GUILLAIN BARRE SYNDROME

I. OBJECTIVES
A. To present a case management on Guillain-Barre Syndrome which was seen at the Philippine Children’s Medical Center
B. Provide Differential Diagnoses to GBS
C. Discuss the Epidemiology, Pathophysiology and Prognosis of GBS
D. Discuss Diagnostic and Treatment Modalities for GBS


II. SALIENT FEATURES
A. HISTORY
We are presented with a 3 year old male who initially had an upper respiratory infection of which two weeks later a progressive ascending weakness of the extremities was noted. No pain, swelling nor erythema was noted. He had no history of trauma, fall, seizure, weight loss and gastro-intestinal losses. There is no similar illness in the family. His birth and maternal history is uneventful. Prior to the illness, his growth and development is at par with age. Fever, dyspnea, dysphagia, urinary and bowel movement changes was not observed. 

B. PHYSICAL AND NEUROLOGIC EXAM
The patient came in wheelchair-borne, not in respiratory distress. He had normal vital signs and normal nutritional status. The pupils were 3-4mm EBRTL . The tympanic membrane was intact with no discharge. He had clear breath sounds and the cardiac rhythm is regular. The vertebral column and the extremities had no gross deformities. However there was limited active motion of the lower and upper extremities, unable to move against resistance. Sensation seem intact with withdrawal to pain. He occasionally follows simple commands. No cranial nerve palsy was noted. No nystagmus, fasciculations nor nuchal rigidity was observed. He had hypotonia and areflexia of the lower extremities. His sensory function were intact. He had no muscular atrophy. 

II. DIFFERENTIAL DIAGNOSES BASED ON HISTORY AND PHYSICAL EXAMINATION
A  . TRAUMA (Spinal Cord Trauma)
Trauma should always be considered clinically as a casue of weakness. However, there is no history of trauma or fall for the patient. There are no deformities or lesions noted on the vertebral area and extremities. The disease process is also acute in spinal cord trauma.

B. METABOLIC (Hypokalemic Periodic Paralysis)
This presents with weakness occurring in infancy until 10 years old. However, gradual recovery is usually observed after a few minutes or hours. The patient’s weakness persisted for more than 2 weeks. The disease is inherited as an autosomal dominant trait. For our patient, there is no similar illness in the family. If electrolyte imbalance is considered, the patient had no gastro-intestinal losses. Furthermore, laboratory results from a local clinic revealed normal electrolyte levels. 

C. AUTOIMMUNE (Myasthenia Gravis) This is an autosomal recessive trait presenting with rapid fatigability, initially presenting with ptosis, dysphagia and facial weakness which are not seen in the patient. The weakness is descending in progression which is in contrast to that of the patient.

D. INFECTIOUS (Botulism) is also ruled out since symmetrical paralysis in Botulism is descending. It initially presents with cranial nerve dysfunction and autonomic dysfunction (dry mouth and trouble focusing the eyes).

E. INFECTIOUS (Poliomyelitis) 1% of those infected individuals develop paralysis. The progression of the paralysis is from the proximal to the distal and usually asymmetrical. Full paralysis is observed in 24 to 48 hours. Reduced deep tendon reflexes are also observed.


F. ACUTE TRANSVERSE MYELITIS or SPINAL CORD COMPRESSION can present with symmetrical lower limb hypotonia. However, this is usually associated with bowel or bladder dysfunction.

E. GUILLAIN-BARRE SYNDROME is the primary consideration for the patient. He had a respiratory infection 2 weeks prior to the weakness. In GBS, 50-70% present with weakness after a gastrointestinal or respiratory infection. It is characterized by ascending symmetrical paralysis progressing within 24 hours to 4 weeks, distally to proximally, without fever. On physical examination decreased motor strength is noted with reduced DTRs. These signs and symptoms were noted in the patient consistent with GBS.


VI. DIAGNOSTIC CONFIRMATION
The diagnostic criteria for GBS developed by Asbur and Cornblath correspond to those of Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP). The other variants of GBS will be discussed further.

The criteria for AIDP require the following: 1.) Progressive, relatively symmetrical weakness of two or more limbs due to neuropathy, 2.) Areflexia, 3.) Disorder course < 4 weeks 4.) Exclusion of other causes.

The above criteria were met by the patient’s disease process. Other causes were further excluded wherein the serum electrolyte done in our institution confirmed that there was no electrolyte imbalance. The CBC w/ PC also suggests a non-infectious disease entity. The CRP, done outside, although positive is nonspecific for an inflammatory process.

The supportive criteria for GBS are as follows: 1.) relatively symmetric weakness accompanied by numbness and/or tingling, 2.) mild sensory involvement, 3.) facial nerve or other cranial nerve involvement, 4.) absence of fever, 5.) typical CSF findings obtained from lumbar puncture, 6.) electrophysiologic evidence of demyelination from electromyogram.   

Numbness or tingling sensation and sensory involvement were difficult to elicit from a 3 year old. He had no fever during the onset and progression of weakness. The CSF findings of albumino-cytological dissociation, an elevated protein level without an accompanying increased cell count pleocytosis and the EMG-NCV result of moderate to severe sensory and motor denervation, further confirmed the diagnosis. Imaging studies (MRI and CT-scan) usually reveal normal findings in GBS.


V. EPIDEMIOLOGY and PATHOPHYSIOLOGY OF GBS
A. DESCRIPTION
The syndrome was first described by Landry in 1857 and by Guillain, Barre and Strohl in 1916.
Landry-Guillain-Barre-Strol Syndrome, commonly called GBS, is a disorder of peripheral nerves, characterized by subacute (days to weeks) progression of motor-sensory dysfunction but not associated with meningismus or fever.

B. EPIDEMIOLOGY
The annual incidence globally is 1-2 per 100,000 population, however, there are differences by region and ethnicity. There is no apparent genetic susceptibility to developing GBS. It is an important cause of weakness among children, but the incidence increases with age. The reported youngest recorded patient is four years old and the oldest patient is 95 years old. Our patient is however 3 years old. GBS affects both males and females, but males are about 1.5 times more likely to be affected than females.

From the Philippine Pediatric Society Registry, 168 GBS patients have been reported from a total of 992, 341 cases. From the Philippine Children’s Medical Center, 108 patients have been seen from 1995 to 2010.

D. VARIANTS OF GBS
1. Acute inflammatory demyelinating  polyneuropathy (AIDP) is the most common form of GBS, and the term is often used synonymously with GBS. It is caused by an auto-immune response directed against Schwann cell membranes. This type corresponds to that of the patient.

2. Miller Fisher syndrome (MFS) is a rare variant of GBS and manifests as a descending paralysis, proceeding in the reverse order of the more common form of GBS. It usually affects the eye muscles first and presents with the triad of ophthalmoplegia, ataxia, and areflexia .

3. Acute motor axonal neuropathy (AMAN),aka Chinese Paralytic Syndrome, attacks motor nodes of Ranvier and is prevalent in China and Mexico. It is likely due to an auto-immune response directed against the axoplasm of peripheral nerves.

4. Acute motor sensory axonal neuropathy (AMSAN) is similar to AMAN but also affects sensory nerves with severe axonal damage. Recovery is slow and often incomplete.

5. Acute panautonomic neuropathy is the rarest variant of GBS, sometimes accompanied by encephalopathy. It is associated with a high mortality rate, due to cardiovascular involvement, and associated dysrhythmias

6. Bickerstaff’s brainstem encephalitis (BBE), is a further variant of Guillain–Barré syndrome. It is characterized by acute onset of ophthalmoplegia, ataxia, disturbance of consciousness, hyperreflexia or Babinski’s sign.

E. PATHOPHYSIOLOGY
The exact cause of GBS is not known. However, it is thought to be an autoimmune disease process in both the demyelinating and axonal forms of the disease. The discovery of antiganglioside antibodies is due to the relationship of infection and autoimmune properties. The presence of antibodies and activated T-cells that react against the peripheral myelin gives rise to the theory that GBS is a type of autoimmune pathology. Macrophages invade the Schwann cell, strip myelin from the axon, and sometimes degeneration of the axon occurs, which may be secondary to an autoimmune attack on the axon or myelin.

Autoreactive T-cells are thought to be “activated” and mediate this response by initiating the cascade to inflammation.  The antiganglioside antibodies appear to cross-react with particular antigens found in the lipopolysaccharide of certain infective agents known to be GBS triggers.

Current literature suggests that molecular mimicry is a likely mechanism of the autoimmune reaction. Molecular mimicry is when the immune system responds to specific antigens (though to be present du to the antecedent infection) or the actual organism implicated in the preceding infection and causes the immune system to attack similar epitopes in the peripheral nervous system.

VI. TREATMENT MODALITIES, PROGNOSIS AND AREAS OF RESEARCH
TREATMENT MODALITIES
A Cochrane Database review of selected trials showed that plasma exchange (PE) or treatment with intravenous immunoglobulin (IVIG) have equivalent efficacy in hastening recovery from GBS in patients when started within the first 2 weeks after onset of weakness. The subcommittee of the American Academy of Neurology recently gave the following recommendations for the treatment of GBS: 1.) Corticosteroids are not recommended in the treatment of GBS. 2.) Plasma exchange or IVIG are treatment options for treating children with severe GBS.

The commonly accepted benefits of IVIG and Plasma Exchange cannot be automatically extrapolated to the paediatric population. Both IVIG and PE show similar reduced recovery time or days of hospitalization. IVIG has been shown further to reduce the need for mechanical ventilator and mortality.

IVIG and PE are commonly used immunotherapies in GBS. Though expensive, IVIG is simple to administer, whether over five days or a single day. For this patient, IVIG was chosen as the form of treatment.The practicalities and expense of administering plasmapheresis makes IVIG the immunotherapy of choice.

In a case report, recovery was shown with supportive care alone and in another case report; IVIG was commenced when no clinical improvement was seen with supportive care alone. Recovery usually occurs spontaneously even without specific intervention. It is noted that GBS in children runs a more benign course than in adults. However, the administration of IVIG to the patient reduced his hospital stay of which he already contracted health care associated infection. In addition, the actue phase of significant disability and disruption to the child’s life and development can be extremely traumatic for both the child and parents. IVIG given to the child shorten the course of the illness which allowed him to return to normal life sooner. It also reduced the risk of complications of immobility.    

ICU REFERRAL
Preparing an intensive-care facility is essential in GBS, hence the patient was referred to the ICU. Indications for ICU referrals are as follows: 1.) Rapid progression of motor weakness involving respiratory muscles, ventilatory insufficiency, pneumonia, severe bulbar weakness, autonomic instability, arrhythmia, or bradycardia. Complication related to therapy that requires intensive care includes fluid overload or anaphylaxis from IV immunoglobulin administration or hemodynamic instability related to plasmapheresis.

PULMONARY MEDICINE REFERRAL
He was also referred to Pulmonary Medicine since respiratory failure is of greatest concern when paralysis of the diaphragm occurs. Respiratory failure requiring ventilation occurs in about 25% of patients with GBS. Early intubation should be considered in any patient with a vital capacity (VC) <20 ml/kg, a negative inspiratory force (NIF) <-25 cmH2O, more than 30% decrease in either Vital Capacity or Negative Inspiratory Force within 24 hours, or autonomic instability.
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REHABILITATION MEDICINE REFERRAL

General care should include regular physiotherapy, with provision of splints to prevent joint contractures, prevention of deep vein thrombosis, keeping a conscious patient comfortable by careful positioning and repositioning, and early enteral nutrition to prevent gastric mucosal atrophy and to reduce the incidence of nosocomial infection. Patients sometimes need psychological counseling to help them adapt to the motor dysfunction.

PROGNOSIS
Recovery usually starts after the fourth week from the onset of the disorder. Approximately 80% of patients have a complete recovery within a few months to a year, although minor findings may persist, such as areflexia. About 5–10% recover with severe disability, with most of such cases involving severe proximal motor and sensory axonal damage with inability of axonal regeneration.  
Persistent Fatigue has been noted in 67% of patients with GBS. 

The estimated mortality in childhood GBS is <5%.  Causes of death due to GBS include respiratory failure and cardiac arrest secondary to dysautonomia. Death may occur because of complications associated with immobility and mechanical ventilation, such as pneumonia, sepsis, acute respiratory distress syndrome, and thromboembolic events.

AREAS OF RESEARCH
The exact causes of GBS are not known. The nature of long-term complaints like fatigue and endurance intolerance is unknown. The exact role of combined treatment remains to be established. There is also a need to identify patients who are at greater risk of an adverse outcome and to determine responses to treatment per subgroup. Some vaccines have also been implicated to cause GBS. 

REFERENCES

Khan, Fary. Rehabilitation in Guillain Barre Syndrome. Clinical Update. Australian Family Physician. Royal Melbourne Hospital. Orthopedic and Musculoskeletal Unit. Vol 33. No 12. December 2004.

Intravenously Administered Immunoglobulin in the Treatment of Childhood Guillain-Barré Syndrome: A Randomized Trial . Rudolf Korinthenberg, MD, Joachim Schessl, MD, Janbernd Kirschner, MD, Jürgen Schulte Mönting, PhD. PEDIATRICS Vol. 116 No. 1 July 2005, pp. 8-14 (doi:10.1542/peds.2004-1324)


Intravenously Administered Immunoglobulin in the Treatment of Childhood Guillain-Barré Syndrome: A Randomized Trial . Rudolf Korinthenberg, MD, Joachim Schessl, MD, Janbernd Kirschner, MD, Jürgen Schulte Mönting, PhD. PEDIATRICS Vol. 116 No. 1 July 2005, pp. 8-14 (doi:10.1542/peds.2004-1324)

Hughes RAC, Raphael JC, Swan AV, van Doorn PA. Intravenous Immunoglobulin for Guillain Barre Syndrome (Cochrane Review). In: The Cochrane Library, Isse 1, 2004. Chichester. John Wiley and Sons, Ltd.

Shanbag P, Amirtharaj C, Pathak A. Intravenous Imunoblobulins in Severe Guillain-Barre Syndrome in Childhood. Indian J Pediatrics 2003; 70 (7): 541-3

Sharief, M.K. IV immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barré syndrome. Neurology. Department of Neurology. Guys Hospital, England. January 2000.

French Cooperative Group. Plasma Exchange in Guillain Barre Syndrome: Role of Replace of Fluids. Ann Neural 1987;22:753-761

American Association of Neurology. Parameters of Treating Guillain Barre Syndrome. 2004.

Guillain Barre Syndrome Steroid Group. Double blind Trial of Intravenous Methylprednisolone in Guillain Barre Syndrome. Lancet 1993; 341:586-590.

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