Pediatrics

Guillain Barre/Miller Fisher Syndrome/Chronic inflammatory demyelinating polyneuropathy

OVERVIEW: What every practitioner needs to know

Guillain-Barré Syndrome (GBS) refers to a set of related disorders that are characterized by an acute-onset, immune-mediated polyneuropathy. It is commonly associated with a preceding infection. The GBS subtypes are differentiated primarily by their clinical features and neurophysiologic findings. The relevance of these subtypes is better applied to prognosis than to treatment, which is nearly identical for all subtypes. GBS is considered a neurological emergency because it can exhibit sudden respiratory failure and/or cardiac arrhythmias, both of which can be fatal if they are unanticipated and untreated. The mortality rate for GBS is around 3%; however, most patients make an excellent recovery.

Are you sure your patient has Guillain-Barré syndrome? What are the typical findings for this disease?

All forms of GBS manifest the following clinical features:

  1. Flaccid weakness

  2. Hyporeflexia

The five subtypes of GBS are:

  1. Acute inflammatory demyelinating polyneuropathy (AIDP)

  2. Acute motor-axonal neuropathy (AMAN)

  3. Acute motor-sensory axonal neuropathy (AMSAN)

  4. Miller-Fisher syndrome (MFS)

  5. Chronic inflammatory demyelinating polyneuropathy (CIDP)

Acute inflammatory demyelinating polyneuropathy (AIDP)

AIDP accounts for about 90% of childhood GBS in the developed world. Due to its relative frequency, the term GBS is sometimes used interchangeably with this subtype. AIDP is characterized by acute, areflexic flaccid paralysis. Weakness ascends in a roughly symmetric fashion up the lower extremities to the arms, trunk, and sometimes head. Weakness progresses over a period of hours to days, with an average time to maximal weakness of one to two weeks. In addition to the motor component, there are often signs of sensory involvement and/or dysautonomia (Table I). The most common signs and symptoms at the time of presentation are weakness, pain and paresthesias.

Table I.

Incidence of Clinical Characteristics of AIDP
Clinical Characteristic Incidence
Weakness 100%
Primarily distal weakness 55%
Primarily proximal weakness 15%
Hyporeflexia/areflexia 94%
Pain (most commonly in legs and back) 80%
Sensory loss (most commonly proprioception) 55%
Paresthesia 50%
Cranial nerve palsies (most commonly VII) 50%
Dysautonomia (diaphoresis, hypertension, hypotension, arrhythmia, priapism) 50%
Ataxia 44%
Sphincter dysfunction 33%

Acute motor-axonal neuropathy (AMAN)

AMAN, is characterized by weakness due to axonal degeneration. It is uncommon in the United States, Canada, and Europe, although it occurs slightly more frequently in Mexico, South America, and parts of Asia. The signs and symptoms are the same as in AIDP, but the onset is more rapid and fulminant. Maximal weakness usually occurs by one week. AMAN is differentiated from AIDP via electrophysiologic studies (see below, Diagnostic Studies). Some studies have suggested a longer and perhaps more limited recovery than among AIDP patients, although this discrepancy has not been demonstrated in a pediatric population.

Acute motor-sensory axonal neuropathy (AMSAN)

AMSAN, which is rare in the United States, is characterized by weakness and sensory changes due to axonal degeneration. Signs, symptoms, and electrophysiologic studies are similar to those of AMAN, except that sensory findings are present.

Miller-Fisher syndrome (MFS)

Miller-Fisher syndrome is characterized by the triad of ophthalmoplegia, ataxia, and areflexia. Symptoms usually progress over approximately one week. Initial diplopia is usually followed by internal ophthalmoplegia and bilateral facial weakness. Approximately one quarter of patients with MFS have some weakness and sensory changes of the extremities. Other associated findings that commonly occur are pupillary abnormalities, ptosis, bulbar palsy, and rarely urinary incontinence. Recovery usually begins within weeks.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

CIDP is characterized by slowly progressive weakness over a period of at least two months, accompanied by hyporeflexia. Maximal weakness usually occurs months after onset of symptoms. Signs and symptoms are similar to those of AIDP, with a slower time course. Some children have a monophasic course that progresses over several months, while others have a relapsing-remitting course. The most frequent signs and symptoms are predominantly distal weakness, areflexia, fatigue, and sensory changes. About half of children with CIDP lose the ability to walk at their nadir of weakness.

What other disease/condition shares some of these symptoms?

Other conditions having similar symptoms to Guillain-Barré syndrome are shown in Table II.

Table II.

Differential Diagnosis of Guillain-Barré Syndrome
Inflammatory/AutoimmuneTransverse myelitisAcute cerebellar ataxiaMyasthenia gravisSystemic lupus erythematosusPolyarteritis nodosa
InfectiousBrainstem encephalitisPoliovirus, West Nile virus, enterovirusTick paralysisLyme diseaseBotulismDiphtheritic neuropathyViral myositis
MetabolicHeavy metal poisoningThiamine deficiencyHypokalemic/hypophosphatemic/hypercalcemic paralysisRhabdomyolysisAcute intermittent porphyriaCritical illness neuropathy
Structural/VascularMass lesion of the posterior fossa or spinal cordBrainstem strokeVasculitic neuropathy
GeneticHereditary motor sensory neuropathiesAtaxia polyneuritiformisMetachromatic leukodystrophyGloboid cell leukodystrophy

What caused the disease to develop at this time?

How frequent is Guillain-Barré syndrome in children?

The spectrum of disorders collectively referred to as Guillain-Barré syndrome constitute the most common cause of flaccid paralysis among children in developed nations, with an annual incidence of 1-2/100,000. Approximately 3,500 children are diagnosed annually in the United States with GBS. There is no difference in incidence between males and females in AIDP, although CIDP appears to be more common in males. AMAN and AMSAN are rare in the United States and Europe, but are more common in China, Mexico and India. Most children have onset of illness between four and nine years of age, although GBS can occur in neonates as well as in the elderly.

The disorder occurs as the result of an immune-mediated attack on the peripheral nerves. About two-thirds of children have an identifiable antecedent viral or bacterial infection in the weeks prior to the onset of weakness. The most commonly identified antecedent pathogen is Campylobacter jejuni, which is especially common before the axonal subtypes. Other common preceding infections include Mycoplasma pneumoniae, Haemophilus influenzae, Cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. Although our understanding of the pathogenesis is still evolving, several lines of evidence suggest a role for molecular mimicry where surface antigens on infectious agents induce the production of antibodies that also cross react with myelin epitopes, thereby causing injury to the sheath or, as may be the case in AMAN, directly damaging the axon at the nodes of Ranvier.

The role of vaccinations in triggering outbreaks of the disorder has garnered interest. However, while the rare possibility of individual genetic susceptibility does exist, there is little evidence to suggest a causal relationship with most vaccines. Exceptions include the 1976/1977 version of the swine flu vaccine, the mouse-derived rabies vaccine and, possibly, the quadrivalent conjugated meningococcal vaccine (MCV4).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of GBS is confirmed with CSF labs and nerve conduction studies.

Cerebrospinal fluid analysis

Cerebrospinal fluid analysis in AIDP and CIDP can provide supportive evidence with albuminocytologic dissociation, in which protein is elevated greater than 45mg/dL, but there are fewer than 10 cells. This CSF finding can be falsely negative within the first one to two weeks, with peak protein concentration four to five weeks after symptom onset. CSF analysis in MFS may show milder elevation in protein.

Nerve conduction study and electromyography

Once GBS is suspected based on clinical presentation, the most sensitive and specific test for the disease is a nerve conduction study (NCS). Unfortunately for those attempting an expedient diagnosis, the earliest electrophysiologic abnormality, partial motor conduction block, does not typically manifest until 3-5 days after symptom onset. The most sensitive NCS finding is absence of the H-reflex, which disappears in nearly all patients within 7 days of symptom onset. Other findings include: slowed conduction velocities and abnormal temporal dispersion. Electromyography (EMG) is less useful, although it may yield denervation potentials 2 weeks or more after onset.

GBS subtypes can also be distinguished on NCS, although it should be noted that these electrophysiologic distinctions do not alter treatment selection and have limited prognostic utility in the pediatric population. In cases of AIDP and CIDP, NCS commonly shows not only reduced motor conduction velocity, but also slowed F-wave response, prolonged distal latencies, and dispersion of proximally evoked compound motor action potentials. AMSAN is characterized by decreased amplitude of compound motor and sensory-evoked potentials, as well as denervation. AMAN is characterized by decreased amplitude of motor, but not sensory, potentials and denervation.

Would imaging studies be helpful? If so, which ones?

In the context of evaluating a patient with possible GBS, magnetic resonance imaging (MRI) is perhaps most useful in ruling out GBS mimics, such as spinal cord lesions. In the setting of AIDP and CIDP, MRI may demonstrate gadolinium enhancement of the spinal nerve roots and cauda equina, although this is insensitive early in the disease course and is a nonspecific finding that can also be seen in other disorders. In the MFS subtype, T2 hyperintensities are occasionally visible in the brainstem.

How should patients with possible Guillain-Barré syndrome be triaged? Which patients need ICU-level care?

GBS should be approached as a neurologic emergency that requires immediate and, just as importantly, sustained vigilance to the patient's respiratory and cardiac status for signs of respiratory failure or cardiac arrhythmias. The formal diagnostic "confirmation" of GBS often takes days to achieve; therefore, it is absolutely critical that such anticipatory measures be initiated promptly at the time the diagnosis is first suspected. (See below, Symptomatic Therapy)

All children with possible or suspected GBS should be admitted to the hospital for observation and further diagnostic confirmation. Cardiac telemetry should be considered in all such patients. Children should be admitted to the ICU if they have flaccid quadriparesis, rapidly progressive weakness, vital capacity less than 20 mL/kg, bulbar palsy, or cardiovascular instability.

If you are able to confirm that the patient has Guillain-Barré syndrome, what treatment should be initiated?

Treatment for GBS can be divided into two types: symptomatic and disease-modifying. Symptomatic therapy in GBS is arguably the more important of the two, as it includes measures intended to anticipate and treat the many disease-related complications that are collectively responsible for the bulk of morbidity and mortality in GBS patients. Disease-modifying therapy, on the other hand, does appear to shorten the duration of illness in children, but it does not substantially reduce the risk of cardiorespiratory failure, nor does it alter the long-term prognosis for motor recovery.

Symptomatic Therapy

The disease-related complications of GBS include: respiratory failure, cardiac dysrhythmias, blood pressure instability, deep venous thrombosis (DVT), pressure sores, joint contractures, and bowel dysfunction.

Weakness can progress with surprising rapidity, which can result in sudden, life-threatening respiratory failure. Forced vital capacity (FVC), mean inspiratory flow (MIF), or pCO2 should be reassessed several times a day on a scheduled basis, generally until patients reach their clinical nadir. Elective intubation should be initiated if FVC falls < 20 mL/kg or the MIF is < 30 cm H2O. In patients too young to cooperate, steadily increasing signs of respiratory distress include increasing use of accessory muscles, respiratory rate, or arterial pCO2 > 50 mm Hg.

Because the myelin and axons of autonomic nerves are also frequently impaired in GBS patients, cardiac arrhythmias and autonomic instability may occur, leading to life-threatening cardiovascular events. Supportive care includes close attention to blood pressure, monitoring with cardiac telemetry, careful fluid management, and avoidance or cautious use of agents (e.g., sedatives) that may have autonomic activity, as these effects can be greatly magnified in patients with GBS.

Prolonged weakness and immobility increase the risk for pressure sores, deep vein thromboses, and joint contractures. Prophylaxis in the form of frequent position changes, compression stockings or anti-coagulation, and physical and occupational therapy should be implemented as indicated.

Decreased bowel (and sometimes bladder) motility is an underappreciated feature of the disorder. Stool softeners and enemas may prove useful and important for patient comfort.

Disease-Modifying Therapy / Immunotherapy (Table III)

Table III.

Immunotherapy options for AIDP / AMAN / AMSAN / MFS
Treatment Administration Effects
IVIG 2 g/kg divided over 5 days Decreases time to independent walking
Plasma exchange Double volume exchange every other day for 1 week Shortens time to independent walkingShortens time on ventilator
Corticosteroids Not recommended Possibly harmful

Disease-modifying therapy for GBS is directed at attenuating the abnormal immune response that leads to the signs and symptoms of the disease. The mainstays of treatment for GBS are intravenous immune globulin (IVIG) and plasma exchange (PLEX). Corticosteroids, once commonly used, lack clinical benefit and should not be used in GBS (with the exception of CIDP).

The most recent American Academy of Neurology (AAN) consensus statement on GBS immunotherapy notes a lack of large randomized controlled trials in children, but suggests that IVIG / PLEX be considered in children with severe clinical manifestations of GBS. The authors recommend against such treatment in children with mild disease or stable symptoms.

Currently, the efficacy of IVIG and PLEX seems equivalent when it comes to reducing the time to maximal recovery. IVIG is usually preferred in children due to safety, ease of administration and cost. Initiation of IVIG or PLEX within two weeks of symptom onset is preferred, although some evidence suggests a positive treatment effect even if started within four weeks of symptom onset. No treatment has been shown to improve the long-term prognosis for full recovery, although mixed evidence suggests a reduced risk of respiratory failure in children treated with PLEX. Strength usually begins to improve within two weeks of either treatment. There is some evidence to support the use of PLEX after IVIG in treatment-refractory children. Conversely, the use of IVIG after PLEX does not appear to offer a clinically measurable benefit.

Treatment options for CIDP also include IVIG and plasma exchange, but unlike AIDP, steroids do show benefit. Although no randomized trials exist comparing these treatments in pediatric CIDP, the three treatment options seem roughly equivalent, based on existing data. Table IV lists possible regimens for these treatments, although optimal treatment regimens have not been established. Individualized therapy with adjustments in the dose and frequency of treatment to prevent exacerbation of symptoms is recommended. Other immunosuppressant medications have been attempted, including azathioprine, cyclophosphamide, cyclosporine, etanercept, interferon alpha-2a, interferon beta-1a, mycophenolate, rituximab, tacrolimus, and methotrexate. However, none have been studied in randomized trials.

Table IV.

Immunotherapy Options for CIDP
Treatment Initial Regimen Subsequent Regimen
IVIG 2 g/kg divided over 5 days 1 g/kg every month
Plasma exchange Double volume exchange every other day for 4 exchanges total Monthly exchange transfusion
Corticosteroids 1 g/kg prednisolone daily for 5 weeks Taper over 27 weeks

What are the adverse effects associated with each treatment option?

IVIG has the possible side effects of fever, headache, aseptic meningitis, myalgia, hypotension, pancytopenia. A serious allergic reaction can develop in patients with severe IgA deficiency, although IgA-depleted IVIG products are available and may be safe in such patients. IVIG Is derived from pooled human blood products and is thoroughly screened for known infectious agents. The risk of bloodborne infection exists, but is extremely small.

Plasma exchange is generally safe at centers with expertise in performing the procedure in children, but possible complications include infection or thrombosis associated with the catheter, as well as hypocalcemia, arrhythmia, hypotension, and cardiac arrest. Available evidence suggests there is no significant difference in adverse events rates in children receiving plasma exchange compared with IVIG.

What are the possible outcomes of Guillain-Barré syndrome?

The long-term outcomes of most children with GBS are excellent. The majority make a complete recovery, although it may take months or even years to fully recuperate. Persistent functional disability occurs in less than 10% of children, although on careful assessment, mild muscle weakness (without meaningful impairment) may be apparent in a somewhat larger portion of patients. The mortality rate averages around 3% at most centers and usually occurs as a result of respiratory failure or cardiac dysrhythmias. Evidence of axonal injury and greater severity of weakness at nadir have both been associated with a less favorable prognosis in adults; however, these correlations have not been robustly demonstrated in children.

In more severe cases of GBS, where children lose the ability to walk or become ventilator-dependent, treatment with IVIG or plasmapheresis may hasten short-term recovery and offers a favorable risk benefit profile. Unfortunately, no treatment has been shown to reduce the risk of long-term disability in this disorder.

Other clinical manifestations that might help with diagnosis and management

Non-classical manifestations of GBS do exist. Papilledema, hyperreflexia, predominantly proximal weakness, and extensor plantar responses have been reported in the setting of GBS. Nonetheless, the appearance of atypical signs or symptoms should prompt reconsideration of the diagnosis. Further exclusion of infectious, structural, or oncologic entities should be given careful consideration in this setting.

While GBS is very rare in children under 2 years of age, it has been reported in some infants as a forme fruste of "the floppy infant" syndrome, perhaps via maternal antibody transmission.

What complications might you expect from the disease or treatment of the disease?

Cardiac dysrhythmias, respiratory failure, and autonomic instability are the most common and the most serious short-term complications from the disorder. They should be approached proactively as outlined above. Neuropathic pain can occur in the short-term or mid-term, but is uncommon and rarely severe.

Are additional laboratory studies available; even some that are not widely available?

Various anti-ganglioside antibodies have been associated with a variety of GBS subtypes and may offer some additional diagnostic confirmation if the diagnosis is in doubt. Antibodies to GQ1b, in particular, have demonstrated reasonable sensitivity and specificity for the MFS subtype. Antibody testing, however, has no definitive role in modifying treatment decisions or prognosis.

How can Guillain-Barré syndrome be prevented?

There are no known preventative measures for GBS.

What is the evidence?

General Overview

Hughes, RA, Cornblath, DR. "Guillan-Barré syndrome". Lancet. vol. 366. 2005. pp. 1653-66.

Legido, A, Tenembaum, SN, Katsetos, CD, Menkes, JH, Menkes, JH, Sarnat, HB, Maria, BL. "Autoimmune and postinfectious diseases". Child neurology. Lippincott Williams & Wilkins. 2006. pp. 600-610.

Hicks, CW, Kay, B, Worley, SE, Moodley, M. "A clinical picture of Guillain-Barré syndrome in children in the United States". J Child Neurol. vol. 25. 2010. pp. 1504-10.

Haber, P, Sejvar, J, Mikaeloff, Y, DeStefano, F. "Vaccines and Guillain-Barré syndrome". Drug Saf. vol. 32. 2009. pp. 309-23.

Diagnostic Studies

Ropper, AH, Wijdicks, EF, Shahani, BT. "Electrodiagnostic abnormalities in 113 consecutive patients with Guillain-Barré syndrome". Arch Neurol. vol. 47. 1990. pp. 881-7.

Treatment

Agrawal, S, Peake, D, Whitehouse, WP. "Management of children with Guillain-Barré syndrome". Arch Dis Child Educ Pract Ed. vol. 92. 2007. pp. 161-8.

Lawn, ND, Fletcher, DD, Henderson, RD. "Anticipating mechanical ventilation in Guillain-Barré syndrome". Arch Neurol. vol. 58. 2001. pp. 893-8.

Hughes, RA, Swan, AV, van Doorn, PA. "Intravenous immunoglobulin for Guillain-Barré syndrome". Cochrane Database Syst Rev. vol. 7. 2010. pp. CD002063.

Raphaël, JC, Chevret, S, Hughes, RA, Annane, D. "Plasma exchange for Guillain-Barré syndrome". Cochrane Database Syst Rev. 2002. pp. CD001798.

Overell, JR, Hsieh, ST, Odaka, M. "Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders". Cochrane Database Syst Rev. 2007. pp. CD004761.

Hughes, RA, Wijdicks, EF, Barohn, R. "Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology.. vol. 61. 2003. pp. 736-40.

Connolly, AM. "Chronic inflammatory demyelinating polyneuropathy in childhood". Pediatr Neurol. vol. 24. 2001. pp. 177-82.

Prognosis

Bradshaw, DY, Jones, HR. "Guillain-Barré syndrome in children: clinical course, electrodiagnosis, and prognosis". Muscle Nerve. vol. 15. 1992. pp. 500-6.

Lee, JH, Sung, IY, Rew, IS. "Clinical presentation and prognosis of childhood Guillain-Barré syndrome". J Paediatr Child Health. vol. 44. 2008. pp. 449-54.

Ongoing controversies regarding etiology, diagnosis, treatment

Vaccinating patients with a history of GBS should be approached individually. In particular, for those patients whose previous GBS symptoms were associated temporally with exposure to a specific vaccine, repeat exposure to the same vaccine may be undesirable. In the absence of a specific vaccine-associated onset, however, routine vaccinations in GBS patients are most likely safe and offer the same net benefit seen in the general population.

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