Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic necrotizing vasculitides that affect predominantly small vessels such as capillaries, venules, and arterioles. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). It is more common in those aged over 60 years males, especially in East Asiaz [1]. The clinical manifestations of AAV largely depend on the affected vasculature. The lungs, kidneys, and skin are typically affected organs [2]. CNS manifestations have rarely been reported [3] in patients with AAV. A few cases have demonstrated stroke, hypertrophic pachymeningitis, massive intracerebral hemorrhage (ICH), SAH, and spinal SAH [4, 5] in MPA. EGPA presents with four distinct neurological characteristics, including cerebral ischemic lesions, ICHs, cranial nerve palsies, and loss of visual acuity [6]. CNS involvement is characterized by pachymeningitis, cerebral ischemic lesions, hemorrhagic lesions, and hypophyseal lesions in patients with GPA [7]. Here, we report a patient who presented with SAH as the initial symptom of MPA and who experienced a relapse of SAH. We also reviewed the clinical characteristics of 34 previously reported cases of AAV with SAH.

Case presentation

A 31-year-old male with a 2-day history of acute headache and fever was admitted to our department. He complained of “tearing” back pain following a sudden sneeze, neck rigidity, and diffuse back pain, preventing him from lying down. The patient had no history of trauma or hypertension. Physical examination revealed blood pressure of 123/83 mmHg and a regular pulse rate of 82 beats/min. The patient had nuchal rigidity with positive Kernig’s and Brudzinski’s signs. Laboratory examinations revealed a white blood cell (WBC) count of 13.22 × 109/L (normal range: 3.5–9.5 × 109/L), a hemoglobin level of 151 g/L, and a platelet count of 293 × 1012/L. Urinalysis showed proteinuria (24-h urine protein 5.9 g), microscopic hematuria (urine sediment red blood cells 254.0/μL), and cast (pathological renal tubules of 1.0/μL). The creatinine level was 115.0 μmol/L (normal range: 57–97 μmol/L), eGFR level was 72.6 mL/min, with an increased erythrocyte sedimentation rate (ESR) of 34 mm/H (normal range: 0–20 mm/H) and a slightly increased C-reactive protein (CRP) of 12.7 mg/L (normal range: 0–10 mg/L). The tests revealed a positive p-ANCA and an elevated myeloperoxidase-ANCA (anti-MPO) level of 3.26 (normal range: normal < 1). Pulmonary computed tomography (CT) scan revealed multiple focal emphysema in bilateral lungs, bullae, and tiny ground-glass nodules in the lower lobe of the right lung. Brain CT and magnetic resonance imaging/magnetic resonance angiogram did not show bleeding, aneurysm, or malformation. A lumbar puncture revealed bloody cerebrospinal fluid (CSF) (Fig. 1a), with a pressure of 180 mmH2O, elevated protein of 2708.8 mg/L, a glucose level of 0.79 mmol/L, whereas blood glucose level of 4.1 mmol/L, chloride level of 121.0 mmol/L, red blood cell of 52,200 × 106/L, and normal WBC count. Cerebrospinal fluid x-pert and metagenomic next-generation sequencing (mNGS) were negative, ruling out the presence of CNS infection. He was diagnosed with SAH.

Fig. 1
figure 1

a Cerebrospinal fluid examination showed bloody fluid at the visit. b Xanthochromia in the cerebrospinal fluid was detected after treatment

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Seven years earlier, the patient presented with a severe headache and vomiting. On examination, his blood pressure was 135/75 mmHg, and his pulse rate was 78 beats/min. Laboratory testing showed an increased CRP of 53.9 mg/dL and an ESR of 70 mm/h. Urinalysis showed microscopic haematuria (2 +) and proteinuria (1.78 g/24 h). Emergent cranial CT revealed SAH, and cerebral digital subtraction angiography was performed, which did not reveal any aneurysms or arteriovenous malformations. Based on his positive MPO-ANCA and renal biopsy findings with pauci-immune necrotizing glomerulonephritis and tubulointerstitial inflammation (Fig. 2), a diagnosis of MPA was made, in accordance with 2012 revised International Chapel Hill Consensus Conference Nomenclature of vasculitides [8]. The patients’ spontaneous intracranial SAH was attributed to MPA. He was administered prednisone (60 mg/day) combined with intravenous pulse CTX administration for 6 months and then switched to mycophenolate mofetil (MMF 1.0 g/day) for maintenance immunosuppression. The patient achieved complete remission in 12 months with normal urinalysis and serum creatinine level without neurologic sequelae.

Fig. 2
figure 2

Renal biopsy showed global (4/23) or segmental (6/23) glomerulosclerosis, focal segmental necrotizing glomerulonephritis with endocapillary lesions, fibrocellular crescents (10/23), and accompanied by marked tubulointerstitial inflammation

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In conjunction with the medical history of the patient, the recurring symptoms of fever and an increase in the urine protein, ESR, CRP, and MPO-ANCA were attributed to active vasculitis. The patient was given intravenous methylprednisolone (0.5 g) daily for 3 days and then tapered to oral prednisone at a dose of 1 mg/kg/day combined with nimodipine and analgesic therapy, followed by an intravenous injection of 0.8 g CTX. His symptoms were relieved within 2 weeks. The second lumbar puncture showed yellow cerebrospinal fluid (Fig. 1b), a pressure of 120 mmH2O, protein of 1056.3 mg/L, glucose level of 3.47 mmol/L, chloride level of 111.0 mmol/L, and normal WBC count. The patient was discharged from the hospital with no neurological symptoms. During the 6-month follow-up, the patient was treated with intravenous CTX every month with prednisone tapering to 10 mg/day. The patient was in good condition, and all symptoms except proteinuria had resolved.

Literature review

The review is based on a literature search of PubMed, Web of Science, and Embase databases up to December 2021. The following MeSH terms or keywords were used: “microscopic polyangiitis,” “granulomatosis with polyangiitis,” “Churg-Strauss syndrome,” “eosinophilic granulomatosis with polyangiitis,” “anti-neutrophil cytoplasmic antibody-associated vasculitis,” and “subarachnoid hemorrhage” without language restrictions. Case reports and case series of patients with the diagnoses of AAV and SAH were eligible for inclusion. Publications were excluded if they did not meet the above criteria, if AAV overlapped other connective tissue diseases, or if they were review articles with no clinical case reports. Our literature review identified 143 citations, 73 were not relevant, and 37 were duplicate records. Ultimately, we included 33 reports with 34 cases.

Discussion

The clinical presentation of AAV depends on the affected vessels, with mostly kidney and lung involvement. Mononeuritis multiplex [1] is the most frequent neurological manifestation of AAV. In contrast, CNS involvement is uncommon, with 5–15% in AAV [9] and 2–8% in MPA [10], including cerebrovascular events, such as hypophysitis, posterior reversible encephalopathy syndrome, isolated mass lesions, hypertrophic pachymeninges, and spinal cord lesions [11]. A retrospective study found that cerebral ischemic lesions were the main manifestations in Chinese patients with AAV [12]. The co-occurrence of AAV and SAH is uncommon and has not been fully elucidated. We describe a rare manifestation of MPA in a young man who presented with relapsing SAH. The patient had no history of hypertension, aneurysm, or arteriovenous malformations, without an increased risk of SAH. SAH was considered to be due to active vasculitis. He received a glucocorticoid pulse and intravenous CTX in combination with decreasing intracerebral hemorrhage (ICH) therapy, achieving remission at follow-up.

A noncontrast CT scan is a sensitive method to identify patients with subarachnoid hemorrhage. But CT imaging depends on patients presenting within 6 h of onset of acute headache and exhibits inadequate sensitivity to detect spontaneous SAH [13]. Lumbar puncture has been found to show evidence of hemorrhage in 3% of patients with a normal head CT [14]. Four of the 34 cases with negative CT were confirmed to have SAH using a lumbar puncture.

Interestingly, the patient showed lower glucose levels in CSF, which frequently accompany intracranial infection. However, an extensive evaluation, including mNGS of CSF, excluded the diagnoses of infection. Hypoglycorrhachia in CSF following SAH has seldom been reported and is associated with multiple reasons [15]. Alterations in the carrier transport system of glucose in and out of the CSF, caused by diffuse meningeal inflammation, increase anaerobic glycolysis. Vasospasm accounts for a decrease in CSF glucose levels.

We reviewed the literature and summarized the clinical characteristics and treatment of 34 cases with SAH (Table 1). Among the 34 cases, six were attributable to MPA, eight to GPA, 19 to EGPA, and one to unclassified AAV. Their ages ranged from 17–85 years, and 55.9% of them were women. The disease duration was up to 20 years. Three patients presented with SAH as the initial symptom of AAV. Three patients experienced a recurrence of SAH. Nephritis was the major non-CNS system disorder in MPA. EGPA was associated with more concomitant peripheral neuropathy. Renal and pulmonary manifestations were more common in patients with GPA and SAH. Ruptured saccular aneurysms are the main cause of nontraumatic SAHs [12]. As illustrated by the cases, only ten patients with aneurysmal SAH and two patients with intracranial artery dissection had similar incidences in different types of AAV. All the cases appeared to have evidence of active vasculitis, organ or life-threatening features, including active glomerulonephritis, progressive peripheral or cranial neuropathy, and gastrointestinal and cardiac disease due to vasculitis. Other manifestations included arthritis, myalgia, rhinosinusitis, skin vasculitis, pulmonary nodules, and asthma. They were accompanied by enhanced high-titer ANCA, elevated inflammatory factors, or increased eosinophilic granulocytes.

Table 1 Clinical characteristics and treatment of previously reported AAV patients with SAH
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Patients with concomitant other CNS manifestations or cardiac abnormalities contributed substantially to the overall mortality. Ten patients had one or more cerebrovascular events, one with combined idiopathic late-onset cerebellar ataxia, two with cerebral infarction, six with ventricular hemorrhage, two with occipital hematoma, and spinal epidural hematoma in one patient. Cardiac abnormalities were observed in six patients with AAV and SAH, with four cases causing lethality.

SAH is often associated with a poor outcome, with a mortality rate of over 50%, irrespective of treatment [12]. In the case series, all patients with SAH had a mortality rate of 38.2%. Thirty-one patients were treated with glucocorticoids, and 18 patients also received immunosuppressive therapy. CTX was the most commonly used immunosuppressant. Three patients received rituximab (RTX) treatment and achieved remission. Patients with SAH benefited from combined therapy with corticosteroids and immunosuppressants. All cases of AAV with SAH had a mortality rate of 38.2% and benefited from combined therapy with corticosteroids and immunosuppressants. However, the data demonstrated that concomitant cerebrovascular events or cardiac involvement in patients with AAV and SAH could progressively deteriorate the prognosis with a mortality rate of 64.3%.

Conclusion

Our study suggests that SAH is a rare severe manifestation and associated with active AAV, which should be considered in patients with AAV due to the high rate of fatality, even in patients with a negative CT scan. Early diagnosis and immunosuppressive therapy are crucial to achieving a favorable prognosis.