Recent advances in GBS

1. RECENT ADVANCES IN PATHOGENESIS
AND MANAGEMENT OF GBS
DR. VAISHAL SHAH
SR NEUROLOGY
GMC, KOTA

2. INTRODUCTION
• Most frequent cause of acute flaccid paralysis.
• Usually monophasic & Immune mediated disorder.
• A common misconception - GBS has a good
prognosis
20% of patients remain severely disabled and
approximately 5% die, despite immunotherapy.

3. INTRODUCTION
• 0.89 – 1.89 / lakh. Increase of 20% every 10 years rise in
age
• Male / female – 1.78 / 1.
• 2/3rd cases preceded by URTI or diarrhoea.
• 30% infection attributed to C. Jejuni. Incidence of GBS
0.25-0.65/1000
• 10% attributed to CMV. 0.6 -2.2/1000 cases.

4. INTRODUCTION
• Other infectious agents - EBV, VZV and Mycoplasma
pneumoniae.
• Recently zika virus and hepatitis E have been found to
cause GBS.

7. INTRODUCTION
• Vaccine
1) Meningococcal vaccine
In a study using the Vaccine Safety Datalink (VSD), a
surveillance database, no cases of GBS were identified
within six weeks following administration of more
than 8,80,000 Menactra doses between 2005 and
2010
Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). Cohn AC, MacNeil JR et al.,,
Centers for Disease Control and Prevention (CDC) MMWR Recomm Rep. 2013;62(RR-2):1.

8. INFLUENZA
VACCINE

9. INTRODUCTION
• Other triggering events
Hodgkin lymphoma, SLE, sarcoidosis
Surgey, Trauma
Bone marrow transplantation
TNF-alpha therapy
Use of isotretinoin
Ropper AH. The Guillain-Barré syndrome. N Engl J Med 1992;
326:1130.Rudant J, Dupont A, Mikaeloff Y, et al. Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study. Neurology 2018; 91:e1220.
Shin IS, Baer AN, Kwon HJ, et al. Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy. Arthritis Rheum 2006;
54:1429. Pritchard J, Appleton R, Howard R, Hughes RA. Guillain-Barré syndrome seen in users of isotretinoin. BMJ 2004; 328:1537.

10. VARIANTS

11. INTRODUCTION
• In Europe and north America – AIDP --- 90%.
• South America, china, india, japan, Bangladesh – AMAN ---
30-65%
AIDP --- 22-46%
• Italian cohort – Pattern changed from AIDP to AMAN
AIDP - decreased from 67% to 58%,
AMAN - increased from 18% to 38%
Uncini A, Manzoli C, Notturno F, Capasso M. Pitfalls in electrodiagnosis of Guillain-Barré syndrome subtypes. J Neurol Neurosurg Psychiatry
2010;81:1157-63.

12. INTRODUCTION
• Infection with CMV and EBV is a/w AIDP. C. Jejuni
is a/w AMAN and MFS.

13. PATHOGENESIS

14. PATHOGENESIS - AMAN
• Humorally mediated.
• Old myelin protein specific T cell mediated allergic
neuritis model vs newer antibody mediated nerve
axolemma damage model in rabbit & mouse.
Successful in showing molecular mimicry

15. PATHOGENESIS - AMAN
• Molecular mimics – Glycans ( sugars ) expressed on
lipooligosaccharides (LOS ) generates antibody
response, binds to structurally identical glycan present
on nerve ganglioside.
• Anti carbohydrate antibody response is T cell
independent.

17. NODAL
PERSPECTIVE
Nodo
paranodopath
y

18. PATHOGENESIS - AMAN
• Why few develop AMAN after C. jejuni infection???
1. Small proportion of C.jejuni having ganglioside
mimics.
2. Immunological tolerance to self glycans on LOS.
Nachamkin I, Liu J, Li M, et al. Campylobacter jejuni from patients with Guillain-Barre syndrome preferentially expresses a GD(1a)-like epitope. Infect
Immun 2002; 70: 5299–303.

19. PATHOGENESIS - AIDP
• Less well understood
1. Wider range of immune stimulus including
bacterial/viral infections & vaccines
2. Specific antibody biomarkers are not characterised
yet.

20. PATHOGENESIS - AIDP
• Few antigens are found in few studies.
1. Myelin proteins P0, P22, PM22 – in old studies.
2. Proteins like gliomedin, contactin, TAG-1,meosin,
neurofascin
3. Glycolipids on glial memranes like LM1,
sulphoglucuronosyl paragloboside,
galactocerebroside, sulfatide.
4. Small amount of GM1 and GQ1b.
• Makowska A, Pritchard J, Sanvito L, et al. Immune responses to myelin proteins in Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry
2008; 79: 664–71.
• Samukawa M, Hamada Y, Kuwahara M, et al, for the Japanese GBS Study Group. Clinical features in Guillain-Barre syndrome with anti-Gal-C
antibody. J Neurol Sci 2014; 337: 55–60.

21. PATHOGENESIS - AIDP
• New area for exploration emerged from Japanese
studies.
• Glycolipid domains, composed of multiple glycolipid
and lipid components, can associate to form
neoantigens that are not present in any single
molecule.
• Anti-complex antibodies, difficult to detect.
• Kaida K, Morita D, Kanzaki M, et al. Ganglioside complexes as new target antigens in Guillain-Barre syndrome. Ann Neurol 2004;
56: 567–71.
• Rinaldi S, Brennan KM, Kalna G, et al. Antibodies to heteromeric glycolipid complexes in Guillain-Barre syndrome. PLoS One 2013; 8: e82337.

22. CLINICAL MANIFESTATIONS
Typical features
• Ascending quadriparesis. Nadir in 4 weeks. Preceding
infection history might be vague.
• Pain is frequent initial symptom.
• Sensory signs, ataxia and autonomic dysfuction can
be seen.
• Oculomotor and bulbar weakness can be seen,
common in MFS.
• 20-30 % develops respiratory failure needing
ventilatory support.

23. CLINICAL MANIFESTATIONS
Atypical features
• Reflex can be exaggerated initially in AMAN variant.
• Miller Fischer Guillain Barre overlap syndrome.
• Paraparetic variant – eventually absent reflex/NCV
finding can be seen in UL.
• Diagnosis is difficult in preschool children because of
predominant complaint of pain.
• 25% deteriorates during or shortly after IVIg.

24. HUGHAS’
FUNCTIONAL
GRADING SCALE

25. DIFFERENTIALS
• Porphyria Lyme disease
• Vasculitis Tick paralysis
• Sarcoidosis Acute arsenic
poisoning
• Severe vitamin B1 deficiency Leptomeningeal
disease
• Critical illness neuropathy
• Muscle disorder (polymyositis, periodic paralysis),
• NMJ ( Botulism, MG ), Myelitis.

26. DIAGNOSIS
• Traditional
NCV
CSF analysis
• New
Antibody testing
MRI

27. ELECTRODIAGNOSTIC STUDY

28. Meena AK, Khadilkar SV, Murthy JM. Treatment guidelines for Guillain-Barré Syndrome. Ann Indian Acad Neurol. 2011;14(Suppl
1):S73-81.

29. ELECTRODIAGNOSTIC STUDY
• New points
Sural sparing in AIDP – low to moderate sensitivity
but high specificity. – seen in later stages.
MFS – Reduced or absent SNAP, more in upper limb
with normal CMAP.

30. ELECTRODIAGNOSTIC STUDY
• The best indicator of good recovery is maintained
CMAP.
• Needle EMG - Decreased recruitment initially.
Extensive denervation potentials in case of axonal
damage.

31. CSF ANALYSIS
• Albuminocytogenic dissociation – 50-66% in 1st week,
>75% in 3rd week.
• Protein – 45-200 mg/dl, Cells - <5, 15% shows 10-50
cells.
• If pleocytosis present, R/O infective cause, sarcoid,
carcinomatous, lymohomatous meningitis.

32. By Nobuhiro yuki et al., Guillain–
Barré syndrome and anti-
ganglioside antibodies: a
clinician-scientist’s journey, Proc.
Jpn. Acad., Ser. B 88 (2012)
ANTIBODY
TESTING

33. MRI
• Gadolinium enhancement of nerve roots.
• To eliminate transverse myelitis, subacute
compressive myelopathy, and infiltrating illnesses of
the roots and the spinal cord.
• 95% of children with GBS show enhancement of the
lumbar roots.

34. MRI

36. LATEST
DIAGNOSTIC
CRITERIA

37. TREATMENT - SUPPORTIVE
• Respiratory failure – 30%.
• 397 GBS patients study found that independent
predictors
Fewer days between onset of weakness and admission
Presence of facial or bulbar weakness
Severe muscle weakness
• Erasmus GBS respiratory insufficiency score ( EGRIS )
Walgaard C, Lingsma HF, Ruts L, et al. Prediction of respiratory insufficiency in Guillain-Barré syndrome. Ann Neurol 2010;

39. TREATMENT - SUPPORTIVE
• French study. 722 GBS patients – 313 (43%) ventilated.
1. Time of onset to admission less than seven days
2. Inability to cough
3. Inability to stand
4. Inability to lift the elbows 4/6 85%
ventilated.
5. Inability to lift the head
6. Liver enzyme increases
1.Sharshar T, Chevret S, Bourdain F, et al. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med 2003;
31:278.

40. TREATMENT - SUPPORTIVE
• Autonomic dysfunction – 70%
Postural hypotension – Adequate fluid. Phenylephrine low
dose.
Tachycardia – Beta blocker.
Severe hypertension ( MAP > 125 ) – Labetalol, esmolol,
nitroprusside.
Arrhythmia – Antiarrhythmic, Atropine and pacing SOS in
asystole.
Daily abdominal auscultation – Erythromycin/neostigmine
for ileus.

41. TREATMENT - SUPPORTIVE
• Pain control – Gabapentin, pregabalin, CBZ
NSAIDs, opioids
Epidural morphine
• Rehabilitation.
• DVT prophylaxis.
• 40-45 kcal/kg & 2-2.5g/kg nutrition.

42. DISEASE MODIFYING TREATMENT
• Plasma exchange
In an updated (2012) meta-analysis of 6 RCTs and 649
patients with GBS, treatment with PE was superior to
supportive care.
Most effective in 1st 7 days. North American study
proved efficacy till 30 days.
Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev 2012;
:CD001798.

43. DISEASE MODIFYING TREATMENT
• Each time 1-1.5 times plasma volume to be exchanged.
Plasma volume in ltr = 0.07 * weight(kg) * (1-haematocrit)
5% Albumin Albumin–saline combination ( 60-
80%/20-40%) as a replacement fluid.
• 4 to 6 treatments over eight to 10 days.
( more might require due to IgG antibody )

44. DISEASE MODIFYING TREATMENT
• 2014 systematic review and meta-analysis and by a
2012 American Academy of Neurology guideline on
IVIG in the treatment of neuromuscular disorders
concluded
IVIG is as effective as PE for the treatment of GBS
• No RCT comparing IVIG with placebo.
Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics
and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78:1009.
Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev 2014;
:CD002063.

45. DISEASE MODIFYING TREATMENT
• IVIG
Pooled IgG from thousands of blood donors, which
results in a fivefold increase in serum IgG.
Preferred since it is easier to administer.
Dosage – 0.4g/kg/day for 5 days

49. AAN RECOMMENDATIONS
• PE is recommended for
Nonambulantory patients within 4 weeks of onset
(level A, class II evidence)
Ambulantory patients within 2 weeks of onset (level B,
limited class II evidence).

50. AAN RECOMMENDATIONS
• IVIG is recommended for
Nonambulatory patients within 2 weeks (level A
recommendation) or 4 weeks from the onset of
neuropathic symptoms ( level B recommendation ).

51. TREATMENT-RELATED
FLUCTUATIONS
• TRF are defined as worsening of weakness after an initial
improvement or after stabilization following treatment
with IVIg or PE.
• Seen up to 10%. Usually within 2 months.
• Rx not defined. IVIG(2g/kg) course is given in clinical
practice.

52. NOVEL
IMMUNOMODULATORY
APPROACHES

53. COMPLEMENT INHIBITION
1) Eculizumab
Prevent formation of C5a and C5b.
Impressive result in in vivo mouse MFS model.
Japan phase 2 trial published. UK trial not
published.
2) Soluble complement receptor 1 – Under phase 1
trial
Inhibit classical & alternate pathway.

54. COMPLEMENT INHIBITION
• Animal studies. Official human trial not started
Nafamostat – synthetic serine protease inhibitor
rEV576 –recombinant form of saliva protein of soft
tick.
APT070 - APT070 is well tolerated when given
systemically to healthy volunteers (Inflazyme
Pharmaceuticals, British Columbia, Canada).

56. ANTI C1Q TRIAL IN PHASE 1

57. OTHER COMPOUNDS
• Flacainide
• MMF
• Brain derived neurotrophic factor Ineffective
• IFN – beta

60. PROGNOSIS

61. Predicted fraction of patients unable to walk independently at 4 weeks (black lines), 3 months (red lines), and 6 months
(green lines) on the basis of the mEGOS at hospital admission (A) and at day 7 of admission (B). The gray areas around
the colored lines represent 90% confidence intervals

63. 2ND IVIG DOSE
• Arguments suggesting second IVIG dose.
1. 10% develop TRF for whom 2nd IVIG is required.
2. 2nd IVIG was effective in small uncontrolled trials of
severe unresponsive GBS.
3. Recent data shows, patients with relatively minor
increase in serum IgG after IVIg shows delayed and
incomplete recovery.

64. 2ND IVIG DOSE
• SID
SID– GBS trial including 176
patients in Netherland is
planned

65. RECOVERY
• Begin to recover – 2-4 week
• Mean time to complete recovery – 200 days in 80%
• Major residual deficit remains in 10-15%.
• AMAN recovery is delayed compared to AIDP. Some
cases are quicker to improve.
• MFS improves rapidly in 3 months. Role of treatment
is doubtful. ( No RCTs till now ).

67. REFERENCES
1. Alex Y. Doets et al., Advances in management of Guillain–Barre´
syndrome, Curr Opin Neurol 2018, 31:541–550
2. Hugh J Willison, Bart C Jacobs, Pieter A van Doorn, Guillain-
Barré syndrome, Lancet 2016; 388: 717–27.
3. H. C. Lehmann et al., New and emerging treatments of Guillain--
Barre´ syndrome, Expert Opinion on Orphan Drugs (2014)
4. Meena AK, Khadilkar SV, Murthy JM. Treatment guidelines for
Guillain-Barré Syndrome. Ann Indian Acad Neurol.
2011;14(Suppl 1):S73-81.
5. Nobuhiro Yuki, M.D., Ph.D., and Hans-Peter Hartung, M.D.,
Guillain–Barré Syndrome, N Engl J Med 2012;366:2294-304.
6. www.uptodate.com

68. THANK YOU