An Unusual
Manifestation of
Wegener’s
Granulomatosis in a
4-Year-Old Girl
Johannes-Peter Haas, MD*†,
Markus Metzler, MD*, Hans Ruder, MD‡,
Rüdiger Waldherr, MD§,
Michael Böswald, MD¶, and
Thomas Rupprecht, MD*

We report a female who was diagnosed with Wegener’s
granulomatosis at 4 years of age with life-threatening
intracranial bleeding. The patient’s serum was positive
for c-antineutrophilic cytoplasmic antibodies, and histologic analysis of the lung biopsy revealed evidence of
granulomatous vasculitis. Initial treatment with steroids and cyclophosphamide was successfully converted to a long-term medication regimen consisting of
azathioprine, trimethoprim, and sulfamethoxazole.
Thereafter the patient showed no signs of disease
activity for more than 3 years and manifested only a
low-grade neurologic handicap. In February 2001, 5
years after the initial diagnosis, she presented with
altered consciousness and myoclonic multifocal seizures. Subsequent diagnostic studies confirmed the
diagnosis of disseminated cerebral vasculitis unresponsive to steroid treatment. Acute neurologic symptoms
relented immediately after cyclophosphamide pulse
therapy. Magnetic resonance imaging of the brain
demonstrated complete remission within 8 weeks. Her
current treatment includes steroids and monthly pulses
of cyclophosphamide. © 2002 by Elsevier Science Inc.
All rights reserved.

From the *Department of Pediatrics, Friedrich-Alexander University,
Erlangen, Germany; the †Department of Pediatrics, Division of
Neonatology and Intensive Care, Ernst-Moritz-Arndt University,
Greifswald, Germany; ‡Caritashaus, Feldberg, Germany; the
§
Laboratory for Pathology, Heidelberg, Germany; and the ¶Department
of Pediatrics, St. Franziskus Hospital, Muenster, Germany.

© 2002 by Elsevier Science Inc. All rights reserved.
PII S0887-8994(02)00392-2 ● 0887-8994/02/$—see front matter

Haas J-P, Metzler M, Ruder H, Waldherr R, Böswald M,
Rupprecht T. An unusual manifestation of Wegener’s
granulomatosis in a 4-year-old girl. Pediatr Neurol 2002;
27:71-74.

Introduction
Intracranial hemorrhage during childhood is most frequently caused by vascular malformations, coagulation
disorders, and brain tumors [1]. Cerebral vasculitis can
also be a cause of cerebral bleeding [4]. Wegener’s
granulomatosis is a rare disorder in pediatric patients.
Most pediatric patients with Wegener’s granulomatosis
demonstrate involvement of the kidneys, lungs, and the
nasal mucosa [17]. In adults 50% of patients suffering
from Wegener’s granulomatosis have been reported to
have neurologic symptoms, although in fact only 10% of
the patients have involvement of the central nervous
system [2]. We report a rare case of Wegener’s granulomatosis with involvement of the central nervous system
beginning in early childhood.
Case Report
On hospital admission in January 1996, a 4-year-old female presented
with headache, seizures, altered consciousness, inappropriate language,
and various degrees of coma (Glasgow Coma Scale 6-10). There was no
history of trauma or infection. The physical examination revealed signs
of increased intracranial pressure including papilledema. Cranial computed tomography revealed a massive intracerebral hemorrhage in the
right frontotemporal region (Fig 1). Craniotomy was performed immediately, and the child recovered with the residual of a moderate spastic
hemiplegia of the left side. On day 25 after craniotomy an acute
respiratory distress syndrome occurred with poor oxygenation and
bilateral nodular infiltrates on chest radiography, but normal cardiac
function (Fig 2). At that time the erythrocyte sedimentation rate was
25/52 mm, C-reactive protein 10.6 mg/dL, and values for amylase and
lipase were consistent with acute pancreatitis. Tests for coagulation
disorders revealed no abnormalities, there was no skin involvement, nor
impaired liver or kidney function. Despite negative microbiologic studies
acute respiratory distress syndrome was thought to result from infection.
Under treatment with antibiotics (including imipenem and tobramycin)
and prednisolone (0.5 mg/kg), mechanical ventilation was gradually
withdrawn and discontinued after 9 days.
Consequently pulmonary function improved, and pancreatic function
parameters returned to normal. As a consequence of the complete
withdrawal of prednisolone therapy, acute respiratory distress syndrome
relapsed at day 60 and was suspected to be triggered by systemic

Communications should be addressed to:
Dr. Haas; Department of Pediatrics, Division of Neonatology and
Intensive Care, Ernst-Moritz-Arndt University, Soldmannstr. 15, 17487
Greifswald, Germany.
Received November 13, 2001; accepted February 4, 2002.

Haas et al: Wegener’s Granulomatosis in 4-Year-Old Girl 71

Figure 1. Cranial computed tomography
on the day of admission demonstrating
extensive intracerebral hemorrhage in the
right frontotemporal region.

vasculitis. Blood tests revealed erythrocyte sedimentation rate of 43/121
mm and c-antineutrophil cytoplasmic antibody (c-ANCA) titer of 1:40
and a negative antiproteinase 3 (PR-3)-enzyme-linked immunosorbent
assay test. C3 levels were unaltered, and tests for antinuclear antibodies
were negative. The patient responded well to steroids (2 mg/kg/day) and
was discharged from hospital 4 weeks later. Steroids were administered
over 4 months, and the dose was gradually decreased to 0.1 mg/kg/day.
Six weeks after the steroid treatment had been discontinued the patient
developed acute respiratory distress syndrome again along with microalbuminuria (69 mg/L). Lung biopsy revealed the histology of a focal
necrosis, palisading granulomas, and giant cells, characteristically typical
for chronic necrotizing granulomatous vasculitis. The c-ANCA titer
continued to be positive (1:40). Again the patient was started on
prednisolone treatment (2 mg/kg/day) with doses that were gradually
decreased by 0.2 mg/kg each week down to a final dose of 0.1 mg/kg.
Moreover, treatment with oral cyclophosphamide was begun (3 mg/kg

administered 5 days per week) with a cumulative dose of 750 mg/kg/
year, as published elsewhere [5]. A rapid and complete remission of the
acute respiratory distress syndrome and proteinuria was achieved within
6 weeks, and inflammation parameters including the c-ANCA titer
returned to normal. After 12 months, cyclophosphamide was replaced by
azathioprine (2 mg/kg/day), which was administered for an additional 12
months. Because the patient’s stable remission continued, steroids were
discontinued, and azathioprine was replaced by cotrimoxazole/SMX (T/S
2 mg/kg twice daily), which was administered for another 12-month
period [16]. During this time the patient was in good health with no signs
of active inflammation, and the lung function parameters were within
normal limits. She was mentally and physically rehabilitated and spastic
hemiplegia of the left side was the only residual condition. She was able
to walk, run, and perform simple functions with her left hand and
successfully attended a regular school. In February 2001 she presented
with altered consciousness and head pain. There were no other symptoms

Figure 2. Anteroposterior chest x-ray
on day 25 depicts bilateral nodular infiltrates as characteristic indications of
acute respiratory distress syndrome.

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Figure 3. Cerebral magnetic resonance imaging in February 2001 after
5 days of multifocal symptoms demonstrates a right frontotemporal
hyperdense area that corresponds with the encephalomalacia scar
resulting from the intracerebral bleeding in 1996. There are no signs of
active vasculitis. (Siemens open magnetom T2-weighted sequence.)

Figure 4. Cerebral magnetic resonance imaging in March 2001, 12
days after initial presentation of symptoms, illustrates disseminated
multifocal cerebral vasculitis, indicated by hyperdense spots of gadolinium in both hemispheres, the thalamus, and the cerebellum. (Siemens
open magnetom T2-weighted sequence.)

of vasculitis. Analysis of blood and cerebral fluid revealed no signs of
inflammation. c-ANCA results were negative, and the patient had no
detectable pulmonary disease. Magnetic resonance imaging of the brain
did not reveal any changes characteristic of cerebral vasculitis. The
encephalomalacia from her initial intracerebral bleeding did not reveal
any alterations as compared with previously performed imaging studies
(Fig 3). Her overall condition deteriorated quickly, and she subsequently
developed myoclonic multifocal seizures that were resistant to therapy
with benzodiazepine and phenytoin. Because the initial suspicion was
that a relapse of her intracerebral vasculitis might have occurred,
treatment was immediately begun with high-dose steroids (2 mg/kg/day).
Cranial magnetic resonance imaging was repeated at day 10 and revealed
that multilocular lesions had developed involving supratentorial and
infratentorial areas of the brain (Fig 4). Blood and cerebrospinal fluid
analyses did not demonstrate an systemic inflammatory response, although c-ANCA results were slightly positive with a titer of 1:80.
Neurologic symptoms did not respond to steroid therapy, and it was
therefore decided to add an IV cyclophosphamide pulse with 750 mg/m2
of body surface. This treatment improved the patient’s symptoms
dramatically and resulted in cessation of seizures within 12 hours and a
complete recovery from the neurologic symptoms within 3 days. The
patient was able to leave the hospital on day 10 after the first cyclophosphamide pulse. Since then she received three IV pulses of cyclophosphamide, and steroids were gradually decreased to a final dose of 0.2 mg/kg
administered every second day. Cerebral recovery was documented, with
magnetic resonance imaging of the brain performed at the time of the
third IV cyclophosphamide pulse in June 2001. At this time, all signs of
the acute vasculitis had recovered completely. Cyclophosphamide was

discontinued after six pulses, and immunosuppressive treatment was
maintained with azathioprine administered orally with a dosage of 2
mg/kg/day and the steroid treatment described above.

Discussion
Central nervous system bleeding can result from a
variety of causes [1,12]. The patient described in this
report had no history of trauma, coagulopathy, hypertension, or brain tumor. The reasons most likely responsible
for the patient’s initial intracerebral bleeding in 1996 seem
to be vascular malformation and cerebral vasculitis. No
signs of vascular malformations have been revealed in any
of the cerebral angiograms performed with magnetic
resonance imaging since the initial presentation in our
patient. Although this does not exclude a malformation
completely, the further course of the patient led us to
conclude that cerebral vasculitis seems to be most likely
responsible for the cerebral hemorrhage. Because our
patient had also lung involvement, isolated angiitis of the
central nervous system, which is a rare disease with a poor
prognosis, was excluded [9]. Histology demonstrated
granulomatous vasculitis, and there was a relapse of the
cerebral vasculitis in 2001. Therefore, retrospectively we

Haas et al: Wegener’s Granulomatosis in 4-Year-Old Girl 73

propose the intracerebral bleeding in 1996 to be the initial
presentation of Wegener’s granulomatosis. Cerebral manifestations of Wegener’s granulomatosis occur in approximately 5% of the cases with thrombosis obstructing
intracerebral arteries and veins [10]. Cranial magnetic
resonance imaging with intermediate weighted and T2weighted imaging can be helpful in detecting central
nervous system involvement of vasculitis [14]. Although
nonspecific for cerebral vasculitis in Wegener’s granulomatosis, most patients were found to have had diffuse
white matter lesions with high signal intensity on T2weighted magnetic resonance imaging [10]. Treatment and
prognosis of cerebral vasculitis in childhood is an area in
which there is little clinical experience and data. Observations in adult patients with cerebral vasculitis caused by
lupus erythematosus indicated that the long-term outcome
may benefit from aggressive treatment involving cyclophosphamide [8]. The data for treatment of childhood
granulomatous diseases are limited; therefore the first
course of treatment in our patient was based on protocols
that are used for the treatment of Wegener’s granulomatosis in adults [5,16]. During the relapse in 2001 a cerebral
vasculitis was present without lung or kidney involvement.
Again therapy was based on protocols published for
treatment of cerebral vasculitis in adults [8]. To prevent
future relapses the immunosuppressive treatment with
azathioprine and low-dose steroids should potentially be a
lifelong treatment.
The patient reported herein exhibited a clinical and
histologic picture consistent with granulomatous vasculitis. It fits in well with Wegener’s granulomatosis, although
we have not observed signs of kidney involvement.
Wegener’s granulomatosis is classified as a small-vessel
vasculitis according to the Chapel Hill consensus conference [7]. The differential diagnosis of small vessel vasculitis includes Churg-Strauss syndrome, which demonstrates central nervous system involvement more
frequently than Wegener’s granulomatosis [6]. However,
we could not detect signs of eosinophilia, either in blood
smears or in the biopsy of our patient. Wegener’s granulomatosis is a systemic vasculitis that is diagnosed only
rarely in children during the first decade of life [3,17].
Symptoms and course of the disease seem to be similar to
those observed in adults with Wegener’s granulomatosis.
There are very little data on the prognosis of Wegener’s
granulomatosis in young children. A limited disease without renal involvement has been described in children and
adults [11,13]. We observed another female who began
with lung disease at 6 years of age without kidney
involvement and experienced renal failure at 10 years of
age. Patients such as these might indicate that Wegener’s
granulomatosis and related vasculitides may be underdiagnosed in children [15]. The initial manifestation as an
intracerebral hemorrhage is a rare complication of Wege-

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ner’s granulomatosis and has only been reported in some
cases [18]. This report emphasizes the importance of
considering Wegener’s granulomatosis even in young
children who present with unexplained intracerebral
bleeding or acute respiratory distress syndrome.

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