Clinical manifestations

Presentation and course

Acute inflammatory demyelinating polyneuropathy. Guillain-Barré syndrome is now recognized to be a diverse disorder that can be divided into several patterns based on the predominant mode of fiber injury (demyelinating vs. axonal) and on nerve fibers involved (motor, sensory and motor, cranial). The most frequent pattern in Western countries is the acute inflammatory demyelinating polyneuropathy. The major complaint is weakness, which usually evolves symmetrically over a period of several days. Evolution is complete after 2 weeks in 50% of cases, after 3 weeks in over 80%, and after 4 weeks in over 90% (73; 04). In most instances, weakness is noticed initially in the legs, but it can begin in the arms or the face. The severity of weakness varies from mild gait difficulty to total paralysis with death from respiratory failure. Aside from facial diplegia, which is found in at least half of the cases, involvement of extraocular muscles has been described. In a large series, 5% of patients presented with isolated cranial nerve involvement, but all subsequently developed limb weakness (73). Other symptoms include pain and muscle aches, which occur in 30% to 55% of cases. Early in the course of illness, subjective dysesthesias and paresthesias are common. At later times, objective sensory loss can be demonstrated in three-fourths of cases. Tendon reflexes are usually abolished or diminished. Dysautonomia is common and can manifest as heart rate or blood pressure instability, blood pressure fluctuations, pupillary dysfunction, and bowel or bladder dysfunction (73). Acute inflammatory demyelinating polyneuropathy is a monophasic illness, though treatment-related fluctuations or relapses occur in a minority of patients (74).

Variants of Guillain-Barré syndrome. Axonal involvement in Guillain-Barré syndrome has traditionally been considered secondary to severe demyelination until Feasby and colleagues (24) called attention to a small group of patients that had primary axonal degeneration, now termed acute motor-sensory axonal neuropathy. These patients typically have severe, fulminant paralysis, sensory loss, and incomplete recovery. Autopsy findings demonstrate axonal degeneration without demyelination and with minimal inflammation (30).

In comparison, acute motor axonal neuropathy, also called “Chinese paralytic syndrome,” is characterized by acute weakness or paralysis without sensory loss and is closely associated with antecedent Campylobacter infection (55; 37). Patients with acute motor axonal neuropathy usually have a more rapid progression and an earlier nadir than those with acute inflammatory demyelinating polyneuropathy (36). A subset of patients with acute motor axonal neuropathy recovers rapidly. Electrodiagnostic studies confirm the selective involvement of motor fibers with preservation of sensory responses. High titers of IgG anti-GM1, GM1b, or GD1a antibodies are more common in the acute motor axonal neuropathy than in acute inflammatory demyelinating polyneuropathy (70; 38). These antibodies cause a pathophysiological spectrum ranging from reversible conduction block to axonal degeneration of motor fibers (49).

A third disorder considered as a Guillain-Barré syndrome variant is Fisher syndrome, which is characterized by ophthalmoplegia, ataxia, areflexia, and association with antibodies that recognize the ganglioside GQ1b, GT1a, or GD3 (26; 73; 12; 86; 89). Facial nerves may be involved in addition to ocular motor nerves, but limb weakness is infrequent. Another condition that is associated with anti-GQ1b antibody is Bickerstaff brainstem encephalitis, which is characterized by a disturbance of consciousness, hyperreflexia, ataxia, and ophthalmoplegia (08; 59). Brain MRI is abnormal in 30% of these patients. The prognosis for recovery is good. Some patients have concomitant limb weakness and electrodiagnostic evidence of an axonal subtype of Guillain Barré syndrome (59). The immunological profile in Bickerstaff brainstem encephalitis and Fisher syndrome suggests common pathogenetic mechanisms, but the nosological relationship between these disorders remains controversial.

Other variants of Guillain Barré syndrome include pharyngeal-cervical-brachial variant, acute pandysautonomia, and sensory Guillain-Barré syndrome. The pharyngeal-cervical-brachial variant manifests as dysphagia, neck and shoulder muscle weakness, and may be associated with IgG anti-GT1a antibody (61; 47). In the sensory form of Guillain-Barré syndrome, patients have acute sensory loss but no weakness although demyelinating features are present in motor nerve conduction studies (60). Acute/subacute pandysautonomia without concomitant motor or sensory deficits is rare and is associated with antibody against ganglionic acetylcholine receptor in some cases (82).

Two sets of criteria are often used for the diagnosis of Guillain Barré syndrome: NINDs criteria and Brighton collaboration. The criteria are listed in tables 1 and 2.

Table 1. NINDS Criteria (1978) and Subsequently Modified in a Review Paper by Asbury and Cornblath (1990)

Table 2. Brighton Collaboration

Prognosis and complications

Recovery ranges from complete and rapid to slow with significant residual disability, depending on the relative proportions of segmental demyelination and axonal degeneration in patients with acute inflammatory demyelinating polyradiculoneuropathy. Little or no further recovery can be expected after 2 years. Most patients recover spontaneously and almost completely. Between 3% and 8% of patients die from complications. Permanent disabling weakness, imbalance, or sensory loss occurs in 5% to 10%, whereas mild residual signs of neuropathy persist in 50% of patients (21). Electromyographic evidence of severe axonal degeneration, as shown by reduction in CMAP amplitude (0% to 20% of the lower limit of normal) and abundant spontaneous activity, is associated with a poor outcome (15). Factors associated with poor prognosis include advanced age, history of diarrhea, severe limb weakness poor disability score at 2 weeks, inexcitable nerves, and peroneal conduction block (22; 81; 20). A notable exception to the prognostic value of early axonal involvement is with acute motor axonal neuropathy where there is often good recovery. Studies revealed that CSF tau and serum neurofilaments may serve as biomarkers for axonal damage, with high levels predicting a poor outcome (42; 03; 54).

Approximately 3% of patients with acute inflammatory demyelinating polyradiculoneuropathy suffer one or more recurrences. The clinical symptoms of relapses do not differ from those of the acute monophasic form of the disease. Each episode is characterized by rapid onset of symptoms over a few days, with subsequent complete or near-complete recovery. In patients with multiple relapses, nerves may become palpably enlarged. Such cases are to be distinguished from chronic inflammatory polyradiculoneuropathy, which evolves over many weeks, months, or years.

Clinical vignette

A 40-year-old nondiabetic woman presented to the emergency room with weakness of her legs that had started 5 to 6 days earlier and had begun to involve her upper extremities. Tingling and numbness of her toes and fingertips accompanied her symptoms. The patient had a flu-like illness 2 weeks before the onset of symptoms and no history of tick bites. Exam showed mild facial weakness, 4/5 strength in her proximal muscles and 3+/5 in her distal muscles, slightly decreased light touch and pinprick sensation distally, and absent deep tendon reflexes throughout. Her CSF showed elevated protein (150 mg/dl) with no cells. Nerve conduction studies showed normal compound motor action potential amplitudes, mildly slowed conduction velocities, but prolonged distal motor and F wave latencies. Her forced vital capacity was 2 L. She improved significantly after a course of plasmapheresis.

Biological basis

Etiology and pathogenesis

Acute inflammatory demyelinating polyradiculoneuropathy is thought to be a cell-mediated autoimmune disease of the peripheral nerves, based on lymphocytic inflammation (06) and the analogy to experimental allergic neuritis (04). The latter is caused by CD4+ T cells against peripheral myelin peptides such as P2 and P0 (11; 57). There has been increasing emphasis on humoral mechanisms in recent studies (85). The nature of the antigens in acute inflammatory demyelinating polyradiculoneuropathy is not known, whereas myelin glycolipids are a target of humoral immunity in variants of Guillain-Barré syndrome such as acute motor axonal neuropathy (70; 38). Some studies suggest that antibody attack against nodal antigens such as gliomedin and neurofascin participates in the etiology of Guillain-Barré syndrome (69; 19). Host factors might influence the susceptibility to develop Guillain-Barré syndrome. An association between HLA-DQ beta and DR-beta with susceptibility to acute inflammatory demyelinating polyradiculoneuropathy has been identified, but not with acute motor axonal neuropathy (53).

The pathological features in acute inflammatory demyelinating polyradiculoneuropathy consist of segmental demyelination and mononuclear cellular infiltration (06; 48). Infiltrates are scattered at random along peripheral nerves, cranial nerves, nerve roots, dorsal root ganglia, and sympathetic ganglia. Sural nerve biopsies may show minimal abnormalities, perhaps reflecting the motor predominance of the disorder. Ultrastructurally, the earliest change in the myelin sheath is paranodal retraction resulting in a widened nodal gap. As the myelin sheath degenerates, ovoid formation and phagocytosis of myelin debris by macrophages become prominent (68). Axonal degeneration is seen in severe lesions, usually at sites of intense inflammatory changes (68). In the study by Koike and colleagues, macrophage-associated lesions can be seen at Node of Ranvier and at the internode, which seems to correspond to the pattern of complement deposition (48).

The acute axonal variant is characterized by lengthening of the nodal gap and distortion of the paranodal myelin by macrophages with paucity of lymphocyte infiltration, followed by Wallerian-like degeneration of motor fibers in the spinal roots and peripheral nerves in severe cases (29). The presence of either immunoglobulin G or complement activation products along the outer surface of Schwann cells or the axolemma provides further evidence for immune attack on acute inflammatory demyelinating polyradiculoneuropathy and acute motor axonal neuropathy, respectively (32; 33).

Electrophysiologically, conduction of impulses through areas of segmental demyelination is severely compromised. Conduction failure may occur at the junction between normally myelinated and demyelinated regions where the outward leakage current exceeds the safety factor for impulse conduction and where exposure of paranodal K+ channels leads to shortened action potential duration. This results in conduction block or temporal dispersion, which are the hallmarks of acquired demyelinating neuropathy (46). Axonal damage causes abnormal spontaneous activity and a decrease in the number of motor units. It is agreed that the most plausible explanations for weakness and sensory loss are conduction block and axonal degeneration.

Possible effector mechanisms of immune-mediated injury to peripheral nerves include cytotoxic T cell-mediated lysis, cytokines and free radicals, and antibody and complement-mediated mechanisms. The findings of increased serum concentrations of tumor necrosis factor-alpha and soluble E-selectin in patients with Guillain-Barré syndrome suggest that proinflammatory cytokines and adhesion molecules are involved in the pathogenesis of this disease (77; 35). There is evidence supporting the role of costimulatory molecules in inflammatory neuropathies, likely by affecting the balance between effector T cells and regulatory T cells. This is exemplified by reports of Guillain-Barré syndrome and other inflammatory neuropathies precipitated by cancer immunotherapy with checkpoint inhibitors targeting CTLA-4 or PD-1 such as ipilimumab, pembrolizumab, or nivolumab (44; 43; 23).

Molecular mimicry has been postulated as a potential mechanism triggering autoimmunity. There is a report demonstrating antibodies against moesin in patients with cytomegalovirus-related acute inflammatory demyelinating polyradiculoneuropathy (75). Moesin is expressed in the Schwann cell processes at the nodes of Ranvier. For patients with antecedent diarrhea, the fact that lipopolysaccharide of C jejuni has a ganglioside-like structure suggests that acute motor axonal neuropathy and Miller Fisher syndrome involve molecular mimicry in their pathogenesis (89; 88). Animal studies reveal that anti-ganglioside antibodies act not only on peripheral nerves but also at the motor nerve terminals. Effects of anti-ganglioside antibodies include: (1) complement-mediated disruption of Na+ channel clusters resulting in decreased Na+ current; (2) an alpha-latrotoxin-like effect on motor endplates resulting in dramatic release of acetylcholine followed by depletion; and (3) destruction of peri-synaptic Schwann cells and nerve terminals (79; 41; 78; 67).

Epidemiology

Acute inflammatory demyelinating polyradiculoneuropathy occurs in all parts of the world and at all ages, with an incidence ranging from 0.6 to 2.4 cases per 100,000 population per year (02). The oldest recorded patient was 95 years old. In most series, there is a modest male predominance. Approximately two-thirds of cases of acute inflammatory demyelinating polyradiculoneuropathy follow an infection, usually viral but sometimes mycoplasmal or bacterial (Campylobacter jejuni). The association of C jejuni with Guillain-Barré syndrome is interesting because these patients tend to develop acute motor axonal neuropathy; the latter predominates in the yearly summer outbreaks in China (55; 37; 70).

The viruses associated with the disease include cytomegalovirus; Epstein-Barr virus; smallpox-vaccinia; hepatitis B, C, or E; and HIV. In the United States, an outbreak of Guillain-Barré syndrome occurred in 1976 in conjunction with the swine flu vaccination program, with an excess risk of 10 cases per million vaccinations. In contrast, a surveillance study revealed that the 2009 H1N1 vaccine safety profile is similar to that for current seasonal influenza vaccine, with an excess risk of 0.874 cases per million vaccinations (87). During Zika virus outbreaks in French Polynesia and Latin America, there was an increase in the incidence of Guillain-Barré syndrome that manifested as acute motor axonal neuropathy or as acute inflammatory demyelinating polyradiculoneuropathy, and it was associated with reactivity to gangliosides (13; 63; 71). COVID-19 pandemic is also associated with increased incidence of Guillain-Barré syndrome, predominantly the demyelinating type and often with facial paresis, although not all studies are in agreement (25; 52; 01). Interestingly, COVID-19 vaccines that utilize adenovirus vectors such as ChAdOx1 nCoV-19 (AstraZeneca) or Ad.26.COV2.S (Janssen) exhibit slightly increased risk of developing Guillain-Barré syndrome within 6 weeks of injection, albeit less than that occurring after COVID infection (65; 45; 34). Guillain-Barré syndrome represents the second most common immune checkpoint inhibitors-related neuromuscular complication, after myasthenia, occurring in about 0.1% of patients (50). The incidence was higher in patients receiving CTLA-4 inhibitors than PD-1/ PD-L1 inhibitors and the risk was even higher when patients receiving combination therapies (23). The recommended treatment, besides to stop the immune checkpoint inhibitors, is to add prednisone to the standard treatment of intravenous immunoglobulins (see management below) (50). Aside from infections and immune checkpoint inhibitors, other antecedent events associated with acute inflammatory demyelinating polyradiculoneuropathy include surgery, epidural anesthesia, thrombolytic agents, and heroin use.

Differential diagnosis

In any case of acute motor paralysis, it is necessary to distinguish acute inflammatory demyelinating polyradiculoneuropathy from acute myelopathy (either transverse myelitis or acute spinal cord compression). Hyporeflexia or areflexia can be seen in both disorders at the onset, but the presence of bowel or bladder dysfunction early on or the finding of a sensory level should alert one to the prospect of acute myelopathy. Acute myelitis due to an infection caused by enteroviruses (eg, poliovirus, Coxsackievirus, etc.), West Nile virus, or another virus can produce a pure motor syndrome. However, there is usually an associated CSF pleocytosis. It is also important to exclude myasthenic crisis or acute botulism. A history of fatigability or fluctuating ocular symptoms favors the diagnosis of myasthenia. The presence of dilated unreactive pupils and severe constipation and the appearance of symptoms within 12 to 36 hours of ingestion of tainted food suggest botulism. Lyme disease should be considered, especially when a patient presents with facial palsy or facial diplegia. Other differential diagnoses include tick paralysis, porphyric neuropathy, meningeal carcinomatosis, vasculitic neuropathy, paraneoplastic neuropathy, polymyositis, acute steroid myopathy, and, rarely, heavy metal intoxication, hypophosphatemia, and organophosphate poisoning. In patients in intensive care units, an axonal polyneuropathy occurring on a background of sepsis and multiple organ failure has been recognized as an entity distinct from Guillain-Barré syndrome.

Diagnostic workup

Support for the clinical diagnosis of acute inflammatory demyelinating polyradiculoneuropathy may be provided by laboratory and electrodiagnostic data. The CSF is acellular in all but 10% of patients, who may have 11 to 50 cells/mm3. About 1 week after the onset of symptoms, the protein levels rise, reaching a peak in 3 to 4 weeks. Pleocytosis may signify Lyme disease, sarcoid, neoplasia, Guillain-Barré syndrome associated with HIV, Epstein-Barr virus, or other diseases. Electrophysiologic studies reveal a predominance of demyelinating features such as multifocal conduction block, slowing of nerve conduction velocities with prolonged distal and F-wave latencies, and various degrees of denervation (72).

Conduction studies are frequently normal early. Criteria for conduction block with or without temporal dispersion as well as other parameters for demyelination have been reviewed by other investigators (05; 09). Sural sparing pattern is often seen in Guillain-Barré syndrome (18). Ancillary electrophysiologic studies include blink reflexes and assessment of autonomic function with sympathetic skin response and heart rate variability. In axonal forms of Guillain-Barré syndrome, a severe reduction in CMAP amplitudes with minimal demyelinating features is detected, with or without abnormalities in sensory nerves. In Miller-Fisher syndrome, slowing of conduction velocities in the limbs may be absent, but F-wave latencies and blink response latencies are usually abnormal, and decreased amplitudes of sensory responses may be observed.

Management

Corticosteroids were used to treat patients with Guillain-Barré syndrome for many years, but randomized controlled trials revealed no benefit from such treatment (40; 39). On the other hand, three controlled trials that included 500 patients have established that plasmapheresis is beneficial in acute inflammatory polyradiculoneuropathy (62; 27). When compared to untreated controls, time spent in the hospital, time on a respirator, and time to resumed ambulation are shortened in patients treated with plasmapheresis (56). Studies suggest that at least 2 sessions of plasmapheresis are required for mild cases and 4 sessions for the severe cases (28; 90).

A favorable response to intravenous immunoglobulin has been described in controlled trials (80; 66). Treatment-related fluctuations can occur with intravenous immunoglobulin or plasma exchange early in the disease course (within 8 weeks of onset) and usually respond to additional treatment with intravenous immunoglobulin or plasma exchange (74). The obvious advantages of intravenous immunoglobulin are the ease of administration and its relative safety. Intravenous immunoglobulin should be the first choice of treatment in pediatric cases in which plasmapheresis may be impractical or in patients with cardiovascular instability.

Prevention of complications, such as respiratory failure and vascular collapse, remains the cornerstone of management. In patients with rapid disease progression or bulbar dysfunction, forced vital capacity and respiratory muscle strength should be monitored closely. Up to 22% of patients require mechanical ventilation within first week of admission (84). Nasogastric tube feeding or gastrostomy may be required in patients with significant dysphagia. The prevention of nosocomial infection is important because 25% acquire pneumonias and 30% acquire urinary tract infections. Once the illness reaches the plateau phase, a systematic rehabilitation program starting with active resistive strengthening exercise should be instituted.

The most appropriate approach to patients who do not improve or progress after intravenous immunoglobulins or plasma exchange or who present with treatment-related fluctuations is presently unclear. In a randomized, double blind, placebo controlled trial, no benefit was observed from a second course of intravenous immunoglobulin in patients with poor prognosis as defined by the modified Erasmus GBS Outcome Score at days 7 to 9 (83). Similarly, the effect of a second cycle of therapy after a treatment-related fluctuation, a common clinical practice, has not been determined in randomized trials. Potential treatment on the horizon in Guillain-Barré syndrome consists of targeting the inhibition of complement cascade. The efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, was investigated in 2 multicenter, placebo-controlled, double-blind phase 2 trials where patients received 4 weeks of intravenous immunoglobulin plus either eculizumab or placebo. In both studies, the interpretation of efficacy was limited by small sample size (17; 58). Eculizumab appears to be well-tolerated and safe when administered in conjunction with IVIg, though anaphylaxis was observed in 1 patient and intracranial hemorrhage and abscess in another patient in the study (58). These findings do not preclude larger controlled trials on eculizumab in Guillain-Barré syndrome in the future. Another therapeutic strategy consists of targeting neonatal Fc receptor (FcRn) to inhibit recycling of endogenous IgG resulting in decreased IgG levels, which is currently being planned for chronic inflammatory demyelinating polyradiculopathy, but not yet in Guillain-Barré syndrome (64; 16).

Special considerations

Pregnancy

There have been at least 35 reported cases of acute inflammatory demyelinating polyradiculoneuropathy during pregnancy. Patients respond to plasmapheresis, but there are no controlled studies assessing the safety of plasmapheresis in pregnant women with acute inflammatory demyelinating polyradiculoneuropathy (14).

Anesthesia

Patients with acute inflammatory demyelinating polyradiculoneuropathy are sensitive to succinylcholine, muscle relaxants, and local anesthetics. Epidural or spinal anesthesia has been used with caution in these patients (10).