Wegener granulomatosis (WG) is a granulomatous, necrotizing, small-vessel vasculitis. The etiology of this rare disorder is unknown, although its close association with antineutrophil cytoplasm antibodies (ANCA), present in about 90% of patients, strongly suggests an autoimmune mechanism. Initially described as a combination of ear, nose, and throat (ENT), lower airway disease, and pauci-immune extracapillary glomerulonephritis, WG is now recognized as a highly polymorphous, multisystemic disorder that also frequently affects joints, skin, eyes, and virtually any tissue or organ.
Neurologic involvement is not uncommon in WG, with reported frequencies ranging from 22% to 54% of patients3,20,21,23,36,63,74,94. In most instances, neurologic signs reflect peripheral disease, whereas WG-related central nervous system (CNS) involvement is much rarer3,20,21,23,36,63,74,94. According to previous studies, CNS involvement was observed in 7%-11% of WG patients20,21,36,63,74,94. Slightly higher CNS-involvement rates of 8%-18%3,23,36 were found when isolated cranial nerve palsies were also included in the spectrum of CNS symptoms.
To increase clinicians' awareness of this manifestation, we describe in detail 6 patients with WG-related CNS involvement and review the literature on this topic.
PATIENTS AND METHODS
The cases reported in this study were retrieved from our department's computerized database, where patients are registered who have been diagnosed as having primary systemic vasculitides, primarily based on clinical grounds. This accessible database includes patients who were followed in our institution and/or who had been enrolled in various multicenter therapeutic trials of the French Vasculitis Study Group, and contains their main baseline and outcome characteristics. In April 2003, when this study was launched, a database search yielded 80 patients with WG followed in our department. Among them, 6 had WG-related CNS disease at some time during the course of WG, including 1 reported in the pilot study on infliximab treatment of primary systemic vasculitides7; peripheral nerve involvement was recorded in 17 patients. For the purpose of this study, histories of these 6 cases of WG-related CNS disease were extracted upon review of medical files. In addition, we searched the MEDLINE-indexed (National Library of Medicine, Bethesda, MD) literature for publications on WG-related CNS disease by combining the term "Wegener granulomatosis" with each of the following terms: "central nervous system," "pituitary gland involvement," "meningitis," and "cerebral vasculitis."
In October 1999, a 54-year-old man was admitted for isolated frontal headaches. This patient had a history of undifferentiated vasculitis diagnosed 6 years earlier based on intra-alveolar hemorrhage and ANCA-positivity with perinuclear-labeling pattern (P-ANCA) in indirect immunofluorescence assay. From 1991 to 1993, he experienced several bouts of hemoptysis that culminated in September 1993 in an acute respiratory distress syndrome requiring mechanical ventilation. At that time, he also suffered from arthralgia and mononeuropathy multiplex. Under high-dose oral corticosteroids (CS) (1 mg/kg per day), the patient entered remission, while P-ANCA remained detectable. CS were tapered and stopped in 1995.
At admission, the patient reported a 6-month history of progressively persistent frontal headaches that were not relieved by analgesics. Physical examination was unremarkable. Laboratory investigations showed an erythrocyte sedimentation rate (ESR) of 15 mm/1st hour and P-ANCA with antimyeloperoxidase activity in enzyme-linked immunosorbent assay (ELISA). Computed tomography (CT) scan of the sinuses showed asymptomatic mucosal thickening leading to the diagnosis of WG. CT and magnetic resonance imaging (MRI) of the brain showed pachymeningitis of the tentorium cerebelli and falx cerebri (Figure 1A and B) with 3 ventricle hydrocephalus. Lumbar puncture was contraindicated because he was considered to be at risk of cerebellar tonsil herniation. Nine cyclophosphamide (CYC) pulses (0.6 mg/m2) were given, 1 every 3 weeks, leading to the disappearance of the headaches and partial attenuation of the MRI abnormalities. The patient was then started on azathioprine (1.5 mg/kg per day) and his WG course was unremarkable. In April 2002, the last of several brain MRI scans showed persistent gadolinium enhancement of the meninges (Figure 1C). In October 2003, the patient's status and imaging findings were unchanged under azathioprine (0.75 mg/kg per day) and CS (5 mg/d).
In January 2000, a 42-year-old man was admitted because of frontal headaches, dysarthria, numbness and weakness of the right hand. He had been diagnosed in 1982 with WG based on fever, weight loss, right maxillary sinusitis, bloody gingivitis, conjunctivitis, a pulmonary nodule on chest X-ray, and compatible changes on a nasal biopsy specimen. Under oral CYC (2 mg/kg per day), CS and hydroxychloroquine (600 mg/d), symptoms resolved only partially and, consequently, in April 1983, the CYC dose was increased to 3 mg/kg per day with adjunctive plasma exchanges. Patient's status improved but 4 months later, a second course of plasma exchanges was started because he developed seizures and behavioral disturbances that were suspected to be WG-related. The neurologic symptoms regressed, but 6 months later, an oroantral communication was detected and surgically repaired. In September 1985, the patient was in sustained remission and treatment was stopped. In March 1986, ENT symptoms recurred and CYC and CS were reintroduced. In May 1988, serology detected ANCA with a cytoplasmic-labeling pattern (C-ANCA). In 1990, development of a left orbital inflammatory pseudotumor led to reintroduction of CYC, CS, and plasma exchanges, followed by intravenous immunoglobulins and surgery, and then telecobalt irradiation. In June 1994, the pseudotumor was considered stable and treatment was discontinued, but it recurred in September 1996, with sensory loss involving the maxillary branch of the trigeminal nerve; long-term methotrexate (15 mg/wk) and CS were prescribed.
At admission, the patient complained of a 3-month history of headaches and recent onset of dysarthria, numbness and weakness of the right hand. ESR was 10 mm/1st hour, C-ANCA serology was positive with anti-proteinase 3 (anti-PR3) specificity in ELISA. Cerebrospinal fluid (CSF) analysis was normal and the electroencephalogram was consistent with subclinical left temporal epilepsy. Brain MRI showed pachymeningitis with diffusely thickened gadolinium-enhanced dura mater. Therapy combining CYC pulses (0.6 mg/m2) every 3 weeks, oral CS (1 mg/kg per day), and valproate initially provided relief of the symptoms. Six months later, during CS tapering, neurologic, ocular, and ENT signs recurred. CS pulses and CYC pulses (0.7 mg/m2) led to a complete disappearance of the neurologic signs, but the MRI, performed in January 2001, was unchanged. Subsequently, the patient suffered cornea perforation due to an eyelid closure defect, which required a corneal transplant and prompted replacement of CYC by mycophenolate mofetil (2 g/d) and repeated infliximab (3 mg/kg) infusions. In November 2001, another ENT flare was diagnosed, and, despite replacing infliximab with etanercept (50 mg/wk), the patient's deterioration continued, with paresis of the lower limbs and reappearance of seizures in January 2002. Brain MRI showed further meningeal thickening and cerebral thrombophlebitis. The patient's status did not improve markedly after reinitiating CYC pulses and anticoagulants. In July 2002, hydrocephalus required a ventriculoperitoneal drainage, and alemtuzumab and high-dose CS were prescribed. The patient died in August 2003 from intractable grand mal epilepsy. No postmortem examination was performed.
In November 2000, a 50-year-old woman was admitted for amenorrhea and galactorrhea of 6-months' duration. WG had been diagnosed in 1995 based on weight loss, polyarthralgia, crusty rhinitis, nasal septum necrosis, bilateral conjunctivitis, mouth ulcers, purpura of the lower limbs, positive C-ANCA/anti-PR3 and necrotizing granulomatous vasculitis with giant cells in a nasal mucosa biopsy. Methotrexate (15 mg/wk) and CS were started and led to symptom regression, but she subsequently experienced several minor flares with episcleritis and scleritis, and an orbital inflammatory pseudotumor developed. Methotrexate was then switched to CYC pulses (0.6 g/m2) every 3 weeks for 9 months, followed by oral CYC (1.5 mg/kg per day), both combined with CS. In December 1999, she was in stable remission, but ANCA remained detectable. At that time, she had sustained amenorrhea with high plasma levels of follicle-stimulating and luteinizing hormones suggestive of age-related or CYC-induced menopause.
At admission, the patient had galactorrhea and an otherwise normal physical examination. Laboratory tests revealed an ESR of 32 mm/1st hour and hyperprolactinemia. Although she did not have polyuria, a water deprivation test was performed and showed no increase of urine osmolality consistent with the diagnosis of diabetes insipidus (DI). An in-depth hormone workup indicated corticotropic, gonadotropic, and thyrotropic deficiencies. Brain MRI detected nodular enlargement of the pituitary gland (10 mm in diameter), with homogenous gadolinium enhancement and the loss of normal posterior lobe hyperintensity on T1-weighted images (Figure 2). Shortly thereafter, ENT and ophthalmologic signs recurred and CYC was switched to azathioprine (2 mg/kg per day) in combination with repeated infliximab (5 mg/kg) perfusions. Fifteen months later, she felt well while taking azathioprine (2.5 mg/kg per day), and no hormone-replacement therapy was necessary. Galactorrhea had disappeared but the MRI abnormalities persisted. In October 2003, the patient was in stable remission under azathioprine (2 mg/kg per day) and CS (5 mg/d), except for chronic minor episodes of bloody and crusty rhinitis.
A 41-year-old woman was admitted in January 2002 for polydipsia and polyuria. In 1987, WG had been diagnosed based on nasal obstruction, bloody-crusty rhinitis, septum necrosis, saddle-nose deformity, arthralgia, positive C-ANCA/anti-PR3 serology, and a nasal mucosal biopsy demonstrating necrotizing arteritis and granulomas without giant cells. She was started on oral (1.5 mg/kg per day) and subsequently intravenous (0.6 mg/m2 every 3 wk) CYC and CS (1 mg/kg per day) and achieved long-term remission except for several minor flares of ENT disease. CYC and CS were discontinued in 1993 and 1996, respectively, but the amenorrhea persisted. In November 1997, WG relapsed with episcleritis and a histologically proven extracapillary pauci-immune glomerulonephritis prompting the reintroduction of CYC and CS. The symptoms regressed and 6 months later, CYC was switched to azathioprine (1.5 mg/kg per day). In October 2001, she suffered another relapse with ENT symptoms, episcleritis, and renal involvement that was treated with intravenous immunoglobulins in combination with CS and azathioprine (2.5 mg/kg per day).
While on that regimen, the patient complained, in January 2002, of polydipsia and polyuria exceeding 5 L/d. The response to a water deprivation test with vasopressin was consistent with central DI. ESR was 20 mm/1st h, and serum pituitary hormones levels were normal. Brain MRI showed nodular enlargement and gadolinium enhancement of the pituitary gland extending to the floor of the 3rd ventricle. Immunosuppressive therapy was changed for repeated infliximab (5 mg/kg) infusions subsequently associated with methotrexate (15 mg/wk) because of recurring ENT symptoms. Polyuria and polydipsia disappeared with associated vasopressin substitution. In November 2002, the patient was symptom-free and started maintenance therapy with mycophenolate mofetil (2 g/d) alone. In July 2003, she experienced a disease flare with fever and polyarthralgia that responded well to low-dose CS (10 mg/d).
In 2000, a 57-year-old man was admitted for polydipsia and polyuria. In 1992, he suffered a transient ischemic attack of the middle cerebral artery and a left central retina artery occlusion. The etiologic workup was unremarkable and symptoms resolved completely with no specific treatment. In November 1998, the patient suffered a right central retina artery occlusion, peripheral polyneuropathy, acute ischemia of the left foot, and renal infarction associated with bilateral orchitis and arthralgia. Laboratory findings revealed positive C-ANCA/anti-PR3 serology, and a sural neuromuscular biopsy showed ischemic injury of the peripheral nerve but no vasculitis. Therapy with a monthly CYC pulse (0.5 g/m2) and CS was initiated, combined with anticoagulants. In December 1999, he developed cough, dyspnea, rhinitis, and gingivitis. CT scan disclosed mucosal thickening in the sinuses and bilateral pulmonary infiltrates with 5 cavitated nodules. The diagnosis of WG was corroborated by a surgical biopsy of a nodule showing granulomas, angiitis, and necrosis. A CYC pulse (0.6 mg/m2) every 3 weeks and CS were again prescribed. Throughout the entire disease course, ANCA remained positive. In retrospect, it was considered that the patient's earlier transient ischemic attack and left central retina artery occlusion were also related to WG.
In September 2000, the patient developed polyuria-polydipsia concomitant with enlargement, once again, of the pulmonary nodules. Laboratory analyses showed an ESR of 8 mm/1st h, panhypopituitarism, hyperprolactinemia, and a water deprivation test consistent with a diagnosis of DI. Brain MRI revealed heterogeneous enlargement of the pituitary gland (13 mm in diameter), with central necrosis and loss of normal posterior lobe hyperintensity on T1-weighted sequences. Replacement nasal vasopressin and L-thyroxine were prescribed, and immunosuppressive therapy with 15-deoxyspergualin was initiated in a therapeutic trial. Three months later, the patient's status deteriorated suddenly and aseptic neutrophilic meningitis was diagnosed. Concomitant intake of co-trimoxazole prophylaxis favored the hypothesis of falsely culture-negative bacterial meningitis. Deoxyspergualin was discontinued, and, after completing antibiotic therapy, CYC (2 mg/kg per day) and CS were started again. Subsequently, disease remission was obtained and maintained with azathioprine (2 mg/kg per day). MRI findings had returned to normal. In May 2004, the patient was well under co-trimoxazole (800/160 mg/d).
In August 2000, a 35-year-old man with no remarkable medical history presented with acute vomiting, headache, and diplopia. He complained of asthenia for about 6 months, and headaches starting 1 month earlier. Physical examination detected left abducens nerve palsy and cerebellar symptoms with multidirectional nystagmus. CT scan of the brain found a hematoma in the left lobe of the cerebellum with dilatation of all 4 ventricles. The hematoma was removed surgically. Histologic analysis of a cerebellar sample taken intraoperatively was consistent with granulomatous vasculitis with giant cells (Figure 3A and B); no caseous necrosis was detected, and Ziehl-Neelsen, periodic acid-Schiff, and Gomori-Grocott stainings revealed no microorganisms. CSF examination showed pleocytosis (15 cells/mm3) and elevated protein level (0.56 g/L). ESR was 36 mm/1st h. Tuberculosis skin test was positive with a 13-mm induration, but blood, sputum, urine, and CSF samples cultivated on Löwenstein-Jensen medium remained sterile. Antinuclear antibodies, rheumatoid factor, and ANCA were not detected.
One month postoperatively, the patient suddenly became comatose because of acute hydrocephalus requiring emergency insertion of ventriculoperitoneal drain. At that time, because of a presumed diagnosis of WG, intravenous CYC (0.6 mg/m2) and oral CS were prescribed and associated with isoniazid and rifampin. Three months later, although the patient had clinically improved with only minor persistent cerebellar signs, MRI showed a new T2-weighted hyperintense and gadolinium-enhanced left temporal tumor and frontotemporal T2-weighted hyperintense signal associated with no specific white matter lesions consistent with vasculitis (Figure 3C). CSF analysis revealed markedly increased pleocytosis (69 leukocytes/mm3), elevated protein level (0.90 g/L), and normal glucose level (4.2 mmol/L). Although cultures remained negative, this exacerbation was thought to be due to neuromeningeal tuberculosis. Consequently, immunosuppressants were stopped and tuberculosis therapy combining isoniazid, rifampin, ethambutol, pyrazinamide, and ofloxacin was started.
While taking this regimen, repeated brain MRIs were unchanged, but in February 2001, pulmonary CT scan visualized 3 pulmonary nodules. A surgical pulmonary biopsy was performed and showed periarterial, granulomatous inflammation without necrosis. Despite persistently negative ANCA testing, a definitive diagnosis of WG with pulmonary involvement and CNS angiitis was retained. Therapy combining oral CYC (2 mg/kg per day), CS, and preventive antituberculous agents (isoniazid, rifampin) led to rapid regression of pulmonary and cerebral lesions. Six months later, CYC was switched to long-term azathioprine (2 mg/kg per day) in combination with co-trimoxazole (1600/320 mg/d). In January 2003, remission was maintained with imaging showing only residual anomalies.
For the 6 cases reported here, the diagnosis of WG had been established based on the presence of-at some time during the disease course-ENT disease, lung involvement, and/or glomerulonephritis. Moreover, all 6 patients had histologic evidence of granulomatous inflammation, small and medium-sized vessel vasculitis, and/or positive ANCA serology (Table 1). The CNS manifestations observed were attributed to WG because they were present at disease onset or at the time of a disease flare also involving extracranial sites, other etiologies of CNS disease had been ruled out, and/or they had responded to sustained immunosuppressive therapy.
According to the seminal review of Drachman21, WG-related CNS disease is thought to be caused by 3 distinct pathogenic mechanisms. First, granulomatous tissue may spread out from the nasal or paranasal cavities and contiguously invade the adjacent structures, for example, orbit, optic nerve, chiasma, cranial nerves, meninges, and/or pituitary gland. The second, supposedly least frequent mechanism, refers to remote granulomatous intracerebral lesions of the brain, meninges, cranial nerves, or parietal bone. Third, vasculitis may affect the cerebral or spinal cord vessels. However, Drachman21 stressed that in up to 30% of the cases, CNS involvement may result from a combination of those pathogenic mechanisms.
In agreement with our findings and those reported in the literature, WG-related CNS disease can be categorized according to 3 predominant clinical patterns: chronic hypertrophic pachymeningitis (CHP), pituitary gland involvement, and cerebral vasculitis. CHP refers to an inflammatory thickening of the dura mater, which may also be seen in other illnesses, such as tuberculosis and sarcoidosis52. Other WG-related CNS diseases, for example, intracranial tumors67,80, have been described anecdotally. Some authors have also considered isolated cranial neuropathies among the WG-related CNS manifestations3,23, but because cranial nerves appear to be predominantly affected along their extracranial pathways3, this feature is not addressed here. The respective frequencies of these 3 main clinical patterns in the overall occurrence of WG-related CNS disease are difficult to evaluate. Based on large patient cohorts, cerebral vasculitis was the most frequently reported for about 4% of the patients3,63, with CHP20,23,36,63 and pituitary gland involvement20,23,36,63 occurring in less than 1%, but our findings suggest the opposite (Table 2).
Although CNS disease may arise at any time during the course of WG, it is thought to occur principally at later stages36. This finding fits fairly well with our observations of only Patients 5 and 6 having CNS involvement at disease onset. Conversely, the fact that ANCA had been detected in 5 of our 6 patients would not support the hypothesis of CNS involvement being a hallmark of ANCA-negative WG75.
Cerebral CHP was diagnosed in our Patients 1 and 2. Our literature review identified a further 33 detailed reports of WG-associated cerebral CHP3,4,11-13,26,28,35,39,41,60,62,64-66,72,75,76,79,81,83,84,88-90,97,99,100 and 5 other cases of WG-related CHP of the spinal cord2,43,54,61,64. In the publications reporting CHP, it was an initial manifestation of WG in almost 60% (19/33) of patients 3,4,11-13,28,35,62,64,72,76,81,88-90,99,100, a finding tempering the above-mentioned postulate of CNS disease being uncommon at disease onset4. As in our Patients 1 and 2, WG-related cerebral CHP was almost always (31/33) responsible for severe and usually analgesic-resistant chronic headaches3,4,11-13,28,35,39,41,60,62,64-66,72,75,76,79,81,83,84,88-90,100. In accordance with our observations, 40% (12/30) of the patients with CHP had no signs of active extracranial disease11,13,28,39,41,60,62,66,75,83,84,89. For about 50% of cases (18/33), CHP caused palsies mainly involving cranial nerve pairs III, V, VI, VII, and VIII3,4,11-13,28,35,39,62,64,72,79,88-90. Additional features, for example, seizures62,88-90,97, encephalopathy62, meningism12,66, and/or limb palsy13,62,66,81,88,97,100, were experienced by less than 25% of patients, whereas a single case of communicating hydrocephalus due to the impaired resorptive capacity of arachnoid granulations was reported79. All 5 reported cases of CHP of the spinal cord presented with paraplegia2,43,54,61,64.
For the 28 CHP cases for which lumbar puncture results were reported, CSF examination showed pleocytosis with lymphocyte predominance and/or elevated protein concentrations in about 70% (20/28)4,12,13,28,35,39,41,61,62,65,75,79,81,84,88,90,97,99,100. However, as suggested by our Patient 2's normal CSF, the poor relationship between CSF abnormalities and clinical or imaging CHP severity has been emphasized83. Imaging techniques, particularly MRI, which has proven to have higher sensitivity than CT14,57, provided the most valuable diagnostic contribution. For the 30 patients with detailed MRI findings, focal (16/30) or diffuse (14/30) thickening of the dura mater with enhanced gadolinium uptake60,72 was present. Meningeal biopsies taken from 20 patients3,12,13,28,39,41,62,64-66,75,79,83,89,90,97,99 showed inflammatory granulomatous changes in all cases (20/20), whereas features of associated vasculitis were observed in only 25% (5/20)62,66,75,97. Pertinently, CHP has also been described in granulomatous angiitis28, but not in polyarteritis nodosa21,87.
In the current study, our WG Patients 3, 4, and 5 were diagnosed with pituitary gland involvement, as in 24 previously reported cases1,8,9,16,17,19,27,29,31,34,37,42,48-51,56,77,78,85,93,98, that manifested as posterior lobe insufficiency resulting in central DI in 23/24 cases1,8,9,16,17,19,27,29,31,34,37,42,48,49,51,56,77,78,85,93,98. Diagnosis of central DI was confirmed by a 24-hour water deprivation test, yielding increased plasma osmolality and/or no increase of urine osmolality with both being corrected by vasopressin injection. Associated hyperprolactinemia, most probably via compression of the pituitary stalk, was diagnosed in our Patients 3, 4, and 5, and in 50% (6/12) of the previously reported cases17,19,34,42,56. Hyperprolactinemia also resulted in galactorrhea8 and, less frequently, amenorrhea. Our Patients 3 and 5 moreover had anterior pituitary failure of the thyrotropic, gonadotropic, and corticotropic axes. Based on 17 patients for whom complete hormonal workups had been undertaken, panhypopituitarism was found in almost 25% (4/17)9,27,50,77. Two other patients were described as having selective anterior pituitary deficiencies involving gonadotropic56 and thyrotropic29 functions. Visual disturbances, for example, bitemporal hemianopsia, were also uncommon features of pituitary gland involvement found in 17% (4/24)9,29,77,85.
In addition to laboratory investigations, MRI again had an important diagnostic contribution, although imaging could remain normal31. Reported MRI abnormalities included enlarged and gadolinium-enhanced pituitary gland19 and, inconstantly, the loss of the normal, posterior lobe hyperintense signal on T1-weighted sequences. Under successful treatment, serial MRI evaluations suggested that the pituitary gland usually returned to normal size within a short time42. Histopathologic studies of the pituitary glands yielded polymorphous inflammatory changes and/or granulomata with lymphocytes and plasma cells43,77,98. As for CHP, granulomatous inflammation would appear to be the predominant pathogenic mechanism implicated in WG-related pituitary gland disease70 and, pertinently, pituitary gland involvement in other vasculitides is uncommon6,33,40,51,73,91,92.
In contrast, CNS vasculitis, diagnosed in our Patients 5 and 6, is also a well-recognized feature of other primary systemic vasculitides23,58,87. In WG, CNS vasculitis has been held responsible for intracerebral or subarachnoid hemorrhages18, transient ischemic attacks, strokes82, cerebral infarctions, ischemic myelopathy75, and arterial or venous thrombosis32,55. Moreover, encephalopathy, seizures, altered consciousness, visual loss36, dementia, cortical blindness69, and cognitive impairment53 have been observed. Diagnosing CNS vasculitis is challenging, especially because of the difficulty of accurately distinguishing it from vascular atherosclerotic disease. Although brain MRI might visualize vasculitic disease with high sensitivity, these findings are nonspecific. The diagnostic input of cerebral angiography is presumably low because this technique is not able to visualize small-vessel disease accurately44,63,64. Consequently, the diagnosis of CNS vasculitis must also take into account indirect variables, such as active disease in extracranial sites and, eventually, response to immunosuppressive therapy. In the absence of extra-CNS symptoms requiring initiation or intensification of immunosuppressive therapy, diagnostic confirmation may be obtained by cerebral biopsy, as highlighted by our Patient 6.
Because of the lack of a specific hallmark, the diagnostic workup for CNS symptoms in patients with suspected or definite WG is often delicate. In a setting of CNS manifestations present at disease onset, it can be particularly difficult to distinguish WG from multifocal tuberculosis, and this situation prompted us to prescribe alternatively antituberculous and immunosuppressive agents for our Patient 6. Accurate discrimination between these 2 diseases might be all the more difficult since tuberculosis has been described as frequently associated with ANCA synthesis25,71, but those observations remain controversial86. CNS disease occurring during the course of WG also needs to be carefully evaluated to rule out infection. Our Patient 5 was diagnosed with a probable intercurrent culture-negative meningitis. A variety of other CNS infections, for example, progressive multifocal leukoencephalopathy10,15,22,59,68,95, cerebral toxoplasmosis, meningeal tuberculosis, and pyogenic brain abscess10, have been reported to occur during treatment for WG. Conversely, although solid tumors and lymphomas36,45 have been cited as other adverse events of WG therapy, we are not aware of any published case of CNS neoplasia.
Given the rarity and heterogeneity of WG-related CNS diseases, no recommendations exist for managing them specifically. Combining CYC and high-dose CS remains the mainstay of systemic WG therapy23,24,36,74, with recent data indicating that once disease remission is obtained, less toxic immunosuppressants, for example, azathioprine, might be a potent alternative to CYC38. In our cohort, CNS disease regressed in 3 of the 4 patients treated with CYC and CS. Conversely, for 4 patients, CNS manifestations developed under immunosuppressive therapy, thereby suggesting that CNS disease might not always be sensitive to immunosuppressants. No firm conclusions can be drawn from single publications describing treatment of WG-related CNS involvement with methotrexate31,42 or alternative agents, such as intravenous immunoglobulins98. Our Patients 3 and 4 achieved sustained good responses on infliximab, but it was ineffective in Patient 2, whose disease remained refractory to all administered agents. Moreover, the potential benefit of TNF blockage in WG7,46 was recently questioned by the results of a randomized trial suggesting no beneficial effect of routine addition of another anti-TNF agent, etanercept, to standard therapy96. The response of CNS manifestations to therapy should be monitored by clinical, laboratory, and imaging findings, while keeping in mind that MRI abnormalities may not completely disappear despite clinical recovery83.
Although these findings need to be interpreted in the light of follow-up from the onset of CNS manifestations, which did not exceed 3 years in any of our patients, all of our patients achieved prolonged clinical remission from CNS symptoms, and 1 patient died. For other primary systemic vasculitides, for example, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome, CNS involvement has been suggested as a predictor of shortened survival30, but its prognostic impact in WG remains unknown. Bajema et al5 postulated that CNS involvement might be associated with higher mortality, but that possibility is controversial47. Regarding the heterogeneous presentations, it can be hypothesized that the distinct patterns of WG-related CNS disease might carry different prognoses. Indeed, it has been emphasized that CNS granulomatous diseases might be characterized by a longer and rarely lethal course, whereas CNS vasculitis might reflect a more active or aggressive disease5. Pertinently, this theory is supported by the results of another study, whose authors postulated that the prognosis of systemic WG might depend on the respective contributions of granulomatosis and vasculitis to the disease phenotype10.
In conclusion, WG-related CNS involvement manifests in polymorphous but now well-characterized clinical pictures. Its accurate diagnosis requires clinical, laboratory, imaging, and eventually biopsy findings, with cautious exclusion of etiologies not related to WG, particularly infection. Further investigation is warranted to assess better the potential prognostic impact of this uncommon feature and, perhaps, to define specific therapeutic strategies for WG-related CNS involvement.
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