Induction Therapy
Steroid pulse: Methylprednisolone 1 g/day for 3–5 days.
Oral steroids: Transition to prednisolone 1 mg/kg/day, then taper.
Cyclophosphamide: 500 mg/month for 6 months (NIH protocol). Combination with steroids is standard.
Primary Angiitis of the Central Nervous System
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Primary Central Nervous System Vasculitis?
Section titled “1. What is Primary Central Nervous System Vasculitis?”Primary angiitis of the central nervous system (PACNS) is a vasculitis in which inflammation occurs exclusively in the arteries and veins of the brain, spinal cord, and meninges, and is clearly distinguished from secondary CNS vasculitis (associated with systemic diseases).
Harbitz first reported it in 1922, and Calabrese proposed diagnostic criteria in 1988 5).
Epidemiologically, the annual incidence is about 2.4 cases per million, making it a rare disease 1, 2). The median age at diagnosis is approximately 50 years, but it can occur at any age, including in children. Regarding sex, a male predominance of 2:1 was previously reported, but some recent case series suggest no sex difference.
Vasculitis syndromes are a group of conditions classified by the size of the affected blood vessels, and PACNS is positioned as a subtype limited to CNS vessels.
The cause is unknown; involvement of inflammatory reactions triggered by infectious agents such as VZV and Mycoplasma has been proposed, but there is no definitive evidence.
Q
How is PACNS different from secondary CNS vasculitis?
A
PACNS is vasculitis limited to the CNS and is characterized by the absence of systemic disease. Secondary CNS vasculitis occurs in association with systemic diseases such as SLE, Sjögren’s syndrome, infections, and malignancies, and is much more common. If fever or markedly elevated ESR is present, secondary vasculitis should be strongly suspected.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”
A Case of Presumed Tuberculosis Uveitis with Occlusive Vasculitis from an Endemic Region. Turk J Ophthalmol. 2017 Jun 1; 47(3):169-173. Figure 1. PMCID: PMC5468532. License: CC BY.
Occlusive vasculitis and choroiditis focus in the left eye
Subjective Symptoms
Section titled “Subjective Symptoms”Symptoms of PACNS are often nonspecific, which can lead to delayed diagnosis.
- Headache: The most common initial symptom. Observed in up to 63% of patients, progressively worsening.
- Cognitive impairment: Second most common, up to 54%. Includes memory loss, decreased concentration, and disorientation.
- Stroke-like symptoms: Focal neurological deficits such as hemiparesis, aphasia, and sensory disturbances; transient symptoms similar to TIA.
- Seizures: Focal seizures may be the initial presentation10).
- Lack of systemic symptoms: Fever, weight loss, and elevated ESR are rare because the lesion is confined to the CNS.
In children, hemiparesis (up to 80%), sensory loss (79%), and fine motor impairment (73%) are frequent, while headache and cognitive impairment are less common than in adults (56% and 37%).
Clinical Findings (Findings Confirmed by Physician Examination)
Section titled “Clinical Findings (Findings Confirmed by Physician Examination)”Ophthalmological Findings
Section titled “Ophthalmological Findings”- Visual impairment due to afferent pathway disorders: Transient monocular blindness (amaurosis fugax) and homonymous hemianopia (binocular).
- Diplopia due to efferent pathway disorders: Caused by ocular motor nerve palsy.
- Papilledema: Relatively rare but reported. Cases with bilateral papilledema and macular exudates have been described.
- Balint syndrome: Triad of ocular motor apraxia, simultanagnosia, and optic ataxia. Occurs with parieto-occipital lesions.
- Uveitis/retinal vasculitis: Not common in PACNS. If present, secondary CNS vasculitis should be strongly suspected.
Zhuo et al. (2022) reported a 5-year-old girl with tumor-like PACNS who presented with left homonymous hemianopia and imaging showed tumor-like lesions in the left occipital and temporal lobes2).
Q
Can PACNS cause ocular symptoms?
A
When the visual pathway (optic nerve, optic chiasm, occipital lobe) or oculomotor nerves are affected, decreased vision, visual field defects, and diplopia may occur. Uveitis and retinal vasculitis are not typical in PACNS; if present, secondary diseases such as systemic vasculitis must be ruled out.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The exact etiology of PACNS remains unknown, and no specific risk factors have been proven.
The following are causes of secondary CNS vasculitis, which must be excluded when diagnosing PACNS.
| Cause Category | Representative Diseases/Factors |
|---|---|
| Infections | VZV, HIV, HCV, CMV, syphilis, tuberculosis, aspergillosis |
| Connective Tissue Diseases | SLE, RA, Sjögren’s syndrome, dermatomyositis |
| Other systemic diseases | Antiphospholipid antibody syndrome, malignant lymphoma, neurosarcoidosis |
| Drugs | Cocaine, amphetamine, ephedrine |
4. Diagnosis and Testing Methods
Section titled “4. Diagnosis and Testing Methods”PACNS is a diagnosis of exclusion, and there is no single definitive biomarker.
Diagnostic Criteria
Section titled “Diagnostic Criteria”The criteria by Calabrese & Mallek (1988) are widely used1).
- Presence of focal neurological deficits not explained by other causes
- Positive cerebral angiography findings or histological confirmation of vasculitis by brain biopsy
- No evidence of systemic vasculitis
The Rice & Scolding classification further divides cases into “definite” (with histological evidence) and “probable” (based on clinical, imaging, and CSF findings) 5).
Various Tests
Section titled “Various Tests”- Blood tests: There are no specific biomarkers for PACNS. CBC, ESR, and CRP are usually normal or mildly abnormal. Markedly elevated ESR and CRP suggest secondary CNS vasculitis. ANA, ANCA, and antiphospholipid antibodies are used to rule out secondary causes.
- CSF analysis: Abnormalities are found in up to 90% of confirmed patients. Typical findings include elevated protein and mild leukocytosis. Culture, PCR, and flow cytometry are used to rule out infection and malignancy. In the case by Lopes et al. (2023), CSF showed 44 leukocytes/L and protein 0.52 g/L 3).
- MRI: First-line initial imaging. Multiple bilateral cortical and subcortical infarcts are most common. Gadolinium-enhancing lesions, intracranial hemorrhage, and mass-like lesions may also occur. Findings are nonspecific and diverse. In children, unilateral white matter lesions are more common.
- Cerebral angiography: Characteristic findings include “beaded” changes (alternating stenosis and dilation), occlusion, and collateral circulation formation4). Sensitivity varies and is nonspecific, but it is useful for differential diagnosis.
- Transcranial Doppler ultrasound: Useful for initial evaluation when PACNS is suspected. It can monitor hemodynamic changes and assess treatment response. In a case by Campos et al. (2023), right MCA systolic flow velocity reached 470 cm/s and improved to 285 cm/s 10 days after starting steroids1).
- Brain biopsy: Gold standard for diagnosis. However, due to segmental involvement, sensitivity is approximately 75%, with some systematic reviews reporting 35.4%3). A negative result does not rule out the disease.
Differential Diagnosis
Section titled “Differential Diagnosis”The most important differential diagnosis is RCVS (reversible cerebral vasoconstriction syndrome). RCVS is more common in younger individuals, presents with severe recurrent thunderclap headaches, and CSF is often normal. Unlike PACNS, immunosuppressive therapy is contraindicated for RCVS.
Giant cell arteritis typically presents with headache in individuals over 60 years of age and is confirmed by arterial biopsy. Since 25–50% of cases are complicated by anterior ischemic optic neuropathy, ophthalmologic findings are important.
Q
What tests are needed to confirm a diagnosis of PACNS?
A
The gold standard is histological confirmation via brain biopsy, but its sensitivity is only about 75% 3). A combination of MRI, cerebral angiography, and cerebrospinal fluid analysis is used to comprehensively diagnose after excluding secondary causes. It is recommended to perform multiple tests in parallel to complement sensitivity.
5. Standard Treatment
Section titled “5. Standard Treatment”Treatment for PACNS primarily involves immunosuppressive therapy. Management should be carried out in collaboration with neurologists and rheumatologists.
Induction Therapy
Section titled “Induction Therapy”- Corticosteroids: Methylprednisolone pulse therapy (1 g/day for 3–5 days) is administered, followed by oral prednisolone at 1 mg/kg/day 3).
- Cyclophosphamide (CYC): Combination with steroids is more standard. The NIH protocol is used, and intravenous administration of 500 mg/month for 6 months may be performed 3, 7). There are reports that combining CYC results in fewer relapses than steroids alone 6).
Maintenance Therapy
Start timing: Switch after 4–6 months of induction therapy.
Drug selection: Use either mycophenolate mofetil (MMF), methotrexate, or azathioprine.
Example MMF dose: Start at 500 mg twice daily, then increase to 1000 mg twice daily4).
Maintenance therapy
Section titled “Maintenance therapy”Switch after 4–6 months of induction therapy. MMF, methotrexate, or azathioprine is used6).
In a 35-year-old male case by Kuruvilaa et al. (2022), treatment was started with steroids plus MMF (500 mg twice daily → 1000 mg twice daily) and a good outcome was obtained4).
In an 8-year-old child with SV-cPACNS (GFAP antibody positive) reported by Datyner et al. (2023), treatment followed the Brainworks protocol: dexamethasone → methylprednisolone pulse for 5 days → taper over 12 months + CYC 7 times → MMF maintenance 8).
Second-line therapy (treatment-resistant cases)
Section titled “Second-line therapy (treatment-resistant cases)”- Rituximab: Efficacy in treatment-resistant cases has been reported at the case report level. In the case by Sarhan et al. (2022), rituximab 500 mg infusion was given twice (2 weeks apart), followed by maintenance dosing of 1 g every 6 months 6).
- TNF-α inhibitors: Infliximab and etanercept have been reported to show good response in rapidly progressive cases.
Q
How long does treatment for PACNS last?
A
Induction therapy (steroids + CYC) is given for about 6 months, then transitioned to maintenance therapy such as MMF. Long-term follow-up is needed due to risk of relapse, and treatment duration varies by case. Taper while monitoring treatment response with regular imaging and clinical evaluation.
6. Pathophysiology and Detailed Pathogenesis
Section titled “6. Pathophysiology and Detailed Pathogenesis”Histopathological subtypes
Section titled “Histopathological subtypes”PACNS has three main histopathological subtypes.
Granulomatous
Frequency: Most common subtype.
Pathological findings: Well-defined granulomas involving the full thickness of the vessel wall.
Association with beta-amyloid: Up to 50% of cases have beta-amyloid deposition, suggesting overlap with inflammatory cerebral amyloid angiopathy.
Lymphocytic
Pathological findings: Infiltration of the vessel wall by lymphocytes and plasma cells.
Characteristics in children: Lymphocytic pattern is common in pediatric PACNS5).
Necrotizing
Pathological findings: Fibrinoid necrosis of the vessel wall.
Rare subtype: Cases with eosinophilic infiltration have also been reported, showing pathological findings of EGPA but not meeting the diagnostic criteria for systemic EGPA7).
Inflammatory Mechanism
Section titled “Inflammatory Mechanism”Inflammation of the vascular wall is primarily driven by immune cell infiltration and the cytokine/chemokine network 5).
- Immune cell infiltration: Lymphocytes, mainly CD4-positive T cells, infiltrate the vascular wall.
- Chemokines and cytokines: IL-6, IL-8, CXCL1, CXCL10, etc., amplify inflammation.
- Matrix metalloproteinases and TIMPs: They destroy the vascular wall structure, leading to stenosis due to fibrous thickening (→ ischemia) and aneurysm formation due to wall weakening (→ hemorrhage).
- Characteristics in children: Predominantly affects the anterior circulation and occurs frequently in proximal vascular regions. In children, von Willebrand factor has been suggested as a potential biomarker 5).
7. Latest Research and Future Prospects (Research Stage Reports)
Section titled “7. Latest Research and Future Prospects (Research Stage Reports)”Unilateral (Focal) PACNS Subtype
Section titled “Unilateral (Focal) PACNS Subtype”While PACNS is typically bilateral (95.6% of the Mayo Clinic cohort F was bilateral), a rare subtype with recurrent episodes limited to one side has been reported. Immune response asymmetry between cerebral hemispheres is considered a cause, and 7 cases have been reported to date10).
Vibha et al. (2023) reported a case of PACNS in a 35-year-old man who presented only with recurrent focal aware seizures 10). He initially had focal seizures only, and biopsy confirmed granulomatous vasculitis; seizures resolved with steroids plus MMF.
Vessel wall MRI for differentiating PACNS from RCVS
Section titled “Vessel wall MRI for differentiating PACNS from RCVS”Vessel wall MRI is a promising technique for differentiating PACNS from RCVS. PACNS often shows vessel wall enhancement (inflammatory changes), whereas RCVS typically does not. Brain MRA sensitivity is reported to be 90–100% 1).
Diagnosis of tumor-like PACNS
Section titled “Diagnosis of tumor-like PACNS”Tumor-like PACNS accounts for about 5% of all PACNS cases and is difficult to differentiate from tumors on imaging 2). A combination of SWI (susceptibility-weighted imaging) and ASL (arterial spin labeling) has been reported useful for differentiation. PACNS tends to show hypoperfusion, while tumors show hyperperfusion.
Hydrocephalus complication
Section titled “Hydrocephalus complication”Hydrocephalus has been reported in 1.8% of CNS vasculitis cases and is a major cause of in-hospital mortality 3). It is extremely rare in PACNS, with only 2 reported cases. The mechanism is presumed to be CSF flow obstruction due to fibrous scarring of the meninges.
Complement-mediated CNS vasculitis and anakinra
Section titled “Complement-mediated CNS vasculitis and anakinra”Levit et al. (2023) reported a case of complement-mediated CNS vasculitis due to complement factor I (CFI) deficiency 9). CFI inactivates C3b and C4b, suppressing C3 convertase formation; its deficiency leads to abnormal activation of the alternative pathway and neutrophilic vasculitis. After treatment with the IL-1 inhibitor anakinra, no recurrence was observed for 20 months.
8. References
Section titled “8. References”- Campos A, et al. Primary Central Nervous System Vasculitis: A Rare Cause of Stroke. Cureus. 2023;15(5):e39541.
- Zhuo X, et al. A 5-year-old child presenting with tumor-like primary angiitis of the central nervous system. Pediatr Investig. 2022;6(2):140-143.
- Lopes J, et al. Hydrocephalus: a rare complication of primary central nervous system vasculitis. BMJ Case Rep. 2023;16:e253187.
- Thekkekarott Kuruvila A, et al. Primary Angiitis of the Central Nervous System: An Uncommon Cause of Stroke in the Young. Cureus. 2022;14(8):e27799.
- Hassan A, Allinson K. Vertebrobasilar circulation hemorrhages in childhood primary angiitis of the central nervous system. Autops Case Rep. 2022;12:e2021391.
- Sarhan FMA, et al. Right arm weakness and mouth deviation as a presentation of Primary Angiitis of the Central Nervous System treated with rituximab: A case-report. Ann Med Surg. 2022;79:104040.
- Yamashita K, et al. Primary Angiitis of the Central Nervous System with Pathological Findings of Eosinophilic Granulomatosis with Polyangiitis. Intern Med. 2024;63:1939-1943.
- Datyner E, et al. Small vessel childhood primary angiitis of the central nervous system with positive antiglial fibrillary acidic protein antibodies. BMC Neurol. 2023;23:57.
- Levit E, et al. Pearls & Oy-sters: Homozygous Complement Factor I Deficiency Presenting as Fulminant Relapsing Complement-Mediated CNS Vasculitis. Neurology. 2023;101:e220-e223.
- Vibha D, et al. Focal CNS vasculitis masquerading as new-onset focal aware seizures. BMJ Case Rep. 2023;16:e255535.