rheum.reviews

Primary CNS vasculitis (PCNSV) / Primary angiitis of the CNS (PACNS)

Contents

    BOTTOM LINE

    PCNSV is an extremely rare vasculitis confined to the central nervous system, affecting vessels of varying caliber in the brain parenchyma, spinal cord, and leptomeninges. Presentation is nonspecific but typically includes insidious headache, focal neurologic deficits (often from ischemic strokes), unexplained cognitive decline, or features of aseptic meningitis. CSF often shows mild lymphocytic pleocytosis and/or elevated protein (~65–75% of cases), but may be normal. MRI can show multiple multi-territory infarctions of varying age, white matter changes, parenchymal or leptomeningeal enhancement, hemorrhage, or tumor-like lesions. The combination of a normal MRI and normal CSF has a high negative predictive value and makes PCNSV very unlikely. Angiographic studies may show smooth-wall segmental stenosis with or without beading of medium-to-large vessels. Brain biopsy can confirm granulomatous, lymphocytic, or necrotizing vasculitis and is most sensitive for small-vessel disease. PCNSV is rare and frequently misdiagnosed: PCNSV is rare: if the diagnosis of PCNSV is being considered, the correct diagnosis is often something else. Rigorous exclusion of mimics (especially RCVS, intracranial atherosclerosis, infection, and intravascular lymphoma) is essential. Treatment involves glucocorticoids with or without cyclophosphamide for induction, followed by maintenance immunosuppression for at least 2 years.
    [🕑15 minute read]

    CONDITIONS ASSOCIATED WITH CNS VASCULITIS

    —Primary CNS Vasculitis

    • Primary CNS vasculitis, aka PCNSV, Primary Angiitis of the Central Nervous System “PACNS”

    —Secondary CNS Vasculitis/Mimics

    • Infectious vasculitis
      • Viral: VZV/HSV, CMV, HIV, Hepatitis B, Hepatitis C, Parvo B19
      • Bacterial: Meningitis, endocarditis, nocardiosis, Mycoplasma pneumoniae
      • Other bacterial: Tuberculosis, syphilis, neuroborreliosis, Rickettsia, Bartonella
      • Fungal: aspergillosis, cryptococcus, histoplasmosis, mucormycosis, coccidioidomycosis, candidiasis,
      • Parasitic: cysticercosis, toxoplasma
    • Drug Induced Vasculitis
      Most drug-induced “vasculitis” on angiography is actually vasospasm; histologically confirmed drug-induced vasculitis is rare
      • Cocaine/levamisole
      • Sympathomimetics
      • Amphetamines
      • Ephedrine
      • Phenylpropanolamine
      • Heroin
      • Checkpoint inhibitors
      • Allopurinol
    • Hematological malignancy and Hematological disorders
      • Hodgkin’s and Non-Hodgkin’s’ lymphoma
      • Langerhans cell histiocytosis
      • Hairy cell leukemia
      • Neoplastic meningitis
      • Intravascular lymphoma
      • Idiopathic hypereosinophilic syndrome
    • Systemic rheumatic disease and other autoimmune disease
      • Systemic lupus erythematosus
      • Antiphospholipid antibody syndrome
      • Dermatomyositis
      • Systemic sclerosis
      • Rheumatoid arthritis
      • Sjogren’s Disease
      • Neuro-sarcoidosis
      • Inflammatory bowel disease
    • Systemic vasculitis with CNS involvement
      • ANCA-Associated vasculitis (GPA, MPA, EGPA)
      • PAN
      • Bechet’s Disease
      • Immune complex vasculitis (ex: IgAV, HUVS)
      • Cogan’s Syndrome
      • Giant Cell arteritis
      • DADA2
      • Takayasu’s arteritis
      • Kawasaki disease
    • Mimics
      • Reversible cerebral vasoconstriction syndrome (RCVS) — the single most important mimic
      • Intracranial atherosclerosis
      • Moyamoya disease/syndrome
      • CADASIL/CARASIL (genetic small-vessel disease mimics)
      • MOG-associated encephalomyelitis
      • Susac syndrome
      • Graft-versus-host disease

    EPIDEMIOLOGY

    • Rare: Annual incidence rate 2.4/1,000,000, prevalence unknown
    • Age:  Median age 50 years; 50% of patients between 37 and 59 years-old at diagnosis. Wide age range, some cohorts report younger median ages
    • Male = Female; approximately equal sex distribution

    CLINICAL MANIFESTATIONS

    PCNSV is usually insidious in onset; rarely it can present acutely including a rapidly progressive catastrophic course (8–11% of cases). Diagnosis is made within 6 months of symptom onset in ~75% of patients, though diagnostic delay can be substantially longer.
    PCNSV can affect any part of the CNS, so presentation is highly variable — no pathognomonic signs exist.
    The most common manifestations at presentation (Mayo Clinic N=101 / French N=52)
    Small-vessel disease is more associated with cognitive impairment and seizures,
    Medium-to-large-vessel disease more commonly presents with focal neurologic deficits suggestive of stroke
    • Focal neurologic deficits: 67–83%
      • Most common initial presentation, often suggestive of stroke or TIA, including aphasia, ataxia, and visual-field defects
    • Headaches: 54–63%
      • Usually severe and persistent; thunderclap headache is rare and more typical of RCVS
    • Cognitive impairment: 35–50%
    • Speech disorders (aphasia or dysarthria): 35–43%
    • Visual symptoms: 15–32%
    • Seizures: 16–33%
    • Ataxia: 12–19%
    • Vertigo/dizziness: 9–29%
    • Fever: 9–13%
    • Intracranial hemorrhage: 8–19%
    • Psychiatric disorders: up to 25% (French cohort)
    • Amnestic syndrome: 9% (Mayo cohort)
    • Fever: 9–13%
    • Spinal cord involvement: ~5%
    • Tumor-like mass lesion: 4–12%

    If systemic symptoms are the dominant manifestation, consider an alternate diagnosis.

    INVESTIGATIONS

    —BASELINE TESTING

    Suggested baseline tests
    Not every test below necessarily needs to be done in every patient

    • Baseline studies
      • Normal CBC, ALT, Creatinine, Urinalysis
      • Anemia, renal failure & active sediment suggests diagnosis other than PCNSV
    • ESR, CRP
      • ESR, CRP are often normal in PCNSV; elevation may suggest alternate diagnosis

    After any stroke: CRP peaks ~5–7 days post-stroke and may remain elevated for 3–6 months

    • Serology and other work-up
      • To consider other underlying disease
        • ANA, ENA panel with dsDNA
        • Rheumatoid factor
        • ANCA antibodies
        • Antiphospholipid antibodies
        • C3, C4
        • Serum cryoglobulins
        • SPEP, IgG, IgA, IgM
        • Vitamin B12, TSH (metabolic/toxic mimics of white matter disease and cognitive decline)
        • Traditional stroke risk factors stratification including lipids and HbA1c
        • Serum ACE level (neurosarcoidosis, limited sensitivity for sarcoid)
        • Serum LDH (lymphoma)
    • Infectious
      • Routine blood, urine, and CSF cultures
      • To exclude other underlying disease, depending on clinical suspicion:
        • Treponema pallidum
        • Borrelia burgdorferi
        • Bartonella species
        • Tuberculosis
        • Herpes viruses (varicella zoster virus, cytomegalovirus)
        • Hep B, Hep C, HIV
        • Cysticercosis
        • Listeria
        • Whipples
        • Mycobacterium
        • Toxoplasma (especially in immunocompromised)
        • JC virus (PML can mimic white matter vasculitis)
    • CSF studies
      • CSF abnormal in ~65–90% of cases (higher in biopsy-confirmed/small-vessel disease).
        • 65% reported in angiogram-confirmed PCNSV
        • 90% reported in pathologically documented cases
    • CSF protein:
      • Elevated (>45 mg/dL) in 59–72% (higher in biopsy-confirmed disease).
      • Median <120 mg/dL (range 5–1034 mg/dL).
    • CSF WBC:
      • Elevated (>5 cells/mL) in 35–61% (higher in biopsy-confirmed disease).
      • Median <20 cells/mL (range 0–575). Predominantly lymphocytic.
    • Occasional presence of oligoclonal bands and CSF IgG
      • Presence of oligoclonal bands should prompt consideration of MS and other demyelinating diseases as alternative diagnoses
    • Cytology, flow cytometry, and molecular analysis for clonal rearrangements (CNS lymphoma and neoplastic meningitis)
    • CSF ACE level (neurosarcoidosis)
    • CSF LDH (lymphoma)
    • Metagenomic next-generation sequencing (mNGS) of CSF is increasingly becoming part of standard evaluative practice for excluding occult infection

    Elevated CSF protein and pleocytosis is seen in variety of ischemic, infectious, neoplastic processes

    • Non-CNS imaging for differential
      • Echocardiogram: for underlying embolic etiology  +/- TEE and Holter monitor
      • CT neck/chest/abdomen/pelvis for underlying malignancy, particularly lymphoma
      • PET-CT can help identify systemic vasculitis or occult malignancy (particularly lymphoma) that would reclassify the diagnosis as secondary CNS vasculitis.

    —NEUROLOGICAL IMAGING

    Neuroimaging: no specific imaging finding is pathognomonic; diagnosis cannot be made solely on imaging.
    Imaging should be interpreted by an expert neuroradiologist familiar with CNS vasculitis and its radiologic mimics

    —MRI Brain: Abnormal ~100%

    Normal findings make CNS vasculitis very unlikely

    • Infarcts: Multiple, bilateral, different territories, varying stages (acute/chronic), varying size, involving cortex, sub-cortex, and leptomeninges
      • Biopsy-confirmed PCNSV: Infarcts in 34%,
      • Angiogram-confirmed PCNSV: infarcts in 68%.
    • GAD-enhancement
      • Biopsy-confirmed PCNSV: 69%
      • Angiogram-confirmed PCNSV: 22%.
      • Parenchymal enhancement (37%) was more frequent than meningeal enhancement (16%)
    • Intracranial hemorrhage
      • Biopsy confirmed PCNSV: 25%
      • Angiogram confirmed PCNSV: 18%
    • Acute convexity Subarachnoid hemorrhage: 26%
      • Convexity SAH can also occur in RCVS; distinguishing the two is critical
    • Microhemorrhages on SWI:
      • Reported in up to 96% of biopsy-confirmed cases in one series (Agarwal et al., 2024)
    • T2/FLAIR white matter lesions: 45%
    • Tumor-like lesions (12%)

    —Vascular imaging: MRA, CTA, DSA (MR, CT, or Digital Subtraction Angiography)

    • MRA/CTA
      • MRA shows high concordance with DSA (κ = 0.82–0.87) but is less sensitive for posterior circulation and distal vessels.
      • Findings
        • Smooth-wall segmental stenosis of multiple cerebral arteries
        • Stenoses occasionally accompanied by post-stenotic dilatation or beading.
    • DSA
      • Abnormal in many of patients with medium-to-large-vessel PCNSV (40-90%, depending on population studied)
      • Sensitivity low compared to biopsy (~15–43%): small-vessel vasculitis is below angiographic resolution.
      • Specificity can be as low as 30%

    Angiographic techniques lack resolution for distal small-vessels; better at imaging proximal medium vessels

    • High-resolution vessel wall MRA (high resolution 3T MR)
      • Segmental, concentric, and homogeneous enhancement helps distinguish vasculitis from atherosclerotic plaques (eccentric enhancement) and RCVS (no or minimal enhancement)
      • Specificity of this enhancement for the identification of vasculitis lesions has not been established

    —Findings suggesting alternate diagnoses

    • Arterial occlusions are uncommon (not absent) in PCNSV
    • Aneurysmal dilatation is rare but not pathognomonic for an alternate diagnosis.
    • Microaneurysms are more suggestive of PAN.
    • Long-segment smooth tapered stenoses are more typical of atherosclerosis or moyamoya.

    Narrowing of multiple proximal intracranial arteries may suggests atherosclerosis, dissection, moya moya, RCVS

    Angiographic changes typical of vasculitis (smooth-wall segmental stenosis) are commonly seen in non-vasculitic disorders
    Can be seen in atherosclerosis, post-radiation, neurofibromatosis, atrial myxomas, neurofibromatosis, infection, vasospasm, RCVS

    —Repeat imaging

    • Repeat vascular imaging may clarify the diagnosis
      • Reversible arterial stenoses may be in patients with primary CNS vasculitis, but without treatment, it typically progresses
      • RCVS is reversible without treatment

    —HISTOPATHOLOGY

    —Brain biopsy

    European Stroke Organization guidelines recommend brain biopsy in patients with a normal angiogram when there is diagnostic suspicion of small-vessel vasculitis,
    If angiography indicates a high probability of medium-to-large-vessel vasculitis, biopsy is recommended only to rule out other diagnoses.
    Early biopsy after symptom onset/worsening significantly increases diagnostic yield
    • Test Characteristics
      • Sensitivity for detecting PCNSV 54–78%
      • 30 to 50% of positive cases have nondiagnostic or normal findings
      • Biopsy more likely to be negative in patients with medium vessel involvement (i.e.: vessels not amenable to biopsy but whose abnormalities are detectable with angiography).
      • Brain biopsy for suspected PCNSV reveals an alternate diagnosis in 30-39% of cases
        • Common alternative diagnoses: infection, cerebral amyloid angiopathy, encephalitis, demyelination, and CNS lymphoma
      • Complications
        • Serious complication rate ~1–4%
        • Minor/transient complications ~13–16%
    • Target
      • More sensitive if targeting area with abnormal MRI imaging
      • If not possible, may do right (nondominant) frontal lobe with overlying leptomeninges (though yield is lower)
    • Findings
      • Transmural inflammation of vessel wall, with 3 different (but overlapping) histological patterns:
        • Granulomatous (32-61%, ± amyloid-ß angiitis (ABRA) with ß-amyloid depositions in the brain vessel walls)
        • Lymphocytic (24-79%, N.B.: rule out lymphoma; immunohistochemistry and molecular analysis for T-cell and B-cell clonality should be performed in all cases to exclude CNS lymphoma)
        • Necrotizing (14-42%)

    Necrotizing vasculitis is associated with intracranial hemorrhage, while lymphocytic vasculitis may have a more benign course 

    ANGIOGRAPHY vs. BIOPSY-DEFINED PCNSV

    • Angiography and biopsy are both helpful for diagnosis of PCNSV but are not interchangeable
      • Angiography is better at detecting medium-to-large vessel disease
      • Biopsy is better at detecting distal-small vessel disease

    When both angiography and biopsy are performed, agreement between the diagnostic modalities is low
    These two modalities detect fundamentally different disease subsets

    • Prognosis
      • Isolated small-vessel disease (biopsy+/angiogram−)
        • Lower mortality, better treatment response (90%), fewer cerebral infarctions
      • Isolated medium/large-vessel disease (angiogram+/biopsy−):
        • Higher mortality, lower treatment response
    • Medium-to-large vessel PCNSV
      • More likely detectable by angiography, less amenable to biopsy
      • More likely to present with focal deficits and ischemic lesions on MRI
      • More likely to have a normal CSF
    • Distal-small vessel PCNSV
      • Less likely detectable by angiography, more amenable to biopsy
      • More likely to present with subacute/progressive onset, cognitive impairment and seizures
      • More likely to have abnormal CSF, gadolinium enhancement, and tumor like lesions on MRI

    SUMMARY

    FeatureSmall-vessel
    (biopsy-defined)    		Medium-to-large vessel
    (angiography-defined)
    Primary diagnostic modalityBrain biopsyDSA / MRA / CTA
    Typical presentationCognitive impairment, seizures, subacute onsetFocal neurologic deficits (stroke/TIA), acute onset
    MRI findingsGadolinium enhancement (69%), tumor-like lesions, meningeal involvementCerebral infarctions (68%), fewer enhancing lesions (22%)
    CSF abnormalitiesMore frequent (~75–80%)Less frequent (~65%; normal in ~20%)
    Treatment responseBetter (~90%)Lower (~72%); worst with combined involvement (~43%)
    MortalityLower (~14%)Higher (~23%); worst with combined involvement (~56%)
    Relapse rateHigher (54%)Lower (24%)

    DIAGNOSIS

    When PCNSV is a suspected diagnosis, the correct diagnosis is often something else.

    PCNSV should be suspected in a patient usually presenting with months of prodromal insidious headache, cognitive decline, or aseptic meningitis followed by multiple multi-territory strokes of varying age evident on MRI. MRI may also show microangiopathic white matter changes, GAD enhancement, hemorrhage, or tumour-like lesions. CSF should be abnormal in nearly all patients, with non-specific elevations in CSF protein and WBC. The combination of a normal MRI and normal CSF has a high negative predictive value and makes PCNSV very unlikely, but does not absolutely exclude it. Diagnosis of PCNSV should be supported by DSA/MRA and biopsy, if feasible. DSA or MRA can detect medium-to-large vessel disease, which manifests as smooth-wall segmental stenosis of multiple cerebral arteries, occasionally with post-stenotic dilatation or beading; clinically, this presents as focal deficits and ischemia. Biopsy can detect distal-small vessel disease, which presents more often with subacute/progressive onset, cognitive impairment and seizures. Histopathology shows granulomatous, lymphocytic, or necrotizing changes. Because PCNSV is so rare, it is crucial to consider and rule out many mimickers of PCNSV.

    DIAGNOSTIC CRITERIA

    Calabrese and Mallek 1988 diagnostic criteria, commonly used (though unvalidated); these require:

    1. (1) Acquired neurological deficit unexplained after thorough evaluation
    2. (2) Classic angiographic or histopathological features of vasculitis
    3. (3) no evidence of systemic vasculitis or other condition to which findings could be secondary.

    Definite versus Probable Classification (not prospectively validated)

    • “Definite”: biopsy-proven
    • “Probable”: high-probability angiogram + abnormal MRI + CSF consistent with PCNSV, without histological verification

    DIFFERENTIAL DIAGNOSIS

    —(1) MUST RULE OUT: INFECTION

    Infectious arteritis can simulate virtually every feature of PCNSV. VZV is the single most important infectious mimic, as it can cause both large-vessel and small-vessel vasculitis, and can occur without a skin rash. 

    • Viral:
      • VZV, HSV, CMV, HIV, Hepatitis B, Hepatitis C, Parvovirus B19
    • Bacterial:
      • Endocarditis/emboli, basilar meningitis (TB, fungal), syphilis, Lyme (Borrelia burgdorferi), Bartonella, Rickettsia, Listeria, Whipple’s disease, Mycobacterium (including atypical)
    • Fungal:
      • Aspergillosis, mucormycosis, cryptococcus, histoplasmosis, coccidioidomycosis, candidiasis
    • Parasitic:
      • Cysticercosis, toxoplasma (especially immunocompromised)
    • Other:
      • JC virus (PML can mimic white matter vasculitis)
    • Para-infectious:
      • ADEM

    —(2) MUST RULE OUT: MALIGNANCY

    • Intravascular lymphoma (IVL):
      • Most dangerous malignant mimic. Presents with recurrent multi-territory infarcts, cognitive decline, and angiographic abnormalities closely mimicking PCNSV.
      • Distinguishing features include
        • B symptoms (fever, weight loss, night sweats)
        • Elevated LDH
        • DWI-positive lesions with unusual characteristics (progressive growth, persistent DWI hyperintensity >1 month)
        • Biopsy is essential for differentiation.
    • Primary CNS lymphoma
    • Lymphomatoid granulomatosis
    • Neoplastic/leptomeningeal carcinomatosis
    • Paraneoplastic syndromes
    • Hodgkin’s and Non-Hodgkin’s lymphoma (associated with secondary CNS vasculitis)
    • Langerhans cell histiocytosis
    • Hairy cell leukemia
    • Angiocentric lymphoma

    — (3) Most Common Mimic: RCVS

    See below

    —(4) Medium-to-Large Vessel Mimics (Angiographic)

    These conditions produce angiographic findings that can be mistaken for PCNSV on DSA/MRA/CTA. High-resolution vessel wall MRI may help differentiate (concentric homogeneous enhancement in vasculitis vs. eccentric enhancement in atherosclerosis vs. minimal/no enhancement in RCVS). 

    • Intracranial atherosclerosis (most common cause of intracranial large vessel narrowing; eccentric vessel wall enhancement)
    • Moyamoya disease/syndrome
    • Fibromuscular dysplasia
    • Recanalized cerebral embolism
    • Post-subarachnoid hemorrhage vasospasm
    • Radiation vasculopathy
    • Embolic sources: atrial fibrillation, endocarditis, atrial myxoma
    • Neurofibromatosis

    —(5) Small-Vessel Mimics (MRI/Biopsy)

    These conditions mimic the white matter lesions, cognitive decline, and progressive course of small-vessel PCNSV.

    • Demyelinating: Multiple sclerosis, MOG encephalomyelitis (mimic of small-vessel PCNSV), ADEM
    • Genetic cerebral small vessel diseases: CADASIL, CARASIL, retinal vasculopathy with cerebral leukoencephalopathy (RVCL), MELAS, Fabry disease
    • Autoimmune encephalitis: Anti-NMDA receptor, MOG-IgG, others
    • Susac syndrome
    • Neurosarcoidosis (granulomatous, not demyelinating)
    • Hypertensive angiopathy
    • Cerebral amyloid angiopathy

    —(6) Secondary CNS Vasculitis

    Systemic diseases causing secondary CNS vasculitis must be ruled out. These typically present with constitutional symptoms and evidence of active disease outside the nervous system.

    • Systemic vasculitis with CNS involvement:
      • ANCA-associated vasculitis (GPA, EGPA): CNS vasculitis in <2–4%
      • Polyarteritis nodosa: CNS manifestations in 5–25%
      • Behçet’s disease: neurologic symptoms in 5–14%
      • Giant cell arteritis
      • Takayasu arteritis
      • Cryoglobulinemic vasculitis (Hepatitis C-related)
      • IgA vasculitis
      • DADA2
      • Cogan’s syndrome
    • Systemic Autoimmune Rheumatic diseases
      • Systemic lupus erythematosus
      • Antiphospholipid antibody syndrome (thrombotic vasculopathy rather than true vasculitis)
      • Sjögren’s syndrome
      • Rheumatoid arthritis (associated with seropositive, erosive, nodular disease)
      • Idiopathic inflammatory myopathies
      • Systemic sclerosis
    • Other systemic conditions:
      • Neurosarcoidosis
      • Inflammatory bowel disease (Crohn’s)
      • Graft-versus-host disease

    —(7) Drug Induced

    Most cases of drug-induced “cerebral vasculitis” identified by angiography alone are actually vasospasm and should be classified as RCVS; histologically confirmed drug-induced vasculitis is rare.

    • Cocaine/levamisole
    • Amphetamines/sympathomimetics
    • Checkpoint inhibitors (increasingly recognized)
    • Heroin, ephedrine, allopurinol
    • SSRIs, triptans (more commonly associated with RCVS than true vasculitis)

    —(8) Hypercoagulable/Prothrombotic States

    • Antiphospholipid antibody syndrome
    • Other prothrombotic states (protein C/S deficiency, Factor V Leiden, etc.)
    • Sickle cell disease

    —RCVS: Reversible Cerebral Vasoconstriction

    • Non-autoimmune diagnosis; most straight-forward differential based on history
    • Presents as (often recurring) acute severe thunderclap headache in a typically younger patient <45 years.
    • Described triggers: pregnancy, post partum, orgasm, Valsalva, cocaine, marijuana, SSRIs, triptans/sumatriptan and sympathomimetic drugs
    • Recurrent or single thunderclap headache combined with either normal neuroimaging, border zone infarcts, or vasogenic edema has 100% positive predictive value for diagnosing RCVS or RCVS-spectrum disorders.
    FeaturePCNSVRCVS
    EpidemiologyM>F, 40-60 yearsF>M, ~45 years
    HeadacheInsidious, chronicRecurrent thunderclap
    Focal symptoms (ex: stroke)Yes, rare at onset of headacheYes, may occur with onset headache
    Infarct PatternMultiterritorial, bilateral, varying sizeWatershed
    Lobar hemorrhageMore commonLess common
    Cortical SAHLess commonCommon
    Angiographic findingsSmooth-wall segmental stenosissymmetric, concentric, smooth taper lesions
    with segmental dilation “Sausage on a string”
    Dynamic imaging changesVariableImproves after 3 months
    CSF changesOften abnormalOften normal
    High resoluition MR vessel wallConcentric, homogeneous enhancementMinimal or no vessel wall enhancement
    Unique lesionsMultiple diffuse small deep infarcts
    Extensive deep white matter lesions
    Tumor-like lesions
    Multiple gadolinium-enhanced lesions    		Reversible vasogenic edema

    RCVS₂ Score for Reversible Cerebral Vasoconstriction Syndrome Calculator: Validated clinical tool

    • Score ≥5 has 99% specificity and 90% sensitivity for diagnosing RCVS
    • Score ≤2 has 100% specificity and 85% sensitivity for excluding RCVS. 

    TREATMENT

    Initial treatment should be stratified by vessel size, histology, and severity at presentation

    FeatureSmall-vessel PCNSV (biopsy-defined)Medium-to-large vessel PCNSV (angiography-defined)Rapidly progressive/catastrophic
    Initial therapyGlucocorticoids alone may be reasonableGlucocorticoids + cyclophosphamide (or MMF)Immediate IV methylprednisolone + cyclophosphamide
    Add CYC/MMF ifNon-response, relapse, or worseningFirst-line in most casesFirst-line
    Histologic patternLymphocytic (may have milder course)VariableNecrotizing or granulomatous
    PrognosisBetter treatment response
    Lower mortality    		Lower treatment response
    Higher mortality    		Poor treatment response
    High mortality

    —INDUCTION

    • Steroids
      • IV methylprednisolone 1g IV x 3-5 days, then prednisone 1mg/kg/d
      • Taper to 5mg/d of less over 6-12 months (extrapolated from systemic vasculitis protocols)
    • Cyclophosphamide
      Cyclophosphamide should be initiated in patients with multiple infarcts, necrotizing or granulomatous vasculitis, and medium-to-large vessel involvement. If a patient does not respond promptly to steroids alone, cyclophosphamide should be started.
      • Oral 2mg/kg/d
      • IV 0.5–1.0 g/m² monthly × 6 months (IV preferred over oral due to lower cumulative drug exposure and toxicity)
    • Mycophenolate mofetil
      • MMF 2-3g/day may be as effective as cyclophosphamide in 2 observational uncontrolled studies
    • Rituximab (second line/refractory)
      • Very little data; may be option for patients with disease relapse and refractory disease or unable to receive traditional immunosuppressants
      • Rituximab 1g IV x 2 separated by 14 days, then 500-1000mg IV q6mo
    • Tocilizumab: also described for use in relapsing/refractory disease

    —MAINTENANCE

    • May continue low-dose steroid for ~2 years, optimal duration is uncertain
      • Azathioprine 1-2mg/kg/d
      • Mycophenolate mofetil 1-2g daily
      • Methotrexate 20-25mg/week
    • Rituximab, Infliximab, etanercept therapy has been described in case reports
    • Duration of therapy unclear; expert opinion is at least 2 years usually longer
    • Maintenance therapy is associated with better outcomes

    —ADJUNCTIVE

    • As indicated: PPI therapy, bisphosphonate, Vitamin D supplementation PJP prophylaxis
    • Low-dose aspirin, particularly for medium-to-large vessel disease
    • Fertility counselling for patients receiving cyclophosphamide

    —MONITORING

    • Consider serial MRI and MRA 3–4 months after diagnosis, then every 4–6 months, or when new neurologic symptoms arise.
    • If stable imaging but worsening clinical symptoms, consider repeat CSF, angiography, and biopsy if not done
    • Persistent vessel wall enhancement
      • Without other signs of active vasculitis: does not clearly warrant intensification of immunosuppressive therapy
    • Refractory Disease
      • Revisit differential diagnosis and consider repeat cerebral biopsy

    PROGNOSIS

    • Induction remission:
      • 68–95% across major cohorts
    • Long-term remission:
      • 21.5–66% depending on criteria used 
    • Relapse rate:
      • 12–59% across cohorts; risk concentrated in the first 3 years 
    • Good functional outcome (mRS ≤2):
      • 46–73% 
    • Mortality:
      • 8–18% across cohorts 
    • Poor prognostic factors:
      • Older age
      • Delayed diagnosis
      • Cognitive dysfunction at presentation
      • Spinal cord involvement
      • Medium-to-large vessel disease
      • Cerebral infarctions
      • Necrotizing histology
    • Relapse predictors:
      • Male sex
      • Gadolinium-enhanced lesions
      • Small-vessel disease (more frequent relapses but better treatment response) 

    REFERENCES

    Berlit, P., & Kraemer, M. (2014). Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls. Clinical and experimental immunology, 175(3), 419–424. https://doi.org/10.1111/cei.12221

    Beuker, C., Strunk, D., Rawal, R., Schmidt-Pogoda, A., Werring, N., Milles, L., Ruck, T., Wiendl, H., Meuth, S., Minnerup, H., & Minnerup, J. (2021). Primary Angiitis of the CNS: A Systematic Review and Meta-analysis. Neurology(R) neuroimmunology & neuroinflammation, 8(6), e1093. https://doi.org/10.1212/NXI.0000000000001093

    Beuker, C., Schmidt, A., Strunk, D., Sporns, P. B., Wiendl, H., Meuth, S. G., & Minnerup, J. (2018). Primary angiitis of the central nervous system: diagnosis and treatment. Therapeutic advances in neurological disorders, 11, 1756286418785071. https://doi.org/10.1177/1756286418785071

    Birnbaum, J., & Hellmann, D. B. (2009). Primary angiitis of the central nervous system. Archives of neurology, 66(6), 704–709. https://doi.org/10.1001/archneurol.2009.76

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    Updated on August 13, 2026
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