CNS Vasculitis – Inpatient Pediatric Evaluation

Overview of CNS Vasculitis in Children

Central nervous system (CNS) vasculitis is an inflammatory disease that targets the blood vessels of the brain and spinal cord. An immune-mediated attack on vessel walls causes wall swelling, narrowing of the lumen, and downstream ischemic damage to brain tissue. Affected children may present with seizures, strokes, transient ischemic attacks (TIAs), focal neurologic deficits (such as hemiparesis, vision or speech impairments), headaches, cognitive or behavioral changes, and even psychiatric symptoms. Importantly, CNS vasculitis in pediatric patients is categorized as either primary (isolated) or secondary. Primary angiitis of the CNS (PACNS)—also called childhood primary angiitis of the CNS (cPACNS)—refers to idiopathic, isolated inflammation of the CNS vessels in an otherwise healthy child. Secondary CNS vasculitis is diagnosed when an underlying condition (such as an infection, systemic rheumatic disease, or malignancy) causes the vascular inflammation. In any child with suspected CNS vasculitis, a thorough search for underlying causes is essential, because management differs significantly between infectious and non-infectious (rheumatologic) etiologies.

Infectious vs. Rheumatologic Causes of Pediatric CNS Vasculitis

Distinguishing infectious from rheumatologic (non-infectious) causes of CNS vasculitis is a vital first step in the inpatient assessment, as it directs treatment (antimicrobial therapy versus immunosuppression). In children, infection is the most common trigger of secondary CNS vasculitis, making a broad infectious workup essential. Key infectious causes include:

• Bacterial Infections: Tuberculous meningitis is a classic cause of pediatric CNS vasculitis, typically resulting in basilar meningitis with inflammation of cerebral arteries and stroke in children, especially in endemic areas. Syphilis (congenital or acquired) and Lyme disease (neuroborreliosis) are other spirochetal infections that can cause CNS arteritis. Chronic bacterial endocarditis with septic emboli can also mimic CNS vasculitis. Rarely, organisms like Mycoplasma pneumoniae or Salmonella have been implicated in CNS vasculitic syndromes.
  
• Viral infections: Varicella zoster virus (VZV) is a well-known trigger of childhood arteriopathy. A post-varicella angiopathy, also called transient or focal cerebral arteriopathy, can occur weeks to months after chickenpox, leading to unilateral arterial stenosis—often of the proximal anterior or middle cerebral artery—and stroke. This is typically a monophasic, localized large-vessel arteritis triggered by the infection. Other viral causes include enterovirus, Epstein-Barr virus (EBV), cytomegalovirus, HIV, and others, especially in immunocompromised hosts. Herpes zoster reactivation in cranial vessels is an important cause of vasculitic stroke even in immunocompetent children, often detected by VZV PCR or antibodies in cerebrospinal fluid.
  
• Fungal and Other Pathogens: Invasive fungal infections (e.g., aspergillosis or candida in an immunosuppressed child) can directly invade vessel walls and cause CNS vasculitis. Protozoal infections (like Trypanosoma in Chagas or Plasmodium in cerebral malaria) and parasites (e.g., Schistosoma or Toxocara) are rare causes but should be considered in relevant epidemiologic settings.
  

In contrast, non-infectious (rheumatologic) causes of CNS vasculitis include primary idiopathic vasculitides and systemic autoimmune diseases. Notable examples are:

• Primary CNS vasculitis (cPACNS): an isolated, idiopathic vasculitis limited to the CNS with no systemic disease. This will be detailed below, but it is a diagnosis of exclusion (made only after ruling out infections and systemic causes). It can involve large or medium vessels (angiography-positive cPACNS) or only small vessels (angiography-negative, biopsy-proven).
  
• Systemic rheumatic diseases: Several pediatric rheumatologic conditions can involve the CNS blood vessels. Systemic lupus erythematosus (SLE) is one notable example—children with lupus can develop cerebral vasculitis or lupus “cerebritis” caused by autoantibody-mediated inflammation of small vessels, often accompanied by other lupus features (such as rashes, nephritis, positive ANA/DsDNA, etc.). Primary systemic vasculitides like polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or eosinophilic granulomatosis can all affect the CNS, although this is rare in children. For instance, classic PAN infrequently affects the brain (<5% of cases), but when it does, it may cause strokes or neuropathies. ANCA-associated vasculitides (like GPA) mainly target the respiratory tract and kidneys; however, granulomatous lesions or vasculitic hemorrhages can sometimes occur in the CNS. Behçet disease, an autoinflammatory vasculitis, often leads to venous sinus thrombosis or brainstem inflammation, known as “Neuro-Behçet,” though true arterial vasculitis in Behçet’s disease is less common. Central nervous system involvement in Kawasaki disease or IgA vasculitis (HSP) is very rare, but severe systemic vasculitis such as Takayasu arteritis (large-vessel vasculitis) could potentially impair cerebral blood flow through carotid artery involvement.
  
• Monogenic autoinflammatory syndromes: A growing list of genetic disorders can present with vasculitic brain disease in children. Foremost is Deficiency of Adenosine Deaminase 2 (DADA2), discussed separately below, which causes a PAN-like vasculitis with strokes. Others include PTPN22-associated vasculitis and ADA2-unrelated polyarteritis nodosa in specific genetic contexts, but these are exceedingly rare.
  

Clinical clues can sometimes help distinguish between infectious and rheumatologic causes. Infectious vasculitis often shows signs of infection such as fever, meningitis, systemic illness, or recent exposure (e.g., recent varicella illness in post-varicella angiopathy). Laboratory tests may identify the pathogen, such as positive TB tests, Lyme titers, or VZV DNA in CSF. Conversely, primary or autoimmune vasculitis may develop more slowly without fever, and might have other inflammatory markers or autoantibodies (like elevated ESR/CRP in lupus or positive ANA)—although, notably, pure primary CNS vasculitis often has normal systemic inflammatory markers. The presence of systemic features like rash, arthritis, or kidney involvement suggests a systemic disease rather than a CNS-limited process. If an underlying cause is identified, the CNS vasculitis is by definition secondary, and treatment should address that cause. Only after ruling out infections, systemic rheumatic diseases, malignancy, and other mimics can one confidently diagnose primary (idiopathic) CNS vasculitis.

Moyamoya Syndrome and Hyperthyroidism (Differential Diagnosis)

Not all pediatric cerebral arteriopathies result from inflammation. Moyamoya disease is a significant non-inflammatory arteriopathy that can imitate CNS vasculitis by causing strokes in children. It is characterized by progressive, bilateral narrowing or occlusion of the distal internal carotid arteries and the proximal anterior and middle cerebral arteries, with the development of a network of fragile collateral vessels at the base of the brain (the classic “moyamoya” angiographic appearance, meaning “puff of smoke”). The cause of primary Moyamoya disease is idiopathic (possibly genetic; more common in Asian populations). However, Moyamoya syndrome refers to Moyamoya-like arteriopathy that occurs secondary to another condition. It has been reported in association with conditions such as Down syndrome, neurofibromatosis type 1, prior cranial irradiation, and certain hematologic disorders. Notably, Graves’ disease (hyperthyroidism) is one recognized association: children, especially adolescents, with thyrotoxic Graves’ disease can very rarely develop Moyamoya vasculopathy. Excess thyroid hormone is thought to increase sympathetic nervous system activity, which may contribute to arterial stenosis or spasm in susceptible individuals. Therefore, a child with uncontrolled hyperthyroidism who presents with recurrent TIAs, headaches, or strokes should be evaluated for Moyamoya syndrome triggered by thyrotoxicosis. In reported cases, cerebrovascular symptoms often coincide with the hyperthyroid state and may improve once a euthyroid state is achieved.

Distinguishing Moyamoya from CNS vasculitis: Imaging findings and clinical context are key in differentiating these conditions. In Moyamoya, conventional angiography typically shows bilateral steno-occlusion at the distal ICA along with an extensive collateral network; there is no evidence of arterial wall inflammation or the ‘beading” pattern, and inflammatory markers are usually normal. Children with Moyamoya associated with Graves’ disease often present during thyrotoxic episodes with ischemic strokes triggered by hyperventilation or exertion due to reduced cerebrovascular reserve. Conversely, primary CNS vasculitis frequently presents with segmental arterial narrowing and alternating dilations on angiography, known as ‘‘beads on a string,’’ along with vessel wall enhancement on MRI. It can also present with more subacute neurologic decline or multifocal deficits. Management varies greatly: Moyamoya is not treated with immunosuppressants but rather by controlling hyperthyroidism (in the case of Graves’) and performing surgical revascularization when necessary. Pediatric Moyamoya cases with Graves’ disease have been successfully treated with antithyroid medications to normalize thyroid levels combined with indirect surgical bypass procedures, such as encephalo-duro-arterio-synangiosis, to improve cerebral blood flow. Recognizing Moyamoya syndrome in the differential diagnosis of CNS vasculitis is critical—especially since starting high-dose steroids, which are appropriate for vasculitis, would be unnecessary and potentially harmful in Moyamoya. In any child showing evidence of intracranial arterial stenoses, clinicians should consider non-inflammatory causes like Moyamoya, especially if there are risk factors such as hyperthyroidism or known genetic syndromes, alongside vasculitic causes.

Deficiency of Adenosine Deaminase 2 (DADA2)

One specific monogenic vasculitis that pediatricians and rheumatologists must keep on their radar is Deficiency of Adenosine Deaminase 2, often abbreviated DADA2. This rare autosomal recessive disease (caused by biallelic mutations in the ADA2 gene) was first described in 2014 and is now recognized as a monogenic form of polyarteritis nodosa (PAN) that typically presents in early childhood. Clinically, DADA2 is characterized by a combination of systemic vasculitic and inflammatory features. Common manifestations include recurrent fevers and systemic inflammation, livedo reticularis or livedo racemosa skin rash (mottled vascular pattern on the skin), early-onset strokes (often recurrent lacunar infarcts starting in childhood), peripheral neuropathy, and immunologic abnormalities such as hypogammaglobulinemia or cytopenias. These features led to the recognition of DADA2 as a distinct entity causing childhood vasculitis with prominent CNS involvement. In fact, DADA2 is now believed to account for about 25% of “idiopathic” polyarteritis nodosa cases in children. A key difference between DADA2 and classic PAN is the high rate of cerebrovascular disease: more than half of DADA2 patients have experienced at least one ischemic or hemorrhagic stroke, whereas CNS involvement occurs in less than 5% of traditional PAN cases. Because of these strokes, DADA2 is an important consideration in any child with unexplained vasculitic infarcts. Certain clinical clues—such as recurrent strokes, livedo rash, and a family history of consanguinity—may raise suspicion for DADA2 and should prompt testing.

Workup and diagnosis: Laboratory testing can support the diagnosis of DADA2, including low ADA2 enzyme activity in plasma or identifying mutations in the ADA2 (formerly CECR1) gene. This testing should be considered for any child or young adult with unexplained strokes in the context of systemic inflammation. Early diagnosis is crucial because the treatment of choice for DADA2 is anti–tumor necrosis factor (TNF) therapy, which has dramatically improved outcomes. TNF inhibitors (such as etanercept or adalimumab) have shown remarkable efficacy in preventing strokes and controlling systemic inflammation in DADA2. Studies report a drastic reduction in new infarcts after starting TNF blockade, with improvements in all disease parameters; in many cases, this obviates the need for traditional cytotoxic immunosuppressants. Therefore, if DADA2 is confirmed, prompt initiation of TNF inhibitor therapy is recommended and often leads to disease remission. Other treatments like corticosteroids or cyclophosphamide tend to be much less effective in DADA2, and they do not prevent strokes as reliably as TNF blockade. Hematopoietic stem cell transplant has been used in the most severe refractory cases (especially those with bone marrow failure phenotypes), but for most patients, lifelong TNF inhibitor therapy remains the main treatment. Close monitoring for infections (especially tuberculosis reactivation) is necessary during TNF therapy. The key point for the general pediatrician is to recognize the possibility of DADA2 in a child with vasculitic strokes and refer to a pediatric rheumatologist or immunologist for appropriate genetic testing and targeted treatment.

Diagnostic Workup of Suspected CNS Vasculitis

When a child is hospitalized with suspected CNS vasculitis (for example, a previously healthy child with an acute ischemic stroke, hemorrhagic stroke, or unexplained encephalopathy with imaging showing vascular lesions), a systematic diagnostic approach is necessary. The goals are to confirm the presence of CNS vasculitis (versus a mimic) and to identify any underlying cause (infectious, systemic, or genetic), as this will determine the treatment. Key components of the workup include:

• Neuroimaging: Brain MRI with contrast is typically the first major diagnostic test. MRI can reveal ischemic infarcts (acute or chronic), hemorrhages, or inflammatory lesions. Certain MRI features, such as leptomeningeal enhancement, can indicate small-vessel vasculitis (seen in cPACNS), while multiple cortical infarcts across different vascular territories might suggest an embolic or vasculitic process. If MRI results are suggestive, or if clinical suspicion remains high, vascular imaging is performed. Magnetic resonance angiography (MRA) or CT angiography can sometimes detect larger vessel abnormalities, but conventional cerebral angiography remains the gold standard for diagnosing large- or medium-vessel CNS vasculitis because of its higher resolution. On angiography, typical signs of vasculitis include alternating segments of arterial narrowing and dilation (beading), areas of vessel tapering or occlusion, and slow distal blood flow. A normal angiogram does not exclude vasculitis, as small-vessel vasculitis can evade detection on angiography. In practice, if noninvasive imaging (MRA/CTA) appears normal but suspicion persists—especially for small-vessel disease—many centers proceed to conventional angiography or brain biopsy for a definitive diagnosis. It is important to note that a completely normal MRI along with normal CSF studies makes primary CNS vasculitis very unlikely; in such cases, a careful reassessment for alternative diagnoses (such as complex migraine, metabolic or genetic stroke syndromes, etc.) is warranted.
  
• Lumbar puncture and laboratory studies: Nearly all children with suspected CNS vasculitis should undergo cerebrospinal fluid (CSF) analysis unless contraindicated. CSF often provides critical clues; most pediatric CNS vasculitis cases show some CSF abnormality such as lymphocytic pleocytosis and/or elevated protein. A normal CSF is uncommon in active CNS vasculitis and argues against it, especially if MRI is also normal. More importantly, CSF can be tested for infections: e.g., PCR for VZV, enteroviruses, HSV, and Mycobacterium tuberculosis (Xpert TB PCR or cultures) if TB meningitis is a concern, as well as cytology to rule out malignant cells if malignancy is in the differential. Simultaneously, blood tests should evaluate systemic causes and overall health: complete blood count, inflammatory markers (ESR, C-reactive protein), metabolic panel, and markers of rheumatic disease. Although ESR or CRP may be elevated in systemic vasculitides, they are often normal in primary CNS vasculitis. Autoimmune labs are important: an ANA panel for lupus or other connective tissue diseases, ANCA antibodies for Wegener’s/MPA, etc., cardiolipin or beta-2 glycoprotein antibodies for antiphospholipid syndrome (which can cause vasculopathy with strokes), and possibly thyroid function and antibodies, since severe thyrotoxicosis could indicate Moyamoya as mentioned above. Infectious labs should be ordered based on exposure risks: e.g., Quantiferon-TB Gold or tuberculin skin test for TB, blood cultures (and echocardiogram) if infective endocarditis is possible, respiratory virus panel or mycoplasma titers if prior infection is suspected, Lyme titer in endemic areas, HIV test, etc. A comprehensive infectious workup is essential before diagnosing primary rheumatologic vasculitis.
  
• Genetic and specialized tests: If the patient’s presentation suggests a specific syndrome like DADA2, targeted genetic testing should be performed (e.g., send ADA2 enzyme activity or gene sequencing in a child with early strokes and systemic features). Similarly, if clinical clues indicate another monogenic vasculopathy or a thrombophilia, appropriate genetic tests or advanced labs (such as for clotting disorders) should be included. These tests often run alongside first-line evaluations or when initial workup is unrevealing.
  
• Brain biopsy: In certain scenarios, a brain biopsy is performed to secure a definitive diagnosis. This is typically reserved for cases where CNS vasculitis is strongly suspected but angiographic studies are normal or inconclusive (suggesting possible small-vessel vasculitis), or when a specific diagnosis like CNS lymphoma or neurosarcoidosis is also considered. A leptomeningeal or cortical biopsy of an affected area (guided by MRI lesions) can reveal the characteristic histopathology of CNS vasculitis—an infiltrating inflammatory cell population within vessel walls (in pediatric PACNS, usually a lymphocytic infiltrate without granulomas)—and can rule out mimickers such as infection or tumor. Brain biopsy is regarded as the diagnostic gold standard for CNS vasculitis. In practice, if angiography is positive and consistent with vasculitis, many experts skip brain biopsy in children (especially for large-vessel cPACNS) because the angiographic pattern plus clinical context may be enough for diagnosis. However, if all other evaluations are negative and treatment decisions need certainty, a biopsy is invaluable. The risks (neurologic deficit, seizure) must be weighed and discussed with the family.
  

Overall, the diagnostic approach is multidisciplinary. Pediatric rheumatology, neurology, infectious disease, and often stroke specialists collaborate in the workup. The motto is “treat for infection unless proven otherwise”—meaning one should aggressively search for and manage infectious causes and avoid immunosuppressive therapy until infections are reasonably excluded. Conversely, don’t delay immunosuppressive treatment too long if an inflammatory vasculitis seems likely, as early treatment can prevent irreversible neurologic damage. Often, clinicians may start empirical high-dose corticosteroids after sending off critical infectious tests (such as CSF cultures, PCRs, etc.), especially if the child’s condition is deteriorating, while continuing the search for infection in parallel.

Initial Treatment and Management

The management of pediatric CNS vasculitis depends on the underlying cause and the severity of the clinical presentation. Key principles include treating any identified underlying disease, especially infections, promptly starting immunosuppressive therapy for primary inflammatory vasculitis, and providing supportive care for neurologic deficits.

• If an infectious cause is identified or strongly suspected, targeted antimicrobial therapy is essential. For example, tuberculous CNS vasculitis (TB meningitis with vasculitic complications) is treated with a full course of anti-tuberculous therapy, often combined with corticosteroids to reduce inflammation and edema. VZV vasculitis is treated with high-dose acyclovir (usually IV) alongside corticosteroids in some cases. Bacterial endocarditis causing septic emboli requires antibiotics and sometimes surgery. In these situations, immunosuppression is usually avoided or used cautiously because it can worsen the infection if misused. The main approach is to prioritize treating the underlying infection. Once the infection is properly managed or ruled out, residual vessel inflammation such as post-infectious vasculitis may still benefit from anti-inflammatory therapy, but this decision should be made in consultation with specialists.
  
• Primary or rheumatologic CNS vasculitis (non-infectious): For confirmed or highly suspected primary CNS vasculitis (cPACNS) and CNS vasculitis secondary to systemic rheumatic disease, the main treatment is immunosuppressive therapy. The first-line treatment is corticosteroids. Typically, high-dose IV methylprednisolone (for example, 20–30 mg/kg/day, up to approximately 1 g daily) is administered for 3–5 days during acute severe presentations (such as stroke or vasculitic encephalopathy), followed by high-dose oral prednisone (about 1–2 mg/kg/day, up to approximately 60 mg daily). If the disease is milder and detected early, some patients may start with oral prednisone alone. Steroids work quickly to reduce vessel inflammation and are often effective in reversing symptoms or at least stopping progression. However, to achieve long-term remission and reduce steroid exposure, cyclophosphamide is commonly used as a second-line or adjunct therapy, especially in moderate to severe cases. Cyclophosphamide (CYC) is usually administered as monthly IV pulses (e.g., 500–750 mg/m² per pulse) for about 6 months during induction, in combination with a steroid taper. In some adult series, cyclophosphamide has been used for up to 12–18 months, but in pediatric cases, a shorter induction (6–7 pulses) followed by transition to a steroid-sparing agent is preferred. For example, one pediatric protocol for small-vessel cPACNS involved corticosteroids plus 7 monthly cyclophosphamide pulses for induction, then switching to maintenance therapy with an oral immunosuppressant (such as azathioprine or mycophenolate mofetil) for 1–2 years. This approach yielded good outcomes in most patients. Maintenance therapy (with azathioprine, mycophenolate, or methotrexate) aims to prevent relapse after the initial aggressive treatment; it is typically continued for 1–2 years and then carefully tapered if the child remains in stable remission. If a secondary autoimmune disease like lupus is present, additional treatments specific to that disease (e.g., cyclophosphamide or rituximab for severe lupus cerebritis, IVIG or plasmapheresis in certain vasculitic syndromes, etc.) may be needed according to standard guidelines for that condition.
  
• Biologic therapies: In refractory cases or specific conditions, biologic immunomodulators are considered. As discussed, TNF-α inhibitors are the treatment of choice for DADA2-related vasculitis and can be lifesaving. In primary angiitis of the CNS that does not respond to steroids/CYC, some case reports support using rituximab (anti-CD20), especially if there is a suspicion of an autoimmune antibody–mediated process, or tocilizumab (anti-IL6) in certain inflammatory CNS syndromes. However, these decisions are made on a case-by-case basis. For pediatric PACNS, there is not yet a definitive second-line biologic, so these choices are made in collaboration with pediatric rheumatology specialists. If thrombosis or antiphospholipid syndrome is involved, anticoagulation may also be part of the treatment plan.
  
• Monitoring and adjunctive care: Children with CNS vasculitis often require inpatient supportive management, especially if they have suffered a stroke or severe neurologic deficits. Seizure control with anticonvulsants (if presenting with seizures or if vasculitis involves the cortex) is important. Neuroprotective measures (head elevation, ICU care for increased intracranial pressure if needed) may be required in acute encephalopathic presentations. Once stabilized, rehabilitation therapies (physical therapy, occupational therapy, speech therapy) are crucial to help regain lost function. From a monitoring standpoint, serial clinical exams and periodic imaging are performed to gauge response. Follow-up MRI/MRA imaging every 3–6 months is often used to monitor disease activity and ensure no new vessel lesions are developing. Inflammatory markers are trended (though they may not always reflect CNS activity, they can help in systemic cases). Medication side effect management is also a big part of care: children on high-dose steroids need gastric protection, blood sugar monitoring, blood pressure monitoring, and bone health management; those on cyclophosphamide need uroprotection (mesna), hydration, and blood count monitoring, etc. Families should be counseled on infection prevention since immunosuppression will elevate risk.
  
• Prognosis: Outcomes for pediatric CNS vasculitis have improved with early detection and aggressive treatment. Many children, particularly those with angiography-positive non-progressive cPACNS (such as post-varicella angiopathy), experience a single, monophasic illness and recover with minimal deficits if treated promptly. Progressive or small-vessel CNS vasculitis can be more difficult to manage, but remission is achievable in most cases with the appropriate therapies. Reported mortality rates for CNS vasculitis vary, but in modern pediatric series, most children survive and a significant number regain considerable function. Neurologic sequelae, such as persistent hemiparesis, cognitive or academic difficulties, or epilepsy, do occur in some cases, emphasizing the importance of long-term follow-up and supportive services. Relapses are possible, so children often require ongoing monitoring by rheumatology and neurology for years.
  

In summary, inpatient management of pediatric CNS vasculitis requires a balanced approach: first address infections, and if inflammatory vasculitis is confirmed or strongly suspected, initiate high-dose corticosteroids (adding cyclophosphamide in severe or refractory cases). It is advisable to consult pediatricrheumatology and neurology early, as these cases benefit from specialized input such as arranging diagnostic angiography or biopsy and guiding immunosuppressive therapy. Equally important is involving other disciplines for comprehensive care—such as rehabilitation medicine for recovery and neuropsychology for cognitive evaluations after illness. With timely diagnosis and appropriate treatment, many children with CNS vasculitis can experience meaningful recovery and prevention of further neurological injury.