1. The document discusses various variants of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). It describes clinical features and electrodiagnostic patterns of AIDP subtypes including AMAN and AMSAN as well as regional and atypical variants of GBS like Miller Fisher Syndrome. 2. Rare autoimmune nodopathies caused by antibodies targeting nodes of Ranvier are described. Clinical features associated with antibodies to contactin-1, neurofascin 155, neurofascin isoforms and contactin-associated protein 1 are summarized. 3. Diagnostic criteria and variants of CIDP
2. Introduction
– Inflammatory demyelinating polyradiculoneuropathies are
acquired immunologically mediated polyneuropathies
– Classified on the basis on their clinical course into two major
groups:
(1) GBS, and (2) CIDP.
– GBS = the maximal deficits develop over days or weeks (max 4
weeks), f/b a plateau phase and gradual recovery.
– CIDP = Either a slowly progressive ( ≥ 2 months) or a Relapsing-
Remitting course.
5. AMSAN
– Acute & Rapidly Progressive course; Max deficit in <7 days.
– Profound Quadriparesis; severe muscle wasting and
– Prolonged ventilatory support.
– Poor prognosis for recovery.
– NCV- Reduced / Absent CMAPs, Absent SNAPs. without
significant conduction slowing, and
6. AMAN
– 1st reported in Northern China (Summer); “Chinese
Paralysis”
– The most common GBS subtype in Asia.
– Campylobacter jejuni infection (76% of AMAN); Anti-GM1
or Anti-GD1a
– NCV - Normal SNAPs; Reduced CMAP.
10. – Triad of Ophthalmoplegia, Ataxia & Areflexia.
– Diplopia f/b Gait & Limb ataxia. Other Cranial nerves;
Motor Power - Preserved
– Ocular signs:- Complete Ophthalmoplegia; Dilated &
Non-reactive Pupils; External ophthalmoparesis ± ptosis.
– C. jejuni (20%) and Haemophilus influenzae (8%)
– Anti-GQ1b (98%) (Anti-GT1a, Anti-GD3 and Anti-GD1b).
– 50 % of MFS develop PCB, BBE, and classic GBS in the
first 7 days after onset.
Miller Fisher syndrome (MFS)
11. Miller Fisher syndrome (MFS)
– EDX studies:- Axonal process (Sensory) with no or only mild Motor
Conduction abnormalities. SNAP- Normal (50%).Reduced or Absent
– Sural sparing pattern (one-third) .
– Brain MRI is usually Normal; Rare- Brainstem lesions or Contrast
enhancement of 3rd nerves.
– Favorable prognosis, Mean recovery time:- >10 weeks
12. Bickerstaff Brainstem Encephalitis (BBE)
– Progressive, relatively Symmetric External Ophthalmoplegia and Ataxia
by 4 weeks’ and ‘Disturbance Of Consciousness or Hyperreflexia’
– `BBE without Limb Weakness' and `BBE with Limb Weakness'.
– Others:- Ptosis; Facial Palsy; Dysarthria; Areflexia / Normal DTR;
Extensor plantars.
– CSF- Albuminocytological Dissociation; Absence does not preclude
diagnosis.
– Edx:- Normal (majority); Axonal; Demyelinating (Rare)
– MRI Brain:- T2 Hyperintensity Brainstem, Cerebellum, Thalamus,
or Subcortical White Matter.
14. Acute Pandysautonomia
– Rapid onset of combined Sympathetic & Parasympathetic failure
– No Sensory and Motor involvement.
– DTR are usually lost during the course of the illness.
– Severe Orthostatic Hypotension, Heat Intolerance, Anhidrosis, Dry
Eyes & Mouth, Fixed Pupils, Fixed Heart Rate & Disturbances Of
Bowel & Bladder Function.
– Autoantibodies to Ganglionic Acetylcholine Receptors (50%)
15. Regional
GBS
Pharyngeal-cervical-brachial Variant:-
Polyneuritis Cranialis:-
Rapid onset of symmetrical multiple Cr Nerve
palsies.
Isolated Facial Diplegia With Distal Paresthesias
Forme fruste of PCB variant.
Sensory Ataxic Variant:-
Acute Ataxia, Sensory loss, Areflexia;
NCV s/o Demyelination; SNAPs - Normal (60%);
Reduced or absent (40%)
GQ1b antibodies
Acute And Painful Small-fiber Neuropathy:-
Following CMV
Good response to Steroids
16. Sural Sparing Pattern:-
• Reduced amplitude or absent SNAPs in UL +Normal Sural
SNAPs - Specific; 50% positive during first 2 weeks.
Sural sparing combined with abnormal F waves:-
• 96% specific
• Present in about 50% of AIDP.
• Two-thirds of patients <60 years during the first 2 weeks of
illness
Sensory ratio:-
• Sural + Radial SNAPs/Median + Ulnar SNAPs
• Substitute for sural sparing pattern, (Elderly)
• High ratio (>1) is fairly specific
• Distinguishes GBS from other Axonal polyneuropathies.
NCV
Patterns
Normal NCS:- 50% in first 4 days; 10% in first week.
17.
18. 15% - Mild condition, remain Ambulatory, and recover
after a few weeks.
5%–20% - Fulminant course ; Ventilator dependence &
Axonal Degeneration (Within 2 days from Onset)
Up to 30% - Require Ventilatory support.
Between 2% and 5% - Die of complications.
20% - Residual Motor Weakness – At 1 year later.
Complete Recovery - 70% in 12 months &
82% in 24 months.
Recurrence - Up to 5%.
About 5% of patients – Acute onset CIDP.
21. Pattern of Evolution:-
Continuous /
Stepwise
Middle & Elderly
Relapsing
Young
Pregnant ( 3rd Trimester
/ Post partum )
Acute onset
CIDP
GBS alongwith ≥1 of
following
1. Deteriorate after 8 wks
2. TRF > 2
3. Multiple focal
enlargement of nerve
(USG)
4. Sensory Prominent
5. Demyelinating features
on f/u (months later)
22. Clinical Features:-
– All Ages; 5th & 6th decade
– Symm Motor & Sensory; P=D; LL > UL ( majority)
– Sensory = Stocking Glove distribution
– Children = Precipitous onset; Gait disturbances.
– Others:-
– Postural tremors
– Enlarged peri nerve
– Facial / Bulbar weakness.
– Rare:- RF; ANS involm.
23.
24.
25.
26.
27. Clinical Criteria CIDP
Typical CIDP
All the following:
1. Prog. or Relapsing, symm., P & D weakness of UL & LL &
Sensory involvement of at least 2 limbs.
2. Developing over at least 8 weeks.
3. Absent or Reduced DTR in ALL limbs.
29. CIDP Variants
• Distal CIDP: Distal sensory loss & weakness (LL)
• Multifocal CIDP: Sensory loss & weakness in a multifocal pattern
(asymmetric, UL, in >1 Limb)
• Focal CIDP: Sensory loss & weakness in Only one Limb.
• Motor CIDP: Motor s/s
• Sensory CIDP: sensory s/s
30. Acute onset CIDP
also k/a…. A-CIDP
– 13% of CIDP
– Deteriorate >8 weeks after onset or Relapse at least 3 times
after initial improvement.
– Often, remain ambulatory.
– Facial weakness, Respiratory or ANS involvement – Less likely
– Sensory signs – More likely
– No specific clinical features or laboratory tests that can
distinguish GBS from A-CIDP in the acute stage of the disease.
– IgG antibodies to Contactin 1
31. Multifocal Form Of CIDP
– Also K/a Lewis-Sumner variant; MADSAM (Multifocal Asymmetric
Demyelinating Sensory And Motor) Neuropathy.
– Multifocal distribution of weakness and sensory deficits.
– Usually affects UL first. LL later on. (sometimes at the onset)
– Cranial nerves (III, V, VII, X, XII) more frequently involved than in other
CIDP forms
– NCV -- Focal CB
– Good response to Steroids
32. DADS (Distal Acquired Demyelinating
Symmetric Neuropathy)
– Sensory loss in the Distal UL & LL , Gait Instability.
– Edx :- Symmetrical and Uniform slowing of Distal Latencies
more than CV; Rare CB.
– IgM monoclonal against MAG (50-70%)
– Usually respond poorly to therapy.
– Some patients respond favorably to IVIG or Rituximab.
33. Focal CIDP:-
Rare
Usually affects the Brachialor Lumbosacralplexus,
But can affect individual peripheralnervesas well.
Motor CIDP :-
RelativelySymmetric P & D Weakness.
Normal sensationClinically and EDx.
If sensory nerve conduction is abnormal in Clinically Motor CIDP; then the diagnosisis Motor-
PredominantCIDP.
Patients with Motor CIDP may deteriorate after corticosteroids.
Sensory CIDP :-
Distrurbed cutaneous sensation
Gait Ataxia,
Impaired Vibration & Position sense
If Motor nerve conduction Slowing or CB are present -- then diagnosis is
Sensory-PredominantCIDP.
Sensory CIDP is often a transient clinical stage that precedes the appearance of weakness in
about 70% of patients
35. Chronic Immune Sensorimotor
Polyradiculopathy (CISMP)
– Both weakness & sensory symptoms
– Progressive / Stepwise / Recurrent symptoms.
– EDX studies -- Normal SNAPs & Normal CMAP
(Some: Reduction of CMAP amplitudes)
Abnormal F-waves and H-reflexes.
Slowing or CB.
– MRI LS spine -- Enhancing caudal and lumbosacral roots.
36. 1) Sensory CIDP
• Sensory :- Prolonged Distal Latency, or Reduced SNAP
Amplitude, or Slowed CV in at least TWO nerves.
(2) Possible CIDP
• As in (1) but in only 1 nerve.
• Sensory CIDP with normal motor nerve conduction studies
• Needs to fulfil a. or b:
a.) Sensory Study: CV <80% of LLN (for SNAP Amplitude >80%
of LLN) or <70% of LLN (for SNAP Amplitude <80%
of LLN) in at least TWO nerves
b.) Sural Sparing Pattern
Sensory Nerve Conduction Criteria
41. Autoimmune Nodopathies
– IgG4 subclass
– Don’t Activate Complement or Cell-Mediated
Cytotoxicity
– (Exception: IgG3 CNTN1)
– Bind with high affinity to Antigens that, results
in disruption of the Axoglial interactions.
42. Anticontactin 1 Ab (CNTN1)
– Rapid-progressive CIDP;
– Ataxia;
– Early Axonal involvement
– a/w Nephrotic syndrome.
– Poor response to IVIG.
– Good response to Rituximab.
Miura Y, Devaux JJ, Fukami Y, Manso C, Belghazi M, Wong AH, et al. Contactin 1 IgG4 associates to chronic inflammatory
demyelinating polyneuropathy with sensory ataxia. Brain 2015; 138: 1484–91.
43. Anti-Neurofascin 155 Ab
(NF 155)
– c/f:- Subacute onset; Younger Age;
– Distal Motor Symptoms, Ataxia, Tremor with Cerebellar
features.
– Tremor of Head, Voice & Tongue tremor. Cr nerve involvement
– HLA DRB1*15
– Poor response to IVIG
– Ultrasound:- Nerve Enlargement (All).
– MRI Neurography:- Symmetric Hypertrophy of Cx & LS roots.
Devaux JJ, Miura Y, Fukami Y, Inoue T, Manso C, Belghazi M, et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology 2016; 86: 800–7.
44. AntiNeurofascin 140 ( NF140) &
AntiNeurofascin 186 (NF186)
– Acute Aggressive onset,
– Edx:-Conduction Blocks
– may a/w Nephrotic Syndrome
Stengel H, Vural A, Brunder AM, Heinius A, Appeltshauser L, Fiebig B, et al. Anti-pan-neurofascin IgG3 as a marker of fulminant
autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm 2019; 6: e603.
45. Contactin-Associated Protein 1
(Caspr1)
C/f:-
– Acute/ Subacute Neuropathy;
– Ataxia,
– Neuropathic Pain,
– Cranial nerve involvement
– Poor response to IVIg.
Doppler K, Appeltshauser L, Villmann C, Martin C, Peles E, Kramer HH, et al. Auto-antibodies to contactin-associated protein 1
(Caspr) in two patients with painful inflammatory neuropathy. Brain 2016; 139: 2617–30.
46.
47. Nerve biopsies should be considered only when:
– Skilled Surgeons, Neuropathologists &
Specialized & Experienced Pathology laboratory
facilities are available.
– Symptoms are severe enough to justify the
potential morbidity associated with a nerve
biopsy.
– The low accuracy of the test is fully understood by
the patient before undergoing the biopsy.
48. Nerve Biopsy
CIDP is suspected
– But cannot be confirmed with the Clinical, Laboratory,
Imaging & Edx.
– There is little or no response to treatment, such that
an alternative diagnosis such as CMT, Amyloidosis,
Sarcoidosis, or Nerve sheath Tumours
/Neurofibromatosis might be considered.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory
demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision 2021
49. – Sural Nerve / Superficial Peroneal Nerve.
– But Biopsy of a Clinically affected nerve (useful)
– Factors probably supporting the diagnosis of CIDP
may be:
o Thinly myelinated axons and small onion bulbs.
o Thinly myelinated or demyelinated internodes in teased
fibres
o Perivascular macrophage clusters.
– Features of Demyelination (EM).
53. Multifocal and Focal CIDP :-
• Diabetic radiculopathy/plexopathy
• Entrapment neuropathies
• Hereditary neuropathy with liability to pressure
palsies (HNPP)
• Multifocal motor neuropathy (MMN)
• Neuralgic amyotrophy
• Peripheral nerve tumours (such as Lymphoma,
Perineurioma, Schwannoma, Neurofibroma)
• Vasculitic neuropathy (Mononeuritis Multiplex)
54. Motor CIDP:-
• Hereditary Motor Neuropathies (such as
Distal Hereditary Motor Neuropathies,
Spinal Muscular Atrophy, Porphyria)
• Inflammatory Myopathies
• MND
• NMJ d/o (MG, LEMS)
55. Sensory CIDP:-
• Cerebellar Ataxia, Neuropathy, Vestibular Areflexia
Syndrome (CANVAS)
• CISP
• Dorsal column lesions (such as Syphilis,
Paraneoplastic, Copper deficiency, vit B12 deficiency)
• Hereditary Sensory Neuropathies
• Idiopathic Sensory Neuropathy
• Sensory Neuronopathy
• Toxic neuropathies (such as ACA and vit B6 toxicity)
56. Antibodies Disease
GM1 (IgM)
MMNCB (70%)
AMAN (30%)
AMSAN .
GQ1a Non Specific (No diagnostic value)
GQ1b (IgG)
MFS
BBE
GD1a (IgG)
AMAN (30%)
AMSAN .
GD1b (IgM)
CANOMAD
Pure Sensory Ataxic variant
GT1a Pharyngeal-cervical-brachial variant
GT1b Acute Ataxic variant
MAG (IgM) DADS (50-70%)
Antibodies
in AIDP &
CIDP
57.
58. Azathioprine
Methotrexate,
Mycophenolate Mofetil
May be Used As Corticosteroid-
sparing Adjunctive Agents In
Long-term Management
Bedi G, Brown A, Tong T, et alChronic inflammatory demyelinating polyneuropathy responsive to mycophenolate mofetil therapyJournal of
Neurology, Neurosurgery & Psychiatry 2010;81:634-636.
59.
60. Six years after onset of illness,
56% - Good outcome,
24% - Deteriorated & Failed
to respond to all treatments,
11% - Died of complications
of the disease.
71. Scores for Monitoring
– Bedside tool to monitor grip strength is the Martin Vigorimeter
– Rasch-built Overall Disability Scale (R-ODS):- validated for CIDP, GBS and
polyneuropathy associated with MGUS.
– INCAT-Overall Disability Sum Score (ODSS) :- poorly detects discrete
changes of disability or sensory symptoms
– INCAT sensory sumscore (ISS) :- records sensory symptoms GBS & CIDP
72.
73.
74.
75.
76.
77. ANX 005 is an inhibitor of C1q protein complex designed to block the activation of the classical pathway
Editor's Notes
In Ataxic variant Rhomberg sign can be negative
molecular mimicry Ab against neural antigens ganglioside-like epitopes with the lipopolysaccharides of the organism.
GQ1b antigen is expressed in the Oculomotor, Trochlear & Abducens Nerves, Muscle Spindles In The Limbs, and probably Reticular Formation in the brainstem. Infection by microorganisms bearing the GQ1b epitope may induce production of immunoglobulin G (IgG) anti-GQ1b antibodies in susceptible patients. The binding of anti-GQ1b antibodies to GQ1b antigens expressed on the relevant cranial nerves and muscle spindles induces Fisher syndrome. In some cases, the anti-GQ1b antibodies may also enter the brainstem and bind to GQ1b, inducing Bickerstaff brainstem encephalitis. A continuous spectrum exists between these conditions presenting with variable central and peripheral nervous system (CNS and PNS) involvement. Modified from reference6 with permission.
In Ataxic variant Rhomberg sign can be negative
Facial palsies (at times presenting as a delayed feature after other features have started to improve)
GQ1b is abundantly present in PARANODAL regions of ocular nerves: association between high titers of this antibody and ophthalmoplegia.
GQ1b is abundantly present in PARANODAL regions of ocular nerves: association between high titers of this antibody and ophthalmoplegia.
CSF albuminocytological dissociation
37% of FS & 25% of BBE in the first week,
CSF pleocytosis
32% of BBE & 4% of FS patients
Ganglionic Acetylcholine receptors blocking cholinergic transmission in autonomic ganglia
Are elevated in both acute pandysautonomia & Paraneoplastic Autonomic Neuropathy.
Forme fruste= incomplete forms
Sensory ratio:- patients who have absent sural SNAP or those with preexisting CTS.
Precipitous= sharp
Replaced the label “atypical CIDP,” used in the 2010 EFNS/PNS guideline,3,4 by “CIDP variants”
Paranode:- Schwann cells insulate the axon of a nerve cell by tightly binding to the axolemma.
Neurofascin isoform 155(NF-155) which interacts with the heterodimers of contactin (CNTN)-1 and contactin-associated protein (Caspr) on the axolemma.
Anti GQ1b
Sulfatide another autoimmune target in CIDP is essential for the stabilization of the PN region.
juxtaparanodal (JPN) region is characterized by voltage-gated potassium channels on the axolemma and the presence of Caspr2 and CNTN-2 complexes.
internode (IN) region consists of the compact myelin sheath around the corresponding axon region
Nodes of Ranvier:- Gangliosides GM1 & GD1a; voltage-gated sodium (Nav) channels
Paranodes and juxtaparanodes:- Contactin-associated protein (Caspr) and voltage-gated potassium (Kv)
Macrophages subsequently invade from the nodes into the periaxonal space, scavenging the injured axons.
Anti-CNTN1 and anti-NF155 antibodies are the first two CIDP-associated autoantibodies that have formally proven to be pathogenic in animal models.
Nerve biopsies should be considered only when:
Skilled Surgeons, Neuropathologists & Specialized & Experienced Pathology laboratory facilities are available.
Symptoms are severe enough to justify the potential morbidity associated with a nerve biopsy.
The low accuracy of the test is fully understood by the patient before undergoing the biopsy.
Teased fibre:- Specimens about 10 mm long are stained for 24-48 hours in Sudan black and then transferred to glycerin, where, using a pair of fine forceps and a stereomicroscope, they are separated into smaller fiber bundles from which single fibers are isolated; Following drying in an oven, the slides are mounted with glycerin-gelatine (same as used for frozen sections). The changes are then observed.
Steroids:- Improvement can be anticipated to start within 2 months but may not be evident till 3–5 months.
PLEX:- optimal schedule has not been established; 3 cycles (50 mL/kg) weekly for the first 2 weeks, f/b 1-2 cycles per week from 3rd to 6th week.