Subarachnoid Hemorrhage in Wegener Granulomatosis: A Case Report and Review of the Literature J. Douglas Miles, MD, PhD, Laurie McWilliams, MD, Wendy Liu, MD, PhD, and David C. Preston, MD
Wegener granulomatosis (WG) is an uncom-
• Wegener granulomatosis (WG) is an uncommon disease whose symptoms arise as a result of granulomatous inflammation and of vasculitis involving small and medium-sized vessels. Any organ system can be affected, but involvement of the respiratory tract and kidneys is typical. Specific symptoms depend on the location of the vasculitis and granulomata. • The nervous system is frequently affected in WG. Vasculitis of the vasa nervorum often produces mononeuritis multiplex. Granulomata in the upper respiratory tract may extend, causing involvement of the central nervous system (CNS) or cranial nerves. Rarely, granulomata may occur within CNS structures and vasculitis within the CNS is rare. • Subarachnoid hemorrhage is a rare complication of WG. The etiology of subarachnoid hemorrhage in the setting of WG is uncertain and usually not associated with a detectable aneurysm. • WG is fatal if untreated. The standard treatment is combined therapy with corticosteroids and cyclophosphamide. Less toxic agents may be substituted only after remission is established.
mon, idiopathic disorder that is characterized by granulomatous inflammation of the upper and lower respiratory tract, disseminated vasculitis involving small and medium-sized vessels, and focal segmental glomerulonephritis. Approximately 25% to 50% of patients have nervous system involvement. The brain is less frequently involved. We report a case of a 74 year-old previously well woman who presented with rapidly progressing WG that culminated in subarachnoid hemorrhage. Only six cases of subarachnoid hemorrhage in the setting of WG have previously been reported. We review the common presenting signs and symptoms, diagnosis, treatment, and complications of WG.
Dr. Miles is assistant professor in the Department of Neuroscience at the Marshall University Joan C. Edwards School of Medicine in Huntington, WV. Dr. McWilliams is Neurocritical Care Fellow at the Neurological Institute at the Cleveland Clinic in Ohio. Dr. Liu is assistant professor in the Department of Pathology at the Case Western Reserve University in Cleveland, Ohio. Dr. Preston is professor in the The Neurological Institute at the University Hospitals Case Medical Center at Case Western Reserve University. Faculty Disclosures: The authors report no affiliations with or financial interest in any organization that may pose a conflict of interest. Date Submitted: May 19, 2010; Date Accepted: August 8, 2010; First published online: May 1 , 2011 . Correspondence: J. Douglas Miles, MD, PhD, Assistant Professor, Department of Neuroscience Marshall University Joan C. Edwards School of Medicine, 1600 Medical Center Drive, Huntington, WV, 25701; Tel: (XXX) XXX-XXXX, Fax: (XXX) XXX-XXXX; E-mail:
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INTRODUCTION Wegener granulomatosis (WG) is a granulomatous vasculitis that can affect any organ system and is characterized by involvement of the respiratory tract, kidneys, and a diffuse necrotizing vasculitis. The nervous system is often involved, with the peripheral nervous system affected more frequently than the central nervous system (CNS). Because of the protean nature of the disease, manifestations of nervous system vary greatly from person to person. Subarachnoid hemorrhage has been reported but is a rare complication. When treatment is initiated early, complete remission can be accomplished in the majority of cases of WG. A 74-year-old woman developed diplopia, otitis, a urinary tract infection, mononeuritis multiplex, and flu-like symptoms over the course of a month. Magnetic resonance imaging (MRI) of the head led to the finding of a nasopharyngeal mass, which on biopsy proved to be a granulomatous lesion, leading to the diagnosis of WG. Renal failure, which was felt to be part of her disease process, developed during hospitalization. She was started on appropriate treatment, but expired a few days later from a subarachnoid hemorrhage. Her case, the clinical and pathologic features, and the treatment of WG are discussed.
CASE REPORT We report a case of a 74-year-old female who presented to our hospital with tingling and numbness which began three weeks earlier in the left foot and gradually progressed to the left knee. She also complained of 11.5 weeks of constant vertical diplopia. The night prior to her hospital admission she developed dizziness and vomiting. She had previously been healthy except for a recent urinary tract infection, arthritis affecting the wrists, elbows, and shoulder, and otitis media one month prior to her admission. Pertinent positives on her review of systems included night sweats, fevers, chills, anorexia, cough, and a sore throat. On exam, she had a pulse of 104 beats/minute and blood pressure of 140/77 mmHg. There were multiple ulcerative lesions on the oral mucosa, and an erythematous left tympanic membrane. Mentation was normal. She had a left hypertropia with diplopia that worsened with upward gaze. Mild weakness was observed in the left lower extremity on knee extension, knee flexion and plantar flexion. She was unable to dorsiflex the left foot. Achilles and patellar reflexes were absent on the left. Sensation was decreased to pinprick, CNS Spectr 16:5
light touch, vibration, and temperature on the left lower extremity distal to the knee. On admission, her white blood cell count was 15 X 109/L, with 71.4% neutrophils and 6% eosinophils. Platelet count was 715 X 109/L. Serum creatinine was 1.1 mg/dL, serum sodium was 130 mmol/L, and blood urea nitrogen was 24 mg/dL. partial thromboplastin time and international normalized ratio were normal. C-reactive protein was elevated at 20.26 mg/dL, and erythroyate sedimentation rate was 73 mm/h. An antinuclear antibody panel was negative. An assay for antineutrophil cytoplasmic auotantibodies (ANCA) demonstrated a cytoplasmic staining pattern (C-ANCA), at a titer of 1:64. Proteinase-3 (PR3) was elevated at 53.0 u/mL. An assay for rheumatoid factor was positive, with a concentration of 234 IU/mL. Additional blood work included creatine kinase, complement 3, complement 4, and angiotensin-converting enzyme levels, which were within normal limits, and an assay for cryoglobulins, which was negative. Urinalysis on hospital day two was suggestive of a urinary tract infection. A urine culture obtained on hospital day two grew Methicillinresistant Staphylococcus aureus, and vancomycin was initiated as treatment. Microscopic analysis of the urine showed 21–51 red blood cells/highpower field. A lumbar puncture was performed, and evaluation of cerebrospinal fluid (CSF) showed leukocytosis, with up to 12 cells/mm3. Cytology showed reactive lymphocytes. CSF glucose and protein were normal. Bacterial cultures were negative. An MRI of the brain showed a soft tissue enlargement in the left nasopharynx, suggestive of a mass blocking the Eustachian tube. There was also opacification of the left mastoid air cells and left middle ear. An additional MRI of the orbits showed no parenchymal or leptomeningeal enhancement or restrictive process of the muscles. An MRI of the spine was unremarkable. Chest X-ray showed blunting of both costophrenic angles, a 5.5 x 2.8 cm pleural-based right apical density, thickening involving the left apical region, and evidence of focal infiltrate. A transthoracic echo showed no vegetations. A nerve conduction study and needle electromyography were performed on the patient’s third day in house. The findings were consistent with mononeuritis multiplex. A biopsy of the nasopharyngeal mass revealed necrotizing granulomatous inflammation (Figure). Stains for acid-fast bacili and gomori methenamine silver were nega-
tive. The patient was placed on corticosteroids and cyclophosphamide. By hospital day seven, the patient’s serum creatinine had risen to 1.9 mg/dL. Urinalysis obtained on hospital day eight showed mild proteinuria (30 mg/dL), granular and hyaline casts. A magnetic resonance angiography of the kidneys and a Doppler ultrasound were performed. Both were unremarkable. The Nephrology service was consulted, and their impression was that the renal failure was due to the patient’s systemic necrotizing vasculitis. By hospital day 10, the renal failure was improving, and the patient was discharged to a skilled nursing facility. Three days after discharge, she was found with depressed mental status. She was taken to
an outside hospital, where a head CT revealed a subarachnoid hemorrhage in the brain stem, extending into the foramen magnum. Hemorrhage was also present in the third ventricle, fourth ventricle, and the atrium of the lateral ventricles. Hydrocephalus was also noted. She expired hours later and an autopsy was not performed.
DISCUSSION WG granulomatosis is an uncommon disorder characterized by the triad of necrotizing granulomatous inflammation of the upper and lower respiratory tract, disseminated necrotizing vasculitis, and focal segmental glomerulonephritis.1-5 It is the most common pulmonary granulomatous vasculitis.6 It can occur at almost any age, but most com-
Biopsy speciemn showing granulomatous inflammation H&E stain
The left pharyngeal mucosa is ulcerated. On the upper left corner there are residual mucinous glands. The majority of this image is filled with granulomatous inflammation with basophilic central necrosis and mixed inflammatory infiltrate. Vasculitis with neurophils is also present. H&E-hematoxylin and eosin. Miles JD, McWilliams L, Liu W, Preston DC. CNS Spectr. Vol 16, No 5. 2011.
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monly affects adults between 50–60 years of age. The incidence is equal in men and women7 and caucasians are the most frequently affected ethnic group. It is closely related to Churg-Strauss disease and microscopic polyangiitis.8 All three diseases are associated with ANCA.9 The diseases are differentiated by clinical presentation. In Churg-Strauss disease, asthma, eosinophilia, and granulomatous inflammation are present. In WG, granulomatous inflammation is present but asthma is not. Neither asthma nor granulomatous inflammation are present in microscopic polyangiitis. These diseases virtually always affect small vessels, such as arterioles, capillaries, and venules, and often affect arteries as well.9 Vessels in any organ systems can be affected10 and presentation will vary depending on which organs and tissues are involved. Patients with WG often present with systemic signs and symptoms, such as fever, myalgias, arthralgias, malaise and a flu-like syndrome.9,11 Skin changes, such as tender erythematous nodules, ulcerations, focal necrosis, and livedo reticularis may occur. Ocular manifestations occur in 28% to 58% of patients, 12,13 and all patients should receive a complete ophthalmic evaluation. Necrotizing vasculitis may also affect the viscera. Respiratory tract disease is part of the classic presentation of WG and is seen in >90% of patients.9 Sinusitis, oral lesions, otitis, and hearing loss may result from involvement of the upper respiratory tract.12 Pulmonary manifestations range from focal infiltrates to fatal pulmonary hemorrhage, and some form of pulmonary involvement is eventually seen in 85% of patients.7 Approximately 80% of patients develop glomerulonephritis, 9 which is also one of the classic hallmarks of the disease. Even with appropriate therapy, chronic renal disease may result.12 Limited forms of the disease may lack renal involvement.11 Initial reports 14,15 suggested that the nervous system is directly affected in about half of the cases of WG, but more recent studies suggest that if diagnosis is made early and treatment started promptly, nervous system involvement occurs only in ~25% of cases.2,16,17The peripheral nervous system is involved much more frequently than the CNS, and the most common manifestation is a mononeuropathy multiplex caused by small vessel vasculitis and ischemia of the vasa nervorum of peripheral nerves.9 The brain is less commonly involved, and consequent subarachnoid hemorrhage has been documented but is rare.2,3,14,18,19 CNS Spectr 16:5
Drachman14 observed that there are three mechanisms by which WG can affect the nervous system. Granulomatous lesions from the nasal or paranasal sinuses may expand, thereby invading nervous system structures. Granulomatous encroachment upon cranial nerves II, III, IV, or VI is a common example. Invasion of vestibuloauditory structures may produce sensorineural deafness or vertigo. Other cases of contiguous spread may result in basal meningitis. In rare cases, spread to the pituitary can cause diabetes insipidus. The second mechanism Drachman14 observed is the development of granulomata in regions remote from the nose and sinuses, such as within the meninges, brain, skull, or cranial nerves. Neurologic deficits reflect the structures involved. This phenomenon occurs less frequently than contiguous spreading. Intracerebral granulomata have been found on autopsy, but are rare. Drachman’s third mechanism is vasculitis of nervous system structures.14 This is the most common mechanism of nervous system involvement, occurring in 28% of cases of WG. A common example is the development of inflammation of the vasa nervorum, resulting in neuropathy. Drachman14 suggests that this may be the responsible etiology of these rare cases in which subarachnoid hemorrhage, intracranial hemorrhage, or ischemic stroke complicate WG. Drachman14 also noted that headaches may result from destructive sinusitis, and seizures, mental status change, and coma may be seen in those patients who develop uremia secondary to WG. Musculoskeletal complaints are prominent in up to 67% of patients7 and myopathy may develop as a result of necrotizing vasculitis in the muscles.9 Subarachnoid hemorrhage in WG has been previously described,2,3,14,19,20 but it is a rare complication of this uncommon disease. Estimates of the prevalence of WG range from 24 to 157 cases/million persons.20 Despite the relatively large number of people with this disease, our patient is only the seventh reported to suffer a subarachnoid hemorrhage in the setting of WG and the first reported female (Table). A commonly reported feature of subarachnoid hemorrhage in WG is the lack of obvious abnormality in the cerebral vessels. The patient described by Drachman14 was found at autopsy to have inflammatory cells infiltrating the walls of a branch of the anterior cerebral artery. Takei and colleagues3 confirmed the presence of an aneurysm at the origin of the anterior choroid artery, and that is the
only known case of an aneurysm in patient with WG who suffered a subarachnoid hemorrhage. In all of the other documented cases, the source of hemorrhage was not identified. Tuhy and colleagues18 note that in their patient, no aneurysm or rupture of the vessels was visible on autopsy. Venning and colleagues2 described two cases who survived, each with a normal 4-vessel angiogram. During our patient’s initial hospitalization, an MRA did suggest an aneurysm in the precavernous segment of the right internal carotid artery, but as her subarachnoid hemorrhage was located within the posterior cranial fossa, it is unlikely that these were related. Venning and colleagues2 observed that 15% to 27% of subarachnoid hemorrhages are idiopathic,21-24 and that limited forms of WG may occur.11 They further note that in most cases of subarachnoid hemorrhage in the setting of WG, an aneurysm is never found.3 They postulate that some proportion of angiogram-negative subarachnoid hemorrhages may actually be due to “occult” vasculitides, including WG. Another hypothesis is proposed by Takei and colleagues.3 They suggest that subarachnoid hemorrhage in WG may result from rupture of an aneurysm too small to be seen on angiography, or that is obliterated upon rupture. They further suggest a theoretical chain of events by which this may
occur. The release of PR2 and human leukocyte elastase (HLE) by polymorphonuclear neutrophils (PMNs) has been noted in animal models of WG and these substances are thought to be integral to the pathogenesis of the disease. They are also felt to be important in the development of an aneurysm. Takei and colleagues 3 surmise that PMNs adhering to the endothelium may release PR3 and HLE, which then proceed to destroy the internal elastic lamina and arterial smooth muscle cells, resulting in an aneurysm. The patient described by Drachman underwent autopsy, during which “a vessel damaged by inflammation was found in the center of an area of subarachnoid hemorrhage.” Infiltration of the vessel wall by inflammatory cells was noted on microscopic examination, seemingly consistent with the proposed mechanisms of Takei and colleagues. 3 It is unlikely that such a lesion would be obvious on angiography and if typical of subarachnoid hemorrhage in WG, may suggest why a source of bleeding is usually elusive. It must be emphasized however, that the only other autopsy performed in a case of subarachnoid hemorrhage in the setting of WG did not reveal any vascular lesion, 18 and Drachman’s autopsy was performed months after the patient’s hemorrhage. It is unclear, therefore, what can be inferred from this one finding.
Summary of Documented Cases of Subarachnoid Hemorrhage in WG Author(s)
Tuhy et al (1958)18
Fatigue, cough, arthralgias, weight loss
Antibiotics for presumed tuberculosis
Death from SAH
Chronic rhinitis, persistent skin ulcers
Death attributed to cardiac arrhythmia
Venning et al (1991)2
Epistaxis, nasal discharge, nasal polyp
Cyclophosphamide and corticosteroids
Venning et al (1991)2
Weight loss, hemoptysis, night sweats
Cyclophosphamide and corticosteroids
Cruz and Segal (1997)19
Cyclophosphamide and corticosteroids
Takei et al (2004)3
Recurrent nasal obstruction
Aneurysm clipped; cyclophosphamide and corticosteroids
Miles et al (2010)
Paresthesias, diplopia, dizziness
Cyclophosphamide and corticosteroids
Death from SAH
Miles JD, McWilliams L, Liu W, Preston DC. CNS Spectr. Vol 16, No 5. 2011.
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Fortunately, since the advent of effective treatment, most patients with WG–even those with subarachnoid hemorrhage–do not come to autopsy. Given the very rare incidence of this complication, it is unlikely that a definitive explanation for its etiology will be determined in the near future. At this time, WG remains a clinicopathologic diagnosis.10 At least two of the following four findings are required for diagnosis: Urinary sediment with either red cell casts or >5 red blood cells per high-power field, abnormalities on chest radiograph, oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. An alternative diagnostic scheme, using a classification tree, may also be used, and has comparable specificity and sensitivity. Laboratory testing for ANCA is usually positive, but is not required for diagnosis.25
CONCLUSION WG was once considered a uniformly fatal disease.5,6,14,26 Fauci and Wolf27 described an effective combination treatment of corticosteroids and cyclophosphamide, which has dramatically improved survival, resulting in complete remission in 75% to 93% of cases.7,16 For active cases of WG, recommended therapy includes intravenous methylprednisolone 7 mg/kg/day for three days, followed by an oral prednisone taper. Cyclophosphamide should be given simultaneously, and is usually given in oral form at 2 mg/kg/day. Patients may need treatment with these agents for up to two years before complete remission is attained.12 The mean time required is 1 year. Steroids and cyclophosphamide both carry risks of potentially serious side effects. Less toxic regimens have been suggested for remission induction in less serious cases,6 and vary based on the extent of disease. Mubashir and colleagues26 observed that once remission has been established, less toxic agents may be substituted to prevent relapse. Among the agents they recommend are methotrexate, mycophenolate mofetil, leflunomide, or azathioprine. CNS
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