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GBS - Guillian Barre Syndrome

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GBS - Guillian Barre Syndrome

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History of GBS
Pathophysiology of GBS
Clinical features and diagnosis
Differential diagnosis and Mimics
Treatment, Monitoring and prognostic scores

History of GBS
Pathophysiology of GBS
Clinical features and diagnosis
Differential diagnosis and Mimics
Treatment, Monitoring and prognostic scores

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GBS - Guillian Barre Syndrome

  1. 1. Immune-mediated Polyneuropathy L-GBS – Guillian Barre Syndrome Dr. Dhananjay Gupta Dept. Of Neurology Ramaiah Medical College, Bangalore
  2. 2. Causes of PN GBS/ AIDP
  3. 3. Axonal/ Demyelinating Axonal – Physical disruption of nerve Toxic, Metabolic or Genetic causes
  4. 4. Axonal/ Demyelinating Demyelination – loss or dysfunction of sheath 1. Entrapment/ compressive 2. Immunological - GBS 3. Toxic – diphtheria 4. Genetic – CMT
  5. 5. DYS-IMMUNE POLYNEUROPATHY ACUTE CHRONIC AIDP AMAN AMSAN Pandysautonomia Mixed Motor Sensory Misc - CIDP - MADSAM (lewis-sumner) - MGUS - WM (anti-MAG) MMN – CB CISP DADS CANOMAD • Autoimmune autonomic neuropathy • Vasculitic neuropathy
  6. 6. 1. AIDP 2. CIDP 3. MADSAM – lewis sumner 4. CISP
  7. 7. GBS/ AIDP
  8. 8. Definition DEFINITION  Prototypical Immune-mediated, monophasic,  Poly-radiculo-neuropathy, characterised by  Acute onset, areflexic, predominantly motor weakness, Progressing in an ascending manner *Lehmann HC, zu Horste GM, Kieseier BC, Hartung H-P. Pathogenesis and Treatment of Immune-Mediated Neuropathies. Therapeutic Advances in Neurological Disorders. 2009;2(4):261-281. doi:10.1177/1756285609104792. **Dimachkie MM, Barohn RJ. Guillain-Barré Syndrome and Variants. Neurologic clinics. 2013;31(2):491-510.
  9. 9. History 'The sensory and motor systems may be equally affected. However the main problem is usually a motor disorder -a gradual diminution of muscular strength with flaccid limbs and without contractures, convulsions or reflex movements of any kind. In almost all cases micturition and defaecation remain normal. The first symptoms always affect the extremities of the limbs and the lower limbs particularly. When the whole body becomes affected the order of progression is more or less constant: (1) toe and foot muscles, then the hamstrings and glutei, and finally the anterior and adductor muscles of the thigh; (2) finger and hand, arm and then shoulder muscles; (3) trunk muscles; (4) respiratory muscles, tongue, pharynx, oesophagus, etc. Jean Baptiste Octave Landry de Thézillat (1859) Landry O. Notesur la paralysie ascendante gigue. Gazette Hebdomadaire. 1859;6:472–474.
  10. 10. Georges Guillain Jean-Alexander Barre Andre Strohl 1916 – French army doctors – 2 soldiers - hypo-reflexic weakness with raised CSF protein levels, without a high WBC - ? Cause ?? Infection ?? Poisoning History *Guillain G, Barré JA, Strohl A. Radiculoneuritis syndrome with hyperalbuminosis of cerebrospinal fluid without cellular reaction. Notes on clinical features and graphs of tendon reflexes- 1916. Ann Med Interne (Paris). 1999 Jan; 150(1):24-32. ** Guillain G, Barré JA. Paralysie ascendante gigue de Landry consecutive a Line vaccination antiryphoi-dique. Rev Neurol. 1919;3:595–598.
  11. 11. 1949 – landmark description of 50 fatal cases. Emphasized prominent damage to proximal nerves – at the junction of ventral and dorsal roots. Unified the findings of Landry, Guillain, Barre and Strohl -- LGBS History
  12. 12. 1927 – Dragonescu and Claudian - GBS Guillain – never believed the Landry ascending paralysis = GBS : afebrile : essential was raised CSF protein : non- fatal, no respiratory distress in GBS 1958 – Charles Miller Fischer – acute external ophthalmoplegia 1965 – Thomas Munsat : “GBS is easy to diagnose but difficult to define 1969 – Asbury, Aranson, Adams – diagnostic criteria History
  13. 13. Epidemiology EPIDIMEOLOGY  Incidence : 1-4/ 1,00,000 (*AAN)  MCC of AFP in children  MC acute NM-disorder seen in ICU  M: F 1.1-1.7: 1  Age : 2 months – 95 years  Childhood GBS – average age 4-8 years
  14. 14. Epidemiology  MC seen in 3rd – 5th decade  Most cases in June-july, Sept-October *  Seasonal variation – winters **  Males > Females *  Incidence higher in South-Asia as compared to America/ Europe * Sharma G, Sood S, Sharma S. Seasonal, Age and Gender variation in GBS in a tertiary care centre in India. Neurosciences and Medicine. 2013: 4, 23-28. ** Sudulagunta SR, Sodalagunta MB, Sepehrar M, et al. Guillain-Barré syndrome: clinical profile and management. German Medical Science. 2015;13:Doc16. doi:10.3205/000220. INDIA
  15. 15. * Kuwabara S, Yuki N. Axonal Guillain-Barré syndrome: concepts and controversies. Lancet Neurol 2013; 12: 1180–88 PREVALENCE OF AXONAL GBS
  16. 16. C. Jejuni GBS :  pure motor axonal form (AMAN)  More severe clinical disease,  Less recovery chances  More commonly a.w Anti-GM1 antibodies Anti GM1 GBS  rapidly progressive, severe neuropathy  Predominantly distal distribution  Motor  No sensory/ cranial nerve disturbances
  17. 17. A Dutch study evaluated the relationship between vaccinations and GBS, more specifically recurrent GBS. 245 GBS and 76 CIDP patients were studied with 106 GBS patients having received flu vaccination (n=775). None of them had a recurrence of GBS after vaccination. Thus it was concluded that flu vaccines are relatively safe. The most common symptoms post GBS and CIDP were pain and fatigue.
  18. 18. PATHOGENESIS
  19. 19. Pathophysiology
  20. 20. Pathophysiology
  21. 21. Fehmi J, Scherer SS, Willison HJ, et al. Nodes, paranodes and neuropathies. J Neurol Neurosurg Psychiatry 17 August 2017
  22. 22. Node of Ranvier disruption as a cause of neurological diseases. Susuki K - ASN Neuro (2013)
  23. 23. * Kuwabara S, Yuki N. Axonal Guillain-Barré syndrome: concepts and controversies. Lancet Neurol 2013; 12: 1180–88
  24. 24. * Kuwabara S, Yuki N. Axonal Guillain-Barré syndrome: concepts and controversies. Lancet Neurol 2013; 12: 1180–88
  25. 25. Presentation Summary of Pathogenesis 1. AIDP : Molecular mimicry  leading to lymphocytic mononuclear infiltrate of nerve roots, peripheral nerves  with macrophage associated segmental demyelination 2. AMAN:  paucity of lymphocytic infiltration  sparing of the dorsal nerve roots, DRG, and peripheral sensory nerves.  lengthening of the node of Ranvier  followed by the recruitment of macrophages  Lengthening of node is reversible , results in acute conduction block neuropathy  Late Wallerian degeneration
  26. 26. CLINICAL PRESENTATION
  27. 27. 7-10 days prior to onset of weakness WEEKS ----
  28. 28. Nadir - 2 weeks – 50% 4 weeks – 90% Recovery begins 2-3 weeks after progression stops WEEKS ----Ropper AH, Wijdicks EFM, Truax BT. In:Guillain-Barré Syndrome,Contemporary Neurology Series. Davis FA, editor. Vol.34. Philadelphia, PA: 1991.
  29. 29. Natural History
  30. 30. The onset of the paralysis can be preceded by a general feeling of weakness, pins and needles and even slight cramps. The weakness spreads rapidly from the lower to the upper parts of the body with a universal tendency to become generalised. The paralysis then becomes generalised but more severe in the distal parts of the extremities. When the paralysis reaches its maximum intensity the danger of asphyxia is always imminent. When the paralysis recedes it demonstrates the reverse of the phenomenon which signaled its development. The upper parts of the body, the last to be affected, are the first to recover their mobility which then returns from above downwards.' Presentation Jean Baptiste Octave Landry de Thézillat (1859) Landry O. Notesur la paralysie ascendante gigue. Gazette Hebdomadaire. 1859;6:472–474.
  31. 31. Presentation 1. Progressive ascending, areflexic* weakness 2. Pain/Paraesthesia often precede by 1-2 days Lower back/ hip/ thigh pain is common – 50% Finger tips should be paresthetic once sensory sx have ascended till midcalves 3. Weakness : starts in legs, proximal + distal muscles Progress – UL --- neck, intercoastal, cranial muscles Descending weakness/ onset in UL – 10-12% 4. Reflexes : 1st week – absent ankle --- progress to generalized DTR invariable absent in limbs with power <3/5
  32. 32. Presentation 5. Cranial nerve palsies : Facial weakness – 40-50% at presentation Facial diplegia, maybe at onset or sequentially  Paediatric : 9th 10th common  Adults : 7th nerve most common 6. Autonomic dysfunction – 2/3rd at onset MC – sinus tachycardia, less often bradycardia facial flushing fluctuating hypo/ hypertension loss of sweating/ episodic diaphoresis syncope/ pre-syncope/ retention/ constipation
  33. 33. Presentation 7. Oro-pharyngeal/ respiratory : 40% 1/3rd patients – may require mechanical ventilation 8. Bowel/ bladder/ sphincter disturbances rare in early course of disease (<10%) presence should raise a suspicion of myelopathy 9. MFS: Ophthalmoplegia, Ataxia, Areflexia 10. Psychotic – ONEIRIC hallucinations (bizzarre walking dreams) After weeks of immobilization
  34. 34. AIDP AMAN 1. Infection CMV, EBV Campylobacter jejuni 2. Epidemics None China - children 3. Target Unknown GM1, GD1a 4. Onset – pain Common Absent 5. DTR Absent (preserved/ exaggerated in 5%) Usually absent (preserved/ exagerrated in 20%) 6. Cranial nerve Common 60% Uncommon 20% 7. Sensory loss Frequent – 70% Absent usually 8.Autonomic involvement Frequent Rare 9. Recovery Relatively uniform 2 patterns – fast and slow 10. Electrophysiology Demyelination Axonal degeneration, CB
  35. 35. Variants AMAN China Young population Preceded by diarrhoea Prognosis similar to AIDP Mortality <5% AMSAN Abrupt onset C. Jejuni diarrhoea Respiratory distress common Longer recovery More residual deficits Mortality 10-15% MFS Ataxia +Areflexia+ ophthalmoplegia VARIANTS: Acute MMN-CB Reflexes unaltered High titres anti- GM1
  36. 36. Variants
  37. 37. Variants ANTI – GQ-1b Ropper’s variant, 1994
  38. 38. Presentation Bickerstaff Brainstem Encephalitis (BBE) 1. Variant of MFS, Ataxia + Ophthalmoparesis + 2. Altered consciousness + paradoxical hyper-reflexia 3. Antecedent infection – 92% 4. Anti-GQ1b antibody – 66% 5. Elevated CSF protein – 59% 6. MRI abnormalities – 30% 7. Absent H-reflex may be the only finding in 75% MFS/BBE * Yuki N, Sato S, Tsuji S, Hozumi I, Miyatake T. An immunologic abnormality common to Bickerstaff ’s brain stem encephalitis and Fisher’s syndrome. J Neurol Sci. 1993;118(1):83–87. ** Ito M, Kuwabara S, Odaka M, et al. Bickerstaff's brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases. J Neurol. 2008 May;255(5):674–682.
  39. 39. DIAGNOSIS
  40. 40. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barre syndrome. Ann Neurol 1990; 27 (suppl): S21–24. – NINDS criteria
  41. 41. Christiaan Fokke, Bianca van den Berg, Judith Drenthen, Christa Walgaard, Pieter Antoon van Doorn, Bart Casper Jacobs; Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria, Brain, Volume 137, Issue 1, 1 January 2014, Pages 33–43
  42. 42. Presentation CONSIDER ALTERNATE DIAGNOSIS IF : 1. Fever at onset 2. Early, persistent bowel/ bladder disturbances 3. Marked asymmetry of weakness 4. A definite sensory level, significant sensory signs 5. Severe pulmonary dysfunction at onset 6. CSF pleocytosis >50 cells 7. Slowly progressive/ non-monophasic illness, without respiratory involvement
  43. 43. Diagnosis 1. Lumbar Puncture: ACD CSF is characteristically acellular (<10) Or contain only few lymphocytes (10-50/mm) 80% patients Proteins rise during 2-3 weeks (100-1000 mg) IF CSF cells > 50 : consider - HIV, Lymes, Sarcoidosis - CMV polyradicupathy/ cauda equina syndrome - Carcinomatous polyradiculitis, Aseptic meningitis
  44. 44. Peak in 4-6 weeks Start to rise in 1-2 weeks May persist at variable elevated levels for many weeks CSF PROTEIN LEVELS
  45. 45. Other CSF findings Antibodies in CSF: • IgG, IgM cerebroside – 38% • IgG cardiolipin – 50% • Gangliosides GM1, GM2, GM3, GD1a, GD1b • Heat shock proteins HSP60, HSP70, HSP90 • Αβ- crystallin Inflammatory mediators: • Complement C3a, C5a, C4b, C5-9 • Chemokines IL17, IL18, IL22, IL37 • IL17, 37 correlate with disability • Osteopontin levels – AMAN/ AIDP • AIDP : IL1ra, IL8 • CIDP : CCL2, CCL7, CCL27, CXCL 9,10,12
  46. 46. Other CSF findings Neuronal and Glial Markers: • NfH – neuronal filament heavy chain • NSE – neuron specific enolase • S100 • 14-3-3 protein • Glial fibrillary acetic protein, NfH, S100 correlate with worse prognosis Proteonomics: ↑ haptoglobin, ↓ transthyretin (usually neuroprotective ↑ cathepsin, ↓ cystatin C
  47. 47. Cerebrospinal fluid findings in Guillain–Barre syndrome and chronic inflammatory demyelinating polyneuropathies. ZSOLT ILLES1, MORTEN BLAABJERG. Handbook of Clinical Neurology, Vol. 146 (3rd series)
  48. 48. Diagnosis CSF findings in AMAN  ACD may be +  CSF/ SERUM albumin ratio – increased (~ AIDP)  IgG index {CSF/SERUM IgG ÷ CSF/SERUM albumin} - increased (~ AIDP)  CSF tau and NfH lvels correlate with poor outcomes
  49. 49. Diagnosis CSF findings in MFS  ACD may be +  GQ1b – expressed in paranodal regions in of axons and in MNJ in CNS  Presence suggests good response in CNS disease  Most recover within 6 months  CSF hypocretin-1 is reduced (similar to AIDP)  CSF transthyretin and prostaglandin D2 synthetase not elevated
  50. 50. Diagnosis
  51. 51. ROOT : Prolonged or absent F- response Delayed or absent H-reflex Axonal :Reduced CMAP Prolonged distal latencies Slowed conduction velocity Distal conduction blocks
  52. 52. Diagnosis
  53. 53. Diagnosis
  54. 54. Diagnosis
  55. 55. Diagnosis 2. Edx – NCS : “ Sural sparing “  A normal sural sensory response in the setting of abnormal UL sensory potentials, more commonly in the later stages  Differentiates GBS from its mimics (infectious, toxic, metabolic and spinal cord disorders.  Specificity – 95%, Sensitivity – 41%, LLR positive – 8.20 * Derksen A, Ritter C, Athar P, et al. Sural sparing pattern discriminates Guillain-Barré syndrome from its mimics. Muscle & nerve. 2014;50(5):780-784. doi:10.1002/mus.24226.
  56. 56. Diagnosis 3. MRI Spine (contrast)  Surface thickening and Contrast Enhancement of  Conus medullaris and cauda equina nerve roots  Most common site of enhancement – ventral roots  Though enhancement of posterior roots also seen  MRI esp useful in paraparetic GBS to identify site of lesion • Alkan O, Yildirim T, Tokmak N et-al. Spinal MRI findings of guillain-barré syndrome. J Radiol Case Rep. 2009;3 (3): 25-8. doi:10.3941/jrcr.v3i3.153
  57. 57. Diagnosis
  58. 58. Diagnosis 5. Metabolic abnormalities  Raised CPK : in some  ↑ ESR : infective/ neoplastic/ autoimmune cause  LFT – abnormal in 10% : recent viral hepatitis – CMV/ EBV  ↓ Na : SIADH – specially in ventilated patients, excess ANF  ECG : Non specific ST-T changes may be seen  Marked vomiting, hair loss, Mee’s line : Indicate Heavy metal toxicity
  59. 59. Differential Diagnosis D/d: 1. AFP - Polio 2. Hypokalemic periodic paralysis 3. Thyrotoxic Periodic paralysis 4. N-M diseases – MG/ LEMS 5. OP poisoning 6. Botulism 7. Heavy metal toxicity (Lead) 8. Tick paralysis 9. MFS : MS/ VBI/ Encephalitis/ MG Always Rule out Lymes disease/ HIV/ Syphillis/ metal toxicity
  60. 60. 1. GBS 2. Lymes disease 3. CMV radiculitis 4. HIV radiculitis 5. Leptomeningeal malignancy D/D ACUTE ONSET LIMB WEAKNESS WITH/WITHOUT RESPIRATORY INVOLVEMENT 1. GBS 2. Toxic 3. Vascuilitic 4. Diphtheria/ Lymes 5. Porphyria 6. Thiamine deficiency 7. Metabolic/ electrolytes 8. HYPO-K/ Mg/ Po4/ glycem NMJ disorders 1. MG 2. Botulism 3. Intoxications Muscle disorders 1. Poly/ DM 2. Periodic paralysis 3. Criticle illness myopathy 4. Rhabdomyolysis 5. Mitochondrial disease Acute Spinal cord lesion
  61. 61. D/B GBS and TICK PARALYSIS – nearly impossible!! 1. Worldwide USA/ AUSTRALIA 2. Sensory loss may be + No sensory loss 3. CSF protein ↑ Normal D/B GBS and PORPHYRIA 1. Mild pain Episodic Painful paralytic attacks 2. Predominant motor Sensory - motor 3. CSF protein ↑ Normal D/B GBS and INFECTIVE (polio, West-Nile, enterovirus) 1. No fever at onset Episodic Painful paralytic attacks 2. More symmetrical Pure motor asymmetrical weakness 3. CSF acellular Pleocytosis 4. No meningitis Meningo-encephalitis syndrome +
  62. 62. D/B GBS and CARCINOMATOUS MENINGITIS with polyradiculopathy 1. Pain at onset + Painless 2. Acute Sub-acute 3. Mildly asymmetrical Fairly symmetrical 4. Proximal + distal Mainly distal, less proximal 5. Facial diplegia in 50% No facial weakness 6. Simultaneous weakness in limbs Sequential weakness in limbs D/B cranial GBS/MFS and Myasthenia (bulbar) 1. Pain at onset + Painless 2. No diurnal variation Diurnal variation + 3. Mild sensory symptoms Pure motor weakness 4. Ocular muscles – advanced disease Early in disease 5. Mandibular muscles normal Exercised jaw hangs open 6. Areflexic DTR preserved
  63. 63. D/B cranial GBS/MFS and BASILAR ARTERY THROMBOSIS 1. Pain at onset +/- Painless 2. Areflexic Lively reflexes 3. Reactive pupils Sluggish/ locked in state 4. Plantar flexor Babinski + 5. F-wave abnormalities + Absent D/B cranial GBS/MFS and Botulism 1. Preserved pupils Early Pupillary paralysis 2. Sinus tachycardia in 10% Bradycardia common 3. Ascending Descending paralysis
  64. 64. D/B GBS and CRITICAL ILLNESS NEUROPATHY 1. Acute Acute- subacute 2. Difficulty in weaning from ventilator 3. Sensory-motor Predominantly motor, mild sensory 4. Infections +/- Preceding sepsis/ overwhelming infection 5. Cranial nerve +/- Usually spared 6. Autonomic dysfunction +/- No dysautonomia 7. Demyelinating typically Primary axonal process ICU patient with weakness and wiped out CMAPs, always consider toxic effects of drugs, antibiotics and nutritional deficiencies in addition to the above two. High dose steroids, NM-blocking agents can cause acute quadriplegic myopathy – differentiated by high levels of CPK and myogenic potentials on EMG.
  65. 65. Treatment TREATMENT  GBS – a clinical diagnosis – symmetric  Early intervention is essential to halt progression  Immunotherapy is the standard of care  In addition, supportive therapy
  66. 66. *Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD001798. DOI: 10.1002/14651858.CD001798.pub3.
  67. 67. Treatment PlEx regimen :  200 – 250 mL/Kg plasma removed  In 4-6 treatment cycles, Usually on alternate days.  Daily cycles can also be given, if no coagulopathy  Replacement fluid : Saline + 5% albumin  If FFP used – chances of infections, HIV, hepatitis  S/E : hypotension, hypo-prothrombinemia, bleeding, arrythmias * French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Appropriate number of plasma exchanges in Guillain-Barré syndrome. Ann Neurol. 1997;41:298–306.
  68. 68. 1. No adequate trials comparing IVIG with placebo in adults (*moderate evidence) 2. In severe disease, IVIG started within 2 weeks, hastens recovery as much as PLEX 3. Adverse events are not significantly more with either treatment 4. But IVIG is significantly more likely to be completed 5. Giving IVIG after PLEX did not confer extra benefit (*moderate evidence) 6. More research is needed in mild patients and in whom treatment starts >2 weeks.
  69. 69. 1. Data comparing IVIg with placebo in GBS is lacking ?well estb plasmaphresis 2. Lack of RCT for IVIg in children -- Expert Recommendation only! 3. IVIg has been found to be NON-INFERIOR to PLEX in trials 4. Dose of IvIg – 0.4 g/Kg/ day --- 3 vs 6 days --- no difference 5. No difference/ benefit of adding MePred to IVIg
  70. 70. Treatment IVIG - MOA:  Interferes with co-stimulatory molecules involved in APC  Modulation of auto-antibodies, cytokines, adhesion molecules  Modulation of the macrophage Fc receptor  Disrupts complement activation and formation of MAC  Upregulation of inhibitory Fc receptor – attenuates Ab-initiated inflammation * Dalakas MC. Intravenous Ig in autoimmune neuromuscular diseases. JAMA. 2004 May 19;291(19): 2367–2375.
  71. 71. Treatment IVIG - infusion:  Total of 2g/Kg, Each bottle – 5gm  Start slow infusion, @ 25-50 mL/ hour  Watch closely for any reactions  Every 15-30 minutes, Increase the rate slowly  Increase the rate @50 mL/hour  Subsequently, 1 bottle can be given over 4-5 hours
  72. 72. Treatment Side effects of IVIG - rare:  Headache  Inflammatory local venous thrombosis at infusion site  Anaphylaxis – esp. in IgA deficient patients  Delayed red macular skin reactions of palms, soles, trunk, desquamation  Renal failure (in dehydrated patients)  Proteinuria  Aseptic meningitis  Hyperviscosity syndrome – stroke, MI, pulmonary embolism (in old, immobile, DM, TCP, hypercholesterolemia patients)
  73. 73. Treatment Severe Patients not improving: PlEx f/b IVIG * The Dutch Guillain-Barré Study Group. Treatment of Guillain-Barré syndrome with high-dose immune globulins combined with methylprednisolone: a pilot study. Ann Neurol. 1994 Jun;35(6):749–752.
  74. 74. Treatment – AAN
  75. 75. 1. Multi-centre double blind RCT --- 242 patients 2. IV MP 500 mg x 5 days vs placebo 3. Primary outcome – disability at 4 weeks 4. Steroids were shown to be INEFFECTIVE for treatment of GBS
  76. 76. *Hughes RAC, Brassington R, Gunn AA, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD001446. DOI: 10.1002/14651858.CD001446.pub5. Moderate quality evidence show CS alone donot significantly hasten recovery from GBS or affect long- term outcome. According to very low quality evidence, oral CS delay recovery. Diabetes requiring insulin was more common and hypertension less common with corticosteroids based on high quality evidence.
  77. 77. * Wang, Y.-Z. et al. Action mechanism of corticosteroids to aggravate Guillain-Barré syndrome. Sci. Rep. 5, 13931; doi: 10.1038/srep13931 (2015).
  78. 78. I-SID-GBS TRIAL – currently data being evaluated – results awaited Large, prospective, open label, observation trial studying the effect of a second dose of IVIG given shortly after the first dose.
  79. 79. JET-GBS TRIAL – Japanese Eculizumab Trial - GBS prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers, to evaluate efficacy and safety of ECULIZUMAB (against C5) for GBS treatment.
  80. 80. Treatment SUPPORTIVE THERAPY : 1. Monitor vitals, SBC, TLC 2. Tachycardia/ brow sweating 3. Pain – opiods/ gabapentin/ CBZ 4. High protein diet 5. Eye protection 6. ?paralytic ileus/ autonomic dysfunction 7. ?Bed sores 8. SIADH – 10-15% 9. DVT prophylaxis 10. Nosocomial infections
  81. 81. Treatment Monitor Resp Insufficiency on Daily Rounds: 1. Severe impairment of resp. can occur before dyspnoea appears 2. Tachypnoea may indicate incipient resp. failure 3. Strength of neck muscles/ trapezii parallel Diaphragm weakness 4. SBC >20 : indicates Vital Capacity > 1.5 L.
  82. 82. Treatment Managing Pain : 1. Most common residual abnormality – pain, cramps 2. Radicular back pain and neuropathic pain 3. NSAIDs, Opiods, Anti-depressants 4. Gabapentin, pregabalin, CBZ, tramadol, Mexilitene
  83. 83. Prognosis:  Recovery starts – 4 weeks  Avg period of mechanical vent – 22 days  Time to walk unaided – 50 days  Complete recovery – 200 days  MC residual – pain, fatigue, cramps, depression  20% patients cannot walk un-aided even after 6 months  Axonal regeneration may take 6-18 months  Most improvements happen during 1st year, minimal after that Prognosis * Drenthen J, Jacobs BC, Maathuis EM, van Doorn PA, Visser GH, Blok JH. Residual fatigue in Guillain-Barre syndrome is related to axonal loss. Neurology 2013; 81: 1827–31. * Merkies IS, Faber CG. Fatigue in immune-mediated neuropathies. Neuromuscul Disord 2012; 22 (suppl 3): S203–07.
  84. 84. Poor Prognostic factors: x Age > 40 x Preceding diarrhoea (4 weeks), CMV, C. jejuni x Rapid progression (<7 days) x More duration of disease x Higher CSF protein x Higher anti-GM1 titres x Severe reduced distal CMAPs (<20% LLN) x Requirement of mechanical ventilation x Erasmus GBS outcome score at 2 weeks ≥ 5 AMAN/ AMSAN : though less autonomic/ cranial, rapid muscle atrophy Prognosis
  85. 85. Prognostic Scores : Prognosis
  86. 86. Prognostic Scores – EGOS: Prognosis EGOS scores at 2 weeks and MRC sum scores at 1 or 2 weeks have the highest predictive value for prognosis. EGOS – simple score, based on 3 parameter, accurately predicts outcomes ** van Koningsveld R, Steyerberg EW, Hughes RA, Swan AV, van Doorn PA, Jacobs BC. A clinical prognostic scoring system for Guillain-Barre syndrome. Lancet Neurol 2007; 6: 589–94.
  87. 87. Prognostic Scores – mEGOS: Prognosis mEGOS scores – uses MRC sum scores instead of disability scores Can be used as early as 1 week Age at onset, preceding diarrhoea and MRC sum scores individually a.w. unable to walk at 4 weeks, 3 months and 6 months ** Walgaard C, Lingsma HF, Ruts L, van Doorn PA, Steyerberg EW, Jacobs BC. Early recognition of poor prognosis in Guillain-Barre syndrome. Neurology 2011; 76: 968–75. Modified Erasmus GBS Outcome Score Prognostic Factor Score Prognostic factor Score Age at onset <40 41-60 >60 0 1 2 Age at onset <40 41-60 >60 0 1 2 Preceding diarrhoea Absent Present 0 1 Preceding diarrhoea Absent Present 0 1 MRC sumscores (admission) 51-60 41-50 31-40 0-30 0 2 4 6 MRC sumscores (day 7) 51-60 41-50 31-40 0-30 0 3 6 9 mEGOS SCORE 0-9 mEGOS SCORE 0-12
  88. 88. Prognostic Scores – EGRIS: Prognosis Erasmus GBS respiratory insufficiency score – used to predict respiratory depression. Most of these score are tested in AIDP and need to be validated for children and axonal variants ** Walgaard C, Lingsma HF, Ruts L, et al. Prediction of respiratory insufficiency in Guillain-Barre syndrome. Ann Neurol 2010; 67: 781–87.
  89. 89. Take Home Message: ► Besides the classical GBS, variants, forms fruste are known ► Treatment should not be delayed even if electrophysiology non-confirmatory ► All patients should be treated with IVIG/PlEx even In mild cases ► Therapy should be initiated within 2 weeks ► Though in worsening patients, treat even ≥ 2 weeks ► PlEx C/I in hemodynamically unstable patients ► IVIG – careful in patients with hypercoagulability or renal insufficiency ► No justification to use recurrent IVIG or PE unless recurrent disease Prognosis

Editor's Notes

  • CANOMAD : Chronic Ataxic Neuropathy, Ophthalmoplegia, Monoclonal IgM protein, cold Agglutinins and Disialosyl antibodies. All autoimmune including sle, sjogrens, RA, coeliac ds, amyloidosis
  • Jean Baptiste octave landry described the first case of distal sensory formications followed by ascending motor weakness following a prodrome of fever, who died of respiratory failure
  • Almost half a century after landry published his findings, GBS described a similar condition with 2 distinctive features – 1. better prognosis, 2. unique CSF findings. They described 2 French soldiers with similar condition of AREFLEXIC motor weakness with muscle tenderness and parasthesias with abnormal NCS. Though guillian resisted any similarity to landrys case and even went on to say that landrys case was different as it had poor outcome, whereas HIS disease was benign. Poor old Strohl, being a young fresh graduate in radiology found his name dropped in favour of other eminent senior neurologists.
  • In their landmark paper in 1949, Haymaker and kerhnhohn unified the findings of LGBS and emphasized the pathology is in the proximal nerve roots, and involves nerve edema leading to breakdown of myelin with lymphocytic infilteration occurring late in course of disease
  • As happens with many eponymous diseases.. Difficult to define exactly. 1927 when the term Guillain-Barré syndrome was first used at a presentation by Dragonescu and Claudian. . in 1949 Haymaker and Kernohan suggested a wider definition of the illness, suggesting that Landry's ascending paralysis and Guillain-Barré syndrome were indistinguishable and called the condition Landry-Guillain-Barré syndrome
  • GBS is the most common and most severe acute paralytic neuropathy. Under the umbrella terms of GBS, a number of variants have been described – with 20-30% patients having the generalized disease with resp insufficiency. Although case reports mention all ages, GBS prevalence is presumed to increase with age and is slightly more common in males. Nearly 70-90% cases are AIDP, upto 20% AMAN, less than 5% MFS
  • Typically GBS is a non-seasonal non epidemic disease, though Seasonal variations, presumably due to varying infection rates have been noticed. Incidence rates have been shown to be higher in certain geographical regions, again probably secondary to increased infection rates.
  • Outbreaks of GBS – typically axonal variants have been reported in China after exposure of children to C.jejuni through chicken feces deposited in rice paddies.
  • The classical antecedent infection is a non-descript URTI. Almost every febrile infection and immunization at one point or the other has been linked to GBS, though recent serological studies have shown Campylobacter jejuni is the most prevalent – in 25-50% cases. Trauma and surgeries have also been reported in temporal association with GBS though causality is still to be established.
  • GBS secondary to arboviral diseases like dengue and chickungunya and zika is of interest now as global epidemic spreads
  • The nature of infection is important in terms of clinical phenotype and prognosis. As we said C.jejuni is the most common infection, and commonly it leads to axonal forms. CMV infection leads to more severe illness with cranial neuropathies and higher likelihood of resp failure.
  • Risk of vaccination leading to GBS is a growing concern and is preventing parents from getting children vaccinated. Specifically the Semple rabies and the Influ A vaccines and more recently the H1N1 vaccines have been reported to cause gbs, though the prevalence and incidence rates are barely over the baseline population rates. Also Generally there are no C/I to vaccination except maybe in patients who have had GBS in last 3 months or have a proven vaccination related GBS. Though risk-benefit must be discussed on case to case basis.
  • CMI directed towards myelin sheath, possibly triggered by molecular mimickry b/w epitopes found in CW of microbes.. LPS and gangliosides in schwann cells and axonal memb. .. f/b complememnt mediated destruction of myelin sheath or axon
  • When these antibodies attack axon membrane – damaged – axonopathy – now regeneration of axon takes time and is usually incomplete – so prognosis is relatively poor. Now by the same thought these antibodies may damage myelin sheath causing AIDP. However if we really go into the details.
  • AIDP segmental demyelination and remyelination are seen and macrophages invade the outer surface of the myelin sheath. However the problem with this model of pathogenesis is it does not explain the rapis reversal following PLEX/IVIG as remyelination would take time. Some authors have thus proposed that it is due to removal of blocking effect on saltatory conduction. This is usually due to involvement of nodes of ranvier which contain a large no of ion channels, proteins which can be a target of autoantibodies.
  • So authors have put forward a concept of NODOPARANODOPathy. So the ranvier nodes consist of 3 domains – node, paranode and juxtaparanode. Each has a distinct molecular structure.
  • There are 4 gps of molecules in nodes – 1. ion channels and related proteins, 2. cellular adhesion and ecm associated proteins, 3. signal transduction proteins and 4.cytoskeletal structural proteins. What we can remember is that Na 1.6 isimportant here and Na 1.6 knockout mice have shown decreased conduction velocities.
  • Paranode consists of axo-glial septate like junctions which attach myelin loops to axon
  • Juxtaparanode is located within myelin sheath and separates the internodal space from axon.
  • IgG antibodies are deposited. Autoimmune attack occurs at the nodes first then extends to the paranodes. Clusters of
    nodal voltage-gated sodium channels and paranodal contactin-associated protein are destroyed. What ultimately happens is that the node elongates and the expression of these nodal proteins is disrupted – causing a block in transmission of signal.
  • With timely intervention, this process is reversible. However ongoing damage ultimately leads to axonal degenration and permanent dysfunction. Cutting long story short, GBS is mainly due to molecular mimickry leading to lymphocytic mononuclear infilterate with macrophage associated segmental demyelintion.
  • Most patients report preceding URT/ Gi infections within last 4 weeks, mostly 7-10 days
  • Symptom progression beyond 4 weeks reflects sub-acute inflammatory polyneuropathy and that beyond 8 weeks indicated CIDP
  • If we go back to the case described by Landry, the typical onset is with sensory symptoms including numbness and parasthesias in toes and fingers. Only in a minority of cases they would be absent throughout. More than half of the patients would c/o accompanying pain and aching discomfort in muscles of hips, thighs and the back. These c/o precede weakness and may be confused for a lumbar disk disease or an orthopaedic disorder.
  • Weakness is classically ascending, starting in distal lower limbs.
  • Weakness is classically ascending, starting in distal lower limbs.
  • Most patients with MFS have 2 of the 3 with a supporting elevated csf protein and autoantibody
  • AMAN is basically a pure motor weakness, though a minority of patients might report pins and needle sensation. There is usually no cranial nerve or autonomic involvement. Easy way to remember is all clinical findings are more in AIDP excpt more rapid progression and early peak in AMAN. DTR are also more preserved in AMAN and patients might develop hyperreflexia at peak of illness or during recovery. The early rapid recovery is due to reversal of CB, late recovery is aw axonal degeneration.
  • Rupperts variant – 6th and 7th nerve
    Polyneuritis cranialis
  • Though classically ascending paresis, onset can be with pharyngo-cervico-brachial muscles or this may constitute the entire illness, causing bulbar symptoms and bibrachial paresis. Ptosis, occasionally with ophthalmoplegia may be added to this. Clinically it is imperative to then differentiate with myasthenia, diphtheria, botulism or a brainstem or central cord lesion
  • A syndrome comprising of complete ophthalmoplegia with ataxia and areflexia was described by Fischer – so called the. Opthalmoplegia if present is almost universally a.w. anti GQ1b. Opthalmoplegic variant again needs to d/d with MG, tick paralysis, botulism, diphtheria
    B/L but asymmetrical facial and abducens palsy coupled with distal parasthesias has also been described by Roppers. Lymes disease and sarcoidosis then become clinically important differentials. Whether isolated Polyneuritis cranialis
  • The diagnosis of GBS is mainly clinical. And it hardly matters if its AIDP, AMAN – from a treatment point of view.
  • Developing a diagnostic criteria for such ds with varied manifestations and presentations is challenging. Absence of clinical biomarkers adds to the difficulty of the task.
  • Brighton collaborative GBS working group definition. Either csf or NCS not consistent – level 2, if both – level 3
  • Routine tests are ususally normal.. Mild inc in cpk. Even if pleocytosis is present, cells decrease in a matter of 2-3 days, however, persistent pleocytosis suggests alternate or additional diagnosis.
  • CSF protein levels are normal in the first few days of illness and reach a peak in 4-5 weeks , then may persist. The increase inprotein reflects a widespread inflammatory disease of the nerve roots, but high values have no correlation with clinical or prognostic significance. In fewer than 10% patient, CSF protein levels may remain normal throughout the illness of the disease
  • Proteonomics have been applied which has shown
  • Routine tests are ususally normal.. Mild inc in cpk
  • Routine tests are ususally normal.. Mild inc in cpk
  • Routine tests are ususally normal.. Mild inc in cpk. Electrodiagnostic tests are early dependable diagnostic indicators of GBS.
  • The most common abnormalities are reduced conduction velocities and prolonged distal latencies – signifying a demyelinating pattern, which may be associated with distal conduction blocks. Reduced CMAPS are frequently associated, signifying axonal pathology.
  • Routine tests are ususally normal.. Mild inc in cpk
  • Routine tests are ususally normal.. Mild inc in cpk
  • Sensitivity of NCS in early GBS may only be about 20%, rising to nearly 90% after 5 weeks of illness. Thus a normal NCS does not rule out GBS in clinically suspected cases. One reason for this may be the involvement of roots which are beyond the reach of NCS and involvement of entrapment sites which are usually excluded.
  • Routine tests are ususally normal.. Mild inc in cpk
  • Serial (SNAP) recordings – ulnar, sural nerves in two patients with (GBS). Patient 1 has normal ulnar and sural sensory recordings - day 3 after onset. Serial studies at day 6 and day 14 - developing “sural nerve sparing pattern” with decreased ulnar SNAP but normal sural SNAP. Patient 2 had already “sural nerve sparing pattern” with inexcitable ulnar sensory nerve fibers on admittance (day 4 after symptom onset). Repeated shows decreasing sural nerve SNAP which became abnormal low at day 10 (dotted line = normal levels).
  • Routine tests are ususally normal.. Mild inc in cpk
  • As discussed the axonal variants are a.w. GM1 and GD1a while ophthalmoplegic and ataxic variants are a.w. GQ1b. The pharyno cervico brachial variant has a tendency to be a.w. GT1a.
  • Routine tests are ususally normal.. Mild inc in cpk
  • The most common clinical mimics of GB causing a flaccid areflexic acute onset paralysis are jypokalemic and thyrotoxic PP. Polio is largely eliminated, so comes down in the list of d/d
  • Acute onset flaccid motor weakness may be caused due to involvement of either root, peripheral nerve, NMJ or the muscles.
  • It is important to d/b GBS from other infective polyneuropathies like,…, which are usually pure motor weakness. Viral neuropathies may also be a.w. meningoencephalitic syndrome, resulting in CSF pleocytosis. Tick paralysis, uncommon in india, may be impossible to differentiate from GBS unless one finds the tick. It may also cause ataxia and ophthalmoplegia in addition to an ascending quadriparesis. An episodic painful mixed sensory-motor presentation with normal CSF and associated systemic symptoms may point towards porphyrias
  • Carcinomatous meningitis with polyradiculopathy may be confused with GBS, however, a relative subacute onset with fairly symm distal distribution may help in diagnosis. There is absence of cranial nerve deficits. Cranial variants of GB including Fishers syndrome need to be d/d from MG, botulism and basilar artery thrombosis in rare cases.
  • Presence of quadriparesis with Opthalmoparesis in GBS may need differentiation from basilar A thrombosis, however a UMN type of weakness with pupillary paralysis and Babinski may support a diagnosis of BAT rather than GB. A descending flaccid weakness a.w. early pupillary paresis may signify Botulism
  • Sepsis. MODS, SIRS
    As such differentiating critical illness neuropathy from axonal GBS becomes difficult
  • Efficacy of Plex in GBS has been well estb by large RCTs. Plex during initial 2 weeks results in halving of the hosp stay, duration of mech vent and of the time to recover non supportive ambulation. All trials prefer PE in terms of muscle strength recovery at 1 year.
  • While efficacy of Plex is well estb, there is relative paucity of data on IVIG is still
  • Whether IVIG is to be given over 2 or 5 days is debatable but some authors have reported more treatment related fluctuations in children receiving faster IVIG. In view of easy availability, convenience and minor side effects, it has become the preferred treatment. Though cost is a major limiting factor esp in resource poor countries
  • The first study to demonstrate the efficacy of IVIG was dutch GBS cooperative study group in 1992
  • The first study to demonstrate the efficacy of IVIG was dutch GBS cooperative study group in 1992
  • So good practice to pre-medicate with PCM (headache), anti-histamine, steroids (anaphylaxis), fluid challenge, and place IVIG patients on prophylactic ecosprin in at risk individuals
  • Studies have not demonstrated added advantage of a combination therapy over mono-therapy and as such There is no added benefit of giving IVIG after Plex in non responding patients
  • Lets look at what the AAN recommendations say. For non ambulant patients within 2 weeks, both PE, IVIG are level A, within 4 weeks, only PE is level A, IVIG is level B
  • The value of steroids in treatment of GBS has been debated for years and though some clinicians have reported efficacy, the same has not been proven.
  • Corticosteroids are the most commonly used drugs worldwide for autoimmune diseases because of its cost effectiveness. However, the application of corticosteroids in the treatment of GBS remains to be disappointing for long time. Macrophages engulf and digest the cellular debris and foreign microbes, being divided into a killing/inhibitory type (M1 macrophage) and a heal/growth promoting type (M2 macrophage)7 .
    Recruitment of large numbers of macrophages did not occur until the fiber degeneration is underway8 . In AIDP, at the stage of complement deposition and early myelin vesiculation, macrophages were rarely associated with fibers. However, at later times, when myelin disruption was more advanced, macrophages were abundantly recruited3 . It has been demonstrated that high concentration of steroids exerts immunosuppressive effects on macrophages9 and inhibits the accumulation of macrophages into the injury site10. In this study, we observed significantly less macrophage infiltration and higher frequency of axonal degeneration in AMAN rabbits treated with methylprednisolone
  • Same segmental innervation
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