Journal club

• Dr Ranjith kumar

Resident in neurology

Gandhi Hospital & Medical college

• Vasculitis or angiitis refers to a group of inflammatory disorders of the blood vessels that cause structural damage to the affected vessel, including thickening and weakening of the vessel wall, narrowing of its lumen, and, usually, vascular necrosis.

• Immunecomplex formation , deposition in the vessel wall.• invasion of endothelial cells and perivascular spaces. • alteration of endothelial cell functions by infectious

microorganisms, neoplastic or autoimmune process or toxins.• granuloma formation.• presence of autoantibodies, such as antiendothelial cell

antibodies or antineutrophil cytoplasmic antibodies (ANCA).• proinflammatory cytokines and adhesion molecules.

• Annual incidence of the systemic vasculitides (excluding giant cell arteritis) is approximated at 39 per 1,000,000.

• Systemic vasculitis is classified according to vessel size and histopathologic and clinical features.

• small vessel involvement - Henoch-Scho¨ nlein purpura and cryoglobulinemia.

• small- and medium-sized vessel vasculitides -Polyarteritis nodosa and Wegener granulomatosis

• large vessels- temporal arteritis (TA) and Takayasu arteritis i

Temporal arteritis

• Giant cell arteritis ,older than 50 years, with a mean age of onset of 70 years

• 15 to 25 per 100,000 individuals. Women >men.• permanent blindness in one or both eyes in

25% to 50% of affected individuals; timely diagnosis and aggressive treatment.

• typically, affects the cranial branches of the arteries that originate from the arch of the aorta.

• Transmural inflammation of the affected arteries and intimal hyperplasia cause luminal occlusion

• insidious or sudden.

• visual loss and neurologic impairments, are usually acute.

• systemic manifestations, such as fatigue, anorexia, weight loss, arthralgia, myalgia, low-grade fever, anemia, and leukocytosis, may be present weeks or months before the time of clinical diagnosis.

• Alterations of mental status characterized by delusional thinking, confusion, insomnia, lack of attention, and cognitive decline .

• headache with a lancinating quality, commonly localized to the areas along the affected arteries of the scalp. persistent and usually unilateral.

• development of a new headache or prominent alteration of the pattern of a chronic headache in an elderly patient is the most frequent symptom of TA

• Diffuse tenderness of the scalp or face is usually present over the temporal or occipital arteries.

• Jaw pain and claudication and oral mucosa or scalp ulceration can also be presentations of TA.

• 30% of affected individuals, peripheral neuropathy, transient ischemic attack, and stroke.

• Peripheral neuropathy : mono- or polyneuropathy and may affect upper or lower extremities.

• median nerve is the most commonly affected peripheral nerve, other nerves, such as ulnar, radial, tibial, sciatic and trigeminal nerve,

• On electromyographic and nerve conduction studies, axonal damage and demyelination.

• Angiographic and neuropathologic examinations reveal that diffuse arteritis of the vessels supplying the damaged nerves causes peripheral neuropathy in TA.

• Cranial neuropathies are also significant presentations of TA.

• The optic nerve is the most frequently affected cranial nerve; 23% of affected patients develop permanent visual loss because of anterior ischemic optic neuropathy (AION).

• optic nerve involvement is the anterior optic nerve, resulting from posterior ciliary arteritis

• Transient visual loss experienced with TA is similar to that in patients with atherosclerotic cerebrovascular disease.

• Patients with acute AION develop an altitudinal visual field defect.

• Other ocular complications of TA include uni- or bilateral central retinal artery occlusion

• Compromise of the blood circulation through the ophthalmic or central retinal arteries due to inflammation or thrombosis in TA seems to cause the retinal ischemia.

• Vasculitis of the vessels supplying the optic chiasm is associated with bitemporal visual field defects

• vasculitis of the vascular system of the retro chiasmal visual sensory pathway can cause homonymous visual field defects.

• bilateral blindness due to TA may experience visual hallucinations originating from loss of visual input to the cerebral cortex

• Patients with TA may develop diplopia caused by vasculitis affecting the ocular motor system.

• The oculomotor nerve is commonly affected• Combination of ophthalmoparesis and ptosis

raises the possibility of oculomotor nerve ischemic infarction.

• Paralysis usually does not affect the pupil.• Uni- or bilateral internuclear ophthalmoplegia • Pupillary disturbances, such as tonic pupils and

light-near pupillary dissociation.

• Vertigo• Hearing loss, tinnitus• Transient hemi anesthesia of the tongue,• Lingual paralysis,• Facial pain. • Between 10% and 20% of patients with TA have

carotid bruits • Commonly bilateral and indicate carotid artery

involvement.• Almost 40% of these patients develop some

form of ischemic ocular or cerebral syndrome

• Histopathologically, transmural inflammation of the media, intima, and adventitia.

• Lymphocytes, macrophages, and multinucleated giant cells are present in the arterial wall in a patchy distribution.

• Arterial narrowing is thought to be caused by mural hyperplasia resulting in occlusive ischemia .

• Similar inflammatory changes are observed in the related disease, polymyalgia rheumatica (PR).

• Symptoms of PR are more widespread and systemic than TA and include pain, fever, malaise, stiff muscles, and weight loss.

• proposed that they may be different symptomatic manifestations of the same underlying disease process.

• Almost 50% of patients with TA present with PR and 10% of patients with PR develop TA.

• A diagnosis of TA should be considered in any patient older than 50 years who presents with new-onset headache, jaw claudication, ear pain, scalp tenderness, unexplained fever, anemia, double vision, and visual loss.

• Patients with TA usually have normochromic normocytic anemia, markedly high erythrocyte sedimentation rate (ESR>40 mm/h), and elevated C-reactive protein.

• On 4-vessel cerebral angiography, vasculitic changes appear as alternating stenotic segments or complete occlusion of the affected vessels.

• Biopsy of the temporal artery is performed to confirm the diagnosis before aggressive treatment.

• The pitfall of this procedure, due to the patchy nature of the underlying inflammation, is that biopsy achieves a sensitivity of up to 70%, considerable number of patients with TA may have a negative biopsy result.

Temporal arteritis-criteria

At least three of the following 5 items must be present (sensitivity 93.5%, specificity 91.2%):

• 1. Age of onset greater than 50 years• 2. New-onset headache or localized head pain• 3. Temporal artery tenderness to palpation or

reduced pulsation• 4. ESR greater than 50 mm/h• 5. Abnormal arterial biopsy (necrotizing

vasculitis with granulomatous proliferation and infiltration)

• Once a clinician suspects a diagnosis of TA in an elderly patient on clinical grounds treatment should be initiated to save the patient’s vision.

• The mainstay of treatment is systemic corticosteroids.• Treatment begins immediately with prednisone at a

dosage of 40 mg/day to 80 mg/day. • This high dose treatment plan is maintained for up to a

month and then prednisone dosage should be tapered by 50% during one month and then after slowly reduced by no more than 1 mg/month.

• The oral prednisone should be tapered slowly to prevent relapses, with the tapering periods as long as 2 years.

• To lessen corticosteroid-associated osteoporosis, concurrent treatment with alendronate should be initiated.

Takayasu arteritis

• Pulseless disease• Systemic necrotizing vasculitis that may result in post

inflammatory stenosis or occlusion of the entire aorta, the abdominal aorta, the ascending aorta, or just the aortic arch and its proximal branches.

• The innominate, common carotid, and subclavian arteries and the celiac, mesenteric, renal, pulmonary, iliac, and coronary arteries are frequently affected.

• Takayasu disease occurs worldwide, most of the patients are women, and the age of onset is between 10 and 30 years.

• It seems that hypoperfusion of the affected organ due to the underlying arterial occlusive process causes the clinical manifestations of Takayasu disease.

(1) the acute stage, characterized by nonspecific systemic manifestations, such as low-grade fever, fatigue, malaise, anorexia, nocturnal sweating, and widespread aching

(2) the stage of acute inflammation of the affected vessels, characterized by the presence of vascular bruits, diminished or absent pulses, and tenderness

(3) the chronic obliterative phase due to vascular occlusion, identified by decreased pulses, development of vascular bruits, claudication, and even development of ischemic ulcers in affected extremities.

• Occlusion of the vertebral or carotid arteries may cause ischemic stroke; and patients may present with headache, syncope, and blurred vision.

• May also develop intracranial aneurysms, with symptoms originating from either ruptured or unruptured aneurysms.

• Pathologically, Takayasu disease manifests with granulomatous inflammation of the vessel adventitia and the outer part of the media, with infiltration of lymphocytes, plasma cells, histiocytes, and multinucleated giant cells.

• Diagnosis of Takayasu disease rests on clinical suspicion in any young patient, particularly women, with clinical manifestations of vascular ischemia and the presence of bruits, decrease or absence of pulses, ischemic ulcers, or a combination of these findings.

• Aortic angiography confirms the diagnosis and one may observe occlusion or dilatation of vascular segments, stenotic segments, aneurysm formation, and increased collateral circulation.

TA treatment

• Systemic corticosteroids, prednisone 1 mg/kg/d for 3 months, is followed by a gradual tapering regimen based on suppression of the systemic manifestations.

• Takayasu disease does have a prolonged, relapsing, and remitting course;

• In cases of unsuccessful treatment with corticosteroids, treatment with cytotoxic agents, such as cyclophosphamide or methotrexate, should be considered.

• Certain patients may benefit from surgical procedures, such as bypass of the obstructed arteries or percutaneous transluminal angioplasty

Wegeners granulomatosis

• Necrotizing granulomatous lesions of the upper and/or lower respiratory tract and kidney (necrotizing glomerulonephritis), and disseminated vasculitis.

• WG develops in association with antineutrophil cytoplasmic antibodies (ANCA) and is a member of the family of ANCA-associated vasculitides (AAV).

• It is more common in men, and the age range varies from 8 to 80 years, with a mean age of 40 years.

• In many patients, WG initially presents with granulomatous lesions of the upper respiratory tract.

• Systemic manifestations of WG consist of chronic sinusitis, chronic rhinitis, nasal ulceration, epistaxis, upper respiratory sero sanguineous discharge, serous otitis media, cough and hemoptysis, and dyspnea.

• Fever, weight loss, anorexia, and arthralgia.

• Ocular involvement presents with orbital pseudotumor, scleritis, and uveitis,

• Renal involvement manifests with proteinuria, hematuria, and renal failure

• At any stage of the disease process, up to 50% of patients develop neurologic complications affecting both peripheral and central nervous systems.

• Almost half of those with neurologic complications suffer from recurrent mononeuropathies, mononeuritis multiplex, or symmetric polyneuropathy.

• Patients with CNS involvement present with cranial neuropathies, most frequently cranial nerves II, VI, and VII

• nonspecific evidence of cerebral vasculitis, such as hemiparesis, seizures, aphasia, and visual field defects.

• Ischemic strokes, encephalopathy, granulomatous basilar meningitis, pachymeningitis, and myelitis are other CNS manifestations of WG

• Involvement of hypersensitivity mechanisms.• Diagnosis of WG can be based on the combination of

the clinical picture along with the presence of classical antineutrophil cytoplasmic antibodies (C-ANCA) in the serum and the demonstration of necrotizing vasculitis on histopathologic examination

• . On neuroimaging, the spectrum of brain computed tomographic (CT) and magnetic resonance (MR) abnormalities in WG include dural thickening and enhancement, and abnormal signals within the brainstem and white matter.

• systemic corticosteroids may be associated with clinical improvement in only some

• Does reduce the overall mortality rate. • Various immunosuppressive agents, such as

cyclophosphamide, azathioprine, methotrexate, chlorambucil, and nitrogen mustard, have been used for treatment of corticosteroid failures

• In many instances, patients are treated with a combination of prednisone and cyclophosphamide.

• The cumulative toxicity and side effects of these medications over several years are fairly high, and even under this therapeutic regimen, between 10% and 50% of patients relapse.

• The regimen of prednisone and cyclophosphamide should be continued until systemic presentations improve, and then it should be slowly tapered.

• The therapeutic response can be measured by serial clinical assessment and a declining pattern of the ESR, serum C-reactive protein, and C-ANCA

cryoglobulinemia

• Cryoglobulins are serum proteins that precipitate at 4C and re-dissolve after warming to 37C,.

• Immunoglobulins and are usually composed of either IgG or IgM. or can be mixed.

• Cryoglobulins, which have a single monoclonal immunoglobulin, are most commonly associated with lympho proliferative disorders, such as multiple myeloma, lymphomas and leukemias.

• Mixed cryoglobulins are frequently detected in patients with connective tissue diseases, systemic vasculitic syndromes, and infections such as hepatitis C viral infection; and this condition is called essential mixed cryoglobulinemia (EMC).

• Mainly middle-aged women, presents with purpura, arthralgia, weakness, and mixed cryoglobulinemia.

• Patients with EMC develop cutaneous vasculitis and progressive renal insufficiency because of glomerulonephritis.

• Similar to many other hypersensitivity vasculitides, EMC seems to occur due todeposition of immune complexes in small vessels.

• In any patient with the combination of hypocomplementemia, cutaneous vasculitis, and elevated liver function tests, a diagnosis of mixed cryoglobulinemia must be considered.

• A vasculitic motor and sensory peripheral neuropathy commonly occurs in patients with EMC at some point during their disease course

• Sensory-motor mononeuritis multiplex is another form of neuropathy that may be present in these patients.

• CNS are rare and include diffuse encephalopathic syndromes with focal signs, seizures, myelopathy, and sometimes, ischemic stroke.

• The pathogenetic mechanisms of neuropathy include immune-mediated demyelination and nerve ischemia due to occlusion of the vasa nervorum by cryoglobulins or vasculitis

Henoch schonlein purpura• The most common forms of systemic vasculitis seen in

children,

• Nonthrombocytopenic purpura, arthralgia, and abdominal pain.

• Certain conditions, such as malignancies and infections, and certain drugs are associated with HSP.

• Systemic complaints include fever, malaise, and edema; nephritis occurs in 40% of affected patients.

• headache, encephalopathy, intracranial and intraparenchymal hemorrhage, nonhemorrhagic vasculitic involvement of cerebral tissue.

• peripheral neuropathy, and entrapment neuropathy due to focal edema.

• The presence of elevated serum IgA or IgA deposits in the vascular wall indicate that HSP is due to IgA-mediated inflammation.

• The clinical diagnosis is further supported by detection of leukocytoclastic vasculitis on skin biopsy and IgA immunofluorescence in small vessels of skin and renal glomeruli.

• Differential diagnosis of HSP includes infectious endocarditis, systemic lupus erythematosus, meningococcemia, disseminated intravascular coagulation, and Waldenstro¨m hyperglobulinemic purpura.

• Although there is no specific treatment for HSP, these patients benefit from supportive therapy and brief courses of corticosteroids.

Vasculitis due to drug abuse• Drugs, particularly sympathomimetics, have been

associated with several neurologic disorders, including cerebral ischemic infarcts and intracerebral and subarachnoid hemorrhage.

• The most commonly abused drugs that are associated with these neurologic complications include cocaine, heroin, ephedrine, phenylpropanolamine, and amphetamines.

• These illicit drugs may be taken orally or intravenously or may be snorted.

• Ischemic or hemorrhagic complications usually affect younger individuals.

• A brain MR imaging case-controlled study of individuals who were cocaine dependent demonstrated the presence of multiple, small, silent, subcortical ischemic lesions.

• Cerebral angiography in many cases of illicit drug use has demonstrated vasculitic changes of CNS vessels, including widespread segmental narrowing of the affected vessels with a beading pattern.

• Some of these illicit drugs are capable of causing vasospasm, and thus, the mechanism behind vascular insufficiency within the CNS may be a vasculopathy rather that true vasculitis.

• A compounding issue in making a clear-cut diagnosis of illicit drug-induced CNS vasculitis is that there are usually multiple exposures to multiple illicit substances and coexisting infections present, such as syphilis, hepatitis C, and AIDS.

• Treatment of these patients rests on identification and discontinuation of the offending drug, search for other concurrent infections, particularly human immunodeficiency virus (HIV), control of hypertension when present, and supportive treatment.

• Administration of systemic corticosteroids or immunosuppressive therapy is not recommended unless diagnosis of CNS vasculitis is supported by histo pathologic examination

Vasculitis due to medication• Vasculitic syndromes may occur in association with use

of prescribed drugs • most common drug-associated vasculitis is usually

restricted to the skin. • widespread and presents with fever; arthralgia; evidence

of cardiac, hepatic, or renal dysfunction; and eosinophilia.

• Ahe attachment of the drug to proteins, generating haptens that are able to elicit potent immune responses.

• Neurologically, the central and peripheral nervous system and muscles may be involved.

• Antibiotics being a major type. The penicillins are probably the best known members of this group.

• Treatment of drug-related vasculitis begins with immediate discontinuation of the offending drug followed by use of corticosteroids (prednisone 1 mg/kg/d for up to 30 days).

Polyarteritis nodosa

• periarteritis nodosa• Inflammatory necrotizing vasculitis that affects small- to

medium-sized arteries. • Idiopathic, or it can be associated with other disorders,

such as cryo globulinemia, leukemia, arthritis, Sjogren syndrome, hepatitis C, hepatitis B, and HIV infection.

• PAN is a systemic disease and may affect any organ; however, the skin, kidney, peripheral nerves, and gastrointestinal tract are most commonly involved.

• The annual incidence of PAN is about 0.2 to 0.7 per 100,000 and it affects men more than women.

• PAN is more common in individuals 40 to 60 years of age.

• PAN affects the central and peripheral nervous systems

• Between 23% and 53% of patients with PAN develop CNS pathology.

• CNS involvement is less common than that of the peripheral nervous system and usually presents late in the course of disease.

• The two most frequent central neurologic pictures of PAN include diffuse encephalopathy and focal or multifocal disturbances of the brain or spinal cord.

• Focal neurologic deficits, which may occur suddenly, are due to ischemic stroke affecting the cerebral cortex, brainstem, or cerebellum.

• Patients with PAN may develop anterior optic neuropathy and posterior (retrobulbar) optic neuropathy; and they tend to experience acute and painless visual loss.

• These forms of optic neuropathy stem from vasculitis-induced ischemia in the distribution of the posterior ciliary arteries, or inflammation of the optic nerve

• Cranial nerve III, IV, VI, VII, and VIII involvement rarely occurs.

• Mononeuritis multiplex is common in the context of PAN and presents with asymmetric motor and sensory findings that mainly affect the lower extremities, particularly the sciatic, peroneal, or tibial nerves.

• Less commonly, the radial, cubital, and median nerves may be affected.

• The onset of mononeuritis multiplex in these patients is usually sudden, whereas the distal symmetric peripheral neuropathy in these patients develops slowly.

• Examination of the cerebrospinal fluid may not reveal any diagnostic abnormalities

• Histopathologically, PAN manifests with focal but pan-mural necrotizing inflammatory lesions that affect small- and medium-sized arteries .

• Further examination of these inflammatory lesions reveals disruption of the normal infrastructure of the vessel wall, fibrinoid necrosis, and pleomorphic cellular infiltration with mainly polymorphonuclear cells and a variable number of lymphocytes and eosinophils

• Diagnosis of PAN is made based on clinical suspicion when a patient presents with constitutional symptoms, such as fever, chills, weight loss, fatigue, and multisystem dysfunction.

• Anemia, elevated ESR, and evidence of thrombosis further support the diagnosis of PAN.

• Brain CT and MR neuroimaging illustrates infarctions in the cortical and subcortical regions of the cerebral hemispheres, basal ganglia, internal capsule, brainstem, and cerebellum .

• Arteriography may reveal the presence of arterial saccular or fusiform aneurysms and narrowing and tapering of the affected vessels.

• Histopathologic examination of affected tissue, such as skin, sural nerve, muscle, or kidney, confirms the clinical diagnosis

• Treatment of PAN consists of the administration of systemic corticosteroids along with cytotoxic agents, such as cyclophosphamide or azathioprine.

• If a patient does not tolerate this regimen’s side effects, other therapeutic interventions that need to be considered include plasma exchange, intravenous immune globulin, mycophenolate

mofetil, and rituximab

Microscopic polyangiitis

• Microscopic polyangiitis (MPA) is another member of AAV that predominantly affects small vessels (capillaries, venules, and arterioles).

• Granulomata are not present. • ANCA is directed against myeloperoxidase.• MPA is associated with rapidly progressive focal

segmental necrotizing glomerulonephritis. • The average age of onset is 50 years and men are more

often affected than women. • may have an indolent course before clinical diagnosis.• Systemic symptoms, such as arthralgia and hemoptysis,

may be present.

• . Peripheral neuropathy is less common in MPA than PAN, whereas pulmonary involvement occurs more frequently.

• Diagnostic workup for MPA reveals the presence of serum ANCA and absence of surface hepatitis B antigen or antibody.

• Histopathologic examination of a biopsied specimen from the kidney reveals the presence of focal segmental thrombosing and necrotizing glomerulonephritis.

• Treatment of MPA is based on immunosuppression with the combination of systemic corticosteroids and cyclophosphamide.

• Potential therapies under clinical investigation include intravenous immune globulin and rituximab

Thank you