Vasculitic Wallenberg syndrome with detection of anti-proteinase 3 antibodies in the cerebrospinal fluid of a patient with severe Wegener's granulomatosis and only mild kidney involvement

Justus Faust1,, Anke Visbeck2, Sabine Fitzek2, Clemens Fitzek3, Thomas Orth1, Eveline Wandel1 and Werner J. Mayet1

1 Departments of Internal Medicine, 2 Neurology and 3 Neuroradiology, Johannes Gutenberg-Universität Mainz, Mainz, Germany

Keywords: ANCA; proteinase 3; Wallenberg syndrome; Wegener's granulomatosis; vasculitic neurological involvement



   Introduction
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 Introduction
 Case
 Discussion
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Neurological involvement of Wegener's granulomatosis (WG) is usually accompanied by affection of upper airways, lungs and kidneys. In a large study of patients with WG [1], neurological manifestation was associated with lung disease in 67%, upper airway disease in 77% and kidney disease in 66%. In patients with peripheral neuropathy the percentage of renal involvement was significantly higher (83%) than in patients showing other neurological manifestations.

We report the case of a patient with vasculitic WG and the clinically-leading involvement of the brainstem (lateral medullary syndrome or Wallenberg syndrome) and peripheral nerves (multiple mononeuropathy).

Moreover, we were able to detect C-ANCA with the target antigen proteinase 3 (PR 3) in the cerebrospinal fluid (CSF). Despite marked involvement of the lungs and upper airways the patient developed only minimal kidney disease.

Because C-ANCA could be detected in the CSF without disturbance of the blood–brain barrier, and also because of the histological diagnosis of vasculitis in maxillary mucosa and the absence of granuloma-like lesions in the magnetic resonance imaging (MRI) scan of the brain, the hypothetical mechanism of brainstem and peripheral nerve involvement is vasculitic.



   Case
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 Introduction
 Case
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A 49-year-old man was admitted to hospital in January 1998 with a 4-week history of fever, diffuse pain in his limbs and ulcerations at the bottom of the tongue and right buttock. In December 1996, when similar symptoms had occured, the patient was admitted to another hospital. At that time an X-ray revealed congestion of both maxillary sinuses, histological examination of the maxillary mucosa showed vasculitis without granulomatous lesions and the patients serum was C-ANCA positive with specifity against PR 3. Owing to spontaneous remission, the patient was discharged without definite diagnosis and therapeutic intervention. In December 1997 repeated ulcerations of his buttock and tongue occurred and led to treatment with 250 mg methylprednisolone i.v. for 3 days, followed by 25 mg methylprednisolone per os daily.

The patient had no history of other illnesses and had stopped smoking 16 years ago (3-pack-year).

On admission to our hospital, examination showed a flat ulceration on the right buttock and a slightly bleeding ulceration at the bottom of the tongue. Rectal temperature was 38.5°C. Laboratory tests showed: white blood cells 16.1x109/l, platelets 578x109/l, fibrinogen 599 mg/dl, C reactive protein (CRP) 44 mg/l, serum glutamic pyruvate transaminase (GPT) 60 U/I, glutamate dehydrogenase (GLDH) 14.2 U/I, {gamma}-glutamyltranspeptidase ({gamma}-GT) 70 U/I and C-ANCA pattern on ethanol fixed neutrophils 1 : 160 (Immunofluorescence: INOVA Diagnostics, San Diego, CA, USA). The target antigen PR 3 was identified by enzyme-linked immunosorbant assay (ELISA; ORGENTEC Diagnostika GmbH, Mainz, Germany).

Four days after admission the patient suddenly developed a lateral medullary syndrome with numbness of the left side of the face, left Horner syndrome, vertigo and falling to the left side, ataxia of the left limbs and a dissociated sensory deficit over the right half of the body (Wallenberg syndrome). Cranial computer tomography (CT) of the brain revealed no abnormalities, but an MRI scan with diffusion-weighted imaging showed increased signal intensities of the left medulla oblongata and proved the suspected brainstem infarction (Figure 1Go). Late blink reflex latencies were abnormal, whereas brainstem auditory evoked potentials, electro-oculography and masseter reflex showed no abnormalities. CSF showed 3 cells (norm: <5) and lactate, glucose and protein were within the normal range. C-ANCA titre of the CSF was 1 : 10 (Figure 2Go) with specifity for PR 3 and the Delpech and Lichtblau protein quotient (IgGCSF/IgGserum: albuminCSF/albuminserum=0.49) did not reveal a disturbance of the blood–brain barrier or an autochtone IgG production. Oligoclonal IgG bands were not detected. In contrast to the Delpech and Lichtblau protein quotient a specific calculated C-ANCA index (C-ANCACSF/C-ANCAserum: albuminCSF/albuminserum) was elevated to 8.6, which indicated intrathecal synthesis of C-ANCA.



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Fig. 1. Arrow: diffusion-weighted MRI shows increased signal intensity in the left medulla oblongata indicating the acute lateral medullary infarct.

 


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Fig. 2. Immunofluorescence showing a cytoplasmic staining pattern (target antigen: PR 3) on neutrophils with the patient's cerebrospinal fluid (a), the patient's serum (b) and a control serum (c).

 
Chest X-ray revealed reticulonodular infiltration and high-resolution CT of the lung confirmed a single 3-cm granuloma-like lesion in the left lower lobe (Figure 3Go) and multiple smaller nodular lesions in both lobes. Despite mild proteinuria (216 mg/day), erythrocyturia (30–99/µl) with up to 3% acanthocyturia and slightly reduced creatinine clearance (78 ml/min), a kidney biopsy showed only minimal sclerosis in one glomerula and no patterns of glomerulonephritis.



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Fig. 3. HR-CT of the lung showing a 3 cm large granuloma-like lesion (arrow) of the left lower lobe.

 
The diagnosis of Wegener's granulomatosis with predominant cerebral manifestation was made and oral treatment with methylprednisolone 125 mg for 11 days (followed by a daily dose of 75 mg methylprednisolone) and cyclophosphamide 150 mg daily was started. The patient improved clinically and was discharged on 10 February 1998. One month later he was readmitted to hospital with dyspnoea on exertion, fever of 39°C and a right median and left ulnar nerve palsy. The CT of the lung revealed marked infiltration of the right upper lobe without positive bacteriology on bronchoalveolar lavage. Nerve conduction studies revealed axonal neuropathy affecting the right median and left ulnar nerves. These findings were consistant with the diagnosis of a multiple mononeuropathy. Methylprednisolone (125 mg) per os was administered for 5 days and, with the exception of the peripheral neuropathy, the patient's condition improved and he was transferred to a rehabilitation centre. Nevertheless, further repeated attempts to taper the steroids below 40 mg/day led to marked deterioration of peripheral neuropathy and ulcerations mainly in the oropharynx: therefore, seven cycles of cyclophosphamide i.v. pulse therapy (1300 mg every 28 days) were performed with continuos intermittent doses of 100–150 mg cyclophosphamide per os each day. Since December 1998 no worsening of peripheral neuropathy and ulceration has occurred with daily doses of 25 mg methylprednisolone and 100 mg cyclophosphamide per os. There has also been no progression of haematuria, proteinuria or deterioration in renal function.



   Discussion
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 Introduction
 Case
 Discussion
 References
 
Neurological manifestations occur in 13–54% of WG patients [1–5]; hereby peripheral neuropathy (8.8–45%) is more common than CNS manifestations (4.2–11.5%). Wegener himself reported a incidence of 8.3% for peripheral neuropathy and 4.6% for CNS manifestations in a sample of 108 patients with WG [6]. Cerebral involvement is caused by three different mechanisms [2,7]: direct intracranial invasion of granulomas from the paranasal sinuses, remote granulomas in the meninges or cerebrum and vasculitis, which also is mainly responsible for peripheral neuropathy with multiple mononeuropathy as its most frequent form [8]. Cerebral vasculitis in WG is a rare manifestation, only five of 109 patients with neurologic involvement in a large study of 324 patients with WG showed clinical signs of cerebral vasculitis [1]. Cerebral angiography often fails to confirm the diagnosis of vasculitis because of the small size of the affected vessels (50–300 µm) [9]. MRI studies of the brain in patients with WG often show different cerebral lesions, but specifity with regard to vasculitis or ischaemia is not yet satisfactory [10]. New MRI techniques, such as diffusion-weighted imaging, result in earlier detection of ischaemic lesions in the brain, but are not more specific for vasculitis. The detection of C-ANCA in the CSF has been reported only in a young WG patient with meningeal involvement [11]. In contrast to our findings, a lymphocytic pleocytosis with autochtone IgG production and oligoclonal bands was found with a fluctuating degree of disruption of the blood–brain barrier. In our case we also calculated a specific C-ANCA index, which revealed a significantly elevated index in comparison with the original Delpech and Lichtblau protein quotient. Because a disturbance of the blood–brain barrier had been excluded, an intrathecal synthesis of C-ANCA, probably caused by cerebral vasculitis, must also be considered, although no autochtone IgG production could be demonstrated using the Delpech and Lichtblau protein quotient alone.

To our knowledge this is the first case report of Wallenberg syndrome in a patient with WG and the second case in which C-ANCA against PR 3 in the CSF was detected. Although cerebral angiography was not performed for the reasons mentioned above, the absence of granuloma-like lesions, MRI findings, neurophysiological findings and CSF examinations strongly suggest a vasculitic brainstem lesion. In addition, the presence of multiple mononeuropathy, which in this context is most commonly caused by vasculitis, underlines the probability of a primary vasculitic process.



   Notes
 
Correspondence and offprint requests to: J. Faust, 1. Medizinische Klinik Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, 55101 Mainz, Germany. Back



   References
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 Introduction
 Case
 Discussion
 References
 

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Received for publication: 12. 8.99
Revision received 12. 1.00.