Aseptic meningitis as an uncommon presentation of polyarteritis nodosa: a case report with focused literature synthesis

Abstract

Background

Central nervous system (CNS) involvement in polyarteritis nodosa (PAN) is uncommon and typically manifests as ischemic or hemorrhagic events. Presentation as sterile meningitis is rare and may lead to diagnostic delay.

Case presentation

A 31-year-old man presented with persistent headache, high - grade fever, and nodular erythema on both calves. Cerebrospinal fluid (CSF) analysis demonstrated lymphocyte-predominant pleocytosis with elevated protein levels, initially suggesting a viral meningitis–like presentation. Despite empirical antiviral therapy, his symptoms failed to improve. On hospital day 7, the development of testicular discomfort and the presence of cutaneous nodules prompted further evaluation. Histopathological examination of a skin biopsy revealed fibrinoid necrosis of small arteries with inflammatory cell infiltration, confirming the diagnosis of PAN. Initiation of glucocorticoid therapy resulted in rapid clinical improvement.

Literature synthesis

A focused review of previously reported cases indicates that PAN may rarely present with meningitis-like features characterized by sterile CSF pleocytosis and lack of response to antimicrobial therapy, with marked improvement following immunosuppressive treatment.

Conclusion

Aseptic meningitis–like presentation may represent an underrecognized CNS phenotype of PAN. In patients with persistent meningitis-like symptoms, negative infectious workup, and concomitant systemic manifestations such as skin nodules or testicular pain, vasculitis should be considered early to avoid diagnostic delay and improve outcomes.

Introduction

Polyarteritis nodosa (PAN) is a rare systemic necrotizing vasculitis that predominantly affects small- and medium-sized arteries. Its clinical manifestations are heterogeneous and commonly include fever, weight loss, subcutaneous nodules, and myalgia [1–4]. Peripheral neuropathy is reported in approximately 50–70% of patients, whereas central nervous system (CNS) involvement is considerably less frequent [4].

When CNS involvement occurs, it typically presents as ischemic or hemorrhagic events; however, symptoms may also be nonspecific—such as headache and fever—and can closely resemble infectious meningitis, thereby leading to diagnostic delay or misdiagnosis [5]. Aseptic meningitis with inflammatory cerebrospinal fluid (CSF) findings represents a particularly uncommon and underrecognized phenotype of PAN [6, 7]. Here, we report a case of PAN initially presenting with fever, headache, and CSF abnormalities suggestive of viral meningitis, underscoring the importance of early recognition of vasculitic etiologies in patients with atypical meningitis-like presentations.

Case presentation

A 31-year-old man presented with a two-week history of persistent headache, high-grade fever (up to 40 °C), and nodular erythema on both calves. Although he reported intermittent headaches in the past, he noted that the current episode differed in both intensity and character. His medical history was otherwise unremarkable, and he denied substance use.

One week prior to admission, a lumbar puncture performed at another hospital revealed cerebrospinal fluid (CSF) leukocytosis (99/µL; 80% lymphocytes) with elevated protein (0.84 g/L). Based on these findings, viral meningitis was suspected, and empirical therapy with ceftriaxone and acyclovir was initiated. However, his symptoms persisted without clinical improvement. Serial cerebrospinal fluid findings obtained during the clinical course are summarized in Table 1.

Table 1.

Serial cerebrospinal fluid findings during the clinical course

Date	Protein (g/L)	Glucose (mmol/L)	Chloride (mmol/L)	WBC (/µL)	LY (%)	RBC (/µL)	Pressure (mmH2O)
2021-07-06	0.84	3.39	121.4	99	80	100	110
2021-07-13	0.64	3.76	121.1	35	82	0	145
2021-07-23	0.70	3.29	124.5	50	82	0	205
2021-08-13	0.57	3.72	123.9	8	NA	0	190
Reference range	0.15–0.45	2.3–4.1	119–129	0–8	60–70	0	80–180

CSF analyses demonstrated persistent lymphocyte-predominant pleocytosis and elevated protein levels during the disease course. Persistent inflammatory changes were observed despite antimicrobial therapy, supporting a non-infectious etiology

LY (%) = Percentage of lymphocytes

NA Not available

Upon admission to our institution, physical examination demonstrated diffuse muscle weakness, patchy nodular erythema on both calves (Fig. 1A), and neck stiffness. Laboratory tests showed a white blood cell count of 5,900/µL (80% neutrophils), an erythrocyte sedimentation rate of 72 mm/h, and a high-sensitivity C-reactive protein level of 197.33 mg/L. Liver and renal function tests were within normal limits. Autoimmune serological testing, including antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), complement levels, rheumatoid factor (RF), and cryoglobulins, did not reveal abnormalities suggestive of alternative autoimmune or vasculitic conditions.

Fig. 1.

Clinical course of skin lesions on the patient’s right calf. A At admission: multiple bright nodular erythemas observed (biopsy site indicated by black arrow). B Prior to biopsy: lesions became more numerous and darker; biopsy performed at indicated site. C Four-month follow-up: skin largely healed with minimal residual dark-red pigmentation. Notes: Black arrow indicates the biopsy site corresponding to the histopathological findings shown in Fig. 2. Sequential images demonstrate progression of cutaneous lesions prior to diagnosis and their resolution following immunosuppressive therapy, paralleling systemic disease activity

Serological testing indicated previous exposure to hepatitis B virus. Specifically, hepatitis B surface antigen (HBsAg) was negative, indicating no evidence of active infection. Tests for hepatitis C virus, human immunodeficiency virus, and syphilis were negative.

Repeat CSF analysis on hospital day 2 again demonstrated leukocytosis (35/µL; 82% lymphocytes) with persistently elevated protein concentration (0.64 g/L). CSF cultures and metagenomic next-generation sequencing were negative for infectious pathogens. CSF polymerase chain reaction (PCR) testing for specific neurotropic viruses (e.g., herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Epstein–Barr virus) was not performed. Brain magnetic resonance imaging revealed small chronic ischemic lesions in the bilateral frontal lobes, which were considered unrelated to the acute presentation. Electroencephalography (EEG) was not performed, as there were no clinical features suggestive of cortical dysfunction.

On hospital day 7, the patient developed new-onset testicular discomfort. In light of the persistent inflammatory CSF findings, lack of response to antimicrobial therapy, and the presence of systemic manifestations, systemic vasculitis was suspected. A skin biopsy was performed, and histopathological examination demonstrated fibrinoid necrosis of small arterial walls with infiltration of neutrophils and lymphocytes (Fig. 2), confirming the diagnosis of PAN. Computed tomography angiography of the abdomen showed only mild calcified plaques without evidence of aneurysm or stenosis.

Fig. 2.

Histopathology of skin biopsy from the right calf. Hematoxylin-eosin staining, ×200. A Fibrinoid necrosis of small artery walls within subcutaneous fat lobules (black arrow). B Inflammatory infiltration composed of neutrophils, lymphocytes, and histiocytes surrounding affected arteries, consistent with PAN. Legend update: Arrows highlight areas of diagnostic significance (vascular necrosis and mixed inflammatory infiltrate). Features are diagnostic of polyarteritis nodosa, directly corresponding to the biopsy site in Fig. 1B. Histopathological findings were decisive in differentiating vasculitis from infectious meningitis

According to the 1990 American College of Rheumatology (ACR) classification criteria, the patient fulfilled three criteria consistent with PAN. However, these criteria are intended for classification rather than definitive diagnosis, and the diagnosis in this case was primarily supported by the overall clinical presentation and histopathological confirmation [6] (Table 2).

Table 2.

1990 American College of Rheumatology (ACR) criteria for Polyarteritis nodosa (PAN) and patient fulfillment

Criterion	Definition	Patient meets?
1. Weight loss ≥ 4 kg	Unintentional loss of ≥ 4 kg since illness onset, not due to dieting or other factors	✖
2. Livedo reticularis	Mottled, net-like pattern on skin of extremities or torso	✖
3. Testicular pain or tenderness	Pain or tenderness of testicles not due to infection, trauma, or other causes	✔
4. Myalgias, weakness, or leg tenderness	Diffuse myalgia (excluding shoulder/hip girdle) or tenderness/weakness of leg muscles	✔
5. Mononeuropathy or polyneuropathy	Development of single or multiple mononeuropathies, or polyneuropathy	✖
6. Diastolic BP > 90 mmHg	Hypertension with diastolic BP > 90 mmHg	✖
7. Elevated BUN or creatinine	BUN > 40 mg/dL or creatinine > 1.5 mg/dL, not due to dehydration or obstruction	✖
8. Hepatitis B virus	Presence of HBsAg or HBV antibody in serum	✖
9. Arteriographic abnormality	Arteriogram showing aneurysms or occlusions of visceral arteries, not due to arteriosclerosis or other non-inflammatory causes	✖
10. Biopsy of small/medium artery containing PMNs	Histologic changes showing granulocytes or mixed granulocyte/mononuclear infiltration in artery wall	✔

Three criteria were fulfilled, meeting the 1990 ACR classification criteria for PAN

Bolded ✔ items highlight the key diagnostic features for clarity

Following confirmation of the diagnosis, antimicrobial therapy was discontinued. However, no clinical improvement was observed during antiviral therapy. Intravenous dexamethasone (10 mg/day) was initiated, resulting in rapid clinical improvement, with resolution of fever and gradual alleviation of headache and meningeal signs. Intravenous dexamethasone was initiated for rapid control of systemic inflammation and neurological symptoms, and subsequently transitioned to oral methylprednisolone as maintenance therapy following clinical stabilization. The patient was subsequently treated with oral methylprednisolone (24 mg/day) combined with low-dose cyclophosphamide (0.1 g every other day), administered as a divided dosing regimen. This approach was selected to balance immunosuppressive efficacy with tolerability, in line with commonly used strategies for systemic vasculitis in clinical practice. Following the initiation of glucocorticoid treatment, the patient’s fever and neurological symptoms rapidly improved, supporting a non-infectious inflammatory etiology.

At discharge, the patient’s fever and meningeal irritation had completely resolved, and inflammatory markers had normalized. At four-month follow-up, the calf lesions had healed with minimal residual hyperpigmentation (Fig. 1C). Only occasional mild headaches persisted, without recurrence of systemic manifestations. A timeline summarizing the clinical course, diagnostic evaluation, and treatment response is presented in Fig. 3.

Fig. 3.

Timeline of clinical course, diagnostic evaluation, and treatment response

Discussion

Polyarteritis nodosa (PAN) is characterized by necrotizing inflammation of small- and medium-sized arteries with fibrinoid necrosis and mixed inflammatory infiltrates [2–4]. Although peripheral nervous system involvement is relatively common, central nervous system (CNS) involvement is uncommon, occurring in approximately 2–10% of cases [5]. When present, CNS manifestations are typically described as ischemic or hemorrhagic events; however, they may also present with nonspecific symptoms such as headache, altered consciousness, seizures, or focal neurological deficits, thereby mimicking infectious or inflammatory disorders of the CNS. Among these, a meningitis-like presentation with inflammatory cerebrospinal fluid (CSF) changes may represent a rare and underrecognized clinical phenotype of PAN [6, 7]. To our knowledge, only a limited number of cases describing PAN presenting with meningitis-like CSF abnormalities have been reported.

In the present case, lymphocyte-predominant CSF pleocytosis and elevated protein levels initially suggested viral meningitis [8, 9]. Nevertheless, the absence of identifiable pathogens, the lack of clinical response to antiviral therapy, and the coexistence of systemic manifestations—including nodular erythema, diffuse myalgia, and testicular pain—prompted reconsideration of the initial diagnosis. These findings highlight that PAN should be considered in patients presenting with meningitis-like symptoms refractory to standard antimicrobial therapy, particularly when accompanied by systemic inflammatory features such as cutaneous nodules or testicular involvement. Although a direct causal relationship between PAN and the observed CSF abnormalities cannot be definitively established in this case due to the lack of direct evidence of CNS vasculitis (e.g., vascular imaging abnormalities or biopsy confirmation), the temporal association between systemic vasculitic manifestations and neurological symptoms, together with the lack of response to antimicrobial therapy and the rapid improvement following immunosuppressive treatment, supports a potential pathogenic link rather than a coincidental coexistence. Nevertheless, we acknowledge that a coincidental occurrence of PAN and a separate meningitis-like illness cannot be completely excluded. However, this possibility is considered less likely given the consistently negative microbiological investigations and the discordant response to antiviral versus immunosuppressive therapy. Histopathological confirmation through skin biopsy proved decisive in establishing the diagnosis. Therefore, in cases of presumed infectious meningitis that fail to respond to appropriate antimicrobial treatment, a structured reassessment for systemic vasculitis—including careful dermatologic examination and timely biopsy—may be warranted. Although CSF PCR testing for common viral pathogens was not performed, the combination of negative mNGS results, lack of response to antiviral therapy, and rapid improvement following immunosuppressive treatment supports a non-infectious etiology. This designation is based on the absence of identifiable pathogens using available diagnostic methods and should be interpreted with caution.

The mechanisms underlying meningitis-like presentations in PAN are not fully established; however, several plausible pathways can be inferred based on prior reports of central nervous system involvement in systemic vasculitis. First, inflammation of small- and medium-sized meningeal vessels may disrupt the blood–brain barrier, facilitating the influx of inflammatory cells and proteins into the cerebrospinal fluid. Second, ischemic injury to adjacent brain parenchyma secondary to vasculitic involvement may trigger secondary meningeal inflammation, contributing to CSF abnormalities. Third, systemic immune activation in vasculitis may promote a cytokine-driven inflammatory milieu that extends to the meninges.

The lymphocyte-predominant CSF profile observed in this case, although commonly associated with viral infections, has also been reported in inflammatory and autoimmune CNS conditions. This pattern may reflect a predominantly adaptive immune response within the CNS rather than direct infectious invasion.

Aseptic meningitis may arise from a broad spectrum of etiologies, including viral infections, autoimmune and inflammatory disorders, medications, malignancy, and post-procedural reactions such as those following spinal anesthesia [10]. Therefore, distinguishing infectious from non-infectious causes requires careful integration of microbiological studies, systemic clinical features, treatment response, and histopathological findings. In the present case, the persistently negative infectious workup, lack of response to antiviral therapy, and rapid improvement following immunosuppressive treatment collectively supported a vasculitis-related inflammatory process.

The absence of active hepatitis B infection was confirmed by negative HBsAg, although prior exposure cannot be excluded based on serological markers. A structured evaluation of differential diagnoses was undertaken. ANCA-associated vasculitis (AAV) was considered; however, the absence of typical clinical features such as upper or lower respiratory tract involvement, renal impairment, and ANCA positivity argued against this diagnosis. Behçet’s disease was also considered, but the lack of recurrent oral or genital ulcers, ocular involvement, or characteristic mucocutaneous findings made this unlikely. Secondary vasculitis related to infection or systemic autoimmune disease was evaluated, but extensive microbiological investigations were negative, and there was no serological or clinical evidence of systemic autoimmune disorders. In addition, primary infectious meningitis remained an important consideration. However, the persistently negative microbiological studies, lack of response to antiviral and antibiotic therapy, and rapid improvement following immunosuppressive treatment collectively supported a non-infectious inflammatory process. Other inflammatory CNS disorders were also considered less likely given the absence of characteristic imaging findings and the presence of systemic vasculitic features. Taken together, the integration of clinical, laboratory, and histopathological findings supported the diagnosis of PAN with CNS involvement.

To further contextualize this presentation, we summarized previously reported cases of PAN presenting with meningitis-like manifestations (Table 3). Previous reports have described PAN presenting as meningoencephalitis in both adult and pediatric populations [6, 7]. Moreover, other systemic vasculitides—including ANCA-associated vasculitis and granulomatosis with polyangiitis—have also been associated with lymphocytic CSF abnormalities and meningeal symptoms [11–13]. Collectively, these observations suggest that inflammatory CSF changes in the absence of infection may represent a shared but infrequent manifestation of systemic vasculitis. In PAN, inflammation of meningeal arteries may facilitate inflammatory cell migration into the cerebrospinal fluid, while ischemic injury to the brain parenchyma may elicit secondary meningeal responses, thereby contributing to meningitis-like presentations [13].

Table 3.

Reported cases of polyarteritis nodosa presenting with aseptic meningitis or meningoencephalitis

Study	Age/Sex	CSF Findings	Initial Diagnosis	Diagnostic Confirmation	Treatment	Outcome
Smith et al., 1987 (JRSM) [6]	49/F	88 WBC/mm³ (90% neutrophils), ↑protein	Meningoencephalitis (initially suspected aseptic)	Renal angiography (microaneurysms)	Prednisolone	Rapid improvement; recurrent flares
Pediatric case (PMID 15115570IF: 4.5 Q1 B2) []	9/M	Pleocytosis (lymphocyte-predominant), ↑protein	Infectious meningoencephalitis	Skin biopsy	Corticosteroid	Marked improvement
Present case	31/M	Lymphocyte-predominant pleocytosis (99/µL), ↑protein	Viral meningitis	Skin biopsy	Steroid + cyclophosphamide	Rapid improvement; stable at 4 months

CSF Cerebrospinal fluid, PAN Polyarteritis nodosa. All cases demonstrated inflammatory CSF changes in the absence of identified infectious pathogens and showed clinical improvement following immunosuppressive therapy

Based on available reports and the present case, a recognizable clinical pattern may emerge: CSF pleocytosis without identifiable pathogens, negative microbiological investigations, lack of response to antimicrobial therapy, and rapid improvement following immunosuppressive treatment. Awareness of this pattern may assist clinicians in distinguishing vasculitis-related CNS involvement from primary infectious meningitis at an earlier stage [6, 7]. This pattern should be interpreted in the context of available diagnostic testing and does not completely exclude all potential infectious etiologies.

Hepatitis B virus infection is a well-established trigger for PAN, although its incidence has declined with widespread vaccination [1]. Infectious agents have also been implicated in rare cases of PAN [14]. In the present patient, no clinical or microbiological evidence of active infection was identified, supporting a non-infectious inflammatory process.

The cornerstone of PAN management remains systemic glucocorticoid therapy, with the addition of immunosuppressive agents such as cyclophosphamide in cases of severe or organ-threatening disease [2, 15]. Early recognition of atypical CNS involvement is critical, as delayed diagnosis and inappropriate antimicrobial treatment may result in prolonged disease activity and potentially irreversible neurological injury.

In the context of meningitis-like presentations, persistent inflammatory CSF changes in the absence of identifiable pathogens, failure to respond to antimicrobial therapy, and the coexistence of systemic inflammatory features should prompt timely evaluation for systemic vasculitis. Increased awareness of this underrecognized CNS phenotype of PAN may shorten diagnostic delay, facilitate earlier initiation of immunosuppressive therapy, and ultimately improve clinical outcomes.

Conclusion

This case suggests that polyarteritis nodosa may be associated with a meningitis-like CNS presentation that can mimic infectious meningitis. In patients with persistent inflammatory cerebrospinal fluid findings, negative microbiological investigations, and poor response to antimicrobial therapy—particularly when accompanied by systemic features such as cutaneous nodules or testicular pain—systemic vasculitis should be actively considered in the differential diagnosis.

Early recognition of this underrecognized CNS phenotype is essential. Careful systemic examination and timely biopsy can facilitate accurate diagnosis, and prompt initiation of immunosuppressive therapy may prevent diagnostic delay and improve neurological outcomes.

Authors’ contributions

Yao Li, Guanhua Nie, and Lili Lian drafted the manuscript. Yan Yu, Yu Wang, Zixun Wang, Xinran Cui, Siyu Qian, and Kaiyue Xie contributed to literature review and manuscript revision. Haining Zhang supervised the study and conceived the work. All authors read and approved the final manuscript.

Funding

None.

Data availability

The data that support the findings of this study are available from the First Hospital of Jilin University, but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. De-identified data may be available from the corresponding author upon reasonable request and with permission from the First Hospital of Jilin University.

Declarations

Ethics approval and consent to participate

Ethics approval was obtained from the Ethics Committee of the First Hospital of Jilin University. Written informed consent was obtained from the patient for participation in this study.

Consent for publication

Written informed consent for publication of this case, including images and clinical data, was obtained from the patient.

Competing interests

The authors declare no competing interests.