Neuro-ophthalmic Manifestations

of Meningocerebral Inflammation From the

Limited Form of Wegener's Granulomatosis
NANCY J. NEWMAN, MD., THOMAS L. SLAMOVITS, MD.,
SHMUEL FRIEDLAND, MD., AND W. BRUCE WILSON, M.D.

PURPOSE: Wegener's granulomatosis is classically a systemic necrotizing granulomatous vasculitis that involves the upper and lower respiratory
tracts and kidneys. Ophthalmologic and neurologic manifestations are common. The limited form of
Wegener's granulomatosis may have pathologic
characteristics consistent with the disease but
lacks the complete clinical triad. We studied the
clinical, pathologic, laboratory, and radiologie
findings of four patients with Wegener's granulomatosis so that others will recognize the disease,
even when it occurs in its limited form.
METHODS: From three clinical centers, a chart
review disclosed four patients with neuroophthalmic findings and the limited form of
Wegener's granulomatosis.
RESULTS: Three men and one woman, ranging
in age from 4 0 to 73 years, were studied. All four
patients had ocular motor abnormalities (one with
oculomotor and trochlear nerve palsies, one with
oculomotor nerve palsy, one with trochlear and
abducens nerve palsies, and one with horizontal
Accepted for publication June 1, 1995.
From the Departments of Ophthalmology, Neurology, and Neurosurgery (Dr. Newman), Emory University School of Medicine, Atlanta,
Georgia; the Departments of Ophthalmology and Visual Sciences (Drs.
Slamovits and Friedland), Neurology, and Neurosurgery (Dr.
Slamovits), Albert Einstein College of Medicine and the Montefiore
Medical Center, Bronx, New York; and the Department of Ophthalmology, University of Colorado Medical Center, Denver, Colorado
(Dr. Wilson). This study was supported in part by an unrestricted
grant from Research to Prevent Blindness, Inc., New York, New York
(to the Department of Ophthalmology, Emory University, and the
Department of Ophthalmology, Albert Einstein College of Medicine),
and a fellowship grant from the American-Israeli Ophthalmological
Society, New York, New York (Dr. Friedland).
No reprints are available.

VOL.

120, No. 5

gaze deviation) in addition to other cranial nerve

and cerebral abnormalities. Neuroimaging showed
prominent meningeal, as well as intraparenchymal,
abnormalities. In all patients, results of antineutrophil cytoplasmic antibody tests were initially negative but in one patient were positive at a late stage of
the disease. In all patients, results of a biopsy
demonstrated necrotizing granulomatous inflammation consistent with Wegener's granulomatosis.
CONCLUSIONS: Neuro-ophthalmic findings may
be the earliest manifestations of the limited form
of Wegener's granulomatosis. Extensive meningocerebral inflammation can occur before systemic
involvement or laboratory confirmation. Early diagnosis by biopsy of affected tissues may facilitate
appropriate treatment and prevent progression of
the disease.
EGENER'S GRANULOMATOSIS IS A SYSTEMIC
necrotizing granulomatous vasculitis that
in its classic form involves the upper and
lower respiratory tracts and kidneys.1 Neurologic involvement is present in up to 54% of cases, and
ophthalmic involvement in up to 50% of cases.2'15
The presence of antineutrophil cytoplasmic antibodies is a highly sensitive indicator of the disease.16 A
limited or partial form of Wegener's granulomatosis17'20 has been proposed, in which the pathologic
characteristics were consistent with the disease, but
the complete triad of upper and lower respiratory tract
and kidney involvement did not occur. Patients with
the limited form of Wegener's granulomatosis may
have a protracted, atypical clinical course and nega-

AMERICAN JOURNAL OF OPHTHALMOLOGY 1995;I 20:613-621

613

TABLE

PATIENT NO.,
AGE (VHS),
GENDER

1,73, M

2, 60, F

NEURO-OPHTHALMIC
SYMPTOMS AND SIGNS

Right trochlear nerve palsy,

right oculomotor
nerve palsy
Left oculomotor nerve
palsy

3, 40, M

Right trochlear nerve

palsy, right abducens
nerve palsy, left abducens
nerve palsy

4, 71, M

Left gaze deviation

OTHER NEUROLOGIC
SYMPTOMS AND SIGNS

NEURO-IMAGING
FINDINGS

Headaches

None

Meningeal thickening
and enhancement

Hoarseness, headaches

Shortness of breath,
weight loss, joint
pain and stiffness,
buttock rash

Meningeal and gyral enhancement, abnormal frontal lobe

white matter, pansinusitis

Headaches, encephalopathy,
dysphagia, dysphonia,
dysarthria, and right facial,
acoustic, glossopharyngeal, vagus, accessory,
and hypoglossal nerve
palsies, left facial
nerve palsy
Seizures, left hand and leg
weakness, confusion

Fever, scrotal rash,

weight loss

Meningeal enhancement,
right more than left

None

Meningeal enhancement
and thickening, left
maxillary sinus disease

tive results of antineutrophil cytoplasmic antibody

titers. Early diagnosis and treatment are essential to
prevent multiorgan involvement and renal failure. We
studied four patients, who initially had neurologic and
neuro-ophthalmologic problems because of extensive
meningocerebral inflammation, in whom the limited
form of Wegener's granulomatosis was diagnosed by
biopsy. All four patients initially had negative results
of antineutrophil cytoplasmic antibody tests.

PATIENTS AND METHODS

NEURO-OPHTHALMOLOGISTS FROM THREE ACADEMIC

centers conducted chart reviews to identify patients

with neuro'Ophthalmic manifestations of biopsyproven necrotizing granulomatous inflammation consistent with Wegener's granulomatosis. Patients were
included if they had the limited form of Wegener's
granulomatosis, defined as lacking the complete clinical triad of upper and lower respiratory tract and
kidney involvements. Additionally, all patients initial-

614

SYSTEMIC SYMPTOMS
AND SIGNS

ly had to have negative results of antineutrophil

cytoplasmic antibody titers. Cases 1 and 2 are described in detail, and all cases are summarized in the
Table.

CASE REPORTS
CASE l: Six weeks before referral, a right trochlear
nerve palsy was diagnosed in a 73-year-old white
man. Over the next several weeks, diplopia persisted
and he developed severe headaches.
Results of his neuro-ophthalmic examination were
normal, except for mild blepharoptosis of the right
upper eyelid, limited depression of the right eye in
both adduction and abduction, and limited adduction
of the right eye, consistent with right trochlear and
partial oculomotor nerve palsies.
Magnetic resonance imaging with gadolinium disclosed meningeal enhancement and thickening, more
over the right cerebrum than the left, with a few
parenchymal lesions (Fig. 1). Lumbar puncture

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1995

TABLE (Continued)
CLINICAL CHARACTERISTICS OF CASES
LABORATORY FINDINGS
CEREBROSPINAL RYTHROCYTE
FLUID
SEDIMENTATION
{CELLS/ML)

RATE (MIWHOUR)

While cells: 10;

protein: 83
White cells: 0;
protein: 61

65

92-104

Normal

29

ANTINEUTROPHIL
CYTOPLASMIC
ANTIBODIES

URINALYSIS

Negative

Normal

Negative

Normal

COMPUTED
TOMOGRAPHY

Chest, abdomen,

and pelvis: left

hydronephrosis
Chest: normal
Gallium scan:
normal

Initially negative,
later positive
{cytoplasmic)

Negative

Normal

showed cerebrospinal fluid of normal pressure, with

ten white blood cells, a protein level of 83 mg/dl, a
glucose level of 61 mg/dl, and negative results of the
rapid plasma reagin test, stains and cultures for
bacteria, fungi, or mycobacteria, cryptococcal antigen, and cytologie analysis. Results of computed
tomography of the chest, abdomen, and pelvis were
normal, except for left hydronephrosis. Antineutrophil cytoplasmic antibodies were not detected in the
serum, and results of urinalysis were normal.
A meningeal biopsy disclosed necrotizing granulomatous vasculitis with numerous eosinophils, consistent with Wegener's granulomatosis (Fig. 2). Special stains and cultures for acid-fast organisms, fungi,
or spirochetes were negative. No viral inclusions were
seen.
CASE 2: A 60-year-old black woman was healthy
until four months before admission, when she developed hoarseness. Over the subsequent several
months, her weight decreased by 20 pounds, despite a

VOL.120,

NO. 5

OTHER

BIOPSY FINDINGS

Meningeal: necrotizing
granulomatous vasculitis with eosinophils
Durai: necrotizing granulomatous inflammation; vocal cord:
granulomatous inflammation;
nasal mucosa: nonspecific
inflammation
Durai: necrotizing granulomatous inflammation
with possible vasculilis;
nasopharyngeal: necrotizing vasculitis; skin:
necrotizing vasculitis

ElectroencephaloMeningeal: necrotizing
granulomatous
gram: right epileptiform discharges
vasculitis

good appetite, and she developed slowly progressive

shortness of breath. She also noted pain and stiffness
in the joints of her hands and feet. For two weeks
before initial examination she had intermittent nonlocalizing headaches. She had a 30- to 35-pack-year
history of cigarette use.
Results of her general physical examination were
normal, except for a herpetiform vesicular rash on her
buttocks. Results of a neuro-ophthalmic examination
were normal, except for moderate left eye adduction
and infraduction deficits consistent with a partial left
oculomotor nerve palsy.
Computed tomography of the head disclosed areas
of low density in the frontal lobe white matter
bilaterally. Magnetic resonance imaging of the brain
with gadolinium showed markedly abnormal meningeal and gyral enhancement and abnormal bright
signal in the frontal lobe white matter on T2-weighted
imaging (Fig. 3). Pansinusitis, most prominent in the
frontal and ethmoid sinuses, was also observed. A
chest x-ray disclosed mild bilateral hyperinflation.
Results of computed tomography of the chest were

NEURO-OPHTHALMIC SYMPTOMS OF LIMITED WEGENER'S GRANULOMATOSIS

615

Fig. 1 (Newman and associates). Case 1. Left, ^-weighted magnetic resonance image after gadolinium, coronal view.
Right, ,-weighted magnetic resonance image after gadolinium, axial view. Note meningeal thickening and
enhancement, greater on the right side (arrowheads).

normal. Lumbar puncture disclosed cerebrospinal

fluid under normal pressure that was clear and
colorless, with no red or white blood cells, a protein
level of 61 mg/dl, and a glucose level of 75 mg/dl. All
stains and cultures for bacterial and fungal organisms
were negative. The Westergren erythrocyte sedimentation rate was 65 mm/hour. Serum chemistry and
hmatologie values, angiotensin converting enzyme
levels, antineutrophil cytoplasmic antibody levels,
urinalysis, purified protein derivative skin testing,
urine and sputum cultures for mycobacteria and fungi,
and gallium scan were normal.

Treatment was begun with prednisone, 80 mg daily,

for the presumed diagnosis of the limited form of
Wegener's granulomatosis. The partial oculomotor
nerve palsy resolved completely after five days of
treatment, as did the headaches and shortness of
breath. Computed tomography with intravenous contrast ten days after beginning corticosteroid therapy
showed decreasing sinus opacification with better
aeration, but no changes in the durai enhancement or
frontal white matter abnormalities. The patient was
discharged taking prednisone, 60 mg/day.

A frontal durai biopsy showed areas of necrotizing granulomas consistent with the diagnosis of
Wegener's granulomatosis, although no active vasculitis was observed. Results of all histochemical stains
and cultures for fungi, mycobacteria, and bacteria
were negative. A rigid bronchoscopic biopsy showed
granulomatous inflammation of the right false vocal
chord. Nasal mucosa biopsy showed chronic nonspecific inflammatory changes.

CASES 3 AND 4: A 40-year-old white man initially

had a febrile illness complicated by acute encephalopathy, diplopia, and multiple progressive cranial nerve
palsies, including the right trochlear, abducens, facial,
acoustic, glossopharyngeal, vagus, accessory, and hypoglossal cranial nerves and the left abducens and
facial nerves. He suffered progressive neurologic dysfunction until his death.
A 71-year-old white man initially had left focal

616

AMERICAN JOURNAL OF OPHTHALMOLOGY

NOVEMBER 1995

Fig. 2 (Newman and associates). Case 1. Histologie section of meningeal biopsy. Top, An area of granulomatous
inflammation composed of epithelioid histiocytes (arrow) surrounded by lymphocytes (arrowhead) and an area of
necrosis (asterisk). Inflammatory infiltrates are present in the walls of vascular channels (V) (hematoxylin and eosin,
X63). Bottom, An area of necrosis (asterisk) surrounded by a zone of pallisading histiocytes (between arrows) and an
outermost rim of lymphocytes (arrowheads) (hematoxylin and eosin, X160).

VOL.120, No. 5

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617

Fig. 3 (Newman and associates). Case 2. Left, Tj-weighted magnetic resonance image after gadolinium, axial view,
showing frontal meningeal and gyral enhancement (arrowheads). Right, T2-weighted magnetic resonance image, axial
view, showing abnormal bright signal in the frontal lobe white matter bilaterally (arrowheads).

motor seizures with secondary generalization, left gaze

deviation, and transient confusion. A neurologic
examination disclosed mild weakness of the left arm
and leg. Treatment with phenytoin and high-dose
corticosteroids prompted resolution of his seizures and
clinical improvement.
Neuroimaging showed asymmetric meningeal enhancement and thickening in both patients and
extensive left maxillary sinus disease in Case 4 (Fig.
4). Laboratory values were all normal, including
urinalysis and cerebrospinal fluid evaluation, except
for increased erythrocyte sedimentation rates in Case
3. Antineutrophil cytoplasmic antibodies were initially negative in both patients, but cytoplasmic
antineutrophil cytoplasmic antibodies were positive
late in the hospital course of Case 3.

magnetic resonance imaging. None of the patients

had evidence suggestive of renal disease, and two
patients (Cases 1 and 3) had no findings indicating
respiratory tract involvement. The patient described
in Case 2 had extensive pansinusitis and upper airway
disease, and the patient described in Case 4 had
asymptomatic unilateral maxillary sinusitis noted on
computed tomography. All our patients had necrotizing granulomatous inflammation on durai biopsies,
and one had similar findings with vasculitis on
nasopharyngeal and skin biopsies. Extensive histopathologic investigation failed to show a causative
infectious agent. At the time of initial examination,
all our patients had negative results of antineutrophilic cytoplasmic antibody tests. Cytoplasmic antineutrophilic cytoplasmic antibodies were eventually detected in one patient (Case 3), late in the course of
his disease.

RESULTS
DISCUSSION

THREE MEN AND ONE WOMAN, RANGING IN AGE FROM 40

to 73 years, were studied (Table). Three patients had

cranial neuropathies, and all four patients had meningeal and cerebral abnormalities as demonstrated on
618

WEGENER'S GRANULOMATOSIS IS A SYSTEMIC NECROTIZ-

ing granulomatous vasculitic inflammation that, in its

AMERICAN JOURNAL OF OPHTHALMOLOGY

NOVEMBER 1995

Fig. 4 (Newman and associates). Left, Case 3. ^-weighted magnetic resonance image after gadolinium, axial view,
showing durai enhancement, primarily along the right skull base and tentorium (arrowheads). Right, Case 4.
^-weighted magnetic resonance image after gadolinium, coronal view, showing meningeal enhancement and thickening
in the right parietal region with enhancement of the underlying parenchyma (arrowheads).

classic generalized form, characteristically involves

the upper and lower respiratory tracts and kidneys.1
Ophthalmologic involvement is reported in 25% to
50% of patients with Wegener's granulomatosis.2'9
Ocular and orbital manifestations result from vasculitic injury to these structures or through contiguity
with diseased adjacent paranasal sinuses. Anterior
segment disease (conjunctivitis, episcleritis, scleritis,
and corneal inflammation) is more frequent than
posterior segment disease (uveitis, optic nerve disease, and retinal vasculitis). Orbital inflammation
may cause painful swelling, proptosis, nasolacrimal
duct obstruction, or dacryocystitis.
Neurologic involvement is reported in 22% to 54%
of patients with Wegener's granulomatosis.10'15,21 The
most common neurologic manifestation is peripheral
neuropathy, particularly mononeuropathy multiplex.
Other reported manifestations include multiple cranial neuropathies, ophthalmoplegia, Horner's syndrome, papilledema, hearing loss, headache, meningitis, meningeal thickening, myelopathy, myopathy,
cerebritis, strokes, and seizures. Among the cranial
nerves, the optic, abducens, and facial nerves are
most frequently affected, followed by the trigeminal,
VOL.120, No. 5

acoustic, oculomotor, trochlear, hypoglossal, glossopharyngeal, and vagus nerves. Drachman 10 proposed
the following three mechanisms for central nervous
system involvement in Wegener's granulomatosis: direct invasion from the adjacent paranasal sinuses,
remote effect of the granulomatous inflammation, and
vasculitis of the central nervous system. Cranial
neuropathies may also result from extensive meningeal involvement.1315
The diagnosis of Wegener's granulomatosis is made
clinicopathologically. The clinical differential diagnosis is broad and includes polyarteritis nodosa;
lymphomatoid granulomatosis; Behet's disease; primary central nervous system vasculitis; lymphoproliferative disorders; sarcoidosis; Churg-Strauss syndrome; Erdheim-Chester disease; and infectious,
inflammatory, or neoplastic meningeal infiltration.
Conclusive diagnosis often may be extremely difficult.
Results of a biopsy of involved tissues should show
necrotizing granulomatous vasculitis, and special
stains must be used to rule out infectious causes of
similar pathologic characteristics, such as mycobacteria and fungi. However, histopathologic analysis does
not always confirm the classic triad of granulomatous

NEURO-OPHTHALMIC SYMPTOMS OF LIMITED WEGENER'S GRANULOMATOSIS

619

inflammation (with or without giant cells), tissue

necrosis, and vasculitis. Kalina and associates22 found
the complete histopathologic triad in only 54% of the
orbital biopsies performed in patients with otherwise
well documented Wegener's granulomatosis.
Radioimmunoassay tests for autoantibodies have
helped greatly in the diagnosis of Wegener's granulomatosis.18,23'26 Testing of antineutrophil cytoplasmic
antibodies by indirect immunofluorescent methods
can disclose two patterns: cytoplasmic antineutrophil
cytoplasmic antibodies and perinuclear antineutrophil cytoplasmic antibodies. Perinuclear antineutrophil cytoplasmic antibodies have been reported with
a variety of autoimmune disorders, such as inflammatory bowel diseases and arthropathies, including
rheumatoid arthritis; perinuclear antineutrophil cytoplasmic antibodies with specificity against myeloperoxidase have been reported with microangiopathic
vasculitides, such as microscopic polyangiitis. Positive
results of a cytoplasmic antineutrophil cytoplasmic
antibody titer are highly specific for Wegener's granulomatosis, including the limited form of the disease;
however, the diagnosis of Wegener's granulomatosis
cannot be excluded when the cytoplasmic antineutrophil cytoplasmic antibody test results are negative.
When there is involvement of only the respiratory
tract, the sensitivity of cytoplasmic antineutrophil
cytoplasmic antibodies for Wegener's granulomatosis
is about 65%, but it increases to more than 90%
when the disease is active and generalized. In patients
whose Wegener's granulomatosis is in remission, the
sensitivity of cytoplasmic antineutrophil cytoplasmic
antibodies is about 30%.
In the limited form of Wegener's granulomatosis,
patients initially do not have the classic clinicopathologic features. They may have primarily upper respiratory tract or lung involvement in the absence of renal
disease; the classic histopathologic triad is less frequently demonstrated on biopsy of affected tissues;
and antineutrophil cytoplasmic antibodies are not
found as often.16'28 In these patients, the disease can
have a relatively benign course, and ocular or neurologic involvement may be the prominent or initial
manifestation.15,17
Wegener's granulomatosis is life-threatening, and
early diagnosis and therapy may be beneficial. Highly
aggressive immunosuppressive therapy with cyclophosphamide, either orally or intravenously, is fre620

quently combined with corticosteroid therapy.29

Treatment itself may be associated with severe morbidity.16 Relapse can occur after successful treatment,
even in those patients with the limited form of the
disease.9
The four patients in the present study initially had
neurologic and neuro-ophthalmologic abnormalities
and had clinical courses and findings compatible with
the limited form of Wegener's granulomatosis. The
diagnosis of Wegener's granulomatosis was established primarily by biopsy results. Wegener's granulomatosis encompasses a spectrum of disease, including
limited forms in which all the classic clinicopathologic criteria are not present. Ocular and neurologic
involvement may be the initial manifestation in these
patients. When clinical srologie findings are inconclusive, a biopsy remains indispensable for the correct
diagnosis. Early diagnosis and treatment of the limited form of Wegener's granulomatosis may reverse
progressive neurologic dysfunction and prevent subsequent multiorgan involvement and renal failure.

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