Clinical manifestations

Presentation and course

The clinical manifestations of Guillain-Barré syndrome in children are often anteceded within 2 to 4 weeks by recent illness or immunization. An antecedent infection is reported in 75% of children with Guillain-Barré (09; 21).

The hallmark of Guillain-Barré syndrome is an ascending weakness. Older, more verbal children and adults will present with complaints of weakness and unsteadiness. The weakness typically starts in the lower extremities and ascends into the upper extremities. This progression may extend from hours to days to weeks. In younger, less verbal children, the symptom of gait unsteadiness may be the initial presenting symptom, and an apparent gait ataxia is a clinical presentation that is distinct to childhood Guillain-Barré syndrome. In preschool-aged children (younger than 6 years of age), refusal to walk, with or without leg pain, is the most frequent presenting symptom, occurring in 65% (51).

Although weakness is the most common clinical feature, the most frequent initial presenting complaint in children is pain. Pain was the initial presenting complaint in 47% in a series (09) and is reported during the clinical course in 55% to 67% of cases in children (04; 57). Pain complaints mainly consist of headaches or muscular pain of the back and legs and can sometimes be severe in nature. This accentuates a pertinent feature of childhood Guillain-Barré syndrome: when severe pain is manifested in younger children who are unable to verbalize or tolerate the pain, it often confounds the underlying diagnosis (29) and can result in unnecessary referrals to other subspecialists, such as orthopedic surgeons (38). Specifically, in preschool-aged children, this prominent symptom of pain contributes to misdiagnosis. Misdiagnosis occurred in two thirds of preschool-aged children in a series, resulting in a delay until correct diagnosis of more than one week in one fourth (51).

Sensory symptoms and paresthesias have been noted in 18% to 54% of children (04; 57); it should be noted, though, that sensory symptoms are often difficult to elicit from younger, less verbal children. These sensory symptoms occur most commonly in the distal extremities (04).

On physical examination, an ascending motor weakness is noted with areflexia. This weakness tends to be symmetric and usually begins in the legs. Ataxia has been reported in almost half of the children with Guillain-Barré syndrome (57). Cranial neuropathies are also a common finding, seen in 15% to 69% of these children (04; 09; 57; 21). The most common cranial neuropathy is of the facial nerve, seen in 33%, but ophthalmoplegia (16% to 21%) is also frequently reported (04; 09). Although areflexia or significantly diminished deep tendon reflexes is nearly universally present, there are rare cases reported of hyperreflexia (59).

An autonomic neuropathy involving both the sympathetic and parasympathetic systems is also frequently seen, reported in 18% to 46% of children with Guillain-Barré syndrome (04; 57; 21). Manifestations can include orthostatic hypotension, pupillary dysfunction, sweating abnormalities, and sinus tachycardia (13). In addition, respiratory failure due to involvement of the muscles of respiration results in ventilator dependence in 16% to 28% of children (33; 09).

Laboratory evaluation reveals an elevated CSF protein out of proportion to CSF pleocytosis, although this may not be seen within the first 48 hours of symptom onset. In addition, the syndrome of inappropriate antidiuretic syndrome (SIADH) can also be associated with Guillain-Barré syndrome in adults (55), especially those requiring ventilator support, and should be monitored for and treated in patients of all ages. After several days, abnormalities in conduction velocities, F waves, and compound motor action potential can be seen in electrophysiologic studies. The lumbosacral MRI can demonstrate enhancement of the nerve roots.

Although the term Guillain-Barré syndrome traditionally refers to the syndrome of acute inflammatory demyelinating polyneuropathy (AIDP), other variants exist to include acute motor and sensory axonal neuropathy (AMSAN), acute motor axonal neuropathy (AMAN), Miller Fisher syndrome, and polyneuritis cranialis. Miller Fisher syndrome is a variant seen in children and is characterized by the triad of ophthalmoplegia, ataxia, and areflexia with relatively little weakness and is associated with serum anti-GQ1b antibodies (37; 52). MRI neuroimaging of the brain in patients with Miller Fisher syndrome may also reveal nerve enhancement, specifically of the cranial nerves (24).

Prognosis and complications

In general, most children (over 90%) with Guillain-Barré syndrome show a full recovery of motor function (33; 32). In a series, the median time from onset of symptoms to first recovery was 17 days, to walk unaided, 37 days, and to be symptom-free, 66 days (33). Patients with the axonal form of Guillain-Barré syndrome have a poorer prognosis in adult series, with a median time to walk with assistance about 32 days (22). The full recovery period is longer than the period of time the child was sick, often requiring weeks to months, with a median estimated time to maximum recovery of 7 months (04). Although the majority of patients achieve their maximum amount of functional improvement within the first 6 months, some recovery does continue to occur even after the first year (32). However, some children will have persistent symptoms of paresthesias, unsteadiness of gait in the dark, painful hands or feet, or fatigue (50). Prognostic scales and indicators for pediatric Guillain-Barré syndrome–utilizing factors such as age, presence of diarrhea, Guillain-Barré syndrome disability scales, and nerve conduction studies to predict outcome to include independent walking—are available but require further validation in children (07; 46).

The most serious complications occur with weakness of the respiratory muscles. Many seriously affected individuals will need respiratory support, from 16% to 28% (33; 09; 32). During the progression of the disease, attention should be paid to the child's respiratory status, and measurements such as vital capacity can provide objective data to follow. Although the overall outcome for childhood Guillain-Barré syndrome is favorable, the need for ventilation is a risk factor associated with those with a poor functional outcome (32). In addition, residual fatigue can be reported after Guillain-Barre syndrome and may be related to more pronounced axonal loss (10). Residual symptoms such as fatigue (34%) and depression (32%) can occur and persist in children with Guillain-Barré syndrome (15).

Recurrences are uncommon but can occur in children. Some may have a chronic progressive course, whereas others may show recurrences or relapses. When this occurs, the possibility of chronic inflammatory demyelinating polyneuropathy (CIDP), should also be considered.

Clinical vignette

A 5-year-old girl presented with inability to walk for two days. She had an illness characterized by fever and runny nose but seemed to recover fully from these symptoms. On exam, she had weakness in her legs and arms. Sensory exam appeared normal. Reflexes were not elicitable.

A lumbar puncture showed five white blood cells, zero red blood cells, a protein of 160 mg/dl, and a normal glucose.

After Guillain-Barré syndrome was suspected, the child was started on intravenous immunoglobulin. During the first two days of treatment, she showed progressive weakness. Daily pulmonary function testing showed progressive worsening. A nerve conduction velocity test at that time showed prolonged distal latencies and abnormal F waves.

On the third treatment day, she stabilized, and by the fifth treatment day she had slightly improved from her nadir.

One month later, follow-up showed continued improvement, but she was still weak and reflexes remained difficult to obtain. By 6 months, she was back to normal.

Biological basis

Etiology and pathogenesis

Guillain-Barré syndrome is believed to be an autoimmune mediated process. A preliminary study indicates macrophage migration inhibitory factor may play a role (44). Several infections (Epstein-Barr virus, cytomegalovirus, mycoplasma, campylobacter), as well as immunizations, have been known to precede the illness (58). Guillain-Barré syndrome cases in children have been reported in association with COVID-19 (coronavirus disease 2019) during the pandemic (08), and continue to be reported, though still rare, in larger national cohort studies (49). In a large case-control study, COVID infection was associated with an increased risk of Guillain-Barré syndrome, whereas Pfizer-BioNTech vaccination against COVID was associated with a decreased risk (03). The role of mycoplasma pneumonia has been reported, occurring more frequently in children than adults, and it has been associated with IgG antibodies against galactocerebroside, a major glycolipid found in both the peripheral and central nervous system (40). The immune-mediated targets in Guillain-Barré syndrome can include the myelin sheaths of the peripheral nerves or the axons themselves. Occasionally, surgery is noted to be a precipitating factor.

In the demyelinating form of Guillain-Barré syndrome, demyelination and mononuclear infiltration are seen. Lymphocytes and macrophages surround endoneural vessels and cause an adjacent demyelination. These lesions can be discrete and are scattered through the peripheral nervous system although there may be a predilection for inflammation of the nerve roots (52). The conduction block and demyelination of the motor nerves results in the progressive weakness of this syndrome. Similarly, the involvement of the sensory nerves leads to pain and paresthesias.

Many authors believe that the mechanism of disease involves an abnormal T-cell response, precipitated by a preceding infection (52). A variety of specific antigens may be involved in this response, including myelin P-2, GM1, and GQ1 gangliosides (54). GD1b is a ganglioside associated with primary sensory neurons, and anti-GD1b antibodies are seen in a small percentage of patients (41). Although rare, other antiganglioside antibodies have been found in children with Guillain-Barré syndrome; the antibodies are seen most often in patients with a preceding Campylobacter jejuni infection (56).

There does appear to be a regional geographic difference in the incidence of Guillain-Barré subtypes. The classic demyelinating subtype, AIDP, is the predominant subtype in most western countries to include the United States and Europe. In contrast, the axonal subtype of AMAN is the predominant subtype in Asia, to include China and Japan, and also in Mexico (43). In Mexican children, AMAN was often associated with Campylobacter infection, and many of these patients also had detectable serum antiglycolipid antibodies. In Northern China, epidemics of the AMAN variant of Guillain-Barré syndrome, particularly during the summer months, have also been associated with Campylobacter jejuni infection, with many of these patients also having detectable antiglycolipid antibodies (18; 23). In this axonal form of Guillain-Barré syndrome, biopsy specimens reveal Wallerian-like degeneration of fibers in the ventral and dorsal nerve roots, with only minimal demyelination or lymphocytic infiltration (19). These axonal lesions affect both sensory and motor fibers. Although this form of Guillain-Barré syndrome has been associated with Campylobacter infection, it appears to be a rare complication of such infection (39). Guillain-Barré syndrome is associated with the HS:19 serotype of Campylobacter jejuni, but it can be seen in other serotypes as well (12).

Epidemiology

The age-specific incidence of Guillain-Barré syndrome is 1.5/100,000 in persons younger than 15 years of age (45). Approximately one third of cases in children occur before the age of 3 years, with a mean age of 6 years, when defining children as younger than 15 years of age (09).

Prevention

No specific methods of prevention are known. Over time, some vaccines have been modified to include less neural antigens in the hopes of reducing the incidence of Guillain-Barré syndrome.

Differential diagnosis

The differential diagnosis of Guillain-Barré syndrome in childhood is primarily that of a progressive, symmetric weakness. Myelopathy (eg, cord compression syndromes, transverse myelitis) can sometimes present with progressive weakness and is the most important etiology to rule out in a patient with acute or subacute weakness. The physical exam (or spinal MRI) should help differentiate a spinal cord syndrome from a diffuse neuropathy. Although the finding of upper motor neuron signs can point the examiner more toward a central process such as a myelopathy, it is especially important to note that a myelopathy can present initially with a flaccid paralysis with absent deep tendon reflexes in the acute stage of injury, thus, resembling the examination of the patient with Guillain-Barré syndrome. This includes the more contemporary diagnosis of acute flaccid myelitis for which spinal cord lesions are visualized on MRI, but tend to have a shorter interval to nadir and asymmetric limb weakness, compared to Guillain-Barré syndrome (20).

In infants particularly, botulism should be a consideration. In botulism there is early involvement of the extraocular muscles as well as constipation. Additionally, when ophthalmoplegia is present, myasthenia gravis is a consideration. Fatigability on examination and nerve conduction velocity and EMG findings can help distinguish between these conditions. A presentation similar to Guillain-Barré syndrome can occur in certain infections such as poliomyelitis, Lyme disease, and HIV. In these latter cases, the lumbar puncture will typically show a CSF pleocytosis. Other acute neuropathies from lead, heavy metals, or vincristine also cause a predominantly motor neuropathy. Tick paralysis can also cause an ascending paralysis; all children with suspected Guillain Barré syndrome should have a complete examination of the skin for ticks. Often improvement is dramatic after the tick removal, especially in North America, as opposed to Australian cases. Occasional reports of organophosphate poisoning present with a Guillain-Barré syndrome-like picture. Finally, when dealing with a population that is not completely immunized, diphtheria should also be in the differential diagnosis, especially in children with a recent history of pharyngitis.

Diagnostic workup

The diagnosis is made by the presence of a progressive ascending weakness with areflexia. A lumbar puncture, electrodiagnostic studies, or, occasionally, MRI findings can give support for this diagnosis.

The lumbar puncture will be suggestive of a demyelination (increased protein) without evidence of active infection (lack of CSF pleocytosis). Guillain and Barré originally noted this. The spinal fluid findings may be normal within the first 48 hours of symptoms, and occasionally, the protein may not rise for a week (13). Most patients will have less than 10 leukocytes per cubic mm, but occasionally, a mild elevation of between 10 and 50 cells is seen (13; 09).

Electrodiagnostic studies within the first week of the onset of symptoms reveal a prolonged or absent F response (88%), prolonged distal latencies (75%), conduction block (58%), and reduced conduction velocity (50%). By the second week of the illness, reduced compound muscle action potential (100%), prolonged distal latencies (92%), and reduced motor conduction velocities (84%) are seen (09). The results on nerve conduction studies closely correlate with pathological changes seen by nerve biopsy (36).

Spinal MRI looking at lumbosacral root enhancement appears to be a sensitive diagnostic test in children with Guillain-Barré and should be considered when there is clinical uncertainty, or at the preference of the clinician. In a study looking at MRI findings at a mean of 13 days after start of symptoms, enhancement of the cauda equina nerve roots with gadolinium on lumbosacral MRI was 83% sensitive of acute Guillain-Barré syndrome, and present in 95% of "typical" cases (17). Nerve root enhancement can be seen as early as two days after symptom onset, and a study reported that 100% of patients eventually had spinal nerve root enhancement on repeat imaging (42). Anterior nerve root enhancement is usually the predominant pattern (61).

Guillain-Barré in children is also associated with an increased neutrophil/lymphocyte ratio, which decreased with treatment with intravenous immunoglobulin (28). Further observation is needed to understand how this can be used diagnostically and prognostically as a potential biomarker.

Management

Multiple studies have used intravenous immunoglobulin to treat the symptoms of Guillain-Barré syndrome. Studies have demonstrated that an effect of IVIg is to neutralize neuromuscular blocking antibodies (06). Intravenous immunoglobulin seems most helpful in reducing the severity of the disease, as well as the duration of symptoms. Long-term outcome may not be affected. However, there may be different subtypes and patient populations in which treatment with IVIg exerts variable levels of efficacy. In a nonrandomized study, children with Guillain-Barré syndrome with or without IVIg treatment had similar outcomes (hospital length of stay, need for or duration of mechanical ventilation, 3- and 6-month functional outcome), but those with AMAN showed better recovery outcomes with IVIg treatment (31); further study is needed to understand if the results can be generalized to other patient populations.

Several IVIg treatment regimens have been utilized in the literature. One regimen includes daily intravenous immunoglobulin for 5 days at a dose of 0.4 gm/kg per day (60; 01; 34), which results in an improvement within a mean of 2 to 3 days after the start of therapy (01). Other authors use 2 gm/kg of intravenous immunoglobulin given as a single dose or 1 gm/kg for 2 days (62; 34). One study compared the outcome of 0.4 gm/kg per day given for 3 days versus 6 days (47). In that study, the 6 days of IVIg was superior when “time to walking” was used as an endpoint. When comparing treatments of 1 gm/kg for 2 days versus 0.4 gm/kg over 5 days, no significant difference in the effectiveness was noted in the two treatment regimens. However, early “relapses” were more frequently observed in the shorter treatment group (34).

Plasmapheresis is also an option. Studies in children using both historical and case controls indicate that plasmapheresis may decrease the severity and shorten the duration of Guillain-Barré syndrome (14; 35; 16). Plasma exchange was most beneficial when started within 7 days of the onset of symptoms but is still beneficial in patients treated up to 30 days after disease onset (48). For most studies, the results of plasmapheresis and intravenous immunoglobulin seem similar, with possibly fewer side effects seen with intravenous immunoglobulin (60; 05). However, in a prospective randomized study in children comparing plasma exchange and intravenous immunoglobulin, the group treated with plasma exchange had a shorter duration of mechanical ventilation (11). However, no significant differences in PICU stay or short-term neurologic outcome were noted (11). Although steroids have been previously used to treat Guillain-Barré syndrome, current data as of 2021 suggest that these agents provide no benefit (25). If IVIg and plasmapheresis are unavailable, exchange transfusion as a lower-cost alternative has been suggested but is not an accepted first-line therapy (02).

A practice parameter by the American Academy of Neurology states that both IVIg and plasmapheresis are treatment options for children with severe Guillain-Barré syndrome although there are no adequate randomized controlled trials specifically in children (27). Both IVIg and plasmapheresis are efficacious, and combining the treatments provides no significant benefit (26).

Patients' vital signs and respiratory capacity should be monitored. When vital capacity falls below 15 ml/kg of body weight, arterial PO2 falls below 70 mm/Hg, or there is significant fatigue, intubation and mechanical ventilation should be considered (53). Orthostatic hypotension and urinary retention may also cause patients significant problems during the acute phase of the illness.

Attention should also be paid to possible decubitus ulcers and contractures in patients who are severely ill or who have a particularly prolonged course. In addition, chronic pain should be addressed using standard medications for neuropathic pain, although corticosteroid therapy has also been reported to decrease pain in pediatric Guillain-Barre syndrome (30). Long-term physical therapy may provide a benefit to patients during the recovery phase of the illness.