Manifestaciones neurológicas de las vasculitis sistémicas.

1. Neurologic
Presentations of
Systemic Vasculitides
Alireza Minagar, MD, FAAN
a,
*, Marjorie Fowler, MD
b
,
Meghan K. Harris, MD
a
, Stephen L. Jaffe, MD
a
Vasculitis or angiitis refers to a group of inflammatory disorders of the blood vessels
that cause structural damage to the affected vessel, including thickening and weak-
ening of the vessel wall, narrowing of its lumen, and, usually, vascular necrosis.1
Proposed pathogenetic mechanisms for development of vasculitis include immune
complex formation and deposition in the vessel wall; invasion of endothelial cells
and perivascular spaces and alteration of endothelial cell functions by infectious
microorganisms, underlying neoplastic or autoimmune process (such as systemic
lupus erythematosus), or toxins; granuloma formation; presence of autoantibodies,
such as antiendothelial cell antibodies or antineutrophil cytoplasmic antibodies
(ANCA); and orchestrated action of cellular and molecular immune responses
involving proinflammatory cytokines and adhesion molecules.2–4
The overall annual incidence of the systemic vasculitides (excluding giant cell arter-
itis) is approximated at 39 per 1,000,000.5
Systemic vasculitis is classified according
to vessel size and histopathologic and clinical features. Vasculitides with small vessel
involvement typically include Henoch-Scho¨ nlein purpura and cryoglobulinemia. Poly-
arteritis nodosa and Wegener granulomatosis are small- and medium-sized vessel
vasculitides, whereas temporal arteritis (TA) and Takayasu arteritis involve large
vessels. Because of the complex and heterogeneous nature of vasculitic syndromes
and diffuse organ distribution, diagnosis and treatment of these disorders pose
a formidable challenge to clinicians. The authors of this article review the neurologic
presentations of the major systemic vasculitides.
a
Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings
Highway, Shreveport, LA 71130, USA
b
Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings
Highway, Shreveport, LA 71130, USA
* Corresponding author.
E-mail address: aminag@lsuhsc.ed (A. Minagar).
KEYWORDS
Vasculitis Arteritis Cryoglobulinemia Purpura
Neurol Clin 28 (2010) 171–184
doi:10.1016/j.ncl.2009.09.015 neurologic.theclinics.com
0733-8619/09/$ – see front matter ª 2010 Published by Elsevier Inc.

2. TEMPORAL ARTERITIS
TA, also known as giant cell arteritis (GCA), is a systemic disease that almost exclu-
sively affects individuals older than 50 years, with a mean age of onset of 70 years
and a range of 50 to more than 90 years of age. Its estimated occurrence is 15 to
25 per 100,000 individuals.6,7
TA may cause permanent blindness in one or both
eyes in 25% to 50% of affected individuals; therefore, timely diagnosis and aggressive
treatment is of obvious significance. Women are affected more frequently,8
and it is
more common in Caucasians than African Americans. Postmortem studies have
demonstrated that TA is more frequent than is clinically apparent.9
TA primarily, but
not exclusively, affects the cranial branches of the arteries that originate from the
arch of the aorta. Transmural inflammation of the affected arteries and intimal hyper-
plasia cause luminal occlusion. The initial presentation of TA may be insidious or
sudden. Certain presentations, such as visual loss and neurologic impairments, are
usually acute, whereas systemic manifestations, such as fatigue, anorexia, weight
loss, arthralgia, myalgia, low-grade fever, anemia, and leukocytosis, may be present
weeks or months before the time of clinical diagnosis. Alterations of mental status
characterized by delusional thinking, confusion, insomnia, lack of attention, and
cognitive decline may occur with TA. Many patients complain of headache with a lanci-
nating quality, commonly localized to the areas along the affected arteries of the scalp.
The headache associated with TA is persistent and usually unilateral. Indeed, develop-
ment of a new headache or prominent alteration of the pattern of a chronic headache
in an elderly patient is the most frequent symptom of TA and should alert the physician
to the possibility of this diagnosis. Diffuse tenderness of the scalp or face which stems
from the inflammatory ischemic changes associated with widespread arteritis of the
extracranial arteries, presents along with the headache, and is usually present over
the temporal or occipital arteries. Jaw pain and claudication and oral mucosa or scalp
ulceration can also be presentations of TA.
Other neurologic presentations of TA, which occur in at least 30% of affected indi-
viduals, consist of peripheral neuropathy, transient ischemic attack, and stroke.10
Peripheral neuropathy in patients with TA can occur as a mono- or polyneuropathy
and may affect upper or lower extremities. Although the median nerve is the most
commonly affected peripheral nerve, other nerves, such as ulnar, radial, tibial, sciatic,
spinal, and trigeminal nerve, may also be involved in the pathologic process. On elec-
tromyographic and nerve conduction studies, one observes abnormalities of action
potential amplitudes and conduction velocities of the affected nerves, indicative of
axonal damage and demyelination. Angiographic and neuropathologic examinations
reveal that diffuse arteritis of the vessels supplying the damaged nerves plays a signif-
icant role in pathogenesis of the peripheral neuropathy in TA.
Cranial neuropathies are also significant presentations of TA. The optic nerve is the
most frequently affected cranial nerve; and based on clinical observations over the
past 3 decades, up to 23% of affected patients develop permanent visual loss
because of anterior ischemic optic neuropathy (AION).11,12
Indeed, visual loss is the
most significant symptom of TA and may be temporary or permanent, monocular or
binocular. Transient visual loss experienced with TA is similar to that in patients with
atherosclerotic cerebrovascular disease, except in rare instances of TA, where it
may alternate between the two eyes. In patients with TA, the most common site of
optic nerve involvement is the anterior optic nerve, resulting from posterior ciliary
arteritis. Less frequently, ophthalmoscopic examination may reveal retrobulbar optic
neuropathy without papillitis. Patients with acute AION develop an altitudinal visual
field defect. Other ocular complications of TA include uni- or bilateral central retinal
Minagar et al172

3. artery occlusion. Although most of these patients develop sudden and permanent
visual loss, some may experience transient visual loss in 1 eye before the visual
loss becomes permanent. Compromise of the blood circulation through the
ophthalmic or central retinal arteries due to inflammation or thrombosis in TA seems
to cause the retinal ischemia. Vasculitis of the vessels supplying the optic chiasm is
associated with bitemporal visual field defects, whereas vasculitis of the vascular
system of the retrochiasmal visual sensory pathway can cause homonymous visual
field defects. Some patients with bilateral blindness due to TA may experience visual
hallucinations originating from loss of visual input to the cerebral cortex.
Patients with TA may develop diplopia caused by vasculitis affecting the ocular
motor system. The oculomotor nerve is commonly affected, and the presence of
a combination of ophthalmoparesis and ptosis raises the possibility of oculomotor
nerve ischemic infarction. In such cases, paralysis usually does not affect the pupil.
Other ocular abnormalities that may be observed in patients with TA include uni- or
bilateral internuclear ophthalmoplegia and pupillary disturbances, such as tonic pupils
and light-near pupillary dissociation.
Other neurologic presentations of TA, although fairly uncommon, include vertigo
and hearing loss, tinnitus, transient hemianesthesia of the tongue, lingual paralysis,
and facial pain. Between 10% and 20% of patients with TA have carotid bruits that
are commonly bilateral and indicate carotid artery involvement. Almost 40% of these
patients develop some form of ischemic ocular or cerebral syndrome.
Histopathologically, TA shows transmural inflammation of the media, intima, and
adventitia. Lymphocytes, macrophages, and multinucleated giant cells are present
in the arterial wall in a patchy distribution. Arterial narrowing is thought to be caused
by mural hyperplasia resulting in occlusive ischemia (Fig. 1 A and B).13,14
Similar
inflammatory changes are observed in the related disease, polymyalgia rheumatica
(PR). Symptoms of PR are more widespread and systemic than TA and include
pain, fever, malaise, stiff muscles, and weight loss. There is a significant relationship
between the 2 diseases, and it has been proposed that they may be different symp-
tomatic manifestations of the same underlying disease process.15
Almost 50% of
patients with TA present with PR and 10% of patients with PR develop TA.16
A diagnosis of TA should be considered in any patient older than 50 years who pres-
ents with new-onset headache, jaw claudication, ear pain, scalp tenderness, unex-
plained fever, anemia, double vision, and visual loss. Patients with TA usually have
normochromic normocytic anemia, markedly high erythrocyte sedimentation rate
(ESR40 mm/h), and elevated C-reactive protein. On 4-vessel cerebral angiography,
vasculitic changes appear as alternating stenotic segments or complete occlusion of
the affected vessels. Biopsy of the temporal artery is performed to confirm the diag-
nosis before aggressive treatment. However, the pitfall of this procedure, due to the
patchy nature of the underlying inflammation, is that biopsy achieves a sensitivity of
up to 70%, and thus, a considerable number of patients with TA may have a negative
biopsy result. Based on the 1990 American College of Rheumatology17
criteria for
classification of TA, at least three of the following 5 items must be present (sensitivity
93.5%, specificity 91.2%):
1. Age of onset greater than 50 years
2. New-onset headache or localized head pain
3. Temporal artery tenderness to palpation or reduced pulsation
4. ESR greater than 50 mm/h
5. Abnormal arterial biopsy (necrotizing vasculitis with granulomatous proliferation
and infiltration)
Neurologic Presentations of Systemic Vasculitides 173

4. Once a clinician suspects a diagnosis of TA in an elderly patient on clinical grounds,
treatment should be initiated to save the patient’s vision. The mainstay of treatment is
systemic corticosteroids. Treatment begins immediately with prednisone at a dosage
of 40 mg/day to 80 mg/day. This high dose treatment plan is maintained for up to
a month and then prednisone dosage should be tapered by 50% during one month
and then after slowly reduced by no more than 1 mg/month. The oral prednisone
should be tapered slowly to prevent relapses, with the tapering periods as long as 2
years. To lessen corticosteroid-associated osteoporosis, concurrent treatment with
alendronate should be initiated.
TAKAYASU ARTERITIS
Takayasu arteritis, also called pulseless disease, is a systemic necrotizing vasculitis
that may result in postinflammatory stenosis or occlusion of the entire aorta, the abdom-
inal aorta, the ascending aorta, or just the aortic arch and its proximal branches. The
innominate, common carotid, and subclavian arteries and the celiac, mesenteric, renal,
pulmonary, iliac, and coronary arteries are frequently affected. Currently, the exact
cause and cure for Takayasu disease are unknown. Takayasu disease occurs world-
wide, most of the patients are women, and the age of onset is between 10 and 30 years.
It seems that hypoperfusion of the affected organ due to the underlying arterial occlu-
sive process causes the clinical manifestations of Takayasu disease. For example,
Fig. 1. Neuropathology of TA. (A) Early lesion of a large muscular artery. Necrosis, inflamma-
tion and giant cell formation can be noted immediately adjacent to the internal elastic
lamina, which is undergoing degenerative changes. There is some intimal proliferation
(hematoxylin and eosin [HE], original magnification Â100). (B) In this more advanced
lesion, there is complete segmental destruction of the internal elastic lamina and virtually
the entire media. Marked intimal proliferation has nearly occluded the lumen. Few inflam-
matory cells remain (HE, original magnification Â50). (Courtesy of William E. Ballinger,
MD, Gainesville, FL; From Nadeau SE. Neurologic manifestations of systemic vasculitis.
Neurol Clin 2002 Feb;20(1):123–50; with permission.)
Minagar et al174

5. systemic hypertension occurs because of narrowing of the aorta, renal artery stenosis,
decreased elasticity of the aortic wall, or a combination of these effects.
Systemic presentations of Takayasu disease are divided into 3 clinical stages: (1)
the acute stage, characterized by nonspecific systemic manifestations, such as
low-grade fever, fatigue, malaise, anorexia, nocturnal sweating, and widespread
aching; (2) the stage of acute inflammation of the affected vessels, characterized by
the presence of vascular bruits, diminished or absent pulses, and tenderness; and
(3) the chronic obliterative phase due to vascular occlusion, identified by decreased
pulses, development of vascular bruits, claudication, and even development of
ischemic ulcers in affected extremities. Frequently, neurologic involvement occurs
and sometimes, this may be the initial presentation of the disease process. Occlusion
of the vertebral or carotid arteries may cause ischemic stroke; and patients may
present with headache, syncope, and blurred vision. Patients with Takayasu disease
may also develop intracranial aneurysms, with symptoms originating from either
ruptured or unruptured aneurysms. Pathologically, Takayasu disease manifests with
granulomatous inflammation of the vessel adventitia and the outer part of the media,
with infiltration of lymphocytes, plasma cells, histiocytes, and multinucleated giant
cells. Diagnosis of Takayasu disease rests on clinical suspicion in any young patient,
particularly women, with clinical manifestations of vascular ischemia and the presence
of bruits, decrease or absence of pulses, ischemic ulcers, or a combination of these
findings. The American College of Rheumatology 1990 criteria for the classification
of Takayasu arteritis is presented in Box 1.18
Aortic angiography confirms the diag-
nosis and one may observe occlusion or dilatation of vascular segments, stenotic
segments, aneurysm formation, and increased collateral circulation. Treatment of
Box 1
1990 criteria for the classification of Takayasu arteritisa
1. Age at disease onset less than 40 years
Development of symptoms or findings related to Takayasu arteritis at 40 years or younger
2. Claudication of extremities
Development and worsening of fatigue and discomfort in muscles of one or more
extremities while in use, especially the upper extremities
3. Decreased brachial artery pulse
Decreased pulsation of one or both brachial arteries
4. Blood pressure (BP) difference greater than10 mm Hg
Difference of more than 10 mm Hg in systolic blood pressure between arms
5. Bruit over subclavian arteries or aorta
Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta
6. Arteriogram abnormality
Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large
arteries in the proximal upper or lower extremities, not due to arteriosclerosis,
fibromuscular dysplasia, or similar causes; with changes usually focal or segmental.
a
For purposes of classification, a patient shall be said to have Takayasu arteritis if at least 3 of
these 6 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 90.5%
and a specificity of 97.8%. BP 5 blood pressure (systolic; difference between arms). (Data from
Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for
the classification of Takayasu arteritis. Arthritis Rheum 1990;33(8):1129–34.)
Neurologic Presentations of Systemic Vasculitides 175

6. Takayasu disease with systemic corticosteroids, prednisone 1 mg/kg/d for 3 months,
is followed by a gradual tapering regimen based on suppression of the systemic mani-
festations. Takayasu disease does have a prolonged, relapsing, and remitting course;
in cases of unsuccessful treatment with corticosteroids, treatment with cytotoxic
agents, such as cyclophosphamide or methotrexate, should be considered. Certain
patients may benefit from surgical procedures, such as bypass of the obstructed
arteries or percutaneous transluminal angioplasty.
WEGENER GRANULOMATOSIS
Wegener granulomatosis (WG) is a vasculitic disorder of small- and medium-sized
vessels that produces necrotizing granulomatous lesions of the upper and/or lower
respiratory tract and kidney (necrotizing glomerulonephritis), and disseminated vascu-
litis. WG develops in association with antineutrophil cytoplasmic antibodies (ANCA)
and is a member of the family of ANCA-associated vasculitides (AAV).1
It is more
common in men, and the age range varies from 8 to 80 years, with a mean age of
40 years. In many patients, WG initially presents with granulomatous lesions of the
upper respiratory tract. Systemic manifestations of WG consist of chronic sinusitis,
chronic rhinitis, nasal ulceration, epistaxis, upper respiratory serosanguineous
discharge, serous otitis media, cough and hemoptysis, and dyspnea. Other presenta-
tions include fever, weight loss, anorexia, and arthralgia. Clinically, ocular involvement
presents with orbital pseudotumor, scleritis, and uveitis, and renal involvement mani-
fests with proteinuria, hematuria, and renal failure.
At any stage of the disease process, up to 50% of patients develop neurologic
complications affecting both peripheral and central nervous systems. Almost half of
those with neurologic complications suffer from recurrent mononeuropathies, mono-
neuritis multiplex, or symmetric polyneuropathy. Patients with CNS involvement
present with cranial neuropathies, most frequently cranial nerves II, VI, and VII and
nonspecific evidence of cerebral vasculitis, such as hemiparesis, seizures, aphasia,
and visual field defects. Ischemic strokes, encephalopathy, granulomatous basilar
meningitis, pachymeningitis, and myelitis are other CNS manifestations of WG that
occur less frequently.
Although the exact cause of WG remains unknown, existing evidence indicates
involvement of hypersensitivity mechanisms. Diagnosis of WG can be based on the
combination of the clinical picture along with the presence of classical antineutrophil
cytoplasmic antibodies (C-ANCA) in the serum and the demonstration of necrotizing
vasculitis on histopathologic examination. On neuroimaging, the spectrum of brain
computed tomographic (CT) and magnetic resonance (MR) abnormalities in WG
include dural thickening and enhancement, and abnormal signals within the brainstem
and white matter (Fig. 2 A, B, and C).19
Before the 1960s, WG was a lethal disorder and
most patients succumbed to the progressive renal insufficiency. Administration of
systemic corticosteroids may be associated with clinical improvement in only some
of the treated patients but does reduce the overall mortality rate. Various immunosup-
pressive agents, such as cyclophosphamide, azathioprine, methotrexate, chlorambu-
cil, and nitrogen mustard, have been used for treatment of corticosteroid failures. Of
these, cyclophosphamide has improved the prognosis for these patients significantly.
In many instances, patients are treated with a combination of prednisone and cyclo-
phosphamide. However, one should recognize that although this combination
improves 5-year prognosis of the treated patients remarkably, the cumulative toxicity
and side effects of these medications over several years are fairly high, and even under
this therapeutic regimen, between 10% and 50% of patients relapse.20
The regimen of
Minagar et al176

7. prednisone and cyclophosphamide should be continued until systemic presentations
improve, and then it should be slowly tapered. The therapeutic response can be
measured by serial clinical assessment and a declining pattern of the ESR, serum
C-reactive protein, and C-ANCA.
CRYOGLOBULINEMIA
Cryoglobulins are serum proteins that precipitate at 4
C and re-dissolve after warming
to 37
C, and they occur in patients with various clinical conditions. These serum
proteins are mainly immunoglobulins and are usually composed of either IgG or
IgM. Alternatively, they can be mixed, being composed of 2 different immunoglobu-
lins, most commonly a combination of IgG and IgM. Cryoglobulins, which have a single
monoclonal immunoglobulin, are most commonly associated with lymphoproliferative
disorders, such as multiple myeloma, lymphomas and leukemias. Mixed cryoglobulins
are frequently detected in patients with connective tissue diseases, systemic vascu-
litic syndromes, and infections such as hepatitis C viral infection; and this condition
is called essential mixed cryoglobulinemia (EMC).
Clinically, EMC, which affects mainly middle-aged women, presents with purpura,
arthralgia, weakness, and mixed cryoglobulinemia. Patients with EMC develop cuta-
neous vasculitis and progressive renal insufficiency because of glomerulonephritis.
Similar to many other hypersensitivity vasculitides, EMC seems to occur due to
Fig. 2. Neuroimaging findings of Wegener’s granulomatosis- (A) Contrast-enhanced axial CT
scan of brain at the level of the tentorium of a 35-year-old male patient with new-onset head-
ache, which demonstrates dural thickening with contrast enhancement (arrows). (B) Contrast-
enhanced coronal T1-weighted MR image (500/11/1) of a 41-year-old man with severe daily
headaches, which reveals dural enhancement (arrows). (C) T2-weighted axial MR image
(2500/80/2) of a 56-year-old man with multiple cranial neuropathies, which shows hyperin-
tense signal throughout much of the pons. (From Provenzale JM, Allen NB. Wegener granulo-
matosis: CT and MR findings. AJNR Am J Neuroradiol 1996;17:785–92; with permission.)
Neurologic Presentations of Systemic Vasculitides 177

8. deposition of immune complexes in small vessels. In any patient with the combination
of hypocomplementemia, cutaneous vasculitis, and elevated liver function tests,
a diagnosis of mixed cryoglobulinemia must be considered. A vasculitic motor and
sensory peripheral neuropathy commonly occurs in patients with EMC at some point
during their disease course. Sensory-motor mononeuritis multiplex is another form of
neuropathy that may be present in these patients. CNS complications of mixed cryo-
globulinemia are rare and include diffuse encephalopathic syndromes with focal signs,
seizures, myelopathy, and sometimes, ischemic stroke.21–24
The pathogenetic mech-
anisms of neuropathy include immune-mediated demyelination and nerve ischemia
due to occlusion of the vasa nervorum by cryoglobulins or vasculitis.
HENOCH-SCHO¨ NLEIN PURPURA
Henoch-Scho¨ nlein purpura (HSP) is one of the most common forms of systemic
vasculitis seen in children, and it is recognized by a combination of nonthrombocyto-
penic purpura, arthralgia, and abdominal pain. Certain conditions, such as malignan-
cies and infections, and certain drugs are associated with HSP. Systemic complaints
include fever, malaise, and edema; nephritis occurs in 40% of affected patients.
Although the underlying vasculitis is leukocytoclastic, the exact cause of HSP remains
unknown. Neurologic manifestations of HSP consist of headache, encephalopathy,
intracranial and intraparenchymal hemorrhage, nonhemorrhagic vasculitic involve-
ment of cerebral tissue, peripheral neuropathy, and entrapment neuropathy due to
focal edema. The presence of elevated serum IgA or IgA deposits in the vascular
wall indicate that HSP is due to IgA-mediated inflammation. In 1990, the classification
criteria for HSP were proposed by the American College of Rheumatology (Table 1).25
The clinical diagnosis is further supported by detection of leukocytoclastic vasculitis
on skin biopsy and IgA immunofluorescence in small vessels of skin and renal
glomeruli. Differential diagnosis of HSP includes infectious endocarditis, systemic
lupus erythematosus, meningococcemia, disseminated intravascular coagulation,
and Waldenstro¨ m hyperglobulinemic purpura. Although there is no specific treatment
for HSP, these patients benefit from supportive therapy and brief courses of
corticosteroids.
Table 1
1990 criteria for classification of Henoch-Scho¨ nlein purpura
Criterion Definition
Probable purpura Slightly raised ‘‘palpable’’ hemorrhagic skin lesions, not related
to thrombocytopenia
Age %20 years Patient 20 years or younger at onset of first symptoms
Bowel angina Diffuse abdominal pain, worse after meals, or the diagnosis of
bowel ischemia, usually including bloody diarrhea
Wall granulocyte on biopsy Histologic changes showing granulocytes in the walls of
arterioles or venules
For purposes of classification, a patient shall be said to have Henoch-Scho¨ nlein purpura if at least 2
of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 87.1%
and a specificity of 87.7%. (Data from Mills JA, Michel BA, Bloch DA, et al. The American College of
Rheumatology 1990 criteria for the classification of Henoch-Scho¨ nlein purpura. Arthritis Rheum
1990;33(8):1114–21.)
Minagar et al178

9. NERVOUS SYSTEM VASCULITIS ASSOCIATED WITH DRUG ABUSE
Drugs, particularly sympathomimetics, have been associated with several neurologic
disorders, including cerebral ischemic infarcts and intracerebral and subarachnoid
hemorrhage. The most commonly abused drugs that are associated with these neuro-
logic complications include cocaine, heroin, ephedrine, phenylpropanolamine, and
amphetamines. These illicit drugs may be taken orally or intravenously or may be
snorted. Ischemic or hemorrhagic complications usually affect younger individuals.
A brain MR imaging case-controlled study of individuals who were cocaine dependent
demonstrated the presence of multiple, small, silent, subcortical ischemic lesions.26
Cerebral angiography in many cases of illicit drug use has demonstrated vasculitic
changes of CNS vessels, including widespread segmental narrowing of the affected
vessels with a beading pattern. Some of these illicit drugs are capable of causing
vasospasm, and thus, the mechanism behind vascular insufficiency within the CNS
may be a vasculopathy rather that true vasculitis. A compounding issue in making
a clear-cut diagnosis of illicit drug-induced CNS vasculitis is that there are usually
multiple exposures to multiple illicit substances and coexisting infections present,
such as syphilis, hepatitis C, and AIDS. Treatment of these patients rests on identifi-
cation and discontinuation of the offending drug, search for other concurrent infec-
tions, particularly human immunodeficiency virus (HIV), control of hypertension
when present, and supportive treatment. Administration of systemic corticosteroids
or immunosuppressive therapy is not recommended unless diagnosis of CNS vascu-
litis is supported by histopathologic examination.
MEDICATION-INDUCED VASCULITIS
Vasculitic syndromes may occur in association with use of prescribed drugs and the
most common drug-associated vasculitis is usually restricted to the skin. This form of
skin vasculitis presents with a maculopapular or vesicular rash, and, less frequently, as
palpable purpura. Rarely, vasculitis is widespread and presents with fever; arthralgia;
evidence of cardiac, hepatic, or renal dysfunction; and eosinophilia. The pathophysi-
ology of this form of vasculitis is hypothesized to involve the attachment of the drug to
proteins, generating haptens that are able to elicit potent immune responses. Neuro-
logically, the central and peripheral nervous system and muscles may be involved. The
list of offending drugs that may cause vasculitis contains several general types, anti-
biotics being a major type. The penicillins are probably the best known members of
this group. Treatment of drug-related vasculitis begins with immediate discontinuation
of the offending drug followed by use of corticosteroids (prednisone 1 mg/kg/d for up
to 30 days).
POLYARTERITIS NODOSA
Polyarteritis nodosa (PAN), also called periarteritis nodosa, is a rare inflammatory
necrotizing vasculitis that affects small- to medium-sized arteries. Although it is often
idiopathic, it can be associated with other disorders, such as cryoglobulinemia,
leukemia, arthritis, Sjogren syndrome, hepatitis C, hepatitis B, and HIV infection.27
PAN is a systemic disease and may affect any organ; however, the skin, kidney,
peripheral nerves, and gastrointestinal tract are most commonly involved. The annual
incidence of PAN is about 0.2 to 0.7 per 100,000 and it affects men more than
women.28
PAN is more common in individuals 40 to 60 years of age. PAN affects
the central and peripheral nervous systems. The classification scheme proposed by
the American College of Rheumatology for PAN is presented in Table 2.29
Neurologic Presentations of Systemic Vasculitides 179

10. Between 23% and 53% of patients with PAN develop CNS pathology. CNS involve-
ment is less common than that of the peripheral nervous system and usually presents
late in the course of disease. The two most frequent central neurologic pictures of PAN
include diffuse encephalopathy and focal or multifocal disturbances of the brain or
spinal cord. Diffuse encephalopathy associated with PAN presents with rapid decline
in level of consciousness and with seizures. Focal neurologic deficits, which may
occur suddenly, are due to ischemic stroke affecting the cerebral cortex, brainstem,
or cerebellum. Patients with PAN may develop anterior optic neuropathy and posterior
(retrobulbar) optic neuropathy; and they tend to experience acute and painless visual
loss. These forms of optic neuropathy stem from vasculitis-induced ischemia in the
distribution of the posterior ciliary arteries, or inflammation of the optic nerve. Cranial
nerve III, IV, VI, VII, and VIII involvement rarely occurs. Rarely, patients with PAN
may experience intracranial hemorrhage. Mononeuritis multiplex is common in the
context of PAN and presents with asymmetric motor and sensory findings that mainly
Table 2
American College of Rheumatology 1990 criteria for the classification of Polyarteritis Nodosa
Criterion Definition
(1) Weight loss 4 kg Loss of 4 kg or more body weight since
illness began, not due to dieting or
other factor
(2) Livedo reticularis Mottled reticular pattern over the skin of
portions of the extremities or torso
(3) Testicular pain or tenderness Pain or tenderness of the testicles, not
due to the infection, trauma, or other
causes
(4) Myalgias, weakness, or polyneuropathy Diffuse myalgias (excluding shoulder and
hip girdle) or weakness of muscles or
tenderness of leg muscles
(5) Mononeuropathy or polyneuropathy Development of mononeuropathy,
multiple mononeuropathies, or
polyneuropathy
(6) Diastolic BP90 mm Hg Development of hypertension with
diastolic BP 90 mm Hg
(7) Elevated blood urea nitrogen or
creatinine
Elevation of blood urea nitrogen 40 mg/
dL (14.3 mmol/L) or creatinine 1.5/dL
(132 mmol/L), not due to dehydration or
obstruction
(8) Hepatitis B virus Presence of hepatitis B surface antigen or
antibody in serum
(9) Arteriographic abnormality Arteriogram showing aneurysm or
occlusion of the visceral arteries, not
due to arteriosclerosis, fibromuscular
dysplasia, or other noninflammatory
causes
(10) Biopsy of small- or medium-sized artery
containing polymorphonuclear cells
Histologic changes showing the presence
of granulocytes and mononuclear
leukocytes in the artery wall
For classification purposes, a patient with vasculitis is diagnosed with PAN if at least 3 criteria of the
above criteria are met. (Data from Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American
College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis
Rheum 1990;33(8):1088–93.)
Minagar et al180

11. affect the lower extremities, particularly the sciatic, peroneal, or tibial nerves. Less
commonly, the radial, cubital, and median nerves may be affected. The onset of
mononeuritis multiplex in these patients is usually sudden, whereas the distal
symmetric peripheral neuropathy in these patients develops slowly. Examination of
the cerebrospinal fluid may not reveal any diagnostic abnormalities.
Histopathologically, PAN manifests with focal but pan-mural necrotizing inflamma-
tory lesions that affect small- and medium-sized arteries (Fig. 3). Further examination
of these inflammatory lesions reveals disruption of the normal infrastructure of the
vessel wall, fibrinoid necrosis, and pleomorphic cellular infiltration with mainly
polymorphonuclear cells and a variable number of lymphocytes and eosinophils.
Diagnosis of PAN is made based on clinical suspicion when a patient presents with
constitutional symptoms, such as fever, chills, weight loss, fatigue, and multisystem
dysfunction. Anemia, elevated ESR, and evidence of thrombosis further support the
diagnosis of PAN. Brain CT and MR neuroimaging illustrates infarctions in the cortical
and subcortical regions of the cerebral hemispheres, basal ganglia, internal capsule,
brainstem, and cerebellum (Fig. 4 A and B).30
Arteriography may reveal the presence
of arterial saccular or fusiform aneurysms and narrowing and tapering of the affected
vessels. Histopathologic examination of affected tissue, such as skin, sural nerve,
muscle, or kidney, confirms the clinical diagnosis.
Treatment of PAN consists of the administration of systemic corticosteroids along
with cytotoxic agents, such as cyclophosphamide or azathioprine. If a patient does
not tolerate this regimen’s side effects, other therapeutic interventions that need to
be considered include plasma exchange, intravenous immune globulin, mycopheno-
late mofetil, and rituximab.
Fig. 3. A small muscular artery from the muscle of a patient with PAN, which illustrates the
proliferative phase in which neutrophils have been replaced by chronic inflammatory cells
and there is evidence of necrosis of the media, early intimal proliferation, and fibrosis
(HE, original magnification Â250). (Courtesy of William E. Ballinger, MD, Gainesville, FL;
From Nadeau SE. Neurologic manifestations of systemic vasculitis. Neurol Clin 2002
Feb;20(1):123–50; with permission.)
Neurologic Presentations of Systemic Vasculitides 181

12. MICROSCOPIC POLYANGIITIS
Microscopic polyangiitis (MPA) is another member of AAV that predominantly affects
small vessels (capillaries, venules, and arterioles). In MPA, granulomata are not
present. In MPA, ANCA is directed against myeloperoxidase.2
MPA is associated
with rapidly progressive focal segmental necrotizing glomerulonephritis. The average
age of onset is 50 years and men are more often affected than women. Savage and
colleagues31
observed that MPA may have an indolent course before clinical diag-
nosis. Systemic symptoms, such as arthralgia and hemoptysis, may be present
long before the explosive phase of the disease occurs. Peripheral neuropathy is
less common in MPA than PAN, whereas pulmonary involvement occurs more
frequently. Diagnostic workup for MPA reveals the presence of serum ANCA and
absence of surface hepatitis B antigen or antibody. Histopathologic examination of
a biopsied specimen from the kidney reveals the presence of focal segmental
thrombosing and necrotizing glomerulonephritis. Treatment of MPA is based on
immunosuppression with the combination of systemic corticosteroids and cyclophos-
phamide. Potential therapies under clinical investigation include intravenous immune
globulin and rituximab.
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