Definition

1. Vasculitis and Central Nervous SystemGhaffarpour. MIranian Center of Neurological Research Tehran University of Medical Sciences Tehran – Iran29 April 2012

2. Definition • Vasculitis is a clinicopathologic process that results when autoimmune mechanisms are directed against blood vessel’s wall. • It may be primary or sole manifestation of the disease or may be secondary to other conditions such as drugs, infection, serum sickness, malignancy and connective tissue diseases. • May be confined to a single organ such as skin, or may simulta-neously involves several organ systems, thus broad & heterogeneous syndromes may develop, depending on type, size and location of involved vessels.

3. Classification There is no universally agreed classification for vasculitis, because of heterogeneity and overlapping. For the purpose of our speak, we mention to classifications of: 1) Scott 2) Harrison

4. Scott’s Classification of vasculitis syndromes (1988) I- Systemic nectrotizing vasculitis • PAN and microscopic polyangiitis • Allergic angiitis and granulomatosis (Churg – Strauss) • Polyangiitis overlap syndrome II- Wegener’s granulomatosis III-Temporal arteritis (common form of giant cell infiltration: Extracranial) IV-Takayasu’s arteritis (rare form of giant cell infiltration: Aortic) V- Henoch-schonlein purpura (anaphylactoid purpura)

5. IV – Predominantly cutaneous vasculitis (Hypersensitivity) A- Exogenic stimuli - Serum sickness and serum sickness – like reactions - Infections - Drugs B – Endogenous stimuli - Neoplasms (particularly lymphoid malignancies) - Connective tissue diseases - Congenital deficiency of complement system - Other underlying diseases (SLE, RA, Cryoglobulinemia, Sjogren’s syndrome, SBE, EB and HIV infections, Chronic active hepatitis, Biliary cirrhosis, 1-antitrypsin deficiency, Intestinal bypass surgery, Relapsing polychondritis)

6. VII – Other vasculitis syndromes - Buerger’s disease (thromboangiitis obliterance) - Behcet’s disease - Kawasaki disease - Isolated CNS vasculitis - Miscellaneous vasculitis

7. Harrison’sclassification of the major vasculitis syndromes * : On the basis of the smaller size of the affected vessels and presence of P-ANAC, Lhote et al have differentiated this entity.

8. Pathophysiolog and pathogenesis Generally, most of the vasculitis syndromes are assumed to be mediated, at least in part, by immune-pathogenic mechanisms. However, evidence supporting this hypothesis is for the most part indirect and may reflect epiphenomena as opposed to true causality. Potential mechanisms of vessel damage are: • Pathogenic immune – complex formation and / or deposition. Vacuities is generally considered within the broader category of immune-complex disease that include serum sickness and certain connective tissue diseases, of which SLE in the prototype. Others include: • Henoch – Schonlein purpura • Serum sickness and cotaneous vasculitis syndromes • Hepatitis C – associated mixed cryoglobulinemia • Hepatitis B – associated polyarteritis nodosa

9. Production of Antineutrophilic cytoplasmic abs (ANCA). ANCA are antibodies against certain proteins in the cytoplasmic granules of neutrophils and monocytes, that are found in a high percentage of patients with systemic vasculitis syndromes, particularly: Wegener’s granulomatosis Microscopic polyangiitis Necrotizing and crescentic glumerulonephritis Churg- strauss (in 50%)

10. •There are two major categories of ANCA : 1) Perinuclear (P-ANCA) Has several targets. However only antibodies to myeloperoxidase have been convincingly associated with vasculitis. P-ANCA occurs in variable percentage of: - Polyarteritis nodosa - Churg - Strauss - Crescentic glumerulonephritis - Goodpasture’syndrome - Microscopic polyangiitis - Wegener’s granulomatosis

11. - It was also been associated with nonvasculitic entities such as rhaumatic and non-rheumatic diseases including: IBD Certain drugs Infections such as endocarditis and bacterial airway infections in patients with cystic fibrosis

12. 2) Cytoplasmic (C-ANCA) Found in more than 90% of patients with typical active wegener’s granulomatosis and active glomerulonephritis. C-ANCA may also be found in intravascular lymphoma (Adams, P:732). C-ANCA is specific for Wegener’s granulomatosis and churg- strauss and helps to differentiate it from polyarteritis (which display P-ANCA) and from carcinoma, chordoma, sarcoidosis and zoster (Adams, P:1138).

13. There is no conclusive evidence that ANCA are directly involved in the pathogenesis of vasculitis syndromes because : Patients may have vasculitis in the absence of ANCA. The absolute ANCA titers dose not correlate well with disease activity and remission of vasculitis, particularly in patients with wegener’s granulomatosis. High titers of C-ANCA may continue for years.

14. Pathogenic T – lymphocyte responses and granuloma formation Mechanisms other than immune – complex – mediated mechanisms as well as ANCA , may be involved in damage to vessels. • The most prominent mechanism of this type are delayed hypersensitivity and cell-mediated immune injury as reflected in the histological feature of granulomatous vasculitis. • Vascular endothelial cells can express HLA class II following activation of cytokines such as IFN-y, that allows these cells to participate in immunologic reactions such as interaction with CD + T cells.

15. • Other factor is secretion of IL-1 from endothelial cells, which may activate endothelial leukocyte and vascular cell adhesion molecules (ELAM1 and VCAM1) that enhance the adhesion of leukocytes to endothelial cell in the blood vessel wall. • Related disorders to this mechanism include: Giant cell arteritis Takayasu’s disease Wegener’s granulomotosis Churg – Strauss syndrome

16. Approach to the patient withvasculitis • The diagnosis of vasculitis is often considered in any patients with an unexplained systemic illness. However , there are certain clinical abnormalities that when present alone or in combination, should suggest a diagnosis of vasculitis. These include: - palpable purpura - Pulmonary infiltrates and Microscopic hematuria - Mononeuritis multiplex - Chronic inflammatory sinusitis - Unexplained ischemic events - Unexplained cerebral or spinal lesions. - Glumerulonephritis with evidence of multi-system disease.

17. • A number of nonvasculitic diseases may also produce some or all of these abnormalities, thus the first step in the workup of patient with suspected vasculitis is to exclude the conditions that can mimic vasculitis such as: A - Infections Bacterial endocarditis Disseminated gonococcal infection Pulmonary histoplasmosis Coccidioidiomycosis Syphilis and Lyme disease Rocky Mountain spotted fever Whipple’s disease B – Coagulopathies / thrombotic microangiopathies Antiphospholipid ab syndrome Thrombotic thrombocytopenic purpura

18. C- Neoplasms Artial myxoma,carcinomatosis, Hodgkin & non- Hodgkin lymphoma, Lung cancer. D- Drug toxicity Amphetamines, Arsenic, Cocaine, crack, Heroin Ergot alkaloids and Methysergide. E- Others: Sarcoidosis, Atheroembolic disease, Goodpasture, Amyloidosis, Migraine,Cryofibrinogenemia. Once diseases that mimic vasculitis have been excluded, the workup should follow a series of progressive steps, that establish the diagnosis of vasulitis and determine, where possible, the category of the syndromes according to the following algorithm, demonstrated below.

20. • Angiogram of organs with suspected involvement should be performed when syndromes such as the following are suspected. 1) PAN 2) Takayasu’s disease 3) CNS vasculitis However angiograms should not be performed routinely when patients present with localized cutaneous vasculitis with no clinical indication of visceral involvement.

21. The definitive diagnosis of vasculitis is made upon biopsy of involved tissue. The yield of blind biopsies of organs with no subjective or objective evidence of involvement is very low and should be avoided. The constellation of clinical, laboratory, biopsy and radiographic findings usually allows proper categorization to a specific syndrome, and therapy (where appropriate). Treatment should be initiated according to the treatment guidelines.

22. Treatment guidelines • If an offending antigen that precipitates the vasulitis is recognized, it should be removed where possible. • If the vasulitis is associated with underlying disease, the latter should be treated. • If the syndrome does not resolve following removal of the offending antigen or treatment of an underlying disease, treatment should be initiated according to the category of the vasculits syndrome. • Treatment options will be considered under the individual syndromes and general principles of therapy.

23. General principles of therapy  Glucocorticoids and / or immunosuppressives should be used immediately in diseases where irreversible organ system dysfunction and high mortality and morbidity have been clearly established.  In patients with Wegener’s granulomatosis and PAN combination therapy with glucocorticoid and cyclophosphamide is initiated, in others prednisone is the first step of treatment.

24. Methotrexate may be useful In refractory Takayasu’s disease. Methotrexate is an acceptable alternative in patients who do not tolerate cyclophosphamide or who do not wish it because of side effects such as infertility or sterility.  PE and cyclophosphamide are beneficial in rapidly progressive cases of Henoch – Schonlein.  Cyclophosphamide (2mg/kg for one or more) is a choice drug. Cystistis occurs in 30% and bladder cancer in at least 6%. The latter may occur several years after dicontinaction of cyclophosphamide.

25. Leukocyte count should be maintained > 3000 / µL, which maintains the neutrophil count at approximately 1500 / µL. Nutropenia may become more pronounced as glucocorticoid is tapered.  Aggressive therapy should be avoided for cases that revely result in irreversible organ system disfunction and that usually do not respond to such therapy. For example, Idiopathic cutaneous vasculitis usually resolves with symptomatic treatment and prolonged steroid therapy uncommonly result in clinical benefit.

26. Nervous system involvement may be an early or presenting feature of systemic vasculitis and in some cases the sole manifestation of an autoimmunity. In general CNS vasulitis may be: 1) Primary (vasculitis limited to CNS) 2) Secondary (to systemic vasculitis) which is much more common than primary or isolated CNS vasculitis.

27. A brief review of secondary CNS vasculitis • Cerebral vasculitis is uncommon in: - Essential cryoglobulinemia - Microscopic polyangiitis - RA (mostly JRA) and diffuse sclerosis - Henoch – Schonlein purpura (usually in children aged 4-7 years) SLE Nervous system involvement and psychological problems had been reported in 25-75% and 59% respectively. SLE is frequently complicated by stroke. The most common cause of stroke is embolism from cardiac mural thrombosis. A prothrombotic state is other mechanism. CNS vasculitis is found in 12.5% of cases. PAN Affects men twice as often as women and neurological abnormalities occur in 50% of cases (PNS>CNS).

28. Churg-strauss The frequency of cerebral vasculitis in patients with Churg Straussis similar to PNA, but is more prevalent in females & is characterized bye asthma, peripheral and tissue eosinophilia, extravascular gramuloma and vasculitis of multiple organ system. Patient often exhibit fever, malaise, anorexia and weight loss. Pulmonary findings clearly dominated the clinical picture. Mononeuritis multiplex is the second most common manifestation that occurs in 72%. Allergic rhinitis or sinusitis (61%) skin lesions (51%) and are other manifestations.

29. The renal disease is less common and generally less severe than those with Wegener’s granulomatosis and microscopic polyangitis. Eosinophilia (>1000 cells/ µL) occurs in >80% evidence of inflammation (increased ESR, α2-globulins) can be found in 81%. Approximately 48% shows circulating ANCA.That is usually antimyelo-peroxidase. MI is the must common cause of death. Glucocorticoids alone appear to be effective in many patients. In steroid failure or in the with fulminant multisystem involvement combination of steroid and cyclophosphamide is used.

30. Wegener’s granulomatosis Is an uncommon (3/100000) disease, that can be seen at any age but affects usually adults and is rare before adolescence (M /F ratio is : 1 / 1:1) Pulmonary involvement occurs in 85%- 90%. CNS involvement is reported in 11-44% and occurs in the late of the course of the disease and usually takes two common clinical forms: 1) Polyneuropathy and more frequently mononeuropathy multiplex. 2) Multicranial neuropathy as a result of direct extension of the nasal and sinus granulomas, often with severe paranasal pain and usual discharge. There may be septal perforation leading to saddle nose. Serious otitis media may occur.

31. Arterial thrombosis, ICH and SAH may also be seen. Cerebral vasculitis and/or granuloma are rare presentations. Diagnosis is made by biopsy (necrotizing granulomatous vasculitis). Positive C-ANCA has high specificity, but false positive titers have been reported in certain infections and neoplastic diseases. Treatment: combination of glucosteroid and cyclophosphamide.

32. Giant cell arteitis occurs almost exclusively in individuals > 50 years and is more common in women. The superficial temporal, vertebral, ophthalmic and posterior ciliary arteries are more often affected than the ECA or ICA, and intracranial arteries almost never (HU Rehman 2000). Michel (1992) reported that CNS involvement occurs in 4% of cases as TIA or stroke, with predilection to posterior circulation. Multi-infarct dementia, myelopathy, seizures, tremor and encephalopathy are less common.

33. Takayasu’s disease Incidence: 1.2 to 2.6 / million. is similar in many ways to giant cell arteritis except for its propensity to involve the proximal rather than the distal brunches of the aorta. The affected arteries no longer pulsate (Pulse less disease). Most of patients have been young Asian women (usually before age 30: Merritt) However in non-Asian individuals pulse less disease is usually due to atherosclerosis. The disease may be asymptomatic. Symptomatic cases show both generalized (identical to T-arteritis) and vascular manifestations. HTN occurs in 32 to 93% and contributes to renal, cardiac and cerebral injury.

34. Neurologic manifestations arise from HTN (renal artery occlusion) or vertebral artery involvement. CHF may be prominent. Headaches are frequent, visual blurring specially during activity, dizziness, hemiparesia, hemisenory loss are usual neurological manifestations. Some authors have emphasized the frequency of posture induced symptoms as well as infrequent strokes, despite of multiple TIAs. Some have reported syncope and visual disturbances as the main neurological manifestations.

35. Diagnosis depends on 3 from 6 criteria: - Age under 40 - Claudication of arms or logs - Diminished brachial artery pulse - Blood pressure differences in arms - Subclavian bruit - Diagnosis is confirmed by arteriography, that shows irregular walls, stenosis, post stenotic dilatation, aneurism , occlusion and evidence of increased collaterals.

36. Behcet’s vasculitis Neurological signs and symptoms are reported in up to 49% (Harrison: 6-10%) of patients, 5% of which occur at presentation. Headache, pyramidal, cerebellar signs and dysarthria are the most common presentations. Neurological insult appears mainly in parenchymal form (80% of cases). it is often associated with brainstem involvement thus has a serious prognosis. Dural sinus thrombi occur in 20% of patients. Diagnostic criteria include: Recurrent oral ulceration plus two of the following: - recurrent genital ulceration - Eye lesions - Skin lesions - Positive pathergy test.

37. Sjogren’s syndrome The disease affects predominantly middle-aged women (F/M:9/1) although it may occur in all ages including children. It can be seen alone (primary :0.5 -1%). 30% of other autoimmune disease such as RA, SLE, Sclerodermia and mixed connective tissue disease suffer from secondary sjogren’s syndrome. Is defined by clinical triad of 1) Xerophthalmia 2) Xerostomia 3) and non-deforming arthritis A small but significant number may develop malignant lymphoma and 1/3 of patients present with systemic manifestations.

38. It is characterized by lymphocytic infiltration of the exocrine glands and B lymphocyte hypersensitivity, as illustrated by circulating antibodies. Enlargement of the parotid or other major salivary glands occurs in two third of patients with primary sjogren’s syndrome but is uncommon in patients with the secondary type. Sera of patients often contain a number of autoantibodies, rhematoid factors and RO/SS-A, LA/SS-B. Diagnostic tests include sialometry, sialography and scintigraphy. The labial minor salivary gland biopsy permits histopathoologic confirmation of the focal lymphocytic infiltrates. The latter is needed when the diagnosis is uncertain.

39. Extraglandular (systemic) manifestations are seen in 1/3 of the Patients with primary syndrome.

40. Cutaneous vasculitis may present as a picture of non-thrombocytopenic purpura or utricaria. Arthritis of small joints occurs in more than 80% (generally symmetrical). PNS complications occur in 10-32% of patients and includes Sensory neuropathy: (60%), sensorimotor neuropathy: (17%),polyradiculopathy: (11%) and less commonly mononeuropathy. Among CNS complications(which are <PNS) mild cognitive dysfunctionand aseptic meningitis (may be recurrent) are common. Hemiparesia, aphasia, hemianopia, focal seizures, INO, nystagmus, and ataxia have all been reported.

41. Spinal involvement may take one of the following forms: 1) Acute transverse myelitis 2) Intraspinal hemorrhage 3) Progressive myelopathy Sensorineural hearing loss was found in 50% of cases and correlates with the presence of APL antibodies. CSF shows increased protein and IgG ,and positive OCB.

42. Cogan’s syndrome Is non-syphilitic interstitial keratitis together with vestibulo- auditory symptoms. Complications include aortic insufficency and mesenteric sichemia. It occurs predominently in young adults with sudden onset of keratitis, nausea, vomiting, tinnitus, progressing to complete hearing loss. The vestibular symptoms gradually subsides. It may be associated with a systemic vasculitis, particularly with involvement of the aortic valve. Glucocorticoids are the mainstay of treatment.