Dr
Caroline Cunningham1, Dr Steve Cleland1, Dr Hilary Wilson1,
Dr Robert Barnetson2
1Stobhill
Hospital, Glasgow 2Dept Pathology, Western Infirmary, Glasgow
Corresponding
author: Dr
Caroline Cunningham, Medical SHO, Stobhill Hospital, Glasgow
Email: cc.doctors@ntlworld.com
SMJ 2007 52(2): 56
Abstract
We report a clinical case of a young, previously well woman who presented with multiple neuropathies, both peripheral and cranial and who was subsequently confirmed to have Wegener’s Granulomatosis with minimal respiratory symptoms or renal involvement. The case illustrates the difficulties in diagnosing this rare condition when the cardinal features are not present, but serves to illustrate the importance of disease identification when other, atypical sites, that have a particular preponderance for morbidity i.e. the nervous system, are involved.
Key words; Wegener’s granulomatosis, polyneuropathy, neurology.
A 49-year-old female non-smoker was initially admitted to hospital with a suspected Bells palsy. There was no past medical history of note, though at the time the patient had complained of non specific myalgia, thought to relate to a previous viral illness. She was otherwise well. On examination, there was clearly a lower seventh cranial nerve lesion, though there was no other neurological abnormality of note, although there was some right-sided unilateral hearing loss at this stage. The remainder of the clinical examination and otoscopy were normal. Initial investigations including a chest radiograph were unremarkable. Full blood count, renal function and inflammatory indices were normal. An elevated ESR was noted at 136. She was commenced on prednisolone and discharged, with follow up arranged in the medical clinic for investigation of the elevated ESR.
The patient presented again to accident and emergency the following month. Her facial palsy had temporarily resolved with prednisolone, but had returned when steroid free. She had now developed bilateral hearing impairment for which she had attended ENT. Here, she was managed with antibiotic drops and aural toilet for an inflammatory process. Audiology demonstrated a mixed picture of sensorineural and conductive deafness. New symptoms had also developed. She complained of numbness in her left foot and right hand, accompanied by painful paraesthesia and weakness of her left foot. She now required assistance to mobilise and her hearing impairment had progressed to the degree that only written communication was possible.
On examination,
she had a borderline temperature though other observations were normal. There
was a mild residual right lower seventh nerve palsy and hearing impairment as
described above, though other cranial nerves were noted to be intact. There was
reduced sensation in the distribution of the median nerve of the right hand, and
weakness of left foot dorsiflexion and eversion, with loss of sensation over the
S1 distribution. Otherwise neurological examination was unremarkable. Chest
radiograph was now abnormal with a suspicious opacity at the right hilum, and a
diffuse increase in lung markings in the left mid zone. Blood tests demonstrated
an elevated ESR of 109, C Reactive Protein of 169 and mild renal impairment with
a urea of 11.1 and a creatinine of 125. Liver function tests were also abnormal.
Further investigations were arranged to determine the aetiology of what now had the appearance of a mononeuritis multiplex. Rheumatoid factor was negative as were tumour markers (CEA, CA125, Ca19 - 9), and there was a weakly positive ANA with homogeneous staining (1/ 40). Immunoglobulins were diffusely increased in keeping with an acute inflammatory response. Serum ACE was normal and serology for Borrelia was negative.
Imaging did not initially aid the diagnosis. CT chest demonstrated multiple nodules throughout both lung fields, the largest in a potentially accessible position for biopsy. Similarly, there were multiple low attenuation lesions in the liver and a splenic appearance suggestive of vascular compromise.
Fig. 1
|
|
Computed
tomography showing multiple lesions of low attenuation in both lung fields, with
biopsy accessible lesion from right posterior chest wall, and dense splenic
appearance consistent with vascular compromise
These findings were concluded to most likely represent widespread metastatic disease and CT head suggested the possibility of meningeal involvement. Her renal function remained mildly deranged and at this point she was noted to have microscopic haematuria and had developed splinter haemorrhages. An urgent ANCA and glomerulonephritis screen was requested the same day and a percutaneous CT guided biopsy of lung was arranged. C-ANCA was strongly positive (at a titre of 1:640, directed against PR3 antigen at a titre of 85.4) and C4 levels reduced, in keeping with a possible diagnosis of Wegener’s Granulomatosis. Pathology from the lung biopsy demonstrated granuloma formation and an early destructive vascular lesion, without necrosis, suggestive of Wegener’s.
Fig. 2
Fig. 3 a
Fig. 3b
Fig. 2 Core of
lung parenchyma, H&E (medium power)
There is a diffuse
lymphohistiocytic inflammatory cell infiltrate with occasional multinucleate
giant cells (arrowhead) and loosely formed granulomas (open arrow).
Intra-alveolar fibrin is also present (solid arrow).
Fig. 3a Core of
lung parenchyma, H&E (medium power)
A loosely formed granuloma (arrow) is identified adjacent to a vessel. There is no necrosis.
Fig. 3b Core of
lung parenchyma, EMSB (high power)
An elastic stain
showing early destruction of a vessel characterised by intimal thickening and
inflammation.
The patient was commenced on methylprednisolone and cyclophosphamide. There was dramatic improvement in her symptoms, with hearing improving to almost normal over 72 hours. Subsequently however her renal function deteriorated and a renal biopsy confirmed necrotising glomerulonephritis consistent with Wegener’s. She was commenced on oral prednisolone 60mg daily. Pneumocystis and osteoporosis prophylaxis was achieved with cotrimoxazole and alendronate/adcal D3 respectively. Inflammatory indices also normalised with the above treatment. In retrospect, there had been several episodes in the preceding months of recurrent sinusitis and epistaxis, both of which had been so minor, as to not have been immediately recalled by the patient. She continued to improve on a reducing course of oral steroids by 2.5 mg per week and cyclophosphamide 100mg daily for 6 months thereafter switching to oral methotrexate weekly. She has regular follow up with rheumatology and renal physicians.
Wegener’s granulomatosis is a necrotising vasculitis which has a prevalence of 3 per 100000 in the United States, an equal sex incidence and a mean age at diagnosis of 40 –55.1 The disease process has a predilection for the upper respiratory tract, lungs and kidneys and is an inflammatory condition with typical lesions including necrosis, granulomatous change and vasculitis. The ACR criteria for classification are;
Nasal or oral inflammation
Abnormal chest radiograph – nodules, infiltrates or cavities
Urinary sediment / haematuria / red cell casts
Granulomatous inflammation on biopsy
Antineutrophil cytoplasmic antibody (c – ANCA) is a useful, cheap and non-invasive test often used in the diagnosis. C - ANCA has a sensitivity of 83% and a specificity of greater than 90% when defined by biopsy criteria and clinical symptoms, but a sensitivity of only 28% when ACR criteria used, though specificity remained over 90%.6 The use of image guided biopsy is a safe, useful tool in the assessment of disease activity in patients with Wegener’s as well as in initial diagnosis, and can be used to facilitate informed decisions on further immuno-suppressive therapy.7
The aetiology remains unclear, however it is postulated to involve a variety of immune mediated mechanisms. C - ANCA, usually with a specificity to PR 3, is thought to enhance the inflammatory process and contribute to vascular injury, though this does not explain the organ specificity. The presence of an infectious agent or trigger is also possible. Many patients initially present with symptoms of an infectious condition, in particular the upper airway is almost always involved. Indeed in many known viral conditions, EBV, Hep C, HIV, vasculitis is a recognised, albeit uncommon, feature. Granuloma formation is known to be precipitated by sensitised CD4 T cells that produce pro-inflammatory cytokines (IL- 2, IFN, TNF) All of these have been reported in high levels in those patients with Wegener’s. As in other inflammatory conditions, regulation of these cytokines may be of use in treatment.
Most patients will initially present with respiratory tract symptoms – cough, wheeze, haemoptysis. Nasal and sinus problems in particular are common, including epistaxis. Subglottic stenosis is a surprisingly common and potentially fatal presentation and occurs in up to 20%. Radiographic features (infiltrates or nodules) are present in up to 45%.2 Glomerulonephritis is present at diagnosis in 20% but develops in over 80% and is manifest by deteriorating renal function, proteinuria and urinary sediment, progressing to acute renal failure.2
Neurological features are much less common at presentation. There are several mechanisms by which it is postulated that the nervous system is involved, including contiguous spread from the sinuses or middle ear, formation of granuloma directly in the nervous system and vasculitis affecting the brain or peripheral nervous system.
Hearing loss is an uncommon feature. 50% of patients do have otological findings, but only 2.8% - 13% have documented sensorineural hearing loss.3 This may result in significant morbidity, and may be irreversible. Conductive hearing loss also occurs, but this is usually responsive to immuno-suppressants. In one series of 36 patients with Wegener’s, 20 patients (56%) had hearing loss, of whom 47% had sensorineural loss, 33% conductive loss, rest had mixed loss. In the conductive loss group 7 of 12 cases improved with immuno suppressants, however in the sensorineural group, only 3 of 17 improved with the remainder worsening or staying the same.3. The early identification and assessment of hearing is an important aspect of management, though there is no clear evidence that earlier treatment alters outcome
There are conflicting reports regarding the frequency of neurological manifestations of Wegener’s. Incidences range from 15%1 to 34% (Mayo clinic) to 49%.4 A large prospective analysis of 180 patients in 1998 suggested nervous system involvement is rare at presentation, but 15% develop mononeuritis multiplex, and 8% have central nerve involvement (cranial neuropathies, stroke) during the illness course.2 However, a more recent prospective analysis, using imaging and electrophysiological modalities as well as clinical examination would estimate this figure as higher. In a cohort of 131 patients, 64 (49%) had involvement of the peripheral or central nervous system. Polyneuropathy was most common (56 patients), central nervous system was involved in 7 cases, and cranial nerves involved in 6. There was a significant (p<0.05) difference in the occurrence of polyneuropathy in men more than women. Polyneuropathy presented either as a symmetrical distal lesion, or a mononeuritis multiplex, but was only present at diagnosis in a minority. Patients with polyneuropathy had a significantly larger disease extent, and overall response to treatment was poor, only 3/56 patients achieved full remission.4
There are other neurological symptoms that can manifest. Meningitis is a rare, but recognised complication with 16 biopsy proven reports in the literature since 1964. However, it may be more common than that, and may be responsible for some of the other manifestations, e.g cranial neuropathies, and opthalmoplegia.5
In conclusion, our patient presented with predominantly neurological signs and a relative absence of the classical clinical features of this disease (except that she had hearing loss and aural discharge). The initial suspicion was of widespread malignant disease, based on imaging and unusual presentation of symptoms. The case highlights the importance of careful clinical history and full examination of patients with unexplained neurological symptoms. Wegener’s granulomatosis mimicking malignancy is not uncommon and several cases have been reported in the literature.8 This differential diagnosis requires careful consideration in patients with mulitifocal lung lesions for example, where a wrong or delayed diagnosis may lead to inappropriate treatment, especially if histopathology is inconclusive.
Langford, C et al. Wegener’s Granulomatosis. Thorax, Volume 57(7). July 1999, 629-637
Hoffman, G et al. Wegener Granulomatosis: An Analysis of 158 Patients. Annals of Internal Medicine, Volume 116 (6). March 1992, 488-498
Bsthavachalam, S et al. Hearing Loss in Wegener’s Granulomatosis. Otol Neurotl, Volume 25 (5). September 2004, 833-837
de Groot, K et al. Wegener’s Granulomatosis – a Disease for the Neurologist. Clinical and Experimental Immunology. Volume 112 (1). April 1998, 24-26
Jinnah, H A et al. Chronic Meningitis with Cranial Neuropathies in Wegener’s Granulomatosis. Case report and review of the Literature. Arthritis Rheum, Volume 40 (3). March 1997, 573 - 577
Rao, J et al.. A Prospetive Study of c-ANCA and Clinical Criteria in Diagnosisng Wegener’s Granulomatosis. Lancet, Volume 346 (8980). October, 1995, 926-931
Carruthers D et al. Percutaneous image-guided biopsy of lung nodules in the assessment of disease activity in Wegener’s Granulomatosis. Rheumatology 2000; 39; 776-782
Uppal, S et al. Pulmonary Wegener’s Misdiagnosed as Malignancy. BMJ 2001: 322: 89-90
