길랑바레 증후군 진단, 치료 - 2019 nature 논문

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Diagnosis and management of Guillain–Barré syndrome in ten steps

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• Consensus Statement
• Open access
• Published: 20 September 2019

EVIDENCE-BASED GUIDELINES

Diagnosis and management of Guillain–Barré syndrome in ten steps

• Sonja E. Leonhard, 
• Melissa R. Mandarakas, 
• Francisco A. A. Gondim, 
• Kathleen Bateman, 
• Maria L. B. Ferreira, 
• David R. Cornblath, 
• Pieter A. van Doorn, 
• Mario E. Dourado, 
• Richard A. C. Hughes, 
• Badrul Islam, 
• Susumu Kusunoki, 
• Carlos A. Pardo, 
• Ricardo Reisin, 
• James J. Sejvar, 
• Nortina Shahrizaila, 
• Cristiane Soares, 
• Thirugnanam Umapathi, 
• Yuzhong Wang, 
• Eppie M. Yiu, 
• Hugh J. Willison & 
• Bart C. Jacobs 

Nature Reviews Neurology volume 15, pages671–683 (2019)Cite this article

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Abstract

Guillain–Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

길랑-바레 증후군(GBS)은 드물지만 잠재적으로 치명적인 말초 신경 및 신경근의 면역 매개 질환으로, 보통 감염에 의해 유발됩니다. 따라서 2013년 프랑스령 폴리네시아와 2015년 라틴 아메리카에서 지카 바이러스가 유행했을 때와 같이 감염병이 유행하는 동안 GBS의 발병률이 증가할 수 있습니다. GBS는 임상 양상과 질병 경과가 이질적이기 때문에 진단과 관리가 복잡할 수 있으며, 현재 국제적인 임상 지침이 마련되어 있지 않습니다. 특히 발병 상황에서 임상의를 지원하기 위해 전 세계적으로 적용 가능한 GBS 진단체계 진단 및 관리 가이드라인을 개발했습니다. 이 가이드라인은 최신 문헌과 전문가 합의를 기반으로 하며, 임상에서 쉽게 사용할 수 있도록 10단계로 구성되어 있습니다. 먼저 GBS의 진단 기준, 임상적 변이 및 감별 진단에 대한 소개를 제공합니다. 그런 다음 10단계에서는 GBS의 조기 인지 및 진단, 중환자실 입원, 치료 적응증 및 선택, 질병 진행의 모니터링 및 치료, 임상 경과 및 결과 예측, 합병증 및 후유증 관리에 대해 다룹니다

Key points

• Classic Guillain–Barré syndrome (GBS) is an acute-onset ascending sensorimotor neuropathy, but the disease can present atypically or as a clinical variant.

• Abnormal results in electrophysiological studies and a combination of an increased protein level and normal cell count in cerebrospinal fluid are classic features of GBS, but patients with GBS can have normal results in both tests, especially early in the disease course.

• Respiratory function should be monitored in all patients as respiratory failure can occur without symptoms of dyspnoea.

• Intravenous immunoglobulin and plasma exchange are equally effective in treating GBS; no other treatments have been proven to be effective.

• The efficacy of repeat treatment in patients who have shown insufficient clinical response is uncertain; nevertheless, this practice is common in patients who show deterioration after an initial treatment response.

• Clinical improvement is usually most extensive in the first year after disease onset and can continue for >5 years.

클래식 길랑-바레 증후군(GBS)은 급성 발병 상승성 감각운동 신경병증이지만, 이 질환은 비정형적으로 또는 임상적 변종으로 나타날 수 있습니다.

전기생리학 연구(근전도 검사)에서의 비정상적인 결과와 뇌척수액의 단백질 수치 증가 및 정상 세포 수의 조합은 GBS의 전형적인 특징이지만, GBS 환자는 특히 질병 진행 초기에 두 검사에서 모두 정상 결과를 보일 수 있습니다.

호흡곤란 증상 없이 호흡 부전이 발생할 수 있으므로 모든 환자의 호흡 기능을 모니터링해야 합니다.

정맥 내 면역글로불린과 혈장 교환은 GBS 치료에 똑같이 효과적이며, 다른 치료법은 효과가 입증되지 않았습니다.

불충분한 임상 반응을 보인 환자에서 반복 치료의 효과는 불확실하지만, 초기 치료 반응 후 악화를 보이는 환자에서 흔히 시행됩니다.

임상적 개선은 일반적으로 질병 발병 후 첫 해에 가장 광범위하게 나타나며 5년 이상 지속될 수 있습니다.

Introduction

Guillain–Barré syndrome (GBS) is an inflammatory disease of the PNS and is the most common cause of acute flaccid paralysis, with an annual global incidence of approximately 1–2 per 100,000 person-years1. GBS occurs more frequently in males than in females and the incidence increases with age, although all age groups can be affected1. Patients with GBS typically present with weakness and sensory signs in the legs that progress to the arms and cranial muscles, although the clinical presentation of the disease is heterogeneous and several distinct clinical variants exist. Diagnosis of GBS is based on the patient history and neurological, electrophysiological and cerebrospinal fluid (CSF) examinations2,3,4. Other diseases that have a similar clinical picture to GBS must be ruled out4. Electrophysiological studies provide evidence of PNS dysfunction and can distinguish between the subtypes of GBS: acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN)5. Disease progression can be rapid, and most patients with GBS reach their maximum disability within 2 weeks. About 20% of patients with GBS develop respiratory failure and require mechanical ventilation. Cardiac arrhythmias and blood pressure instability can occur owing to involvement of the autonomic nervous system6. This involvement of the autonomic nervous system contributes to mortality, which is estimated at 3–10% for patients with GBS even with the best medical care available7,8,9. After the initial progressive phase, patients with GBS reach a plateau phase that can last from days to weeks or months, after which they start to recover, and 60–80% of patients with GBS are able to walk independently 6 months after disease onset, with or without treatment10,11. GBS is a monophasic illness, although some patients can deteriorate after first stabilizing or improving on therapy — a phenomenon that is referred to as a treatment-related fluctuation (TRF). Relapses of GBS can occur in 2–5% of patients10,12,13,14,15.

GBS is thought to be caused by an aberrant immune response to infections that results in damage to peripheral nerves, although the pathogenesis is not fully understood. In a subgroup of patients with GBS, serum antibodies are found against gangliosides, which reside at high densities in the axolemma and other components of the peripheral nerves16,17. Complement activation, infiltration of macrophages and oedema are typical characteristics of affected peripheral nerves and nerve roots in patients with GBS16.

길랑-바레 증후군(GBS)은

말초신경계의 염증성 질환으로

급성 이완성 마비의 가장 흔한 원인이며,

전 세계적으로 연간 10만 명당 약 1~2명의 발병률을 보입니다1.

GBS는

여성보다 남성에서 더 자주 발생하며,

모든 연령대에서 발병할 수 있지만

나이가 들수록 발병률이 증가합니다1.

GBS 환자는

일반적으로 다리의 쇠약과 감각 징후가 나타나고

팔과 두개골 근육으로 진행되지만,

질병의 임상 양상은 이질적이며 여러 가지 뚜렷한 임상 변이가 존재합니다.

GBS의 진단은

환자의 병력과 신경학적, 전기생리학적 및 뇌척수액(CSF) 검사를 기반으로 합니다2,3,4.

GBS와 유사한 임상 양상을 보이는 다른 질환을 배제해야 합니다4.

전기생리학 연구는 PNS 기능 장애의 증거를 제공하며

급성 염증성 탈수초성 다발성 근신경병증(AIDP),

급성 운동 축삭 신경병증(AMAN) 및

급성 운동 감각 축삭 신경병증(AMSAN)5과 같은 GBS의 하위 유형을 구분할 수 있습니다.

acute inflammatory demyelinating polyradiculoneuropathy (AIDP),

acute motor axonal neuropathy (AMAN) and

acute motor sensory axonal neuropathy (AMSAN)

질병의 진행 속도는 매우 빠르며

대부분의 GBS 환자는

2주 이내에 최대 장애에 도달합니다.

GBS 환자의 약 20%는

호흡 부전이 발생하여

기계식 인공호흡기가 필요합니다.

자율 신경계의 관여로 인해

심장 부정맥과

혈압 불안정성이 발생할 수 있습니다6.

이러한 자율신경계의 관여는

사망률에 영향을 미치며,

GBS 환자는 최선의 치료를 받더라도 사망률이 3~10%에 이르는 것으로 추정됩니다7,8,9.

초기 진행기 이후 GBS 환자는

수일에서 수주 또는 수개월까지 지속될 수 있는 정체기에 도달한 후

회복하기 시작하며,

치료 여부에 관계없이 발병 6개월 후 60-80%의 환자가

독립적으로 보행할 수 있게 됩니다10,11.

GBS는 단상성 질환이지만,

일부 환자는 치료를 통해 처음 안정화되거나

호전된 후 악화될 수 있으며,

이를 치료 관련 변동(TRF)이라고 합니다.

GBS의 재발은

환자의 2~5%에서 발생할 수 있습니다10,12,13,14,15.

GBS는 

감염에 대한 비정상적인 면역 반응으로 인해 말초 신경이 손상되어 발생하는 것으로 생각되지만, 

발병 기전은 완전히 이해되지 않았습니다. 

GBS 환자의 하위 그룹에서는 말초 신경의 축삭 및 기타 구성 요소에 고밀도로 존재하는 강글리오사이드에 대한 혈청 항체가 발견됩니다16,17. 보체 활성화, 대식세포의 침윤 및 부종은 GBS 환자에서 영향을 받은 말초 신경과 신경근의 전형적인 특징입니다16.

The incidence of GBS can increase during outbreaks of infectious illnesses that trigger the disease18. Most recently, the Zika virus epidemics in French Polynesia in 2013 and in Latin America and the Caribbean in 2015–2016 were linked to an increase in individuals being diagnosed with GBS19,20,21.

The Zika virus outbreaks brought to light the lack of globally applicable guidelines for the diagnosis and management of GBS. Such guidelines are necessary because the diagnosis of GBS can be challenging owing to heterogeneity in clinical presentation, an extensive differential diagnosis, and the lack of highly sensitive and specific diagnostic tools or biomarkers. Guidance for the treatment and care of patients with GBS is also needed because disease progression can vary greatly between patients, which complicates an entirely prescriptive approach to management. In addition, treatment options are limited and costly, and many patients experience residual disability and complaints that can be difficult to manage.

GBS의 발병률은 이 질환을 유발하는 감염성 질환이 유행하는 동안 증가할 수 있습니다18. 가장 최근에는 2013년 프랑스령 폴리네시아와 2015~2016년 라틴 아메리카 및 카리브해에서 발생한 지카 바이러스 유행이 GBS 진단을 받은 개인의 증가와 관련이 있습니다19,20,21.

지카 바이러스 발생으로 인해 전 세계적으로 적용 가능한 GBS 진단 및 관리 지침이 부재하다는 사실이 드러났습니다. 임상 증상의 이질성, 광범위한 감별 진단, 고도로 민감하고 구체적인 진단 도구 또는 바이오마커의 부재로 인해 GBS 진단이 어려울 수 있기 때문에 이러한 지침이 필요합니다. 또한, 환자마다 질병의 진행 양상이 크게 다를 수 있어 전적으로 처방적인 관리 접근 방식이 복잡해지기 때문에 GBS 환자의 치료와 관리를 위한 지침이 필요합니다. 또한 치료 옵션이 제한적이고 비용이 많이 들며, 많은 환자들이 관리하기 어려운 잔존 장애와 불만을 경험합니다.

GBS를 유발하는 새로운 병원균이 앞으로도 계속 발생할 가능성이 있기 때문에 전 세계적으로 적용 가능한 임상 지침의 가용성은 특히 중요합니다. 전 세계적으로 적용 가능한 GBS 임상 지침을 마련하기 위해 국제 GBS 전문가 그룹은 진단, 치료, 모니터링, 예후 및 장기 관리를 포함하는 GBS 관리에서 가장 중요한 10가지 단계를 확인했습니다(그림 1). 각 단계마다 문헌 및/또는 전문가 의견의 근거를 바탕으로 권고안을 제시하고 각 권고안에 대한 합의를 도출하여 가이드라인을 확정했습니다. 이러한 권고사항은 의료진의 임상적 의사결정을 돕기 위한 것이지만, 이 문서에 포함된 정보의 사용은 자발적으로 이루어집니다. 저자는 이 정보의 사용으로 인해 또는 이와 관련하여 발생하는 인명 또는 재산상의 부상이나 손해, 또는 오류나 누락에 대해 어떠한 책임도 지지 않습니다.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10964449/

Availability of globally applicable clinical guidelines for GBS is especially important as new outbreaks of pathogens that trigger GBS are likely to occur in the future. To generate this globally applicable clinical guideline for GBS, the ten most important steps in the management of GBS, covering diagnosis, treatment, monitoring, prognosis and long-term management, were identified by a group of international experts on GBS (Fig. 1). For each step, recommendations were provided on the basis of evidence from the literature and/or expert opinion, and consensus was sought for each recommendation to finalize the guideline. These recommendations are intended to assist providers in clinical decision-making; however, the use of the information in this article is voluntary. The authors assume no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.

Fig. 1: Ten-step approach to the diagnosis and management of Guillain–Barré syndrome.

This bullet point summary provides an overview of each of the ten steps described in the guideline. *Frequency of monitoring is dependent on the clinical picture and should be assessed in individual patients. CSF, cerebrospinal fluid; EGRIS, Erasmus GBS Respiratory Insufficiency Score (Box 3); GBS, Guillain-Barré syndrome; ICU, intensive care unit; mEGOS, modified Erasmus GBS Outcome Score (Supplementary Table 3).

Methods

Following the outbreak of Zika virus and its association with an increase in the incidence of GBS, the European Union-funded Zika Preparedness Latin American Network (ZikaPLAN) was established22. Our new guideline was initially prepared by participants of the ZikaPLAN network, comprising experts on GBS from the Netherlands (S.E.L., M.R.M. and B.C.J.), Brazil (F.d.A.A.G. and M.E.D.) and the United Kingdom (H.J.W.). These members brought specific clinical and research expertise to the guideline from their leading roles in large international projects on GBS (such as the International GBS Outcome Study (IGOS)), along with direct experience in managing the large increases in GBS cases in Zika virus-affected regions of Latin America23. To develop the preliminary guidelines, a series of in-person meetings were held between lead authors on the writing committee (S.E.L., M.R.M., B.C.J. and H.J.W.), along with smaller individual meetings with colleagues in Latin America (S.E.L., F.d.A.A.G. and M.E.D.) and continuous e-mail correspondence to review drafts and receive input. On the basis of their expert opinion and through consensus, this group identified ten of the most important steps in the diagnosis and management of GBS.

For each step, structured literature searches were performed in October 2018 by members of the writing committee (S.E.L and M.R.M), using PubMed and Embase, and the results of these searches provided the basis for the first draft of the guideline. The main inclusion criterion for the literature searches was any study, trial, review or case report published from 2015 onwards that provided detail on the diagnosis, treatment, management or prognosis of patients with GBS. Publications on the pathogenesis of GBS, or those with a focus on diseases not related to GBS, along with publications written in a language other than English or Dutch were excluded from the review. Keywords used in the search strategy included the following Medical Subject Headings (MeSH) terms: “Guillain–Barré syndrome” AND [“diagnosis” OR “therapeutics” OR “treatment outcome” OR “prognosis”]. To obtain literature for more specific topics, additional MeSH terms were combined with primary search keywords, including “intravenous immunoglobulins”, “plasma exchange”, “intensive care units”, “pregnancy”, “Miller Fisher syndrome” and “HIV”. Following this review of the most recent literature, landmark studies published prior to 2015 were identified for inclusion by the writing committee (S.E.L., M.R.M., B.C.J. and H.J.W.), along with additional papers selected by screening the reference lists of already included manuscripts and consultation with the authors. Where possible, our recommendations regarding treatment were based on systematic reviews. Expert opinion from the authors was sought for recommendations when more limited evidence (for example, cohort studies or case–control studies) was available, for instance on topics regarding the differential diagnosis or rehabilitation of GBS.

In consideration of the global variation in healthcare context and variants of GBS, this first draft was subsequently reviewed by an international group of experts on GBS from Argentina (R.R.), Australia (E.M.Y.), Bangladesh (B.I.), Brazil (M.L.B.F. and C.S.), China (Y.W.), Colombia (C.A.P.), Japan (S.K.), Malaysia (N.S.), the Netherlands (P.A.v.D.), Singapore (T.U.), South Africa (K.B.), the United States (D.R.C. and J.J.S.) and the United Kingdom (R.A.C.H). In total, seven rounds of review were held to reach a consensus. To consider the perspective of patients with GBS on the management of the disease, the GBS/CIDP Foundation International, a non-profit organization that provides support, education, research funding and advocacy to patients with GBS or chronic inflammatory demyelinating polyneuropathy (CIDP) and their families, reviewed the manuscript and provided comment during the development of the guideline.

Step 1: when to suspect GBS

Typical clinical features

GBS should be considered as a diagnosis in patients who have rapidly progressive bilateral weakness of the legs and/or arms, in the absence of CNS involvement or other obvious causes. Patients with the classic sensorimotor form of GBS present with distal paraesthesias or sensory loss, accompanied or followed by weakness that starts in the legs and progresses to the arms and cranial muscles. Reflexes are decreased or absent in most patients at presentation and in almost all patients at nadir10,24. Dysautonomia is common and can include blood pressure or heart rate instability, pupillary dysfunction, and bowel or bladder dysfunction25. Pain is frequently reported and can be muscular, radicular or neuropathic26. Disease onset is acute or subacute, and patients typically reach maximum disability within 2 weeks11. In patients who reach maximum disability within 24 h of disease onset or after 4 weeks, alternative diagnoses should be considered2,3. GBS has a monophasic clinical course, although TRFs and relapses occur in a minority of patients12,13.

Atypical clinical presentation

GBS can also present in an atypical manner. Weakness and sensory signs, though always bilateral, can be asymmetrical or predominantly proximal or distal, and can start in the legs, the arms or simultaneously in all limbs6,26. Furthermore, severe and diffuse pain or isolated cranial nerve dysfunction can precede the onset of weakness26. Young (<6 years old) children in particular can present with nonspecific or atypical clinical features, such as poorly localized pain, refusal to bear weight, irritability, meningism, or an unsteady gait27,28. Failure to recognize these signs as an early presentation of GBS might cause delay in diagnosis28. In a minority of patients with atypical GBS, particularly those with only motor signs (pure motor variant) and an AMAN subtype on electrophysiological examination, normal or even exaggerated reflexes might be observed throughout the disease course29.

Variants

Some patients have a distinct and persistent clinical variant of GBS that does not progress to the classic pattern of sensory loss and weakness. These variants include: weakness without sensory signs (pure motor variant); weakness limited to the cranial nerves (bilateral facial palsy with paraesthesias), upper limbs (pharyngeal–cervical–brachial weakness) or lower limbs (paraparetic variant); and the Miller Fisher syndrome (MFS), which in its full manifestation consists of ophthalmoplegia, areflexia and ataxia6,30,31 (Fig. 2 and Table 1). In general, GBS variants are rarely ‘pure’ and often overlap in part with the classic syndrome or show features that are typical of other variant forms32.

Fig. 2: Pattern of symptoms in variants of Guillain–Barré syndrome.

Graphic representation of the pattern of symptoms typically observed in the different clinical variants of Guillain–Barré syndrome (GBS). Symptoms can be purely motor, purely sensory (rare) or a combination of motor and sensory. Ataxia can be present in patients with Miller Fisher syndrome and both decreased consciousness and ataxia can be present in patients with Bickerstaff brainstem encephalitis. Symptoms can be localized to specific regions of the body, and the pattern of symptoms differs between variants of GBS. Although bilateral facial palsy with paraesthesias, the pure sensory variant and Miller Fisher syndrome are included in the GBS spectrum, they do not fulfil the diagnostic criteria for GBS. Adapted with permission from ref.113, ©2019 BMJ Publishing Group Limited. All rights reserved.

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Table 1 Variants of Guillain–Barré syndrome

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Besides the variants listed above, pure sensory ataxia, Bickerstaff brainstem encephalitis (BBE) and a pure sensory variant are often included in the GBS spectrum because they share clinical or pathophysiological features with GBS. However, the inclusion of these clinical variants is subject to debate as they do not fulfil the diagnostic criteria for GBS2,3,31 (Box 1). The pure sensory variant shares clinical features with the classic sensorimotor form of GBS, with the exception of the presence of motor symptoms and signs31,33; pure sensory ataxia and MFS have overlapping clinical profiles, and patients with BBE usually present with symptoms resembling MFS and subsequently develop signs of brainstem dysfunction, including impaired consciousness and pyramidal tract signs30,31,32,34,35,36. Similar to patients with MFS, individuals with sensory ataxia or BBE can exhibit IgG antibodies to GQ1b or other gangliosides in their serum30,34. However, whether pure sensory GBS, pure sensory ataxia and BBE are variants of GBS and/or an incomplete form of MFS is subject to debate, and careful diagnostic work-up is required when these variants are suspected31,33,35 (Boxes 1 and 2).

Box 1 Diagnostic criteria for Guillain–Barré syndrome

This box lists the diagnostic criteria for Guillain–Barré syndrome (GBS) developed by the National Institute of Neurological Disorders and Stroke (NINDS)3 and subsequently modified in a review paper6. We have added some features that cast doubt on the diagnosis, which were not mentioned in the original criteria2,3,6, and have made some adaptations to improve readability. These criteria are not applicable to some of the specific variants of GBS, as described in Table 1.

Features required for diagnosis

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Features that strongly support diagnosis

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Features that cast doubt on diagnosis

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Minor adaptations were made by the authors to a simplified version of the original NINDS criteria6. aStatements in NINDS criteria that were adapted by authors to improve readability. bAdditional features which were not included in the NINDS. Note: for clarity, we have omitted ‘Features that rule out the diagnosis’ from the original NINDS criteria for this adapted version.

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Box 2 Differential diagnosis of Guillain–Barré syndrome

The differential diagnosis of Guillain–Barré syndrome is broad and highly dependent on the clinical features of the individual patient. Here, we present an overview of the most important differential diagnoses categorized by location in the nervous system.

CNS

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Anterior horn cells

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Nerve roots

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Peripheral nerves

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Neuromuscular junction

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Muscles

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Other

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aDifferential diagnosis for Bickerstaff brainstem encephalitis.

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Preceding events

About two-thirds of patients who develop GBS report symptoms of an infection in the 6 weeks preceding the onset of the condition11. These infections are thought to trigger the immune response that causes GBS6. Six pathogens have been temporally associated with GBS in case–control studies: Campylobacter jejuni, cytomegalovirus, hepatitis E virus, Mycoplasma pneumoniae, Epstein–Barr virus and Zika virus18,20,37. It has been suggested that other pathogens are linked to GBS on the basis of evidence from case series or epidemiological studies, but their role in the pathogenesis of GBS is uncertain38,39,40,41,42,43. In general, the absence of an antecedent illness does not exclude a diagnosis of GBS, as putative infections or other immunological stimuli can be subclinical.

Vaccines were first linked to GBS in 1976 when a 7.3-fold increase in the risk of GBS was observed among nonmilitary individuals in the United States who had received the ‘swine’ influenza vaccine44. The epidemiological link between other vaccines and GBS has been examined many times since, but only two further studies showed a relationship between GBS and influenza vaccines45,46. These studies suggested an increase of approximately one additional GBS case per one million vaccinations, which is several orders of magnitude lower than that observed for the 1976 influenza vaccine47,48. No other vaccines have been convincingly linked to GBS15.

A relationship between administration of immunobiologicals (for example, tumour necrosis factor antagonists, immune checkpoint inhibitors or type I interferons) and GBS has been reported on the basis of case series information and biological plausibility49. Other events, including but not limited to surgery and malignancy, have been temporally related to GBS, but these relationships lack a clear biological rationale and the epidemiological evidence is limited50,51.

Step 2: how to diagnose GBS

In the absence of sufficiently sensitive and specific disease biomarkers, the diagnosis of GBS is based on clinical history and examination, and is supported by ancillary investigations such as CSF examination and electrodiagnostic studies. The two most commonly used sets of diagnostic criteria for GBS were developed by the National Institute of Neurological Disorders and Stroke (NINDS) in 1978 (revised in 1990)2,3 (Box 1) and the Brighton Collaboration in 2011 (ref4) (Supplementary Table 1). Both sets of criteria were designed to investigate the epidemiological association between GBS and vaccinations but have since been used in other clinical studies and trials. We consider the NINDS criteria to be more suited to the clinician as they present the clinical features of typical and atypical forms of GBS, although the criteria from the Brighton Collaboration are also important, widely used, and can help the clinician to classify cases with (typical) GBS or MFS according to diagnostic certainty. Various differential diagnoses must also be kept in mind when GBS is suspected, and some symptoms should raise suspicion of alternative diagnoses (Boxes 1 and 2). The role of ancillary investigations in confirm‎ing a GBS diagnosis is described in more detail in the following section.

Laboratory investigations

Laboratory testing is guided by the differential diagnosis in individual patients, but in general all patients with suspected GBS will have complete blood counts and blood tests for glucose, electrolytes, kidney function and liver enzymes. Results of these tests can be used to exclude other causes of acute flaccid paralysis, such as infections or metabolic or electrolyte dysfunctions (Box 2). Further specific tests may be carried out with the aim of excluding other diseases that can mimic GBS (Box 2). Testing for preceding infections does not usually contribute to the diagnosis of GBS, but can provide important epidemiological information during outbreaks of infectious diseases, as was seen in previous outbreaks of Zika virus and C. jejuni infection19,52. The diagnostic value of measuring serum levels of anti-ganglioside antibodies is limited and assay-dependent. A positive test result can be helpful, especially when the diagnosis is in doubt, but a negative test result does not rule out GBS53. Anti-GQ1b antibodies are found in up to 90% of patients with MFS17,54 and therefore have greater diagnostic value in patients with suspected MFS than in patients with classic GBS or other variants. When GBS is suspected, we advise not to wait for antibody test results before starting treatment.

Cerebrospinal fluid examination

CSF examination is mainly used to rule out causes of weakness other than GBS and should be performed during the initial eval‎uation of the patient. The classic finding in GBS is the combination of an elevated CSF protein level and a normal CSF cell count (known as albumino-cytological dissociation)55. However, protein levels are normal in 30–50% of patients in the first week after disease onset and 10–30% of patients in the second week10,11,24,56. Therefore, normal CSF protein levels do not rule out a diagnosis of GBS. Marked pleocytosis (>50 cells/μl) suggests other pathologies, such as leptomeningeal malignancy or infectious or inflammatory diseases of the spinal cord or nerve roots. Mild pleocytosis (10–50 cells/μl), though compatible with GBS, should still prompt clinicians to consider alternative diagnoses, such as infectious causes of polyradiculitis10,11 (Box 2).

Electrodiagnostic studies

Electrodiagnostic studies are not required to diagnose GBS. However, we recommend that these studies are performed wherever possible as they are helpful in supporting the diagnosis, particularly in patients with an atypical presentation. In general, electrophysiological examination in patients with GBS will reveal a sensorimotor polyradiculoneuropathy or polyneuropathy, indicated by reduced conduction velocities, reduced sensory and motor evoked amplitudes, abnormal temporal dispersion and/or partial motor conduction blocks6,57. Typical for GBS is a ‘sural sparing pattern’ in which the sural sensory nerve action potential is normal while the median and ulnar sensory nerve action potentials are abnormal or even absent6,57. However, electrophysiological measurements might be normal when performed early in the disease course (within 1 week of symptom onset) or in patients with initially proximal weakness, mild disease, slow progression or clinical variants5,58,59. In these patients, a repeat electrodiagnostic study 2–3 weeks later can be helpful. In patients with MFS, results of electrodiagnostic studies are usually normal or demonstrate only a reduced amplitude of sensory nerve action potentials4,60.

Electrodiagnostic studies can also differentiate between the three electrophysiological subtypes of classical GBS: AIDP, AMAN, and AMSAN. Several sets of electrodiagnostic criteria exist that aim to classify patients into these different electrophysiological subtypes on the basis of the presence of specific electrodiagnostic characteristics in at least two motor nerves. International consensus is yet to be reached on which set of criteria best defines the electrophysiological subtypes5,52,61. However, about one-third of patients with GBS do not meet any of these criteria and are labelled ‘equivocal’ or ‘inexcitable’. Studies have demonstrated that repeating electrodiagnostic studies 3–8 weeks after disease onset might aid electrodiagnostic classification by allowing classification of cases that were initially unclassifiable, or reclassification of cases that were initially classified as AIDP, AMAN or AMSAN, although this practice is controversial62,63,64.

Imaging

MRI is not part of the routine diagnostic eval‎uation of GBS, but can be helpful, particularly for excluding differential diagnoses such as brainstem infection, stroke, spinal cord or anterior horn cell inflammation, nerve root compression or leptomeningeal malignancy (Box 2). The presence of nerve root enhancement on gadolinium-enhanced MRI is a nonspecific but sensitive feature of GBS65 and can support a GBS diagnosis, especially in young children, in whom both clinical and electrophysiological assessment can be challenging66. In light of recent outbreaks of acute flaccid myelitis in young children, the clinical presentation of which can mimic GBS, the potential use of MRI to distinguish between these two diagnoses should be given special attention67,68. However, clinicians should be mindful that nerve root enhancement can be found in a minority of individuals with acute flaccid myelitis69.

A new potential diagnostic tool in GBS is ultrasound imaging of the peripheral nerves, which has revealed enlarged cervical nerve roots early in the disease course, indicating the importance of spinal root inflammation as an early pathological mechanism70,71. This technique might, therefore, help establish a diagnosis of GBS early in the disease course, although further validation is required.

Step 3: when to admit to the ICU

Reasons to admit patients to the intensive care unit (ICU) include the following: evolving respiratory distress with imminent respiratory insufficiency, severe autonomic cardiovascular dysfunction (for example, arrhythmias or marked variation in blood pressure), severe swallowing dysfunction or diminished cough reflex, and rapid progression of weakness72,73. A state of imminent respiratory insufficiency is defined as clinical signs of respiratory distress, including breathlessness at rest or during talking, inability to count to 15 in a single breath, use of accessory respiratory muscles, increased respiratory or heart rate, vital capacity <15–20 ml/kg or <1 l, or abnormal arterial blood gas or pulse oximetry measurements.

As up to 22% of patients with GBS require mechanical ventilation within the first week of admission, patients at risk of respiratory failure must be identified as early as possible74. The Erasmus GBS Respiratory Insufficiency Score (EGRIS) prognostic tool was developed for this purpose and calculates the probability (1–90%) that a patient will require ventilation within 1 week of assessment74 (Box 3).

Risk factors for prolonged mechanical ventilation include the inability to lift the arms from the bed at 1 week after intubation, and an axonal subtype or unexcitable nerves in electrophysiological studies75. Early tracheostomy should be considered in patients who have these risk factors.

Box 3 Erasmus GBS Respiratory Insufficiency Score

The Erasmus Guillain–Barré syndrome (GBS) Respiratory Insufficiency Score (EGRIS) calculates the probability that a patient with GBS will require mechanical ventilation within 1 week of assessment and is based on three key measures. Each measure is categorized and assigned an individual score; the sum of these scores gives an overall EGRIS for that patient (between 0 and 7). An EGRIS of 0–2 indicates a low risk of mechanical intervention (4%), 3–4 indicates an intermediate risk of mechanical intervention (24%) and ≥5 indicates a high risk of mechanical intervention (65%). This model is based on a Dutch population of patients with GBS (aged >6 years) and has not yet been validated internationally. Therefore, it may not be applicable in other age groups or populations. An online resource that automatically calculates the EGRIS for a patient based on answers to a series of questions has been made available by the International GBS Outcome Study (IGOS) consortium (see Related links). The Medical Research Council (MRC) sum score is the sum of the score on the MRC scale for: muscle weakness of bilateral shoulder abduction; elbow flexion; wrist extension; hip flexion; knee extension; and ankle dorsiflexion. A higher MRC sum score denotes increased disability, up to a maximum score of 60.

Table 2

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NA, not applicable. Adapted with permission from ref.74, Wiley-VCH.

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Step 4: when to start treatment

Immunomodulatory therapy should be started if patients are unable to walk independently for 10 m (refs76,77). Evidence on treatment efficacy in patients who can still walk independently is limited, but treatment should be considered, especially if these patients display rapidly progressive weakness or other severe symptoms such as autonomic dysfunction, bulbar failure or respiratory insufficiency78,79,80. Clinical trials have demonstrated a treatment effect for intravenous immunoglobulin (IVIg) when started within 2 weeks of the onset of weakness and for plasma exchange when started within 4 weeks76,77. Beyond these time periods, evidence on efficacy is lacking.

Step 5: treatment options

Treatment strategies

IVIg (0.4 g/kg body weight daily for 5 days) and plasma exchange (200–250 ml plasma/kg body weight in five sessions) are equally effective treatments for GBS76,80. IVIg and plasma exchange carry comparable risks of adverse events, although early studies showed that plasma exchange was more likely than IVIg to be discontinued76,81. As IVIg is also easier to administer and generally more widely available than plasma exchange, it is usually the treatment of choice. Besides IVIg and plasma exchange, no other procedures or drugs have been proven effective in the treatment of GBS. Although corticosteroids would be expected to be beneficial in reducing inflammation and, therefore, disease progression in GBS, eight randomized controlled trials on the efficacy of corticosteroids for GBS showed no significant benefit, and treatment with oral corticosteroids was even shown to have a negative effect on outcome82. Furthermore, plasma exchange followed by IVIg is no more effective than either treatment alone and insufficient evidence is available for the efficacy of add-on treatment with intravenous methylprednisolone in IVIg-treated patients82,83. In clinical settings where resources are limited, small-volume plasma exchange might be an economical and relatively safe alternative to conventional plasma exchange, but this approach cannot be recommended for general use until its efficacy has been established in further trials84.

Antimicrobial or antiviral treatment can be considered in patients with GBS who have an ongoing infection; however, preceding infections have usually resolved before the onset of weakness.

Specific patient groupsGBS variants

Patients with pure MFS tend to have a relatively mild disease course, and most recover completely without treatment within 6 months85. Therefore, treatment is generally not recommended in this patient group but patients should be monitored closely because a subgroup can develop limb weakness, bulbar or facial palsy, or respiratory failure32,80. The severity of the disease course of BBE justifies treatment with IVIg or plasma exchange, although evidence for the efficacy of treatment in this context is limited34,85. For the other clinical variants, no evidence regarding treatment is currently available, although many experts will administer IVIg or plasma exchange86.

Pregnant women

Neither IVIg nor plasma exchange is contraindicated during pregnancy. However, as plasma exchange requires additional considerations and monitoring, IVIg might be preferred87,88,89.

Children

There is no indication that it is necessary to deviate from standard adult practice when treating children with GBS76,78,90. Evidence on the relative efficacies of plasma exchange and IVIg in children is limited90. However, as plasma exchange is only available in centres that are experienced with its use and seems to produce greater discomfort and higher rates of complications than IVIg in children, IVIg is usually the first-line therapy for children with GBS91. Although some paediatric centres administer IVIg as 2 g/kg (body weight) over 2 days, rather than the standard adult regimen of 2 g/kg (body weight) over 5 days, one study indicated that TRFs were more frequent with a 2-day regimen (5 of 23 children) than with the 5-day regimen (0 of 23 children)78.

Step 6: monitoring disease progression

Regular assessment is required to monitor disease progression and the occurrence of complications. First, routine measurement of respiratory function is advised, as not all patients with respiratory insufficiency will have clinical signs of dyspnoea. These respiratory measurements can include usage of accessory respiratory muscles, counting during expiration of one full-capacity inspiratory breath (a single breath count of ≤19 predicts a requirement for mechanical ventilation), vital capacity, and maximum inspiratory and expiratory pressure73,92. Clinicians should consider using the ‘20/30/40 rule’, whereby the patient is deemed at risk of respiratory failure if the vital capacity is <20 ml/kg, the maximum inspiratory pressure is <30 cmH2O or the maximum expiratory pressure is <40 cmH2O (ref93). Second, muscle strength in the neck, arms and legs should be assessed using the Medical Research Council grading scale or a similar scale, and functional disability should be assessed on the GBS disability scale (Supplementary Table 2), a widely used tool for documenting GBS disease course94. Third, patients should be monitored for swallowing and coughing difficulties. Last, autonomic dysfunction should be assessed via electrocardiography and monitoring of heart rate, blood pressure, and bowel and bladder function.

The nature and frequency of monitoring depends on the rate of deterioration, the presence or absence of autonomic dysfunction, the phase of the disease, and the healthcare setting, and should be carefully assessed in each individual patient. Up to two-thirds of the deaths of patients with GBS occur during the recovery phase and are mostly caused by cardiovascular and respiratory dysfunction6,7,11. We therefore advise clinicians to stay alert during this phase and monitor the patient for potential arrhythmias, blood pressure shifts, or respiratory distress caused by mucus plugs. This monitoring is especially important in patients who have recently left the ICU and in those with cardiovascular risk factors.

Step 7: managing early complications

Complications in GBS can cause severe morbidity and death95. Some of these complications, including pressure ulcers, hospital-acquired infections (for example, pneumonia or urinary tract infections) and deep vein thrombosis, can occur in any hospitalized bed-bound patient, and standard-practice preventive measures and treatment are recommended. Other complications are more specific to GBS, for example, the inability to swallow safely in patients with bulbar palsy; corneal ulceration in patients with facial palsy; and limb contractures, ossification and pressure palsies in patients with limb weakness (Table 2). Pain, hallucinations, anxiety and depression are also frequent in patients with GBS, and caregivers should specifically ask patients whether they are experiencing these symptoms, especially if patients have limited communication abilities and/or are in the ICU. Recognition and adequate treatment of psychological symptoms and pain at an early stage is important because these symptoms can have a major impact on the wellbeing of patients. Caregivers should also be aware that patients with GBS, even those with complete paralysis, usually have intact consciousness, vision and hearing. It is important, therefore, to be mindful of what is said at the bedside, and to explain the nature of procedures to patients to reduce anxiety. Adequate management of complications is best undertaken by a multidisciplinary team, which might include nurses, physiotherapists, rehabilitation specialists, occupational therapists, speech therapists and dietitians.

Table 2 Important complications of Guillain–Barré syndrome

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Step 8: managing clinical progression

Insufficient response to treatment

About 40% of patients treated with standard doses of plasma exchange or IVIg do not improve in the first 4 weeks following treatment80,82. Such disease progression does not imply that the treatment is ineffective, as progression might have been worse without therapy6. Clinicians may consider repeating the treatment or changing to an alternative treatment, but at present no evidence exists that this approach will improve the outcome96,97. A clinical trial investigating the effect of administering a second IVIg dose is ongoing98.

Treatment-related fluctuations

TRFs are observed in 6–10% of patients with GBS and are defined as disease progression occurring within 2 months following an initial treatment-induced clinical improvement or stabilization12,13. TRFs should be distinguished from clinical progression without any initial response to treatment. The general view is that a TRF indicates that the treatment effect has worn off while the inflammatory phase of the disease is still ongoing. Therefore, patients with GBS who display TRFs might benefit from further treatment, and repeating the full course of IVIg or plasma exchange in these patients is a common practice, although evidence to support this approach is lacking80.

CIDP

In ~5% of patients with GBS, repeated clinical relapses suggest a more chronic disease process, and the diagnosis is changed to acute-onset CIDP12. Acute-onset CIDP typically presents with three or more TRFs and/or clinical deterioration ≥8 weeks after disease onset12.

Step 9: predicting outcome

Most patients with GBS, even those who were tetraplegic at nadir or required mechanical ventilation for a long period of time, show extensive recovery, especially in the first year after disease onset11,99. About 80% of patients with GBS regain the ability to walk independently at 6 months after disease onset11. The probability of regaining walking ability can be calculated in individual patients using the modified Erasmus GBS outcome score (mEGOS) prognostic tool100 (Supplementary Table 3).

Despite the generally positive prospects for patients with GBS, death occurs in 3–10% of cases, most commonly owing to cardiovascular and respiratory complications, which can occur in both the acute and the recovery phase7,8,9. Risk factors for mortality include advanced age and severe disease at onset7. Long-term residual complaints are also common and can include neuropathic pain, weakness and fatigue101,102,103. However, recovery from these complaints may still occur >5 years after disease onset103.

Recurrent episodes of GBS are rare, affecting 2–5% of patients, but this percentage is still higher than the lifetime risk of GBS in the general population (0.1%)14,15. Many vaccines carry a warning about GBS, although prior GBS is not a strict contraindication for vaccination. Discussion with experts might be useful for patients who were diagnosed with GBS <1 year before a planned vaccination or who previously developed GBS shortly after receiving the same vaccination. In these patients, the benefits of vaccination for specific illnesses (for example, influenza in elderly individuals) must be weighed against the small and possibly only theoretical risk of a recurrent GBS episode14.

Step 10: planning rehabilitation

Patients with GBS can experience a range of long-term residual problems, including incomplete recovery of motor and sensory function, as well as fatigue, pain and psychological distress103. Before the patient is discharged, these possible long-term effects of GBS should be considered and managed104,105.

Physical function

Arranging a rehabilitation programme with a rehabilitation specialist, physiotherapist and occupational therapist is a crucial step towards recovery. Programmes should aim to reduce disability in the early stages of recovery and later to restore motor and sensory function and physical condition to predisease levels106. Exercise programmes for patients with GBS, which include range-of-motion exercises, stationary cycling, and walking and strength training, have been shown to improve physical fitness, walking ability and independence in activities of daily living106. However, the intensity of exercise must be closely monitored as overwork can cause fatigue106.

Fatigue

Fatigue, unrelated to residual motor deficits, is found in 60–80% of patients with GBS and is often one of the most disabling complaints107,108. Other causes should be considered before concluding that fatigue in a patient is a residual result of GBS. As with recovery of physical function, a graded, supervised exercise programme has been shown to be useful in reducing fatigue109.

Pain

Severe pain is reported in at least one-third of patients with GBS 1 year after disease onset and can persist for >10 years14,26. Chronic pain in GBS is characterized by muscle pain in the lower back and limbs, painful paraesthesias, arthralgia, and radicular pain. Although the pathogenesis of this pain is not fully understood, muscle pain and arthralgia might be attributable to immobility, and neuropathic pain might be caused by regeneration of, or persistent damage to, small nerve fibres26. Management strategies include encouraging mobilization and administering drugs for neuropathic or nociceptive pain104.

Psychological distress

Rapid loss of physical function, often in previously healthy individuals, can be severely traumatic and may cause anxiety and/or depression. Early recognition and management of psychological distress is important in patients with GBS, especially as mental status can influence physical recovery and vice versa; referral to a psychologist or psychiatrist might be beneficial for some patients110. Providing accurate information to patients on the relatively good chance of recovery and low recurrence risk (2–5%) can help reduce their fear11,14. Connecting patients with others who have had GBS can also help guide them through the rehabilitation process. The GBS/CIDP Foundation International — the international patient association for GBS — and other national organizations can help establish these networks.

Conclusions

GBS can be a complex disorder to diagnose and manage as the clinical presentation is heterogeneous and the prognosis varies widely between patients. Managing GBS can be especially challenging during outbreaks triggered by infectious disease, as was most recently seen during the Zika virus epidemic. In the absence of an international clinical guideline for GBS, we have developed this consensus guideline for the diagnosis and management of GBS. This guideline was developed by a team of clinical neurologists from around the world and is designed for general applicability in all clinical environments, irrespective of specialist capabilities or availability of resources. The step-by-step design was used to focus attention on the most important issues in GBS and to make the guideline easy to use in clinical practice.

As the field of GBS research develops, and ongoing studies aim to improve diagnostics, treatment and prognostic modelling, this guideline will need to be updated regularly. For example, ultrasound imaging of the peripheral nerves is emerging as a potential diagnostic tool and might require further comment in future versions of this guideline. In relation to treatment, the efficacy of complement inhibitors, IgG-cleaving enzymes and a second course of IVIg is being investigated78,111,112. Little is known about how to measure and predict long-term outcome in patients with GBS, and validation studies of known prognostic models (for example, mEGOS and EGRIS) and research into new outcome measures are needed. We intend to seek feedback on this guideline and provide updates based on results from ongoing studies and future research.

To further improve the worldwide management of GBS, we aim to use this consensus report as a basis for the development of online information resources, training material and teaching courses. These resources will be directed towards healthcare workers, including clinical neurologists, as well as patients with GBS and their relatives.

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