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Treatment of Acute Immune-mediated Neuropathies: Guillain-Barr Syndrome and Clinical Variants

Benson H. Sederholm, Pharm.D., B.C.P.S. Semin Neurol. 2010;30(4):365-372.

Abstract and Introduction

Abstract

The author reviews current treatment approaches for the management of acute immune-mediated peripheral neuropathies, including the Guillain-Barr syndrome together with the clinical variants, which are acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and the Fisher syndrome. A summary of clinical evidence for drug therapies is provided, with additional recommendations for commonly used treatment modalities including a focus on the approach to using intravenous immune globulin and plasma exchange therapy.
Introduction

The acute immune-mediated peripheral neuropathies represent a challenging but treatable array of disorders for the clinical neurologist. Commonly used treatment strategies include therapeutic plasma exchange (PE) and intravenous immune globulin (IVIG). Although these therapies are effective, questions regarding dosing, timing, and concern for adverse events or poor tolerability often hinder their use in clinical practice. For some immune neuropathies, sufficient clinical evidence and guidelines are available to aid the clinician in providing appropriate therapy, as in the case of IVIG for the treatment of Guillain-Barr syndrome (GBS). The term GBS can be used to denote a syndrome that includes acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and variants, or for AIDP alone. Variant neuropathies of GBS include acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and the Fisher syndrome (FS). In the context of treatment, there are more data for AIDP and only limited data for the rare variants. The purpose of this article is to provide helpful information to guide the clinician on the appropriate use of PE and IVIG in GBS, and to provide a brief summary of the evidence for these and other therapies used in the treatment of acute immune-mediated neuropathies.

Use of Plasma Exchange in Immune-mediated Neuropathies

Therapeutic PE is an efficacious treatment option for patients with inflammatory neuropathies and is considered a first-line therapy in conditions such as AIDP.[1,2] The basic mechanism for PE is the elimination of offending toxins or pathologic autoimmune antibodies from the bloodstream through extracorporeal separation from blood components. During PE, a patient's plasma and cells are separated through centrifugation or a filtration process.[3] While the cells are reinfused into the patient, the plasma is replaced by a substitute fluid, usually albumin or fresh frozen plasma at a volume of 45 to 50 mL/kg. Plasma exchange requires two large bore access sites at alternate locations with a central line generally necessary due to the high flow volumes associated with treatment. Although effective, PE is invasive and can be time consuming, inconvenient, and overly burdensome to some. It also requires specialized personnel within an institutional setting who are able to run the necessary equipment. In addition to vascular access or technical complications, the use of PE may be further thwarted by troublesome or intolerable adverse reactions. Patients undergoing PE should be closely monitored for hypotension, infection, bleeding complications, and hypocalcemia.[4] Chest pain, tachycardia, bradycardia, fever, rash, itching, nausea, vomiting, flushing, and dizziness may also occur in patients undergoing PE.[5] More severe complications, including pulmonary embolism, sepsis, and anaphylactic shock have also been reported.[2] Blood pressure instability is a common adverse event with PE and patients who are hemodynamically unstable are poor candidates for treatment. Drops in mean systolic blood pressure of ~10 mmHg do occur; however, mild hypotensive events (SBP < 95 mmHg) are more common than severe (SBP < 85 mmHg) events.[5] Antihypertension medications should be used judiciously in patients undergoing PE. Angiotensin-converting enzyme (ACE) inhibitors are often withheld for 48 to 72 hours before initiating PE. Patients taking ACE inhibitors and undergoing PE are at a higher risk for bradykinin-mediated adverse events, including hypotension, flushing, bradycardia, and dyspnea. The hypocalcemic events seen during PE are typically associated with the use of anticoagulant citrate solutions. Baseline measurements of ionized calcium help guide the need for calcium replacement, either as an oral substitute or as an intravenous (IV) infusion, such as 1000 mg of calcium gluconate. Fibrinogen, platelet count, and other coagulation parameters should also be closely monitored in patients undergoing PE. Fibrinogen and clotting factors are readily removed during PE and a drop in platelet count is often reported. In general, platelet counts and clotting factors return to baseline within 24 to 48 hours following a PE session. For patients undergoing a series of exchanges, usually a 24-hour separation period between sessions helps avoid a too rapid depletion of hemostatic factors. Additional replacement infusions of platelets or fresh frozen plasma may be necessary in some. Because of the potential complications of therapy and the availability of treatment alternatives, it is important to keep in mind that some patients are not suitable candidates for PE. Patients who are pregnant, hemodynamically unstable, or who are actively infected should not undergo PE. In addition PE is costly, and may not be feasible to administer in some treatment centers. Although IVIG is likewise expensive, available clinical data suggest that patients receiving PE are more likely to experience complications and have a higher dropout rate compared with IVIG.[6]

Use of IVIG in Immune-mediated Neuropathies

IVIG is a first-line agent for the treatment of many neurologic disorders including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and GBS. The mechanism of action is not fully known, but it is thought to involve modulation of cellular and humoral immune system processes including antibody neutralization, complement attenuation, and the regulation of cytokine, B cell, and T cell activity. Therapeutic IVIG product is derived from the isolation of immunoglobulin from multiple human donor sources. The final product comes from a highly involved process involving plasma fractionation, purification, stabilization, and virus inactivation and removal. Commercially available IVIG products vary in how they are formulated and manufactured. Because of this, clinical impact is not insignificant and product differences should be considered when evaluating the clinical efficacy and safety of IVIG therapy for a given patient. Components to consider include volume load, infusion rate, osmolality, sodium content, sugar content, pH, and IgA content. Products with a higher sugar component may not be suitable for patients who are elderly, have diabetes, or at risk for renal dysfunction. Likewise products high in salt or osmolality may be a problem in patients with cardiac diseases, renal dysfunction, risk for venous thromboembolism, and in elderly or pediatric populations. As the incidence of adverse events may be related to patient characteristics, individualized products and their unique components should be evaluated judiciously. lists the currently available IVIG products

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and how they differ.

Table 1. Intravenous Immunoglobulin Product Comparison
8,9

Product

Labeled Available Product Indication Doses Form

Half-life IgG IgA Sodium Osmolality (days) Content Content Content

Sugar Content

pH

Infusion Rate

Filtration

Carimune NF (CSL Behring PID ITP LLC, Kankakee, IL)

3, 6, 12 gram vials

Lyophilized 21 powder

96%

720 g/mL

<20 mg per gram of protein

192-1074 mOsm/kg based upon diluent and concentration

Initial: 0.5 1.67 mg/kg/min grams of Titrate as sucrose 6.46.8 tolerated to Not required per gram maintenance of protein infusion of 3 mg/kg/min Initial: 0.5 mg/kg/min 5 g/100 Titrate as Recommended mL 5.06.0 tolerated to 1520 micron D-sorbitol maintenance infusion of 5 mg/kg/min Initial: 0.8 mg/kg/min Titrate as tolerated to 4.65.1 Not required maintenance infusion of 8.9 mg/kg/min Initial: 0.5 mL/kg/h Titrate as tolerated to maintenance Required 15 6.47.2 rate of 4 micron mL/kg/h (8 mL/kg/h for 10% solution) Initial: 12 mg/kg/min Titrate as 4.04.5 tolerated to Not required maintenance infusion of 8 mg/kg/min Initial: 0.5 mg/kg/min Titrate as tolerated to 5.16.0 Not required maintenance infusion of 3.33 mg/kg/min Initial: 0.5 mg/kg/min Titrate as tolerated to 4.65.0 Not required maintenance infusion of 48 mg/kg/min

Flebogamma 5% DIF (Grifols Biologicals Inc., PID Los Angeles, CA)

0.5, 2.5, 5, 10, 20 Liquid gram vials

3045

97%

<50 g/mL

<3.2 mEq/L

240370 mOsm/L

Gammagard liquid 10% (Baxter Healthcare Corporation, Westlake Village, CA)

PID

1, 2.5, 5, 10, 20 Liquid gram vials

35

98%

Average Not 240300 37 detected mOsmol/kg g/mL

None

Gammagard S/D (Baxter Healthcare Corporation, Westlake Village, CA)

PID ITP KS CLL

2.5, 5, 10 gram vials

Lyophilized 37.7 powder

90%

<1 g/mL 8.5 in 5% mg/mL solution

636 - 1250 5%: 20 mOsm/L mg/mL based upon glucose concentration

Gamunex (Talecris Biotherapeutics, PID ITP Inc., Research CIDP Triangle Park, NC)

1, 2.5, 5, 10, 20 Liquid gram vials

35

98%

Average 46 Trace g/mL

258 mOsmol/kg

None

Octagam 5% (Octapharma USA Inc., Hoboken, NJ)

PID

1, 2.5, 5, 10, 25 Liquid gram vials

40.7

96%

0.2 mg/mL

30 mmol/L

310380 mOsmol/kg

100 mg/mL maltose

Privigen 10% (CSL Behring PID ITP LLC, Kankakee, IL)

5, 10, 20 gram Liquid vials

36.6

98%

25 g/mL

Trace

240440 mOsmol/kg

None

CIDP, Chronic inflammatory demyelinating polyradiculoneuropathy; CLL, chronic lymphocytic leukemia; ITP, idiopathic thrombocytopenic purpura; KS, Kawasaki syndrome; PID, primary immunodeficiency. The primary component of IVIG is immunoglobulin G, which is responsible for its therapeutic effects. The usual effective dose of IVIG for inflammatory neuropathies

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is 2 g per kg body weight, typically divided over 2 to 5 days. The rationale for this dose was initially based upon earlier studies of patients with idiopathic thrombocytopenia. The optimal dose of IVIG for neurologic disorders is not conclusively known. Following IVIG infusion, immunoglobulin G rapidly distributes within the intravascular and extravascular compartments with a peak serum concentration typically seen within 72 hours of infusion.[7] Although serum levels of IVIG are generally not measured, a recent pharmacokinetic study of IVIG in AIDP patients suggested that the change in serum immunoglobulin G levels may be predictive of therapeutic responses.[7] The half life of IVIG is ~20 days and immunoglobulins are primarily cleared in the plasma. Dosing of IVIG is typically done using total body weight. For obese patients (>100 kg), many clinicians use an adjusted body weight based upon IVIG pharmacokinetics. IVIG is generally well tolerated. Common adverse reactions include chills, fever, headache, fatigue, rigors, tremor, nausea, myalgias, malaise, and infusion-related reactions. More serious adverse events occur less frequently and include anaphylaxis, aseptic meningitis, acute renal failure, and venous thromboembolism. All patients receiving IVIG should have their vital signs checked at least every 15 minutes during the first hour of infusion and periodically thereafter. Surveillance for tolerability and adverse events should be done judiciously with each infusion session. Pretreatment with acetaminophen, antihistamines, such as diphenhydramine, or corticosteroids may help prevent or minimize adverse events.[8] Markers of renal function should be monitored before each IVIG infusion and periodically thereafter. Appropriate chemical or physical prophylaxis for venous thromboembolism is also warranted. Too rapid rate of infusion may contribute to the incidence of adverse effects. Typically, IVIG infusions are initiated at a slow rate and increased based upon patient tolerability. At any point during an infusion the rate can be decreased to improve tolerability. In general, patients with renal dysfunction should have their rate of infusion decreased by one half of the normal infusion rate. IVIG is expensive and its availability may be limited in some centers. The clinical decision to use IVIG over alternative therapies should be done on an individualized basis and include such factors as pregnancy, disease severity, patient comorbidities, and tolerability.

Treatment of Guillain-Barr Syndrome

The Guillain-Barr syndrome includes the clinical variants AIDP, AMAN, AMSAN, and FS. In general, early clinical studies either did not distinguish between these variants or excluded patients with axonal forms of GBS when conducting clinical trials with PE or IVIG in the 1980s and 1990s. As AIDP is the most common variant in North America and Europe, it is likely that the early trials from these regions largely consisted of patients with this variant. In more recent years, a few studies have reported on the efficacy and safety of PE and IVIG in patients with solely AMAN, AMSAN, and FS. However, more data for these individual variants are sorely needed and the bulk of the current clinical evidence for GBS treatment consists largely of patients with the AIDP variant.

Summary of Plasma Exchange Therapy in GBS/AIDP

Numerous trials over the past 30 years provide ample evidence for the efficacy of PE in the treatment of AIDP.[2,10,11] The beneficial effects of PE was summarized in a Cochrane systematic review published in 2008.[2] Results of this review found significant short- and long-term outcomes in favor of PE compared with supportive care. Reported outcomes at 4 weeks in favor of PE included a higher proportion of patients able to walk with or without assistance, improvement in disability scores by one point or more, less dependence upon ventilator support, and a shorter duration of ventilator days, as compared with patients receiving supportive care alone. Significant long-term outcome measures taken at 1-year endpoints demonstrated a higher proportion of patients with recovered muscle strength, less likelihood of motor dysfunction, and fewer relapses in patients receiving PE compared with supportive measures. In a large North American trial, 245 adults and children with severe GBS (of which the majority were likely the AIDP variant), were randomly assigned to receive three to five exchanges over a period of 7 to 14 days or a regimen of supportive care only.[12] By the end of 4 weeks, a higher proportion of patients who received PE required significantly fewer days of ventilator support and recovered the ability to walk without assistance more rapidly than those who received supportive care only. The necessary number of therapeutic exchanges was also evaluated in clinical trials.[2,10] In one trial of severe AIDP patients, no significant difference was seen in the time to recovery in patients undergoing four versus six exchanges. A similar trial found four exchanges more effective than two exchanges. In another trial of mild AIDP patients, beneficial outcomes were noted with two exchanges compared with none.[2,10] A practice parameter by the Quality Standards Subcommittee of the American Academy of Neurology in 2003[1] endorsed the use of PE within 4 weeks of disease onset in nonambulatory patients and within 2 weeks of onset in ambulatory patients with AIDP. The typical PE regimen consists of five exchanges given over a 1- to 2-week period. Each session involves the exchange of ~50 mL/kg of plasma volume, with albumin replacement typically preferred over fresh frozen plasma.[1,13] Ideally, PE should be started within 7 days of symptom onset, although patients receiving treatment within 30 days of disease onset are also likely to benefit.[2] Although PE effectively hastens recovery from AIDP, not all patients will tolerate it.[2] Additionally, some will demonstrate an inadequate response and others may subsequently relapse following initial benefit.[2] For these patients, repeat exchanges or alternative therapies are warranted.[14]

Summary of IVIG Therapy in GBS/AIDP

Clinical trials comparing IVIG to PE indicate equal benefit between the two treatment options in GBS. A Cochrane systematic review of six clinical trials found no difference in the change of disability scores with IVIG compared with PE at 4 weeks (RR = 1.09; 95% CI: 0.94-1.27).[6] Other nonsignificant differences between IVIG and PE included no difference in the time needed to recover unassisted walking and the time until discontinuation of ventilator support in severe AIDP patients. This review also found that patients treated with IVIG tended to have fewer adverse events, fewer treatment complications, and were less likely to discontinue therapy as compared with PE.[6] Complications with PE included infection, thrombosis, and hypotension. The largest trial in the systematic review included 383 severe AIDP patients who were randomized to receive IVIG 0.4 g/kg daily for 5 days, a course of five plasma exchanges administered over 8 to 13 days, or a combination of a 5-day course of PE followed by a 5-day course of IVIG therapy.[15] All patients received interventions within 14 days of symptom onset. For the primary outcome of mean improvement in disability score at week 4 from randomization, no difference was observed between treatment groups. Combination therapy was not superior to IVIG or PE alone. Study authors suggested that due to the convenience of IVIG administration, as compared with PE, it represents a more favorable treatment option in the bulk of circumstances.[15] A Quality Standards Subcommittee of the American Academy of Neurology endorsed IVIG as equivalent therapy to PE for AIDP patients.[1] Combination therapy with PE and IVIG was not recommended. The Subcommittee further recommended that IVIG be used promptly within 2 to 4 weeks of disease onset in severe AIDP patients unable to walk without assistance.[1] The usual IVIG treatment regimen is 0.4 g/kg given daily for 5 days.[16] For patients with inadequate response or who relapse following IVIG administration, a repeat course of IVIG may be beneficial.[17] provides a summary of PE and IVIG regimens used in AIDP, and lists the more common adverse reactions and severe complications associated with the use of these therapies.
Table 2. Summary of Plasma Exchange and Intravenous Immunoglobulin in the Management of Guillain-Barr Syndrome/Acute Inflammatory Demyelinating Polyradiculoneuropathy

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Interventional Regimen

Common Adverse Reactions

Severe Complications

Plasma exchange 5 treatments over Hypotension, arrhythmias, infection, malaise, fever, 7 to 14 days flushing, dizziness, hypocalcemia Intravenous immune globulin 0.4 g/kg daily for 5 days Headache, myalgia, chills, fever, nausea, vomiting, fatigue, tremor, infusion site reactions

Pneumothorax, hemorrhagic complications, sepsis, thromboembolism, anaphylaxis Acute renal failure, thromboembolism, aseptic meningitis, myocardial infarction, anaphylaxis

Summary of Corticosteroid Therapy in GBS/AIDP

Corticosteroids have failed to show conclusive benefit either alone or in combination with IVIG in clinical trials of patients with AIDP.[18,19] A Cochrane systematic review of six trials found no difference in the change of disability grade at 4 weeks in patients receiving corticosteroids or placebo.[18] In addition, trials evaluating the use of oral corticosteroids, such as prednisone 1 mg/kg daily, found that these agents delay rather than hasten recovery in AIDP.[18] One study of IVIG 0.4 g/kg daily for 5 days in combination with IV methylprednisolone 500 mg daily for 5 days or placebo showed a nonsignificant trend toward benefit in the change of disability scores at 4 weeks for combination therapy compared with IVIG alone (68% vs. 56%; p = 0.06).[19] This difference did reach significance when study authors adjusted study parameters for disease severity and age.[18,19] For the remaining secondary outcomes, no significant differences were noted in the time to walk independently, the number of days on ventilator support, or disability scores at 6 months between treatment groups.[19] Available clinical guidelines suggest that corticosteroids not be used in the treatment of AIDP.[1] However, IV methylprednisolone in combination with IVIG may offer a small short-term benefit.[16]

Additional and Supportive Therapies in GBS/AIDP

A few other immunomodulatory agents in AIDP have been evaluated for potential efficacy. A small, randomized, placebo-controlled clinical trial with interferon failed to show significant benefit in the rate of improvement when used in combination with IVIG therapy.[20] No difference in improved outcomes was likewise found in a small open-label trial comparing combination mycophenolate and IVIG to IVIG alone.[21] Supportive interventions play a critical role in the management of patients with GBS.[22] For the most part, data supporting the use of these agents in AIDP are limited to a few reports or small studies.[23,24] However, these agents are typically used in clinical practice and their place in therapy is recommended by expert opinion.[22] Chief among supportive pharmacotherapies is the need to adequately address the painful component of AIDP.[22] Neuropathic as well as nociceptive processes likely contribute to the pain processes experienced by many AIDP patients.[24] Therefore, analgesic regimens should include acetaminophen or nonsteroidal antiinflammatory drugs as well as antiepileptic drugs, such as gabapentin or carbamazepine as first-line therapies.[23,24] For patients inadequately controlled with these agents, opioid analgesics are warranted.[23] Significant pain relief has been noted in patients receiving oral, parenteral, and in more severe cases, epidural administration of opioid analgesics.[23,25] Other adjunctive agents that may play a role in pain management include tricyclic antidepressants and the weak opioid tramadol. Additional pharmacotherapies used as supportive measures include subcutaneous heparin or enoxaparin for deep vein thrombosis prophylaxis and low-dose neostigmine for prevention of gastrointestinal ileus formation.[22]

Treatment of Aman and Amsan

AIDP is the most common GBS variant in North America and European nations; the axonal variant AMAN is most often seen in Asian nations, including Japan and China. Although there are many clinical trials including patients with the demyelinating AIDP variant from European and North American centers, data outlining the use of immunomodulatory therapies in AMAN are limited. One small retrospective study found that patients who received IVIG recovered more rapidly than those who received PE.[26] Similar results were reported elsewhere.[27,28] However, another retrospective review reported better outcomes with PE in severe axonal GBS patients, some of whom had failed prior IVIG therapy.[29] Another analysis of 44 AMAN patients reported no difference in the rate of recovery between those who received IVIG or PE.[30] Because AMAN generally follows a similar clinical course as AIDP, IVIG and PE are assumed to be appropriate treatment interventions, especially in patients with severe presentations. Another axonal variant, AMSAN, is closely related to AMAN, but occurs much less frequently and with a painful sensory component. Unlike AMAN, it follows a more prolonged course and has a much higher severity.[31] Data are scarce on which therapies are most appropriate for AMSAN. One case report described a 15-year-old boy with AMSAN who received three courses of IVIG combined with corticosteroids. Full recovery occurred 2 months after the start of therapy.[32] Currently, it is unknown if IVIG is the most appropriate therapy for AMSAN. However, given the severe nature of this variant and the current lack of data, the use of IVIG or PE should be considered as rational treatment options in patients with AMSAN, as with the other GBS variants.[33]

Treatment of Fisher Syndrome

Fisher syndrome is another clinical variant of GBS. It is characterized by a triad of symptoms, including ophthalmoplegia, ataxia, and areflexia. Although FS is considered a self-limiting disease, immunomodulatory therapies, including PE and IVIG, have been used to hasten time to disease recovery. A Cochrane systematic review found no randomized controlled clinical trials for either agent in the treatment of FS or for its more severe variant Bickerstaff brainstem encephalitis.[34] A retrospective review of 92 patients published in 2007 evaluated whether immunomodulatory therapy hastens the time to recovery in FS.[35] In this review, 28 patients received IVIG 0.4 g/kg per day for 5 days, 23 received up to six sessions of PE administered every other day, and 41 patients received neither therapy. IVIG therapy slightly decreased the time to recovery from ophthalmoplegia and ataxia as compared with control; nevertheless, no overall benefit was found between any group in the overall time to recovery from FS or in the prevalence of residual symptoms at one year from disease onset. The study authors suggested that the use of immunomodulatory agents such as IVIG or PE are unnecessary, given the high recovery rates from FS and its self-limiting nature.[35] Reviewers from the Cochrane group reached a similar conclusion. However, they also further emphasized that given the more convincing data from AIDP trials, IVIG therapy may be warranted in severe FS patients who present with overlapping AIDP symptoms including profound ataxia, respiratory impairment, severe limb weakness, or severe bulbar palsy.[34] Given the lack of data, current clinical guidelines offer no recommendations for using IVIG in the treatment of FS.[16] Of further interest, a recent report linked adalimumab therapy with new-onset FS in a 77-year-old woman with rheumatoid arthritis.[36]

Summary
Current treatment guidelines recognize PE and IVIG as equally efficacious agents for the treatment of GBS/AIDP.[1] Both agents are clinically proven to hasten the time to recovery and improve disability scores when administered within the early stages of disease progression.[2,6] Due to a lack of data, recommendations for IVIG and PE in the treatment of AMAN, AMSAN, and FS are less well defined, but they are likely reasonable treatment options. The clinical decision as to which agent should be used should be made on an individual basis. In comparative trials, IVIG appeared to be better tolerated and have fewer complications than PE.[6,15]

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Because of this, along with its ease of administration, IVIG is often recommended over PE therapy.[6,15] Despite strong efficacy with these two agents, ~10% of patients will relapse or have an inadequate response following treatment intervention.[14] Risk for relapse is high in patients receiving PE. Repeat administrations of the initial agent may be beneficial in some patients.[14,17] Combination therapies are not recommended.[1] A small number of patients will fail to respond to any treatment and may go on to develop a chronic disability or not survive the initial disease course.[18] For patients with only mild forms of AIDP, few data are available to clarify the role of PE and IVIG. Despite effective therapies and supportive measures, residual functional deficits may persist in approximately one third of patients who experience AIDP.[37]
References

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Anesth Analg 2002;95(6):17191723 25. Rosenfeld B, Borel C, Hanley D. Epidural morphine treatment of pain in Guillain-Barr syndrome. Arch Neurol 1986;43(11):11941196 26. Kuwabara S, Mori M, Ogawara K. et al. Intravenous immunoglobulin therapy for Guillain-Barr syndrome with IgG anti-GM1 antibody. Muscle Nerve 2001;24(1):5458 27. Visser LH, Van der Mech FG, Van Doorn PA. Dutch Guillain-Barr Study Group. et al Guillain-Barr syndrome without sensory loss (acute motor neuropathy). A subgroup with specific clinical, electrodiagnostic and laboratory features. Brain 1995;118(Pt 4):841847 28. Jacobs BC, van Doorn PA, Schmitz PI. et al. Campylobacter jejuni infections and anti-GM1 antibodies in Guillain-Barr syndrome. Ann Neurol 1996;40(2):181187 29. Dada MA, Kaplan AA. Plasmapheresis treatment in Guillain-Barr syndrome: potential benefit over IVIg in patients with axonal involvement. Ther Apher Dial 2004;8(5):409412 30. Hiraga A, Mori M, Ogawara K. et al. Recovery patterns and long term prognosis for axonal Guillain-Barr syndrome. J Neurol Neurosurg Psychiatry 2005;76(5):719722 31. Griffin JW, Li CY, Ho TW. et al. Pathology of the motor-sensory axonal Guillain-Barr syndrome. Ann Neurol 1996;39(1):1728 32. Rostsy KM, Huppke P, Beckers B. et al. Acute motor and sensory axonal neuropathy (AMSAN) in a 15-year-old boy presenting with severe pain and distal muscle weakness. Neuropediatrics 2005;36(4):260264 33. Chowdhury D, Arora A. Axonal Guillain-Barr syndrome: a critical review. Acta Neurol Scand 2001;103(5):267277 34. Overell JR, Hsieh ST, Odaka M, Yuki N, Willison HJ. Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders. Cochrane Database Syst Rev 2007; (1): CD004761 35. Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller-Fisher syndrome. Neurology 2007;68(14):11441146 36. Kurmann PT, Van Linthoudt D, So AK. Miller-Fisher syndrome in a patient with rheumatoid arthritis treated with adalimumab. Clin Rheumatol 2009;28(1):9394 37. Bernsen RA, Jager AE, Schmitz PI, van der Mech FG. Long-term sensory deficit after Guillain-Barr syndrome. J Neurol 2001;248(6):483486

Semin Neurol. 2010;30(4):365-372. 2010 Thieme Medical Publishers

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