syndromes. In both trials, children were 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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S87
LAMBERT-EATON MYASTHENIC SYNDROME
Clinical Description
The Lambert-Eaton myasthenic syndrome
(LEMS) is a rare acquired autoimmune disorder
with autoantibodies directed against voltage-gated
calcium channels (VGCC) on the presynaptic
nerve terminal of the neuromuscular junction and
of autonomic synapses. Patients have weakness
and autonomic symptoms. The differential 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).
Interpretation and Consensus
Given the positive results from the randomized
trial, the severity of this condition and its
underlying pathogenesis, which is similar to
myasthenia gravis, the panel agreed it is 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
patients Intervention Outcome P
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
No significant difference
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
Intravenous immune globulin is recommended
as an option for treatment of LEMS. Objective
evidence of clinical improvement is needed for
sustained use of IVIG.
Dose and Duration
Based on consensus by the expert panel, a
total dose of 2 g/kg given over 2 to 5 days is a
reasonable initial treatment option. For patients
requiring IVIG maintenance therapy, a 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
Clinical Description
Multifocal motor neuropathy (MMN) presents as
slowly progressive muscle weakness and wasting
within the territory of individual motor nerves and
with a predilection for the distal upper limbs. Focal
cramps and fasciculations are common, particularly
after exercise. Sensory symptoms and signs are
notably absent on both clinical and 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
Study Design No. of patients Intervention Outcome P
Perlmutter et al118 RCT 29 IVIG vs PLEX vs
placebo
At 1 mo:
No significant difference
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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S89
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.
Interpretation and Consensus
The expert panel agreed IVIG is the only
treatment demonstrated by clinical trial to be
effective for MMN, and it is widely accepted as
first-line therapy for this condition. Patients with
MMN who do not respond to IVIG should not be
retreated with IVIG.
Based on clinical experience, members of the
panel noted that the effect of IVIG is variable, and
over time, the interval between treatments may
shorten as the therapeutic benefit of IVIG declines.
The panel emphasized the importance of 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
Study Design and participants No. of patients Intervention Outcome
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
Intravenous immune globulin is recommended
as first-line treatment of for MMN.
Based on consensus by the expert panel,
diagnosis of MMN should be made by a neuro-
muscular specialist, as the diagnosis requires very
specific electrodiagnostic expertise.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days is a
reasonable initial treatment option. For patients
requiring repeated treatment, IVIG maintenance
therapy should be tailored to the lowest dose that
maintains clinical efficacy, usually 1 g/kg or less
per treatment course. The frequency of IVIG
treatment will vary and may shorten over time.
MULTIPLE SCLEROSIS
Clinical Description
Multiple sclerosis (MS) is the most common
neurologic disability in young adults with a
prevalence of one in 500 to 1000 in Canada. Most
patients first present with clinical symptoms
between 20 and 40 years of age, although the
disease may have its onset in childhood or late
adulthood. Most patients (approximately 85%)
initially have a relapsing-remitting course that
typically evolves into a secondary progressive
course over 20 or more years. About 10% of
patients experience a predominantly progressive
course from the outset.
The pathobiology of MS is thought to represent
a complex interplay of immune system reactivity
to environmental triggers (eg, viruses) set upon a
background of genetic susceptibility that leads to
immune mediated demyelination, axon loss, and
neurodegeneration. Putative environmental 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
Study Design and participants No. of patients Intervention Outcome P
Polymyositis
Cherin et al123 Case series
Tx refractory
35 IVIG Clinical improvement
with IVIG: 71%
(25/35)
of patients
Significant improvement
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:
baseline, 22.3 F 8.0;
post-IVIG, 10.9 F 6.1
.01
Significant reduction in
mean steroid dose (mg/d)
.05
Significant A in CK levels .01
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:
Significantly more patients
given IVIG + steroids +
CSA maintained complete
remission compared with
steroids + CSA
.001
No significant difference
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:
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
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.
Significant improvement
in mean CK levels
.01
Abbreviations: MDS, Muscle Disability Scale: range 0 (no disability) to 75 (maximum disability); CR, complete remission.
4Muscle power score: used a modified MRC scale; treatment classified as successful if score increase by z18 points.
yDefined as increase in strength of z3 affected muscles with normal creatine kinase levels. For patients with normal baseline
creatine kinase levels, absence of pathological EMG spontaneous activity was required to be classified as CR.
zOther treatments included methotrexale, azathoprine, or plasma exchange.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S91
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
Study Design and participants No. of patients Intervention Outcome P
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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S93
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.
Interpretation and Consensus
Evidence from 2 meta-analyses and several
randomized controlled trials is available to support
IVIG as superior to placebo for treatment for
patients with relapsing-remitting MS. However, the
outcome of the recently completed PRIVIG trial
raises doubt about the efficacy of IVIG in the
routine treatment of relapsing-remitting MS. The
expert panel agreed that the current and appropriate
first-line treatment for patients with 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
Chronic inflammatory
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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S95
evidence for a role for IVIG in antibody-positive
patients. Thus, although the current level of
evidence does not support the use of IVIG in
patients with neuromyelitis optica, future studies
in this area are needed.
The expert panel identified several other areas
that would benefit from further clinical research.
These include a randomized controlled trial of
IVIG for acute exacerbations of MS (in particular,
for patients with severe, refractory, optic neuritis)
and randomized trials that compare IVIG with
current immunomodulatory therapies for 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
Intravenous immune globulin is recommended
as an option for treatment of patients with
relapsing-remitting MS who fail, decline, or are
not able to take standard immunomodulatory drug
therapies. For those patients with rapidly advanc-
ing relapsing-remitting MS, consideration should
first be given to immunosuppression therapy.
Intravenous immune globulin is not recommen-
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.
Based on consensus by the expert panel, IVIG
may be considered as a treatment option for patients
with relapsing-remitting MS who are pregnant or
breastfeeding or in the immediate postpartum
period for women whose exacerbation rate was
high before pregnancy and who were on disease
modifying agents before pregnancy with plans to
recommence therapy after birth or breastfeeding.
Based on consensus by the expert panel, IVIG
may be considered as a treatment option for
patients with Marburg disease, given the 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
Clinical Description
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.
Interpretation and Consensus
The expert panel acknowledged there is a strong
immunologic rationale for the use of IVIG in the
treatment of myasthenia gravis. However, the
panel raised several concerns about the quality
of the available evidence. Problems with the
randomized controlled trials include the patient
populations studied, end points measured, and
methodological issues such as lack of blinding and
early termination.
In the opinion of the panel, mild to moderate
myasthenia gravis can be successfully managed
with symptomatic and immunosuppressive 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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S97
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.
Based on consensus by the expert panel, IVIG
may be considered as an option to stabilize patients
with myasthenia gravis before surgery.
Intravenous immune globulin is not recommen-
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
Clinical Description
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).
Interpretation and Consensus
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
Based on consensus by the expert panel, IVIG
may be considered as an option for treatment of
opsoclonus-myoclonus.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days for adults and
over 2 days for children is a reasonable initial
treatment option. For patients requiring IVIG
maintenance therapy, a systematic approach should
be taken to determine the minimum effective dose,
and continued use of IVIG should be based on
objective measures of its sustained effectiveness.
The maximum dose of IVIG per treatment course
should be 2 g/kg.
PARAPROTEINEMIC NEUROPATHY(IGM VARIANT)
Clinical Description
Most patients with IgM paraproteinemic 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).
Interpretation and Consensus
The available evidence is limited to 3 small
trials of variable quality and mixed results.
Although one placebo-controlled trial by Comi
et 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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S99
Recommendation
Intravenous immune globulin is not recommen-
ded for the treatment of IgM paraproteine-
mic neuropathy.
PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRICDISORDERS ASSOCIATED WITHSTREPTOCOCCAL INFECTIONS
Clinical Description
Simple motor tics are common, affecting up to
1% to 2% of school-age children. The association
of rapid-onset tics associated with 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
The bAppropriateness of IVIGQ evidence reviewidentified one randomized controlled trial that
examined the use of IVIG for PANDAS (level of
evidence: 1b). In this trial, 29 children who had new
onset or severe exacerbations of OCD or tic disorder
after streptococcal infections were randomly
assigned to receive IVIG, PLEX, or placebo.118 At
1 month, there was no significant difference
between the IVIG and PLEX groups. Patients who
received treatment with either IVIG or PLEX
showed significant improvement in obsessive-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).
Interpretation and Consensus
Although the evidence is limited to one small
placebo-controlled trial, the results are compelling.
In the opinion of the expert panel, it is reasonable
to consider IVIG among the options for treatment
of PANDAS. The panel emphasized that this
syndrome is not well understood, and diagnosis
of PANDAS requires expert consultation. The
optimum dose and duration of IVIG for treatment
of PANDAS is uncertain. The randomized trial
used 1 g/kg daily for 2 days and there was
agreement that this is a reasonable option.
Recommendations
Intravenous immune globulin is recommended
as an option for treatment of patients with
PANDAS.
Based on consensus by the expert panel, diag-
nosis of PANDAS requires expert consultation.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 days is recommended
as a reasonable option.
POEMS SYNDROME
Clinical Description
A chronic progressive and predominantly motor
neuropathy resembling CIDP is the major clinical
manifestation of POEMS syndrome. Peak 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).
Interpretation and Consensus
Extremely sparse evidence is available for the
use of IVIG in POEMS. The expert panel
discussed that recently other treatments such as
radiotherapy and autologous peripheral blood stem
cell transplantation have shown benefit for
patients with POEMS. In the opinion of the panel,
there is no role for IVIG in the treatment of
POEMS syndrome.
Recommendation
Intravenous immune globulin is not recommen-
ded for the treatment of POEMS syndrome.
POLYMYOSITIS
Clinical Description
Polymyositis usually presents in adults, with
slowly progressive proximal muscle weakness,
particularly affecting the hip and shoulder girdles.
Some patients will have associated muscle pain.
The disorder can occur as an isolated autoimmune
muscle disease or as part of a specific connective
tissue disease, such as systemic lupus 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.
USE OF IVIG FOR NEUROLOGIC CONDITIONS S101
The only case series, by Cherin et al,123 which
investigated IVIG exclusively in patients with
polymyositis, observed clinical improvement in
71% (25/35) of patients and reported significant
improvement in muscle power, muscle disability
scores, and CK levels (P b .01) after IVIG. There
was also a significant reduction in mean steroid
dose after treatment with IVIG (P b .05).
All 3 studies that included patients with
polymyositis or dermatomyositis presented pooled
data, and it was not possible to determine the
outcome of IVIG treatment for only those patients
with polymyositis.47-49 Refer to Table 28 for
further details.
Interpretation and Consensus
Many patients with polymyositis will respond
to first-line therapies (eg, steroids). The expert
panel discussed and agreed that it is reasonable
to include IVIG among the options for those
patients with polymyositis who fail to respond to
first-line therapies. The panel also agreed a
skeletal muscle biopsy is required to diagnosis
polymyositis and that the biopsy specimen
should be examined by an expert in 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.
Based on consensus by the expert panel, IVIG
may be considered among the treatment options for
patients with polymyositis who fail to respond to
first-line therapies (eg, steroids).
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days is a
reasonable initial treatment option. For patients
requiring IVIG maintenance therapy, a systematic
approach should be taken to determine the 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
Clinical Description
Rasmussen’s encephalitis is a rare progressive
form of epilepsy with onset in the first decade of life.
The disorder is associated with severe focal 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).
Interpretation and Consensus
The rationale for use of IVIG is based on the
premise of an infectious or peri-infectious etiology
for Rasmussen’s encephalitis and the possibility of
circulating GLUR2 antibodies. The expert panel
agreed that, although the available evidence is
quite limited, it does suggest IVIG may be of
transient benefit for some patients with 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
Intravenous immune globulin is not recommen-
ded for long-term therapy for Rasmussen’s en-
cephalitis as surgical treatment is the current
standard of care.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days for adults and
over 2 days for children is a reasonable option.
STIFF PERSON SYNDROME
Clinical Description
Stiff person syndrome is an uncommon 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
The bAppropriateness of IVIGQ evidence reviewidentified one randomized controlled trial that
assessed use of IVIG for stiff person syndrome
(level of evidence: 1b). This small crossover trial
of 14 patients reported a significant direct effect of
treatment with IVIG compared with placebo on
improvements in both mean stiffness scores (P =
.01) and mean sensitivity scores (P = .03). A
carryover treatment effect of IVIG was identified
with patients who received IVIG first maintaining
improvements in stiffness during the 1-month
washout period and into the placebo phase (P b
.001) (Table 30).
Interpretation and Consensus
The available evidence, although limited to
1 small randomized controlled trial, suggests IVIG
could play a role in the treatment of stiff person
syndrome. In the opinion of the panel, gabaergic
medications should remain first-line treatment of
this disorder. Based on consensus by the expert
panel, IVIG is a reasonable treatment option if
gabaergic medications fail or for patients who have
contraindications to gabaergic medications.
Recommendation
Intravenous immune globulin is recommended
as an option for treatment of stiff person syndrome
if gabaergic medications fail or for patients who
have contraindications to gabaergic medications.
Dose and Duration
Based on consensus by the expert panel, a total
dose of 2 g/kg given over 2 to 5 days for adults and
over 2 days for children is a reasonable initial
treatment option. For patients requiring IVIG
maintenance therapy, a systematic approach should
be taken to determine the minimum effective dose,
and continued use of IVIG should be based on
objective measures of its sustained effectiveness.
The maximum dose of IVIG per treatment course
should be 2 g/kg.
EXTERNAL REVIEW
Process
Feedback on this practice guideline was
obtained from neurologists in Canada. The process
was informed by the Practitioner Feedback 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
USE OF IVIG FOR NEUROLOGIC CONDITIONS S103
agreed or strongly agreed with the draft guideline’s
recommendations for use of IVIG. Approximately
90% (11/12) of respondents indicated that the
guidelines would be useful in optimizing practice
and 83% (10/12) of respondents agreed that they
would use the guidelines in their practice. Overall,
33% (9/27) of respondents provided written 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
RENCES
intravenous immunoglobulin. Transfus Med Rev 17:241-251,
2003
2. Chalmers Research Institute. IVIG systematic reviews.
Unpublished
3. Feasby TE. Appropriateness of IVIG—Hematology
summaries. Unpublished
4. Phillips B, Ball C, Sackett D, et al: Levels of evidence.
www.eboncall.org/content/levels.html, 2002
5. Browman GP, Newman TE, Mohide EA, et al: Progress of
clinical oncology guidelines development using the practice
guidelines development cycle: The role of practitioner feedback.
J Clin Oncol 16:1226-1231, 1998
6. Andersen JB, Rasmussen LH, Herning M, et al:
Dramatic improvement of severe acute disseminated enceph-
alomyelitis after treatment with intravenous immunoglobulin
in a three-year-old boy. Dev Med Child Neurol 43:136-138,
2001
7. Assa A, Watemberg N, Bujanover Y, et al: Demyelinative
brainstem encephalitis responsive to intravenous immunoglob-
ulin therapy. Pediatrics 104:301-303, 1999
8. Balestri P, Grosso S, Acquaviva A, et al: Plasmapheresis in
a child affected by acute disseminated encephalomyelitis. Brain
Dev 22:123-126, 2000
9. Jaing TH, Lin KL, Chiu CH, et al: Acute disseminated
encephalomyelitis in autoimmune hemolytic anemia. Pediatric
Neurology 24:303-305, 2001
10. Kleiman M, Brunquell P: Acute disseminated encepha-
lomyelitis: Response to intravenous immunoglobulin. J Child
Neurol 10:481-483, 1995
FEASBY ET ALS104
11. Nishikawa M, Ichiyama T, Hayashi T, et al: Intravenous
immunoglobulin therapy in acute disseminated encephalomy-
elitis. Pediatr Neurol 21:583-586, 1999
12. Pradhan S, Gupta RP, Shashank S, et al: Intravenous
immunoglobulin therapy in acute disseminated encephalomy-
elitis. J Neurol Sci 165:56-61, 1999
13. Shahar E, Andraus J, Savitzki D, et al: Outcome of severe
encephalomyelitis in children: Effect of high-dose methylpred-
nisolone and immunoglobulins. J Child Neurol 17:810-814,
2002
14. Straussberg R, Schonfeld T, Weitz R, et al: Improvement
of atypical acute disseminated encephalomyelitis with steroids
and intravenous immunoglobulins. Pediatr Neurol 24:139-143,
2001
15. Apak RA, Anlar B, Saatci I: A case of relapsing acute
disseminated encephalomyelitis with high dose corticosteroid
treatment. Brain Dev 21:279-282, 1999
16. Hahn JS, Siegler DJ, Enzmann D: Intravenous gamma-
globulin therapy in recurrent acute disseminated encephalomy-
elitis. Neurology 46:1173-1174, 1996
17. Mariotti P, Batocchi AP, Colosimo C, et al: Multi-
phasic demyelinating disease involving central and periph-
eral nervous system in a child. Neurology 60:348-349,
2003
18. Pittock SJ, Keir G, Alexander M, et al: Rapid clinical and
CSF response to intravenous gamma globulin in acute dissem-
inated encephalomyelitis. Eur J Neurol 8:725 2001
19. Revel-Vilk S, Hurvitz H, Klar A, et al: Recurrent acute
disseminated encephalomyelitis associated with acute cytomeg-
alovirus and Epstein-Barr virus infection. J Child Neurol
15:421-424, 2000
20. Finsterer J, Grass R, Stollberger C, et al: Immunoglobu-
lins in acute, parainfectious, disseminated encephalo-myelitis.
Clin Neuropharmacol 21:258-261, 1998
21. Fox RJ, Kasner SE, Galetta SL, et al: Treatment of
Bickerstaff’s brainstem encephalitis with immune globulin.
J Neurol Sci 178:88-90, 2000
22. Marchioni E, Marinou-Aktipi K, Uggetti C, et al:
Effectiveness of intravenous immunoglobulin treatment in adult
patients with steroid-resistant monophasic or recurrent acute
disseminated encephalomyelitis. J Neurol 249:100-104, 2002
23. Nakamura N, Nokura K, Zettsu T, et al: Neurologic
complications associated with influenza vaccination: Two adult
cases. Intern Med 42:191-194, 2003
24. Sahlas DJ, Miller SP, Guerin M, et al: Treatment of acute
disseminated encephalomyelitis with intravenous immunoglob-
ulin. Neurology 54:1370-1372, 2000
25. Rodriguez M, Lennon VA: Immune globulins promote
remyelination in the CNS. Ann Neurol 27:12 -17, 1990
26. Cappa M, Bertini E, del Balzo P, et al: High dose
immunoglobulin IV treatment in adrenoleukodystrophy. J Neurol
Neurosurg Psychiatry 57:71[Suppl 69-70] 1994
27. Meucci N, Nobile-Orazio E, Scarlato G: Intravenous
immunoglobulin therapy in amyotrophic lateral sclerosis.
J Neurol 243:117 -120, 1996
28. Dalakas MC, Stein DP, Otero C, et al: Effect of high-dose
intravenous immunoglobulin on amyotrophic lateral sclerosis
and multifocal motor neuropathy. Arch Neurol 51:861-864,
1994
29. Gupta S, Aggarwal S, Heads C: Dysregulated immune
system in children with autism: Beneficial effects of intravenous
immune globulin on autistic characteristics. J Autism Dev
Disord 26:439-452, 1996
30. DelGiudice-Asch G, Simon L, Schmeidler J, et al: Brief
report: A pilot open clinical trial of intravenous immunoglobulin
in childhood autism. J Autism Dev Disord 29:157-160, 1999
31. Plioplys AV: Intravenous immunoglobulin treatment of
children with autism. J Child Neurol 13:79 -82, 1998
32. Van Schaik IN, Winer JB, De Haan R, et al: 1. Cochrane
Review: Intravenous immunoglobulin for chronic inflammatory
demyelinating polyradiculoneuropathy. (Download in two
parts). Cochrane Database Syst RevCD001797 2002
33. Hahn AF, Bolton CF, Zochodne D, et al: Intravenous
immunoglobulin treatment in chronic inflammatory demyelin-
ating polyneuropathy. A double-blind, placebo-controlled,
cross-over study. Brain 119:1067-1077, [Pt 4] 1996
34. Mendell JR, Barohn RJ, Freimer ML, et al: Randomized
controlled trial of IVIG in untreated chronic inflammatory
demyelinating polyradiculoneuropathy. Neurology 56:445-449,
2001
35. Thompson N, Choudhary P, Hughes RA, et al: A novel
trial design to study the effect of intravenous immunoglobulin in
chronic inflammatory demyelinating polyradiculoneuropathy.
J Neurol 243:280 -285, 1996
36. Vermeulen M, van Doorn PA, Brand A, et al: Intravenous
immunoglobulin treatment in patients with chronic inflamma-
tory demyelinating polyneuropathy: A double blind, placebo
controlled study. J Neurol Neurosurg Psychiatry 56:36 -39,
1993
37. Van Doom PA, Brand A, Strengers PF, et al: High-dose
intravenous immunoglobulin treatment in chronic inflammatory
demyelinating polyneuropathy: A double-blind, placebo-con-
trolled, crossover study. Neurology 40:209-212, 1990
38. Dyck PJ, Litchy WJ, Kratz KM, et al: A plasma
exchange versus immune globulin infusion trial in chronic
inflammatory demyelinating polyradiculoneuropathy. Ann
Neurol 36:838-845, 1994
39. Hughes R, Bensa S, Willison H, et al: Randomized
controlled trial of intravenous immunoglobulin versus oral
prednisolone in chronic inflammatory demyelinating polyradi-
culoneuropathy. Ann Neurol 50:195-201, 2001
40. Kubori T, Mezaki T, Kaji R, et al: The clinical usefulness
of high-dose intravenous immunoglobulin therapy for chronic
inflammatory demyelinating polyneuropathy and multifocal
motor neuropathy (Japanese). No to Shinkei 51:127-135, 1999
41. Mohr M, Englisch L, Roth A, et al: Effects of early
treatment with immunoglobulin on critical illness polyneurop-
athy following multiple organ failure and gram-negative sepsis.
Intensive Care Med 23:1144-1149, 1997
42. Wijdicks EF, Fulgham JR: Failure of high dose
intravenous immunoglobulins to alter the clinical course of
critical illness polyneuropathy. Muscle Nerve 17:1494-1495,
1994
43. Dalakas MC, Illa I, Dambrosia JM, et al: A controlled trial
of high-dose intravenous immune globulin infusions as treat-
ment for dermatomyositis. N Engl J Med 329:1993-2000, 1993
44. Al-Mayouf SM, Laxer RM, Schneider R, et al: Intrave-
nous immunoglobulin therapy for juvenile dermatomyositis—
Efficacy and safety. J Rheumatol 27:2498-2503, 2000
45. Sansome A, Dubowitz V: Intravenous immunoglobulin in
juvenile dermatomyositis—Four year review of nine cases. Arch
Dis Child 72:25 -28, 1995
USE OF IVIG FOR NEUROLOGIC CONDITIONS S105
46. Tsai MJ, Lai CC, Lin SC, et al. Intravenous immuno-
globulin therapy in juvenile dermatomyositis. Zhonghua Min
Guo Xiao Erke Yi Xue Hui Za Zhi 1997;38:111-5.
47. Danieli MG, Malcangi G, Palmieri C, et al: Cyclosporin A
and intravenous immunoglobulin treatment in polymyositis/
dermatomyositis. Ann Rheum Dis 61:37 -41, 2002
48. Cherin P, Herson Serge: Indications for intravenous
gammaglobulin therapy in inflammatory myopathies. J Neurol
Neurosurg Psychiatry50 -54,[57 Suppl] 1994
49. Cherin P, Piette JC, Wechsler B, et al: Intravenous gamma
globulin as first line therapy in polymyositis and dermatomyo-
sitis: An open study in 11 adult patients. J Rheumatol 21:1092-
1097, 1994
50. Sharma KR, Cross J, Farronay O, et al: Demyelinating
neuropathy in diabetes mellitus. Arch Neurol 59:758-765, 2002
51. Cocito D, Ciaramitaro P, Isoardo G, et al: Intravenous
immunoglobulin as first treatment in diabetics with concomitant
distal symmetric axonal polyneuropathy and CIDP. J Neurol
249:719-722, 2002
52. Jaradeh SS, Prieto TE, Lobeck LJ: Progressive poly-
radiculoneuropathy in diabetes: Correlation of variables and
clinical outcome after immunotherapy. J Neurol Neurosurg
Psychiatry 67:607-612, 1999
53. Krendel DA, Costigan DA, Hopkins LC: Successful
treatment of neuropathies in patients with diabetes mellitus.
Arch Neurol 52:1053-1061, 1995
54. Zochodne DW, Isaac D, Jones C: Failure of immuno-
therapy to prevent, arrest or reverse diabetic lumbosacral
plexopathy. Acta Neurol Scand 107:299-301, 2003
55. Bril V, Ilse WK, Pearce R, et al: Pilot trial of
immunoglobulin versus plasma exchange in patients with
Guillain-Barre syndrome. Neurology 46:100-103, 1996
56. Diener HC, Haupt WF, Kloss TM, et al: A preliminary,
randomized, multicenter study comparing intravenous immuno-
globulin, plasma exchange, and immune adsorption in Guillain-
Barre syndrome. Eur Neurol 46:107-109, 2001
57. Plasma Exchange/Sandoglobulin Guillain-Barre Syn-
drome Trial Group: Randomised trial of plasma exchange,
intravenous immunoglobulin, and combined treatments in
Guillain-Barre syndrome. Lancet 349:225-230, 1997
58. van der Meche FG, Schmitz PI: A randomized trial
comparing intravenous immune globulin and plasma exchange
in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group.
N Engl J Med 326:1123-1129, 1992
59. Nomura T, Hamaguchi K, Hosakawa T, et al: A
randomized trial comparing intravenous immunoglobulin and
plasmapheresis in Guillain-Barre syndrome. Neurol Therapeut
18:68 -81, 2001
60. Hughes RAC, Raphael JC, Swan AV, et al: Systematic
review: Intravenous immunoglobulin for Guillain-Barre syn-
drome. Cochrane Database Syst Rev NeurolCD002063 2003
61. Hosokawa T, Hamaguchi K, Tomioka R, et al: Compar-
ative study of efficacy of plasma exchange versus intravenous
gammaglobulin treatment on acute postinfectious polyradiculo-
neuropathy: A preliminary report. Ther Apher 2:288-291, 1998
62. Martinez YA, Huerta VM, Olive PM, et al: Treatment of
Guillain-Barre syndrome: Immunoglobulins or plasmapheresis?.
Neurologia 134:166-169,(Spanish) 1998
63. El Zunni S, Prakash PS, Saiti KM, et al: Guillain-Barre
syndrome (GBS): An appraisal. Cent Afr J Med 43:99 -103,
1997
64. Gurses N, Uysal S, Cetinkaya F, et al: Intravenous
immunoglobulin treatment in children with Guillain-Barre
syndrome. Scand J Infect Dis 27:241-243, 1995
65. Raphael JC, Chevret S, Hughes RA, et al: 1. Systematic
review: Plasma exchange for Guillain-Barre syndrome.
Cochrane Database Syst RevCD001798(in 2 parts) 2001
66. Haupt WF, Rosenow F, van der Ven C, et al: Sequential
treatment of Guillain-Barre syndrome with extracorporeal
elimination and intravenous immunoglobulin. J Neurol Sci
137:145-149, 1996
67. Walter MC, Lochmuller H, Toepfer M, et al: High-dose
immunoglobulin therapy in sporadic inclusion body myositis: A
double-blind, placebo-controlled study. J Neurol 247:22-28,
2000
68. Dalakas MC, Sonies B, Dambrosia J, et al: Treatment of
inclusion-body myositis with IVIG: A double-blind, placebo-
controlled study. Neurology 48:712-716, 1997
68a. Dalakas MC, Koffman B, Fujii M, et al: A controlled
study of intravenous immunoglobulin combined with predni-
sone in the treatment of IBM. Neurology 56:323-327, 2001
69. van Rijckevorsel-Harmant K, Delire M, Schmitz-Moor-
man W, et al: Treatment of refractory epilepsy with intravenous
immunoglobulins. Results of the first double-blind/dose finding
clinical study. Int J Clin Lab Res 24:162-166, 1994
70. Illum N, Taudorf K, Heilmann C, et al: Intravenous
immunoglobulin: A single blind trial in children with Lennox-
Gastaut syndrome. Neuropediatrics 21:87 -90, 1990
71. Bain PG, Motomura M, Newsom-Davis J, et al: Effects of
intravenous immunoglobulin on muscle weakness and calcium-
channel autoantibodies in the Lambert-Eaton myasthenic
syndrome. Neurology 47:678-683, 1996
72. van Schaik IN, van den Berg LH, de Haan R: Intravenous
immunoglobulin for multifocal motor neuropathy. Cochrane
Database Syst RevCD004429 2005
73. Azulay JP, Blin O, Pouget J, et al: Intravenous immuno-
globulin treatment in patients with motor neuron syndromes
associated with anti-GM1 antibodies: A double-blind, placebo-
controlled study. Neurology 44:429-432,[3 Pt 1] 1994
74. Federico P, Zochodne DW, Hahn AF, et al: Multifocal
motor neuropathy improved by IVIg: Randomized, double-
blind, placebo-controlled study. Neurology 55:1256-1262, 2000
75. Leger JM, Chassande B, Musset L, et al: Intravenous
immunoglobulin therapy in multifocal motor neuropathy: A
double-blind, placebo-controlled study. Brain 124:145 -153,
[Pt 1] 2001
76. Van den Berg LH, Kerkhoff H, Oey PL, et al: Treatment
of multifocal motor neuropathy with high dose intravenous
immunoglobulins: A double blind, placebo controlled study.
J Neurol Neurosurg Psychiatry 59:248-252, 1995
77. Poehlau D: Treatment of chronic progressive multiple
sclerosis with intravenous immunoglobulins–interim results on
drug safety of an ongoing study. IVIG study group. Mult Scler
6:S21[Suppl 2] 2000
77a. Fazekas F, Freedman MS, Hartung HP, et al: Prevention
of relapse with intravenous immunoglobin study: Initial results
of a dose-finding trial in relapsing-remitting multiple sclerosis.
European Neurological Society, May 2006
78. Sorensen PS, Fazekas F, Lee M: 1. Meta analysis:
Intravenous immunoglobulin G for the treatment of relapsing-
remitting multiple sclerosis: A meta-analysis. Eur J Neurol
9:557-563, 2002
FEASBY ET ALS106
79. Achiron A, Gabbay U, Gilad R, et al: RRMS: Intravenous
immunoglobulin treatment in multiple sclerosis. Effect on
relapses. Neurology 50:398-402, 1998
80. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al:
RRMS: Randomised placebo-controlled trial of monthly intra-
venous immunoglobulin therapy in relapsing-remitting multiple
sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study
Group. Lancet 349:589-593, 1997
81. Lewanska M, Siger-Zajdel M, Selmaj K: RRMS: No
difference in efficacy of two different doses of intravenous
immunoglobulins in MS: Clinical and MRI assessment. Eur J
Neurol 9:565-572, 2002
82. Oztekin NaO: Intravenous immunoglobulin treatment in
relapsing-remitting multiple sclerosis: A double blind cross over
study. Mult Scler 4:391 1998
83. Sorensen PS, Wanscher B, Jensen CV, et al: RRMS:
Intravenous immunoglobulin G reduces MRI activity in
relapsing multiple sclerosis. Neurology 50:1273 -1281, 1998
84. Achiron A, Barak Y, Goren M, et al: Intravenous immune
globulin in multiple sclerosis: Clinical and neuroradiological
results and implications for possible mechanisms of action. Clin
Exp Immunol 104:67-70,[Suppl 1] 1996
85. Teksam M, Tali T, Kocer B, et al: RRMS: Qualitative and
quantitative volumetric evaluation of the efficacy of intravenous
immunoglobulin in multiple sclerosis: Preliminary report.
Neuroradiology 42:885-889, 2000
86. Hommes OT, Sorensen PS, Fazekas F, et al: for the
European Study on Immunoglobulin in Multiple Sclerosis
trialistsIntravenous immunoglobulin in secondary progressive
multiple sclerosis: Randomised placebo-controlled trial. Mult
Scler 364:1149-1156, 2003
87. Noseworthy JH, O’Brien PC, Weinshenker BG, et al: IV
immunoglobulin does not reverse established weakness in MS.
Neurology 55:1135-1143, 2000
88. Noseworthy JH, O’Brien PC, Petterson TM, et al: A
randomized trial of intravenous immunoglobulin in inflamma-
tory demyelinating optic neuritis. Neurology 56:1514-1522,
2001
89. Poehlau D: Results of double-blind, randomised, placebo-
controlled pilot study on the treatment of multiple sclerosis with
intravenous immunoglobulin. Eur J Neurol 3, 1996 (Suppl 4)
90. Gajdos P, Chevret S, Toyka K: 1. Systematic review:
Intravenous immunoglobulin for myasthenia gravis. Cochrane
Database Syst RevCD002277 2003
91. Gajdos P, Chevret S, Clair B, et al: Clinical trial of plasma
exchange and high-dose intravenous immunoglobulin in myas-
thenia gravis. Myasthenia Gravis Clinical Study Group. Ann
Neurol 41:789-796, 1997
92. Ronager J, Ravnborg M, Hermansen I, et al: Immuno-
globulin treatment versus plasma exchange in patients with
chronic moderate to severe myasthenia gravis. Artif Organs
25:967-973, 2001
93. Wolfe GI, Barohn RJ, Foster BM, et al: Randomized,
controlled trial of intravenous immunoglobulin in myasthenia
gravis. Muscle Nerve 26:549-552, 2002
94. Achiron A, Barak Y, Miron S, et al: Immunoglobulin
treatment in refractory myasthenia gravis. Muscle Nerve
23:551-555, 2000
95. Cosi V, Lombardi M, Piccolo G, et al: Treatment of
myasthenia gravis with high-dose intravenous immunoglobulin.
Acta Neurol Scand 84:81 -84, 1991
96. Hilkevich O, Drory VE, Chapman J, et al: The use of
intravenous immunoglobulin as maintenance therapy in myas-
thenia gravis. Clin Neuropharmacol 24:173-176, 2001
97. Huang CS, Hsu HS, Kao KP, et al: Intravenous
immunoglobulin in the preparation of thymectomy for myas-
thenia gravis. Acta Neurol Scand 108:136-138, 2003
98. Wegner B, Ahmed I: Intravenous immunoglobulin
monotherapy in long-term treatment of myasthenia gravis. Clin
Neurol Neurosurg 105:3 -8, 2002
99. Wilson JR, Bhoopalam H, Fisher M: Hemolytic anemia
associated with intravenous immunoglobulin. Muscle Nerve
20:1142-1145, 1997
100. Herrmann DN, Carney PR, Wald JJ: Juvenile myasthe-
nia gravis: Treatment with immune globulin and thymectomy.
Pediatr Neurol 18:63 -66, 1998
101. Selcen D, Dabrowski ER, Michon AM, et al: High-dose
intravenous immunoglobulin therapy in juvenile myasthenia
gravis. Pediatr Neurol 22:40 -43, 2000
102. Tagher RJ, Baumann R, Desai N: Failure of intrave-
nously administered immunoglobulin in the treatment of
neonatal myasthenia gravis. J Pediatr 134:233-235, 1999
103. Bassan H, Muhlbaur B, Tomer A, et al: High-dose
intravenous immunoglobulin in transient neonatal myasthenia
gravis. Pediatr Neurol 18:181-183, 1998
104. Bataller L, Graus F, Saiz A, et al: Clinical outcome in
adult onset idiopathic or paraneoplastic opsoclonus-myoclonus.
Brain 124:437-443, [Pt 2] 2001
105. Pless M, Ronthal M: Treatment of opsoclonus-myoclo-
nus with high-dose intravenous immunoglobulin. Neurology
46:583-584, 1996
106. Pranzatelli MR, Tate ED, Kinsbourne M, et al: Forty-one
year follow-up of childhood-onset opsoclonus-myoclonus-atax-
ia: Cerebellar atrophy, multiphasic relapses, and response to
IVIG. Mov Disord 17:1387-1390, 2002
107. Sugie H, Sugie Y, Akimoto H, et al: High-dose i.v. human
immunoglobulin in a case with infantile opsoclonus polymyo-
clonia syndrome. Acta Paediatr 81:371-372, 1992
108. Yiu VW, Kovithavongs T, McGonigle LF, et al:
Plasmapheresis as an effective treatment for opsoclonus-
myoclonus syndrome. Pediatr Neurol 24:72 -74, 2001
109. Penzien JM, Speck S, Vassella F: Opsoclonus poly-
myoclonia syndrome. Acta Paediatr 82:319-320, 1993
110. Petruzzi MJ, de Alarcon PA: Neuroblastoma-associated
opsoclonus-myoclonus treated with intravenously administered
immune globulin G. J Pediatr 127:328-329, 1995
111. Eiris J, del Rio M, Castro-Gago M: Immune globulin G
for treatment of opsoclonus-polymyoclonus syndrome. J Pediatr
129:175 1996
112. Borgna-Pignatti C, Balter R, Marradi P, et al: Treatment
with intravenously administered immunoglobulins of the neu-
roblastoma-associated opsoclonus-myoclonus. J Pediatr 129:
179 -180, 1996
113. Fisher PG, Wechsler DS, Singer HS: Anti-Hu antibody
in a neuroblastoma-associated paraneoplastic syndrome. Pediatr
Neurol 10:309-312, 1994
114. Lunn MP, Nobile-Orazio E: 1. Cochrane review:
Immunotherapy for IgM anti-myelin-associated glycoprotein
paraprotein-associated peripheral neuropathies. Cochrane Data-
base Syst RevCD002827 2003
115. ComiG, Roveri L, SwanA, et al: A randomised controlled
trial of intravenous immunoglobulin in IgM paraprotein associ-
ated demyelinating neuropathy. J Neurol 249:1370-1377, 2002
USE OF IVIG FOR NEUROLOGIC CONDITIONS S107
116. Dalakas MC, Quarles RH, Farrer RG, et al: A controlled
study of intravenous immunoglobulin in demyelinating neurop-
athy with IgM gammopathy. Ann Neurol 40:792-795, 1996
117. Mariette X, Chastang C, Clavelou P, et al: A randomised
clinical trial comparing interferon-alpha and intravenous immu-
noglobulin in polyneuropathy associated with monoclonal IgM.
The IgM-associated Polyneuropathy Study Group. J Neurol
Neurosurg Psychiatry 63:28 -34, 1997
118. Perlmutter SJ, Leitman SF, Garvey MA, et al: Thera-
peutic plasma exchange and intravenous immunoglobulin for
obsessive-compulsive disorder and tic disorders in childhood.
Lancet 354:1153-1158, 1999
119. Dispenzieri A: POEMS syndrome. Hematology (Am
Soc Hematol Educ Program) 360-367, 2005
120. Benito-Leon J, Lopez-Rios F, Rodriguez-Martin FJ, et al:
Rapidly deteriorating polyneuropathy associated with osteo-
sclerotic myeloma responsive to intravenous immunoglobulin
and radiotherapy. J Neurol Sci 158:113-117, 1998
121. Henze T, Krieger G: Combined high-dose 7S-IgG and
dexamethasone is effective in severe polyneuropathy of the
POEMS syndrome. J Neurol 242:482-483, 1995
122. Huang CC, Chu CC: Poor response to intravenous
immunoglobulin therapy in patients with Castleman’s disease
and the POEMS syndrome. J Neurol 243:726-727, 1996
123. Cherin P, Pelletier S, Teixeira A, et al: Results and
long-term follow up of intravenous immunoglobulin infu-
sions in chronic, refractory polymyositis: An open study
with thirty-five adult patients. Arthritis Rheum 46:467-474,
2002
124. Granata T, Fusco L, Gobbi G, et al: Experience with
immunomodulatory treatments in Rasmussen’s encephalitis.
Neurology 61:1807-1810, 2003
125. Korn-Lubetzki I, Bien CG, Bauer J, et al: Rasmussen
encephalitis with active inflammation and delayed seizures
onset. Neurology 62:984-986, 2004
126. Frucht S: Dystonia, athetosis, and epilepsia partialis
continua in a patient with late-onset Rasmussen’s encephalitis.
Mov Disord 17:609-612, 2002
127. Villani F, Spreafico R, Farina L, et al: Positive response
to immunomodulatory therapy in an adult patient with
Rasmussen’s encephalitis. Neurology 56:248-250, 2001
128. Leach JP, Chadwick DW, Miles JB, et al: Improve-
ment in adult-onset Rasmussen’s encephalitis with long-
term immunomodulatory therapy. Neurology 52:738-742,
1999
129. Dalakas MC, Fujii M, Li M, et al: High-dose intravenous
immune globulin for stiff-person syndrome. N Engl J Med
345:1870-1876, 2001
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