Anti‐neutrophil cytoplasmic antibody‐associated vasculitis with headache and stroke as the main symptoms: A case report

A 64-year-old male with a nearly 40-year history of migraine (2–6 attacks/month, lasting up to 1 day each time, symptoms relieved with oral nonsteroidal anti-inflammatory drugs NSAIDs) visited the Neurology Department due to intermittent low-grade fever for 6 months, numbness in the left limb for 55 days, and persistent headache for 50 days. On approximately Day −180 (for convenience of description, this article defines the day of admission to our hospital as Day 0, the number of days before admission is marked as "−", and the number of days after admission is marked as "+"), the patient had a recurrent fever (37.3–38°C) that was relieved by self-administration of oral NSAIDs, and he did not seek medical care. On Day −55, the patient experienced numbness in his left limb, and a new infarct lesion was found in the right thalamus via magnetic resonance imaging (MRI) (Figure 1A,B) at a local hospital, which was thought to be possibly secondary to small-artery occlusion. After being treated with "aspirin and atorvastatin," his symptoms improved. On Day −50, he suddenly developed an intolerable persistent headache with nausea and vomiting that was not relieved by NSAIDs. On Day −10, he presented with bilateral hearing loss and blurred vision in the left eye with intermittent fever and a maximum temperature of 38°C. Between Day −50 and Day −1, he visited 3 hospitals successively and underwent lumbar puncture and cranial imaging several times. The intracranial pressure was not high, the protein concentration in the cerebrospinal fluid (CSF) was slightly increased (51–135 mg/dL), and other routine and biochemical tests of CSF showed no abnormalities (Table 1). Cranial imaging revealed a new asymptomatic abnormal signal on the left side of the pons, which was considered a microhemorrhage (Figure 1H–J,L). Other biochemical and ancillary tests are presented in the relevant paragraphs below (Figure 2A–C and Table 2). In all three hospitals, central nervous system (CNS) infections were suspected and treated with "ganciclovir and ceftriaxone sodium," but the patient's symptoms were not relieved. He was admitted to our hospital for further diagnosis and treatment. The chronological course of the disease is shown in Table 2. There was no history of hypertension, diabetes, or atrial fibrillation. He had not smoked or consumed alcohol, and he denied any family history of similar diseases. Physical examination upon admission revealed bilateral bulbar conjunctival edema (more severe on the right side), decreased vision in the left eye (counting fingers), and bilateral hearing loss. His bilateral Babinski signs were positive. The remainder of his neurological examination was normal. On Day +10, the patient developed new vision loss in his right eye, and vision in the left eye worsened from counting fingers to observing hand movement. Bulbar conjunctival edema in both eyes was worse than before. The neurological examination showed some changes and some new neurological signs appeared. The left eye was closed loosely (mild), and the pupillary light reflex was abnormal. Specifically, the left eye had a slow direct light reflex and a sensitive indirect light reflex, whereas the right eye had a sensitive direct light reflex and a slow indirect light reflex. The distance from chin to chest was 2 finger widths. These findings suggested that the damage to the left optic nerve had worsened, and there was new damage to the left facial nerve and meningeal involvement. New identified asymptomatic abnormal signals on the left side of the pons, combined with follow-up imaging, were considered microhemorrhages (Figure 1H–J,L) Day 0 (hospitalization) Multiple diseases vs. single disease? Multiple diseases vs. single disease? Biochemical tests revealed that the white blood cell (WBC) count, blood neutrophil (NEUT) count, and D-dimer level (1.15 mg/L, reference value: 0-1 mg/L) were increased. Liver function tests showed total protein of 61.0 g/L (reference value: 65.0–85.0 g/L), albumin of 30.5 g/L (reference value: 40.0–55.0 g/L), and globulin of 30.5 g/L (reference value: 20.0–40.0 g/L). No noticeable abnormalities were observed in other biochemical examinations, such as routine urine values, renal function, urine protein quantification, or infectious indicator analyses (human immunodeficiency virus, hepatitis B, hepatitis C, syphilis, toxoplasma/rubella/cytomegalovirus/herpes viruses) and tumor marker levels. Repeated blood cultures during hospitalization were negative. The patient's WBC count (Figure 2A), NEUT count (Figure 2A), erythrocyte sedimentation rate (ESR) (Figure 2B), and C-reactive protein (CRP) (Figure 2C) persistently increased from onset until initiation of glucocorticoid therapy on Day +14, which suggested a persistent systemic inflammatory response. Calcitoninogen levels in the blood were normal. Laboratory tests related to rheumatism and immune diseases, including rheumatoid factor, serum protein electrophoresis, anti-streptococcal hemolysin "O" antibody, autoantibody profile, eight immune items, anti-cyclic citrulline peptide antibody, human leukocyte antigen B27, and anti-cardiolipin antibody, were completed. An anti-neutrophil cytoplasmic antibody (ANCA) test at another hospital that the patient visited before admission showed a positive anti-myeloperoxidase antibody (anti-MPO). Anti-proteinase 3 antibody, cytoplasmic ANCA (c-ANCA), and perinuclear ANCA (p-ANCA) tests were negative. After admission to our hospital, the ANCA was rechecked, and the results suggested that the anti-MPO concentration was 56.91 RU/mL (reference value: <20 RU/mL), the p-ANCA level was weakly positive, and the anti-proteinase 3 antibody and c-ANCA levels were negative. From the onset to the initiation of intravenous steroids, the patient underwent lumbar punctures six times; additionally, the protein concentration was mildly elevated (51.0–135.0 mg/dL), and no obvious abnormalities were found in the other indicators (Table 1). Three cytological examinations of CSF revealed no pathological cells. Microbial etiological examinations of CSF samples, including pathogenic microorganism next-generation sequencing, were performed three times, and no significant abnormalities were observed. In addition, no oligoclonal bands were found in the serum or CSF, and demyelinating disease-related antibodies in the serum and CSF were negative. From Day −55 to Day +10, the patient underwent cranial imaging examinations five times, and an old lesion (right thalamus, Figure 1A,B, red arrows) and three new lesions (right thalamus, Figure 1A,B, green arrows; left side of the pons, Figure 1H–J,L,Q–T,X, red arrows; right corpus callosum, Figure 1M–O,W, yellow arrows) were found successively. Magnetic resonance spectroscopy did not reveal a neoplastic lesion (Figure 1U,V). No significant enhancing lesions were observed on the cranial MRI enhancement scans (CE-MRI) (Figure 1W,X). All of the cranial imaging dynamic changes are shown in Figure 1. Cranial vascular examinations showed no significant abnormalities in the arterial or venous trunks. Medical records from other hospitals showed that the patient had persistent bulbar conjunctival hyperemia. An ophthalmologist at our hospital found a relative afferent pupillary defect in the left eye on Day +3. Flash visual evoked potential imaging showed that bilateral optic nerves were damaged. Other ancillary examinations did not suggest branch retinal artery occlusion (BRAO). Orbital noncontrast MRI and CE-MRI revealed a slightly increased signal in the bilateral optic nerves, slight tortuosity and thickening (left-most), mild uneven enhancement (poor imaging), and optic neuritis (Figure 3). The otolaryngologist considered the patient to have otitis media. Electroaudiometry on Day +7 (Figure 4A) suggested that both neural hearing loss and conductive hearing loss existed, and that conductive hearing loss was more severe. Otoscopy revealed congestion of the external auditory canals on both sides and the tympanic membranes on both sides were intact. Middle ear computed tomography (CT) showed middle ear mastoiditis. The middle ear analysis results are shown in Figure 4B and indicate the presence of middle ear damage. Other examinations, including 24-hour video electroencephalography, electromyography of both lower extremities, dynamic electrocardiogram, cardiac ultrasound, chest CT, and whole-body positron emission tomography (PET)/CT, revealed no obvious abnormalities. A 64-year-old male with a total clinical course of 6 months presented with low-grade fever, stroke-like symptoms, persistent headache based on long-term intermittent headache, vision loss, and hearing loss. In addition to general symptoms such as fever, the patient's CNS, immune system, eyes, ears, and cranial nerves were also damaged, with the CNS being the most affected. The detailed patient characteristics are shown in Figure 5. The ocular findings revealed the following characteristics: (1) bilateral optic nerve damage; and (2) bilateral bulbar conjunctival edema. Otologic findings included the middle ear and bilateral hearing loss. Electroaudiometry (Figure 4A) suggested that the hearing loss was mainly due to conductive hearing loss, although neural hearing loss coexisted; additionally, middle ear analysis indicated the presence of middle ear damage (Figure 4B). According to the development of the disease (Table 2), the characteristics of the patient (Figure 5), and the localization diagnosis, multisystem impairment was the key feature of this patient. Qualitative diagnosis focuses on malignant causes, vascular causes, infectious diseases, and immune-mediated diseases, among which immune-mediated diseases are most likely. MOH is characterized by experiencing 15 or more headache attacks per month for more than 3 months accompanied by the use of simple NSAIDs 15 or more days per month. Additionally, the use of triptans, dihydroetorphine hydrochloride, combined analgesics, and other agents should occur 10 or more days per month.1 It was reasonable to suspect MOH in this patient, who frequently took NSAIDs; however, MOH was unable to explain some of the other clinical characteristics of the patient. When tumors metastasize to the CNS, there may be headache, low-grade fever, neurological deficit symptoms, or meningeal irritation signs. Biochemical examinations may reveal elevated inflammatory indices and abnormal CSF protein levels. Brain metastases most commonly present as multiple lesions. These features suggest that this patient's neoplastic disease is an essential distinguishing point; however, the serum tumor marker levels and cranial CE-MRI, magnetic resonance spectroscopy, whole-body PET/CT, and CSF cytology results did not support the presence of tumors. Vascular causes need to be differentiated from cardiogenic stroke. The emboli that cause cardiogenic cerebral embolism originate from various heart diseases. In contrast to cerebral thrombosis, cardiogenic cerebral embolism tends to result in multiple infarcts, which are usually more extensive and prone to recurrence and bleeding. Infective endocarditis should be considered in patients with prolonged low-grade fever and elevated inflammatory marker levels; however, other patient features, including normal calcitoninogen levels and blood cultures, negative rheumatoid factor and anti-streptolysin "O" antibodies, normal echocardiography, and small intracranial lesions, did not support the diagnosis of cardiogenic stroke. Patients who develop CNS infections often present with fever and headache. This patient had mildly elevated protein levels according to multiple CSF examinations, whereas the WBC counts, as well as glucose and chloride ion levels in the CSF, were not abnormal. CSF changes were inconsistent with CNS infections caused by bacteria, fungi, cryptococcus, or tuberculosis and need to be differentiated from neurologic viral infections. Viral infection is a self-limiting disease that usually resolves within 3–4 weeks. This patient's disease was active for 6 months and continued to progress. Furthermore, pathogenic microbial next-generation sequencing revealed no abnormalities. In summary, the possibility of CNS infection is low, but infection by some particular intracellular bacteria could not be completely ruled out. Demyelinating diseases (such as neuromyelitis optica spectrum disorder NMOSD and multiple sclerosis MS), Susac syndrome (SS), primary CNS vasculitis, and CNS damage from ANCA-associated vasculitis (AAV) need to be considered. NMOSD and MS are most common in young women and are characterized by the destruction or loss of myelin sheaths in the brain and spinal cord, both of which can present with optic nerve damage; however, this patient was an elderly male with no abnormalities in the serum or CSF oligoclonal band analyses or aquaporin-4, which did not meet the diagnostic criteria for NMOSD2, 3 or McDonald MS.4 Furthermore, there were clinical signs, such as persistent low-grade fever, headache, otitis media, and meningeal irritation, that could not be explained by CNS demyelinating diseases. In conclusion, this patient had a low likelihood of developing demyelinating disease of the CNS. SS is most common in young women, and BRAO, hearing impairment, and encephalopathy are the typical triad. Cranial imaging revealing a "snowball" signal in the corpus callosum is a relatively common imaging feature in SS.5 Notably, the visual impairment caused by SS is due to BRAO. Hearing impairment manifests itself as neural deafness with impaired low and middle frequencies due to damage to the inner ear.6 This older individual did not meet these criteria; therefore, the diagnostic consideration of SS was not a high priority. Primary CNS angiitis commonly manifests with symptoms such as headache, cerebrovascular events, and cerebral cortical dysfunction. Some people may have myelopathy, optic nerve injury, or a slightly elevated CRP concentration and ESR. Imaging suggested that intracranial lesions can exhibit both infarct-like changes and microhemorrhages7-10; however, the patient's serum levels of anti-MPO and p-ANCA were positive and weakly positive, respectively. Otitis media is also uncommon in primary CNS angiitis. Therefore, secondary CNS vasculitis should be considered more than primary CNS vasculitis.11 The patient's ESR and CRP levels were persistently elevated, but no evidence of infections was found. Therefore, immune-mediated vasculitis was more likely than infectious vasculitis. Serum anti-MPO positivity and p-ANCA weakness support the possibility of AAV. AAV may present with systemic fever symptoms, weakness, and multisystem damage. The various forms of eye damage caused by AAV typically include conjunctivitis, blepharitis, and keratitis. Ear damage is more prone to otitis media with conductive deafness. AAV is more likely to cause damage to the peripheral nervous system than to the CNS, but the latter effect can also occur in a small number of patients. AAVs can be utilized to explain CNS damage, including headache, recurrent stroke, and optic nerve damage, as well as bilateral bulbar conjunctivitis, auris media injury, and low-grade fever. Clinical examination revealed no apparent signs of respiratory or renal damage, and this patient was more likely to have granulomatous polyangiitis (GPA); however, according to the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) 2022 classification criteria,12 the GPA and microscopic polyangiitis (MPA) scores were 0 and 6, respectively. The classification criteria support this patient as being an MPA patient. This patient's immune-mediated CNS damage was most consistent with AAV involving the CNS, and MPA was more likely than GPA. Most MPA patients have renal impairment, but the renal function and routine urine values were regular. It was an atypical MPA case, or GPA could not be completely ruled out. In conclusion, the diagnosis of this patient was considered AAV (MPA?), cerebral infarction (right thalamus and other etiology type), cerebral microhemorrhage (left side of the pons), multiple cranial nerve lesions (bilateral optic nerve and left facial nerve), bulbar conjunctivitis (bilateral), and otitis media (bilateral). On Day +14, glucocorticoid therapy was started, and 10 mg dexamethasone was administered daily intravenously. After 3 days of use, the headache was significantly relieved, and the hearing status also improved. However, on Day +17, a new cerebral infarction in the right periventricular region and thalamus was confirmed by MRI (Figure 1Y,Z), because of new left limb weakness (muscle strength, grade 2). Due to these new conditions, the glucocorticoid regimen was changed to 80 mg of methylprednisolone twice daily intravenously and then 80 mg daily 5 days later. The patient experienced occasional (but not severe) headaches during this time. After 10 days of treatment with methylprednisolone, the patient's headache completely resolved. His visual acuity improved in the right eye but remained unchanged in the left eye. His hearing returned to its predisease state (Figure 4C,D). On Day +31, the oral glucocorticoid regimen was adjusted to prednisone 80 mg daily. On Day +33, the patient developed fever and conjunctival hyperemia again, and his interleukin (IL)-6 concentration was significantly increased (109 pg/mL). When considering the possibility of disease activity, tocilizumab (humanized anti-IL-6 receptor monoclonal antibody) at 480 mg was initially administered as an intravenous infusion. The patient was discharged with no headache attacks, grade 5 muscle strength in the left limb, normal right eye vision, improved left eye vision (counting fingers), no bulbar conjunctival edema, and no signs of meningeal irritation 5 days later. After discharge, the methylprednisolone dosage was gradually reduced, and on Day +90, the prednisone dose was 40 mg daily and was further reduced by 5 mg weekly until it was discontinued. Furthermore, 1 g of mycophenolate mofetil (MMF) was added twice daily to maintain remission. During the 12 months of follow-up, the disease was in sustained remission. The patient's CNS, optic nerve, eye, and ear problems gradually resolved after being treated for AAV, thus supporting the diagnosis of the disease. AAV is a rare systemic autoimmune disease affecting small vessels and includes three subtypes: MPA, GPA, and eosinophilic GPA.12 According to most studies, the peak age for AAV onset is more than 55 years, with a slightly greater incidence in men than in women.13 AAV is a highly heterogeneous, multisystem disease. Many patients experience nonspecific symptoms such as fever, and the disease may affect the lungs, kidneys, skin, and other organs.13 CNS damage is typically rarer,14 and headache is one of the most common symptoms of CNS involvement in AAV, occurring in approximately 58% of patients.14 Possible mechanisms for CNS injury in AAV patients include (1) an inflammatory response, which increases the permeability of small intracranial vessels or causes vascular obstruction; (2) invasion or compression by granulomatous lesions in adjacent structures; and (3) granulomatous lesions within the CNS.14 The diagnosis of AAV in this patient was clear; however, the subtype of MPA or GPA remains to be determined. The clinical presentation of this patient was more consistent with GPA; however, the paired positivity of anti-MPO and p-ANCA meets the criteria for MPA classification according to the ACR/EULAR 2022 classification criteria.12 Although MPA is more likely than GPA, a definitive diagnosis requires a biopsy. Currently, under evidence-based medicine guidance, the treatments for GPA and MPA are almost the same. Therefore, although the classification is unclear, it does not affect subsequent treatment.12 Previous studies have shown that the median delay in diagnosis was 2 months (0.5–96) for GPA and 1.5 months (0–18) for MPA.13 This patient's diagnosis was delayed by up to 7 months, and the reasons for the delayed diagnosis could be due to objective reasons and medical factors. The rarity, considerable heterogeneity, and lack of suitable diagnostic methods for AAV were the objective reasons for the delay in diagnosis in this case. First, damage to the CNS, which is the core symptom of AAV, is very rare. Second, AAV is highly heterogeneous and lacks specific clinical manifestations. AAV can cause damage to multiple systems, and the involved organs can vary widely among different cases. The manifestations of neurological damage vary according to the degree of neurological involvement. The simultaneous involvement of multiple organs with elevated inflammatory markers suggests multisystem disease and is usually a clue for identifying AAVs.13 Patients with infectious disorders, neoplastic diseases, or other immune-mediated diseases frequently exhibit AAV-like symptoms. Third, there is no highly accurate diagnostic procedure available for AAV. Biopsy remains the gold standard for AAV diagnosis; however, the performance of a biopsy on every patient suspected of having AAV is not practical. ANCAs, including c-ANCAs and p-ANCAs, are currently the most commonly used biomarkers in clinical applications for diagnosing and classifying AAVs. Notably, ANCAs can be detected in a variety of immune and infectious diseases and may also be induced by drugs.15 Blood ANCAs are undetectable in approximately 10% of patients with GPA and MPA. Therefore, diagnosing AAV solely based on ANCA serology is not feasible. Finally, there are currently only classification criteria for AAV but no diagnostic criteria. The classification criteria should not be used as diagnostic criteria in clinical practice. The ACR/EULAR 2022 classification criteria are designed to differentiate patients diagnosed with AAV into GPA, MPA, and eosinophilic GPA with reasonable accuracy. The diagnosis of AAV or non-AAV has not been validated. Due to the fact that there are no diagnostic criteria for AAV, clinical manifestations, imaging data, laboratory biochemistry, and histology (if available) are necessary for diagnosis. In addition, medical factors such as the doctor's experience and knowledge of the disease also contribute to delayed diagnosis. Over an extended time period, attending physicians failed to explain symptoms in a "monistic" manner. MOH was long considered the primary diagnosis due to a history of migraine caused by the use of NSAIDs. Previously, attending physicians failed to thoroughly collect biochemical test results at all stages, especially for inflammation indicators such as the ESR, CRP concentration, and anti-MPO concentration, which were initially positive in other hospitals. Thus, previous attending physicians missed crucial clues for treating AAV. There is no high-quality, evidence-based medical evidence for some exceptional cases due to the rarity of AAV, and it is reasonable to consider comorbidities, individual medical history, drug toxicity, local drug availability, cost, and patient preference in treatment. Based on some specific considerations, the treatment of this patient did not adopt the highest priority recommended by the current AAV treatment guidelines. For life- or organ-threatening active MPA/GPA, current guidelines preferentially recommend glucocorticoids combined with rituximab or cyclophosphamide for the induction of remission.13 Although the MPA subtype of AAV was highly suspected for this patient, infection could not be completely ruled out. Due to concerns about the risk of infection, the patient and his family refused to start intravenous steroids and immunological therapy with glucocorticoids and rituximab until his symptoms worsened again on Day +10. When considering the possibility of a life-threatening situation, the patient was treated with glucocorticoids according to the opinions of the rheumatology and immunology experts and the patient's preference. After glucocorticoid therapy, some of the patient's symptoms improved, whereas others continued to fluctuate (e.g., new stroke, increased body temperature, and increased inflammatory markers, especially IL-6). Tocilizumab, which is a human anti-IL-6 receptor monoclonal antibody that normalizes circulating levels of proinflammatory cytokines and chemokines,16 was added to the treatment. The reason for choosing tocilizumab is that its risk of immunosuppression is lower than that of rituximab,17, 18 and its onset is faster than that of cyclophosphamide. Patients with MPA who were resistant to conventional treatments achieved long-term complete remission with tocilizumab treatment.16 In this patient, remission was induced by treatment with glucocorticoids combined with tocilizumab, and the expected efficacy was achieved. Guidelines recommend rituximab, methotrexate, or azathioprine for maintenance of remission, and MMF is an alternative for patients who are not candidates for these drugs.12 For this patient, we comprehensively considered the patient's economic affordability and difficulty in follow-up and chose a relatively affordable and safe MMF to maintain remission. Although the patient received glucocorticoids combined with tocilizumab to induce remission, received MMF to maintain remission, and achieved good curative effects, it should be noted that this regimen was not routine but was rather individualized. We reported a rare case of AAV in which CNS damage was the primary symptom. The patient experienced low-grade fever, repeated strokes, persistent severe headache, and hearing and vision loss. In addition, CSF protein levels were mildly elevated, inflammatory markers (such as the ESR and CRP) were increased, and anti-MPO and p-ANCA tests were positive. The final AAV diagnosis was almost confirmed. It is highly likely to be classified as MPA. After multidisciplinary consultations, an evidence-based, individualized treatment plan was developed, thus yielding positive results. Chung SA, Langford CA, Maz MA-O, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care Res (Hoboken). 2021 Aug;73 (8):1088–1105. Suhang Shang, Jing Luo, Fude Liu, Yitong Bian, Qiumin Qu, Guogang Luo, Meiying Deng, Sifan Wang, Le Liu, Xiao Liu, and Xiaoyu Wu contributed in this patient's care, diagnosis, and treatment. Suhang Shang, Mengyuan Zhang, Xiangqi Cao, and Xiaoyu Wu collected the data and drafted this manuscript. Suhang Shang, Jing Luo, Yitong Bian, Qiumin Qu, Guogang Luo, Meiying Deng, Xiao Liu, and Xiaoyu Wu revised the final version of the manuscript. All authors have read and agreed to the published version of the manuscript. We would like to thank our patient's family for allowing us to present this case and for photographs to be used. This work was supported by the Key Research and Development Programs of Shaanxi Province (No. 2022SF-022). Xiaoyu Wu has no competing interests to disclose. Xiao Liu has no competing interests to disclose. Le Liu has no competing interests to disclose. Xiangqi Cao has no competing interests to disclose. Mengyuan Zhang has no competing interests to disclose. Sifan Wang has no competing interests to disclose. Meiying Deng has no competing interests to disclose. Guogang Luo has no competing interests to disclose. Qiumin Qu has no competing interests to disclose. Yitong Bian has no competing interests to disclose. Fude Liu has no competing interests to disclose. Jing Luo has no competing interests to disclose. Suhang Shang has no competing interests to disclose. Written informed consent was obtained from the patient for the publication of this case. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.