Acute immune demyelinating polyneuropathy

1. Guillain Barre syndrome- A
Review
Siva Pesala MD

2. GBS

3. History
• One of the earliest descriptions of what we know today as Guillain-Barré
syndrome is found in Landry's report on 10 patients with “ascending
paralysis” in 1859.
• In 1916, Georges Guillian, Jean Alexandre Barre and Andre
Strohl Georges diagnosed two soldiers with the illness and described the
key diagnostic abnormality—albumino-cytological dissociation—of increased
spinal fluid protein concentration but a normal cell count.

4. Original paper
Guillain, Barre and Sthrol

5. History
• Canadian neurologist C. Miller Fisher described the variant that bears his name in
1956.
• British neurologist Edwin Bickerstaff based in Birmingham, described the brainstem
encephalitis type in 1951 with Philip Cloake, and made further contributions with
another paper in 1957.
• The axonal subtype was first described in the 1990s.

6. Arthur Asbury- 1969
Outlined criteria for GBS diagnosis- Published in 1978

7. T.E. Feasby published pure axonal form
GBS
1986

8. Nobuhiro Yuki- 1990s

9. Introduction
• GBS is most common and most severe acute paralytic neuropathy ,with about 100
000 people developing the disorder every year worldwide.
• Under umbrella term of GBS are several recognisable variants with distinct clinical and
pathological features.
• The severe, generalised manifestation of Guillain-Barré syndrome with respiratory
failure affects 20–30% of cases.

10. GBS
• Acute inflammatory demyelinating polyneuropathy (AIDP) was the first to be
recognized over a century ago and is the most common form of GBS. In AIDP, the
immune attack is directed at peripheral nerve myelin with secondary by-stander axon
loss.
• Axonal motor and sensorimotor variants have been described in the last 3 decades
and are mediated by molecular mimicry targeting peripheral nerve motor axons.
• Besides the Miller-Fisher syndrome (MFS) and descending weakness, other rare
phenotypic variants have been recently described with pure sensory variant, restricted
autonomic manifestations and the pharyngeal-cervical-brachial pattern.

11. Epidemiology
• Most studies that estimate incidence rates of Guillain-Barré syndrome were done in
Europe and North America, and showed a similar range of 0·8–1·9 (median 1·1) cases
per 100 000 people per year
• The annual incidence rate of Guillain-Barré syndrome increases with age (0·6 per
100 000 per year in children and 2·7 per 100 000 per year in elderly people aged
80 years and over) and the disease is slightly more frequent in males than in females.
• Seasonal fluctuations, presumably related to variations in infectious antecedents,
have been reported, but these observations are rarely statistically significant.

12. Epidemiology
• Several outbreaks of Guillain-Barré syndrome have been reported, most recently in
relation to C jejuni infections, Zika infection.
• Overall, based on the incidence rate and life expectancy, the estimated lifetime risk of
developing Guillain-Barré syndrome for any individual is less than one in 1000.

13. Epidemiology
• The proportions of patients with GBS who have AIDP and AMAN vary greatly
around the world.
• AIDP is the predominant subtype (60–80% of patients) in North America
and Europe.
• By contrast, the frequency of AMAN ranges from 6–7% in the UK and
Spain to 30–65% in Asia, Central America and South America.

14. Preceding infections
• Guillain-Barré syndrome is a typical post-infectious disorder, as shown by
the rapidly progressive, monophasic disease course (<1 month) shortly after
infection, usually without relapse.
• 2/3 of adult patients report preceding symptoms of a respiratory or
gastrointestinal tract infection within 4 weeks of onset of weakness.
• Many different preceding infections(CMV,EBV,Hepatitis,Mycoplasma) have
been identified in patients with the disorder, but only for a few microorganisms
has an association been shown in case-control studies.

15. Preceding infections
• C jejuni is the predominant infection, found in 25–50% of the adult patients, with
a higher frequency in Asian countries.
• Other infections associated with Guillain-Barré syndrome are cytomegalovirus
(CMV), Epstein-Barr virus, influenza A virus, Mycoplasma pneumoniae, and
Haemophilus influenzae.
• An association of Guillain-Barré syndrome with hepatitis E has been identified in
patients from both the Netherlands and Bangladesh.
• An emerging relation between Guillain-Barré syndrome and acute arbovirus infection
including Zika and chikungunya is being closely monitored and is the subject of major
interest as the global epidemic spreads.

16. Preceding infections
• The nature of the preceding infection affects the clinical phenotype and
prognosis—for example, C jejuni infections are usually associated with a pure
motor axonal form of Guillain-Barré syndrome, more severe limb weakness, and a
serological antibody response directed against GM1 and GD1a gangliosides.
• These patients generally have a poorer outcome. Whether the preceding infections of
childhood Guillain-Barré syndrome are different has not been established.

17. Vaccination and GBS
• During the 1976 vaccination campaign for H1N1 influenza A virus, roughly 1
in 100 000 people who had been vaccinated developed Guillain-Barré
syndrome.
• Although a similar association was suggested for the H1N1 influenza A
vaccination in 2009, extensive studies showed only 0.8 cases of Guillain-
Barré syndrome per 1 000 000 people vaccinated, a frequency similar to all
seasonal flu vaccinations.

18. Vaccination and GBS
• Vaccination might, in fact, reduce the chance of an individual developing
Guillain-Barré syndrome after natural infection with influenza A, which is itself
a possible candidate to precipitate the disorder.
• In a survey, none of the 106 patients with Guillain-Barré syndrome who had
been vaccinated against influenza (range of vaccinations per person 1–37
times, total 775 vaccinations) reported a recurrence of Guillain-Barré
syndrome after the vaccination.

19. Vaccination and GBS
• Generally, no contraindication to the vaccination of patients who previously have had
Guillain-Barré syndrome seems to exist, except for patients
-> Who had had the disorder in the past 3 months
-> Who had vaccination-related Guillain-Barré syndrome, although risk and benefit might be
discussed on a case-by-case basis.

20. Pathogenesis
• The pathology of most European cases of GBS is perivascular multifocal
lymphocytic infiltration with demyelination (Asbury et al. 196), termed acute
inflammatory demyelinating polyradiculoneuropathy (AIDP).
• Macrophages penetrate the Schwann cell basal lamina and strip myelin
lamellae.
• An axonal form of GBS without inflammation or demyelination has been
particularly studied in China where acute motor axonal neuropathy (AMAN) is
as common as AIDP (Ho et al. 1995). Severe axonal degeneration may be
secondary to primary autoimmune attack on either axon or myelin.

21. Pathogenesis and Immunopathology

22. Pathogenesis
A molecular mimic of gangliosides
in C. jejuni leads to the production of
anti-ganglioside antibodies that bind
to gangliosides in the axonal
membrane at the node of Ranvier.
Consequent activation of
complement leads to disruption of
voltage-gated sodium channel (NaV)
clusters, disruption of the nodal
architecture, and formation of the
membrane attack complex, which
leads to calcium influx.
These changes cause axonal injury
and attract macrophages, which can
then migrate between the axon and
myelin.

23. GBS subtypes, clinical features and relevant antibodies
Van den Berg, B. et al. (2014) Guillain–Barré syndrome: pathogenesis, diagnosis, treatment and prognosis
Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.121

24. Acute inflammatory demyelinating polyradiculoneuropathy-AIDP
• Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the commonest
type of Guillain-Barré syndrome.
• Necropsy studies have shown lymphocytic infiltration of the peripheral nerves
and macrophage mediated segmental demyelination.
• Axonal loss may also occur, especially in severe cases as a secondary event.
• These pathological changes seem to be mediated by both humoral and cellular
immunity in variable degrees. Characteristic electrophysiological features
reflect segmental demyelination.
• Subsequent remyelination is associated with recovery.

25. Acute motor axonal neuropathy
• During summer epidemics of Guillain-Barré syndrome in northern China in 1991
and 1992, a majority of patients was found to have a pure motor axonal form of
neuropathy, and the term “acute motor axonal neuropathy” (AMAN) was
coined.
• Around 55–65% of the patients belonged to this category, of whom 76% were
seropositive forC jejuni, compared with 42% in AIDP cases.Among sporadic cases
of Guillain-Barré syndrome, about 10–20% are of AMAN type.
• Antiganglioside antibodies anti-GM1, GD1a, and GD1b are found in this group.
• Electrophysiologically, compound muscle action potential amplitudes are reduced
but motor distal latencies, motor conduction velocities, sensory nerve action
potentials, and F waves are within the normal range.

26. Acute motor axonal neuropathy
• Necropsy studies have shown Wallerian-like degeneration of motor axons.
• The earliest pathological changes are lengthening of the nodes of Ranvier,
distortion of the paranodal myelin.
• These early nodal and periaxonal changes may be reversible, which probably
explains the rapid recovery in some cases.
• Tendon reflexes could either be preserved or exaggerated, the latter particularly in
AMAN cases.
• Hyperreflexia is seen in about one third of patients, usually during the early
recovery phase and occasionally in the acute phase. This finding is significantly
associated with the presence of anti-GM1 antibodies and less severe disease.

27. Miller Fisher syndrome
• The first GBS variant was Miller Fisher Syndrome (MFS) and consists of
ophthalmoplegia, ataxia, and areflexia without any weakness .
• Most of the patients with MFS present with at least two features and have in
support an elevated CSF protein and characteristic autoantibody(Gq1b).
• Though MFS represents 5 to 10% of GBS cases In Western countries, it is more
common in Eastern Asia, accounting for up to 25% of Japanese cases .
• Some MFS cases may progress to otherwise classic GBS.
• In addition, five percent of typical GBS cases may have ophthalmoplegia.

28. Bickerstaff’s brain stem encephalitis (BBE)
• BBE is a variant of MFS characterized by alteration in consciousness,
paradoxical hyperreflexia, ataxia, and ophthalmoparesis .
• BBE cases represent a variant of MFS with antecedent infection (92%),
elevated CSF protein (59%) and anti-GQ1b antibody (66%).
• Brain magnetic resonance imaging (MRI) abnormalities are present in only
30% of BBE cases and the frequency of BBE variant is 10% of that of MFS.

29. Other variants
• The pharyngeal-cervical-brachial motor variant manifests in up to 3% with ptosis,
facial, pharyngeal and neck flexor muscle weakness that spreads to the arms and
spares leg strength, sensation and reflexes thereby mimicking botulism.
• A less common paraparetic motor variant affects the legs selectively with areflexia
mimicking an acute spinal cord lesion and is associated with back pain.

30. Clinical features
• The most common initial symptom of GBS is acroparesthesia with little objective
sensory loss .
• Severe radicular back pain or neuropathic pain affects most cases.
• Within a few days, weakness ensues commonly in a symmetric “ascending
pattern”.
• Most patients present initially with leg weakness and arm weakness (32%) or
selective proximal and distal leg weakness (56%) often spreading to the arm while
some have onset of weakness in the arms (12%). A descending presentation
mimicking botulism, with onset in the face or arms, is less common.

31. Clinical features
• Fokke et al-Brain -2014-Prospectively collected data from a cohort of 490 patients with GBS, previously involved in
therapeutic or clinical studies, were used to define the demography, clinical presentation, diagnostic investigations, and
clinical course

32. Clinical features
• Besides prominent weakness, patients are hypo- or areflexic within the first few days
but this may be delayed by up to a week.
• Facial nerve involvement occurs in up to 70% of cases, dysphagia in 40%, and
rarely (5%) patients may develop ophthalmoplegia, ptosis, or both suggesting
botulism or myasthenia gravis .
• Hearing loss, papilledema and vocal cord paralysis are less common.

33. Clinical features
• Approximately 25% of patients develop respiratory insufficiency requiring
artificial ventilation.
• Autonomic dysfunction (predominantly cardiovascular dysregulation) is present in
about two-thirds of patients, although its severity is highly variable.
• About one-third of patients remain able to walk throughout the course of the
disease, and are often described as mildly affected.

34. Diagnostic criteria
Ref- Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann
Neurol. 1990;27(Suppl):S21–S24

35. Diagnosis -Features that should raise doubt about the diagnosis of Guillain-Barré syndrome
• CSF: increased number of mononuclear cells or polymorphonuclear cells (>50 cells per μL).
• Severe pulmonary dysfunction with little or no limb weakness at onset.
• Severe sensory signs with little or no weakness at onset.
• Bladder or bowel dysfunction at onset
• Fever at onset.
• Sharp spinal cord sensory level.
•Marked, persistent asymmetry of weakness.
• Persistent bladder or bowel dysfunction.
• Slow progression of weakness and without respiratory involvement (consider subacute inflammatory demyelinating
polyneuropathy or acute onset chronic inflammatory demyelinating polyneuropathy).
·

36. Mimics of GBS presenting as quadriparesis:*
1.Anterior Horn cell: poliomyelitis or West Nile virus infection (asymmetric weakness)
2.Peripheral Nerve:
1. Critical illness neuropathy
2. Lymphoma / leptomeningeal carcinomatous meningitis
3. Toxic neuropathies: solvent or heavy metals
4. Porphyria
5. Lyme
6. Diphtheria
7. Vasculitic neuropathy
3.Neuromuscular Junction:
1. Myasthenia Gravis
2. Botulism
3. Tick paralysis (children)
4.Muscle:
1. Idiopathic inflammatory myopathies
2. Periodic paralysis
3. Critical illness myopathy
4. Rhabdomyolysis
5. Severe hypokalemia or hypophosphatemia
5.Acute spinal cord lesion

37. Diagnosis-CSF studies
• CSF examination typically shows increased protein with normal CSF white-cell
count(Albumino-cytological dissociation).
• CSF protein concentrations in patients with GBS are often normal in the first
week, but increased in more than 90% of the patients at the end of the second
week.
• In a large study of patients with the Miller Fisher syndrome (MFS) subtype of GBS,
the proportion of patients with raised CSF total protein increased from 25% in the
1st week to 84% in the 3rd week.

38. Diagnosis –CSF studies
• CSF analysis is critically important in all GBS cases and reveals albuminocytologic
dissociation; that is an elevated protein up to 1,800 mg/dl with 10 or less white
cells/in most cases.
• Half of GBS cases may have a normal CSF protein in the first week but that
proportion declines to 10% if the test is repeated a week later .
Fokke et al-Brain -2014

39. Diagnosis –CSF studies
• Pleocytosis of 10–20 cells/mm3 is seen in ~5% of cases and should not
dissuade one from a diagnosis if the clinical and electrodiagnostic features
are otherwise typical.
• If there are more than 50 cell/per mm3 particularly two weeks of after the
onset of symptoms, one should consider early HIV infection,
leptomeningeal carcinomatosis, CMV polyradiculitis and sarcoidosis.
• Most MFS cases and half of BBE cases have albuminocytologic
dissociation.

40. Diagnosis- NCS studies
• When GBS is suspected, electrophysiologic studies are essential to confirm the
diagnosis and exclude its mimics.
• The differential of pure motor syndrome includes other diseases associated with
quadriparesis/paralysis such as myasthenic crisis, acute presentation of the
idiopathic inflammatory myopathies and the unusual motor neuron disease
patient presenting with acute respiratory failure.
• Associated clinical features are often helpful in distinguishing these from GBS.
• The finding of multifocal demyelination on early electrodiagnostic testing (or
repeated a week later) is extremely helpful in confirming the diagnosis of AIDP
with a high sensitivity and specificity.

41. NCS

43. Diagnosis and NCS studies
• The earliest findings in AIDP are prolonged F-wave latencies or poor F-wave
repeatability due to demyelination of the nerve roots.
• This is followed by prolonged distal latencies (due to distal demyelination) and
temporal dispersion or conduction block.
• However, the sensitivity of nerve conduction studies (NCS) based on reported
criteria may be as low as 22% in early AIDP , rising to 87% at five weeks into the
illness.

44. NCS
• In AMAN, CMAP amplitudes are significantly reduced in the first few days and then
in severe cases become absent .
• Fibrillation potentials may occur early on in the course of AMAN and needle electrode
examination is helpful.
• In AMSAN the sensory potentials are reduced in amplitude and often absent.
• H-reflexes absence may be the only abnormality in 75% of MFS and BBE cases.

45. NCS
• NCS might also have prognostic value because patients with features of
demyelination more often need mechanical ventilation, and low compound
muscle action potentials (CMAPs) are the most consistent findings predictive of
poor outcome.
• Based on clinical trial evidence so far, distinguishing between acute inflammatory
demyelinating polyneuropathy and acute motor axonal neuropathy does not imply that a
patient needs a specific or tailored immunological treatment.

46. Imaging – MRI contrast
• Radiological studies are ordered to exclude other causes and in cases where nerve
conduction studies and CSF examination are equivocal.
• MRI of the spine is most useful helps excluding other aetiologies such as transverse
myelitis and compressive causes of polyradiculopathy.
• It is essential that contrast is administered if the diagnosis is suspected as non-contrast
sequences are essentially normal .
• Typical findings in GBS are surface thickening and contarst enhancement on the
conus medullaris and the nerve roots of the cauda equina .The most common site of
enhancement in Guillain–Barré syndrome is considered to be anterior nerve roots.

47. Diagnosis and treatment of GBS
Van den Berg, B. et al. (2014) Guillain–Barré syndrome: pathogenesis, diagnosis, treatment and prognosis
Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.121

48. GBS disability scale

49. Plasma exchange
• In 1978, Brettle et al first drew attention to the improved outcome in a patient with
Guillain-Barré syndrome following plasma exchange.
• Subsequently the efficacy of plasma exchange was established by large multicentre
trials.
• Plasma exchange beginning within the first two weeks of the illness reduced the
period of hospital stay, the duration of mechanical ventilation.

50. Plasma exchange
Time to weaning from the ventilator by
13 to 14 days and time to walk unaided
by 32 to 41 days

51. Plasma exchange
• While the PE-treated groups in the North American and French studies did better
than controls, the time to walk and to discharge, and the time spent on a ventilator,
were still fairly long, even in PE-treated patients.
• Therefore, physicians, patients, and family members need to have realistic
expectations about the extent of the effect of both PE and intravenous gamma
globulin (see the following section).
• Dramatic improvement within days of beginning treatment is not the rule and if this
occurs, it may have happened regardless of treatment.

52. Plasma exchange
• Limitations include : Invasive, large IV access .
• Potential complications :
-Pneumothorax
-Hypotension
-Sepsis
-Pulmonary embolism
-Hemorrhage from vein puncture
-Low platelets ,prolonged clotting parameters, hypocalcemia, citrate toxicity and
anemia.

53. IVIG
• The benefits of intravenous immunoglobulin in Guillain-Barré syndrome were first
reported by Kleyweget al in 1988.
• Ease of administration compare to Plasma exchange.
• Moderate rare reactions include chemical meningitis(Aseptic meningitis),
neutropenia and delayed red, macular skin reaction of the palms, soles and trunk
with desquamation.
• Acute renal failure is uncommon and related to patient dehydration and the prior use
of sucrose or maltose diluents.
• Other severe and rare reactions are anaphylaxis, stroke, myocardial infarction or
pulmonary emboli due to hyperviscocity syndrome.

54. IVIG
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
The first large study to demonstrate a
favorable response to IVIg in GBS was
by the Dutch Guillain-Barré Study
Group two decades ago .
They compared the efficacy of IVIg to
PE in 147 patients and there was no
control group. Their results showed that
not only IVIg was effective but it was
possibly more effective than PE.
However there may have been a group
imbalance to account for the later since
PE efficacy in the Dutch trial did not
match up with that of the North
American study such as in the rate of 1-
grade improvement at four weeks.

55. IVIG- PSGBS RCT trial
• A large, multicentre, randomised trial compared PE, IVIG, and combination
treatment of PE followed by IVIG.
• Patients were randomised to three groups to receive plasma exchange (five
exchanges of 50 ml/kg body weight each, completed within 13 days), intravenous
immunoglobulin (0.4 g/kg body weight for five days), or combined treatment.
• In the final analysis, there was no significant difference in efficacy between plasma
exchange and intravenous immunoglobulin.No significant advantage in combined
treatment was evident.

56. IVIG-PSGBS RCT trial
Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Plasma
Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group.
Lancet. 1997 Jan 25;349(9047):225-30

57. Corticosteroids
• Steroid treatment in Guillain-Barré syndrome has yielded disappointing results.A
double blind, placebo controlled, multicentre trial looked into this issue.
• 242 patients were randomised to receive either high dose intravenous
methylprednisolone (500 mg daily for five days within two weeks of onset) or placebo.
The results did not show any significant difference in outcome between the two
groups.

58. AAN guidelines

59. AAN guidelines

60. Outcome and prognosis
• Most patients with GBS begin to recover at 28 days with mean time to complete
recovery being 200 days in 80% of cases.
• However, many (65%) have minor residual signs or symptoms often making
recovery less than complete .
• In a study of 79 cases a year after the onset of GBS, 8% had died (all older than 60),
4% remained bedbound or ventilator dependent, 9% were unable to walk unaided,
17% were unable to run, and 62% had made a complete or almost complete recovery
.
Epidemiological study of Guillain-Barré syndrome in south east England J Rees, R Thompson, N Smeeton, and R Hughes

61. Outcome and prognosis

62. Outcome and prognosis
Modified ERASMUS scale
Neurology. 2011 Mar 15; 76(11): 968–975.doi: 10.1212/WNL.0b013e3182104407
Early recognition of poor prognosis in Guillain-Barré syndrome

63. Outcome and prognosis
• 5 % of GBS cases succumb to their illness due to complications of critical illness
(infections, adult respiratory distress syndrome, pulmonary embolism), and
rarely dysautonomia.
• The relapse rate is 5% and it usually occurs within the first eight weeks. The
alternative diagnosis of relapsing-remitting chronic inflammatory demyelinating
polyneuropathy (CIDP) should be considered in relapsing cases.

64. Outcome and prognosis
• Most AMAN patients have more delayed recovery than AIDP while some cases
recover quicker.
• Most MFS patients recover by six months.

65. Thank you
•Questions???

66. References
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67. References
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