Vasculitic Neuropathies, diagnosis and Management. Systemic and Non Systemic Vasculitic Neuropathies

1. VASCULITIC NEUROPATHIES :
DIAGNOSIS & MANAGEMENT
Dr. Zuber Ali Quazi
Senior Resident (DM Neurology)
GMC Kota

2. INTRODUCTION
• Diverse group of disorders c/b Acute-to-Subacute onset of Painful Sensory and
Motor deficits.
• Due to inflammatory destruction of nerve blood vessels and subsequent ischemic
injury.
• Peripheral nerve involvement of vasculitis ----- up to 60–70% of systemic vasculitis.
• Can occur as a Primary process
or
• As a Secondary phenomenon
(e.g., ranging from rheumatological conditions to viral infections)
Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the
French Vasculitis Study Group cohort. Arthritis Rheum 2013; 65: 270–81.

3. CLASSIFICATION
• Can be classified in terms of
• Clinical characteristics (eg, organ involvement, disease
association),
• Histopathological features (eg, size of involved vessels), &
• Underlying mechanisms.
• International Chapel Hill Consensus Conference classification
• The Peripheral Nerve Society Task Force classification, &
• Classification based on the size of the involved vessels.

4. INTERNATIONAL CHAPEL HILL
CONSENSUS CONFERENCE
CLASSIFICATION
All 3 major categories of vasculitis
can affect any size artery.
• ANCA associated vasculitis
affects a broader spectrum of
vessels than Immune complex
vasculitis

5. • Large vessel vasculitis (LVV)
• Takayasu arteritis (TAK)
• Giant cell arteritis (GCA)
• Medium vessel vasculitis (MVV)
• Polyarteritis nodosa (PAN)
• Kawasaki disease (KD)
• Small vessel vasculitis (SVV)
• Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV)
• Microscopic polyangiitis (MPA)
• Granulomatosis with polyangiitis (Wegener’s) (GPA)
• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)
• Immune complex SVV
• Anti-glomerular basement membrane (anti-GBM) disease
• Cryoglobulinemic vasculitis (CV)
• IgA vasculitis (Henoch-Schönlein) (IgAV)
• Hypocomplementemic urticarial vasculitis (HUV)(anti-C1q vasculitis).
INTERNATIONAL CHAPEL HILL CONSENSUS
CONFERENCE CLASSIFICATION
(CONTD.)

6. • Variable vessel vasculitis (VVV)
• Behcet’s disease (BD)
• Cogan’s syndrome (CS)
• Single-organ vasculitis (SOV)
• Cutaneous leukocytoclastic angiitis
• Cutaneous arteritis
• Primary central nervous system vasculitis Isolated aortitis.
• Others.
INTERNATIONAL CHAPEL HILL CONSENSUS
CONFERENCE CLASSIFICATION
(CONTD.)

7. • Vasculitis associated with systemic disease
• Lupus vasculitis
• Rheumatoid vasculitis
• Sarcoid vasculitis
• Others
• Vasculitis associated with probable etiology
• Hepatitis C virus–associated cryoglobulinemic vasculitis
• Hepatitis B virus–associated vasculitis
• Syphilis-associated aortitis
• Drug-associated immune complex vasculitis
• Drug-associated ANCA-associated vasculitis
• Cancer-associated vasculitis.
• Others
INTERNATIONAL CHAPEL HILL CONSENSUS
CONFERENCE CLASSIFICATION
(CONTD.)

8. THE PERIPHERAL NERVE
SOCIETY TASK FORCE
CLASSIFICATION
Diabetic radiculoplexus neuropathy is categorized
separately from NSVN

9. DIAGNOSTIC CRITERIA FOR
PATHOLOGICALLY DEFINITE VASCULITIC
NEUROPATHY
I. ACTIVE LESION
Nerve biopsy ---- Inflammatory Cells in vessel wall AND ≥1 signs of Acute Vascular Damage
1. Fibrinoid necrosis;
2. Loss/disruption of Endothelium;
3. Loss/fragmentation of Internal Elastic Lamina;
4. Loss/fragmentation/separation of Smooth Muscle Cells in media;
5. Acute thrombosis;
6. Vascular/perivascular hemorrhage; OR
7. Leukocytoclasia. (distinct type of leukocyte disintegration c/b karyorrhexis)

10. II. Chronic lesion with signs of Healing/Repair:
Nerve biopsy ----- Mononuclear Inflammatory Cells in vessel wall AND ≥1 signs of
Acute Vascular Damage with repair:
1. Intimal hyperplasia;
2. Fibrosis of media;
3. Adventitial/periadventitial fibrosis; OR
4. Chronic thrombosis with recanalization.
III. No Evidence of another Primary Disease process that can mimic
vasculitis pathologically, such as Lymphoma, Lyphomatoid
Granulomatosis, or Amyloidosis.
DIAGNOSTIC CRITERIA FOR
PATHOLOGICALLY DEFINITE VASCULITIC
NEUROPATHY (….CONTD)

11. I. Pathologic criteria for Definite Vasculitic Neuropathy not satisfied AND
II. Predominantly Axonal changes; AND
III. Perivascular inflammation accompanied by signs of active or chronic vascular damage
OR
Perivascular/vascular inflammation plus at least one additional pathologic predictor of definite
vasculitic neuropathy:
1. Vascular deposition of complement, IgM, or fibrinogen by direct immunofluorescence;
2. Hemosiderin deposits;
3. Asymmetric/multifocal nerve fiber loss or degeneration;
4. Prominent active axonal degeneration; or
5. Myofiber necrosis, regeneration, or infarcts in concomitant muscle biopsy.
DIAGNOSTIC CRITERIA FOR
PATHOLOGICALLY PROBABLE VASCULITIC
NEUROPATHY

12. I. Pathologic criteria for Definite Or Probable Vasculitic Neuropathy not satisfied;
AND
II. Predominantly Axonal changes;
AND
III. Inflammation in vessel wall without other signs of Definite Vasculitic Neuropathy;
OR
One or more signs of active/chronic vascular damage or pathologic predictors of definite
vasculitic neuropathy, without vessel wall or perivascular inflammation.
DIAGNOSTIC CRITERIA FOR
PATHOLOGICALLY POSSIBLE VASCULITIC
NEUROPATHY

13. DEFINITION OF CLINICALLY PROBABLE VASCULITIC NEUROPATHY
• For nerve/muscle biopsy showing pathologically
‘‘probable’’ vasculitic neuropathy,
Only the most sensitive items (1) and (2) are required;
• For nerve/muscle biopsy showing ‘‘possible’’ vasculitic
neuropathy and for unbiopsied patient with systemic
vasculitis,
All six items (1–6) are required.

14. I. Patient satisfies criteria for Pathologically Definite or
Clinically Probable vasculitic neuropathy
II. Constitutional symptoms may occur.
III. None of the following exclusions, which suggest an
underlying ‘‘systemic’’ vasculitis:
1. Signs, symptoms, or laboratory evidence of involvement
of organ(s) other than peripheral nerve likely due to
vasculitis (e.g., CNS, gastrointestinal, heart, kidney, liver,
lung, skin);
2. Positive visceral angiogram;
3. Laboratory markers of inflammation or CTD:
a. PR3- or MPO-ANCAs;
b. Mixed cryoglobulins (>trace);
c. ESR ≥100 mm/h;
d. SSA, SSB, Smith, RNP, Scl-70, Anti-centromere Ab, ds-
DNA, Anti-CCP Ab.
4. Biopsy evidence of vasculitis in tissue other than
peripheral nerve e.g. Muscle
DIAGNOSTIC CRITERIA FOR NON-SYSTEMIC VASCULITIC NEUROPATHY
5. Serologic, PCR, or culture evidence of specific
infection associated with vasculitis (such as HBV, HCV,
HIV, CMV, leprosy, Lyme disease, HTLV-I);
OR
6. Predisposing conditions or factors:
a. Connective tissue diseases;
b. Sarcoidosis;
c. Inflammatory bowel disease;
d. Active malignancy;
e. Hypocomplementemic urticarial vasculitis
syndrome;
f. Cutaneous polyarteritis nodosa;
g. Drugs likely to be causing vasculitis.

15. CLINICAL PATTERNS OF NEUROPATHIC
INVOLVEMENT IN VASCULITIC NEUROPATHY
 Multiple mononeuropathies with motor and sensory
deficits restricted to the distribution of individual nerves.
 The most common mononeuropathies affected are the
FIBULAR NERVE in the lower extremity &
ULNAR NERVE in the upper extremity.
 Seen in 10%–15%.

16. CLINICAL PATTERNS OF NEUROPATHIC
INVOLVEMENT IN VASCULITIC NEUROPATHY
Overlapping or confluent multiple mononeuropathies in
which anatomically contiguous nerves will eventually be
affected, obscuring individual nerve involvement.
This often results in asymmetrical flaccid weakness and
pansensory loss in one or more extremities.
Seen in 60%–70%.

17. Subacute Symmetrical, Distal Sensorimotor neuropathy
caused by extensive widespread vasculitis.
This presentation of vasculitic neuropathy can be difficult to
distinguish from other types of distal axonopathies and
requires a high index of clinical suspicion.
A detailed history may indicate that the neuropathy began
focally, then followed a course of stepwise progression of
deficits before becoming generalized.
Seen in 30%.
CLINICAL PATTERNS OF NEUROPATHIC
INVOLVEMENT IN VASCULITIC NEUROPATHY

18. INVESTIGATIONS
1. Routinely indicated studies:
 CBC, Eosinophil count, Biochemistry panel (Electrolytes, RFT, LFT) Urinalysis, HBA1c, ESR, CRP, RA
factor.
 ANA, ANCA (c&p), Serum Protein Immunofixation Electrophoresis, Complement (C3, C4, total),
Cryoglobulins, HIV HBsAg, Anti HCV, CXR.
2. Occasionally indicated studies:
 SSA or SSB antibodies, Ab against ENA, ds-DNA Ab, Anti-CCP Ab, ACE, Lysozyme, VEGF, β2-
M, Lyme Ab, CMV Ag or DNA, Paraneoplastic autoantibodies, LDH, HDL cholesterol, Porphyria
screen, DNA for PMP22 deletion, DNA for Transthyretin gene, Chest CT, Visceral Angiography,
salivary gland biopsy, Lumbar Puncture, and other body imaging for malignancy.
3. Nerve conduction studies :-
• Reveal Low Amplitude SNAPs and CMAPs in a multifocal distribution with normal or minimally
reduced conduction velocities.
• Partial Motor Conduction Block may be seen transiently with acute nerve infarcts before the
completion of wallerian degeneration

19.  Combined muscle and nerve biopsies (increase the diagnostic yield).
 Sural nerve or Superficial Peroneal nerve (preferred).
Peroneus Brevis muscle biopsy can be obtained through the same incision
when sampling Superficial Peroneal nerve.
OR
 Gastrocnemius muscle could be sampled through a second incision.
BIOPSY
Vital, Claude, et al. "Combined nerve and muscle biopsy in the diagnosis of vasculitic neuropathy. A 16‐year retrospective study of 202 cases." Journal of
the Peripheral Nervous System 11.1 (2006): 20-29.

20. TREATMENT-- SYSTEMIC NECROTIZING VASCULITIS
Induction : Combination ( Steroid + Immunosuppressant)
Daily Prednisone (1 mg/kg/day) + Cyclophosphamide/ Rituximab -------- For 6 Months.
In Fulminant Cases, IV methylprednisolone (500–1000 mg) daily for 3–5 days followed by oral prednisone.
In Non Life-threatening Mild Systemic Vasculitis, Prednisone with Mtx (20–25 mg/ week)
 CYCLOPHOSPHAMIDE :-
IV = Monthly, 0.75 g/m2 body surface area (15 mg/kg) per month OR
Oral = Daily, 2 mg/kg of body weight (more side effects).
Adjusted monthly upward to 1 g/m2 or downward to 0.5 g/m2 on the basis of Leukocyte count 2 weeks after the infusion.
Target :-
Total Lymphocyte count --- about 750/μL,
Total Leukocyte count ---- above 3000/μL
Total Neutrophil count ---- above 1500/μL.
 RITUXIMAB :
375 mg/m2 body surface area/week for 4 weeks. OR
500mg once every 2 weeks (for 2 doses) f/b 1gm once in 6 month.
Neurologists should work with a Rheumatologist

21. Maintenance :-
 Once clinical remission is achieved, Prednisone can be tapered over a period of 4–6 weeks to a
dosage of 1 mg/kg every alternate day.
 Other:- After 1–2 months (of starting steroids), tapering can be initiated, with a dose reduction
5–10 mg every few weeks.(Tomasson G et al, 2012)
 Patients are kept on both drugs until significant improvement occurs, after which, Prednisone is
gradually tapered further.
• Azathioprine or Mtx to be substituted for cyclophosphamide. (Lancet Neurology 2014)
• Other Agents:- Mycophenolate Mofetil, Leflunomide & Cyclosporin.
• Duration of Maintenance therapy:-
• For 1 year after the disappearance of all traces of disease activity. (Bradley 8th edi.)
• For 18-24 m (Lancet Neurology 2014)
TREATMENT-- SYSTEMIC NECROTIZING VASCULITIS
…Contd

22. TREATMENT-REFRACTORY DISEASE :-
• Unchanged or increased disease activity after 4–6 weeks
OR
• Improved but persistent disease activity after 8 weeks of therapy.
o Drugs used:-
 Rituximab (1st line).
 IV IG, Plasma Exchange, Mycophenolate Mofetil, Alemtuzumab, Infliximab, Antithymocyte
Globulin, & Cyclosporin.
Plasma Exchange:- Fulminant Vasculitis, (life-threatening ANCA +ve vasculitis a/w Severe
Glomerulonephritis or Alveolar Haemorrhage.
o Can be considered in (Although NO RCT has been reported for these vasculitides):-
• HBV-associated PAN,
• HCV associated Cryoglobulinaemic vasculitis, &
• HIV-associated vasculitis.
TREATMENT-- SYSTEMIC NECROTIZING VASCULITIS
…Contd

23. Corticosteroid Monotherapy.
 1mg/kg daily, decreased to 25 mg at 3 months, 15–20 mg at 4 months, and 10 mg at 6 months.
 Continuation of low dose prednisone (5–7.5 mg/day) from 6 to 18 months.
• Pulse IV MPS (optional for Severe, Rapidly Progressive NSVN)
Those who don’t respond or are ‘‘Rapidly Progressive’’ (new motor or sensory deficits within 4 weeks
of presentation):-
• 1st line:- Cyclophosphamide (preferred), Methotrexate, & Azathioprine.
‘‘PROBABLE CLINICAL REMISSION’’ -no e/o clinical worsening by any objective measure and some
e/o improvement by at least one objective measure after 6 months of observation.
 On Prednisone:- can be stopped after 6 months or continued at low doses (5–7.5 mg daily) until 18
months.
 With Combination Therapy:- Maintenance therapy for 18–24 months, to reduce relapses.
 1st line = AZA 1.0–2.0 mg/kg/day or MTX 20–25 mg/week.
TREATMENT– NON SYSTEMIC VASCULITIS

24. MONITORING RESPONSE TO TREATMENT
 Titration of the steroid dose should depend on the patient’s response and disease severity.
 The clinical response should be judged through many outcome measures, but the neurological history & examination are most important.
 In patients with SVN :-
• ESR and other markers of inflammation can also be followed.
• Some follow Serial ANCA levels
(A rise in ANCA levels and persistently positive ANCAs are both significantly associated with disease relapse, but ANCAs cannot be relied upon to guide
management decisions.
 Within several weeks to months of treatment, most patients report reduced pain and improved strength.
 But Maximum improvement can take up to 6–24 months, after initiation of prednisone because of the slow pace of axonal regeneration after nerve
infarction.
 Cyclophosphamide:-
• CBC should be checked weekly after the first dose and then every 2 weeks. The dose should be adjusted downward as necessary to prevent leucopenia.
A URINALYSIS should be monitored every several weeks for the first few months and then monthly (urine cytology every 6 months indefinitely).
• If a patient develops Haematuria, cyclophosphamide should be discontinued and the patient should be referred to a urologist for evaluation of
haemorrhagic cystitis or transitional cell carcinoma. (Routine cystoscopy once every 1-2 yrs)
• Concomitant MESNA and adequate HYDRATION are recommended to reduce bladder toxicity.
• All patients treated with corticosteroids and cyclophosphamide should receive prophylaxis against Pneumocystis jirovecii pneumonia.
 Azathioprine:- Monitor CBC and LFT weekly for the first month and then monthly for 6 months and then every 3 months.

25. REFERENCES
• Bradley 8th edition.
• Collins et al (2010), Peripheral Nerve Society Guideline on the classification, diagnosis,
investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy:
executive summary. Journal of the Peripheral Nervous System, 15: 176-184.
• Jennette J. C. (2013). Overview of the 2012 revised International Chapel Hill Consensus
Conference nomenclature of vasculitides. Clinical and experimental nephrology, 17(5), 603–
606.
• Tomasson G, Grayson PC, Mahr AD, Lavalley M, Merkel PA. Value of ANCA measurements
during remission to predict a relapse of ANCA-associated vasculitis—a meta-analysis.
• Rheumatology (Oxford) 2012; 51: 100–09.
• Lancet Neurology 2014

27. • IV IG, Plasma Exchange & Rituximab ----- unproven treatment options in the small-
to-medium vessel primary systemic vasculitides.
• Infliximab, Mycophenolate mofetil, Alemtuzumab, Anti-thymocyte globulin, & 15-
deoxyspergualin ---- have been used in small-to-medium vessel primary systemic
vasculitides but require further study.

28. DIAGNOSTIC CRITERIA FOR
NON-SYSTEMIC VASCULITIC NEUROPATHY