Variants of AIDP & CIDP.pptx

This presentation consist information about unspoken and less well known variants of GBS as well as CIDP. Also it includes information about diagnosis and management.

1. Variants of AIDP & CIDP Dr Zuber Ali Quazi Senior Resident Neurology

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.

3. AIDP Patterns 30–40% 5–15% 5 –10 % < 5% < 5% <1% 5 – 25% <5%

4. AIDP Types Common Subtypes Acute Inflammatory Demyelinating Polyradiculoneuropathy ( AIDP) Acute Motor Axonal Neuropathy ( AMAN) Acute Motor-sensory Axonal Neuropathy ( AMSAN ) Rare Variants Miller-fisher Syndrome Ataxic variant (Acute Ataxic Neuropathy) Pharyngeal-cervical-brachial variant Multiple Cranial Neuropathy Variant Facial Diplegia With Paresthesias Paraparetic Variant Acute Pandysautonomia

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.

7. Anti- GQ1b Syndromes Miller Fisher syndrome (MFS); Bickerstaff Brainstem Encephalitis (BBE ); Pharyngeal-cervical-brachial Variant

8. Nortina Shahrizaila , and Nobuhiro Yuki J Neurol Neurosurg Psychiatry 2013;84:576-583

9. Fisher–Bickerstaff syndrome Fisher syndrome Incomplete forms:- Acute ophthalmoparesis ( without ataxia) Acute Ptosis Acute Mydriasis Acute Oropharyngeal Palsy Acute Ataxic Neuropathy ( without ophthalmoplegia ) Ataxic Guillain– Barré syndrome Acute Sensory Ataxic Neuropathy Bickerstaff Brainstem Encephalitis Pharyngeal-cervical-brachial weakness Overlap FBS overlapped by PCB weakness. FBS overlapped by GBS.

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 3 rd 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 o r 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.

13. Pharyngeal-Cervical-Brachial Variant (PCB) <5% of GBS Facial palsy, Dysarthria , Weakness & Areflexia in UL. Anti-GQ1b & Anti-GT1a Ab

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 , S ensory 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. 15% - Mild condition, remain Ambulatory , and r ecover 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 .

18. Older age (>60 years), H/o Preceding Diarrheal Illness , Recent CMV infection , Ventilatory support, Rapid progression ( Max Deficit in <7 days, Hyponatremia , Low Distal CMAP amplitudes. Predictors for Poor Recovery:-

19. Typical CIDP

20. Pattern of Evolution :-

21. Clinical Features:- All Ages; 5 th & 6 th 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 invol m .

22. Clinical Criteria CIDP Typical CIDP All the following: Prog. or Relapsing, symm ., P & D weakness of UL & LL & Sensory involvement of at least 2 limbs. Developing over at least 8 weeks. Absent or Reduced DTR in ALL limbs.

23. CIDP Variants

24. 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

25. Acute onset CIDP also k/a …. A-CIDP 13 % of CIDP D eteriorate >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

26. 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

27. 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.

28. Focal CIDP:- R are Usually affects the Brachial or Lumbosacral plexus , But can affect individual peripheral nerves as well . Motor CIDP :- Relatively Symmetric P & D Weakness. Normal sensation Clinically and EDx . If sensory nerve conduction is abnormal in Clinically Motor CIDP; then the diagnosis is Motor- Predominant CIDP. 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-Predominant CIDP . Sensory CIDP is often a transient clinical stage that precedes the appearance of weakness in about 70% of patients

29. Chronic Immune Sensory Polyradiculopathy ( CISP) Sensory Ataxia NCV -- Normal Motor & Sensory conduction studies. Abnormal somatosensory evoked responses, MRI LS spine - Enlarged lumbar roots Nerve root biopsy - Segmental Demyelination, Onion Bulbs & Endoneurial Inflammation Respond to IVIG .

30. 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.

31. 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

32. Autoimmune Nododopathies

33. Node:- GM1 GD1a Paranode :- Neurofascin isoform 155(NF-155) Contactin (CNTN)-1 Contactin -associated protein ( Caspr ) GQ1b Sulfatide Juxtaparanodal (JPN ):- Caspr2. CNTN-2 complexes.

34. Autoimmune Nodopathies Contactin-1 (CNTN1) Neurofascin-155 (NF155) Neurofascin Isoforms ( NF140/186) Contactin -Associated P rotein 1 (Caspr1)

35. 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.

36. Anticontactin 1 Ab ( CNTN1) Rapid-progressive CIDP; Ataxia ; Early A xonal 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 .

37. 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.

38. 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.

39. 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.

40. 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.

41. 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

42. Sural Nerve / Superficial Peroneal Nerve. But Biopsy of a Clinically affected nerve (useful) Factors probably supporting the diagnosis of CIDP may be: Thinly myelinated axons and small onion bulbs. Thinly myelinated or demyelinated internodes in teased fibres Perivascular macrophage clusters . Features of Demyelination (EM).

43. Hypertrophic Nerve Roots are best appreciated in parasagittal image.

44. Typical CIDP :- • AL amyloidosis, ATTRv polyneuropathy • Chronic Ataxic Neuropathy Ophthalmoplegia M-protein Agglutination Disialosyl Antibodies (CANOMAD) • Guillain- barré Syndrome • Hepatic Neuropathy • HIV-related Neuropathy • Multiple Myeloma • Osteosclerotic Myeloma • POEMS Syndrome • Uremic Neuropathy • Vitamin B12 Deficiency

45. Distal CIDP :- • Anti-MAG IgM neuropathy • Diabetic neuropathy • Hereditary neuropathies (CMT1, CMTX1, CMT4, Metachromatic Leukodystrophy , Refsum disease , Adrenomyeloneuropathy , ATTRv polyneuropathy ) • POEMS syndrome • Vasculitic neuropathy

46. 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)

47. Motor CIDP :- • Hereditary Motor Neuropathies (such as Distal Hereditary Motor Neuropathies, Spinal Muscular Atrophy, Porphyria) • Inflammatory Myopathies • MND • NMJ d/o (MG, LEMS)

48. 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 )

49. 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

50. 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.

51. Six years after onset of illness, 56% - Good outcome, 24 % - Deteriorated & Failed to respond to all treatments, 11 % - Died of complications of the disease.

52. Inflammatory Neuropathy Consortium Base (INCbase)

53. IgG4 MAB targeting the classical complement system c1s.

54. ARGX-117 is antibody that binds specifically to C2 inhibiting the function of C2 and downstream complement activation

55. THANK YOU

56. Antibodies in AIDP & CIDP

57. Secondary CIDP Diabetes Mellitus , IgG or IgA Monoclonal Gammopathy of Undetermined Significance [MGUS], IgM Monoclonal Gammopathy without Antibodies to MAG HIV infection Malignancies. Drugs

58. Preceding Infections C. jejuni , Clostridium, Haemophilus influenza, Shigella &  Mycoplasma pneumonia . Viruses :- Zika virus, CMV, Hepatitis viruses (types A, B, C, and E), HIV, EBV, SARS-CoV-19 - GBS following CMV ---- Sensory involvement.

59. Respiratory failure 4 % 24 % 65 % EGRIS ( Erasmus GBS Respiratory Insufficiency Score)

60. 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

61. ANX 005 is an inhibitor of C1q protein complex designed to block the activation of the classical pathway