Josef Bednařík
Neurologická klinika LF MU a FN Brno
8.11.2019
Autoimmune (immune-mediated)
neuropathies
ETIOLOGY OF POLYNEUROPATHIES
8.11.2019
PHENOTYPING OF POLYNEUROPATHIES
 Pathophysiological type (based on electrophysiology):
 Axonal
 Demyelinating
 Type of nerve fibers involved:
 Motor neuropathies/neuronopathies
 Sensory neuropathies/neuronopathies
 Autonomic neuropathies
 Mixed neuropathies
 Symmetry of involvement
 Symmetrical
 Distal (length-dependent, „dying-back“)
 Diffuse (non-length dependent)
 Multifocal (mononeuropathy multiplex)
8.11.2019
PHENOTYPING OF POLYNEUROPATHIES
 Pathophysiological type (based on electrophysiology):
 Axonal
 Demyelinating
 Type of nerve fibers involved:
 Motor neuropathies/neuronopathies
 Sensory neuropathies/neuronopathies
 Autonomic neuropathies
 Mixed neuropathies
 Symmetry of involvement
 Symmetrical
 Distal (length-dependent, „dying-back“)
 Diffuse (non-length dependent)
 Multifocal (mononeuropathy multiplex)
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IDIOPATHIC INFLAMMATORY (MOSTLY
DEMYELINATING) NEUROPATHIES
 Acute (monophasic) form: Guillain-Barré syndrome
• Several clinical and pathogenetic variants
GBS: HISTORY
 First description: Landry 1859
 Description of typical proteino-cytological
dissociation: Guillain, Barré, Strohl 1916
Andy Griffith Joseph Heller FD Roosevelt
GBS: EPIDEMIOLOGY
 incidence 0.5% – 2.0/100.000/year;
 slightly higher prevalence in men
 any age
 2/3 of cases is preceeded by infection, especially
Campylobacter jejuni (4-66%), EBV (2-10%), cytomegalovirus
(5-15%) a Mycoplasma pneumoniae (1-5%), further by
vaccination, surgery.
GBS: CLINICAL MANIFESTATION
Demyelinative form:
 acute inflammatory demyelinative polyradiculoneuropathy (AIDP)
Axonal form:
 acute axonal motor-sensory neuropathy (AMSAN)
 acute axonal motor neuropathy (AMAN)
GBS variants:
 Miller-Fisher syndrome (MFS)
 acute pandysautonomia
 sensory form
 facial diplegia
 oropharyngeal form
GBS: CLINICAL MANIFESTATION
 Self-limited course with progression of clinical signs up to 4
weeks (90%)
 Cranial nerves frequently involved (facial diplegia in 50% of cases)
 Extraocular muscles (with the exception of MFS) and bowel and
bladder are spared
 Motor involvement (weakness) is dominant
 Pain is sometimes prominent (mimicking root lesion) - in 30-50%
of cases)
 Autonomous dysfunction (especially orthostatic hypotension,
cardiac arrhythmias) in 2/3 of cases
GBS: ETIOPATHOGENESIS
 Axonal form (AMAN) is often preceeded by Campylobacter jejuni infection,
whose cells has similar structure as GM1 gangliosides – „molecular mimicry“
hypothesis;
 anti-GM1 antibodies are present in 15-40% of GBS cases
 Miller-Fisher syndrome is associated with anti-GQ1b a GT1a antibodies in
90% of cases
Kamil et al., Front
Neurol 2019
Yu et al.
Infection and
Immunity 2006
GBS: DIAGNOSIS
CSF: typically proteino-cytological dissociation
BUT:
 10% have pleocytosis up to 50 cells/ml
 Hyperproteinorrhachia is common during the 2nd
week, not earlier
GBS: DIAGNOSIS
EMG: typically multifocal demyelinative neuropathy
with conduction blocks, temporal dispersion,
conduction slowing; early signs of axonal
involvement indicate unfavourable prognosis
BUT:
 In axonal forms (AMAN, AMSAN) signs of demyelinative
involvement are lacking
 EMG abnormalities arel lacking during first days
especially in MFS
ELECTRODIAGNOSIS
Main electrophysiological signs of demyelinative
neuropathy
 Conduction slowing
 Temporal dispersion
 Conduction block
ELECTRODIAGNOSIS: MULTIFOCAL TEMPORAL DISPERSION,
CONDUCTION SLOWING AND BLOCK
DIAGNOSTIC CRITERIA FOR GBS
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GBS: COURSE AND PROGNOSIS
Indicators of unfavourable prognosis:
 Electrophysiological signs of axonal
neuropathy (spontaneous activity, decreased
CMAP amplitude)
 Rapid progression, assisted ventilation
 Preceeding gastrointestinal infection,
cytomegalovirus infection, age >50 let,
generalized severe weakness
GBS: COURSE AND PROGNOSIS
 Mortality is 3-8%;
 Moderate to severe residual involvement in 5-
10%;
 Spontaneous improvement after 2 years is no
probable;
 Relapses in 3% of patients.
GBS: TREATMENT
Pathogenetic treatment
 therapeutic plasmapheresis
 intravenous human immunoglobulin
Symptomatic treatment
 Pain
 Depression, anxiety
 Infections
Prevention of complications
 Respiratory failure (early intubation)
 Cardiovascular failure
 dysphagia (nasogastric feeding, gastrostomia)
 nosocomial infections (pneumonia, urinary infections)
 Pressure sores
CHRONIC AUTOIMMUNE DEMYELINATING POLYNEUROPATHIES
 Chronic
 Immune (dříve Inflammatory)
 Demyelinating
 Polyneuropathy
• Including „multifocal CIDP“ (Lewis-Sumner syndrome) and CIDP
variants
• CIDP associated with other disorders (MGUS, DM, HIV, lupus, CNS
demyelinization)
 Uncertain differentiation againts other autoimmune neuropaties with
auto-antibodies (POEMS, GALOP, anti-sulfatidy, anti-MAG) –
„nodopathies“;
 Multifocal motor neuropathy (MMN)
EPIDEMIOLOGY
Rare disorders:
 MMN: prevalence 0.6-2.0/100 tis.
 CIDP: prevalence 1.2-8.9/100 tis.
CIDP: DIAGNOSIS
(EFNS/PNS REVISED CRITERIA CIDP 2010)
CIDP: DIAGNOSIS
(EFNS/PNS REVISED CRITERIA CIDP 2010)
Exclusion criteria
CIDP: DIAGNOSIS
(EFNS/PNS REVISED CRITERIA CIDP 2010)
CIDP MMN
Supportive criteria
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CIDP: MRI FINDINGS
DISEASES ASSOCIATED WITH CIDP
 Diabetes mellitus
 MGUS (IgG, IgA)
 Monoclonal gamapathy IgM non-anti-MAG
 Lupus erytematosus or other vasculitis or collagenosis
 HIV
 Chronic active hepatitis
 Sarkoidosis
 Thyreopathy
 Colitis
 Bone marrow or organ transplantation
CIDP TREATMENT
Induction (initial) treatment:
 CIDP with sensory-motor involvement:
• 1st choice = corticosteroids or IVIG
• 2nd choice: Plasma exchange (less tolerated)
 CIDP with predominantly motor involvement
• 1st choice = IVIG
IVIG VS. CORTIKOSTEROID IN CIDP
IVIG Corticosteroids
Efficacy ++ +
Latency of the onset of effect + +
Duration of remission + +
Side effects + Patient‘s
preference + +
Cost - +
CIDP TREATMENT
Maintenance treatment:
 Continue with treatment of 1st choice, if effective, to
maximum effect, than decrease the dose to minimum
effective
 Try 2nd choice treatment, if 1st choice is ineffective or
not tolerated
CIDP TREATMENT: IMUNOSUPRESANT AND IMUNOMODULATORS
Evidence of effectiveness is lacking, but it is used:
 Alemtuzemab
 Azathioprine
 Cyklofosfamid
 Cyklosporin
 Etanercept
 Interpheron alfa a beta1a
 Mycofenolate mofetil
 Methotrexate
 Rituximab
 Transplantation of haemopoetic stem cells
DIAGNOSTIC CRITERIA FOR MMN
(VAN SCHAIK ET AL. ENS 2006)
DIAGNOSTIC CRITERIA FOR MMN:
(VAN SCHAIK ET AL.. 2006,
Definite conduction block
Area: -80%
Amplitude: -80%
MMN TREATMENT
IVIG treatment is the only treament modality with
proved effectiveness – 1st choice and the only option
Therapeutic scheme in
MMN
Vlam et al.
Nat Rev Neurol 2011
NEW THERAPEUTIC TRENDS
 Patient-tailored IVIG treatment (personalized
therapy)
 Subcutaneous (ScG) immunoglobulin
 Complement blockade:
• Eculizumab – monoclonal antibody against C5 –
blocks MAC synthesis
• Other drugs blocking activation of complement
 Blockade of antoantibodies formation by B
lymphocytes:
• Rituximab – monoclonal antoantibody against CD20
DIFFERENTIAL DIAGNOSIS AMONG CHRONIC
DYSIMMUNE NEUROPATHIES
Symptom/diagnosis MMN CIDP MADSAM
Distribution of weakness - symmetry assymetrical symmetrical assymetrical
Distribution of weakness – upper > lower
extremities
yes no yes
Distinctive sensory syptoms no yes yes
Tendon reflexes in a territory of weak muscles normal or diminished diminished or unelicited diminished
Course of the disease slow progression progressive or relapsing progressive or
relapsing
Hyperproteinorachia >1g/ no yes rarely
Anti-GM1 IgM yes (50%) rarely rarely
Abnormal MRI of the brachial plexus asymmetrically symmetrically asymmetrically
Effect of IVIG yes yes yes
Effect of corticosteroids no yes yes