GBS educational slidedeck

GUILLAIN-BARRÉ SYNDROME INTRODUCTION

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GUILLAIN-BARRE SYNDROME From diagnosis to treatment

1 // Guillain-Barré Syndrome

INTRODUCTION FROM THE STEERING COMMITTEE The Steering Committee welcomes you to the educational slide deck on Guillain-Barré Syndrome (GBS), addressed to neurologists, neurophysiologists, intensivists, emergency medicine doctors and all physicians dedicated to or interested in the medical attention given to this disease.

The principal aim of this educational tool is to improve your medical skills for early diagnosis and timely treatment of GBS patients, based on the best available evidence. This tool will help you investigate and better understand the disease, including epidemiology, clinical features, pathophysiology, diagnostic tools and treatments.

Following an introduction presenting general information on GBS, the slide deck is illustrated through 3 real-life cases, divided into 3 sections which explore the symptoms, pathophysiology, diagnosis and treatment. Short quizzes are proposed throughout the educational tool, allowing you to test your knowledge and understanding. Each section concludes with key learnings and take away messages, helping you to further develop your skills.

The Steering Committee hopes that this educational tool will help you in your clinical practice.

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TABLE OF CONTENTS INTRODUCTION

SECTION 2: DIAGNOSIS

Overview & Epidemiology

Routine laboratory tests raising suspicion of GBS Confirming diagnosis: electrophysiology Confirming diagnosis: CSF analysis Differential diagnosis of GBS: exclusions GBS subtype diagnosis Tracking disability Hughes Scoring System ERASMUS scale Modified ERASMUS scale Patient case examples • Case 1: Axonal GBS • Case 2: Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) form of GBS • Case 3: Acute-onset CIDP vs GBS Summary Test your knowledge

SECTION 1: SYMPTOMS & PATHOPHYSIOLOGY

Typical symptoms Diagnostic symptoms Disease progression GBS subtypes Pathogenesis of axonal form Patient case examples (focus on presentation of symptoms – pictures/videos/with symptom annotations) • Case 1: Axonal GBS • Case 2: Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) form of GBS • Case 3: Acute-onset CIDP vs GBS Summary Test your knowledge

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SECTION 3: TREATMENT & GUIDELINES (TBC)

Supportive care Disease-modifying treatment Intravenous immunoglobulin (IVIg) Plasma Exchange (PE) Patient case examples • Case 1: Axonal GBS • Case 2: Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) form of GBS • Case 3: Acute-onset CIDP vs GBS Summary Test your knowledge

GUILLAIN-BARRÉ SYNDROME INTRODUCTION

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GUILLAIN-BARRE SYNDROME From diagnosis to treatment INTRODUCTION SECTION 1: SYMPTOMS & PATHOPHYSIOLOGY SECTION 2: DIAGNOSIS SECTION 3: TREATMENT & GUIDELINES 4 // Guillain-Barré Syndrome

INTRODUCTION: OVERVIEW OF GBS1,2 INTRODUCTION

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Guillain-Barré Syndrome (GBS) is an immune-mediated disease of the peripheral nerves.1 It is the most frequent auto-immune mediated flaccid polyneuropathy.1 It is characterised by an immunological attack, consisting of autoantibodies and complement deposits on the axons and/or Schwann cell surfaces, accompanied by macrophage and T-cell infiltration into the nerve.

The majority of GBS cases report the occurrence of a preceding infectious disease, weeks before the appearance of neurological symptoms. This is supported by strong epidemiological evidence.1 A typical presentation of GBS is rapidly progressing proximal and symmetric weakness in an ascending pattern, associated with areflexia, distal paraesthesias and varying degrees of sensory and cranial nerve involvement.

Dysautonomia is a life-threatening symptom, consisting of sinus tachycardia or bradycardia, labile blood pressure with hypo- or hypertension, orthostatic hypotension, cardiac arrhythmias and neurogenic pulmonary oedema.1 Molecular mimicry (MM) is the most accepted pathological mechanism for GBS. MM is defined as a dual recognition of microbial structures and host by a single B- or T-cell receptor, triggering a cross-reactive reaction.2

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INTRODUCTION: EPIDEMIOLOGY OF GBS3,4 INTRODUCTION

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GBS is the greatest cause of acute neuromuscular paralysis, accounting for almost 100,000 cases every year worldwide.3 The incidence ranges from 0.8 to 1.9/100,000 inhabitants in North America and western European countries.3 The annual incidence rates increase with age, ranging from 0.6 /100,000 inhabitants in children to 2.7/100,000 inhabitants in adults aged 80 years and older, and is slightly more frequent in males than in females.3 For the rest of the world, there are very few studies, nevertheless, the data presented in these studies suggest that incidence in low in China, Hong Kong and Brazil, similar in Tanzania, Australia and Japan, and slightly higher in the Middle East and Curacao.4 GBS is potentially fatal and is effectively treated with immuno-modulatory therapy.

However, relatively low mortality rates have been reported (2.6% during the first 6 months to 3.9% in the first year). These rates may have been influenced by the introduction of immunomodulatory therapies (IVIg and PE).3

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Fig. 1. Guillain-Barré syndrome incidence worldwide. McGrogan A, et al. Neuroepidemiology.

2009;32(2):150-63.

GUILLAIN-BARRÉ SYNDROME INTRODUCTION

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GUILLAIN-BARRE SYNDROME From diagnosis to treatment INTRODUCTION SECTION 1: SYMPTOMS & PATHOPHYSIOLOGY SECTION 2: DIAGNOSIS & DISABILITY ASSESSMENT SECTION 3: TREATMENT & GUIDELINES 7 // Guillain-Barré Syndrome

SYMPTOMS & PATHOPHYSIOLOGY: DIAGNOSTIC CRITERIA3,5 INTRODUCTION

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Features needed for diagnosis of GBS in clinical practice3,5 Progressive weakness in both arms and legs (may start with weakness in the legs only) Areflexia (or decreased tendon reflexes) Additional symptoms3,5 Progression of symptoms over several days and up to 4 weeks Relative symmetry of symptoms Mild sensory symptoms or signs Cranial nerve involvement, especially bilateral weakness of facial muscles Autonomic dysfunction Pain (often present) High concentration of proteins in cerebrospinal fluid (CSF) Typical electrodiagnostic features Fig. 2. Diagnostic criteria for Guillain-Barré syndrome. Willison HJ, et al. Lancet. 2016; 388: 717-27.

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SYMPTOMS & PATHOPHYSIOLOGY: DIAGNOSTIC SYMPTOMS1,3,5 INTRODUCTION

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Features that should raise doubt about the diagnosis of GBS3,5 Increased number of mononuclear cells in CSF (>50 cells per µI) or polymorphonuclear cell in CSF Severe pulmonary dysfunction with limited weakness at onset Severe sensory signs with limited weakness at onset Bladder or bowel dysfunction at onset Fever at onset Sharp spinal cord sensory level Slow progression with limited weakness and without respiratory involvement Marked persistent asymmetry of weakness Persistent bladder or bowel dysfunction Fig. 3. Diagnostic criteria for Guillain-Barré syndrome. Willison HJ, et al. Lancet. 2016; 388: 717-27.

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SYMPTOMS & PATHOPHYSIOLOGY: DISEASE PROGRESSION3 INTRODUCTION

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GBS is generally preceded by infection or other immune stimulating events that cause an abnormal autoimmune response against epitopes of the peripheral nerves.

The acute phase is characterised by rapidly progressing weakness, usually associated with mild sensory and cranial nerve involvement.

The major neurological deficit appears within 2 to 4 weeks.

A plateau phase follows the maximum neurological deficit, and is distinguished by a stabilization of symptoms.

During a recovery phase, the patient returns to a complete or incomplete (several grades of disability) state of strength. This phase could last from several weeks up to several years.

Fig. 4. Guillain-Barré syndrome time course. Willison HJ, et al. Lancet. 2016; 388: 717-27.

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SYMPTOMS & PATHOPHYSIOLOGY: GBS SUBTYPES1,6 INTRODUCTION

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Subtypes Demyelinating variants • Acute inflammatory demyelinating polyneuropathy (AIDP) • Facial variant: Facial diplegia and paresthesia Axonal Variants • Acute motor axonal neuropathy (AMAN) • Acute motor sensory axonal neuropathy (AMSAN) • Acute motor conduction block neuropathy • Pharingeal-cervical-brachial weakness • Miller Fisher Syndrome • Acute ophthalmoparesis (without ataxia) • Acute mydriasis • Ataxic Guillain Barré syndrome • Acute oropharyngeal palsy • Central nervous system variant: Bickerstaff brainstem encephalitis • Acute sensory ataxic neuropathy Fig. 5. GBS subtypes and relevant antibodies. van den Berg B, et al. Nat Rev Neurol. 2014; 10(8): 469–482.

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IgG autoantibodies Unknown GM1a, GM1b, GD1a, GalNAc-GD1a GM1, GD1a GT1a > GQ1b >> GD1a

GQ1b, GT1a

GD1b

SYMPTOMS & PATHOPHYSIOLOGY: AXONAL FORM2,3,6 INTRODUCTION

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GBS is an immune-mediated disease of the peripheral nerves, characterised by an immunological attack, consisting of immunoglobulin and complement deposits on the axons and/or Schwann cell surfaces, accompanied by macrophage and T-cell infiltration into the nerve.

The majority of GBS cases report the occurrence of a preceding infectious disease, weeks before the appearance of neurological symptoms. This is supported by strong epidemiological evidence.3 Molecular mimicry (MM) is the most accepted pathological mechanism for GBS. MM is defined as a dual recognition of microbial structures and host by a single B- or T-cell receptor, triggering a cross-reactive reaction.2 High concentrations of autoantibodies against gangliosides are found in the serum of patients with GBS during the acute phase. These gangliosides are abundantly expressed in the peripheral nerve system.3 Infections with Campilobacter jejuni (C. jejuni) are associated with autoantibodies against gangliosides GM1, GM1b, GD1a and GalNAc-GD1a.3

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Fig. 6. GBS immunopathogenesis. van den Berg B, et al.

Nat Rev Neurol. 2014; 10(8): 469–482.

SYMPTOMS & PATHOPHYSIOLOGY: AXONAL FORM2,3,6 INTRODUCTION

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Following an infection by C. jejuni, the host mounts an adaptive immune response against C. jejuni antigens, including cell wall lipo-oligosaccharides.

This reaction, associated with specific host-related factors, produces an abnormal immune response with high titres of cross-reactive anti-ganglioside autoantibodies, binding to the outer surface of Schwann cells and nodal regions of the axon.

This causes complement activation, macrophage attacks and induction of other inflammatory mediators.

Nerve damage leads to sensory and/or motor symptoms (conduction dysfunction/block), with a large variation in severity.

The acute phase is followed by a much slower recovery phase.

Then outcome can be influenced by many factors: age, disease severity and presence of diarrhoea appear to be the most important influential factors.

Fig. 6. GBS immunopathogenesis. van den Berg B, et al.

Nat Rev Neurol. 2014; 10(8): 469–482.

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SYMPTOMS & PATHOPHYSIOLOGY: ILLUSTRATIVE PATIENT CASES INTRODUCTION

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CASE 1: AXONAL GBS

CONTROVERSIAL CASES

CASE 2: AIDP FORM OF GBS

CASE 3: ACUTE-ONSET CIDP vs GBS

A 20-year-old Hispanic male patient presents with an unremarkable medical history.

57 year-old woman with a medical history of recent upper respiratory infection

Learn about common symptoms that should raise suspicion of GBS

Learn to recognise the early signs of AIDP

Learn to distinguish acute-onset CIDP from GBS

Click here to learn more

Click here to learn more

Click here to learn more

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A 50-year-old male patient presents with a 3-week history of numbness and tingling in the hands and feet

CASE 1: AXONAL GBS INTRODUCTION

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A 20-year-old Hispanic male patient presents with an unremarkable medical history.

3 weeks earlier he suffered from a gastrointestinal infection and was treated with amoxicillin.

•

Facial reflex examination

All the intestinal symptoms improved.

2 weeks later, the patient was evaluated in a regional hospital with complaints of numbness and pain in his legs and feet.

The following day, worsening of the weakness of the lower extremities was observed.

• • •

The patient was unable to walk without a walking stick, to get up from a chair or to climb stairs without help.

During the afternoon of the same day, he experienced similar symptoms in the upper extremities and had hypophonia.

The patient was referred to the National Institute of Neurology and Neurosurgery at Mexico City and was admitted to the emergency room.

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Hypophonia

CASE 1: QUIZ INTRODUCTION

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QUESTION 1: Which of the following symptoms regarding the polyneuropathy should prompt wider investigation?

CONTROVERSIAL CASES

Select the correct answer

Acute neuropathic signs and symptoms in a young man with unremarkable medical history Sign and symptoms of polyneuropathy with cranial nerve involvement (Hypophonia) Inability to walk within a few hours All of the above

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CASE 1: QUIZ INTRODUCTION

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QUESTION 1: Which of the following symptoms regarding the polyneuropathy should prompt wider investigation?

•

•

Correct answer

Acute neuropathic signs and symptoms that involve four limbs almost simultaneously should prompt the physicians to suspect an immuno-mediated pathophysiology that is potentially treatable.

Acute neuropathic signs and symptoms in a young man with unremarkable medical history

Severe weakness, leading to a loss of walking capacities in a short time, with cranial nerves involvement, should be considered as “red flag” symptoms in any polyneuropathy.

Sign and symptoms of polyneuropathy with cranial nerve involvement (Hypophonia)

Inability to walk within a few hours

!

All of the above

PATIENT CASES

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CASE 2: AIDP FORM OF GBS INTRODUCTION

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A 57 year-old woman, with a medical history of recent upper respiratory infection.

History of 4 days of tingling sensations in the fingers and toes. 3 days later, she notices progressive weakness in the lower limbs associated with lower back pain. One day before being admitted to hospital, she noted increased weakness and difficulties to walk without assistance, as well as minor distal weakness in her upper limbs.

On admission, she had a flaccid-weakness in her lower extremities, mild bilateral facial nerve palsy and loss of tendon reflexes. No respiratory distress was noted.

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CASE 2: QUIZ INTRODUCTION

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QUESTION 2: How common is pain in Guillain Barré Syndrome?

Select the correct answer

Seldom Occasionally Sometimes Frequently

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CASE 2: QUIZ INTRODUCTION

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QUESTION 2: How common is pain in Guillain Barré Syndrome?

•

The sensory disturbances are well-recognised symptoms in the acute phase of Guillain Barré Syndrome, however, pain is a frequent sensory complaint, usually overlooked.

•

The pain usually appears before motor symptoms and sometimes may introduce diagnosis confusion.

•

Pain often occurs during the acute phase of Guillain Barré, but it may persist in later phases and contribute to functional disability.

Correct answer

Seldom Occasionally

Sometimes

!

Frequently

PATIENT CASES

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CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

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A 50-year-old male patient presents with a 3-week history of numbness and tingling in the hands and feet, ascending to the elbows and knees.

The patient is experiencing heaviness and weakness of the limbs and lumbar pain.

The symptoms appeared without any identifiable previous infection and progressed over 10 days.

The patient has been perfectly stable for 5 days pre-admission, without further deterioration. He is able to walk with a frame and reports problems with dexterity.

He has a history of hypertension and dyslipidaemia on an ACE-inhibitor and a statin for 5 years. There is no family history of relevance.

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CASE 3: QUIZ INTRODUCTION

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QUESTION 3: When should you suspect Acute-Onset CIDP in a patient with acute sensory-motor polyneuropathy?

Select the correct answer

No evidence of previous infection The symptoms are relatively stable Absence of cranial nerve involvement Sensory-motor deterioration persists after 8 weeks of onset of symptoms or when deterioration occurs at least three times in 8 weeks

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CASE 3: QUIZ INTRODUCTION

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QUESTION 3: When should you suspect Acute-Onset CIDP in a patient with acute sensory-motor polyneuropathy?

•

•

•

Correct answer

Progression of symptoms after 8 weeks or deterioration occurring at least three times in 8 weeks are strong features suggesting acuteonset CIDP.

No evidence of previous infection

CIDP should be suspected even in cases of Guillain Barré that present without any evidence of infection. Furthermore, an important number of CIDP cases show relatively stable symptoms or no documented cranial nerve involvement.

Early recognition of acute-onset CIDP among patients with apparent GBS is usually a clinical challenge and all cases with progressive deterioration lasting more than 8 weeks should raise suspicion.

The symptoms are relatively stable Absence of cranial nerve involvement

!

Sensory-motor deterioration persists after 8 weeks of onset of symptoms or when deterioration occurs at least three times in 8 weeks

PATIENT CASES

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SYMPTOMS & PATHOPHYSIOLOGY: KEY LEARNINGS INTRODUCTION

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1. GBS is the greatest cause of acute neuromuscular paralysis, accounting for almost 100,000 cases every year worldwide.

2. The key symptoms are symmetrical proximal weakness with distal paraesthesia, often occurring simultaneously with an ascending pattern. In addition to prominent weakness, cranial nerve involvement is often described, including mainly facial bilateral palsy, and less commonly, oculomotor nerve palsy and dysphagia.

3. Weakness ranges from mild to severe flaccid quadriplegia and up to 30% de patients develop ventilatory failure within the first hours or days following onset.

4. Dysautonomia is another life-threatening symptom, consisting of sinus tachycardia or bradycardia, labile blood pressure with hypo- or hypertension, orthostatic hypotension, cardiac arrhythmias and neurogenic pulmonary oedema.

5. GBS is potentially fatal and is effectively treated with immuno-modulatory therapy.

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SYMPTOMS & PATHOPHYSIOLOGY: KEY LEARNINGS INTRODUCTION

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6. Early diagnosis of GBS remains based on early clinical suspicion.

7. An absence of sensory signs or symptoms, asymmetrical weakness, cranial nerve preservation and normal or hyperreflexia should not prompt physicians to give up on the diagnosis of a GBS. 8. Nevertheless, differential diagnoses should be considered based on diagnostic tests and symptoms evolution.

9. Always keep in mind the clinical variants of GBS, based on the type of nerve involved, regional distribution and predominant electrophysiological presentation (demyelinating or axonal form).

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 1: Which of the following features is needed for diagnosis of GBS in clinical practice?

Select the correct answer

Progressive weakness in both arms and legs, and mild sensory symptoms Areflexia and progressive weakness in both arms and legs Progressive weakness in both arms and legs, and cranial nerve involvement, especially bilateral weakness of facial muscles Progressive weakness in four limbs and high concentration of proteins in CSF

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 1: Which of the following features is needed for diagnosis of GBS in clinical practice?

•

•

•

Correct answer

Most patients present distal leg weakness that often spreads to the arm within a few hours or days following a symmetrical ascending pattern.

Besides the pronounced weakness, patients are hyporeflexic or areflexic. Sensory abnormalities and cranial nerve involvement (facial diplegia) can be variable.8 Half of GBS cases may have a normal CSF analysis during the first week. One week later, the CSF is abnormal in only 10% of cases.8

Progressive weakness in both arms and legs, and mild sensory symptoms

!

Areflexia and progressive weakness in both arms and legs Progressive weakness in both arms and legs, and cranial nerve involvement, especially bilateral weakness of facial muscles Progressive weakness in four limbs and high concentration of proteins in CSF

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 2: Which of the following auto-antibodies is associated with the Miller-Fisher Syndrome (MFS) variant?

Select the correct answer

GM1 GQ1b GT1a Unknown

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 2: Which of the following auto-antibodies is associated with the Miller-Fisher Syndrome (MFS) variant?

•

•

Correct answer

Molecular mimicry mediated by antibodies against gangliosides of the peripheral nerve is the most acceptable pathophysiology for acute motor axonal neuropathy and acute motor sensory axonal neuropathy.

Molecular mimicry is also the most plausible mechanism in MFS, in which 90% of cases have antibodies against GQ1b.8

GM1

!

GQ1b GT1a Unknown

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 3: Which of the following infections may cause a patient to develop GBS?

Select the correct answer

Campylobacter jejuni

Pseudomona aeruginosa Mycobacterium tuberculosis Clostridium perfringers

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SYMPTOMS & PATHOPHYSIOLOGY: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 3: Which of the following infections may cause a patient to develop GBS? •

Campylobacter jejuni infection is a well-known important causal factor for GBS. The risk of developing GBS two months following a symptomatic episode of C. jejuni infection is approximately 100 times higher than the risk in the general population.9

Correct answer

! Campylobacter jejuni Pseudomona aeruginosa Mycobacterium tuberculosis Clostridium perfringers

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GUILLAIN-BARRÉ SYNDROME INTRODUCTION

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GUILLAIN-BARRE SYNDROME From diagnosis to treatment INTRODUCTION SECTION 1: SYMPTOMS & PATHOPHYSIOLOGY SECTION 2: DIAGNOSIS & DISABILITY ASSESSMENT SECTION 3: TREATMENT & GUIDELINES 32 // Guillain-Barré Syndrome

DIAGNOSIS: ROUTINE LABORATORY TESTS8,10 INTRODUCTION

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Several laboratory tests are performed that may raise suspicion of GBS. Diagnosis of GBS is determined mainly on the basis of clinical findings, electrophysiological criteria and CSF analysis.

An electrophysiology test is the essential diagnostic tool to confirm the diagnosis and, in some cases, exclude immuno-mediated neuropathies.

Tests to establish GBS diagnosis: 1. Electrodiagnostic tests must include at least three sensory nerves and three motor nerves with F-waves and bilateral tibial nerve H-reflexes. o Multifocal demyelination features, such as prolonged F-wave latency or poor F-wave reproducibility, prolonged distal latency, temporal dispersion, conduction blocks and slowing of nerve conduction velocities are extremely helpful to confirm GBS. o Neurophysiological criteria of axonal forms are as follows: • AMSAN: None of the features of the demyelinating form of GBS with decreased sensory action potential amplitudes • AMAN: None of the features of the demyelinating form of GBS with normal sensory action potential amplitudes

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DIAGNOSIS: ROUTINE LABORATORY TESTS8,10 INTRODUCTION

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2. Cerebrospinal fluid examination (CSF) analysis from a lumbar puncture o CSF analysis is the second most helpful diagnostic tool in GBS and can reveal the distinctive protein-cytologic dissociation. Half of the GBS cases may have a normal CSF in the first week into the illness but this percentage declines to 10% one week later. o CSF includes: glucose, protein, cell count and bacterial culture. o Pleocytosis of 10 to 20 cells/mm3 can be observed in 5% of cases. o Pleocytosis over 50 cells/mm3 may suggest a co-existing illness, such as HIV infection, leptomeningeal carcinomatosos, CMV polyradiculitis, or sarcoidosis among other diagnoses.

Imaging studies are performed to exclude other potential diagnoses.

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DIAGNOSIS: ROUTINE LABORATORY TESTS8,10 INTRODUCTION

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Other routine laboratory tests are not specific for GBS, but can help exclude other diagnoses Suggested tests Urine analysis Complete blood count Erythrocyte sedimentation rate Biochemical screening Coagulation studies ECG Chest radiography Pulmonary function test Fig. 7. Investigative studies for Guillain-Barré syndrome. Hughes RA, Cornblath DR. Lancet. 2005; 366(9497): 1653-66.

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DIAGNOSIS: IMAGING TESTS11,12 INTRODUCTION

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While diagnosis of GBS is determined mainly on the basis of clinical findings, electrophysiological criteria and CSF analysis, imaging studies can also be performed to exclude other potential diagnoses.

There are several reports of Magnetic Resonance Imaging (MRI) findings in GBS, including a marked enhancement of the thickened nerve root in the conus medullaris (the most distal bulbous part of the spinal cord) and cauda equina (collection of nerve roots, horsetail-like in appearance) with no abnormalities on pre-contrast images.

Some tests suggest that serial contrast-enhanced MRI can be useful as a monitoring tool for therapy response.

Nevertheless, enhancement of spinal roots is not a specific finding of GBS, and can be observed in other diseases such as meningeal carcinomatosis, sarcoidosis, lymphoma, AIDS-related cytomegalovirus polyradiculopathy, and lymphoma among others.

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DIAGNOSIS: HUGHES SCORING SYSTEM (HSS) FOR DISABILITY ASSESSMENT13 INTRODUCTION

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The outcome of GBS is clearly influenced by the severity of peripheral nerve damage during an acute phase.

The functional grading scale Hughes Scoring System (HSS) is a simple and reproducible scale that allows classification of the clinical severity of the illness.

Hughes scoring system (HSS) 0

A healthy state

1

Minor symptoms and capable of running

2

Able to walk 10 m or more without assistance but unable to run

3

Able to walk 10 m across an open space with help

4

Bedridden or chair-bound

5

Required assisted ventilation for at least part of the day

6

Dead

Fig. 8. Graded neurological assessment. Hughes RA, et al. Lancet. 1978; 2(8093): 750-3.

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DIAGNOSIS: ERASMUS SCALE FOR DISABILITY ASSESSMENT14 INTRODUCTION

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Age of onset (years) Diarrhoea (<4 weeks)

GBS disability scale (At 2 weeks after entry)

Fig. 9. Predicted fraction of patients unable to walk independently at 6 months. van Koningsveld R, et al. Lancet Neurol. 2007; 6(7): 589-94

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Erasmus GBS outcome score

Categories

Score

>60

1

41 - 60

0.5

<40

0

Absent

0

Present

1

0 - 1

1

2

2

3

3

4

4

5

5 1 - 7

DIAGNOSIS: MODIFIED ERASMUS SCALE FOR DISABILITY ASSESSMENT15 INTRODUCTION

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Prognostic factors

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Score

Age of onset (years)

CONTROVERSIAL CASES

Prognostic factors

Score

Age of onset (years)

<40

0

<40

0

41 - 60

1

41 - 60

1

>60

2

>60

2

Preceding diarrhoea

Preceding diarrhoea

Absent

0

Absent

0

Present

1

Present

1

MRC sumscore (at admission)

MRC sumscore (at day 7 of admission)

51 - 60

0

51 - 60

0

41 - 50

2

41 - 50

3

31 - 40

4

31 - 40

6

0 - 30

6

0 - 30

9

mEGOS

0 - 9

mEGOS

Fig. 10. Risk of poor outcome, defined as inability to walk unaided after entry to the hospital.

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0 - 12

DIAGNOSIS: MODIFIED ERASMUS SCALE FOR DISABILITY ASSESSMENT15 INTRODUCTION

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A predicted fraction of patients are unable to walk independently at: •

4 weeks (black lines)

•

3 months (red lines) and

•

6 months (green lines)

The modified Erasmus Scale is a more precise tool for estimate severity and functional prognosis in patients with GBS.

At hospital admission

At day 7 of admission

Fig. 11. Predicted fraction of patients unable to walk independently according to modified Erasmus GBS Outcome Score (mEGOS) at 4 weeks (black lines), 3 months (red lines), and 6 months (green lines). Walgaard C, et al. Neurology. 2011; 76(11): 968-75.

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DIAGNOSIS: MEDICAL RESEARCH COUNCIL SCALE FOR DISABILITY ASSESSMENT16 INTRODUCTION

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Medical Research Council (MRC) Scale© for muscle strength grades the patient’s strength on a scale of 0 to 516 MRC Scale Grade 5

Muscle contracts normally against full resistance.

Grade 4

Muscle strength is reduced but muscle contraction can still move joint against resistance.

Grade 3

Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner's resistance completely removed.

As an example, the elbow can be moved from full extension to full flexion starting with the arm hanging down at the side.

Grade 2

Muscle can move only if the resistance of gravity is removed. As an example, the elbow can be fully flexed only if the arm is maintained in a horizontal plane.

Grade 1

Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle.

Grade 0

No movement is observed.

Fig. 12. Manual Muscle Testing technique to assess muscle strength.

41 // Guillain-Barré Syndrome

DIAGNOSIS: DIFFERENTIAL DIAGNOSIS OF GBS5 INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Intracraneal/spinal cord abnormalities Brainstem encephalitis, meningitis carcinomatosis/lymphomatosis, transverse myelitis, cord compression.

Anterior horn cell abnormalities Poliomyelitis, West Nile virus.

Spinal nerve root abnormalities Compression, inflammation (eg: cytomegalovirus), leptomeningeal malignancy.

Peripheral nerve abnormalities CIDP, drug-induced neuropathy, porphyria, critical illness polyneuropathy, vasculitis, diphtheria, Vitamin B1 deficiency, heavy metal or drug intoxication, tick paralysis, metabolic disturbances (Hypokalaemia, hypophosphataemia, hypermagnesaemia, hypoglycaemia).

Neuromuscular junction abnormalities Myasthenia gravis, botulism, organophosphate poisoning.

Muscular abnormalities Critical illness polyneuromyopathy, polymyositis, dermatomyositis, acute rhabdomyolysis.

Fig. 13. Differential diagnosis of GBS. van Doorn PA, et al. Lancet Neurol. 2008; 7(10): 939-50.

42 // Guillain-BarrĂŠ Syndrome

DIAGNOSIS: RECOGNISING GBS SUBTYPES17 INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Diagnosis of GBS variants is based on the clinical recognition of the variant’s distinctive phenotype and neurophysiological findings within an appropriated context.

Since the description of Miller Fisher syndrome (1956) as a clinical variant of GBS, and the discovery of anti-ganglioside antibodies in other variants of GBS, such as Bickerstaff´s encephalitis or acute axonal motor neuropathy, several regional variants have been described.

The specific pattern of anti-ganglioside antibodies may determine the pattern of symptoms in GBS variants. Nevertheless further evidence is required to reach such a conclusion.

Fig. 14. Guillain-Barré syndrome subtypes with glial or axonal membrane injury and conduction failure. Willison HJ, et al. Lancet. 2016; 388: 717-27.

43 // Guillain-Barré Syndrome

DIAGNOSIS: ILLUSTRATIVE PATIENT CASES INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CASE 1: AXONAL GBS

CONTROVERSIAL CASES

CASE 2: AIDP FORM OF GBS

CASE 3: ACUTE-ONSET CIDP vs GBS

A 20-year-old Hispanic male patient presents with an unremarkable medical history.

57 year-old woman with a medical history of recent upper respiratory infection

Learn which tests should be carried out to identify axonal GBS

Learn which tests should be carried out to distinguish AIDP form of GBS

Learn which tests will help distinguish acute-onset CIDP from GBS

Click here to learn more

Click here to learn more

Click here to learn more

44 // Guillain-Barré Syndrome

A 50-year-old male patient presents with a 3-week history of numbness and tingling in the hands and feet.

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

A 20-year-old Hispanic male patient presents with an unremarkable medical history.

Upon admittance to the emergency room: Neurological examinations were performed: • • • • • •

The patient was alert and oriented Cranial nerve examination showed bilateral symmetrical facial paraesthesia The patient’s distal and proximal motor strength in all extremities, including the neck flexor muscles, was 0/5, evaluated according to the Medical Research Council (MRC) scale No sensory abnormalities were found Deep tendon reflexes were absent and the patient was unable to walk No autonomic dysfunction was documented.

The patient’s blood work-up was normal.

A lumbar puncture was performed: •

The CSF analysis reported an increase in proteins and normal cellular count.

An electromyogram (EMG) test was performed (see results on next slides).

45 // Guillain-Barré Syndrome

Facial paraesthesia and absent motor strength

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

site

Median

Ulnar

Tibial

Peroneo

SECTION 3

CONTROVERSIAL CASES

Distal latency

Amplitude

Velocities

R

L

R

L

R

L

Wrist

2.6

3.0

3.5

3.0

43

39

Elbow

8.0

7.7

4.4

3.6

Wrist

3.1

2.7

2.9

3.1

41

42

Elbow

6.6

6.4

3.3

3.9

Ankle

4.1

4.1

2.1

1.8

38

44

Knee

13.0

13.9

2.4

2.0

Ankle

4.6

4.2

0.7

1.1

37

40

Knee

10.8

11.1

0.8

1.0

All sensitive potentials are in the normal range

46 // Guillain-BarrĂŠ Syndrome

The electromyogram: Indicates Axonal Motor Polineuropathy.

The distal latencies of peroneo and tibial nerve are prolonged but not into the demyelinating range.

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Fig.15. Ulnar sensory nerve conduction study.

47 // Guillain-Barré Syndrome

The figure shows a decrease of Compound Muscle Action Potential (CMAP) of the left (A1/A2) and right (B1/B2) cubital nerves, with no demyelinating features in latencies and velocities.

This is highly suggestive of Axonal Guillain Barré variant in the appropriated context.

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Fig.16 shows axonal degeneration of left motor median nerve, with normal sensitive potential (Fig.17/ A1), frequently seen in the Acute Motor Axonal Neuropathy variant (AMAN) of Guillain Barré Syndrome.

Fig.16. Median motor nerve conduction study.

48 // Guillain-Barré Syndrome

Fig.17. Median sensory nerve conduction study.

CASE 1: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 1: Concerning anti-ganglioside antibodies in Axonal GBS, which of the following statements is correct?

Select the correct answer

The physiopathology in AMAN remains unclear because biochemical studies have shown that both types of nerves, sensory and motors contain gangliosides GM1 Molecular mimicry suggests that IgG anti-ganglioside antibodies are deposited at nodal and paranodal regions leading to blocking or slowing of electrical conduction Antibodies that bind to GM1 at nodes of Ranvier activate complement and disrupt sodium-channel clusters All above are correct

49 // Guillain-BarrĂŠ Syndrome

CASE 1: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 1: Concerning anti-ganglioside antibodies in Axonal GBS, which of the following statements is correct?

•

Neurophysiological studies play an important role in the classification of GBS variants.

•

Reduction in amplitude of the compound muscle action potential, without demyelinating features, in at least two motors nerves is indicative of acute axonal motor neuropathy (AMAN).

•

Correct answer

The physiopathology in AMAN remains unclear because biochemical studies have shown that both types of nerves, sensory and motor, contain gangliosides GM1 Molecular mimicry suggests that IgG anti-ganglioside antibodies are deposited at nodal and paranodal regions, leading to blocked or slow electrical conduction

Immunological, pathological and bacteriological studies have shown carbohydrate mimicry between GM1 and GD1a gangliosides and the lipo-oligosaccharides of C. jejuni.22

Antibodies that bind to GM1 at nodes of Ranvier activate complement and disrupt sodium-channel clusters

!

All above are correct

PATIENT CASES

50 // Guillain-Barré Syndrome

CASE 2: AIDP FORM OF GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

A 57 year-old woman, with a medical history of recent upper respiratory infection, but no respiratory distress, presented with flaccidweakness in her lower extremities, mild bilateral facial nerve palsy and loss of tendon reflexes.

Upon admittance: An electromyogram (EMG) test was performed (see results on next slides).

51 // Guillain-Barré Syndrome

CASE 2: AIDP FORM OF GBS INTRODUCTION

SECTION 1

SECTION 2

site

SECTION 3

CONTROVERSIAL CASES

Distal latency

Amplitude

Velocities

R

L

R

L

R

L

Wrist

9.8

6.8

3.15

3.35

43

40

Elbow

15.2

11.8

2.97

2.51

Wrist

4.4

4.9

4.91

7.80

43

52

Elbow

7.6

8.2

4.69

5.46

Ankle

7.3

5.4

2.28

1.18

32

45

Knee

17.3

14.8

0.51

0.11

Ankle

6.61

5.4

3.05

3.72

25

34

Knee

17.1

13.4

1.17

1.23

Median

Ulnar

Tibial

Peroneo All sensitive potentials are absent

52 // Guillain-BarrĂŠ Syndrome

Demyelinating sensitive-motor polyneuropathy.

Some of the distal latencies and velocities are in the demyelinating range.

Focus attention on conduction blocks present in the lowers limbs.

CASE 2: AIDP FORM OF GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

The figure illustrates the most important demyelinating criteria in electromyography.

1. Prolonged distal latencies 2. Conduction blocks 3. Reduced velocities 4. Secondary axonal nerve damage

Fig.18. Tibial motor and sensory nerve conduction studies.

53 // Guillain-Barré Syndrome

CASE 2: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 2: Regarding GBS diagnostic criteria, which of the following sentences is correct?

Select the correct answer

Progressive weakness in legs and arms, relative symmetric and autonomic dysfunction Progressive phase lasting several days to 4 weeks, mild sensory symptoms and cranial nerve involvement, particularly bilateral facial palsy Progressive weakness in legs and arms, mild sensory symptoms and uni/ bilateral facial palsy Progressive weakness in legs and arms with areflexia (or decreased tendon reflexes) in weak limbs

54 // Guillain-BarrĂŠ Syndrome

CASE 2: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 2: Regarding GBS diagnostic criteria, which of the following sentences is correct?

•

•

Correct answer

Features required to diagnose GBS include progressive weakness in legs and arms with hypo/areflexia in the weakened limb.

Additional symptoms include a progression phase lasting no longer than 4 weeks, mild sensory symptoms, relative symmetry, cranial nerve involvement, autonomic dysfunction and frequent pain.

Progressive weakness in legs and arms, relative symmetric and autonomic dysfunction Progressive phase lasting several days to 4 weeks, mild sensory symptoms and cranial nerve involvement, particularly bilateral facial palsy

Investigation of demyelinating or axonal features in electromyography is highly recommended.

Progressive weakness in legs and arms, mild sensory symptoms and uni/ bilateral facial palsy

!

Progressive weakness in legs and arms with areflexia (or decreased tendon reflexes) in weak limbs

PATIENT CASES

55 // Guillain-Barré Syndrome

CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

SECTION 1

SECTION 2

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CONTROVERSIAL CASES

A 50-year-old male patient presents with a 3-week history of numbness and tingling in the hands and feet, ascending to the elbows and knees.

The patient is experiencing heaviness and weakness of the limbs and lumbar pain.

Clinical examination on admission shows: Weakness of proximal muscles of the upper and lower limbs at MRC grade 3.

Weakness of distal muscles of the upper limbs at grade 3 and of the distal lower limbs at grade 2.

Distal loss of pain and temperature sensation. Vibration and distal proprioception are abolished in both hands and feet.

Reflexes are all abolished in upper and lower limbs, without Babinski signs.

Cranial nerves are unaffected.

Overall Neuropathy Limitation Score (ONLS) = (3 [upper limps] + 4 [lower limbs]) = 7 Respiratory function is unaffected (Forced Vital Capacity = 3.8 litres)

56 // Guillain-Barré Syndrome

CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

SECTION 1

SECTION 2

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CONTROVERSIAL CASES

Further tests are performed including: EMG: Demyelinating neuropathy meeting criteria for AIDP (see results on next slide) Lumbar Puncture: protein = 1.9 g/L; no cells Blood work-up: All normal, serum immunofixation: negative; serology, including HIV: all negative.

The patient’s symptoms, including tetraparesis, sensory loss and areflexia, and the results from the investigations are characteristic of a GBS. The patient is treated with IVIg (2g/kg). o His condition improves within 7 days. o MRC scores return to normal and ONLS drops to 2. o The patient is discharged from hospital.

57 // Guillain-Barré Syndrome

CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

SECTION 1

site

Median

Ulnar

Tibial

Peroneo

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Distal latency

Amplitude

Velocities

R

L

R

L

R

L

Wrist

5.8

6.1

7.15

5.35

40

38

Elbow

10.2

11.0

4.97

4.51

Wrist

3.8

4.5

6.91

5.80

43

40

Elbow

6.6

7.2

5.69

4.86

Ankle

6.3

5.0

5.28

6.18

33

35

Knee

12.1

10.8

4.51

5.11

Ankle

7.6

4.1

2.05

3.72

31

28

Knee

14.1

9.4

1.17

1.23

All sensitive potentials are reduced, only the sural nerve is spared

58 // Guillain-Barré Syndrome

Sensitive-motor demyelinating polyneuropathy

CASE 3: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3A: Which of the following features supports the diagnosis of GBS by electromyography?

Select the correct answer

Demyelinating features in more than 2 motor nerves All the sensitive potentials are affected, except the sural nerve which is preserved Asymmetric demyelinating sensory motor neuropathy Absence of conduction blocks which is a hallmark in CIDP

59 // Guillain-Barré Syndrome

CASE 3: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3A: Which of the following features supports the diagnosis of GBS by electromyography?

Correct answer

Demyelinating abnormalities can be observed in both CIDP and demyelinating variants of GBS. An exception of this is the sural sparing, which is commonly seen in GBS and can be helpful to differentiate GBS from acute onset CIDP and other GBS mimics.

Demyelinating features in more than 2 motor nerves.

!

All the sensitive potentials are affected, except the sural nerve which is preserved Asymmetric demyelinating sensory motor neuropathy Absence of conduction blocks which is a hallmark in CIDP

60 // Guillain-BarrĂŠ Syndrome

CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

2 weeks later, he is readmitted for similar symptoms that appear over one week.

Upon clinical examination: o Weakness of proximal muscles of the upper and lower limbs at MRC grade 3. o Weakness of distal muscles of the upper limbs at grade 2 and of the distal lower limbs at grade 1. o No respiratory or cranial nerve abnormality. o Marked sensory loss, including sensory loss of vibration and proprioception.

New EMG reveals more severe demyelinating features than on first examination.

Blood work-up: normal

61 // Guillain-Barré Syndrome

CASE 3: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3A: Which diagnosis should be listed first in this situation?

Select the correct answer

Acute-onset CIDP Treatment related fluctuation of Guillain Barré Paraproteinemic demyelinating neuropathy Charcot Marie Tooth 1A

62 // Guillain-Barré Syndrome

CASE 3: QUIZ INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3A: Which diagnosis should be listed first in this situation?

Correct answer

Treatment related fluctuation (TRF) is a worsening of at least one grade on the GBS disability scale, or a decrease in the Medical Research Council sum score after initial stabilization or improvement within the first 8 weeks after treatment.

The mechanism of the TRF remains unclear and there is not a high level of evidence about the best treatment, however, there is wide consensus on treatment with a second dose of immunoglobulins.20

Acute-onset CIDP

!

Treatment related fluctuation of Guillain Barré Paraproteinemic demyelinating neuropathy Charcot Marie Tooth 1A

PATIENT CASES

63 // Guillain-Barré Syndrome

DIAGNOSIS: KEY LEARNINGS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

1. Keep in mind that more than one etiology of polyneuropathy can co-exist in a same patient.

2. Case 2 illustrates a patient with diabetes (a common cause of polyneuropathy) with a typical progression towards GBS in the context of severely uncontrolled diabetes mellitus.

3. Neurophysiology tests need to be performed and interpreted adequately to be useful for diagnostic accuracy and clinical management: o Some neurophysiological findings may be common among different diseases.

In these cases, axonal sensory-motor polyneuropathy can be observed in uncontrolled diabetes and in GBS variant AMSAN. o Combined information of CSF analysis, contrasted MRI and neurophysiology could be useful in diagnostic accuracy. o A raised CSF protein concentration is present in about 80% of patients, but CSF protein is more likely to be normal during the first days of the illness. o With neurophysiological information, individual patients can be classified into one of the three neurophysiological subtypes of GBS: AIDP, AMAN, AMSAN. 4. It is well known that some cases of GBS can begin with cranial nerve symptoms, after which, classical clinical features, including paresthesia and weakness, can appear during the following hours or days.

64 // Guillain-Barré Syndrome

DIAGNOSIS: KEY LEARNINGS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

5. Reflexes, during the first hours or days of the disease, may still be present and diagnosis of GBS should therefore not be abandoned.

6. An acute-onset sensitive-motor polyneuropathy suggests an autoimmune-mediated process that is potentially treatable by immune-modulatory therapy.

7. Atypical presentations, such as pure motor symptoms or early diagnosis of GBS require an immune-modulatory therapy to reduce the need for mechanical ventilation.

8. In the presence of relapsing symptoms, a TRF of GBS should be considered if there have been fewer than 3 symptom relapses occurring in less than 8 weeks from onset.

9. In the presence of relapsing symptoms, CIDP should be considered if there have been over 3 symptom relapses in over 8 weeks from onset.

10. Sparing of Cranial and Respiratory function can be a clue to suggest CIDP rather than GBS. 11. Worsening demyelination on follow-up EMG may suggest CIDP rather than GBS.

65 // Guillain-Barré Syndrome

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 1: Which of the proposed triads characterises a Miller-Fisher Syndrome (MFS)?

Select Tick the allcorrect that apply answer

Ataxia, areflexia and ophthalmoplegia Ataxia, paresthesia and paresis appendicular Areflexia, dysphonia and proximal and distal paresis Areflexia, ophthalmoplegia and dysautonomia

66 // Guillain-Barré Syndrome

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 1: Which of the proposed triads characterises a Miller-Fisher Syndrome (MFS)?

MFS is considered to be a variant of the GBS, characterised by ataxia, areflexia and ophthalmoplegia. It usually has a benign evolution, with a complete recovery in 60 to 100% of patients after 6 months.

There is no difference in terms of outcome between patients treated with PE or IVIg versus supportive care.20

Tick Correct all that answer apply

!

Ataxia, areflexia and ophthalmoplegia Ataxia, paresthesia and paresis appendicular.

Areflexia, dysphonia and proximal and distal paresis Areflexia, ophthalmoplegia and dysautonomia

67 // Guillain-Barré Syndrome

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 2: A 45-years old man is admitted to the emergency unit with mild sensory symptoms in his upper limbs and is unable to walk more than 10 metres. He suffered from diarrhoea 3 weeks earlier.

What is the most likely Erasmus GBS outcome score for this patient?

Select Tick the allcorrect that apply answer

3.5 4.5 5.5 6.0

68 // Guillain-Barré Syndrome

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 2: A 45-years old man is admitted to the emergency unit with mild sensory symptoms in his upper limbs and is unable to walk more than 10 metres. He suffered from diarrhoea 3 weeks earlier.

Tick Correct all that answer apply

What is the most likely Erasmus GBS outcome score for this patient?

3.5

4.5

!

Age of onset (years) Diarrhoea (<4 weeks)

5.5 6.0

Categories

Score

>60

1

41 - 60

0.5

<40

0

Absent

0

Present

1

0 - 1

1

2

2

3

3

4

4

5

5

GBS disability scale (At 2 weeks after entry)

Erasmus GBS outcome score

69 // Guillain-Barré Syndrome

1 - 7

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3: Which of the following options is a reasonable differential diagnosis of MFS?

Select Tick the allcorrect that apply answer

Myasthenia gravis Dysthyroidism Brain stem stroke All of the above

70 // Guillain-Barré Syndrome

DIAGNOSIS & DISABILITY ASSESSMENT: TEST YOUR KNOWLEDGE INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

QUESTION 3: Which of the following options is a reasonable differential diagnosis of MFS?

Tick Correct all that answer apply

MFS is frequently mistaken for myasthenia gravis, dysthyroidism or brain stem stroke.

Myasthenia gravis

The absence of fatigue, along with the presence of reflexes and sudden onset respectively, may help to confirm a differential diagnosis.

Dysthyroidism Brain stem stroke

!

71 // Guillain-Barré Syndrome

All of the above

GUILLAIN-BARRÉ SYNDROME INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

GUILLAIN-BARRE SYNDROME From diagnosis to treatment INTRODUCTION SECTION 1: SYMPTOMS & PATHOPHYSIOLOGY SECTION 2: DIAGNOSIS & DISABILITY ASSESSMENT SECTION 3: TREATMENT & GUIDELINES 72 // Guillain-Barré Syndrome

TREATMENT & GUIDELINES: CLINICAL EVIDENCE FOR EFFECTIVE USE OF IVIG21 INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

There is convincing evidence that, in a large subset of patients, GBS is caused by a phenomenon of molecular mimicry induced by an aberrant autoimmune response.

Several trials have proven that intravenous immunoglobulin (IVIg), based on a regimen of 0.4 g/kg bodyweight daily, for 5 consecutive days, is as effective as Plasma Exchange (PE), administered five times over a 2-week period.

A Cochrane review on the use of immunoglobulin in GBS shows no difference between IVIg versus PE in terms of improvement in disability score after 4 weeks, time with mechanical ventilation, recovery, residual disability and mortality.21 In many centres, IVIg has replaced PE because of its greater convenience, wide availability and good safety profile, with few drug-related sideeffects.

Other immunomodulatory strategies, such as oral corticosteroids or intravenous methylprednisolone, are not useful to treat GBS. Combining IVIg therapy with methylprednisolone has not been demonstrated as more effective than IVIg alone.

73 // Guillain-Barré Syndrome

TREATMENT & GUIDELINES: EXPECTED TREATMENT OUTCOMES INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

A combined use of IVIg, immediately following a course of PE, was not demonstrated to be significantly better than PE or IVIg therapy alone.

“Time is nerve” is a useful statement to keep in mind concerning the importance of starting either of the two immunomodulatory therapeutic options as soon as possible.

About 10% de patients with GBS treated with IVIg or PE, during an acute phase, may deteriorate after improvement or stabilisation. This condition is called Treatment Related Fluctuation (TRF).

There is no agreement on how to manage TRF. However, many centres agree to re-treat patients with IVIg at 0.4 g/kg bodyweight daily for 5 consecutive days.

74 // Guillain-Barré Syndrome

TREATMENT & GUIDELINES: CONSENSUS ON RETREATMENT INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Therapeutic dilemmas may occur in certain contexts or forms of GBS. o Dilemma 1: Treatment for mildly affected patients •

There is no consensus on the definition of “mildly affected” patients, however, it is common to consider the form to be mild when the patient maintains the ability to walk unaided and shows no evidence of progression.

•

It has been suggested that mild forms should be treated when features such as dysautonomia and bulbar or facial weakness are documented. In the absence of these symptoms, a policy of “wait and see” may apply in theses cases.

o Dilemma 2: Some patients with GBS may show no recovery signs following a first cycle of immunomodulatory therapy •

In this context, re-treating the patient or switching to an alternative therapy could be a potential course of action.

At present, there is no evidence that repeating treatment (either with IVIg or PE) or switching to an alternative treatment improves outcomes in patients with GBS.

75 // Guillain-Barré Syndrome

TREATMENT: ILLUSTRATIVE PATIENT CASES INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CASE 1: AXONAL GBS

CONTROVERSIAL CASES

CASE 2: AIDP FORM OF GBS

CASE 3: ACUTE-ONSET CIDP vs GBS

A 20-year-old Hispanic male patient presents with an unremarkable medical history.

57 year-old woman with a medical history of recent upper respiratory infection

Learn about how to treat axonal GBS

Learn about how to treat and manage AIDP

Learn about how to manage acute-onset CIDP following treatment related fluctuation

Click here to learn more

Click here to learn more

Click here to learn more

76 // Guillain-Barré Syndrome

A 50-year-old male patient presents with a 3-week history of numbness and tingling in the hands and feet.

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

Following admittance to the emergency room, the patient underwent medical examination and testing.

Test outcomes were as follows:

Neurological examination • Bilateral symmetrical facial paresthesia • Distal and proximal motor strength in all extremities, including neck flexor muscles: 0/5 on MRC scale • No sensory abnormalities • Absent deep tendon reflexes and inability to walk • No autonomic dysfunction

77 // Guillain-Barré Syndrome

Blood work-up • Normal

CSF analysis • Increase in proteins • Normal cellular count

EMG test • Pure motor axonal polyradiculoneuropathy

CASE 1: AXONAL GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

During the first day of the patient’s in-hospital treatment, the patient was started on 2 g/kg immunoglobulin.

Respiratory deteriorating was evident and mechanical ventilation was required.

Re-gaining muscle strength Patient with mechanical ventilation

After a few days of immunoglobulin infusion, a clear clinical improvement was observed. Withdrawal of mechanical support was possible and a slow recovery of axial and appendicular strength was documented.

The patient was discharge with mild walking difficulties. One month later, walking difficulties were minor, as observed during the ambulatory follow-up.

PATIENT CASES

78 // Guillain-Barré Syndrome

CASE 2: AIDP FORM OF GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

The patient was promptly treated with IVIg (2 g/kg). A few hours after admission, clinical examination showed increased weakness and the patient developed quadriplegia and dysphagia. Nevertheless, mechanical ventilation was not required.

The patient recovered gradually over the next two weeks, was discharged and prescribed physiotherapy.

Three months later, the patient was able to walk independently and continued to gain strength.

PATIENT CASES

79 // Guillain-Barré Syndrome

CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

SECTION 1

SECTION 2

SECTION 3

CONTROVERSIAL CASES

The patient is readmitted to hospital for a third time with very severe weakness in his 4 limbs. He is unable to stand.

Test outcomes were as follows: o MRC scores: 2-3 in all groups. o ONLS: (3+6) = 9 o Severe proprioceptive and vibratory sensory loss, areflexia, no cranial nerve of respiratory involvement. o EMG: unchanged from 2nd study, with severe demyelination o Blood work-up: normal Differential diagnosis: In view of this third episode, occurring 11 weeks after onset of initial symptoms, in a previous IVIg-responsive patient, with perfectly stable cranial nerve and respiratory function, severe proprioceptive sensory loss, severe demyelination on EMG, Acute-Onset CIDP is diagnosed.

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CASE 3: ACUTE-ONSET CIDP vs GBS INTRODUCTION

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Treatment decision 1: The patient is re-treated with IVIg 2g/kg and recovers fully over a period of 2 weeks.

Subsequently, slow deterioration reappears 4 to 5 weeks after each IVIg infusion. This is observed twice.

Treatment decision 2: The patient is put on IVIg 2g/kg every 4 weeks, and stabilises with normal MRC scores and ONLS. After 2 further courses of IVIg at 2 g/kg, the dose is reduced at each course by 20% of the initial dose.

The patient remains stable until he is put on 1 g/kg. He then starts to deteriorate again slowly. o MRC drops to grade 4 o ONLS drops to grade 4 Treatment decision 3: The dose is increased again to 1.2 g/kg every 4 weeks. o The patient has since remained stable for the past 4 months.

Next steps: Re-attempt a dose reduction within one year of disease onset.

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TREATMENT: KEY LEARNINGS INTRODUCTION

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1. GBS is a treatable, but life-threating disease that requires early diagnosis and optimum management and monitoring.

2. Intravenous immunoglobulin (IVIg) is as effective as plasma exchange (PE) in the treatment of GBS in adults, based on the following regimen: o PE: five sessions, each every two days. o IVIg: 0.4 g/kg bodyweight daily for 5 consecutives days.

3. IVIg has become the first treatment option due to its wide availability, fewer side-effects and convenience.

4. The combination of PE and IVIg therapy has not demonstrated any superiority to either treatment alone for the treatment of patients with GBS. 5. There is insufficient evidence of therapeutic benefit to support the inclusion or exclusion of intravenous methylprednisolone, in combination with IVIg, to treat patients with GBS during an acute phase.

6. In cases of symptom relapse, treatment requires careful consideration. Switching treatment from IVIg to PE should be avoided as it may lead to longer treatment.

7. Unnecessary early initiation of steroids should be avoided, as it may cause treatment related fluctuation.

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TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 1: In which of the proposed case(s) should “mild” forms of GBS be treated?

Select Tick the allcorrect that apply answer

Older patients (over 60 years old) A history of diarrhoea Documented dysautonomia Distal paresthesia in four limbs

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TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 1: In which of the proposed case(s) should “mild” forms of GBS be treated?

•

“Mildly affected” patients should be treated when dysautonomia, bulbar or facial weakness is documented.

•

The policy of “wait and see” may apply in some cases.

Tick Correct all that answer apply

Older patients (over 60 years old)

A history of diarrhoea

!

Documented dysautonomia Distal paresthesia in four limbs

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TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 2: Which of the following statements is correct regarding GBS treatment?

Select Tick the allcorrect that apply answer

Intravenous corticosteroids alone may be useful in patients with GBS IVIg 0.8 g/kg bodyweight daily for 5 consecutives days is the recommended regimen for patients with GBS IVIg is more effective than PE to treat patients during acute phases, who require mechanical ventilation and have autonomic dysfunction PE is as effective as IVIg in patients with GBS during as acute phase

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TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 2: Which of the following statements is correct regarding GBS treatment?

•

• •

Tick Correct all that answer apply

PE is beneficial when it is applied during the first 4 weeks of onset.

Its effects are even more beneficial if the treatment is started within the first two weeks of onset.

Intravenous corticosteroids alone may be useful in patients with GBS

The usual regimen is five times during a two-week period, with a total exchange of about five plasma volumes.

IVIg 0.8 g/kg bodyweight daily for 5 consecutives days is the recommended regimen for patients with GBS

Several randomised controlled trials (RCT) have demonstrated that PE is as effective as IVIg to treat patients with GBS.

IVIg is more effective than PE to treat patients during acute phases, who require mechanical ventilation and have autonomic dysfunction

!

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PE is as effective as IVIg in patients with GBS during as acute phase

TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 3: Indicate whether the following statement is true or false.

Treatment related clinical fluctuation (TRF) corresponds to a deterioration of the patient’s symptoms following initial improvement or stabilisation after IVIg treatment. It has been documented in about 5 to 10% of all IVIg-treated patients.

Select Tick the allcorrect that apply answer

True

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False

TREATMENT: TEST YOUR KNOWLEDGE INTRODUCTION

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QUESTION 3: Indicate whether the following statement is true or false.

Treatment related clinical fluctuation (TRF) corresponds to a deterioration of the patient’s symptoms following initial improvement or stabilisation after IVIg treatment. It has been documented in about 5 to 10% of all IVIg-treated patients.

•

About 5 to 10% of patients experience a deterioration after an initial improvement or stabilization following IVIg treatment.

•

TRF is a well-known condition, and can usually be treated with a second course of IVIg, based on reports that symptoms improve following retreatment with a course of IVIg.

•

At present, no RCT has been conducted to investigate the effects of the second dose in this context.

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Tick Correct all that answer apply

!

True False

GUILLAIN-BARRÉ SYNDROME INTRODUCTION

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GUILLAIN-BARRE SYNDROME From diagnosis to treatment CONTROVERSIAL CASES

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UNUSUAL CASES INTRODUCTION

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CASE 4: TETRAPARESIS AND PORPHYRIA vs GBS

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CASE 5: MYASTHENIA GRAVIS vs GBS

CASE 6: FOCAL-ONSET GBS vs DIABETIC COMPLICATIONS

A 21-year old female patient presents with gastrointestinal complaints and progressive quadriparesis

A 41 year-old male presents following 2 weeks of distal weakness, diplopia, dysphagia and drophead

A 58 year-old woman with diabetes mellitus presents after 2 days of weakness and loss of dexterity in her upper right limb

Learn to rule out GBS in patients with porphyria-related tetraparesis

Learn to recognise the key features of Myasthenia Gravis

Learn to diagnose GBS in diabetic patients with poor glycaemic control

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CASE 4: TETRAPARESIS AND PORPHYRIA vs GBS INTRODUCTION

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CASE DESCRIPTION 1.

Controversial symptoms

A female patient aged 21 was admitted to the emergency room complaining of 5 weeks of abdominal pain associated with diarrhoea and vomiting with slow progressive quadriparesis, that has been aggravating over the previous 7 days.

Proposed treatment: High carbohydrate diet.

Clinical examination showed flaccid tetraparesis with generalised areflexia. A lumbar puncture was carried out. Results were normal. An EMG was conducted and suggested axonal motor pure polyneuropathy, based on low amplitudes observed in all the examined motor nerves.

2.

Differential diagnosis

Abdominal pain with persistent diarrhoea and vomiting are unusual features in the typical evolution of GBS. A normal lumbar puncture in patients with tetraparesis during the 5 weeks after the symptoms start does not support the diagnosis of acquired inflammatory demyelinating polyneuropathy.

PATIENT CASES

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CASE 5: MYASTHENIA GRAVIS vs GBS INTRODUCTION

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CASE DESCRIPTION 1.â&#x20AC;Ż

Controversial symptoms

A 41 year-old male, with no relevant past medical history, presented to the emergency room with 2 weeks of previous generalised distal weakness, diplopia, dysphagia and drophead.

Neurological examination showed limited extra-ocular movements with expressionless face by facial muscle weakness, hyporeflexia with sensitivity preserved. Neither symptom fluctuation nor respiratory distress were noted.

Proposed treatment: Pyridostigmine and oral prednisone were started with gradual improvement of all symptoms after a cautious increase of prednisone.

A brain MRI was normal. Myasthenia gravis and GBS were considered as differential diagnoses. The EMG study showed a slight decrease of amplitudes in all motor nerves examined and an additional repetitive nerve stimulation study resulted in a significant decremental response. A trial with pyridostigmine was conducted showing transient improvement of diplopia and drophead. A few days later, antibodies against acetylcholine receptors were documented and Myasthenia Gravis was diagnosed.

PATIENT CASES

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CASE 5: MYASTHENIA GRAVIS vs GBS INTRODUCTION

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CASE DESCRIPTION 2.

Differential diagnosis

Myasthenya gravis should be considered in any patient with an acute onset of diplopia and/ or palpebral ptosis. Fluctuation of symptoms is a key feature in Myasthenia, but in a subset of patients, the fluctuation is slight or not present. GBS with oculo-motor nerve involvement could be a reasonable differential diagnosis, mainly when the fluctuation of symptoms is not clear.

Keeping in mind this information, it is recommended not to rule out myasthenia gravis diagnosis in patients with diplopia without fluctuation.

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Proposed treatment: Pyridostigmine and oral prednisone were started with gradual improvement of all symptoms after a cautious increase of prednisone.

CASE 6: FOCAL-ONSET GBS vs DIABETIC COMPLICATIONS INTRODUCTION

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CASE DESCRIPTION 1.

Controversial symptoms

A 58 year-old woman, with a relevant medical history of diabetes mellitus for over 10 years, and poor adherence to treatment, is admitted to hospital with a history of 48 hours of weakness and loss of dexterity in her upper right limb. Physical examination showed paresis of the right limb, while the rest of muscle strength was normal with generalised normoreflexia and no sensitive signs were documented. A blood work-up demonstrated hyperglycaemia of 159 mg/dl.

Proposed treatment: IVIg was started. The patient improved a few days later, was discharged and prescribed physiotherapy.

Peripheral diabetic neuropathy was diagnosed, and oral antidiabetic drug adjustment was done. The patient was then discharged. Two days later, the patient returned with generalised paresis, areflexia and mild bilateral facial palsy. An EMG demonstrated sensory-motor demyelinating polyneuropathy and GBS was diagnosed.

2.

Differential diagnosis

GBS is always a challenging diagnosis in patients pre-diagnosed with Diabetes Mellitus. We recommend considering alternative diagnoses in any acute neurological deficit in a diabetic patient with poor glycaemic control.

PATIENT CASES

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GLOSSARY OF TERMS GUILLAIN-BARRÉ SYNDROME

GUILLAIN-BARRE SYNDROME From diagnosis to treatment GLOSSARY OF TERMS & ABBREVIATIONS REFERENCES

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GLOSSARY OF TERMS Areflexia

Babinski

Bradycardia

Cauda equine

Conus medullaris

Diplopia

Distal paresthesia

Dysautonomia

Dysphagia

Fasciculation

Oculomotor nerve palsy Neurogenic pulmonary oedema

Paresthesia

Pleocytosis

Absence of neurologic reflexes.

A neurologic examination based on the big toeâ&#x20AC;&#x2122;s reaction to stimulation of the external portion of the sole.

A condition in which an individual has a very slow heart rate, typically defined as a resting heart rate of under 60 beats per minute.

Collection of nerve roots, horsetail-like in appearance.

The most distal bulbous part of the spinal cord.

Double vision.

Tingling, tickling, pricking, numbness or burning sensation in extremities, with no apparent physical cause.

A disorder of autonomic nervous system (ANS) function, involving failure of the sympathetic or

parasympathetic components of the ANS. Difficulty swallowing.

Brief spontaneous contractions affecting a small number of muscle fibres, often causing a flicker of movement under the skin.

Eye condition resulting from damage to the third cranial nerve or a branch of the third cranial nerve.

A relatively rare form of pulmonary oedema caused by an increase in pulmonary interstitial and alveolar fluid.

A burning or prickling sensation that is usually felt in the hands, arms, legs, or feet, but can also occur in other parts of the body.

Presence of an abnormally large number of lymphocytes in the cerebrospinal fluid.

Polyneuropathy

A general degeneration of peripheral nerves that spreads towards the centre of the body.

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GLOSSARY OF TERMS Proximal Quadriplegia Schwann cells Symmetric weakness

Tachycardia per minute.

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Situated nearer to the centre of the body or the point of attachment.

Paralysis caused by illness or injury, resulting in partial or complete loss of use of all four limbs and torso.

Cells in the peripheral nervous system that produce the myelin sheath around neuronal axons.

The most common pattern of muscle weakness in myopathies, affecting predominantly proximal muscles of the legs and arms, or the so-called “limb-girdle” distribution.

A heart rate that exceeds the normal resting rate, typically a resting heart rate over 100 beats

ABBREVIATIONS AIDP AMAN AMSAN CIDP CMAP CSF CT EMG GBS IVIg LP MFS MM MRC MRI PE

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Acute inflammatory demyelinating polyneuropathy Acute motor axonal neuropathy Acute motor sensory axonal neuropathy Chronic Demyelinating Inflammatory Polyneuropathy Compound Muscle Action Potential Cerebrospinal fluid Computed tomography Electromyogram Guillain-Barré Syndrome Intravenous immunoglobulin Lumbar puncture Miller-Fisher Syndrome Molecular mimicry Medical research council Magnetic resonance imaging Plasma exchange

ABBREVIATIONS SYNDROME GUILLAIN-BARRÉ

GUILLAIN-BARRE SYNDROME From diagnosis to treatment GLOSSARY OF TERMS & ABBREVIATIONS REFERENCES

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7. Jin HY, et al. A case of diabetic neuropathy combined with Guillain-Barre Syndrome. Korean J Intern Med. 2010; 25(2): 217–220.

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12. Iwata F, Utsumi Y. MR imaging in Guillain-Barré syndrome. Pediatric Radiology. 1997; 27(1): 36–38.

13. Hughes RA, et al. Controlled trial prednisolone in acute polyneuropathy. Lancet. 1978; 2(8093): 750–753.

14. van Koningsveld R, et al. A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007; 6(7): 589–594.

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16. Medical Research Council. Aids to the examination of the peripheral nervous system, Memorandum no. 45, Her Majesty's Stationery Office, London, 1981.

17. Winer JB. Guillain-Barré syndrome: clinical variants and their pathogenesis. J Neuroimmunol. 2011; 231(1–2): 70–72.

18. Rougé A, et al. Long-term impact after fulminant Guillain-Barré syndrome, case report and literature review. Int Med Case Rep J. 2016; 9: 357–363.

19. Fokke C, et al. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain. 2014; 137(Pt 1): 33–43.

20. Verboon C, et al. Treatment dilemmas in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 2017; 88: 346–352.

21. Hughes RAC, et al. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database of Systematic Reviews. 2014, Issue 9. Art. No.: CD002063.

22. Kuwabara S and Yuki N. Axonal Guillain Barré syndrome: concepts and controversies. The Lancet Neurol. 2013; 12(12): 1180–1188.

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