Guillian Barre Syndrome

Guillain-Barre syndrome is an acute immune-mediated process resulting in injury to the peripheral nerves. It has a slight male predominance and a bimodal age distribution. Symptoms typically develop 3-6 weeks after infection, often viral upper respiratory infections. Patients will complain of weakness that begins in the feet and ascends over time. If left untreated, it can cause weakness of the respiratory muscles and thus respiratory failure. Early diagnosis and treatment are paramount in reducing morbidity and mortality.

Introduction

Guillain-Barre syndrome (GBS) is an immune-mediated process also referred to as acute inflammatory demyelinating polyneuropathy (AIDP). French neurologists Guillain, Barré, and Strohl have been given credit for its description in a pair of WWI soldiers who developed acute areflexic paralysis with spontaneous recovery in 1916. The neuropathy usually affects the motor, sensory, and autonomic nerves in the extremities though it may also involve the ocular motor nerves, respiratory, facial, and bulbar muscles.

There is a broad differential in those presenting with an acute weakness that can include stroke, encephalitis, acute poliomyelitis, acute myelopathy, myasthenia gravis, toxins, metabolic derangements (hypokalaemia, hypophosphatemia), myopathy, and disorders of periodic paralysis. A careful history and exam is able to localize the issue to the peripheral nerves, thus excluding cerebral, brain stem, spinal cord, cauda equina, muscle, or neuromuscular junction causes. The differential for peripheral neuropathy includes AIDP, botulism, tick paralysis, post-rabies vaccine neuropathy, heavy metal/drugs, porphyria, diphtheria, and critical illness neuropathy.

Variants

Miller Fisher Syndrome

This is often thought of as a proximal to distal progression. Symptoms include ataxia, ophthalmoparesis, and areflexia.¹⁰ In children, it is estimated to encompass 2-4% of cases. Antibodies to the GQ1b ganglioside have been found in some cases. This ganglioside is found in cranial and other peripheral nerves which explains its limited region of involvement.

Acute Motor and Sensory Axonal Neuropathy (AMSAN)

This variant is often thought of as a continuum with AIDP. The presentation is clinically identical to the two. Unfortunately, those with a severe amount of axonal degeneration often have incomplete recovery. The diagnostic electromyographic feature of this variant is the absence or decrement of motor and sensory action potential amplitudes with only minor slowing of nerve conduction velocities.

Acute Motor Axonal Neuropathy (AMAN)

The first clear reports of this condition came from outbreaks in rural northern China. The presentation is similar to AIDP and AMSAN but has the involvement of the motor axons and sparing of the sensory axons. EMG hallmarks include normal sensory nerve conduction velocities with reduced compound motor action potential amplitudes and relatively normal motor conduction velocities. Needle EMG shows diffuse denervation injury. There is a stronger association with C. jejuni infections than with the other forms, especially in cases originating from northern China.

Polyneuritis Cranialis

This variant is denoted by acute onset of multiple cranial nerve palsies, typically bilateral VII with sparing of II. Clinically patients will have bilateral facial weakness, dysphonia, and dysphagia. Studies have shown an association with CMV infection. Postcontrast MRI shows enhancement of multiple cranial nerves; the degree of involvement on imaging is more extensive than is seen on clinical exam.

GBS with Central nervous System Manifestations

CNS manifestations range from encephalopathy, transverse myelitis, optic neuritis, brainstem/cerebellar syndromes, or acute disseminated encephalomyelitis (ADEM). Pathologic findings are largely due to the injury of the spinal nerve roots and cranial nerves. Evidence of inflammation in the medulla, pons, and spinal cord can be seen.

In North America and Europe, AIPD accounts for approximately 90% of cases. In China, Japan, Bangladesh, and Mexico, AMAN accounts for 30% to 65% of cases and AIDP is reported at 22% to 46%.¹¹

Presentation

Incidence is estimated at 0.5-1.5 per 100,000 children <16 years.¹ It demonstrates a slight male predominance and a bimodal distribution with peaks in young adults and the very old.²

It is typically considered a monophasic illness, though about 5% of patients have a recurrence. Outbreaks have been reported following immunization campaigns involving the oral polio vaccine.^3,4 Another outbreak was seen in 1976 associated with the H1N1 influenza vaccine; fortunately, this was not seen with the most recent outbreak and vaccine campaign in 2009.^5,6 Up to 2/3 of patients report an infection 3-6 weeks prior to symptom onset, often a viral upper respiratory infection. Given the temporal relation to onset of symptoms, work up for infections causes is often negative. Causative infections that have been substantiated in the literature include Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumonia.⁷ C. jejuni has been associated with cases in endemic areas such as China.

Patients often complain of distal weakness that ascends over time. In younger children, balance difficulties sometimes are the initial symptoms reported by parents, leading to the discovery of muscle weakness. As the weakness progresses, they may find the inability to walk, become easily fatigued, or complain of difficulties with breathing or swallowing. In children, pain is a common symptom seen in up to 79% at the time of presentation.⁸ Reports can vary from leg/back pain, paresthesias, dysesthesias, meningismus, myalgia, visceral discomfort, joint and radicular pain. Fortunately, its presence has a poor correlation with presenting severity and eventual recovery.

Despite the wide clinical presentation, there is a stepwise fashion to the clinical course. It begins with the onset and progression of symptoms until reaching their nadir. This is typically fairly rapid, with 50-75% reaching nadir by 2 weeks, and 90-98% by 4 weeks. Repeat clinical exams note the loss of deep tendon reflexes that begin distally before ascending as the clinical course progresses. Some patients develop hyporeflexia of the upper extremities without progressing to true areflexia. The plateau phase lasts days to 4 weeks followed by the recovery phase. The duration of recovery varies largely dependent on the severity of the neuronal injury.¹

Autonomic dysfunction is reported in up to 25% of cases.¹ Symptoms are usually intermittent and manifest as postural hypotension, variability in blood pressure, supraventricular tachycardia, and bradycardia. Gastrointestinal and urinary complications in terms of constipation, pseudo-obstruction, swallowing difficulties, and urinary retention can be seen. Rarely the autonomic instability can result in cardiac arrest.⁹

Diagnosis

Although GBS can be diagnosed on clinical exam and testing is not specifically needed, most practitioners obtain a lumbar puncture for confirmation (see table 1).¹² The characteristic cerebrospinal fluid (CSF) finding is albuminocytologic dissociation. This means there is a disproportionate elevation in CSF protein with the absence of inflammation (i.e. white blood cells). Caution should be exercised if performed in the first week of symptoms as CSF can still be normal. Evidence of CSF pleocytosis should direct the clinician away from the diagnosis of GBS.

Electromyography (EMG) demonstrates multifocal slowing of nerve conduction velocities or conduction block. For typical AIDP cases, EMG shows asymmetric slowing of nerve conduction velocities in peripheral nerves, unequal conduction velocities incomparable nerve segments, or conduction block. Prolongation or loss of the F-wave is an initial finding and can be seen before the CSF abnormalities. Later, H-waves can have similar findings, both of which indicate injury to the proximal nerve or spinal root. EMG can help assist in prognosis in terms of confirming axonal injury which would result in a long time to reach final recovery.

Postcontrast MRI images can show enhancement of the cauda equine, lumbar nerves, and nerve roots.

On pathologic exam, AIDP cases show segmental demyelination, often resulting in mild secondary axonal degeneration. Antibodies bind to the outer surface of the Schwann cell and through complement activation initiates myelin vesiculation. In AMAN, macrophages bind directly to axolemma at the nodes of Ranvier. The pathology seen with AMSAN resembles that in AMAN, with the exception that the dorsal and ventral, roots are both affected.¹³

Although specific antibody testing is rarely performed, it can uncover antibodies to GM1, GM1b, GD1a, and GalNac-GD1a.¹³ Anti-GalNac-GD1a antibodies in particular are implicated with the acute motor axonal neuropathy variant. GQ1b ganglioside antibodies are found in Miller Fisher Syndrome.

Table 1. Diagnostic Features of GBS

• I. Required for Diagnosis
  • Progressive motor weakness in more than one extremity.
  • Areflexia. Loss of ankle-jerk with hypo-reflexia of biceps and knee jerks will suffice if other features are consistent.
• II. Strongly Supportive of Diagnosis
  • Progression. Weakness develops rapidly but ceases by 4 weeks.
  • Relative symmetry
  • Mild sensory signs or symptoms.
  • Cranial nerve involvement.
  • Recovery, typically begins 2-4 weeks after progression stops.
  • Autonomic dysfunction.
  • Absence of fever at the onset of symptoms.
  • Variants
    1. Fever at onset of symptoms.
    2. Severe sensory loss with pain.
    3. Progression beyond 4 weeks.
    4. Lack of recovery or major residual deficit remaining.
  • Sphincter dysfunction. Transient bladder paralysis may occur.
  • Central nervous system involvement.
• III. Features Casting Doubt on Diagnosis
  • Marked, persistent asymmetric weakness.
  • Persistent bladder or bowel dysfunction.
  • Bladder or bowel dysfunction at onset.
  • More than 50 mononuclear leukocytes/ cu mm in CSF.
  • Presence of polymorphonuclear leukocytes in CSF.
  • Sharp sensory level.
• IV. Features That Rule Out the Diagnosis
  • A current history of hexacarbon abuse.
  • Evidence of porphyria.
  • Evidence of lead neuropathy, and evidence of lead intoxication.
  • A purely sensory syndrome.
  • Diagnosis of a paralytic disorder.

Outcomes

It is reported that children are more likely to have a full recovery compared to adults. Korinthenberg and Mounting found that following the progression phase, 30-40% of children remain able to walk with or without assistance. This is in contrast to the adult literature which reports only 19% of adults remain able to walk. Mechanical ventilation is needed in 15-20% of cases with 35-45% having some degree of impairment in cranial nerve function; these figures are comparable with that seen in adults.²⁰

Roodbol et al. looked at the longterm outcomes in pediatric cases. All patients in their study were able to walk independently within 1 year of disease onset, regardless of disease severity. Two-thirds of patients reported residual issues, mainly severe fatigue and painful/paresthesias of the hands or feet. The neurological exam found signs of residual peripheral nerve damage including limb weakness, areflexia, and sensory deficits. They found 14% in their cohort had a significant residual disability. A large percentage of patients reported school or work problems. Several were held back a grade or dropped out of school following their GBS diagnosis despite the good motor recovery. They found that older age at diagnosis resulted in higher negative effects on education.²¹

Treatment

The main goal of treatment for GBS is to avoid respiratory failure and potential death. Fortunately in industrialized countries death is relatively rare. However, in countries with limited medical care, mortality is reported at around 10% of pediatric cases.¹

One of the biggest problems with GBS is the relative insidious onset of respiratory failure without clear laboratory markers. Practitioners should not wait for there to be evidence of respiratory compromise on ABG or related testing before considering elective intubation and mechanical ventilation.

Patients should be followed with respiratory assessments at periodic intervals to monitor for changes or decline. These are done via two different tests, typically administered by a respiratory therapist; forced vital capacity (FVC), and negative inspiratory force (NIF). A normal FVC is 60 mL/kg and intubation should be considered once below 20 mL/kg. NIF’s have a wide range of normal values, with normal typically being -50 cm H20. The more positive (i.e. closer to zero), the weaker the patient is, and -30 cm H20 suggests impending respiratory failure.¹⁴

With the risks of autonomic instability, continuous heart, respiratory monitoring, and pulse oximetry are recommended until the patient has plateaued.

Whether to treat is often based on the severity of symptoms at the time of presentation and whether it is believed the patient has reached their nadir. There are two mainstays of treatment to help shorten the progression period of the disease. These are intravenous immune globulin (IVIG) and plasmapheresis. The exact mechanism by which these treatments work is not entirely understood. Plasmapheresis likely filters out the circulating antibodies that are directed against the peripheral nerves. IVIG is less well understood. It may bind anti-idiotypic antibodies, absorb complement, or down-regulate B-cell mediated antibody production.

Plasmapheresis has been proven to save in children and has been shown to reduce the time to independent ambulation in non-ambulating patients from 60 to 24 days.¹⁵ Complications are rare and include hemorrhage, hypotension, transfusion reactions, septicemia, hypocalcemia, arrhythmia, cardiac arrest, transmitted infections, and local tissue injury.

IVIG is a blood product and caries associated risks. Additional side effects include ‘flu-like’ symptoms (headache, fever, myalgias) and aseptic meningitis. It is given at a dose of 2 g/kg, however, there is a wide variety in terms of the course. Treatment can be given over 1, 2, or 5 days with studies showing each is well tolerated in children. A study examined a single dose administration in 9 patients, none of which required mechanical ventilation though 2 patients did have cranial nerve involvement. The mean duration of symptoms prior to IVIG was 5.7 days. The mean time to the improvement of one grade on the functional GBS scale (table 2) was 3.5 days and the mean period to regain ambulation was 11.2 days.^16,17 All patients regained full mobility without relapse except for one who had relapsed at 5 months and subsequent full recovery after the second round of IVIG.¹⁷ Shahar et al. studied 26 children who received infusions over 2 days. Twenty had evidence of cranial nerve involvement with oropharyngeal dysfunction, 22 also experienced sensory symptoms at the time of presentation. All 26 deteriorated over a mean of 6 days to the point they were unable to ambulate. Nineteen developed respiratory involvement, 2 to the point they required mechanical ventilation. Following the infusions, 25 noted improvement of 1-2 grades on the functional GBS scale in less than 14 days. Twenty walked independently by 1 week, and one ventilated patient was extubated after 3 days. Eighteen had a full recovery by 2 weeks with the rest by 4 months, and none had evidence of relapse. The single patient with a protracted course did have initial improvement after the infusions but subsequently deteriorated over a period of 4 days. He developed complete paralysis requiring mechanical ventilation for 4 weeks and received a second dose of IVIG 2 weeks after worsening. Improvement was noted after 6 weeks, walking independently after 2 months, and full recovery by 4 months.¹⁸

Yata et al. used a 5-day course of IVIG with a treatment mean of 10 days from the onset of the disease. Mechanical ventilation was not required for any patient at the time of enrolment. The median time to improve at least one grade on the functional GBS scale was 10 days, the time required to improve two or more grades was 27 days. They did note worsening during or after treatment in 3 patients. One patient had worsening respiratory status after the first administration requiring mechanical ventilation. One patient experienced relapse 41 days after initial treatment and one showed no improvement 20 days after completing the infusions. Both patients received alternative treatments. All three did eventually show improvement.¹⁹

Table 2. Motor Grading Scale for Acute GBS