Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) is an autoimmune vasculitis of small- to medium-sized blood vessels. The Chapel Hill 2012 Consensus Criteria define GPA as “necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract and necrotizing vasculitis affecting predominantly small to medium vessels” [1]. In their seminal 1954 review, Godman and Churg recognized that Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome shared certain clinico-pathological features, and comprised a subset of vasculitides distinct from ‘periarteritis nodosa’ (now polyarteritis nodosa) [2]. The discovery that anti-neutrophil cytoplasmic antibodies (ANCA) are present in over 90% of patients with GPA and microscopic polyangiitis, and approximately 30% of those with Churg-Strauss syndrome has led to these three clinical syndromes being classified under the umbrella term ‘ANCA-associated vasculitis’. Patients with GPA typically show a cytoplasmic pattern of ANCA staining on indirect immunofluorescence (‘cANCA pattern’), with antibodies directed against proteinase-3 (PR3), a neutrophil protease.

The generalised form of GPA described by Wegener is characterized histopathologically by the triad of necrotizing vasculitis, pauci-immune focal necrotizing glomerulonephritis and necrotizing granulomatous inflammation of the respiratory tract. This systemic form of the disease can be life-threatening, particularly in the presence of pulmonary haemorrhage or rapidly progressive crescenteric glomerulonephritis. Prior to the introduction of cyclophosphamide [3], mortality was over 80% [4]. Modern treatment involves intensive immunosuppressive therapy with high dose corticosteroids and cyclophosphamide or rituximab to induce remission [5, 6]. Once remission is achieved, patients are switched to less toxic maintenance immunosuppression, such as azathioprine and low dose glucocorticosteroid.

A limited form of Wegener’s granulomatosis, with lesions localised to the lung, was later identified [7]. Patients with limited (now generally referred to as ‘localised’) disease are more likely to be young, female and ANCA negative than those with generalised GPA [8]. Localised GPA typically manifests with middle ear and respiratory tract features such as otitis media, sinusitis, nasal collapse and airway stenosis [8, 9].

Here we describe a patient with localised but severe granulomatosis with polyangiitis (Wegener’s granulomatosis) manifesting with progressive cranial nerve palsies and pituitary dysfunction. This case emphasises that localised cranial Wegener’s granulomatosis can result in serious morbidity in the absence of systemic disease. In such cases intensive induction immunosuppression is required.

Our patient, a white British female, presented at the age of 32 years with epistaxis, nasal congestion, recurrent bilateral otitis media and progressive hearing loss to an Ear, Nose and Throat (ENT) clinic at her local hospital. A year prior to this she had been fitted with bilateral hearing aids for hearing loss of unknown cause. She subsequently developed a left lower motor neurone facial palsy. A computed tomography (CT) scan showed a left nasopharyngeal mass and inflammatory changes in the middle ear and mastoid air cells. Nasolaryngoscopy revealed inflammation and ulceration of the left nasal turbinate, septum and posterior pharyngeal wall. She had never used cocaine. She underwent an exploratory mastoidectomy with grommet insertion.

Biopsies of the right and left nasopharynx, left middle meatus and septum revealed florid acute and chronic inflammation with mucosal ulceration and extensive necrosis of stroma and cartilage. The inflammatory infiltrate consisted of neutrophils, lymphocytes, and plasma cells, with zones of histiocytes representing granulomata (Fig. 1). Large numbers of multinucleated giant cells were present. Eosinophils were inconspicuous. Histological assessment of vasculitis was difficult due to the extensive necrosis and marked tissue inflammation, but necrotizing vasculitis of small vessels was evident. There was no evidence of malignancy, and stains for fungi and mycobacteria were negative.

Anti-neutrophil cytoplasmic antibody (ANCA) testing was positive by immunofluorescence with a cytoplasmic staining pattern. Anti-proteinase-3 (PR3) antibodies measured by enzyme-linked immunosorbent assay (ELISA) were mildly elevated (5.8, normal range < 2). Anti-myeloperoxidase (MPO) antibodies were not detected. CT thorax revealed no pulmonary abnormality and no lymphadenopathy. Serum calcium and angiotensin-converting enzyme (ACE) were normal.

On the basis of the clinico-pathological findings, she was diagnosed with localised granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis). Detailed work-up revealed no evidence of pulmonary, renal or other systemic features. She was treated with methotrexate 25 mg weekly and prednisolone 60 mg daily. The prednisolone was weaned to 10 mg over a period of 6 months. As the steroid dose was reduced she deteriorated. She developed headaches, nausea, diplopia, dysphonia and progressive dysphagia to both solids and liquids, resulting in weight loss of 3 stone.

She was referred to our institution by her general practitioner approximately 1 year after her initial presentation. Physical examination revealed left ptosis, a dilated and unreactive left pupil, paresis of left eye movements consistent with palsies of cranial nerves III, IV and VI, a left lower motor neurone facial palsy, and deviation of the tongue to the right. There was wasting of the right sternocleidomastoid. Laryngoscopy revealed a right-sided vocal cord palsy. Blood tests showed mild elevation of the inflammatory markers; the erythrocyte sedimentation rate (ESR) was 34 mm/hour, and the C-reactive protein (CRP) was 26 mg/L. Renal function, urinalysis and urine microscopy were normal. Repeat ANCA testing revealed cytoplasmic pattern ANCA staining, but antibodies to PR3 and MPO were negative.

A contrast-enhanced CT scan of her head and neck (Fig. 2) demonstrated predominantly dural-based enhancing soft tissue abnormality affecting the central skull base. This chronic inflammatory tissue involved the sella turcica (with resultant erosion of the floor of the sella turcica) and both cavernous sinuses. There was associated abnormality involving the pituitary parenchyma, the pituitary stalk and the hypothalamus. Contiguous chronic inflammatory infiltrative changes were also evident in the orbital apices, the petrous temporal bones encasing the carotid canals and the extra-cranial infratemporal fossae including the pterygopalatine fossae. As a result of the cavernous sinus, petrous temporal bone and infratemporal fossae involvement, both internal carotid arteries were occluded in their skull base carotid canal segments, with the anterior circulation sustained through collateral vessels. The sinonasal region demonstrated chronic inflammatory features, with mucosal and submucosal fibrosis and ulceration. Bilateral chronic middle ear and mastoid inflammatory changes were evident. Radiological features of right Collet-Sicard syndrome (palsy of cranial nerves IX-XII) were also present. The appearances, particularly in relation to the skull base infiltration, had progressed significantly compared to 6 months earlier. Her pituitary hormone profile showed elevated prolactin (1353 munit/L; upper limit of normal range = 496) and reduced thyroid-stimulating hormone (TSH) (0.23 munit/L) with normal free thyroxine. On further enquiry, she reported amenorrhoea for the past year.

She had not yet had any children and was keen to do this in the future. We therefore initially opted for treatment with rituximab over cyclophosphamide. She received Rituximab 1 g, with a plan for a second dose two weeks later. Methotrexate was replaced with Azathioprine. She also received one pulse of intravenous (i.v.) methyl prednisolone 500 mg, and her oral prednisolone was increased from 10 mg to 30 mg. Given her modest baseline immunosuppressive treatment, and because of the insidious presentation and lack of systemic features, at the time we felt this mid-range prednisolone dose rather than 1 mg/kg was reasonable. Her CRP fell to 6 mg/L and she was discharged from hospital.

She was seen as an emergency 10 days later. She had developed complete dysphagia to solids and liquids and was unable to manage even small sips of water. Both pupils were now dilated and reacted sluggishly to light, and she had a new right-sided ptosis, indicating a new right-sided third nerve palsy. She also had a new right-sided sixth nerve palsy. Assessment of her swallowing showed that she was aspirating and had an ineffective cough reflex. She was kept nil-by-mouth, and fed through a nasogastric tube. The safety of her airway was assessed by the anaesthetic and ENT teams because of concern that she was at high risk of life-threatening airway obstruction or aspiration should the vocal cord palsies become bilateral. Her CRP had risen to 33 mg/L.

A cranial magnetic resonance imaging (MRI) scan (Figs. 3 and 4a) confirmed the CT findings, and provided greater imaging sensitivity and specificity regarding the extent and severity of the osseus skull base infiltrative changes, the intracranial dural-based disease burden, and the cranial nerve palsies. Muscle atrophy due to denervation as a result of the latter was particularly well demonstrated. In addition, the MRI provided greater detail on the degree of hypothalamic-pituitary axis involvement, and allowed for subsequent imaging assessment of response to treatment.

She was treated with three pulses of i.v. methyl prednisolone 500 mg, with rapid improvement in her diplopia and normalization of the CRP. The right pupillary abnormality improved but the left pupil remained dilated (Fig. 5). Her oral prednisolone was increased to 60 mg, and she received three fortnightly doses of i.v. cyclophosphamide 750 mg (15 mg/kg) followed by three further doses at three-weekly intervals. Azathioprine was stopped. She also was given the second rituximab dose. She received topical mupirocin to reduce nasal Staphylococcus carriage and was started on oral co-trimoxazole both to reduce the risk of opportunistic infections and because this may reduce relapses in GPA [10]. Her swallowing remained compromised and she remained an inpatient for ongoing feeding via the nasogastric tube. Subsequently a percutaneous gastrostomy tube was inserted.

Her admission was complicated by hypernatraemia with serum sodium rising to 157 mmol/L. She required 4–5 L of fluid per day to maintain her sodium level in the normal range. She had two episodes of syncope due to postural hypotension. Her fluid balance chart revealed polyuria. Blood glucose and calcium were normal. Repeat dedicated pituitary MRI showed pathological enhancement and diffuse thickening of the pituitary (Fig. 4 b&c). She was diagnosed with cranial diabetes insipidus and treated with desmopressin, with normalization of her serum sodium. She was discharged home with feeding via the gastrostomy tube.

After six pulses of cyclophosphamide, she showed marked clinical improvement. Her diplopia had resolved and eye movements had returned to normal. She was able to eat and drink normally. Her right-sided third nerve palsy had entirely resolved. Her left pupil remained dilated and reacted sluggishly to light, and a mild left facial weakness persisted. A further cranial MRI showed marked regression of the inflammatory changes in the skull base (Fig. 6). She was switched to maintenance therapy with azathioprine, and the prednisolone dose was slowly weaned to 5 mg daily. She remained clinically well on this treatment, with no progression of cranial disease on MRI, for 20 months following completion of cyclophosphamide. At this point, she had a relapse of ENT disease with nasal blockage and epistaxis requiring a tapering course of prednisolone 30 mg daily.

Our patient first presented with localised GPA confined to the nasopharynx and ear. Despite initial treatment with full-dose methotrexate and steroids, her disease progressed. She developed the unusual complications of extensive cranial nerve palsies (involvement of nerves II-IV, V₃, and VI-XII) and diabetes insipidus due to granulomatous infiltration of the skull base.

Our report highlights several learning points. First, it demonstrates that localised GPA can be aggressive and result in serious morbidity. Assessment of disease severity is a key aspect of the management of AAV since it guides treatment decisions [5, 6]. Disease severity can be classified as life-threatening, organ-threatening (i.e. disease that will result in permanent tissue damage and/or loss of function unless appropriately treated), or non-organ threatening. Although our patient had anatomically localised cranial GPA, she developed organ-threatening disease with severe progressive cranial nerve involvement as a result of compression by inflammatory tissue. This included a vocal cord palsy, which resulted in dysphonia. If she had not been treated promptly, this could have become bilateral which can lead to life-threatening airway obstruction [11]. Glossopharyngeal, vagus and accessory nerve palsies resulted in severe dysphagia necessitating nasogastric feeding.

Second, this case illustrates central nervous system (CNS) manifestations of GPA, including the rare complication of cranial diabetes insipidus due to pituitary infiltration and compression. In contrast to peripheral nerve involvement, CNS disease in GPA is uncommon. In a European cohort of 128 GPA patients, 56 patients (44%) had peripheral neuropathy (either symmetrical polyneuropathy or mononeuritis multiplex), whilst only 9 patients (7%) had CNS involvement, of whom 6 had cranial nerve palsies [12]. CNS involvement occurred in 8% of cases in a cohort from the National Institutes of Health (NIH) [13], and cranial nerve palsies occurred in 21 of 324 patients (6%) attending the Mayo Clinic [14]. CNS disease in GPA is proposed to develop by three distinct but sometimes co-existing mechanisms [15]: by contiguous spread of granulomatous tissue from adjacent sites in the middle ear and sinuses (as in our patient), by primary granuloma formation within the CNS, or from vasculitis affecting the CNS. Seror et al. described three patterns of GPA-related CNS disease: chronic hypertrophic pachymeningitis, pituitary gland involvement, and cerebral vasculitis [16].

Yokoseki et al. reported a series of 36 patients with hypertrophic pachymengitis, of whom 17 had ANCA against MPO and 4 against PR3 [17]. Although the number of PR3 positive patients was small, this study found a higher frequency of pulmonary and renal disease in PR3 positive cases than in MPO+ cases, and that leptomeningeal and parenchymal involvement in the brain were more common in PR3 positive hypertrophic pachymeningitis compared with MPO positive and idiopathic hypertrophic pachymeningitis. In the presence of leptomengingeal AAV, cerebrospinal fluid analysis may reveal elevated protein and pleiocytosis, but these findings are non-specific. Other causes of hypertrophic pachymeningitis include other immune-mediated diseases (e.g. sarcoidosis and IgG4-related disease), infections, and neoplasms (particularly lymphoma) [17]. Lymphoma mimicking GPA with positive PR3 antibodies has been described [18]. However, in our patient, the radiological picture and the clinical course were not consistent with lymphoma.

The third issue raised by this case is the wisdom of methotrexate treatment at the time of her initial presentation. The NORAM trial compared methotrexate with cyclophosphamide for the treatment of early, non-organ threatening systemic disease [23]. Whilst there was no significant difference in the primary endpoint of overall remission rates at 6 months, relapse rate at 18 months was higher in the methotrexate group, and there was delayed remission in the methotrexate group in patients with more extensive disease or pulmonary involvement. The lack of a difference between methotrexate and cyclophosphamide at 6 months might reflect the fact that patients in both treatment groups were still receiving steroids at this timepoint. Post-trial follow-up has revealed that patients in the methotrexate arm of the trial received more corticosteroids, cyclophosphamide, and other immunosuppressive agents than those in the cyclophosphamide group [24], indicating less effective disease control with methotrexate compared to cyclophosphamide induction therapy. In light of these data and our clinical experience, it is the authors’ personal view that methotrexate should be used for only the mildest cases of GPA, and we have a low threshold for switching to stronger immunosuppressive therapy in the face of active disease. This view is supported by the 2015 EULAR guidelines which reserve methotrexate for the treatment of non-organ threatening disease [6]. The EULAR guidelines specifically spell out that methotrexate is not suitable therapy for meningeal disease, or for nasal/paranasal disease with bony involvement, cartilage collapse or deafness, and thus do not support the use of methotrexate in this patient, even at the time of her initial presentation. The absence of pulmonary or renal disease and the perception that localised disease is benign may have contributed to her initial under-treatment, and the failure to escalate immunosuppression at her local hospital.

The final issue is the choice of rituximab versus cyclophosphamide. We initially opted for rituximab over cyclophosphamide to reduce the risk of infertility. However, in view of rapid clinical deterioration we commenced cyclophosphamide. The RAVE and RITUXIVAS studies both showed non-inferiority of rituximab compared to cyclophosphamide in AAV [25, 26]. However, the results from these trials cannot necessarily be extrapolated to our patient. In the RITUXIVAS trial all patients had glomerulonephritis. The RAVE study was not restricted to patients with renal involvement, but did not have any patients with cranial nerve palsies in the rituximab treatment arm. Nevertheless, case series suggest that rituximab can be effective in cranial GPA [27, 28]. It should be highlighted that rituximab has a relatively slow onset of action, and in retrospect our initial “bridging” steroid therapy (one pulse of 500 mg iv methyl prednisolone and 30 mg oral prednisolone) was insufficient. The patient improved markedly after we commenced high-dose corticosteroids and cyclophosphamide. For severe cases where rapid control of disease is necessary, this combination of cyclophosphamide and rituximab may be preferable to either drug alone. Indeed, in the RITUXIVAS trial i.v. cyclophosphamide 15 mg/kg was given alongside the rituximab doses in weeks 1 and 3 [26].

Pituitary involvement is a rare complication of GPA. It disproportionately affects female patients and tends to occur early in the disease course. Diabetes insipidus is the most commonly associated endocrinological abnormality. Our case report highlights that localised GPA is not necessarily indolent and that methotrexate may be inadequate treatment for localised disease. The presence of adverse features such as neurological involvement requires prompt recognition and aggressive therapy. Organ- or even life-threatening disease can occur in the absence of pulmonary or renal involvement. In this case a good outcome was achieved with high-dose steroid and dual treatment with cyclophosphamide and rituximab with minimal adverse events. In cases of severe neurological compromise due to GPA where a rapid therapeutic effect is required, such combination therapy may be a useful strategy. Finally, such cases should be managed by a multi-disciplinary team in a tertiary referral centre.