Guillain Barre Syndrome (GBS) is an acute immune-mediated inflammatory neuropathy. It is the most common cause of acute flaccid paralysis worldwide. Recent decades have seen progress in understanding the epidemiology, pathogenesis, and prognosis of GBS. The pathogenesis involves molecular mimicry between gangliosides and antigens from preceding infections like Campylobacter jejuni, leading to anti-ganglioside antibody production and complement-mediated nerve damage. Different GBS subtypes are associated with different antiganglioside antibodies and clinical courses.

1. Guillain Barre Syndrome: Current State of Knowledge

2. Introduction GBS is the most frequent cause of acute flaccid paralysis worldwide. It is also among the most dramatic neurologic emergencies. The last decade has been marked by exciting progress in epidemiological and laboratory research in GBS. Animal models have revealed insight into the pathogenesis of GBS and the potential for testing effective drugs. New prognostic models have been unveiled.

3. Epidemiology Sporadic disorder with a stable incidence of 1.2 to 2.3 cases/100,000 in N. America and Europe. Hughes RA et al. Lancet 2005; 366: 1653–66. Reported worldwide, with M: F = 1.5 to 2.0 Lehmann HC et al. J Peripher Nerv Syst 2007; 12: 285. AIDP accounts for 90-95% of cases in the West. In contrast, in China, AMAN comprises 70% of cases. Hughes RA et al. Lancet 2005; 366: 1653–66. In western countries adults are more frequently affected than children. Most studies have found that the incidence increases linearly with age. Alshekhlee A et al. Neurology 2008; 70: 1608–13

4. Definition of GB Syndrome Heterogenous group of disorders characterized by: Acute Monophasic Idiopathic Immune mediated Inflammatory Polyneuropathy Polyradiculopathy Cytoalbumin dissociation

5. Levin KH. The Neurologist 2004;10: 61–74) Currently recognized forms of GB Syndrome AMSAN AMAN Axonal forms Miller Fischer syndrome Pure autonomic form Pure sensory form Facial diplegia with paresthesia Parapretic Pharyngo-cervico-brachial Regional presentations of AIDP Preserved reflexes Prominent sensory loss Pure motor Asymmetric Atypical forms of AIDP AIDP

6. Spectrum of Guillain-Barre’ Syndrome Retrospective study of Demographic, Clinical and Electrophysiological Profile. 478 patients studied between 1985-94. Balamurugan et al. 2001. unpublished ARV 1 Bifacial 2 URTI 8 Ataxic 14 APCBN 2 Multiple events 12 MFS 9 GI symptoms 8 Recurrent GBS 18 Fever 28 Typical 433 Antecedent illness in 57% Subtypes

7. Pathogenesis

8. Antecedent infections 60-70% of GBS cases occur 1–3 weeks after an acute infection, usually respiratory or gastrointestinal. 20–30% of cases in North America, Europe, and Australia are preceded by Campylobacter jejuni infection. C. jejuni has also been implicated in summer outbreaks of AMAN among children and young adults in rural China. HS/0:19 serotype of C. jejuni is common in patients with GBS in northern Chinese, Ireland and USA. Other infections: CMV, EBV, Mycoplasma, H influenzae. Hadden RD et al. Neurology 2001; 56: 758–65.

9. Other Antecedent factors Haber P et al. JAMA 2004; 292: 2478–81. Souayah N et al. Vaccine 2007; 25: 5253–55. Pritchard J et al. J Neurol Neurosurg Psychiatry 2002; 73: 348–49. In a patient with h/o GB syndrome any future vaccination should be done with due deligence, for fear of relapse. Other physical stress SLE Surgery HIV seropositivity Thrombolysis Lymphoma Vaccines: Influenza, hepatitis, rabies (old type), tetanus

10. B cell response It was initially thought that AIDP was primarily a T cell–mediated disorder. Current evidence suggests the pivotal role of autoantibodies against nonprotein determinants. All GBS results from immune responses to nonself antigens (infectious agents, vaccines) that misdirect to host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism. Neural targets: glycoconjugates, specifically gangliosides.

11. Gangliosides Complex glycosphingolipids that contain one or more sialic acid residues. These gangliosides are unique to peripheral nerves and are organised in specialised functional microdomains called “lipid rafts”. Participate in cell-cell interactions, cell membrane integrity, modulation of receptors, and growth regulation. They are exposed on the cell surface, rendering them susceptible to an antibody-mediated attack. Makowska A et al. J Neurol Neurosurg Psychiatry 2008; 79: 664–71. Kwa MS et al. Brain 2003; 126: 361–375.

13. Molecular mimicry C jejuni isolates express LOS (lipo-oligosaccharides) that mimic the carbohydrates of gangliosides. Godschalk PC et al. Infect Immun 2007; 75: 1245–54. Campylobacter CST-II is essential for biosynthesis of ganglioside LOS. Hye JB et al. Neurology 2007: 68:1633–1634. A gene cluster was identified that enables some C jejuni isolates to synthesize these structures. Taboada EN et al. BMC Genomics 2007: 8: 359. The type of ganglioside mimicry determines the specificity of the antibodies and the associated GBS variant.

14. Molecular mimicry Antibodies are usually cross-reactive, and recognise LOS as well as gangliosides or ganglioside complexes. Kuijf ML et al. J Neuroimmunol 2007: 188:69–73. The fine specificity and the ganglioside orientation and exposure contribute to recognition by anti-ganglioside antibodies. This may explain at least partially the differences in clinical manifestations. Lopez PH et al. Brain 2008: 131:1926–1939. Similar mechanisms have also been identified after some types of preceding infection, including H influenzae. Jacobs BC et al. J Neuroimmunol 2008:194:181–190.

16. Anti-ganglioside antibodies Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in those preceded by C. jejuni infection. Willison HJ et al. Brain 2002; 125: 2591–625. Some antibodies might bind to mixtures or complexes of different gangliosides instead of individual gangliosides. Kuijf ML et al. J Neuroimmunol 2007; 188: 69–73. However, the pathological significance of some of these antibodies is yet to be established. Antibodies to other glycolipids, peripheral nerve proteins have also been found in patients with GBS.

17. Anti-Glycolipid Antibodies in GBS Willison HJ et al. J Peripher Nerv Syst 2005; 10: 94–112. Kuijf ML et al. J Neuroimmunol 2007: 188:69–73. These antibodies are specific to defined GBS subgroups. IgG (polyclonal) GT1a (? Most) APCBN IgG (polyclonal) GQ1b (>90%) GT1b MFS IgG (polyclonal) GD1a, GM1, GM1b, GalNAc–GD1a (<50% for any) AMAN, AMSAN IgG (polyclonal) No clear patterns, GM1: most common AIDP Usual isotype Antibody target Subtype

18. Molecular mimicry Antibodies against GD1a/GD1b or GD1b/GT1b are related to severe GBS. Kuijf ML et al. J Neuroimmunol 2007: 188:69–73. Two distinct patterns of cross-reactive antibodies against motor gangliosides are related to different outcomes. IgG1 antibodies against motor gangliosides was associated with diarrhea, anti-Campylobacter LOS antibodies, and a poor prognosis. IgG1 and IgG3 antibodies was related to URTI, anti-H. influenzae LOS antibodies, and a better outcome. Jacobs BC et al. J Neuroimmunol 2008:194:181–190.

19. Complement activation Post-mortem studies have shown that local complement activation occurs at the site of nerve damage (axolemma in AMAN, Schwann cell membrane in AIDP). Hafer-Macko C et al. Ann Neurol 1996; 40: 635–44. A rabbit model immunized with GM1 ganglioside showed that anti-GM1 antibodies caused complement-mediated damage of sodium channels at the nodes of Ranvier. Susuki K et al. Glia 2007: 55:746–757. The neurotoxic effects of these antibodies were inhibited by immunoglobulins and the complement inhibitor Eculizumab.

22. Complement activation A mouse model of GBS showed that some antiganglioside antibodies are highly toxic for peripheral nerves. In this model, IV Eculizumab (which blocks formation of C5a and C5b-9 (MAC) prevented respiratory paralysis and the functional and morphological hallmarks of terminal motor neuropathy. Halstead SK et al. Brain 2008: 131:1197–1208. It was concluded that Eculizumab protects against complement-mediated damage in murine MFS, and has therapeutic potential. Lehmann HC et al. Brain 2008: 131:1168–1170.

23. Host Factors Less than 1 in 1000 C jejuni infected patients develop GBS. No association between HLA class II alleles and GBS. Geleijns K et al. Neurology 2005; 64: 44–49. Single-nucleotide polymorphisms (SNPs) in other immune-response genes showed no consistent association with susceptibility to GBS. Geleijns K et al. J Neuroimmunol 2004; 150: 132–38. Geleijns K et al. J Neuroimmunol 2005; 161: 183–89. There is association between disease severity or outcome and SNPs in genes coding for mannose-binding lectin, Fc gamma receptor III, MMP 9, and TNF α. Geleijns K et al. J Neuroimmunol 2007; 190: 127–30. van Sorge NM et al. J Neuroimmunol 2005; 162: 157–64.

25. AIDP AMAN Other axonal forms Schwann cell membrane Preterminal motor endings Axonal membrane Demyelination, Conduction block, Sec Axonal degen Degeneration of motor endings Axonal degeneration Slow Regeneration Rapid Regeneration Remyelination Rapid recovery Rapid recovery Slow Recovery

26. Relation between infections, antiganglioside antibodies, and clinical course of GBS

27. Apo E genotypes and GBS Apolipoprotein E is involved in axonal regeneration and remyelination. It influences outcome after a variety of central nervous system disorders like MS, diabetes, HIV infection. Apolipoprotein E gene polymorphisms could affect recovery from Guillain-Barré syndrome. A study of 91 patients correlated APOE genotypes with clinical presentation. APOE genotype did not influence susceptibility to Guillain-Barré syndrome or recovery from it. J Pritchard et al. J Neurol Neurosurg Psychiatry 2003; 74:971–973.

28. Pathology

29. AIDP: Inflammation: Lymphocytes appear early, and can persist long after active disease ceases. Lymphocytes in the endoneurium, either in perivenular cuffs or scattered is more specific. Infiltration may be sparse or dense, and usually concentrated in the areas of demyelination. Demyelination: Axonal degeneration: variable degree.

30. AIDP: Demyelination Schwann cells separate from its myelin sheath. They divide, leaving the basal lamina of the fibre to produce a circle of daughter schwann cells around the demyelinated fibres. As myelin is cleared, these cells reenter the basal lamina, ensheath small segments of the fibre and begin production of several short internodes within the previous internode. This is the pathologic hallmark of earlier demyelination with remyelination.

31. Clinical Features

32. Clinical Features Initial manifestations are often sensory. Prickling paresthesias, cutaneous sensory loss, pain may precede weakness by a few hours to more than a week. Flaccid, ascending, weakness, involving proximal and distal muscles. Deep tendon reflexes attenuate or disappear within the first few days of onset. Sensory findings and weakness are usually symmetrical. Facial (50-70% of pts) and bulbar involvement is common. Bladder involvement is late and usually mild.

33. Autonomic Involvement Autonomic dysfunction is an important but frequently overlooked feature Occurs in 65% of patients. It may occur even in patients with mild weakness. These features require close monitoring and management and can be fatal. May contribute to mortality. SIADH is a well known complication of GBS and can cause symptomatic hyponatremia.

34. Evaluation of sleep disorders in GB Syndrome Prospective study during 2008-09. Cohort of 60 patients of 16-65 yr age (mean= 32.75 +/- 12.9). Majority had demyelinating type. Sleep disturbances during hospital stay assessed by Richards score: 31 (51.66%) patients had poor sleep. Factors significantly associated with poor sleep: pain, paraesthesias, anxiety and immobility. PSG: increased stage 1 and 2 sleep, reduced stage 4 and REM sleep, absent REM sleep in 7 patients, decreased sleep efficiency <85% in 28 patients. Karkare K et al. 2010 (unpublished)

35. Natural history Fifty percent of patients progress to their nadir within 2 weeks, 75% within 3 weeks, and more than 90% within 4 weeks of the onset of symptoms. van der Meché FG et al. Eur Neurol 2001; 45: 133–39. In most patients progression of all manifestations ceases at the same time. Rarely, patients can show improvement in some aspects and decline in other aspects. The rate of improvement is variable.

36. Diagnosis

37. Electrodiagnosis Electrodiagnostic features are mild or absent in the early stages of GBS and lag behind the clinical evolution. Essential to subtype various forms of GBS. Ho TW et al. Neurology 1997; 48: 695–700. Demyelination: prolonged distal latencies, conduction velocity slowing, conduction block, and temporal dispersion of CMAPs are the usual features. Primary axonal pathology: reduced amplitude (CMAP/ SNAP) without conduction slowing or prolongation of distal latencies.

38. Electrodiagnostic criteria

39. CSF Analysis Eevated CSF protein [100–1000 mg/dL] without pleocytosis (<10 cells/mm³) is a distinctive finding. CSF is often normal in the first week; protein is elevated in 90% by the end of first week. van der Meché FG et al. Eur Neurol 2001; 45: 133–39. In a series of patients with MFS, 25% of patients had raised CSF protein in Week 1 and 84% in Week 3. Nishimoto Y et al. J Neuroimmunol 2004; 148: 200–05. CSF protein in patients with MFS and APBCN are generally lower and most often normal. No association between protein levels and outcome.

40. CSF analysis Amino acid profile is abnormal indicating breach in the blood- brain barrier. Immunoglobulins: IgG, M, A are elevated in the CSF but not serum, s/o intrathecal synthesis. Oligoclonal bands: seen in 10-30% of patients. Heat shock proteins: Significantly higher IgG antibody titers against HSP27, HSP60, HSP70 and HSP90 family were found in CSF. Serum IgG antibodies against each HSP showed no difference between GB Syndrome patients and normal controls. Yoenekura et al. J Neuroimmunol. 2000; 156 : 204—209.

41. CSF analysis CSF neuron specific enolase, S100b: higher levels correlate with longer duration of disease. Chemokines levels are elevated in the acute phase. Press R et al. J Neuroimmunol 2001; 112 : 129—138. Complement activation products: C3a, C5a are high. Hypocretin: Low levels occur indicating CNS involvement. Nishino S et al. Neurology. 2003; 23; 61: 823-825. Haptoglobin, α1-antitrypsin, apolipoprotein, and neurofilament levels are increased in CSF. Yang YR et al. Cell Mol Neurobiol 2008; 28: 737–44. Pathogenic significance and diagnostic utility is unclear.

42. Diagnostic Criteria for GB Syndrome ºExcluding M. Fisher and other variant syndromes Modified from AK Asbury, DR Cornblath: Ann Neurol 1990; 27: S21, 1990. 6. Electrophysiologic evidence of demyelination 3. Facial or other cranial nerve involvement 5. Typical CSF profile (cytoalbumin dissociation) 2. Mild sensory involvement 4. Absence of fever 1. Relatively symmetrical weakness Supportive 4. Exclusion of other causes [e.g., vasculitis, toxins, botulism, diphtheria, porphyria, localized spinal cord or cauda equina syndrome] 3. Disease course < 4 weeks 2. Areflexia 1. Progressive weakness of 2 or more limbs due to neuropathyº Required

43. Variants of GB Syndrome

44. AMAN Frequently described from China, Japan, Mexico, India. Strongly associated with C. jejuni infection. Exclusively motor syndrome with pattern of weakness similar to AIDP. Sensory findings are absent, however, some children show resistance to neck flexion. DTRs are preserved until severe weakness supervenes, reflecting lack of afferent involvement. Respiratory insufficiency occurs with less frequency compared to AIDP.

45. AMAN: Diagnosis Electrophysiology: Reduced CMAP amplitudes. Preserved SNAP amplitudes. Early evidence of denervation on EMG. No evidence of demyelination. CSF Analysis: Similar to AIDP Prognosis: Good prognosis, similar to AIDP

46. AMSAN Characterised by severe prolonged weakness. Axonal pattern of motor and sensory involvement is seen in NCS. Response to immunotherapy is poor. Prognosis: comparatively poor.

47. Miller Fischer Syndrome This disorder accounts for about 5% of all GBS cases. Classic triad of ophthalmoplegia, areflexia, and ataxia. Benign variant; most do not need immunotherapy. MFS may present with only fragments of the classic picture, or may have additional features that overlap with findings in AIDP. These include unilateral or bilateral facial weakness, dysarthria, dysphagia, abnormal pupillary reactivity, and extremity weakness.

48. Miller Fischer Syndrome The exact pathogenesis is unclear Electrodiagnostic testing may also be normal. The most likely finding is patchy loss of SNAP amplitudes in the arm and leg, without significant abnormalities along motor nerve trunks. Other abnormalities have included loss of facial motor CMAP amplitudes and nonspecific abnormalities of the blink reflexes.

49. Anti-GQ1b in MFS Antibodies to the GQ1b ganglioside are present in the serum of about 95% of patients with the Fisher syndrome. Titers of IgG are highest early in the course of MFS. The GQ1b antigen been found on oculomotor nerves, sensory nerves, DRG, cerebellar neurons, and on the cell membranes of C. jejuni. Anti-GQ1b antibodies are not found in other forms of GBS unless there is extraocular motor nerve involvement.

50. Acute small fibre sensory neuropathy Characterised by: acute onset numbness, and burning dysaesthesia normal muscle strength symmetrical glove and stocking sensory loss for pain and temperature normal proprioception and vibration senses normal or brisk tendon reflexes. Selective involvement of small calibre sensory fibres is postulated. Favourable prognosis. Seneviratne U et al. J Neurol Neurosurg Psychiatry 2002; 72:540-2.

51. Dermatomyositis Hypermagnesemia Muscle abnormalities Porphyria Critical illness myopathy Hypokalemia Polymyositis Hypophosphatemia Toxic, drug-induced neuropathy Vitamin B1 deficiency Acute rhabdomyolysis Carcinomatous meningitis SIDP/CIDP Metabolic causes Other polyneuropathies Tick paralysis Organophosphate poisoning Paralytic rabies Botulism ECHO 70 virus Myasthenia Gravis West nile virus Neuromuscular disorders Coxsackie virus Acute myelopathies Poliomyelitis Acute brainstem syndromes Viral infections Differential diagnosis of GB Syndrome.

52. Recurrent GBS Definition: 2 or more episodes of GBS (NINCDS criteria) with a minimum time between episodes of 2 months (full recovery in between) or 4 months (only partial recovery). The clinical symptoms remain similar, but severity of the symptoms and the nature of the preceding infections vary. Patients are younger (<30 yrs) and more often had MFS. Genetic or immunological host factors may play an important role, since these patients can develop similar symptoms after different preceding infections. K Kuitwaard et al. J Neurol Neurosurg Psychiatry 2009;80:56–59.

53. Kuitwaard et al. J Neurol Neurosurg Psychiatry 2009; 80: 56-59

54. GB syndrome in children GB syndrome does not show any childhood predilection. Both AMAN and AIDP are frequent in children, with AMAN being the dominant type in most studies. C. jejuni infection was commonly associated with both AMAN and AIDP. Children with AMAN were more likely to have a preceding diarrheal illness than AIDP. Nachamkin I et al. Neurology 69:1665–1671. Anti-ganglioside antibodies do not correlate with severity or subtype (but anti GD1a is more common in AMAN). Nagasawa K et al. Muscle Nerve 2006; 33:766–770. Tekgul H et al. Pediatr Neurol 2003;28:295–299.

55. Treatment

56. Treatment Very few randomized controlled trials (RCT) on GBS treatment were published in the last 5 years. 3 components of management: Monitoring, supportive and critical care. Immunotherapy. Rehabilitation.

57. Supportive and Critical Care The single biggest advance in management of GBS. Monitoring vital parameters. Nutrition. DVT prophylaxis. Ventilator assistance. Managing autonomic dysfunction. Chest and general physiotherapy. Frequent turning and assiduous skin care. Management of pain, constipation. Prevention of exposure keratitis. Constant reassurance.

58. Ventilator Assistance Among severely affected patients (those unable to walk), about 25% need artificial ventilation. Indications for intubation: VC of 15 ml/kg Significant hypercarbia, hypoxia Death is not due to ventilatory insufficiency, but due to intercurrent infection, MI or Pulmonary embolism. Serious infections occur in 60% of those on the ventilator for > 3 weeks.

59. Poor prognostic factors Mortality: 10.4% Predictors of mortality Bulbar dysfunction. Autonomic dysfunction Severe weakness. Rapid onset to peak (<3 d) Age > 60 years. Reduced median CMAP amplitude Pulmonary infections Hypokalemia Netto A et al. 2009 (unpublished)

60. Immunotherapy: Options IVIg or plasmapheresis can be initiated, as they are equally effective. Combining these therapies has no additional benefit. Meta-analysis of RCTs indicates that: PE reduces need for mechanical ventilation from 27% to 14%. Increases likelihood of full recovery at 1 year from 55% to 68%. Best documented effect of these agents is to shorten time to recovery. No effect on mortality. Hughes RA et al. Brain 2007. 130:2245–2257.

61. Timing of treatment Start treatment as soon after diagnosis as possible. Greatest effect was observed when PE was started within the first 2 weeks from onset. Each day counts; ~2 weeks after the first motor symptoms, immunotherapy is only minimally effective. The Guillain-Barré Syndrome Study Group. Neurology 1985; 35: 1096–104.

62. Plasmapheresis A course of plasmapheresis consists of ~40–50 mL/kg plasma exchange (PE) 4-5 times over 2 weeks. Two plasma exchanges may be sufficient in mild cases, and six exchanges are not superior to four in severely affected patients. This therapy should ideally be administered within the first 2 weeks and not later than 4 weeks from clinical onset. French Cooperative Group on PE in GBS. Ann Neurol 1997; 41: 298–306. Raphael JC et al. Cochrane Database Syst Rev 2002; 2: CD001798.

63. Immunoglobulins IVIG is as effective as plasmapheresis, at least in the first 2 weeks. IVIg is preferred as initial therapy because of its ease of administration and good safety record. Dose: 5 daily infusions for a total dose of 2 g/kg/wt. Hughes RA et al. Cochrane Database Syst Rev 2006; 1: CD002063. Combining mycophenolate mofetil to the standard IVIg regimen has been ineffective. Garssen MP et al. J Neurol Neurosurg Psychiatry 2007: 78:1012–1013

64. Recent trials Of IVIg No significant difference in the outcome. IVIg 0.4 g/kg/d X 5d vs PE total 200- 250ml/kg In upto 7 sessions over 4 Wks. N=47 Adults Nomura et al. 2000 Early relapse more in 2 d group. No other differences IVIg 1g/kg/day X 2 day Vs 0.4g/kg/day X 5 day. N=50. Children Able to walk without aid. Korinthenberg et al. 2005 No significant difference in the disability score. IVIg 0.5 g/kg/day X 2 days Vs supportive care. N=21. Children Able to walk without aid. Korinthenberg et al. 2005 Result Treatment Subjects Study

65. Recent trials Of IVIg IVIg and PE were more effective than steroids (Dexa). Steroids Vs Steroids + IVIg vs Steroids + PE N= 54 Children. Wang et al. 2001 6d group appeared to benefit, but not statistically significant. IVIg 0.4g/kg/day X 3 days Vs 6 days. N= 39. Adults with CI to PE. Raphael et al. 2001 IVIg and PE were equally effective. IVIg 0.4 g/kg/dX 5d vs PE 40-50ml/kg 5 times in 2 weeks vs immuno-absorption 5 times in 2 weeks. N= 67. Adults and children Diener et al. 2001 Result Treatment Subjects Study

66. Recent trials Of Steroids Steroids (oral, parenteral) alone are not beneficial in GBS. Hughes RA et al. Cochrane Database Syst Rev 2006; 2: CD001446. No difference in outcome. IVIg 0.4g/kg/d X 5d + IV Methylprednisolone 500mg/d for 5 day vs IVIg + placebo. N= 225 Van Koningsveld et al., 2004 No difference in outcome. Prednisone 60 mg/d X 4d, 45mg/d X 3d, 30 mg/d X 10d, then tapered and stopped Vs no treatment N= 20 Bansal et al. 2004 Result Treatment Subjects Study

67. Steroids Explanation for this ineffectiveness is unclear: Steroids have minimal effect on the toxicity of anti- ganglioside antibodies and subsequent complement activation. May adversely affect macrophages that clear myelin debris, thus hampering remyelination. Rich MM et al. Ann Neurol 2001; 50: 26–33.

68. Other experimental therapies Chinese medicine herbal medicine tripterygium polyglycoside compared with dexamethasone. CSF filtration compared with PE. Wollinsky KH et al. Neurology 2001; 57: 774–80. IVIg + brain derived neurotrophic factor. Bensa S et al. Eur J Neurol 2000; 7: 423–6. IVIg + beta-interferon. Pritchard J et al. Neurology 2003; 61: 1282–4. None of these trials were large enough to detect even moderate treatment effects.

69. Treating ‘mildly’ affected patients In Europe, a third of patients with GBS are able to walk. van Koningsveld R et al. Neurology 2000; 54: 620–25. These patients often have residual disabilities. No RCTs comparing PE/ IVIg with placebo. One large French RCT studied the effect of PE in patients who could walk with or without aid, but could not run. French Cooperative Group on Plasma Exchange in GBS. Ann Neurol 1997. Motor recovery was faster in patients who received two PE sessions than in those who received no PE. Mildly affected patients may be treated with PE.

70. Patients who deteriorate despite treatment. These patients might have a severe or prolonged immune attack that causes severe axonal degeneration. Hughes RA et al. Brain 2007; 130: 2245–57 No recent RCTs have addressed this group. PE followed by IVIg is no better than PE or IVIg alone. There was however a slight trend towards a better outcome with combination therapy in this study. Plasma Exchange/Sandoglobulin GBS Trial Group. Lancet 1997. A second course of IVIg in severe unresponsive patients may be effective. Farcas P et al. Lancet 1997; 350: 1747.

71. Treatment Related Fluctuations About 5–10% of patients with GBS deteriorate after initial improvement or stabilisation. This occurs at about 6 weeks after treatment with IVIg. This may reflect the therapeutic effect of IVIg wearing off. Kleyweg RP et al. J Neurol Neurosurg Psychiatry 1991; 54: 957–60. These patients probably have a prolonged immune response requiring a longer duration of treatment. Visser LH et al. J Neurol Neurosurg Psychiatry 1998; 64: 242–44. Some patients suffer several episodes of deterioration. They have to be differentiated from acute onset CIDP. 3% may progress to CIDP.

72. Treatment Related Fluctuations No RCTs have assessed the therapy in this condition. Repeating the initial effective therapy is likely to be effective and has become common practice. Hughes RA et al. Brain 2007; 130: 2245–57 A significant deterioration of more than one clinical grade was considered by consensus, a reasonable threshold for giving a second course of IVIg. There is some weak evidence that a higher dose of IVIg is a little better than a lower dose. Raphael J-C et al. J Neurol Neurosurg Psychiatry 2001; 71:235–8.

73. When do we diagnose A-CIDP? Answer is not yet fully known. GBS and CIDP differs essentially in the duration of progressive weakness. Some with initial presentation like GBS, finally turn out to have CIDP. A-CIDP should be suspected if: 3 or more episodes of deterioration occur in a patient with GBS during the first attack of illness despite treatment. A subsequent deterioration 9 weeks from onset of GBS. The importance is that treatment differ in the 2 groups. Ruts L et al. Neurology 2005; 65: 138–40. Odaka M et al. J Neurol 2003; 250: 913–16.

74. Treatment-related fluctuations (TRF), and acute-onset CIDP (A-CIDP)

75. Recommendations IVIG (0.4 g/kg/d for 5 d) or PE can be used as first line treatment and are equally effective (level A). IVIG has lesser side effects than PE and this would favour IVIG over PE treatment (level B). IVIG treatment after PE, as standard combination, has no significant benefit and can not be recommended (level B). Combining high-dose IV methylprednisolone with IVIG may have a minor short-term benefit (level C). EFNS Guidelines 2008.

76. Recommendations Children, who generally have a better prognosis, should be treated with IVIG as first-line treatment (level C). Treatment related fluctuations after IVIG should preferentially be retreated with a second course of IVIG (good practice point). In patients unresponsive to the first course of IVIG a second course may be tried (good practice point). No recommendations: regarding IVIg in ‘mild GBS’ patients or patients with MFS. EFNS Guidelines 2008.

77. Treatment: Summary GB Syndrome is one of the few neurologic disorders with solid evidence based treatment. Immunotherapies shorten time to recovery and prevent progression to more severe stages. However, quality of critical care is the most important determinant of mortality. Outcome remains unsatisfactory in a substantial number of patients. Newer modalities of treatment, especially focusing on remyelination and axonal regeneration are required.

78. Prognosis

79. Prognosis Around 85% of patients achieve a full functional recovery within few months to a year; minor findings (eg areflexia) may persist for years. The remaining 15% have functionally important residua. 20% of patients not ambulant at presentation remained so even after 6 months, despite immunotherapy. Even 3–6 years later, GBS has a large impact on social life and the ability to perform activities. Hughes RA et al. Brain 2007; 130: 2245–57 de la Dornonville CC et al. Neurology 2005; 64: 246–53.

80. Prognosis The outlook is worst in patients with severe proximal motor and sensory axonal damage. Peroneal nerve conduction block and age above 40 years are independent predictors of disability at 6 months. Durand MC et al. Lancet Neurol 2006; 5: 1021–28. AMAN: Recovery occurs in about 2 months, but the extent of recovery may be less than in AIDP MFS: In general, the prognosis is excellent.

81. Markers of Poor Prognosis Mortality of 1.25% to 2.5% has remained so in the last decade. Death usually results from secondary pulmonary complications. Alshekhlee A et al. Neurology 2008: 70:1608–1613. Degree of axonal damage Sepsis Delay in onset of treatment Cardiac complications Severity of the attack (intubation) Comorbidities Advanced age

82. Koeppen S et al. Neurocrit. Care 2006;05:235–242. 75% sensory 43% muscle weakness 13% orthostatic hypotension 48% residual neuropathy 1-14 40 de la Cour and Jakobsen, 2005 28% normal/ minor symptoms 24% unassisted gait 12% assisted gait 24% wheel chair/ bed bound 1 25 Cheng et al. 2004 31% residua 1 96 Cheng et al. 2003 48% muscle aches and cramps (38% in UL, 66% in LL) 69% sensory 3-6 yrs 122 Bernsen et al. 2001 4% moderate, 6% severe 42% mild residual symptoms 1 yr 53 Chang et al. 2000 Outcome Duration after onset No Author Long-term Neurological outcome in GB syndrome

83. GBS Disability Scale (modified) Most commonly used measure of levels of activity and participation. Plasma Exchange/Sandoglobulin GBS Trial Group, 1997 Death. 6 Requiring assisted ventilation ( for any part of the day or night). 5 Confined to bed or chair bound. 4 Able to walk with a stick, appliance or support (5m across an open space). 3 Able to walk without support of a stick (5m across an open space) but incapable of manual work/running. 2 Minor symptoms or signs of neuropathy but capable of manual work/capable of running. 1 Healthy. 0

84. Other Outcome Measures Primary outcome measures: Overall disability sum score Overall neuropathy limitations scale Rotterdam handicap scale. Secondary Outcome Measures: Medical Research Council sum score Number of days the patient is on the ventilator Quality-of-life measures: SF-36, for fatigue. Merkies IS et al. J Neurol Neurosurg Psychiatry 2002; 72: 596–601. Graham RC et al. J Neurol Neurosurg Psychiatry 2006; 77: 973–76. Garssen MP et al. Neurology 2004; 63: 2393–95.

85. Prognosis using EGOS A large prognostic study introduced the Erasmus GBS outcome scale (EGOS). It is calculated in the first 2 weeks of disease onset using: age, presence of preceding diarrhoea, and GBS disability score. EGOS can accurately predict the chance of independent walking after 6 months. Based on EGOS, the predicted chance of recovery for individual patients varies from 1% to 83%. van Koningsveld R et al. Lancet Neurol 2007; 6: 589–94.

86. Prognosis A study on 76 adult GBS patients admitted to the ICU showed median ICU stay of 3 weeks, 80% of patients required artificial ventilation (median 4 weeks), and 75% of patients had independent ambulation after 3 years. Therefore, even severely affected patients have a good long-term prognosis. Dhar R et al. J Neurol Sci 2008; 264:121–128. A study of 95 children, aged 1-16 years, showed that children often have severe neuropathic pain, but that the neurological long-term prognosis is relatively good. Korinthenberg R et al. Neuropediatrics 2007; 38:10–17.

87. Conclusion Research on various aspects of pathogenesis like Campylobacter genes, single nucleotide polymorphisms in GBS patients, anti-ganglioside antibodies, animal models and the role of complement has progressed. Prognostic modeling for GBS is being fine tuned. Progress on improved treatment lags behind. In the coming years newer strategies like a second IVIg dose in severely ill GBS patients, use of complement inhibitors in GBS will be tested.