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Diagnosis and Management of Guillain-Barré Syndrome
by Susannah Brock Cornes, MD
Department of Neurology, University of California, San Francisco.
Lecture related to:
Chapter 365: Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies
Slide 1: Diagnosis and Management of Guillain-Barré Syndrome
Diagnosis and Management of Guillain-Barré Syndrome.
Slide 2: GBS Definition and History
Guillain-Barré Syndrome (GBS) is a clinical diagnosis that describes an acute, fulminant, autoimmune polyradiculoneuropathy. It was first described by Landry as an "ascending paralysis" in 1859, but it gets its name from Guillain, Barré, and Strohl, who described the syndrome in 1916 and are pictured here. They additionally found that it was accompanied by albuminocytologic dissociation on spinal fluid analysis. In other words, patients typically have elevated protein in the absence of CSF pleocytosis. As we'll discuss, patients present with a rapidly evolving weakness, loss of reflexes, and frequently, with sensory disturbances.
Slide 3: GBS Clinical Phases
GBS has distinct clinical phases of onset, plateau, recovery, and infrequently relapse. Initially, weakness progresses over the course of hours or days, sometimes accompanied by tingling dysesthesias. Deep tendon reflexes disappear within the first few days of onset, and patients generally reach the nadir of their symptoms within 9 days and, by definition, within 4 weeks. Symptoms stabilize during the plateau phase, which lasts from a few days to 2 weeks. The recovery phase occurs over an extended period with 84% of patients back to baseline within 2 years and the remaining 15% with some permanent deficit. 5% remain disabled, and the relapse rate is 3%. The mortality rate is 5%.
Slide 4: GBS Differential Diagnosis
It is worth noting that the presentation of an acute flaccid paresis has a broad differential including many other causes of acute neuropathies as well as disorders involving the neuromuscular junction, muscle, or anterior horn cells of the spinal cord.
Slide 5: GBS is a Clinical Diagnosis
Authors, such as Ashbury, have published clinical criteria to assist in the diagnosis of GBS (Ashbury AK, Arnason BG, Karp HR, McFarlin DE: Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol 3:565-566, 1978). Features required for the diagnosis include progressive weakness in greater than one limb and areflexia. Specific clinical features can support or cast doubt on the diagnosis. Supportive of the diagnosis are rapid progression within 4 weeks with onset recovery within 2-4 weeks, symmetry, mild sensory signs, cranial nerve findings, autonomic dysfunction, and lack of fever. Conversely, clinical features casting doubt on the diagnosis are persistent asymmetry, bladder or bowel dysfunction at onset, spinal fluid pleocytosis, or a sensory level. In addition, alternate diagnoses should be considered and ruled out, and albuminocytologic dissociation and EMG/NCS findings should be sought to support the diagnosis.
Slide 6: GBS Work-up
To summarize, the work-up for GBS will include electrodiagnostic studies, spinal fluid analysis, and additional studies to rule out alternate causes of acute neuropathy, depending on the clinical context and level of suspicion. Studies such as electrocardiogram and measurements of pulmonary function will help guide future supportive care. Finally, there are additional laboratory tests that may be of academic interest both in identifying precipitating illness and associated antibodies. At this point, while these tests may have some prognostic import, they do not currently impact treatment algorithm.
Slide 7: Epidemiology
We will now discuss the epidemiology and risk factors for GBS. With the exception of a subtype occurring in China during the summer months, GBS is a nonseasonal, sporadic illness. With the decline in polio, it has become the most common acute paralytic disease in the West and has an incidence of 1.8 per 100,000. The incidence increases with age, and there is a slight increase in risk for men. Two-thirds of patients with GBS report an antecedent event, leading to the hypothesis that GBS is an autoimmune process resulting from "molecular mimickry" in which an infectious epitope, resembling a host epitope, leads to a misguided immune attack.
Slide 8: Antecedent Events in GBS
Respiratory illness is the most common antecedent event, although gastrointestinal illness has received more attention due to the link between GBS and seasonal outbreaks of Campylobactor jejuni (Govani et al: Curr Op Neurol 14:605-613, 2001). When an infectious agent can be identified, C. jejuni is the most common, but GBS has also been linked to prior infection with CMV, EBV, and mycoplasma. In addition, GBS occurs at a higher incidence in patients with HIV. There is a higher incidence following surgery, in the setting of certain malignancies, and in the postpartum period. GBS has also been associated with certain toxins and medications as well as vaccinations.
Slide 9: Risk of Vaccination
Regarding the risk of vaccination, the first vaccine to be associated with increased risk of GBS was the swine influenza vaccine, administered in the United States in 1976. Older rabies vaccines have also been implicated and continue to be of concern in developing countries. Currently in the United States, concern remains regarding the influenza vaccine, which when studied from 1992 to 1994 was found to be associated with one case per one million vaccinated, for a relative risk of 1.7 (Lasky et al: GBS and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 339:1797-1802, 1998). The majority of cases occur in the second week following vaccination. Despite this, the vaccine is still recommended for patients at risk of contracting influenza, given the high incidence of the virus and the associated morbidity. More recently, the meningococccal conjugate vaccine, menactra, has been associated with increased risk of GBS, accounting for 1.25 cases per one million vaccinated between March 2005 and September 2006 (CDC. MMWR Morb Mortal Wkly Rep. (Oct 20) 55(41):1120-1124, 2006). As is true for the influenza vaccine, the CDC continues to recommend Menactra for patients at increased risk of mengococcal meningitis (Figure from www.hawaii.edu).
Slide 10: Autoimmune Inflammatory Demyelinating Polyneuropathy
We will now discuss the different subtypes of GBS. AIDP or autoimmune inflammatory demyelinating polyneuropathy, is the prototypical form of GBS. It is the most common form in North America and Europe, accounting for 56 to 87% of cases. In China, however, this demyelinating form accounts for only 24% of cases. The demyelinating form is distinguished from other forms using electrodiagnostic studies, which should reveal signs of demyelination, namely, slowed conduction velocities, conduction block, and increased minimum F-wave latencies. The pathogenic mechanism for this form of GBS was felt to be T cell-mediated and analogous to the experimental allergic neuritis model, in which experimental animals are inoculated against peripheral nerve proteins. Pathologic specimens in AIDP reveal perivascular mononuclear cell infiltration with multifocal demyelination, thought to result from T cell-mediated activation of macrophage against the Schwann cells that make up the myelin sheath. There is increasing evidence that humoral factors also play a role in the pathogenesis of the disease, although the bulk of this evidence relates to the axonal form. This low power image of a peripheral nerve in GBS has been stained with a myelin stain (pink). Note the large areas of myelin loss in the center.
Slide 11: Acute Motor Axonal Neuropathy
Acute motor axonal neuropathy occurs in sporadic cases in North America and Europe, but in epidemic proportions among children and young adults during the summer in rural China. Unlike patients with AIDP, 30% of these patients describe an infectious prodrome with fever, diarrhea or URI symptoms (McKhann et al: AMAN: A frequent cause of acute flaccid paralysis in China. Ann Neurol 33:333-342, 1993). Cases tend to be severe, but overall prognosis is good. As we will see, the good prognosis for these young patients may not be generalizable to sporadic axonal forms. In fact, axonal involvement has, overall, been found to be a poor prognostic indicator. Electrophysiologic studies for patients with AMAN reveal reduced compound motor action potentials without signs of demyelination or sensory involvement. Pathologic studies show wallerian degeneration of ventral roots and motor fibers with macrophage invasion of periaxonal space. There is abundant evidence for a humoral immune mechanism in AMAN (Hartung et al: Acute immunoinflammatory neuropathy: Update on GBS. Curr Opin Neurol 15:571-577, 2002). In particular, there appears to be a link to prior infection with Campylobacter jejuni, antibodies which have been found in 91% of specimens sent within 10 days of onset of AMAN. Other studies have looked for antibodies to gangliosides, which are highly expressed on nervous tissue at key sites, such as nodes of Ranvier. Antibodies to one ganglioside, GM1, have been found in 64% of AMAN cases and shown to recapitulate a flaccid paresis when injected into the rabbit hind limb.
Slide 12: Acute Motor Sensory Axonal Neuropathy
Acute motor sensory axonal neuropathy is similar to acute motor axonal neuropathy in many respects but also involves the dorsal roots or sensory nerves and occurs only sporadically. In addition, like the sporadic form of AMAN, this form of GBS is associated with a worse prognosis. Electrophysiologic studies reveal reduced sensory nerve action potentials and compound motor action potentials. The pathology is similar to AMAN but can also be found to involve dorsal roots and sensory nerves (Griffin et al: Pathology of the motor-sensory axonal Guillain-Barré syndrome. Ann Neurol 39:17-28, 1996). The mechanism is felt to be humoral, but there is less data on this small subgroup.
Slide 13: Miller Fisher Syndrome
The Miller Fisher syndrome was described in 1956 and accounts for roughly 5% of GBS cases. The syndrome includes the triad of ophthalmoplegia, ataxia and areflexia in the setting of preserved motor strength. There are, however, overlap syndromes, and it is worth noting that overall cranial nerve involvement in GBS ranges from 45 to 75% of cases. Electrophysiologic studies in MFS may reveal sensory involvement, but motor studies remain intact. The syndrome is highly associated with antibodies to the ganglioside GQ1b, which is present in over 90% of cases, and the prognosis is good.
Slide 14: Supportive Treatment
We will now discuss the treatment of GBS, beginning with supportive care and going on to discuss immunomodulatory therapy. Standard care should include frequent measurement of forced vital capacity and maximum inspiratory flow, as well as continuous pulse oximetry (Hughes et al: Supportive care for patients with Guillain Barré Syndrome. Arch Neurol 62:1194-1198, 2005). Cardiac telemetry is frequently necessary to monitor hemodynamic instability due to autonomic dysfunction, which may occur in half of patients. Other common autonomic symptoms include postural hypotension, hypertension, tachycardia, urinary retention, and ileus. Bed-bound patients should receive DVT prophylaxis, frequent repositioning, and physical therapy. Pain can be a prominent feature of GBS, rated as severe by nearly half. It usually involves the low back with a positive straight leg raise. Management regimens may include anti-inflammatory medications, opiates, and neuropathic pain medications, such as gabapentin or carbamazepine. An aggressive bowel regimen is prudent given the increased risk of ileus. Patients who are too weak to close their eyes should receive exposure keratitis prophylaxis, and nutrition services should be involved early to help minimize wasting.
Slide 15: Predicting Respiratory Failure
There is a 30% rate of respiratory failure in GBS, so it is important to be able to predict which patients will require assisted ventilation and to intervene in a timely manner. One study from Critical Care Medicine found three factors associated with ventilatory failure: time from onset to admission less than 7 days, inability to lift the head, and forced vital capacity (FVC) less than 60% predicted (Sharshar et al: Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med 31(1):278-283, 2003). In general, FVC less than 20 cc/kg, maximum inspiratory flow (MIF) less than 30 cm or maximum expiratory flow less than 40 cm are of concern, as may be remembered by the "20, 30, 40" rule. Standard care should include monitoring of FVC and MIF every 4-6 h until clinical course becomes clear or until patients reach nadir. Intubation is recommended when FVC falls below 12-15 cc/kg or 18 cc/kg in patients with severe oropharyngeal weakness.
Slide 16: Plasma Exchange
We will now discuss immunomodulatory treatments for GBS beginning with plasma exchange. There have been four major clinical trials looking at treatment for GBS. The first was the North American GBS study Group, which randomized patients to receive plasma exchange versus supportive care alone (The GBS Study Group: Plasmapharesis and acute Guillain-Barré syndrome. Neurology 35:1096-1104, 1985). Inclusion criteria and outcome data used the Hughes clinical grading system for GBS, which is based on a point score from 0 to 6, 6 being the worst. Only those patients who could not walk independently were included, corresponding to a clinical grade of 3 or worse. The authors found that PE increased the likelihood to improve one clinical grade at 4 weeks, shortened the number of days to improve one grade or to walk unassisted, and reduced the risk of failure to improve or to walk unassisted. Patients who were already ventilated at randomization did not benefit as highly, underlining the need to initiate treatment early.
Slide 17: Plasma Exchange
The French Cooperative Group on Plasma Exchange in GBS found that plasma exchange reduced the need for assisted ventilation and decreased time to ventilator weaning, onset of motor recovery, and walking with or without assistance [The French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome. Efficiency of plasma exchange in Guillain-Barré syndrome: role of replacement fluids. Ann Neurol 22(6):753-761, 1987]. A later publication by this group looked at the efficacy of plasma exchange in the treatment of mild versus moderate or severe GBS and found that even two plasma exchanges hastened recovery in mild cases, whereas four exchanges were optimal in moderate or severe cases, and there was no added benefit to six exchanges (The French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome: Appropriate number of plasma exchanges in Guillain-Barré syndrome. Ann Neurol 41:298-306, 1997). For this study, patients were defined as "mild" if they were able to stand unassisted. Other studies, enrolling fully ambulatory patients, have not demonstrated a benefit to treatment (Green DM, Ropper AH: Mild Guillain-Barré syndrome. Arch Neurol 58:1098-1101, 2001).
Slide 18: IVIG
Two studies have compared plasma exchange to IVIG in the treatment of GBS. The Dutch GBS Study Group randomized patients to receive plasma exchange or IVIG within 2 weeks of symptom onset and found an overall trend toward speedier recovery in the IVIG group (Van der Meche et al: A randomized trial comparing IVIG and PE in GBS. N Engl J Med 1992; 326:1123-1129). The authors concluded that IVIG was at least as effective as plasma exchange and that the trend toward increased efficacy with IVIG was due to differences in baseline variables despite randomization. The Plasma Exchange/Sandoglobulin GBS Trial Group also found no significant difference between the two treatments and no benefit to combined therapy [Randomized trial of plasma exchange, IVIG and combined treatments in GBS. Lancet 349(9047):225-230, 1997]. In addition, a subgroup analysis found no difference in outcomes according to GBS subtype, presence of preceding diarrhea or presence of anti-GM1 antibodies (Hadden et al: Electrophysiological classification of GBS. Ann Neurol 44:780-788, 1998). Of note, some authors have presented data suggesting that IVIG may be more effective for patients with antibodies to GM1 (Satoshi et al: IVIG therapy for GBS with IgG anti-GM1 antibody. Muscle & Nerve 24:54-58, 2001). Lacking validation by the Plasma Exchange/Sandoglobulin GBS Trial Group, however, there is no recommendation to alter treatment based on ganglioside antibodies.
Slide 19: Adverse Effects
Given that there is no significant difference in the efficacy of plasma exchange versus IVIG, one should weigh the potential adverse effects in individualizing treatment for a given patient. Because institution of plasma exchange requires a central line, the potential complications include those associated with obtaining access, such as hematoma or pneumothorax, and with prolonged access, such as septicemia. Patients may also become coagulopathic following an exchange and require transfusions to maintain levels of fibrinogen and clotting factors. Adverse effects of IVIG include flu-like symptoms such as headache, myalgia and arthralgia as well as a transient hypercoagulability with increased risk of thrombosis. The volume load can be associated with pulmonary edema, and patients who are IgA-deficient may have more serious complications such as anaphylaxis, aseptic meningitis, hepatitis, and renal failure. A typical dose for plasma exchange is 40 to 50 cc/kg daily or every-other-day for four or five treatments. The typical dose for IVIG is 0.4 g/kg daily for 5 days.
Slide 20: Practice Parameters
The American Academy of Neurology published practice parameters for the treatment of GBS in 2003 (Hughes et al: Practice parameter: Immunotherapy for Guillain-Barré syndrome. Neurology 61:736-740, 2003). In brief, there are data to support treatment of nonambulatory patients with PE within 4 weeks and with IVIG within 2 weeks, or possibly 4. Plasma exchange may be of benefit and should be considered in ambulatory patients within 2 weeks, but the benefit remains somewhat uncertain in this population. Overall, the effects of PE and IVIG should be considered to be equivalent, and there is no evidence for sequential treatment. In addition, multiple studies and a Cochrane review have failed to show any benefit to treatment with corticosteroids.
Slide 21: Long-term Prognosis
Finally, we will end with a discussion of long-term prognosis for GBS. The most robust predictor of poor prognosis appears to be the distal compound motor action potential as measured on EMG/NCS. When this parameter is less than 20% of the lower limit of normal 4 weeks after onset, it predicts the inability to walk at 4 months with a high sensitivity and specificity (Hadden et al: Electrophysiological classification of GBS. Ann Neurol 44:780-788, 1998). The same measure taken at 2 weeks has a sensitivity of only 24%. Other EMG/NCS findings do not correlate with outcomes, confirming that it is the extent of axonal involvement that is associated with worse prognosis. Despite this, it has been difficult to demonstrate worse outcomes in patients who have antibodies to various gangliosides or evidence of previous infection with C. jejuni. Finally, the North American GBS Study Group found that, in addition to CMAP amplitude, age >60, maximum deficit within 7 days, and the need for ventilatory support were also associated with decreased probability of walking at 6 months (Visser et al: Prognostic factors of Guillain-Barré syndrome after intravenous immunoglobulin or plasma exchange. Neurology 53:598-604, 1999).
Slide 22: Summary
In summary, GBS is the most common acute paralytic disease in the West after the fall in polio, with an incidence of 1.8 per 100,000. It is a clinical diagnosis, and therefore clinical suspicion is required to avoid missing the presentation. Lumbar puncture and EMG/NCS can additionally be helpful, and alternate diagnoses should be considered and ruled out as appropriate. Patients should be monitored closely until their nadir with aggressive supportive care and particular attention to ventilatory function and autonomic instability. For patients who warrant treatment, plasma exchange and IVIG are equally effective and should be instituted as early as possible. Prognosis correlates with the extent of axonal involvement, age, rate of progression, and need for ventilation.
Slide 23: Thank you!
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