Vasculitis of the nervous system

David S. Younger
Purpose of review Vasculitis refers to heterogenous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. When unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount importance to all clinicians. Recent findings Remarkable progress has been made in the pathogenesis, diagnosis, and treatment of vasculitis of the central (CNS) and peripheral nervous system (PNS). The classification of vasculitis affecting the nervous system includes (1) Systemic vasculitis disorders (necrotizing arteritis of the polyarteritis type, hypersensitivty vasculitis, systemic granulomatous vasculitis, giant cell arteritis, diverse connective tissue disorders; viral, spirochete, fungal, and retroviral infection; (2) Paraneoplastic disorders; (3) Amphetamine abuse; (4) Granulomatous angiitis of the brain; (5) Isolated peripheral nerve vasculitis, each in the absence of systemic involvement; and (6) diabetes mellitus, associated wtih inflammatoy PNS vasculopathy. Summary Vasculitis is diagnosed with assurance after intensive evaluation. Successful treatment follows ascertainment of the specific vasculitic disorder and the underlying cytochemical mechanism of pathogenesis. Clinicians must choose from among the available immunomodulating, immunosuppressive, and targeted immunotherapies, unfortunately without the benefit of prospective clinical trials, tempered by the recognition of all of the possible medication related side effects. Keywords nervous system, vasculitis
Curr Opin Neurol 17:317336.
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Abbreviations ANCA APC CNS CSF GANS IVIg LCV MAC MNM MPA MRI PAN PMN PNS SLE SPECT VZV WG
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antineutrophil cytoplasmic antibody antigen-presenting cell central nervous system cerebrospinal fluid granulomatous angiitis of the nervous system intravenous immunoglobulin leukocytoclastic vasculitis membrane attack complex mononeuritis multiplex microscopic polyangiitis magnetic resonance imaging polyarteritis nodosa polymorphonuclear leukocyte peripheral nervous system systemic lupus erythematosus single photon emission computed tomography varicella zoster virus Wegener granulomatosis

2004 Lippincott Williams & Wilkins 1350-7540

Introduction
Vasculitis is a spectrum of clinicopathological disorders dened by inammation of the blood vessels, including arteries and veins of varying caliber, which result in a variety of clinical neurological manifestations related to ischemic injury of the central nervous system (CNS) and peripheral nervous system (PNS). This article reviews the remarkable progress that has been made in the pathogenesis, classication, diagnosis, and management of vasculitis of the nervous system. Several excellent reviews have been published on this topic [1 .,2].

Classification
2004 Lippincott Williams & Wilkins.

Department of Neurology, New York University School of Medicine, New York, New York 10016, USA Correspondence to David S. Younger, MD, 715 Park Avenue, Ground Floor, New York, NY 10021, USA Tel: +1 212 535 4314; fax: +1 212 535 6392; e-mail: david.younger@med.nyu.edu Current Opinion in Neurology 2004, 17:317336

Vasculitis in its various forms affects blood vessels of varying caliber from the aorta to capillaries and veins (Fig. 1). The diverse forms of vasculitis and autoimmune diseases to be considered in this chapter are summarized in Table 1.

Systemic necrotizing arteritis of the polyarteritis nodosa type

Polyarteritis nodosa (PAN) is the prototypic disorder of the group of systemic necrotizing arteritis, which also includes ChurgStrauss syndrome, microscopic polyangiitis (MPA) syndrome, Kawasaki disease and an overlap syndrome. The early history of vasculitis is debatable, but one fact is clear, the ealiest patients with vasculitis had PAN and neurological involvement, such as the patient described by Kussmaul and Maier in 1886 [3], who presented with leg pains, cramps, and tenderness so prominent that

DOI: 10.1097/01.wco.0000130301.13775.96

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Figure 1. The pathological spectrum of the major vasculitides

Vessels involved Veins

Clinical syndrome

Venules

Capillaries

Arterioles Small muscular arteries (intraorgan vessels) Medium muscular arteries (coronary, hepatic, intracerebral) Large arteries (vertebral, temporal, carotid) Aorta Eales Hypersen- Wegeners Lymphodisease sitivity matoid granulogranuloangitis matosis matosis Usually involved Sometimes involved
Reproduced from Younger [1 .] with permission of the publisher.

Allergic granulomatosis

Microscopic polyangitis

Polyarter- CNS Temporal Takayasus vasculitis arteritis arteritis itis nodosa

trichinosis was contemplated. At postmortem examination there was widespread arteritis that resembled syphilitic periarteritis caused by the frequent occurrence of internal and external elastic lamina necrosis, brin deposition, aneurysmal dilatations, and intimal proliferation resulting in endarteritis obliterans of the brain, nerves, skeletal muscle, and in systemic organs of small and medium size vessels with a diameter of 120 mm or more (Fig. 2). Peripheral neuropathy is the most frequent nding, typically mononeuritis multiplex (MNM) caused by involvement of the arteriae nervorum, followed by CNS manifestations of two types, one resulting from stroke and cerebral hemorrhage (Fig. 3) and the second a diffuse encephalopathy accompanied by seizure phenomena. The arteritis of MPA affects small arterioles, capillaries, and venules of the kidney and lungs; 5080% of patients have circulating antineutrophil cytoplasmic antibodies (ANCA) to myeloperoxidase or perinuclear ANCA. Kawasaki disease is

characterized by viral exanthema that ultimately leads to PAN, focused primarily in the coronary arteries. In 1951, Churg and Strauss [4] delineated a syndrome of asthma, eosinophilia, extravascular granulomas and necrotizing arteritis, involving arterioles, capillaries, and venules that was named in their honor. The extravascular granulomas, epithelioid and giant cell inltrates distinguish ChurgStrauss syndrome from classic PAN and resemble MPA in the tendency to involve the lung and kidney. Early suspected patients present with allergic rhinitis, nasal polyposis, and asthma, followed by tissue eosinophilia and systemic vasculitis, with CNS involvement that includes confusion, seizures, cranial nerve involvement, optic neuropathy, and less common radicular and plexus PNS manifestations.

Hypersensitivity vasculitis
Historically, in the same period as PAN, Zeek et al. [5] described patients with sensitivity to sulfonamides and

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Table 1. Classication of vasculities that affect the nervous system Systemic necrotizing arteritis Polyarteritis nodosa ChurgStrauss syndrome Microscopic polyangiitis Hypersensitivity vasculitis HenochScho nlein purpura Hypocomplementemic vasculitis Cryoglobulinemia Systemic granulomatous vasculitis Wegener granulomatosis Lymphomatoid granulomatosis Lethal midline granuloma Giant cell arteritis Temporal arteritis Takayasu arteritis Granulomatous angiitis of the nervous system Connective tissue disorders associated with vasculitis Systemic lupus erythematosus Scleroderma Rheumatoid arthritis Sjo gren syndrome Mixed connective tissue disease Behc et disease Inflammatory diabetic vasculopathy Isolated peripheral nervous system vasculitis Vasculitis associated with infection Varicella zoster virus Spirochetes Treponema pallidum Borrelia burgdorferi Fungi Rickettsia Bacterial meningitis Mycobacterium tuberculosis HIV-1 Central nervous system vasculitis associated with amphetamine abuse Paraneoplastic vasculitis

other drugs that manifested with skin rash and generalized vasculitis. So-called hypersensitivity vasculitis includes syndromes related to drug reactions, Henoch Scho nlein purpura, hypocomplementemic or urticarial vasculitis and cryoglobulinemia. These disorders demonstrate non-segmental inltration of the walls of small vessels and postcapillary venules, particularly of the dermis and other systemic tissue by polymorphonuclear leukocytes (PMN), which disintegrate leaving nuclear fragments or leukocytoclastic vasculitis (LCV) (Fig. 4), brinoid necrosis, micro-infarction and hemorrhages of affected tissues, including those of the nervous system. Drug reactions are responsible for approximately 20% of cases of dermal vasculitis usually associated with immune complex deposition, and abates with drug withdrawal and all other possibly offending agents. Affected patients present with u-like constitutional signs that include fever and headache, and progresses to skin lesions, and if serious or advanced enough, seizures, encephalopathy, stroke, cranial nerve signs, and myelopathy. In contrast to PAN, lesions are in the same stage of evolution. HenochScho nlein purpura is characterized by nonthrombocytopenic purpura, arthralgia, abdominal pain, LCV, and IgA immune complex deposition with complement activation in affected children. It is characterized histopathologically by varying degrees of arteriolar, capillary, and venular interstitial inltration by PMN cells, eosinophils, and mononuclear cells, with variable brinoid necrosis and perivascular granuloma formation. Affected children present with fever, urticaria, arthralgia, lymphadenopathy, and headache and abdominal pain so severe as to suggest meningitis and acute surgical abdomen, usually after injection with heterologous antiserum. Hypocomplementemic or urticarial vasculitis is characterized by urticaria, migratory arthralgia, angioneurotic edema, and systemic laryngeal, renal, abdominal, and splenic involvement, in middle-aged women. Tissue biopsies showed immune complexes, with binding of IgG and IgM to C1q along basement membranes, which leads to complement activation, with normal C1 esterase inhibitor levels. Cryoglobulins are substances composed of IgG and IgM, complement, lipoprotein, and antigenic moieties that precipitate at temperatures below 378C, which in serum excess lead to hyperviscosity. Their detection of circulating cryoglobulin leads to consideration of one of the three recognized clinical types, based on whether the single monoclonal antibody is of the IgM or IgG type, mixed, or with activity against polyclonal IgG, and associated with lymphoproliferative disorders and hepa-

Figure 2. This small muscular artery from muscle is from a patient with polyarteritis nodosa

In the third, or proliferative, phase illustrated here, chronic inflammatory cells replace the neutrophils of the second phase, there is evidence of necrosis of the media (arrows), early intimal proliferation (arrowheads), and fibrosis. The lumen is almost completely occluded. Ultimately, in the healing phase, this process is replaced by dense, organized connective tissue (stain, hematoxylin and eosin; original magnification 6250). Reproduced from Younger [1 .] with permission of the publisher.

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Figure 3. Magnetic resonance imaging scans of a case of polyarteritis nodosa with cerebral involvement

Multiple small cortical and subcortical regions of increased signal on these proton density weighted images reflect infarcts in the distribution of small, unnamed branch arteries. Reproduced from Younger [1 .] with permission of the publisher.

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Figure 4. This arteriole from muscle is from a patient with leukocytoclastic vasculitis

Figure 5. Wegener granulomatosis

The entire vessel and perivascular tissue is infiltrated with polymorphonuclear leukocytes and some chronic inflammatory cells with necrosis and nuclear debris. The vascular lumen is nearly obliterated (stain, hematoxylin and eosin; original magnification 6400). Reproduced from Younger [1 .] with permission of the publisher.

This small muscular artery is nearly completely destroyed. There is a large confluent area of fibrinoid degeneration (arrows) surrounded by acute and chronic inflammatory cells, and some giant cells. (Stain, hematoxylin and eosin; original magnification 6250). From Younger [1 .], reproduced with permission of the publisher.

titis C virus infection, respectively termed types I, II, and III. Ischemia of affected arterioles and capillaries results from cryoprecipitation, hyperviscosity, and intravascular activation of complement and the clotting cascade by aggregated immunoglobulin and immune complexes, secondary wall damage, cold agglutination or erythrocytes, local tissue reaction, and vascular endothelial proliferation and luminal narrowing. Clinical manifestations include dermatitis and palpable purpura in all three types, and CNS and PNS manifestations in types II and III as a result of vascular occlusion with or without vasculitis, and hyperviscosity.

Systemic granulomatous vasculitis

Granulomatous vasculitis consists of several clinicopathological disorders (Fig. 1), including Wegener granulomatosis (WG), lymphomatoid granulomatosis, and lethal midline granulomas. In 1951, Godman and Churg [6] described a triad of necrotizing granulomatous lesions of the sinuses and lower respiratory tract, with systemic necrotizing vasculitis of the small arteries and veins, and glomerulonephritis. The lesions of WG begin as minute foci of granular necrosis and brinoid degeneration with PMN cells, followed by histiocytes and giant cells along the margins of granulomas of the upper airways and in renal glomeruli. Necrotizing granulomatous lesions secondarily involve small arteries, arterioles, capillaries, and venules with segmental brinoid necrosis in the tissues involved (Fig. 5). Neurological manifestations occur as a result of

systemic vasculitis, granulomatous invasion and extension from the upper airway and remote granulomatous disease. Affected patients often present with multifocal pain, sensory loss, and weakness caused by MNM that can ultimately become disabling. CNS involvement is of several types depending upon whether there is vasculitic, contiguous extension, or remote granulomatous spread. Stroke, intracerebral and subarachnoid hemorrhage, and optic neuritis can result from vasculitis of the anterior and posterior ciliary and retinal vessels. Contiguous extension from nasal and paranasal sinus cavity granulomas can occur through the orbit leading to pseudotumor with exophthalmos, or may involve extraocular muscles, optic and oculomotor nerves, whereas extension through the temporal bone can destroy the middle ear. Patients with WG have circulating ANCA specic for proteinase-3 or circulating ANCA. Lymphomatoid granulomatosis is an inammatory malignant lymphoreticular disorder that results from angiocentric and angiodestructive lesions of small and medium-sized muscular arteries and their endothelia (Fig. 6). Inltration by unifocal and multifocal necrotizing, inammatory masses occurs in systemic organs and the CNS usually without brinoid necrosis or LCV. Focal neurological involvement stems from the invasion of the CNS by unifocal and multifocal necrotizing inammatory masses of the cerebrum, brain stem, cerebellar parenchyma, and meninges, usually associated with chest lesions, which raises the suspicion of WG, sarcoidosis, fungal and mycobacterial infection.

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Figure 6. Lymphomatoid granulomatosis

Takayasu arteritis involves the elastic branches of the aorta and its major extracranial vessels in adolescent girls and women, typically 50 years of age or younger. The inammatory cell inltrate in temporal arteritis and Takayasu arteritis is comprised of activated T cells, macrophages, and multinucleated giant cells, often arranged in granulomas, close to the fragmented internal elastic membrane [9 . .]. Intimal hyperplasia leads to concentric thrombosis and occlusion of the vessel lumen, which in Takayasu arteritis, can lead to vessel dilation and aneurysm formation (Fig. 7). Neurological sequelae occur late in the obliterative phase of the disease as a result of chronic ischemia of the ascending or descending aorta or its major branches, as manifested by headache, orthostatic dizziness, syncope, stroke, amaurosis fugax, monocular blindness, optic nerve atrophy, and corneal opacication.

The vasular lumen is markedly narrowed by the perivascular tissue invasion without well formed granulomas or fibrinoid necrosis. (Stain, hematoxylin and eosin; original magnification 6250). From Younger [1 .], reproduced with permission of the publisher.

Granulomatous angiitis of the nervous system

The concept of a vasculitis with a unique predilection for the CNS emerged in 1959 with the classic description by Cravioto and Fegin [10] of granulomatous angiitis of the nervous system (GANS), and with it problems of nomenclature for decades to come. Before its formal delineation as a distinct clinicopathological entity, there was difculty in separating it from polyarteritis and syphilitic endarteritis because of the occasional nding of vascular necrosis, giant cells and epithelioid cells in those disorders. The association with varicella zoster virus (VZV) infection, lymphoproliferative tumors, sarcoidosis, amyloid angiopathy, and HIV infection has demonstrated the clinical heterogeneity. The pathological heterogeneity has been exemplied by its variability in the predilection for vessels of varying sizes, from small leptomeningeal to large named cerebral vessels (Fig. 8) [11]. Headache, mental change, and cerebrospinal uid (CSF) pleocytosis with protein content above 75 mg/dl are noted in virtually all cases, leading to uncertainty in the diagnosis in the absence thereof. Unrecognized and therefore untreated, up to half the patients develop focal signs, seizures, aphasia, and hemiparesis, progressing to tetraparesis, and coma (Fig. 9). Granulomatous angiitis in association with VZV infection, lymphoma, sarcoidosis, giant cell arteritis, amyloid angiopathy, and HIV infection carries a similarly severe prognosis. The etiology of granulomatous angiitis is not well understood, but a brain and meningeal biopsy are the gold standard for diagnosis. The preferred site is the temporal tip of the non-dominant hemisphere, so guided by the results of neuroimaging and angiography. Neurologists have had to decide the course of therapy of patients with GANS without the benet of controlled trials, and with bias in the literature that has long favored the administration of combined prednisone and cyclo-

Lethal midline granuloma is a destructive and often fatal vasculitis of major midline structures of the head. Historically, this disorder was likened to WG, but systemic disease is not a major feature as in WG, and the latter rarely causes facial mutilation. Neurological manifestations result from direct invasion of the orbit and face, jugular vein, sigmoid and cavernous sinus leading to vascular thrombosis, sepsis, meningitis, and exsanguination.

Giant cell arteritis

The concept of giant cell (temporal) arteritis was rst described in 1937 by Horton et al. [7], and was later named for the site of granulomatous giant cell inammation and vessel involvement by Jennings [8]. Patients with biopsy-conrmed temporal arteritis and associated blindness as a result of the involvement of the ophthalmic and posterior ciliary artery were classied as having cranial arteritis; whereas those with prominent constitutional and musculoskeletal complaints, without neurological involvement, were deemed to have polymyalgia rheumatica. Patients with giant cell lesions along the aorta, its branches, and in other medium and largesized arteries at autopsy warranted the diagnosis of generalized giant cell arteritis. Temporal arteritis is primarily related to disease along the ophthalmic, posterior ciliary, supercial temporal, occipital, facial, and internal maxillary arteries, primarily in old individuals of either sex. This leads to headache, jaw claudication, scalp tenderness, thickened, nodular, or pulseless temporal artery, which if untreated results in visual loss as a result of ischemic optic neuritis.

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Figure 7. Temporal arteritis

Figure 8. Central nervous system vasculitis

(a) In an early lesion of a large muscular artery, necrosis, inflammation, and giant cell formation (single arrow) can be seen immediately adjacent to the internal elastic lamina (arrowhead), which is undergoing degenerative changes, and there is some intimal proliferation (double arrows) (stain, hematoxylin and eosin; original magnification 6100). (b) This more advanced lesion has complete segmental destruction of the internal elastic lamina and virtually the entire media (arrows). Marked intimal proliferation has nearly occluded the lumen, and few inflammatory cells remain (stain, hematoxylin and eosin; original magnification 650). Reproduced from Younger [1 .] with permission of the publisher.

(a) The media and adventitia of this small leptomeningeal artery have been almost completely replaced by multinucleated giant cells (arrowheads). There is intimal proliferation with obliteration of the vascular lumen, and a dense, perivascular, mononuclear inflammatory infiltrate can be seen (stain, hematoxylin and eosin; original magnification 6250). (b) A somewhat larger leptomeningeal vessel shows necrosis of the media and internal elastic lamina, with multinucleated giant cell formation (arrows), intimal proliferation (arrowhead), and lymphocytic infiltration of the adventitia and neighboring meninges (stain, hematoxylin and eosin; original magnification 6250). Reproduced from Younger [1 .] with permission of the publisher.

phosphamide therapy. Common sense dictates that cyclophosphamide at least be reserved for pathologically conrmed patients who fail to improve or progress when taking prednisone, and can be safely monitored for potentially serious medication side-effects [12].

SLE, scleroderma, rheumatoid arthritis, Sjo gren syndrome, mixed connective tissue disease, and Behc et disease.
Systemic lupus erythematosus

Connective tissue disorders

The earliest concepts of the collagen vascular or connective tissue disorders stemmed from the appreciation of brinoid necrosis using collagen staining in patients with systemic lupus erythematosus (SLE). Necrotizing and non-necrotizing vasculitis occurs in

SLE is a multisystem autoimmune disorder, with protein dermal, joint, renal, cardiac, and hematological manifestations. Vasculitis occurs in 1015% of patients at some time, often in the rst year of diagnosis, most often optic neuropathy, transverse myelitis, headache, stroke, and pseudotumor cerebri caused by venous sinus thrombosis, myelopathy, chorea, neuropathy, dementia, and affective

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Figure 9. CNS vasculitis

Figure 10. Systemic lupus erythematosus

MRI FLAIR sequence of a patient with biopsy-proven CNS vasculitis that was largely confined to the left temporal and lower frontal regions. From Younger [1 .], reproduced with permission of the publisher.

This small vessel within brain parenchyma is largely necrotic. Abundant fibrin (darkly stained) is evident in vessel walls and surrounding tissues. There are a few chronic inflammatory cells indicating the presence of vasculitis, which may be seen in 20% of patients (stain, fibrin; original magnification 6250). Reproduced from Younger [1 .] with permission of the publisher.

disorders. Once thought to be an important cause of cerebral lupus, true vasculitis with disruption of the vessel walls and internal elastic lamina and muscular necrosis is exceedingly rare, and should be eschewed especially in those with encephalopathy and stroke, unless there is frank systemic vasculitic involvement. However, when present, cerebral vasculitis results from brinoid necrosis of the small arteries, arterioles, and capillaries, with brinoid necrosis of collagen bers, which swell, fragment, and later dissolve in the course of the disease (Fig. 10). The resulting homogenous hyaline material contains immunoglobulins, antigenantibody complexes, complement, and brinogen. Non-vasculitic cerebral vasculopathy in SLE may be caused by circulating IgG and IgM antiphospholid antibodies, which demonstrate procoagulant activity with prolongation of the activated partial thromboplastic time. The enzyme-linked immunosorbent assay (anticardiolipin antibody test), using cardiolipin as the antigenic probe for antiphospholid antibodies, is abnormal in more than 50% of patients with SLE, and in high titers, especially anticardiolipin IgG, heightens the risk of occlusive cerebral events in cohorts matched for age-related risk of stroke (Fig. 11). A catastrophic syndrome occurs with SLE with or without a history of antiphospholid antibodies, which is rapidly fatal unless treated promptly with plasmapheresis and anticoagulation.
Scleroderma

peripheral neuromuscular manifestations including headache, encephalopathy, seizures, and myositis, and follow the onset of renal involvement with the development of malignant high renin hypertension, and the CREST syndrome, named for Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, often in association with interstitial lung disease. Systemic necrotizing arteritis develops in less than 1% of cases, and can be indolent or can resemble PAN with systemic sclerosis, CREST, dermal vasculitis, stroke, and MNM (Fig. 12). Microvascular disease in scleroderma appears to be mediated by at least three autoantibodies, those against centromere, SCL-70 or topoisomerase, RNApolymerase III determinants, and the HLA-DQB1 haplotype.
Rheumatoid arthritis

Scleroderma or systemic sclerosis is characterized by widespread microvasculopathy and diffuse tissue brosis affecting the skin and other systemic organs, particularly the heart, lungs, and gastrointestinal tract. Central and

Rheumatoid arthritis is a multisystemic nodular, granulomatous disease with prominent constitutional and multiorgan involvement including the nervous system. Rheumatoid lesions begin as proliferative joint synovitis with inltration of T cells and plasma cells and scattered areas of brinoid necrosis. Neutrophils contribute to tissue destruction through the release of lytic enzymes and the production of toxic oxygen free radicals. The inammatory inltrate increases in size with nodule formation with a predilection for serous membranes, or may take the form of sheet-like plaques of necrosis and inammation in the nervous system at sites of connective tissue investment, such as the dura, muscle, and nerve. Rheumatic pachymeningitis results from dural, leptomeningeal plaques, and nodules containing

Vasculitis of the nervous system Younger 325 Figure 11. Thrombotic-embolic cerebral microangiopathy in a patient with antiphospholipid antibody syndrome (see text for details)

Reproduced from Younger [1 .] with permission of the publisher.

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Figure 12. Progressive systemic sclerosis

occur in 10% of patients, including headache, seizures, encephalopathy, transverse myelitis, ataxia, aseptic meningitis, monocular blindness, neuropathy, and ganglioneuritis. The pathological features of mixed connective tissue disease are those expected by the associated tissue disorder, in addition to proliferative changes, capillary involvement and mild diffuse brosis.
Behc et disease

This digital artery has severe intimal hyperplasia and greater than 90% luminal narrowing. There is also severe adventitial fibrosis and marked telangiectasia of the vasa vasorum, but the media and internal elastic lamina are relatively spared (stain, trichrome; original magnification 660). Reproduced from Younger [1 .] with permission of the publisher.

The triad of oral and genital ulceration and uveitis, with variable arthritis, retinal and cutaneous vasculitis, thrombophlebitis, gastroenteritis and chondritis characterizes Behc et disease. The essential pathological changes are foci of LCV with or without brinoid necrosis, and perivascular lymphocytic inltration around small blood vessels of involved tissues of the skin, mucosa and brain,with varying gliosis. CNS involvement leads to headache, focal brain stem meningoencephalitis, cranial nerves, cochlear and vestibular dysfunction, with progressive dementia, seizures and aphasia, and a heightened risk of venous sinus thrombosis, pseudotumor cerebri, axonal peripheral neuropathy and myopathy.

Inflammatory diabetic vasculopathy

lymphocytic inammation and brinoid material that predisposes to seizures, cerebral hemorrhage, encephalopathy and myelopathy. The erosive skeletal manifestations include atlantoaxial, odontoid, atlantoaxial and subaxial subluxation; vertebral collapse, and canal stenosis resulting from extradural pannus that leads to spastic quadriparesis.
Sjo gren syndrome

Sjo gren syndrome is recognized by keratoconjunctivitis sicca, xerostomia, and frequent association with other connective tissue disorders such as SLE, scleroderma, essential mixed cryoglobulinemia, accompanied by lymphoid invasion of the exocrine tissues throughout the body, rarely in renal institium and muscle. Two types of vasculitis occur, LCV of the skin, with palpable purpura, urticaria, erythematous macules and papules, and a second type that resembles PAN, with involvement of the brain, spinal cord, muscle, nerve, and multiple systemic organs, ultimately leading to a heightened risk of stroke, hemorrhage, seizures, aseptic meningoencephalitis, transverse myelitis, sensorimotor neuropathy and myositis. Extractable RNA proteins Ro or Sjo gren syndrome (SS)-A, and intranuclear RNAassociated antigen La or SS-B occur in the majority of cases.
Mixed connective tissue disease

The frequency of necrotizing arteritis in diabetic nerves is not known, but as there are only a handful of reported cases, two of which were reported by this author [13], the occurrence of vasculitic diabetic neuropathy is probably exceedingly rare. Non-necrotizing vasculopathy has been noted for decades, but only recently has its signicance been appreciated. Peripheral nerve perivasculitis, dened as inammation around the walls of epineurial vessels, and microvasculitis, in which inammation invades epineurial vessel walls, occurs in the majority of patients, with severe distal symmetrical sensorimotor, proximal diabetic neuropathy, lumbosacral plexopathy, and diabetic MNM (Fig. 13). The biopsied nerves of such patients, studied intensively by a panel of monoclonal antibodies against lymphocyte cell determinants and inammatory markers, reveal a predominance of CD8 cytotoxic suppressor cells in the vascular inammatory inltrate, with the expression of IL-2, nerve growth factor receptor, and a-IFN, and abnormal activation of C5b-9 membrane attack complex (MAC), consistent with an autoimmune pathogenesis of the neuropathy in such cases [14].

Isolated peripheral nerve vasculitis

Peripheral neuropathy may rarely be the singular manifestation of necrotizing arteritis, as demonstrated in a nerve and muscle biopsy specimen without evidence of systemic necrotizing vasculitis in life or at postmortem examination. Some authorities, including the author, question the premise of an isolated peripheral nerve vasculitis, citing several lines of evidence. First, the absence of long-term follow-up in

Mixed connective tissue disease is characterized by the clinical features of SLE, scleroderma, and polymyositis together or sequentially, with Sm and rib nucleoprotein agglutination antibodies. Neurological manifestations

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Figure 13. Inflammatory diabetic vasculopathy

mised patients. In pathologically studied cases, necrotizing arteritis and thrombosis is noted with viral particles and antigens isolated in the media of affected vessels.
Spirochete infection

Two spirochete infections lead to vasculitis of the nervous system, as described below.
Treponema pallidum

A focal-intense collection of CD8 T cells efface the wall of a small epineurial blood vessel (arrowheads) (hematoxylin and eosin 6400).

most cases, with only a single autopsy-conrmed patient reported more than 60 years ago [15]. Second, the nding of systemic vasculitis in up to two-thirds of patients with histologically conrmed peripheral nerve vasculitis, usually forme fruste of PAN, WG type, or in association with another denable dysimmune disease such as rheumatoid arthritis, Sjo gren syndrome, SLE, scleroderma, monoclonal gammopathy, or mixed connective tissue disease type.

Spirochetes enter the host through a skin or mucous membrane site, with wide dissemination to multiple organs including the CNS, with latent reactivation and cerebral vessel involvement leading to headache and vasculitis. One to 2 years after asymptomatic neurosyphilis caused by CNS seeding by T. pallidum, acute syphilitic meningitis presents with headache, meningeal signs, cranial nerve palsies, seizures, and other focal decits. Meningovascular syphilis, which occurs in approximately 10% of patients, presents with headache, vertigo, behavioral, and mood changes that last weeks to months, and stroke in the setting of meningeal involvement. The vasculitis is believed to result from spirochetal invasion of vascular endothelial cells. Cerebral vessel involvement occurs years later in tertiary parenchymal syphilis syndrome of general paresis and tabes dorsalis, in which there is considerably more neuronal degeneration and gummas indicative of chronic inammation are present.
Borrelia burgdorferi

Central nervous system vaculitis caused by infection

Vasculitis and headache occurs early in the setting of infection by several possible mechanisms. VZV, the spirochetes Treponema pallidum and Borrelia burgdorferi, several fungal agents, and Rickettsiae invade cerebral blood vessels causing CNS vasculitis. Bacteria and mycobacteria cause indirect damage to cerebral blood vessels in fulminant meningitis as they traverse purulent exudate in cisterns at the base of the brain, and along foci of cerebritis. Cerebral vessel damage occurs in association with hepatitis C viral infection through the production of cryoglobulins and cryoprecipitate comprised of immunoglobulin, complement, lipoprotein, and hepatitis C viral antigen; as well as immune complex deposition, cold agglutinin formation, intravascular activation of complement and clotting factors, and vascular endothelial cell proliferation. HIV-1 infection causes neurological vasculitic complications as a result of opportunistic infection and HIV itself.
Varicella zoster virus

The spirochete B. burgdorferi is transmitted by the bite of an infected tick leading to characteristic skin, joint, heart, eye, and nervous system involvement. Lyme neuroborreliosis presents with Garins triad of headache, neuritis, meningitis, and radiculitis. Cerebrovascular manifestations include vasculitis in association with headache, stroke, transient ischemic attack, and subarachnoid hemorrhage caused by focal mononuclear inammatory cell inltration of blood vessels, with vascular endothelial cell swelling. Patients with late Lyme neuroborreliosis manifest with headache, personality change, and cognitive decline after symptomatic infection and appropriate antibiotic therapy. Peripheral nerve biopsy in patients with acute and subacute neuritis may demonstrate perivasculitis mediated by cytotoxic suppressor CD8 cells [16].
Fungi

Herpes zoster ophthalmicus caused by VZV infection is associated with headache and delayed contralateral hemiparesis as a result of granulomatous vasculitis ipsilateral to skin lesions, especially in immunocompro-

Four fungal agents have a predilection for cerebral vessels, leading to vasculitis, particularly in immunocompromised and neutropenic hosts. Aspergillosis invades the CNS in disseminated infection and by contiguous extension from paranasal sinuses and orbital foci of infection, leading to headache, hyphal angiitis, with resultant large and small vessel thromboses, cerebral infarction, and mycotic aneurysm formation.

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Those with candidiasis and coccidioidomycosis demonstrate chronic meningitis, but may also have invasion of the cerebral vessels leading to vasculitis. Mucormycosis is a particularly aggressive fungal infection especially in poorly controlled diabetic individuals, which if unrecognized spreads from the nasopharynx and sinuses to the orbit, cavernous sinus, and brain, resulting in a necrotizing vasculitis of the cerebral vessels. Affected patients have unilateral headache, lethargy, periorbital swelling, proptosis, and ophthalmoplegia. Septic thrombosis of the cavernous sinus and internal carotid artery is suggested by vision loss. Diagnosis requires a high index of suspicion in a predisposed host.
Rickettsia

tions, supraclinoid internal carotid artery narrowing, and distal branch occlusions. The later involvement of cerebral veins leads to septic venous sinus thrombosis and thrombophlebitis.
Mycobacterium tuberculosis

The life cycle of rickettsiae involves insect vectors and mammal reservoirs; humans are accidental hosts. The organism enters the skin as the infected tick feeds, and disseminates throughout the body to infect systemic and cerebral vascular endothelial cells. Two to 14 days after a tick bite, affected patients develop headache, constitutional symptoms and skin rash. Neurological involvement leads to mental change, meningismus, ataxia, seizures, hallucination, and focal cerebral decits, progressing to delirium, stupor, and coma reective of encephalitis. The diagnosis is conrmed by serological and antiendothelial antibody studies, and immunohistological and polymerase chain reaction of the skin lesion. The pathogenesis of cerebral vessel damage is caused by the combined effects of direct infection and associated immunological injury ascribed to the upregulation of cytokines and the production of anti-endothelial antibodies. Neuropathological studies in fatal cases show cerebral edema, angiitis of small and medium-sized blood vessels with microinfarcts, punctate hemorrhage and glial nodules consisting of enlarged endothelial cells, lymphocytes, and macrophages that contain rickettsiae by immunouorescence.
Bacterial meningitis

Headache and vasculitis occur in the setting of tuberculous meningitis caused by miliary infection or rupture of an old tubercle. Most adult patients have obvious clinical signs of meningitis, including headache, meningismus, and fever, but some have no obvious clinical signs, and in these instances a high index of suspicion is necessary such as in elderly and immunocompromised individuals. Blood vessels that traverse the thick gelatinous basilar exudate develop inammation, particularly small and medium-sized arteries, and occasionally capillaries and veins. The inamed adventitia contains cells, tubercles, caseation necrosis, and occasional clumps of mycobacteria. Reactive subendothelial cells proliferate, leading to stenosis of the vascular lumina. The arteritis that ensues leads to cerebral ischemia and infarction, most commonly in the middle cerebral artery territory. All patients that test culture positive for tuberculous meningitis should be tested for HIV-1 exposure.
HIV

Cerebral vasculitis is a known complication of acute septic meningitis caused by a number of bacterial agents, which reect age and underlying host conditions. Purulent infection at the base of the brain leads to true vasculitis as a result of inammatory cell inltration of vessel walls as they traverse the subarachnoid space. The activation of cellular adhesion molecules, complement, platelet factors, cytokine products, reactive oxygen species, excitatory amino acids, and proteolytic enzymes contribute to vessel wall damage and vasculitis. The diagnosis of acute septic thrombosis should be suspected in the presence of headache, fever, meningismus, seizures, focal neurological signs, and increased intracranial pressure; and conrmed by CSF analysis. Brain magnetic resonance angiography and conventional angiography shows vessel wall abnormalities, focal dila-

Necrotizing vasculitis and granulomatous angiitis have both rarely been described in the course of HIV infection. There are patients with GANS in association with HIV infection in whom there was no evidence of opportunistic infection [12]. Peripheral nerve vasculitis is often the rst manifestation of HIV, but also occurs after AIDS has developed, and may be manifest as a symmetrical or overlapping MNM syndrome. The vascular inammatory inltrate usually consists of CD8 T cells and macrophages [17]. HIV antigens in affected patients have been shown in perivascular macrophages by electron microscopy and in-situ hybridization [18]. Pathological ndings include necrotizing arteritis of the epineurial vessels similar to PAN, but without an emphasis of healed lesions in different stages of development. Cryoglobulinemia has also been described in several patients with HIV infection and MNM. Necrotizing vasculitis can be seen in muscle biopsies of patients with peripheral nerve vasculitis, and an examination of both muscle and nerve tissue in suspected patients also increases the yield of a diagnostic biopsy. Vasculitis with HIV infection is more commonly caused by secondary opportunistic infection or is seen in association with lymphoma.

Central nervous system vasculitis associated with amphetamine abuse

Cerebral vasculitis in association with drug abuse was rst reported among 14 drug addicts who used multiple

Vasculitis of the nervous system Younger 329

amphetamine drugs [19]. Necrotizing arteritis of the PAN type was found in cerebral arteries and arterioles at postmortem examination (Fig. 14). The vascular insult followed drug-induced vasospasm, hypertension, and secondary vascular injury, including cerebral infarction, aneurysm formation and rupture with cerebral hemorrhage, transient ischemic attack, or myelopathy as the case is usually self-limited. Interestingly, necrotizing arteritis is not a feature of amphetamine-induced cerebrovascular injury in primate models; and the beading of cerebral vessels develops 2 weeks after parenteral administration of amphetamine, suggesting the participation of other factors. The frequency of cerebral vasculitis caused by drug abuse is difcult to estimate for several reasons, and is probably overexaggerated as a cause of cerebral vasculitis. First, most patients have been diagnosed by vessel beading on cerebral angiography without pathological verication. Second, the vascular insults associated with amphetamine drugs may be caused by factors other than vasculitis. For example, parenteral amphetamine use enhances the risk of endocarditis, cardiac embolism, hemorrhage, stroke, and mycotic aneurysm formation; and all other routes of administration predispose to acute hypertension and cerebral hemorrhage. Third, opportunistic infection associated with HIV infection and AIDS probably accounts for most cases of cerebral vasculitis as

a result of the high frequency of HIV-1 infection in the drug addict population.

Paraneoplastic vasculitis
Paraneoplastic neurological disorders are diseases of nervous system function that occur in association with cancer, but cannot be ascribed to metastases or direction inltration of the nervous system by tumor. In two-thirds of affected patients, the neurological disorder generally precedes the diagnosis of the tumor, and the correct identication of the related neurological disorder directs a search for occult and potentially curable cancer. Necrotizing arteritis and microvasculitis have been described in association with anti-Hu associated paraneoplastic encephalomyelitis and sensory neuropathy [20]. The anti-Hu antibody, when present at high titers in the serum and CSF of affected patients, is a highly sensitive and specic marker for paraneoplastic encephalomyelitis and sensory neuropathy in association with occult small cell lung cancer. Patients develop multifocal neurological symptoms and signs that include headache, limb encephalitis, brain stem decits, cerebellar incoordination, proprioceptive and tactile sensory loss leading to imbalance of stance and gait, pseudoathetosis, numbness and paresthesia, weakness, wasting, fasciculation, active tendon reexes, Babinski signs, Hoffman signs, and clonus. Histopathological examination of the neuraxis reveals widespread neuronal degeneration, neuronal loss, and Wallerian ber degeneration in the hippocampus, brainstem, cerebellum, spinal cord dorsal columns, dorsal root ganglia, and nerve roots, with perivascular collections of chronic inammatory cells, also known as perivasculitis. Paraneoplastic encephalomyelitis should be suspected in patients with subacute sensory neuropathy, a history of cancer or suspected malignancy, weight loss, headache, mental change, and multifocal involvement of the nervous system with upper and lower motor neuron signs, central and peripheral sensory loss, CSF pleocytosis and elevated total protein and IgG content, contrast neuroimaging studies that reveal meningeal or perivascular enhancement, and muscle and nerve biopsy that demonstrates microvasculitis, Wallerian nerve ber degeneration, or inammatory myopathy.

Figure 14. Cerebral vasculopathy in a case of intracerebral hemorrhage associated with the use of phenylpropanolamine as an aid to weight loss

Laboratory diagnosis
The laboratory diagnosis of vasculitis of the nervous system proceeds along a systematic framework of generally accepted principles with an extensive choice of recommended studies as described below.
The profound intimal hyperplasia all but obliterates the vascular lumen. Polymorphonuclear leukocytes are in all three vascular layers but particularly the intima. The media are remarkably well preserved compared with cases of polyarteritis nodosa and leukocytoclastic vasculitis (stain, hematoxylin and eosin; original magnification 6100). Reproduced from Younger [1 .] with permission of the publisher.

General principles

There is general agreement on four principles in the diagnosis of vasculitis: First, vasculitis is a potentially serious disorder with a propensity for permanent disability as a result of tissue ischemia and infarction;

330 Inflammatory diseases and infection

recognition of the neurological manifestations is important in developing a differential etiological diagnosis. Second, undiagnosed and untreated, the outcome of vasculitis is potentially fatal. Third, a favorable response to an empiric course of immunosuppressive and immunomodulating therapy should never be considered a substitute for the absolute proof of the diagnosis of vasculitis. Fourth, histolopathological conrmation of vasculitis in the nervous system is essential for accurate diagnosis, such as by analysis of nerve and muscle biopsy tissue when PNS involvement is postulated, and by brain and meninges when there is CNS involvement.
Recommended laboratory evaluation of suspected vasculitis

Table 2. Laboratory evaluation of headache and vasculitis Blood studies Complete blood count Erythrocyte sedimentation rate Chemistry panel including creatine phosphokinase Antinuclear antibody Complement levels Rheumatoid factor Cryoglobulins Immunofixation electrophoresis Quantitative immunoglobulins T and B cell panels Antibodies (selectively) to: Ro (SS-A), La (SS-B), Sm, SCL-70, hepatitis B and C virus HIV-1, Borrelia burgdorferi (ELISA, Western blot), c-ANCA and p-ANCA Radiographic studies Chest Body computed tomograph Magnetic resonance imaging Magnetic resonance angiography and venography Single photon emission computed tomography Systemic and cerebral angiography Other neurodiagnostic studies Electroencephalography Electromyography and nerve conduction studies Lumbar puncture for cerebrospinal fluid analysis: protein, glucose, cell count, IgG level, cytology, VDRL, Gram stain, culture, India ink; viral antigens, Lyme antibodies and PCR (as indicated) Histopathological studies (as indicated) Muscle and nerve biopsy Temporal artery biopsy Meningeal and cortex Skin Systemic organs Lymph nodes ELISA, Enzyme-linked immunosorbent assay; c-ANCA, circulating antineutrophil cytoplasmic antibody; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; PCR, polymerase chain reaction; SS, Sjo gren syndrome; VDRL, Veneral Disease Research Laboratory.

The laboratory evaluation of vasculitis of the nervous system is summarized in Table 2. The initial diagnosis of vasculitis commences with an investigation of possible associated serological markers in a given patient. The emergence of specic serological studies for many of the connective tissue diseases including vasculitis has transformed our concepts of autoimmune disease. However, their use should be guided by the clinical presentation and postulated etiological diagnosis to avoid excessive cost and spurious results. Electrodiagnostic studies are useful in the initial investigation of systemic vasculitis, because they can identify areas of asymptomatic involvement and sites for muscle and nerve biopsy and distinguish the various neuropathic syndromes associated with peripheral nerve and muscle involvement. A wide sampling of nerves and muscles should be examined, both distal and proximal, using standard recording and needle electrodes for the performance of nerve conduction studies and needle electromyography at skin temperatures of 348C in comparison with normative data. Most patients with peripheral nerve vasculitis show evidence of active axonopathy acutely in an MNM pattern and over time in a distal symmetric or asymmetric pattern. Quantitative motor unit potential analysis can delineate whether proximal wasting and weakness are caused by myopathic or neurogenic disease. CSF analysis, electroencephalography, and neuroimaging studies are integral to the diagnostic evaluation of most CNS disorders, including vasculitis. Properly performed, lumbar puncture carries a minimal risk and provides potentially useful information regarding possible underlying vasculitis so suggested by pleocytosis in excess of 5 cells/mm3, protein elevation greater than 100 mg/dl, and evidence of intrathecal synthesis of immunoglobulin and oligoclonal bands. Molecular genetic, immunoassay, and direct staining techniques to exclude spirochetal, fungal, mycobacterial and viral

infections, as well as cytospin examination of CSF for possible malignant cells should be performed. There are no typical electroencephalography ndings in CNS vasculitis. Magnetic resonance imaging (MRI) is more sensitive than computed tomography, but both methods lack specicity in histologically conrmed cases. The most common MRI ndings are multiple bilateral cortical and deep white matter signal abnormalities, and enhancement of the meninges after gadolinium. Magnetic resonance angiography and functional imaging of the brain provide complementary ndings to conventional MRI. The former is useful in the evaluation of medium and large vessel disease, but misses ne vessel contours better seen on cut-lm or digital subtraction angiography. The abnormal diffuse and focal perfusion patterns seen on single photon emissioncomputed tomography (SPECT) do not always correlate with neurological symptoms or distinguish vasculitic from non-vasculitic vasculopathy. Some authorities claimed that cerebral angiography showed diagnostic

Vasculitis of the nervous system Younger 331

features, but that assertion was later modied. The beading of vessels is found in only approximately a third of patients with histologically conrmed CNS vasculitis, as well as in CNS infection, atherosclerosis, cerebral embolism, and vasospasm of diverse cause (Fig. 15). Multiple microaneurysms, often seen on visceral angiography in systemic vasculitis, are distinctly rare in CNS vessels. Brain and meningeal biopsy are still the gold standard for the diagnosis of CNS vasculitis, but false-negatives occur because of focal lesions and sampling errors. Radiographic studies that guide the biopsy site towards areas of abnormality probably improve the sensitivity, but this has not been formally studied. The risk of serious morbidity related to biopsy is less than 2.0% at most centers, which is probably less than the cumulative risk of an empiric course of long-term immunosuppressive therapy. There are no certain guidelines as to when to proceed to brain and meningeal biopsy. However, it would certainly be warranted if there were no other explanation for the progressive syndrome of fever, headache, encephalopathy, and focal cerebral signs, in association with CSF pleocytosis, and protein content elevation greater than 100 mg/dl, which is suggestive of GANS.

The importance of nerve and muscle biopsy in the diagnosis of vasculitis cannot be overemphasized. It can be approached with condence when a neurologist or surgeon skilled in nerve and muscle biopsy techniques at centers performs the procedure with neuropathologists trained to process and examine the specimens for all of the diagnostic possibilities. The nerve and muscle should be clinically and electrophysiologically affected. However, the muscle should not be so affected, or endstage, as to preclude interpretation. A segment of the sural, supercial peroneal sensory, or femoral intermedius sensory nerve can be surgically removed without incurring a serious decit, along with pieces of muscle tissue, respectively, from the soleus, peroneus brevis, or rectus femoris muscle, thereby providing potentially useful information regarding the severity of the underlying neuropathy and increasing the yield of vasculitic lesions (Fig. 16). Commercially available monoclonal and polyclonal antibodies directed against T- and B-cell subsets, macrophages, immunoglobulins, C3d, C5b-9 MAC proteins, cytokines and other inammatory mediators, and main histocompatibility class I and II antigens add precision to the analysis of peripheral nerve specimens with suspected necrotizing and non-necrotizing peripheral nerve vasculitis [21].

Immunopathogenesis
Early progress in the understanding of vasculitis took a major turn during a discussion of the paper by Kernohan and Woltman [15] on PAN. At that time, in 1938, there was no effective treatment and antemortem diagnosis was rarely possible. Harry Lee Parker conceptualized nerve and muscle biopsy when he commented It occurs to me that in any case in which polyarteritis nodosa may be suspected, it is advisable to take a biopsy from a peripheral nerve, muscle, or artery. The Second World War provided another opportunity for the advancement of our understanding of the blood supply of the peripheral nerves, and these ndings in turn guided our thoughts on vasculitis. In 1943, Coers and Woolf [22] described the surgical approach for biopsy of the supercial peroneal sensory nerve and peroneus brevis muscle now performed routinely for vasculitis. Two years later, Sunderland [23,24] provided a detailed account of neurovascular anatomy by performing dissection of amputated limbs after injection of India ink to opacify the vessels. His ndings were summarized in a concluding statement: Each of the major nerves is generally abundantly vascularized throughout its entire length by a succession of vessels, which by their repeated division and anastomosis within the nerve outline an unbroken vascular net (Fig. 17).
Ectasia and beading in the M1 segment and lack of flow in the A1 segment of the right anterior cerebral artery (arrow).

Figure 15. Radiographic features of cerebral vasculitis

Some nerves such as the median and ulnar nerve between the axilla and elbow and along the sciatic in

332 Inflammatory diseases and infection

Figure 16. Muscle and nerve biopsy technique

(a) The superficial peroneal sensory nerve is palpated laterally along the distal third of the leg along a line between the fibular head and lateral malleolus providing markings for the incision. (b) An incision is made and the area is dissected revealing the nerve (n) obliquely traversing the field (arrow). (c) Incising the muscle aponeurosis reveals underlying peroneus brevis muscle tissue (m) in addition to nerve (n, and arrows) available for biopsy. (d) After the specimens are removed and the site irrigated, a subcuticular closure is performed using absorbable sutures. Reproduced from Younger DS, editor. Motor disorders, peripheral nerve pathology. Philadelphia Lippincott Williams and Wilkins; 1999, p. 84, with permission of the publisher.

the gluteal region had few or no entering nutrient vessels, but vascular insufciency was still an unlikely occurrence as stated by Sunderland. Admittedly there are instances, although uncommon, in which one vessel supplies long stretches of a nerve without reinforcement, but it has been demonstrated in sectioned and injected material that even under such apparently adverse conditions of supply, the anastomosis is of such dimensions at the peripheral limits of the solitary channel that segmental ischemia caused by the blocking of such a single vessel is a remote possibility. On the basis of such studies, there was no convincing evidence for the presence of watershed zones of poor vascular supply along major nerves of the arm or leg, a contention that has permeated the literature with regard

to the clinical sequelae of vasculitis. Nonetheless, Dyck and coworkers [25] ascribed centrofascicular nerve ber loss in a patient with necrotizing vasculitis to poor vascular perfusion along presumed watershed zones of the upper arm and proximal thigh regions. Almost a decade later, Moore and Fauci [26] ascribed ail weakness and mid-level sensory loss of the arms to vasculitis of the arteria nervorum, even though the patient was not studied pathologically. It is now known that under normal circumstances, the nervous system is protected from systemic immunological reactions by the bloodbrain and bloodnerve barriers. Tight junctions between neighboring cells and a paucity of micropinocytotic vessels are unique to the bloodbrain barrier, and along with other local determi-

Vasculitis of the nervous system Younger 333

Figure 17. Vascular supply of the peripheral nerves of the limb

(a) An artist view of the intraneural blood supply. (b) The injection of India ink shows the actual internal architecture of the vascular supply. From Younger [1 .], reproduced with permission of the publisher.

nants, contribute to the prevention of the early involvement of the CNS in the course of systemic inammation. Immune activation requires the interaction of a specic autoantigen, an MHC class II antigen-presenting cell (APC) and an antigen-specic T cell. Macrophages are the principal APCs of the PNS, and their role appears to be that of a local surveillance system, taking up and processing protein antigens and presenting them on their surface. Their interaction with native antigen and antigen-specic T cells leads to a proliferation of specic helper (CD4) and cytotoxic suppressor (CD8) T cells

with the expression of HLA-DR, IL-2 receptor, and TNF-a secretion. T cells that become sensitized early in the course of systemic illness probably later contribute to the cellular immune response directed against crossreacting epitopes present in peripheral nerves and the brain. Vascular endothelial cells play an important role in the pathobiology of vascular inammation along the blood nerve and bloodbrain barriers, because of their potential interaction with elements of the systemic immune

334 Inflammatory diseases and infection

system. They are potentially active participants in vasculitis, not simply passive targets of injury. They satisfy the criteria for an APC because of their native ability to express MHC class I molecules for interaction with cytotoxic T cells; and under certain conditions, they express MHC class II molecules and the necessary costimulatory factors to induce T-cell proliferation in vivo and in vitro. The function of vascular endothelial cells is regulated mainly by IL, TNF, and endotoxins derived from immigrant or resident mononuclear cells. Their action, by virtue of binding to specic receptors, is alteration of the transcription of an array of endothelial genes that programme cellular inammatory secretion, the local expression of leukocyte adhesion molecules, the balance of prothrombotic and antithrombotic vascular functions, the synthesis of matrix molecules and their receptors, and the secretion of growth factors, secondary cytokines, and enzymes related to matrix degradation. The localization and propagation of leukocytes along vascular endothelial cells depend on the local production of IL-1, IL-6, and IL-8, the expression of cell adhesion molecules, namely integrins, selectins, and the immunoglobulin super-family molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, platelet-endothelial cell adhesion molecule 1) constitutively expressed or induced after cellular activation, and the expression of autoantigens such as ANCA and anti-endothelial cell antibodies. Other substances that contribute to vascular integrity include free radical nitric oxide, Von Willebrand factor, tissue plasminogen activator inhibitor, thrombomodulin, and platelet-activating factors. Human mechanisms also contribute to the development of vasculitis and nervous system damage through complement-mediated injury of microvessels. The complement system is composed of 11 proteins that sequentially interact in the activated state to form an assembly of ve proteins referred to as C5b-9 or MAC. The activation of C5b-9 along peripheral nerve microvessels leads to increased local permeability, edema, and inammatory cell inltration. Complement-mediated injury appears to be an important mechanism in the etiopathogenesis of inammatory diabetic vasculopathy; however, the initiating factors are still speculative. One possibility is a defect in the expression of certain regulatory membrane proteins in the walls of microvessels, including complement receptor (CR10), decayaccelerating factor (CD55), membrane co-factor protein (CD46), and membrane inhibitor of reactive lysis (CD59), which normally protect cells by limiting the activation of the complement cascade. Interest in the role of specic pathogenic autoantibodies has evolved over the past two decades as, for example, in our understanding of WG and related disorders in the

elucidation of ANCA. The pathobiology of ANCA was understood through the use of animal models, human neutrophil studies, and monolayers of cultured human umbilical vein endothelial cells. MPO and PR3 antigens, so named for the patterns of staining of normal ethanolxed neutrophils with indirect immunouorescence, granular cytoplasmic ANCA, and perinuclear ANCA, were found to correlate with disease activity in WG and MPA, respectively. The MPO and PR3 antigens are accessible for binding with circulating ANCA and Fc receptors. ANCA-augmented chemotaxis and adhesion bring circulating neutrophils and mononuclear phagocytes into close contact with endothelial cells and induce neutrophil-mediated endothelial cell lysis and vascular permeability.

Treatment
Neurologists treating vasculitis must choose the sequence and combination among available immunosuppressant and immunomodulating therapies, recognizing the possible adverse effects. A modern appreciation of the usefulness of corticosteroid preparations in systemic vasculitis was rst reported in 1950 [27]. Untreated, patients with PAN had a 5-year survival rate of 10%; treatment with corticosteroids increased survival to 48% [28]. Although the effectiveness of corticosteroids is well established, there is uncertainty even among experts as to the optimal regimen. For example, in one analysis [29], a sustained benet in PAN was obtained in patients with a minimum equivalent dosage of 31 mg of prednisone a day for 7 months. The benecial effects of corticosteroids are attributed to a multiplicity of effects on the cell and humoral immune system, including the inhibition of activated T and B cells, APC, and leukocytes at sites of inammation, IFN-g, induced MHC class II expression, macrophage differentiation, pathogenic cytokine expression, complement interactions, and immunomodulating cell adhesion molecules. The effectiveness of a daily oral regimen of cyclophosphamide and prednisone in WG was rst reported by Fahey et al. [30] in 1954, and later by Fauci et al. [31] in 1971, and served as a template for the treatment of virtually all types of systemic vasculitis, including GANS until its long-term side-effects were appreciated in WG. Nonetheless, this alkylating agent is an important adjunct in the treatment of systemic vasculitis. It leads to preferential T-cell lysis resulting from the inhibition of hematopoietic precursors in the bone marrow. Azathioprine is a purine analog that metabolizes to the cytotoxic derivative 6-mercaptopurine. It exerts favorable action in vasculitis by the inhibition of T-cell activation and T-cell-dependent antibody-mediated re-

Vasculitis of the nervous system Younger 335

sponses. It is appropriate alterative therapy to corticosteroids and cyclophosphamide in systemic vasculitis. There are three drawbacks to its use. First, idiosyncratic side-effects, most often gastrointestinal and u-like, occur in approximately 10% of patients and rarely necessitate permanent withdrawal of the medication. However, pancreatitis and gastritis severe enough to warrant hospitalization can occur. Second, bone marrow suppression occurs in nearly all patients, usually manifested by mild pancytopenia. Third, there is typically a long delay in the onset of the therapeutic effect of 3 months or more. Taking all these factors into account, most clinicians concur with the slow advancement of the dose over weeks, commencing with 50 mg a day and achieving maintenance levels of 23 mg/kg a day, with careful monitoring of liver and marrow function. Intravenous immunoglobulin (IVIg) therapy has been widely used in the treatment of autoimmune neurological diseases, and warrants consideration as initial or adjunctive therapy in vasculitis of the PNS and as adjunctive therapy in CNS. This is because of its acknowledged salutary action through the action of blocking antibodies, the suppression of antibodymediated responses, the accelerated catabolism of pathogenic IgG antibodies, the suppression of pathogenic cytokines, and most of all, the inhibition of C5b-9 MAC-mediated cytolysis. The usual dosage is 400 mg/kg per day for 5 days once a month, after the determination of adequate renal clearance and the absence of IgA antibodies that can rarely promote anaphylaxis. A new manufacturing process that employs chromatographic steps in the intravenous immunoglobulin purication scheme yields a purer intravenous immunoglobulin product that more closely reects the IgG subclass distribution found in plasma.

demia, alone or as a side-effect of concomitant corticosteroids, and the cessation of cigarette smoking.

Acknowledgement
This work was supported by the Neurology Research Foundation, Inc.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as: . of special interest .. of outstanding interest Younger DS. Vasculitis and connective tissue disorders. In: Griggs R, Joynt R, editors. Baker and Joynts clinical neurology on CD-ROM, Chapter 59. Philadelphia: Lippincott Williams and Wilkins; 2003. This article is a comprehensive review of vasculitis of the nervous system with excellent tables and figures. 1 2 3 Younger DS, Kass RM. Vasculitis and the nervous system. Neurol Clin 1997; 15:737758. Kussmaul A, Maier R. Ueber eine bisher nicht beschriebene eigaenthumliche Arterienerkrangung (periarteritis nodosa) die mit morbus brightii und rapid fortachreitender allgemeiner muskellahmung einergeht. Deutsches Arch Klin Med 1866; 1:484518. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27:277302. Zeek PM, Smith CC, Weeter JC. Studies on periarteritis nodosa, III: the differentiation between the vascular lesions of periarteritis nodosa and of hypersensitivity. Am J Pathol 1948; 24:889917. Godman GC, Churg J. Wegeners granulomatosis: pathology and review of the literature. Arch Pathol 1954; 58:533553. Horton BT, Magath BT, Brown GE. Arteritis of temporal vessels: report of 7 cases. Proc Staff Meet Mayo Clin 1937; 12:548553. Jennings GH. Arteritis of the temporal vessels. Lancet 1938; 1:424.

4 5

6 7 8 9
..

Weyland CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003; 349:160169. This is an excellent overview of giant cell arteritis with descriptions of new insights into the observed immunohistopathology. 10 Cravioto H, Fegin I. Non-infectious granulomatous angiitis with a predilection for the nervous system. Neurology 1959; 9:599609. 11 Younger DS, Hays AP, Brust JCM, Rowland LP. Granulomatous angiitis of the brain: an inflammatory reaction of nonspecific etiology. Arch Neurol 1988; 45:514518. 12 Younger DS, Calabrese LH, Hays AP. Granulomatous angiitis of the nervous system. Neurol Clin 1997; 15:821834. 13 Younger DS, Rosoklija G, Hays AP. Diabetic peripheral neuropathy. Semin Neurol 1998; 18:95104. 14 Younger DS, Rosoklija G, Hays AP, et al. Diabetic peripheral neuropathy: a clinical and immunohistochemical analysis of sural nerve biopsies. Muscle Nerve 1996; 19:722727. 15 Kernohan JW, Woltman HW. Periarteritis nodosa: a clinicopathologic study with special reference to the nervous system. Arch Neurol Psychiatry 1938; 39:655686. 16 Younger DS, Rosoklija G, Hays AP. Lyme polyradiculoneuritis: immunohistochemical findings in sural nerve. Muscle Nerve 1995; 18:359360. 17 Younger DS, Rosoklija G, Hays AP, et al. HIV-1 associated sensory neuropathy; a patient with peripheral nerve vasculitis. Muscle Nerve 1996; 19:13641366. 18 Younger DS, Rosoklija G, Hays AP. Sensory neuropathy in AIDS: demonstration of vasculitis and HIV antigens in peripheral nerve. J Neurol 1994; 241 (Suppl.):17. 19 Citron BP, Halpern M, Mccarron M, et al. Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283:10031011. 20 Younger DS, Dalmau J, Inghirami G, Hays AP. Anti-Hu-associated peripheral nerve and muscle micro vasculitis. Neurology 1994; 44:181183. 21 Younger DS, Rosoklija G, Hays AP, Latov N. Peripheral nerve immunohistochemistry in diabeteic neuropathy. Semin Neurol 1996; 16:139142. 22 Coers C, Woolf AL. The innervation of muscle: a biopsy study. Oxford: Oxford University Press; 1943. pp. 23.

Conclusion
The comprehensive therapy of patients with vasculitis often requires the commitment of a multidisciplinary team of health professionals and caregivers to optimize recovery while initiating immunotherapy. Physical therapy and orthosis may be warranted for disabling motor and cognitive disorder impairments to maintain a range of motion and strength, to improve function status, and to maintain ambulation. Effective pain management may be an important aspect of their care, not only to provide overall wellbeing, but to permit more aggressive physiotherapy. Agents such as tricyclic antidepressants, gabapentin, mexiletine, opioids, clonazepam, and topical anesthetic creams have all been used with varying success. Finally, efforts should be made to limit the ischemic-enhancing effects of other conditions, such as with diabetes mellitus through improved glycemic control, the regulation of blood pressure and hyperlipi-

336 Inflammatory diseases and infection

23 Sunderland S. Blood supply of the nerve of the upper limb in man. Arch Neurol Psychiatry 1945; 53:91115. 24 Sunderland S. Blood supply of the sciatic nerve and its popliteal divisions in man. Arch Neurol Psychiatry 1945; 53:283289. 25 Dyck PJ, Conn DL, Okazaki H. Necrotizing angiopathic neuropathy. Three dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Proc 1972; 47:461475. 26 Moore PM, Fauci AS. Neurologic manifestations of systemic vasculitis. A retrospective and prospective study of the clinicopathologic features and response to therapy in 25 patients. Am J Med 1981; 71:517524.

27 Bagenstoss AH, Shick RM, Polley HF. The effect of cortisone on the lesions of periarteritis nodosa. Am J Pathol 1950; 26:709. 28 Frohnert PP, Sheps SG. Long-term followup study of periarteritis nodosa. Am J Med 1967; 43:814. 29 Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 1979; 67:941947. 30 Fahey JL, Leonard E, Churg J, et al. Wegeners granulomatosis. Am J Med 1954; 17:168179. 31 Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response in Wegeners granulomatosis. N Engl J Med 1971; 285:14931496.