Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)

I. What every physician needs to know.

Classic Guillain-Barré syndrome (GBS) is an acute to sub-acute onset ascending, flaccid, symmetric, areflexic weakness syndrome, often associated with autonomic instability, typically occurring within days to weeks of an antecedent infection.

The majority of patients will recover, but there is a notable 2-10% case mortality rate, and a quarter of patients may require mechanical ventilation. If the syndrome progresses to require mechanical ventilation, the mortality rate may approach 12-20%.

Additionally, for those with persistent requirements for mechanical ventilation or weakness at 2 years, there may be lifelong impairments in function.

II. Diagnostic Confirmation: Are you sure your patient has Guillain-Barré Syndrome?

Consideration of the diagnosis of GBS is supported by a typical clinical presentation, and cerebrospinal fluid (CSF) and electrophysiologic (EPS) findings consistent with GBS.

Level I diagnostic criteria for Guillain-Barré syndrome consist of:

• Bilateral flaccid limb weakness

• Reduced or lost deep tendon reflexes

• Monophasic illness

• 12-hour to 28-day syndrome evolution, from onset to the nadir weakness

• Consistent electrophysiology findings

• Cerebrospinal fluid analysis revealing cytoalbuminologic dissociation (normal CSF leukocytes but elevated protein)

• Absence of an alternative diagnosis

Some authors have reported the retention or accentuation of deep tendon reflexes (DTR) in acute inflammatory demyelinating polyneuropathy. As is discussed below, retention of DTRs is far more associated with acute motor axonal neuropathy (AMAN). These same authors argue to include presence of DTRs in the diagnostic criteria; however, more importantly, clinicians should recognize the limitations of any test and thus factor in pre-test probability before excluding or ruling in any diagnosis with the presence or absence of a single test.

A. History Part I: Pattern Recognition

The classic acute inflammatory demyelinating polyneuropathy form of Guillain-Barré syndrome is an acute- to subacute onset of progressive, flaccid, areflexic paralysis, often preceded by a recent infection, and associated with paresthesias. Campylobacter is the most commonly isolated triggering infection; however, numerous other gastrointestinal and respiratory infections are also known causes. Recently, GBS has been strongly correlated with hepatitis E infections and Zika virus infections. Additionally, there are numerous non-infectious associations including post-operative GBS, co-existence with systemic lupus erythematosus occurring as part of a paraneoplastic syndrome, and in the setting of the new chemotherapeutic checkpoint inhibitors (e.g., anti-PD1 monoclonal antibody treatment).

The three phases of GBS are the progressive phase (lasting from days to 4 weeks), a plateau phase with little clinical change (lasting from days to months), and a recovery phase. By 7 days, about three quarters of patients will achieve their nadir in neurologic function, and 98% will do so by 4 weeks. Many patients with GBS will have some mild bulbar symptoms, but few progress. However, the occurrence of predominant bulbar findings suggests the possibility of the Miller-Fischer syndrome variant.

Level 1 diagnostic criteria for the Miller Fischer syndrome are:

• Bilateral ophthalmoparesis

• Absence of weakness

• Reduced or lost deep tendon reflexes

• No alteration of consciousness

• Monophasic illness

• 12-hour to 28-day syndrome evolution, from onset to the nadir weakness

• Normal nerve conduction studies (or indicative of only sensory losses)

• Cytoalbuminologic dissociation on cerebrospinal fluid analysis (normal CSF leukocytes but elevated protein)

• Absence of an alternative diagnosis

The other major variants of GBS and their diagnostic criteria are:

• Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

• Miller Fischer Syndrome

• Acute Motor Axonal Neuropathy (AMAN)

• Acute Motor and Sensory Axonal Neuropathy (AMSAN)

B. History Part 2: Prevalence

The annual worldwide incidence of GBS is 1.3 cases per 100,000. While in the United States and Europe acute inflammatory demyelinating polyneuropathy (AIDP) accounts for 90% of cases of GBS, and is thus often used synonymously, in China and Japan, the axonal variant, AMAN accounts for 40-60% of cases of GBS. Additionally, there are differences in these disease processes, suggesting either different pathogenesis or variability of presentation.

The AIDP form is more likely to follow infections by cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae; occur sporadically; present with bulbar, sensory, and autonomic nerve involvement; and demonstrate demyelination on electrophysiologic testing; and it is generally associated with a better outcome. In contradistinction, the AMAN:

• Is more likely to follow infections by Campylobacter jejuni and possibly Haemophilus influenza

• Occurs in epidemics (especially in children)

• Typically is not associated with bulbar, sensory, or autonomic nerve involvement

• Demonstrates axonal degeneration on electrophysiologic testing

• Is generally associated with a bimodal recovery (either early or delayed)

C. History Part 3: Competing diagnoses that can mimic disease Guillain-Barré syndrome

In addition to the variant forms of GBS described above, there are additional diagnostic considerations when evaluating a patient with polyneuropathy and associated weakness, such as:

• Basilar artery occlusion

• Botulism

• Critical illness polyneuropathy

• Heavy metal poisoning

• Metabolic myopathies

• Neoplastic meningitis

• Paraneoplastic neuropathies

• Polymyositis

• Spinal cord compression

• Tick paralysis

• Transverse myelitis

• Vasculitis neuropathies

• Numerous viruses (e.g., West Nile virus, poliovirus, Zika virus, other)

Each of the above syndromes varies to some degree, thus identifying the discriminating features can assist in triaging these during initial assessment. Although historical questions and physical examination should probe for epidemiologic, historical and examination findings supportive of those items noted, early electrophysiologic testing is recommended to identify and differentiate the degree that the syndrome is an axonal, demyelinating or mixed syndrome, and whether the fibers affected are sensory, motor, or both.

D. Physical Examination Findings

The physical examination should focus not only on the neurologic examination suggestive of GBS, but include assessment of hemodynamic and respiratory assessment as well. At the initial presentation the most common presenting findings are areflexia (75%), paresthesias (70%), and weakness in the legs (60%), arms (20%), and bulbar muscles (~ 30%). At this initial stage 95% of patients will have abnormal electrophysiology studies, but only 50% will have elevated CSF protein.

In contrast, when the syndrome is fully developed most patients will demonstrate or experience areflexia (90%), paresthesias (85%), or weakness in the legs (95%), arms (90%), and bulbar muscles (~ 50%). Additionally, by this phase patients also demonstrate or experience sensory loss (75%) and pain (30%), and up to 30% will require mechanical ventilation. By this phase, essentially all patients will have abnormal electrophysiologic examinations (99%) and elevated cerebrospinal fluid protein (90%).

Due to the high rate of progression to ventilatory failure and clinical autonomic instability (up to 50% of patients), a careful focus on hemodynamics is important. Predictors of ventilatory failure will be discussed later in the “Immediate Management” section, but on exam, the presence of bulbar symptoms, autonomic insufficiency and gait instability are all predictive of the need for mechanical ventilation or an adverse prognosis.

E. What diagnostic tests should be performed?

As noted previously, Guillain-Barré syndrome is diagnosed with a combination of clinical, cerebrospinal fluid, and electrophysiologic characteristics (see below). Accordingly, all patients with suspicion for GBS should have formal electrophysiology testing and assessment of cerebrospinal fluid.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

While a provider might order studies to explore some of the other diagnostic possibilities noted above, confirmation of GBS only requires consistent electrophysiology and cerebrospinal fluid studies. Thus, tests and their criteria for the diagnosis of GBS are as follow:

1. Electrophysiology testing consistent with AIDP or GBS

At least one of the following in at least 2 nerves

Or

At least two of the following in one nerve if all others are inexcitable and the dCMAP is greater than 10% of the lower limits of normal (LLN)

• Motor conduction velocity <90% LLN (85% if dCMAP is <50% LLN)

• Distal motor latency >110% upper limit of normal (ULN) (>120% if dCMAP <100% LLN)

• pCMAP/dCMAP ratio <0.5 and dCMAP >20% LLN

• F-response latency >120% ULN.

dCMAP – compound muscle action potential after distal stimulation; pCMAP – compound muscle action potential after proximal stimulation.

2. Cerebrospinal fluid with cytoalbuminologic dissociation (elevated protein and normal white count).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In the absence of physical exam or historical features suggesting a central vascular event, spinal cord compression, transverse myelitis, or suspicion of an occult malignancy, no imaging studies are required to diagnose GBS.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

The most over-utilized test in the setting of syndromes compatible with GBS is MRI imaging of the brain and spinal cord. As noted above, in the absence of ’alarm’ historical or examination findings, it is not indicated. The recommendation (reflex) to obtain advanced imaging is thus likely a compound effect of a) our lack of confidence in our physical diagnosis skills, and b) the defensive fear that it could be something sinister.

III. Default Management

Following the diagnosis of Guillain-Barré Syndrome, routine management should consist of:

• Prophylaxis for venous thromboembolic disease

• Telemetry monitoring for signs of hemodynamic instability

• Baseline and serial (every 4-8 hours) assessment of vital capacity (VC) and negative inspiratory force (NIF)

• Serial (every 4-8 hours) clinical examination to detect rapid respiratory or bulbar decline

• An expectant bowel regimen in case of autonomic involvement

• Incentive spirometry

• Chest physiotherapy and incentive spirometry for patient with a VC below 30 mL/kg

• A functional assessment to gauge motor disability and prognosis

A. Immediate management

Management of GBS is divided into supportive and disease specific management. While evidence is limited, the following recommendations can be made:

Supportive therapy

1. Hemodynamic instability

Clinically significant autonomic dysfunction occurs in approximately 20% of hospitalized patients with GBS. This may present as bradycardia, tachycardia, and either hypo- or hypertension and may result in wide and rapid clinical variability. The findings of hemodynamic instability should raise the question of need of transfer to the ICU.

Hypotension: Occurs in up to 10% of hospitalized patients and typically responds well to intravenous fluids. Failure to respond would meet criteria for ICU-level care.

Hypertension: Is often short lived, but should the blood pressure require treatment it is recommended to use short acting agents.

Arrhythmias: Managed according to current cardiology guidelines, but may necessitate ICU transfer. Additionally, bradycardias may require temporary pacing.

2. Deep vein thrombosis (DVT) prophylaxis

There are no evidence-based guidelines for recommending prophylaxis in hospitalized patients with GBS. Additionally, the incidence is poorly characterized, but a retrospective analysis suggested DVT or PE’s occur in about 7% of patients, even those with anticoagulation. Thus, even in the absence of clear guidelines, DVT prophylaxis is recommended.

3. Respiratory function assessments

Since there is a 25-30% risk of progression to ventilatory failure and mechanical ventilation, it is important to identify patients at risk for ventilatory failure and perform serial clinical and pulmonary function assessments to triage ongoing management. There are classic intubation criteria consisting of:

• Evidence of fatigue

• Concern or witnessed aspiration

• Vital capacity below 15 mL/Kg

• Room air PaO2 below 70 mmHg

Many think these parameters may not identify patients until late in their disease progression, thus recommend not only the absolute pulmonary function values (noted above) but also the degree of change in time. Thus, additional reasonable recommendations for acute management and consideration of intubation or ICU transfer for GBS are (consider ICU transfer and/or intubation for any of the following):

• Clinical evidence of fatigue

• Difficulty controlling airway and risk of aspiration

• VC drops to below 20 mL/kg

• NIF (negative inspiratory force) drops to below – 30 cm H20

• 30% decline in VC or NIF in 24 hours

4. Bowel and bladder regimens

Constipation and bladder outlet dysfunction is common in patients with GBS. Additionally an adynamic ileus may develop in about half of hospitalized patients, thus focus on stool output and diet is important. Besides implementation of a bowel regimen, effort to minimize narcotic analgesics may be beneficial. Likewise, due to bladder outlet dysfunction, patients may require placement of a bladder catheter.

5. Physical therapy

There are no focused studies in patients with GBS to guide recommendations for rehabilitation and conditioning. However, to minimize the impact of immobility on hemodynamics, sensory loss, and metabolism (e.g., calcium metabolism), therapy should be focused on gentle strengthening, proper limb positioning, posture, orthotics, and nutrition.

6. Pain management

Pain is a common symptom in acute GBS, occurring in up to three-quarters of patients. While opioid analgesics are required in approximately 30% of patients, a stepwise progression is recommended, commencing with nonsteroidal anti-inflammatory agents, or acetaminophen. Likewise, tricyclic antidepressants, carbamazepine and other neuropathic agents such as gabapentin and pregabalin have been shown to provide relief.

Disease-specific therapy

It is beyond the scope of this document to provide an evidence-based review of the disease-specific treatment regimens; however, numerous reviews have shown corticosteroids to be ineffective, and that the mainstay of management consists of intravenous immunoglobulin (IVIG) and/or exchange plasmapheresis.

An evidence based review of plasmapheresis in neurologic disorders concluded that plasmapheresis is effective and should be used in severe forms of the AIDP variant of GBS. Patients were considered to have severe AIDP if they either had impairments in walking or required mechanical ventilation. Likewise, it is probably effective in milder forms of AIDP. The regimens evaluated consisted of an exchange of 1.5 plasma volumes for colloid fluid returned.

Another evidence-based analysis reviewed randomized controlled trials comparing the benefits of IVIG versus plasmapheresis. They concluded if IVIG is started within 2 weeks of symptom onset, it is equivalent to plasmapheresis and patients are more likely to complete therapy. While recommendation on dose and duration vary, the most commonly studied IVIG regimen in adults consisted of IVIG 400 mg/kg/day, for 4-5 consecutive days, as opposed to 4-5 plasma exchanges over 10-14 days. It is possible that 2 days of IVIG are sufficient.

There was no evidence that combination therapy, or administration of IVIG after completion of plasmapheresis was beneficial. Older evidence suggested an increased relapse rate with IVIG, but the Cochrane Review did not find enough evidence to support this conclusion.

B. Physical Examination Tips to Guide Management.

The key is to assure that one is performing serial assessments of hemodynamics, bulbar function, and for signs of ascending flaccid paralysis and ventilatory failure.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

During the initial evaluation and stabilization of patients with GBS, serial assessments of forced vital capacity (FVC) and negative inspiratory force (NIF) remain a good adjunctive measure to identify the need for ICU transfer and/or endotracheal intubation.

D. Long-term management

Short of long-term rehabilitation, there are no specific long-term treatment modalities for GBS.

E. Common Pitfalls and Side-Effects of Management

Classically, IVIG is considered to be associated with fewer adverse events than is plasmapheresis. However, a recent Cochrane Review did not reveal a dramatic difference. When all trials were included in the meta-analysis, there was no difference in adverse events. That being said, adverse events associated with IVIG and plasmapheresis are highlighted below.

Contraindication and cautions of administration of IVIG and plasma exchange:

Intravenous immune globulin administration (IVIG)

The rate of serious reactions to IVIG ranges between 3%-15%, and are usually mild and self-limited. Most of the reactions can be avoided by reducing the rate of infusion.

• The administration of IVIG is associated with a variety of complications:

  Acute kidney failure

  Acute respiratory distress syndrome

  Anaphylaxis

  Aseptic meningitis

  Backache

  Chest pain

  Erythema multiforme

  Hemolysis

  Hepatitis

  Hypokalemic nephropathy

  Myocardial infarction

  Rigors

  Seizures

  Stevens-Johnson syndrome

  Tachycardia

  Thrombosis

  Transfusion related acute lung injury (TRALI)

  A false elevation in serum glucose readings may be noted with admission of IVIG (Micromedex)

• The administration of IVIG is contraindicated in a variety of situations:

  Anaphylaxis or severe systemic reactions

  Hyperprolinemia (type I or II)

  IgA deficiency with antibodies to IgA

  Severe thrombocytopenia or coagulation disorder which would contra-indicate IM injections

• Most providers associate plasmapheresis with more complications than that of IVIG. However, as noted above, clinically this has yet to be proven. Overall there are less than 5% adverse reactions to plasmapheresis, and consist of:

  Transfusion reactions: (occurs < 2%) including nausea, emesis, hypotension, and vasovagal reactions, pallor, tachycardia, respiratory distress, muscle spasms, fevers and chills.

  Volume-related reactions: due to volume shifts during apheresis, which may result in either volume overload or hypotension.

  Metabolic reactions: since citrate is the anticoagulant used in plasmapheresis, in patients with pre-existing renal disease one may develop a metabolic alkalosis as well as hypocalcemia. Additionally, hypocalcemia may result from calcium binding to albumin replacement solutions.

Complications and cautions with plasma exchange

A recent prospective evaluation of the complications associated with therapeutic plasma exchange highlighted numerous issues to be aware. While the scope of problems is informative, the biggest limitation to this study is that only about 8% of the patients were being treated for GBS.

Regardless, 36% of treatments were associated with a complication. The majority of the complications were minor and there were no deaths. Fever (7.7%), urticaria (7.4%), and symptomatic hypocalcemia (7.3%) were the most common reactions.

Use of fresh frozen plasma (FFP) as a replacement colloid was associated with more complications than the use of albumin and saline (42% vs 30%). Severe hypotension (SBP < 85mmHg) only occurred in 1.3% of patients, but was 21-fold more common with use of albumin-saline replacement than FFP (2.2% vs 0.1%).

In summary, while the use of albumin-saline as a replacement in plasma exchange was associated with fewer complications, the overall rate of serious complications per treatment was low.

IV. Management with Co-Morbidities

There are no organ specific interactions other than those associated with autonomic system, cardiac dysrhythmias, and pulmonary complications of hypoventilation and resultant risk of aspiration or atelectasis. The below systems focused discussions address considerations and cautions in a variety of pre-existing disorders.

A. Renal Insufficiency

There is a FDA Black Box warning about the association of IVIG and the development of acute kidney injury, and osmotic nephrosis in a small subset of patients. Patients at risk for this complication are those with known kidney disease, diabetes, volume depletion, sepsis, age greater than 65, overweight patients. In such patients, it is recommended that the IVIG be delivered in a minimum concentration fluid, and at the minimum infusion rate.

B. Liver Insufficiency

While mild liver test abnormalities have been seen in association with both GBS and IVIG, it is generally well tolerated.

C. Acute Systolic and Diastolic Heart Failure

Given the osmotic load and volume shifts associated with IVIG and plasmapheresis respectively, fluid status needs to be monitored, and patients may require diuresis.

D. Coronary Artery Disease or Peripheral Vascular Disease

There are numerous direct cardiac complications of GBS, including atrial and ventricular dysrhythmias, hemodynamic instability, myocarditis, widely variable electrocardiogram changes, and very rarely, and thus arguably related, myocardial infarctions.

E. Diabetes or Other Endocrine Issues

No change in standard management, other than to recognize if diabetes is complicated by autonomic neuropathy, as patients may then be more susceptible to the colonic and bladder complications noted above.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, Chronic Steroids, etc).)

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

While there is no change in standard management, given the predisposition of progressive ventilatory dysfunction, one must be vigilant not only assuring that the underlying disease is maximally treated, but monitoring for progressive ventilatory function closely.

I. Gastrointestinal or Nutrition Issues

Since patients are at risk for autonomic dysfunction and ileus, patients with pre-existing motility disorders may require early implementation of bowel regimens.

J. Hematologic or Coagulation Issues

In patients with pre-existing severe thrombocytopenia or coagulopathy IVIG is contraindicated.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Typical ’to-do’ lists for coverage relate to the expected clinical progression:

• Check on serial monitoring of pulmonary function. Transfer to ICU if meets criteria.

• Perform serial bedside assessments of bulbar, hemodynamic and progressive paralysis.

• If called for hypotension, can try IV fluids. If non-responsive, consider ICU transfer.

• If called for hypertension, monitor if possible, but if severe may use short-acting agent.

• If called for respiratory distress a) assure adequate pulmonary reserve, b) consider aspiration or pneumonia, c) consider pulmonary embolism and d) consider cardiac etiology.

• If called for profound tachycardia or bradycardia consider ICU transfer.

B. Anticipated Length of Stay

There is wide variation in hospital length of stay, but the average duration for those discharged is about 7 days (range: 5-13 days). For those who expired, the average length of stay is about 14 days (range: 6-27 days).

C. When is the Patient Ready for Discharge.?

There are no specific guidelines for care transitions home or to a rehabilitation facility.

D. Arranging for Clinic Follow-up

There are no specific guidelines for the timing of follow-up for GBS. However, it is reasonable for neurologists to see patients soon after discharge, and then periodically until resolution of symptoms, and return to function.

1. When should clinic follow up be arranged and with whom?

Neurology within 2 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

None

E. Placement Considerations

A recent evidence based review was unable to identify any randomized controlled trials assessing the benefits of multidisciplinary care in the management of GBS. From three low-quality observational trials there is some suggestion of functional improvement and quality of life from multidisciplinary care. They were unable to make a recommendation.

Regardless, in patients who have completed their immune therapy with continued improving ventilatory function who continue to be unable to care for themselves at home, it is reasonable to recommend a care transition to an inpatient facility, with a multidisciplinary rehabilitation approach.

Likewise, in patients who are in their convalescent stage of illness, but with adequate strength to allow for home discharge, but still weak, referral to outpatient physical therapy is reasonable.

F. Prognosis and Patient Counseling

While some series quote a case mortality rate from 10-20%, a recent review and population study of hospitalized patients in the United States reported an overall in-hospital mortality of 2.6%, but identified a range of 12-20% for those requiring mechanical ventilation.

Approximately two-thirds of patients will recover completely, and efforts at identifying those with a bad prognosis may ultimately allow for more tailored interventions during the early phase of disease. Features predictive of delayed recovery are age of onset, pace of progression, ventilatory failure, the degree of change on electrophysiologic evaluation, and the presence of diarrhea within the prior 4 weeks.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

While there are no guidelines, it is reasonable to continue DVT prophylaxis until mobility is restored.

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