Vasculitis of the nervous system

Vasculitis of the nervous systemDavid 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 17:317–336. # 2004 Lippincott Williams & Wilkins.

Department of Neurology, New York University School of Medicine, New York, NewYork 10016, USA

Correspondence to David S. Younger, MD, 715 Park Avenue, Ground Floor, NewYork, NY 10021, USATel: +1 212 535 4314; fax: +1 212 535 6392; e-mail: [email protected]

Current Opinion in Neurology 2004, 17:317–336

Abbreviations

ANCA antineutrophil cytoplasmic antibodyAPC antigen-presenting cellCNS central nervous systemCSF cerebrospinal fluidGANS granulomatous angiitis of the nervous systemIVIg intravenous immunoglobulinLCV leukocytoclastic vasculitisMAC membrane attack complexMNM mononeuritis multiplexMPA microscopic polyangiitisMRI magnetic resonance imagingPAN polyarteritis nodosaPMN polymorphonuclear leukocytePNS peripheral nervous systemSLE systemic lupus erythematosusSPECT single photon emission computed tomographyVZV varicella zoster virusWG Wegener granulomatosis

# 2004 Lippincott Williams & Wilkins1350-7540

IntroductionVasculitis is a spectrum of clinicopathological disorders

defined by inflammation 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, classification, diagnosis, and management

of vasculitis of the nervous system. Several excellent

reviews have been published on this topic [1.,2].

ClassificationVasculitis 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 thepolyarteritis nodosa typePolyarteritis nodosa (PAN) is the prototypic disorder of

the group of systemic necrotizing arteritis, which also

includes Churg–Strauss syndrome, microscopic polyan-

giitis (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.0000130301.13775.96 317

trichinosis was contemplated. At postmortem examina-

tion there was widespread arteritis that resembled

syphilitic periarteritis caused by the frequent occurrence

of internal and external elastic lamina necrosis, fibrin

deposition, aneurysmal dilatations, and intimal prolifera-

tion 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 finding, 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; 50–80% of patients have circulating antineu-

trophil cytoplasmic antibodies (ANCA) to myeloperox-

idase 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 extravas-

cular granulomas, epithelioid and giant cell infiltrates

distinguish Churg–Strauss 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 vasculitisHistorically, in the same period as PAN, Zeek et al. [5]described patients with sensitivity to sulfonamides and

Figure 1. The pathological spectrum of the major vasculitides

Vessels involved Clinical syndrome

Veins

Venules

Capillaries

Arterioles

Small musculararteries(intraorgan vessels)

Medium musculararteries (coronary,hepatic, intracerebral)

Large arteries(vertebral, temporal,carotid)

Aorta

Usually involved

Sometimes involved

Eales’disease

Hypersen-sitivityangitis

Wegener’sgranulo-matosis

Lympho-matoidgranulo-matosis

Allergicgranulo-matosis

Micro-scopicpoly-angitis

Polyarter-itisnodosa

CNSvasculitis

Temporalarteritis

Takayasu’sarteritis

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

Inflammatory diseases and infection318

other drugs that manifested with skin rash and general-

ized vasculitis. So-called hypersensitivity vasculitis

includes syndromes related to drug reactions, Henoch–

Schonlein purpura, hypocomplementemic or urticarial

vasculitis and cryoglobulinemia. These disorders demon-

strate non-segmental infiltration 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),

fibrinoid 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 ’flu-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 myelo-

pathy. In contrast to PAN, lesions are in the same stage

of evolution.

Henoch–Schonlein purpura is characterized by non-

thrombocytopenic 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 infiltration by

PMN cells, eosinophils, and mononuclear cells, with

variable fibrinoid necrosis and perivascular granuloma

formation. Affected children present with fever, urticaria,

arthralgia, lymphadenopathy, and headache and abdom-

inal pain so severe as to suggest meningitis and acute

surgical abdomen, usually after injection with hetero-

logous antiserum.

Hypocomplementemic or urticarial vasculitis is charac-

terized 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-

Table 1. Classification of vasculities that affect the nervous system

Systemic necrotizing arteritisPolyarteritis nodosaChurg–Strauss syndromeMicroscopic polyangiitis

Hypersensitivity vasculitisHenoch–Schonlein purpuraHypocomplementemic vasculitisCryoglobulinemia

Systemic granulomatous vasculitisWegener granulomatosisLymphomatoid granulomatosisLethal midline granuloma

Giant cell arteritisTemporal arteritisTakayasu arteritis

Granulomatous angiitis of the nervous systemConnective tissue disorders associated with vasculitis

Systemic lupus erythematosusSclerodermaRheumatoid arthritisSjogren syndromeMixed connective tissue diseaseBehcet disease

Inflammatory diabetic vasculopathyIsolated peripheral nervous system vasculitisVasculitis associated with infection

Varicella zoster virusSpirochetesTreponema pallidumBorrelia burgdorferi

FungiRickettsiaBacterial meningitisMycobacterium tuberculosisHIV-1

Central nervous system vasculitis associated with amphetamine abuseParaneoplastic vasculitis

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

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

Vasculitis of the nervous system Younger 319

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

a b

c

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.


titis C virus infection, respectively termed types I, II,

and III. Ischemia of affected arterioles and capillaries

results from cryoprecipitation, hyperviscosity, and in-

travascular 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 endothe-

lial proliferation and luminal narrowing. Clinical mani-

festations 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 vasculitisGranulomatous vasculitis consists of several clinicopatho-

logical disorders (Fig. 1), including Wegener granuloma-

tosis (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 vascu-

litis of the small arteries and veins, and glomerulo-

nephritis. The lesions of WG begin as minute foci of

granular necrosis and fibrinoid 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 fibrinoid necrosis in the tissues involved

(Fig. 5). Neurological manifestations occur as a result of

systemic vasculitis, granulomatous invasion and exten-

sion 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 specific for proteinase-3 or

circulating ANCA.

Lymphomatoid granulomatosis is an inflammatory ma-

lignant lymphoreticular disorder that results from angio-

centric and angiodestructive lesions of small and

medium-sized muscular arteries and their endothelia

(Fig. 6). Infiltration by unifocal and multifocal necrotiz-

ing, inflammatory masses occurs in systemic organs and

the CNS usually without fibrinoid necrosis or LCV.

Focal neurological involvement stems from the invasion

of the CNS by unifocal and multifocal necrotizing

inflammatory 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.

Figure 4. This arteriole from muscle is from a patient withleukocytoclastic vasculitis

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

Figure 5. Wegener granulomatosis

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


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 arteritisThe concept of giant cell (temporal) arteritis was first

described in 1937 by Horton et al. [7], and was later

named for the site of granulomatous giant cell inflamma-

tion and vessel involvement by Jennings [8]. Patients

with biopsy-confirmed temporal arteritis and associated

blindness as a result of the involvement of the

ophthalmic and posterior ciliary artery were classified

as having cranial arteritis; whereas those with prominent

constitutional and musculoskeletal complaints, without

neurological involvement, were deemed to have poly-

myalgia rheumatica. Patients with giant cell lesions along

the aorta, its branches, and in other medium and large-

sized arteries at autopsy warranted the diagnosis of

generalized giant cell arteritis. Temporal arteritis is

primarily related to disease along the ophthalmic,

posterior ciliary, superficial temporal, occipital, facial,

and internal maxillary arteries, primarily in old indivi-

duals 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.

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

inflammatory cell infiltrate 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

opacification.

Granulomatous angiitis of the nervoussystemThe 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 difficulty in separating it from polyarteritis and

syphilitic endarteritis because of the occasional finding 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 demon-

strated the clinical heterogeneity. The pathological

heterogeneity has been exemplified 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 fluid

(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 infec-

tion 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 benefit of controlled

trials, and with bias in the literature that has long favored

the administration of combined prednisone and cyclo-

Figure 6. Lymphomatoid granulomatosis

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


phosphamide therapy. Common sense dictates that

cyclophosphamide at least be reserved for pathologically

confirmed patients who fail to improve or progress when

taking prednisone, and can be safely monitored for

potentially serious medication side-effects [12].

Connective tissue disordersThe earliest concepts of the collagen vascular or

connective tissue disorders stemmed from the apprecia-

tion of fibrinoid necrosis using collagen staining in

patients with systemic lupus erythematosus (SLE).

Necrotizing and non-necrotizing vasculitis occurs in

SLE, scleroderma, rheumatoid arthritis, Sjogren syn-

drome, mixed connective tissue disease, and Behcet

disease.

Systemic lupus erythematosus

SLE is a multisystem autoimmune disorder, with protein

dermal, joint, renal, cardiac, and hematological manifes-

tations. Vasculitis occurs in 10–15% of patients at some

time, often in the first 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

Figure 8. Central nervous system vasculitis

a

b

(a) The media and adventitia of this small leptomeningeal artery havebeen almost completely replaced by multinucleated giant cells(arrowheads). There is intimal proliferation with obliteration of thevascular lumen, and a dense, perivascular, mononuclear inflammatoryinfiltrate can be seen (stain, hematoxylin and eosin; original magnification6250). (b) A somewhat larger leptomeningeal vessel shows necrosis ofthe media and internal elastic lamina, with multinucleated giant cellformation (arrows), intimal proliferation (arrowhead), and lymphocyticinfiltration of the adventitia and neighboring meninges (stain, hematoxylinand eosin; original magnification 6250). Reproduced from Younger [1.]with permission of the publisher.

Figure 7. Temporal arteritis

a

b

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

fibrinoid necrosis of the small arteries, arterioles, and

capillaries, with fibrinoid necrosis of collagen fibers,

which swell, fragment, and later dissolve in the course of

the disease (Fig. 10). The resulting homogenous hyaline

material contains immunoglobulins, antigen–antibody

complexes, complement, and fibrinogen. Non-vasculitic

cerebral vasculopathy in SLE may be caused by

circulating IgG and IgM antiphospholid antibodies,

which demonstrate procoagulant activity with prolonga-

tion 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

Scleroderma or systemic sclerosis is characterized by

widespread microvasculopathy and diffuse tissue fibrosis

affecting the skin and other systemic organs, particularly

the heart, lungs, and gastrointestinal tract. Central and

peripheral neuromuscular manifestations including head-

ache, 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, RNA-

polymerase III determinants, and the HLA-DQB1

haplotype.

Rheumatoid arthritis

Rheumatoid arthritis is a multisystemic nodular, granu-

lomatous disease with prominent constitutional and

multiorgan involvement including the nervous system.

Rheumatoid lesions begin as proliferative joint synovitis

with infiltration of T cells and plasma cells and scattered

areas of fibrinoid necrosis. Neutrophils contribute to

tissue destruction through the release of lytic enzymes

and the production of toxic oxygen free radicals. The

inflammatory infiltrate increases in size with nodule

formation with a predilection for serous membranes, or

may take the form of sheet-like plaques of necrosis and

inflammation in the nervous system at sites of con-

nective tissue investment, such as the dura, muscle,

and nerve. Rheumatic pachymeningitis results from

dural, leptomeningeal plaques, and nodules containing

Figure 9. CNS vasculitis

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

Figure 10. Systemic lupus erythematosus

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


Figure 11. Thrombotic-embolic cerebral microangiopathy in a patient with antiphospholipid antibody syndrome (see text for details)

a b

c

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


lymphocytic inflammation and fibrinoid material that

predisposes to seizures, cerebral hemorrhage, encephalo-

pathy and myelopathy. The erosive skeletal manifesta-

tions include atlantoaxial, odontoid, atlantoaxial and

subaxial subluxation; vertebral collapse, and canal

stenosis resulting from extradural pannus that leads to

spastic quadriparesis.

Sjogren syndrome

Sjogren 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 involve-

ment 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 Sjogren syndrome (SS)-A, and intranuclear RNA-

associated antigen La or SS-B occur in the majority of

cases.

Mixed connective tissue disease

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

occur in 10% of patients, including headache, seizures,

encephalopathy, transverse myelitis, ataxia, aseptic

meningitis, monocular blindness, neuropathy, and gan-

glioneuritis. The pathological features of mixed con-

nective tissue disease are those expected by the

associated tissue disorder, in addition to proliferative

changes, capillary involvement and mild diffuse fibrosis.

Behcet disease

The triad of oral and genital ulceration and uveitis, with

variable arthritis, retinal and cutaneous vasculitis, throm-

bophlebitis, gastroenteritis and chondritis characterizes

Behcet disease. The essential pathological changes are

foci of LCV with or without fibrinoid necrosis, and

perivascular lymphocytic infiltration 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 pro-

gressive dementia, seizures and aphasia, and a heigh-

tened risk of venous sinus thrombosis, pseudotumor

cerebri, axonal peripheral neuropathy and myopathy.

Inflammatory diabetic vasculopathyThe 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

significance been appreciated. Peripheral nerve perivas-

culitis, defined as inflammation around the walls of

epineurial vessels, and microvasculitis, in which inflam-

mation 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 determi-

nants and inflammatory markers, reveal a predominance

of CD8 cytotoxic suppressor cells in the vascular

inflammatory infiltrate, 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 vasculitisPeripheral 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

Figure 12. Progressive systemic sclerosis

This digital artery has severe intimal hyperplasia and greater than 90%luminal narrowing. There is also severe adventitial fibrosis and markedtelangiectasia of the vasa vasorum, but the media and internal elasticlamina are relatively spared (stain, trichrome; original magnification660). Reproduced from Younger [1.] with permission of the publisher.


most cases, with only a single autopsy-confirmed patient

reported more than 60 years ago [15]. Second, the

finding of systemic vasculitis in up to two-thirds of

patients with histologically confirmed peripheral nerve

vasculitis, usually forme fruste of PAN, WG type, or in

association with another definable dysimmune disease

such as rheumatoid arthritis, Sjogren syndrome, SLE,

scleroderma, monoclonal gammopathy, or mixed con-

nective tissue disease type.

Central nervous system vaculitis caused byinfectionVasculitis 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 com-

prised of immunoglobulin, complement, lipoprotein, and

hepatitis C viral antigen; as well as immune complex

deposition, cold agglutinin formation, intravascular acti-

vation 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

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-

mised patients. In pathologically studied cases, necrotiz-

ing 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

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 neurosy-

philis caused by CNS seeding by T. pallidum, acute

syphilitic meningitis presents with headache, meningeal

signs, cranial nerve palsies, seizures, and other focal

deficits. 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 involve-

ment. The vasculitis is believed to result from spiroche-

tal 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 degenera-

tion and gummas indicative of chronic inflammation are

present.

Borrelia burgdorferi

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 Garin’s triad of headache,

neuritis, meningitis, and radiculitis. Cerebrovascular

manifestations include vasculitis in association with

headache, stroke, transient ischemic attack, and subar-

achnoid hemorrhage caused by focal mononuclear

inflammatory cell infiltration of blood vessels, with

vascular endothelial cell swelling. Patients with late

Lyme neuroborreliosis manifest with headache, person-

ality 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

Four fungal agents have a predilection for cerebral

vessels, leading to vasculitis, particularly in immuno-

compromised and neutropenic hosts. Aspergillosis in-

vades 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.

Figure 13. Inflammatory diabetic vasculopathy

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


Those with candidiasis and coccidioidomycosis demon-

strate 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 unrecog-

nized spreads from the nasopharynx and sinuses to the

orbit, cavernous sinus, and brain, resulting in a necrotiz-

ing 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

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, constitu-

tional symptoms and skin rash. Neurological involve-

ment leads to mental change, meningismus, ataxia,

seizures, hallucination, and focal cerebral deficits,

progressing to delirium, stupor, and coma reflective of

encephalitis. The diagnosis is confirmed by serological

and antiendothelial antibody studies, and immunohisto-

logical 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 anti-

bodies. 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 immunofluorescence.

Bacterial meningitis

Cerebral vasculitis is a known complication of acute

septic meningitis caused by a number of bacterial agents,

which reflect age and underlying host conditions.

Purulent infection at the base of the brain leads to true

vasculitis as a result of inflammatory cell infiltration 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 intracra-

nial pressure; and confirmed by CSF analysis. Brain

magnetic resonance angiography and conventional an-

giography shows vessel wall abnormalities, focal dila-

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

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 immuno-

compromised individuals. Blood vessels that traverse the

thick gelatinous basilar exudate develop inflammation,

particularly small and medium-sized arteries, and occa-

sionally capillaries and veins. The inflamed adventitia

contains cells, tubercles, caseation necrosis, and occa-

sional 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

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 first manifestation of HIV, but also occurs after

AIDS has developed, and may be manifest as a

symmetrical or overlapping MNM syndrome. The

vascular inflammatory infiltrate 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 findings 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 associatedwith amphetamine abuseCerebral vasculitis in association with drug abuse was

first reported among 14 drug addicts who used multiple


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 hemor-

rhage, 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 difficult to

estimate for several reasons, and is probably over-

exaggerated as a cause of cerebral vasculitis. First, most

patients have been diagnosed by vessel ‘beading’ on

cerebral angiography without pathological verification.

Second, the vascular insults associated with ampheta-

mine 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, opportu-

nistic 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 vasculitisParaneoplastic neurological disorders are diseases of

nervous system function that occur in association with

cancer, but cannot be ascribed to metastases or direction

infiltration 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

identification 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 para-

neoplastic 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 specific marker for paraneoplastic ence-

phalomyelitis 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 deficits, cerebellar incoor-

dination, proprioceptive and tactile sensory loss leading

to imbalance of stance and gait, pseudoathetosis,

numbness and paresthesia, weakness, wasting, fascicula-

tion, active tendon reflexes, Babinski signs, Hoffman

signs, and clonus. Histopathological examination of the

neuraxis reveals widespread neuronal degeneration,

neuronal loss, and Wallerian fiber degeneration in the

hippocampus, brainstem, cerebellum, spinal cord dorsal

columns, dorsal root ganglia, and nerve roots, with

perivascular collections of chronic inflammatory cells,

also known as perivasculitis. Paraneoplastic encephalo-

myelitis 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 enhance-

ment, and muscle and nerve biopsy that demonstrates

microvasculitis, Wallerian nerve fiber degeneration, or

inflammatory myopathy.

Laboratory diagnosisThe 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.

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;

Figure 14. Cerebral vasculopathy in a case of intracerebralhemorrhage associated with the use of phenylpropanolamine asan aid to weight loss

The profound intimal hyperplasia all but obliterates the vascular lumen.Polymorphonuclear leukocytes are in all three vascular layers butparticularly the intima. The media are remarkably well preservedcompared with cases of polyarteritis nodosa and leukocytoclasticvasculitis (stain, hematoxylin and eosin; original magnification 6100).Reproduced from Younger [1.] with permission of the publisher.


recognition of the neurological manifestations is im-

portant 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 confirmation 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 involve-

ment.

Recommended laboratory evaluation of suspected

vasculitis

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 specific 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 neuroima-

ging 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 pos-

sible 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 findings in

CNS vasculitis. Magnetic resonance imaging (MRI) is

more sensitive than computed tomography, but both

methods lack specificity in histologically confirmed

cases. The most common MRI findings are multiple

bilateral cortical and deep white matter signal abnorm-

alities, and enhancement of the meninges after gadoli-

nium. Magnetic resonance angiography and functional

imaging of the brain provide complementary findings to

conventional MRI. The former is useful in the evalua-

tion of medium and large vessel disease, but misses fine

vessel contours better seen on cut-film or digital

subtraction angiography. The abnormal diffuse and focal

perfusion patterns seen on single photon emission-

computed tomography (SPECT) do not always correlate

with neurological symptoms or distinguish vasculitic

from non-vasculitic vasculopathy. Some authorities

claimed that cerebral angiography showed diagnostic

Table 2. Laboratory evaluation of headache and vasculitis

Blood studiesComplete blood countErythrocyte sedimentation rateChemistry panel including creatine phosphokinaseAntinuclear antibodyComplement levelsRheumatoid factorCryoglobulinsImmunofixation electrophoresisQuantitative immunoglobulinsT and B cell panelsAntibodies (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 andp-ANCA

Radiographic studiesChestBody computed tomographMagnetic resonance imagingMagnetic resonance angiography and venographySingle photon emission computed tomographySystemic and cerebral angiography

Other neurodiagnostic studiesElectroencephalographyElectromyography and nerve conduction studiesLumbar puncture for cerebrospinal fluid analysis: protein, glucose, cellcount, IgG level, cytology, VDRL, Gram stain, culture, India ink; viralantigens, Lyme antibodies and PCR (as indicated)

Histopathological studies (as indicated)Muscle and nerve biopsyTemporal artery biopsyMeningeal and cortexSkinSystemic organsLymph nodes

ELISA, Enzyme-linked immunosorbent assay; c-ANCA, circulatingantineutrophil cytoplasmic antibody; p-ANCA, perinuclear antineutrophilcytoplasmic antibody; PCR, polymerase chain reaction; SS, Sjogrensyndrome; VDRL, Veneral Disease Research Laboratory.


features, but that assertion was later modified. The

beading of vessels is found in only approximately a third

of patients with histologically confirmed CNS vasculitis,

as well as in CNS infection, atherosclerosis, cerebral

embolism, and vasospasm of diverse cause (Fig. 15).

Multiple microaneurysms, often seen on visceral angio-

graphy 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. Radio-

graphic 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 confidence 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 end-

stage, as to preclude interpretation. A segment of the

sural, superficial peroneal sensory, or femoral interme-

dius sensory nerve can be surgically removed without

incurring a serious deficit, 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 under-

lying 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 inflammatory med-

iators, and main histocompatibility class I and II antigens

add precision to the analysis of peripheral nerve speci-

mens with suspected necrotizing and non-necrotizing

peripheral nerve vasculitis [21].

ImmunopathogenesisEarly 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 findings in

turn guided our thoughts on vasculitis. In 1943, Coers

and Woolf [22] described the surgical approach for

biopsy of the superficial 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 perform-

ing dissection of amputated limbs after injection of India

ink to opacify the vessels. His findings 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).

Some nerves such as the median and ulnar nerve

between the axilla and elbow and along the sciatic in

Figure 15. Radiographic features of cerebral vasculitis

Ectasia and beading in the M1 segment and lack of flow in the A1segment of the right anterior cerebral artery (arrow).


the gluteal region had few or no entering nutrient

vessels, but vascular insufficiency 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 fiber

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 flail

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 immunologi-

cal reactions by the blood–brain and blood–nerve

barriers. Tight junctions between neighboring cells and

a paucity of micropinocytotic vessels are unique to the

blood–brain barrier, and along with other local determi-

Figure 16. Muscle and nerve biopsy technique

a b

c d

(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 malleolusproviding 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) Afterthe 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.


nants, contribute to the prevention of the early involve-

ment of the CNS in the course of systemic inflammation.

Immune activation requires the interaction of a specific

autoantigen, an MHC class II antigen-presenting cell

(APC) and an antigen-specific 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-specific T cells leads to a proliferation of specific

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 cross-

reacting epitopes present in peripheral nerves and the

brain.

Vascular endothelial cells play an important role in the

pathobiology of vascular inflammation along the blood–

nerve and blood–brain barriers, because of their potential

interaction with elements of the systemic immune

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

a b

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


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 co-

stimulatory factors to induce T-cell proliferation in vivoand 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 specific receptors, is

alteration of the transcription of an array of endothelial

genes that programme cellular inflammatory 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 immu-

noglobulin super-family molecules (intercellular cell

adhesion molecule 1, vascular cell adhesion molecule

1, platelet-endothelial cell adhesion molecule 1) con-

stitutively 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 acti-

vator 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 com-

plement system is composed of 11 proteins that

sequentially interact in the activated state to form an

assembly of five proteins referred to as C5b-9 or MAC.

The activation of C5b-9 along peripheral nerve micro-

vessels leads to increased local permeability, edema, and

inflammatory cell infiltration. Complement-mediated

injury appears to be an important mechanism in the

etiopathogenesis of inflammatory 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 micro-

vessels, including complement receptor (CR10), decay-

accelerating 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 specific 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 ethanol-

fixed neutrophils with indirect immunofluorescence,

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 phago-

cytes into close contact with endothelial cells and induce

neutrophil-mediated endothelial cell lysis and vascular

permeability.

TreatmentNeurologists treating vasculitis must choose the se-

quence and combination among available immunosup-

pressant and immunomodulating therapies, recognizing

the possible adverse effects.

A modern appreciation of the usefulness of corticosteroid

preparations in systemic vasculitis was first 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 effective-

ness of corticosteroids is well established, there is

uncertainty even among experts as to the optimal

regimen. For example, in one analysis [29], a sustained

benefit in PAN was obtained in patients with a

minimum equivalent dosage of 31 mg of prednisone a

day for 7 months. The beneficial effects of corticoster-

oids 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

inflammation, IFN-g, induced MHC class II expression,

macrophage differentiation, pathogenic cytokine expres-

sion, complement interactions, and immunomodulating

cell adhesion molecules.

The effectiveness of a daily oral regimen of cyclophos-

phamide and prednisone in WG was first reported by

Fahey et al. [30] in 1954, and later by Fauci et al. [31] in1971, 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 favor-

able action in vasculitis by the inhibition of T-cell

activation and T-cell-dependent antibody-mediated re-


sponses. It is appropriate alterative therapy to corticos-

teroids and cyclophosphamide in systemic vasculitis.

There are three drawbacks to its use. First, idiosyncratic

side-effects, most often gastrointestinal and ’flu-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 advance-

ment of the dose over weeks, commencing with 50 mg a

day and achieving maintenance levels of 2–3 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 neurolo-

gical 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 antibody-

mediated responses, the accelerated catabolism of

pathogenic IgG antibodies, the suppression of patho-

genic 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 immunoglo-

bulin purification scheme yields a purer intravenous

immunoglobulin product that more closely reflects the

IgG subclass distribution found in plasma.

ConclusionThe 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 ther-

apy 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-

demia, alone or as a side-effect of concomitant cortico-

steroids, and the cessation of cigarette smoking.

AcknowledgementThis work was supported by the Neurology Research Foundation, Inc.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:. of special interest.. of outstanding interest

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