The Guillain-Barré Syndrome

Asubacute onset of areflexic paralysis with recovery accompanied by acellular cerebrospinal fluid with an elevated protein was described in two soldiers in 1916 by the French neurologists Georges Guillain, Jean-Alexandre Barré, and Andre Strohl. The eponym Guillain- Barré Syndrome (GBS) covers a spectrum of presentations and pathologies.

Classification (see Figure 1)

Classification is according to clinical features; time course, predominance of sensory or motor involvement, and involvement of cranial nerves [1]. Nerve conduction usually distinguishes between demyelination and primary axonal degeneration, but the timing of nerve conduction studies is important – indices may be normal in the very early stages and when the illness is very advanced the nerves may be unexcitable. By definition the onset phase (the time from first to worst symptoms) in GBS is less than four weeks. Classification of variants based upon antibody profile rather than clinical features and neurophysiology has been proposed [2].

Epidemiology

Worldwide, the incidence of GBS is 0.6-4.0 per 100,000. Men are 1.5 times more likely to be affected. In the West, incidence increases with age, but in China the incidence of all forms across age groups is more uniform. Acute motor axonal neuropathy (AMAN) is the commonest form in China and shows a marked seasonal variation and paediatric predominance. [3]; elsewhere, cases are mostly sporadic but clusters and epidemics do occur, often in association with outbreaks of bacterial enteritis. Rabies vaccination (which contains brain material) is followed by GBS in about one in a thousand cases. There may be a very small increase (one per million over background) in risk of GBS after influenza vaccination. A small proportion of patients report symptom recurrence after routine immunisation but relapse is rare [4]. Evidence of preceding Campylobacter jejuni infection is found in about 25% of GBS cases. Cytomegalovirus and Epstein–Barr virus occur in about 10% of cases [5].

Pathogenesis [1]

Antibodies generated by the immune response to infection and directed against neural epitopes (the molecular mimicry hypothesis) may be the basis of axonal GBS and Miller-Fisher Syndrome (MFS). Strains of C jejuni which trigger GBS are more likely to possess lipo-oligosaccharide epitopes similar to gangliosides GM1, GD1a or GQ1b. These antigens seem to induce neuropathy-causing ganglioside antibodies in animal models. The titre of anti-GQ1b correlates with disease severity in MFS, and GQ1b ganglioside is concentrated in nerves supplying extra-ocular muscles.

The pathophysiology of the more common acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is less well understood. T cells appear to play an important part in inducing macrophage attack against Schwann cells or myelin. The correlation between neurophysiology and clinical and immunological markers is only approximate.

Presenting features and diagnosis

Although GBS is generally considered a straight-forward diagnosis by neurologists, multiple physician assessments prior to correct diagnosis are common [6]. Patients may have been screened and signs matured by the time they reach neurological evaluation. In a casualty case series, less than 50% of patients had weakness as their main complaint, with a minority presenting with the ‘typical’ symptoms of weakness and numbness. One fifth presented initially with only sensory complaints [6].

Whilst most patients presenting with an acute flaccid paralysis will have GBS, the differential is wide. GBS is a clincal diagnosis, and in practice, investigations are employed to exclude alternative possibilities. (See Figure 2)

Management

i) Supportive [7] (see Figure 3)

There are no studies specifically addressing thromboprophylaxis in GBS, however this is an important aspect of supportive care.

Dysautonomia – which includes paralytic ileus and bronchial dysfunction as well as instability of pulse and blood pressure – occurs in 20% of patients with GBS. Wide blood pressure swings may augur severe bradycardia, which can precede asystole.

These complications occur mostly in severely affected patients with generalised weakness and respiratory failure.

Neuromuscular respiratory insufficiency ensues in 17-30% of patients with GBS. Accumulating secretions secondary to bulbar and bronchial mucosal dysfunction may further compromise gas-exchange. Rapid progression and pattern of involvement signal risk of respiratory compromise [8], (see Figure 4).

Pain occurs in 90% of patients with GBS and at least six types of pain have been identified [9] (see Figure 3). Commonly, sensory symptoms exceed the signs. Neurogenic pain may arise from the loss of inhibition of the substantia gelatinosa by larger myelinated fibres and from small unmyelinated C fibres. Radicular pain and meningeal irritation may be secondary to inflammation of spinal nerve roots. Weakness of paraspinal muscles may result in mechanical back pain. Rate related cardiac ischaemic pain and discomfort from constipation and urinary retention could be mis-interpreted as radicular pains. Both carbamazepine and gabapentin are effective in reducing pain scores and requirement for opioid analgesia in GBS patients.

Gabapentin seems to have a quicker onset and be most effective [10]. Amitriptyline is also frequently used.

ii) Immunotherapy

When given to non-ambulant patients within four weeks of presentation, intra-venous immunoglobulin (IVIg) and plasma exchange (PE) have a similar efficacy both in terms of disability measured one month after treatment and long term outcome [11]. IVIg is usually used (0.4g/Kg body weight /day for five days) because of convenience despite the theoretical risk of transmission of virus or prion. IVIg may work by multiple mechanisms, including blocking Fc receptors, provision of anti-ideotypic antibodies, interference with complement activation and T-cell regulation.

Monoclonal antibodies show promise as future treatments. Eculizimab disrupts the complement cascade, protecting terminal motor nerves from anti-GQ1b antibody induced injury [12].

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Rehabilitation and outcome

Death or severe residual disability occurs in up to 17% of patients, and lesser degrees of disability and fatigue are common in the remainder; 35 to 45% report persisting adverse changes in their employment, domestic function and leisure activities [13]. Outlook is poorer in the elderly, in those with previous diarrhoea, rapid onset, severe deficit at nadir, initial axonal involvement, unexcitable motor nerves, and C jejuni or CMV infection [5]. One Chinese study with a large population of children showed no difference in recovery time between AMAN and AIDP, with a median time to regain the ability to walk with assistance being one month [3].

Although 40% of patients require inpatient rehabilitation, there is a paucity of systematic research of rehabilitation strategies in GBS. Medium term complications to be aware of in the rehabilitation setting include decubitus ulcers, peripheral nerve compression, hypercalcaemia, and disturbed central respiratory drive secondary to persistent ventilatory compromise [14]. Decreased range of movement in joints may be caused by contractures, muscle injury, pain, thrombosis, fractures and heterotopic ossification (of which elevated alkaline phosphatase is a useful indicator) [15]. Patients should be advised that over-exercise may lead to para- doxical weakening.

Future directions

The clinical phenotype of GBS is likely to be due not only to the immunogenic components of the infecting organism, but also the host immune response and distribution of epitopes. Examination of the immune response in GBS variants will allow the development of more targeted therapies such as complement inhibition, anti-cytokine therapy and specific anti-body adsorption [1].

References

1. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet 2005;366(9497):1653-66.

2. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;70(1):50-5.

3. Ho TW, Li CY, Cornblath DR, Gao CY, Asbury AK, Griffin JW, et al. Patterns of recovery in the Guillain-Barré syndromes. Neurology 1997;48(3):695-700.

4. Pritchard J, Mukherjee R, Hughes RA. Risk of relapse of Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation. J Neurol Neurosurg Psychiatry 2002;73(3):348-9.

5. Hadden RD, Karch H, Hartung HP, Zielasek J, Weissbrich B, Schubert J, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology 2001;56(6):758-65.

6. McGillicuddy DC, Walker O, Shapiro NI, Edlow JA. Guillain-Barré syndrome in the emergency department. Ann Emerg Med 2006;47(4):390-3.

7. Hughes RA, Wijdicks EF, Benson E, Cornblath DR, Hahn AF, Meythaler JM, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol 2005;62(8):1194-8.

8. Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating mechanical ventilation in Guillain-Barré syndrome. Arch Neurol 2001;58(6):893-8.

9. Pentland B, Donald SM. Pain in the Guillain-Barré syndrome: a clinical review. Pain 1994;59(2):159-64.

10. Pandey CK, Raza M, Tripathi M, Navkar DV, Kumar A, Singh UK. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg 2005;101(1):220-5.

11. Hughes RA, Swan AV, Raphael JC, Annane D, van Koningsveld R, van Doorn PA. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain 2007;130(Pt 9):2245-57.

12. Halstead SK, Zitman FM, Humphreys PD, Greenshields K, Verschuuren JJ, Jacobs BC, et al. Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model. Brain 2008;131(Pt 5):1197-208.

13. Bernsen RA, de Jager AE, Schmitz PI, van der Meche FG. Long-term impact on work and private life after Guillain-Barré syndrome. J Neurol Sci 2002;201(1-2):13-17.

14. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil 1997;78(8):872-9.

15. Zeilig G, Weingarden HP, Levy R, Peer I, Ohry A, Blumen N. Heterotopic ossification in Guillain-Barré syndrome: incidence and effects on functional outcome with long-term follow-up. Arch Phys Med Rehabil 2006;87(1):92-5.