A 12 year old Caucasian female presents to the emergency room with a chief complaint of leg weakness. One week prior, she had a fever of 101.4 with vomiting and diarrhea. After 3 days, the vomiting and diarrhea resolved. She was doing well until this morning when she fell while trying to get out of bed and could not stand or walk without support. She has no headache, blurred vision, tinnitus, vertigo, dysphagia, or incontinence. There is no history of toxic ingestion. Her immunizations are up to date. While in the ER she complains that her arms feel weak.

Exam: VS T 37.0, P 84, R 24, BP 102/64. Height and weight are at the 25th percentile. She is alert, slightly tearful but cooperative. HEENT: She has no nystagmus and no papilledema. Her extraocular movements are intact. Pupils are equal and reactive to light. No facial weakness or asymmetry is present. Heart, lung and abdomen exams are normal. Neuro: Strength 4/5 in the upper extremities, 3/5 in the lower extremities. DTRs 1-2+ in the upper extremities and absent in the lower extremities. Sensation is intact in all extremities. Cerebellar function is normal except for the weakness. No cranial nerve abnormalities are noted. She refuses to walk.

CBC, electrolytes, BUN, creatinine, glucose, calcium and liver function tests are normal. Urine toxicology screen is negative. A lumbar puncture is performed. Opening pressure is normal. CSF analysis shows protein 146 mg/dL (high), glucose 70 mg/dL, 5 WBC per cu-mm, 1 RBC per cu-mm, and gram stain shows no WBCs and no organisms.

She is hospitalized for further management with a tentative diagnosis of Guillain-Barre syndrome. An MRI of the brain and spinal cord is normal. She is started on IVIG and over the next few days, she slowly regains strength in her arms and legs. However, she still requires assistance with walking at the time of discharge. She is referred to a rehabilitation hospital to continue outpatient physical therapy. She gradually improves over the next 5 months and eventually returns to normal activity.

Guillain-Barre syndrome (GBS) is an acute demyelinating polyneuropathy of the peripheral nervous system characterized by progressive flaccid paralysis (1). It is an acquired disorder that affects people of all ages, although only rarely in children under one year of age (2,3). It has a slight male predominance of 1.5 to 1 and has an estimated annual incidence rate of 1/100,000 (1,2).

The disease mainly affects motor nerves but can involve sensory nerves as well (3). Although typically presenting as a fairly symmetric ascending paralysis, GBS is now believed to be a heterogenous disorder with a wide range of clinical manifestations. It includes the classic demyelinating form, or acute inflammatory demyelinating polyneuropathy (AIDP), the axonal forms which include the acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN), and clinical variants such as the Miller-Fisher Syndrome characterized by the triad of ataxia, areflexia, and ophthalmoplegia (4,5). AIDP is the most common subtype found in North America and Europe, while the axonal forms are more commonly seen in China (6).

Most cases in developed countries occur following an upper respiratory or diarrheal illness (1). Although the pathogenesis of the disorder remains unclear, GBS is suspected to cause an immune-mediated demyelination and axonal injury due to certain bacteria or viruses sharing antigenic sites with peripheral nerve myelin and/or axons (1,2). Campylobacter jejuni enteritis is the most commonly identified antecedent infection and is associated with more severe symptoms (4,6). Cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae have also been implicated in GBS (2,5).

Current research suggests that antiganglioside antibodies play an important role in the pathogenesis of GBS. Gangliosides are glycolipids containing sialic acid residues and are the surface components of many cells, including nerve cells. Many patients with GBS have antibodies to various gangliosides such as GM1, GD1a, GD1b, and GQ1b. Anti-GM1 antibodies are often found in classic GBS (AIDP), while anti-GQ1b antibodies are more commonly seen in the Miller-Fisher Syndrome (7). The outer membrane of Campylobacter's and other gram-negative bacteria is composed of lipopolysaccharides (LPS) which are complex glycolipids. The LPS of Campylobacter is unique in that it contains sialic acid and therefore resembles human glycoconjugates. It has been found to have antigenic molecules related to ganglioside GM1 and GQ1b (1,7). Through a process called molecular mimicry, antibodies against the C. jejuni LPS may crossreact with peripheral nerve myelin to cause demyelination (1).

Progressive weakness usually develops first in the lower extremities, then the trunk, upper extremities, and bulbar muscles. This pattern of ascending paralysis is fairly symmetric and develops gradually over a period of days or weeks. The child may develop an inability or refusal to walk and may later develop flaccid quadriplegia (3). However, 5-10% of children may initially have more weakness in the upper extremities, and some may have more proximal than distal muscle weakness (2).

Deep tendon reflexes are usually lost early in the course of the disease, although the proximal reflexes may still be present initially (2,3).

Sensory disturbance is also common and may occur in a glove-and-stocking distribution (8). Pain or paresthesias in the extremities, around the mouth, or on the back may be the presenting complaint in about 40% of patients. Pain in a band-like distribution may be present, and position and vibratory senses may be diminished (2). Muscle pain is also common initially in cases where there is an abrupt onset (3).

Approximately 50% of cases have bulbar involvement with the potential for respiratory insufficiency. Cranial nerve involvement may lead to facial weakness, difficulty swallowing, and problems with ocular motility. Dysphagia and facial weakness may herald respiratory failure requiring mechanical ventilation, a complication which occurs in 15-20% of patients (2,3). Autonomic dysfunction is uncommon but may present as arrhythmias and blood pressure instability including orthostatic hypotension (2).

The most common clinical variant of GBS is the Miller-Fisher syndrome with its triad of external ophthalmoplegia, ataxia, and areflexia. It is presumed to have a similar immune-mediated pathogenesis and pattern of recovery to classic GBS (1).

The cerebrospinal fluid (CSF) in affected patients is characterized by an elevated protein level without a WBC count elevation (i.e., normal cell counts)(3). This albuminocytologic dissociation is virtually diagnostic of GBS (1,3). About one-half of patients develop an elevated CSF protein during the first week of illness and most patients will show an elevation after the first several weeks of illness. The CSF protein peaks between 80 to 200 mg/dL. The CSF WBC count should not exceed 10 per cu-mm. A WBC count >50 per cu-mm or a predominance of segmented neutrophils should prompt the search for an alternative diagnosis such as meningitis, encephalitis, or transverse myelitis (2). The CSF glucose level should be normal and the culture negative.

Electrodiagnostic studies should be performed if there are atypical features, a rapid progression of illness, weakness that is severe or very mild, if there is delayed recovery, or if the diagnosis is unclear (2). Nerve conduction studies reveal slowing in both motor and sensory nerves (1,3). Electromyelography (EMG) may show acute denervation of muscle (2,3), but it does not show a primary myopathic process.

The differential diagnosis of GBS is large. A child with acute cerebellar ataxia may present with an acute gait disturbance and diminished tone. CSF pleocytosis is common and the protein level is usually normal (2). Spinal cord disease should be considered in a child presenting with acute lower extremity weakness, especially if there is a distinct spinal level of sensory loss, given the potential for irreversible cord injury by a compressive mass lesion (2). Transverse myelitis can present similarly, with back pain, a distinct sensory level, and rapidly progressive paralysis (2,8). Areflexia will be seen initially below the level of the lesion but hyperreflexia later develops. The CSF may show elevated protein, pleocytosis, and an increase in gamma globulin (8). MRI of the spinal cord should be obtained when the distinction is unclear. Poliomyelitis, now rare due to the routine immunization of children, can manifest as acute diffusely symmetric weakness, although it more commonly causes an asymmetric paralysis (2,8). Fever, meningeal signs, and muscle tenderness and spasm may also be present (8). It does not cause sensory disturbance and bowel and bladder function are almost never affected (2).

Myasthenia gravis may present with weakness which is often episodic and slowly progressive. There is almost always an associated ptosis or ophthalmoplegia, with preservation of sensation and reflexes (2). Botulism should be considered in a child less than 1 year of age presenting with weakness, a poor sucking reflex, weak cry, and constipation (8). Other common findings include swallowing difficulties and poorly responsive pupils. Older children will present with bulbar symptoms and weakness. CSF results will be normal and EMG reveals brief small abundant potentials which are diagnostic (8). Other causes of acute polyneuropathy include heavy metal intoxication, glue sniffing, tick paralysis, porphyria, SLE, and other collagen vascular diseases (2).

GBS is generally self-limited in children and full recovery can usually be expected (9). However, because of the potential for respiratory failure requiring mechanical ventilation, forced vital capacity, negative inspiratory force, and vital signs should be measured every 6 hours early in the course of illness to establish a trend. Rapidly decreasing vital capacity, dyspnea or fatigue, and deterioration of arterial blood gas values are indications for intubation and mechanical ventilation. Patients with dysphagia, shoulder weakness, or cardiovascular instability may also require assisted ventilation (2).

In the past, management of GBS was limited to supportive care, which included nursing and respiratory care, physical therapy, and maintenance of adequate nutrition. However, over the past two decades, treatment has evolved to include plasma exchange (plasmapheresis) and intravenous immunoglobulin (IVIG) (1). Both therapies have been shown to improve the rate of motor recovery (5). The patients most likely to benefit are those who present with moderate or severe progressive weakness, particularly children who are unable to walk, have a rapidly progressive course, or have bulbar paralysis and impending respiratory distress (1,2). Those with mild symptoms or with little progression typically have rapid and complete recovery, and do not require immunotherapy. Patients who present several weeks after the onset of illness are least likely to obtain benefit (1).

Plasma exchange is believed to work by removing antibodies against myelin and other soluble proteins from the circulation (1). The recommended protocol is 250 mL of plasma/kg divided into four to six sessions during the first week of illness, using albumin or fresh frozen plasma as replacement volume (2).

IVIG is generally preferred over plasmapheresis in children since IVIG does not require central venous access and does not decrease blood volume. IVIG has been safely administered in children as young as 2 years of age (1). The recommended dose is 2g/kg divided over two to four days (2).

Spontaneous recovery usually occurs 2-3 weeks after onset of disease, with most patients regaining full muscle strength and deep tendon reflexes. Residual weakness may remain in some patients. Improvement in strength usually occurs in reverse order, with bulbar muscle strength returning first and lower extremity strength returning last. Deep tendon reflexes are often the last function to recover (3).

The mortality rate is 2-5%, usually related to complications from ventilator-dependence or autonomic dysfunction (1). Factors associated with better outcomes include younger age at onset, milder clinical course, and slower progression of disease (9). With modern intensive care management and respiratory support, most children can be expected to have a full recovery from GBS.

Questions

1. What is the most commonly identified antecedent infection in Guillain Barre syndrome?

2. What is meant by albuminocytologic dissociation?

3. True/False: Improvement in strength occurs in the order in which it was affected.

4. Why is IVIG preferred over plasmapheresis in children?

5. When should a child with GBS be intubated?

References

1. Sater RA, Rostami A. Treatment of Guillain-Barre syndrome with intravenous immunoglobulin. Neurology 1998;51(6 Suppl 5):S9-15.

2. Evans OB, Vedanarayanan V. Guillain-Barre Syndrome. Pediatr Rev 1997;18(1):10-16.

3. Haslam RH. Chapter 567 - Guillain-Barre Syndrome. In: Behrman RE, Kliegman RM, Arvin AM (eds). Nelson Textbook of Pediatrics, fifteenth edition. 1996, Philadelphia: W.B. Saunders Company, pp. 1761-1762.

4. Ho T, Griffin J. Guillain-Barre Syndrome. Curr Opin Neurol 1999;12(4):389-394.

5. Hartung HP, Kieseier BC, Kiefer R. Progress in Guillain-Barre Syndrome. Curr Opin Neurol 2001;14(5):597-604.

6. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barre Syndrome. Neurology 2001;56(6):758-65.

7. Allos BM. Campylobacter jejuni infection as a cause of the Guillain-Barre syndrome. Infect Dis Clin North Am 1998;12(1):173-184.

8. Concepcion K. Index of Suspicion. Case 3. Diagnosis: Guillain-Barre Syndrome. Pediatr Rev 2001;22(1):22-31.

9. Graf WD, Katz JS, Eder DN, et al. Outcomes in severe pediatric Guillain-Barre syndrome after immunotherapy or supportive care. Neurology 1999;52(7):1494-1497.

Answers to questions

1. Campylobacter jejuni enteritis.

2. Lack of cellular response (normal WBC count) in the CSF despite an elevated protein level. In the clinical setting of progressive flaccid paralysis, this is diagnostic of Guillain-Barre syndrome.

3. False. Improvement in strength occurs in reverse order (bulbar muscle strength returns first and lower extremity strength returns last).

4. IVIG does not require central venous access and does not decrease blood volume.

5. A child should be intubated if she/he has a rapidly decreasing vital capacity, dyspnea, fatigue, or deterioration of arterial blood gases. Dysphagia, shoulder weakness, and cardiovascular instability are also indications that mechanical ventilation may be necessary.