1.1

Definition and pathophysiology

GBS is an immune-mediated peripheral nerve disease classically characterized by a symmetrical ascending weakness that can progress to paralysis with associated hyporeflexia or areflexia [ ]. The mechanism behind GBS is not fully understood; however, molecular mimicry is the most common hypothesized mechanism [ ]. The theorized pathophysiology is that an inciting infection or process creates antigens that resemble normal host cells or proteins (Schwann cells, gangliosides, etc.), which confuses the host’s natural immune system. The body’s immune system then creates antibodies to destroy the antigen, leading to normal host cells’ death [ ]. The target for these antibodies differs depending on the GBS variant. In acute inflammatory demyelinating polyneuropathy (AIDP), antibodies are directed against a component of Schwann cells. In contrast, in acute motor axonal neuropathy (AMAN), antibodies are directed against the axolemma and nodes of Ranvier [ ]. In GBS, a trigger results in a cascade of immune responses that damage vital parts of peripheral nerves, leading to signaling dysfunction, which causes a sequela of symptoms such as weakness, paralysis, and hyporeflexia [ ].

1.2

Epidemiology

Worldwide there are approximately 100,000 new cases of GBS annually [ ]. The disease has the highest incidence in Bangladesh, with an incidence of 2.5 adult cases per 100,000 person-years and 3.25 cases per 100,000 person-years in pediatric patients, followed by Latin America (2.12 cases per 100,000 person-years), North America and Europe (0.81–1.91 cases per 100,000 person-years), and east Asia (0.44–0.67 per 100,000 person-years) [ ]. The incidence appears to increase by 20% with every 10-year age increase; unlike many autoimmune diseases, males are more commonly affected [ ]. There is a seasonal variation in the disease, with peaks in winter in Western countries, while China, India, Bangladesh, and Latin America appear to have a summer peak [ ]. One study of over 900 patients with GBS found a median age of 51 years, with most patients between 50 and 69 years [ ]. A national registry of pediatric GBS cases from Denmark found a median age of 8 and a peak incidence at 2 years [ ]. The disease can be severe. Despite current immunotherapies, the mortality rate is close to 5%, and up to 20% cannot walk without assistance one year from the onset of the disease [ ].

2.1

Presentation

GBS can present along several phases, including an acute phase (within 2 weeks of symptom onset), a progressive phase (2–4 weeks after onset), and a plateau phase (> 4 weeks after onset) [ ]. The pathognomonic clinical presentation of GBS is symmetrical ascending flaccid paralysis that starts in the lower extremities with decreased or absent reflexes [ ]. Weakness is often preceded or accompanied by bilateral sensory changes such as paresthesias or pain [ ]. Depending on the variant, patients may retain reflexes early in the disease course or even demonstrate hyperreflexia [ ]. Patients may also present in various stages of respiratory distress due to diaphragmatic weakness or hemodynamic instability from dysautonomia [ , ].

The preceding event that results in GBS is most commonly an infection, such as an upper respiratory infection or gastroenteritis. Associated microbes include Campylobacter jejuni , Haemophilus influenzae , Mycoplasma pneumoniae , cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis E virus, influenza, and Zika virus [ ]. Other antecedent events include vaccinations, checkpoint inhibitors, and surgery [ , ]. This antecedent event typically occurs up to 4–6 weeks before signs and symptoms of GBS develop [ ]. Several studies have shown that symptom onset can vary, with subtle symptoms beginning 1 to 2 weeks after immune system excitation, with a slow progression to peak neurologic deficits occurring at 2 to 4 weeks, and sometimes in rare cases, up to 6 weeks [ ]. The plateau phase can last for months and heavily depends upon the type of variant and time to treatment [ , , ]. Recovery begins within a few months of symptom onset, with the most improvement in the first year; however, some patients may take multiple years to recover [ , ].

2.2

ED evaluation

GBS is a clinical diagnosis in the ED setting. However, the evaluation for GBS highly depends upon the clinician’s suspicion and differential diagnosis. The ED evaluation focuses on excluding other organic causes of paralysis or weakness, such as acute ischemic stroke or acute spinal cord compression. Thus, a focused neurologic examination assessing the cranial nerves, motor and sensory system, reflexes, gait, and cerebellar function is necessary. Diagnosing GBS can be difficult, especially with atypical presentations. In one retrospective cohort of 69 patients ultimately diagnosed with GBS, the diagnosis was only considered in 30% of patients on the initial visit by the ED clinician, and the median number of ED visits before GBS was suspected was 2 (range 1 to 5) [ ]. Another retrospective study of 20 patients diagnosed with GBS found that only 5 of 20 patients were diagnosed on their first ED visit [ ]. Thirteen patients had at least 1 visit with a physician before their diagnosis, and 6 of the 20 had at least 2 visits [ ].

There is currently no highly sensitive or specific laboratory assessment that can definitively diagnose GBS. However, laboratory assessments are recommended, including complete blood count, electrolytes, renal and liver function, and thyroid stimulating hormone to evaluate for other conditions [ ]. In addition, lumbar puncture (LP) to obtain cerebrospinal fluid (CSF) can assist in excluding other causes of weakness and increase the clinical probability of GBS [ , ]. The classic finding on CSF analysis is albumino-cytological dissociation (elevated protein levels and normal cell counts) [ ]. While imaging is not necessary to diagnose GBS, advanced imaging such as magnetic resonance imaging (MRI) may be necessary to evaluate for other causes of weakness and sensory changes [ ].

2.3

ED management

The ED management of GBS focuses on stabilizing the patient’s respiratory and hemodynamic status, particularly in the acute phase of the condition. Clinicians should first evaluate the patient’s airway, respiratory, and hemodynamic status, as airway and respiratory compromise are among the main factors associated with mortality in GBS [ , ]. Up to 30% of patients with GBS require respiratory support, such as noninvasive positive pressure ventilation or endotracheal intubation with mechanical ventilation [ ]. In addition, physicians should closely monitor the patient’s hemodynamic status due to the risk of autonomic nervous system dysregulation, known as dysautonomia [ ]. Severe dysautonomia may manifest as severe hypertension or hypotension and necessitate intensive care unit (ICU) admission for blood pressure management, discussed in detail later [ ]. After stabilization, consultation with the neurology specialist and critical care specialist is recommended, as definitive care for GBS includes intravenous immunoglobulin (IVIG) or plasma exchange (PLEX) [ ]. The prognosis can vary despite receiving definite treatment, depending on the patient’s age, level of severity, and inciting event or infection [ ]. Patients with GBS should be admitted for frequent neurological and cardiopulmonary monitoring secondary to their risk of decompensation with a center that has access to these therapies and neurology specialist consultation, which may necessitate transfer.

3.1

What are the ‘must-know’ risk factors for GBS for the emergency clinician?

Various factors are associated with developing GBS, including bacterial infections, viral infections, vaccinations, and surgeries ( Table 1 ). An antecedent event is reported in up to 76% of cases, most often some form of infection [ ]. A large observational study evaluated the presence of recently confirmed infection among GBS patients and found that 30% were infected by C. jejuni , 10% by M. pneumonia , 3% by hepatitis E, 4% by CMV, and 1% by EBV [ ]. A case-control study of GBS during a Zika outbreak found that all 42 patients with GBS had evidence of prior infection with Zika, compared to 55% of a selected control group of patients [ ]. From 2013 to 2016, the Zika virus impacted multiple countries in the Americas and the Pacific, subsequently accompanied by a rise in GBS cases [ ]. GBS has also been reported after COVID-19 infection [ ]. One retrospective study suggested recent surgery was the suspected trigger for GBS in 9.5% of patients, with an estimated attributable risk of GBS of 4.1 per 100,000 surgeries [ ]. There are case reports of GBS occurring after myocardial infarction, during pregnancy, and as the presenting symptom of cancer [ ]. The relationship between receiving a vaccine and the development of GBS has been intensely explored since an earlier version of the influenza vaccination seemed to be associated with a rise in cases of GBS [ ]. Although beyond the scope of this article for emergency clinicians, there may be a rare but increased risk of GBS after the influenza, measles-mumps-rubella, and meningococcal vaccines [ ]. There have also been case reports of GBS after immunization with the Pfizer, Oxford-AstraZeneca, and Johnson&Johnson COVID-19 vaccines [ ]. Some medications have been associated with GBS, particularly immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab [ ]. Importantly, although there are many case reports of GBS and observational studies suggesting an association with infection, medical illness, medication, surgery, vaccination, or other entity, these do not prove causation. Thus, while knowing these common risk factors can assist, not all patients with these risk factors will develop GBS.

3.2

What are high yield factors of the history and examination that suggest GBS?

GBS patients classically present with ascending bilateral symmetric weakness and hypo- or areflexia after some infectious process. However, the signs and symptoms are more complex with various presentations. Two findings have been required since 1978, the creation of the diagnostic criteria of GBS, to diagnose the disease: progressive motor weakness in greater than one limb and areflexia [ ]. However, these criteria include supporting features as well (discussed in section 3.3). In one cohort study of 344 patients with GBS, the most common finding was limb weakness, with >99% of the patients having limb weakness and 98% having hypotonia [ ]. The severity of the weakness varied, with lower limb weakness more severe than upper limb deficits [ ]. However, GBS has multiple variants with various presentations ( Table 2 ). The neuronal targets of autoantibodies distinguish the variants AIDP, AMAN, and acute motor sensory axonal neuropathy (AMSAN) and have different electromyographic characteristics less relevant to the emergency clinician [ ]. Other variants such as the Miller Fisher Syndrome (MFS), Cervico-Brachial-Pharyngeal variant, sensory variant, and acute pandysautonomia variant differ in the localization of affected nerve types and thus have different clinical presentations [ ]. AIDP is the most common form of GBS and presents with classic signs of ascending weakness and decreased reflexes [ ]. AMAN and AMSAN can present similarly to the AIDP variant, although AMAN has a more rapid progression [ ]. In one observational study of patients with GBS, patients with the AMAN variant had more significant extremity weakness than patients with the AIDP variant, and they also tended to have lower recovery rates at three months [ ]. The MFS variant is characterized by ophthalmoplegia, ataxia, and areflexia without weakness [ ]. The Cervico-Brachial-Pharyngeal variant can mimic botulism, with ptosis, difficulty swallowing, weakness in the upper extremities, and preserved sensation and lower extremity strength [ ]. The sensory ataxia variant is characterized by sensory loss without motor weakness [ ]. Finally, the acute pandysautonomia variant is characterized by orthostatic hypotension, ileus, urinary retention, areflexia, and ataxia without motor weakness [ ]. Although ascending weakness is considered a classic symptom of GBS, leg weakness is not always present at the initial visit, with some studies reporting it in only 32–50.7% of patients, thus leading to delays in diagnosis [ , , ]. Decreased sensation may be preceded by neuropathic pain and is often not in the distribution of a specific spinal cord level [ ]. Patients may also present with dysautonomia, which is dysregulation of the autonomic nervous system that causes sympathetic and parasympathetic system alterations. Dysautonomia may develop in up to 66% of patients with GBS [ ]. These alterations can manifest as heart rate and blood pressure changes, gastrointestinal motility, and body temperature [ ]. In a study of factors associated with delay in diagnosis of GBS, intact deep tendon reflexes had an odds ratio (OR) of 0.07 (95% confidence interval [CI] 0.01–0.35) for failure to consider GBS on a differential [ ]. A descending or asymmetric pattern of weakness was also associated with a failure to consider GBS as a diagnosis with an OR of 0.25 (95% CI 0.09–0.74) [ ]. Respiratory fatigue may lead to respiratory failure, necessitating airway intervention. Up to 30% of patients with GBS experience respiratory failure requiring airway intervention and mechanical ventilation [ , ]. In one observational study of patients with GBS, cranial nerve involvement was associated with a need for mechanical ventilation (OR 3.8, 95% CI 1.3–10.5) [ ].

3.3

What diagnostic criteria are available?

GBS is a rare but deadly disorder that is complicated to diagnose. Two well-recognized criteria initially created for epidemiologic studies have been utilized for diagnosis: The National Institute of Neurological Disorders and Stroke (NINDS) and The Brighton Criteria ( Tables 3 and 4 ) [ , ]. The criteria were based on expert opinions and prior scientific knowledge, hoping to assist physicians in ruling out other pathologies [ ]. A study published in 1999 found that the NINDS criteria missed up to 15% of GBS cases, mostly GBS variants [ ]. The Brighton Criteria were published due to recent associations between Swine flu and GBS to classify suspected GBS patients by a level of certainty [ ]. The criteria were later adapted to aid clinicians in diagnosing GBS, with various validation studies showing high sensitivity. One such study in Rotterdam analyzed 46 children, revealing 72%, 96%, and 98% sensitivity rates for diagnostic certainty levels one, two, and three, respectively [ ]. The sensitivities found in these validation studies suggest that the Brighton criteria could assist in the early evaluation of patients with suspected GBS, further augmenting the suspicion of the diagnosis, especially in resource-limited countries. However, these criteria do not display 100% accuracy, do not account for atypical presentations or various GBS variants, and were made as screening tools rather than diagnostic tools. Lastly, data evaluating the Brighton Criteria in the ED setting are limited; the studies previously discussed only included patients with complete data sets in their analysis, which may not be available during the patient’s evaluation in the ED.

3.4

What are the essential laboratory and imaging tests in GBS, and what are pearls and pitfalls concerning testing?

While the diagnosis of GBS is primarily clinical, diagnostic testing is helpful in the ED setting to assist with diagnosing and managing GBS and exclude alternative causes ( Table 5 ). A basic metabolic panel, magnesium, and phosphate should be ordered in a patient presenting with weakness to assess for electrolyte causes of weakness, such as hypokalemia or hypophosphatemia [ ]. Cytoalbuminologic dissociation on CSF testing, defined as elevated CSF protein and a cell count of fewer than 50 cells/microgram of fluid, suggests GBS [ ]. One study of patients with GBS undergoing LP found 64% displayed cytoalbuminologic dissociation on CSF testing [ ]. This relatively low rate was likely due to the timing of when the LP was performed and the onset of weakness. When patients had an LP performed between 0 and 1 days after the onset of weakness, only 49% had cytoalbuminologic dissociation. However, this finding was present in 88% of patients with an LP performed three weeks after the onset of weakness [ ]. Additionally, as patients age, there can be a gradual increase in CSF protein concentration, which can alter the sensitivity and specificity of CSF analysis for diagnosing GBS [ ]. In summation, physicians should not rely on cytoalbuminologic dissociation for diagnosing GBS, as the accuracy of the results can be skewed or not present depending on the timing of the procedure and the patient’s age [ ].

Table 5

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