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Grand Rounds Vol 10 pages L1–L5
Speciality: Landmark case report
Article Type: Case report
DOI: 10.1102/1470-5206.2010.L001
� 2010 e-MED Ltd
Wegener’s granulomatosis and multiple
cranial neuropathies
Saahil Mehtaa, Sebastian Lucasb, Frank Crossc and David P. D’Cruza
aThe Louise Coote Lupus Unit, St. Thomas Hospital, London, SE1 7EH, UK; bDepartment of
Histopathology, St. Thomas Hospital, London, SE1 7EH, UK; cDepartment of Vascular Surgery, Royal
London Hospital, London, E1 1BB, UK
Corresponding address: Dr David P. D’Cruz MD FRCP, Consultant Rheumatologist, The Lupus
Research Unit, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UK.
Email: david.d’cruz@kcl.ac.uk
Date accepted for publication 17 February 2010
Abstract
Wegener’s granulomatosis, first described by Friedrich Wegener in 1936, is a systemic vasculitis
that characteristically causes necrotizing granulomas of the respiratory tract and necrotizing
cresentic glomerulonephritis. This article describes the history and modern treatment of the
disease in conjunction with a clinical case.
Keywords
Wegener’s granulomatosis; treatment; neurological involvement.
Clinical case
A 69-year old Caucasian man developed sinusitis and earache in October 2008. A procedure was
attempted to insert a grommet, however, because of the severity of inflammation, the tympanic
membrane ruptured and the purulent discharge drained naturally.
During the following month he again developed earache and sinusitis in conjunction with a
severe chest infection and striking weight loss and was admitted to hospital. On admission he
looked cachectic and he had multiple cranial nerve palsies affecting cranial nerves VI to XII. He
had lost his cough reflex and had a left facial palsy. Blood tests were positive for anti-neutrophil
cytoplasmic antibody (c-ANCA) and anti-proteinase 3 (PR3) antibodies. A diagnosis of Wegener’s
granulomatosis was made.
He was started on oral cyclophosphamide 50mg daily and a marked, albeit short-lived,
improvement was seen. He was readmitted less than a month later with the same symptoms and
worsening weight loss and he was transferred to our unit.
At St. Thomas’, a magnetic resonance imaging (MRI) scan showed diffuse, non-specific soft
tissue abnormality at the base of the skull and sub-cranial region (Fig. 1a,b). Despite corticosteroid
therapy he failed to improve and he was started on intravenous cyclophosphamide with some
improvement after the first 500mg infusion. However, he developed an aspiration pneumonia due
to the absent cough reflex. He was given antibiotic therapy with some improvement although with
a persisting high C-reactive protein (CRP) titre. He was given a second infusion of intravenous
cyclophosphamide.
This paper is available online at http://www.grandrounds-e-med.com. In the event of a change in the URL
address, please use the DOI provided to locate the paper.
Initially, he appeared to be doing well after the second infusion. Three days afterwards he
became drowsy and very unwell requiring admission to intensive care where he received
intravenous antibiotics for a severe chest infection. Computed tomography (CT) chest showed left
lower lobe consolidation and small areas of ground glass opacity in both lung fields. The patient
showed signs of improvement 2 days after commencing antibiotics. However, he suffered a
sudden pulseless electrical activity (PEA) cardiac arrest and could not be resuscitated.
Postmortem examination found infarction in the upper lobe of the left lung with active
capillaritis and haemorrhage into the trachea. There was acute tubular necrosis and mild
interstitial nephritis, but no active glomerular capillaritis in the kidneys. In the skull, there was
necrosis with giant cells in the dura affecting the adjacent cranial nerves (Fig. 2). There was sterile
osteomyelitis of the sphenoid bone with medullary necrosis (Fig. 3). The histological findings
confirmed a diagnosis of Wegener’s granulomatosis, with pulmonary capillaritis and necro-
granulomatous dural involvement of the skull base resulting in multiple cranial neuropathies.
Discussion
This case report illustrates how Wegener’s granulomatosis can evolve. The patient’s symptoms
began as recurrent earache and sinusitis that later developed into recurrent chest infections,
(a)
(b)
Fig. 1. (a,b) MRI brain showing diffuse, non-specific soft tissue abnormality in the base of the skull.
L2 S. Mehta et al.
which in retrospect may have been episodes of pulmonary capillaritis without haemoptysis, and
continued severe weight loss with increased acute phase markers and positive c-ANCA antibodies.
What is unusual is the involvement of multiple cranial nerves. A study from the Mayo Clinic
found that just over 30% of 324 patients had neurological involvement[1]. The cranial nerves most
commonly affected were II, VI and VII and only 8 patients had involvement of multiple cranial
nerves.
Wegener’s granulomatosis is a systemic vasculitis that characteristically causes necrotizing
granulomas of the upper and lower respiratory tract and necrotizing crescentic glomerulone-
phritis. The disease is strongly associated with c-ANCA antibodies with specificity for PR3, a
neutrophil alpha-granule serine protease.
There is some debate as to when the condition was first described. Although Heinz Klinger, a
medical student, is credited with the first description of the disorder in 1932, he attributed the
findings to a form of periarteritis nodosa[2]. A Scottish surgeon, McBride, is sometimes credited
with a description of this disease[3]. However, Friedmann postulated that McBride was in fact
describing a different disease known as Stewart’s type idiopathic pleomorphic midfacial
granuloma[3]. On closer inspection of this article, this would seem to be the case.
The condition was not formally described until 1936 when a landmark presentation was
published in the Proceedings of the German Pathological Society by Dr Friedrich Wegener
describing 3 patients with a systemic illness affecting the upper and lower respiratory tract and
renal system[4]. These 3 patients all had a disease with very similar features:
1. Preceding septic course
2. Severe necrotizing granulomatous inflammation of the nasal space
Fig. 2. Cranial nerve longitudinal section (lower part of picture) adherent to necrotizing inflammation of the dura (arrows);H&E.
Fig. 3. Sterile necrotizing osteomyelitis of the sphenoid bone; H&E.
Wegener’s granulomatosis and multiple cranial neuropathies L3
3. Microscopic renal changes, specifically, toxic focal glomerulonephritis
4. Generalized arteritis similar to polyarteritis nodosa.
It was from this paper that the disease became known as Wegener’s granulomatosis, a term used
by a Swedish pathologist, Sven Johnson, who distinguished it from periarteritis nodosa[5]. The
nomenclature of the disease has come under scrutiny recently. The use of eponyms has always
divided opinion and Wegener’s granulomatosis featured heavily in an article advocating that the
use of eponyms should be abandoned[6]. This article suggested a link between Friedrich Wegener
and the Nazi Party and that he was wanted as a war criminal after World War II. Many of these
claims are unsubstantiated but despite this various patient groups have called for the disease to
be renamed.
The pathogenesis of Wegener’s granulomatosis is not fully understood. It has been suggested
that there is an association between infection by fimbriated bacteria (which includes several
types of gram-negative bacteria) that can initiate the auto-immune process[7]. Recent data
points towards the involvement of lysosomal associated membrane protein 2 (LAMP-2). LAMP-2
appears to be involved with the activity and maturation of phagosomes. LAMP-2 is an ANCA target
and antibodies to LAMP-2 have been found in patients with ANCA-associated vasculitis.
These antibodies could be pathogenic and activate neutrophils and cause microvascular
endothelial cell injury in vitro. There is recent evidence that interaction between LAMP-2 and
fimbriated bacteria produces a human-like ANCA-associated vasculitis in animals through
molecular mimicry. This mechanism could provide a novel therapeutic target but this data
needs to be confirmed.
Treatment
In 1936 when Wegener described this condition there was no treatment and the outcome was
universally fatal in generalized disease, especially if there was renal involvement. Even by 1956, a
landmark paper by Walton reported that the median time to death was still only 5 months[8].
However, the advent of modern immunosuppression has revolutionized the prognosis for
patients with 5- and even 10-year survival over 80% being commonly reported.
Treatment of Wegener’s granulomatosis, and indeed other ANCA-associated vasculitidies can be
broken down into 4 stages: (1) diagnosis; (2) remission induction; (3) remission maintenance; and
(4) long-term follow-up with early recognition and treatment of relapses. Early diagnosis is
essential to optimize patient survival and prevent further renal disease[9]. Current treatment uses
intravenous or oral cyclophosphamide and glucocorticoids. Cyclophosphamide may be given in
5–6 pulsed intravenous doses over a period of 6 months as this reduces the negative side effects
such as neutropenic sepsis and also reduces the overall exposure to the drug by approximately
50%[10].
The use of other immunosuppressants after 3–6 months of cyclophosphamide treatment has
been shown to be beneficial in remission maintenance of the disease. Jayne et al.[11] and Pagnoux
et al.[12] found that azathioprine or methotrexate were both effective in remission maintenance.
Their use can also reduce the need for long-term glucorticoid therapy.
Developments in the treatment of Wegener’s granulomatosis include promising data
from randomized controlled trials of rituximab versus cyclophosphamide in the induction
of remission; this data is still in abstract form. Although anti-tumour necrosis factor
agents showed initial promise, a randomized trial of etanercept failed to show additional
benefit over standard of care as it was associated with a significant risk of solid malignancies[13].
Randomized controlled trial evidence exists for intravenous immunoglobulin but clinical
improvement is not sustained[14]. Stem cell transplantation to support immune
reconstitution has also been investigated but there is not enough evidence at present to support
its routine use.
Teaching point
Cranial nerve involvement is unusual in Wegener’s granulomatosis but may lead to
significant morbidity. In this patient, the loss of the cough reflex increased the risk of aspiration
pneumonia.
L4 S. Mehta et al.
References
1. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in
Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann
Neurol 1993; 33: 4–9. doi:10.1002/ana.410330103.
2. Klinger H. Glenzformer der Periarteritis nodosa. Frankfurt Z Pathol 1932; 42: 455–80.
3. Friedmann I. McBride and the midfacial granuloma syndrome. The Journal of Laryngology and
Otology 1982; 96: 1–23. J Laryngol Otol, 2002; Vol. 116, pp. 88–292.
4. Wegener F. Uber Generalisierte, septische Gefaesserkrankungen. Verh Dtsch Ges Pathol 1937;
29: 202–10.
5. Johnson S. A case of Wegener’s granulomatosis. Acta Pathol Microbiol Scand 1948; 25: 573–84.
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doi:10.1136/bmj.39308.342639.AD.
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vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16: 2018–27.
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11. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for
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36–44. doi:10.1056/NEJMoa020286.
12. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-
associated vasculitis. N Engl J Med 2008; 359: 2790–803. doi:10.1056/NEJMoa0802311.
13. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard
therapy for Wegener’s granulomatosis. N Engl J Med 2005; 352: 351–61. doi:10.1056/
NEJMoa041884.
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vasculitis. Adv Exp Med Biol 1993; 336: 469–72.
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