Primary CNS Vasculitis of Childhood

Primary CNS vasculitis of childhood is a serious but potentially reversible inflammatory brain disease. With early recognition of this rare condition, effective treatment can be instituted in a timely manner.

CNS vasculitis in children can occur as a primary disease that is isolated to the CNS or as a secondary manifestation of an underlying systemic condition. Although numerous systemic inflammatory diseases and infections have long been recognized as responsible for causing secondary CNS vasculitis, primary CNS vasculitis of childhood has only recently been described as a reversible inflammatory brain disease in case reports and case series.[1, 2, 3]

CNS vasculitis was first described in an adult in 1959.[4] In 1992 the Calabrese diagnostic criteria for primary angiitis of the CNS in adults were described.[5] These consist of the following:

• A newly acquired neurological deficit

• Angiographic and/or histologic evidence of CNS vasculitis

• The absence of a systemic condition associated with these findings

To date no diagnostic criteria for children are available; thus, the adult definition is applied in practice.[6, 7] There are 2 main diagnostic categories: large-medium vessel disease and small vessel disease.

The diagnosis of large-medium disease is based on magnetic resonance angiography and conventional angiography evidence of vasculitis in the CNS, in the absence of underlying systemic inflammatory disease.[8] Lesions typically conform to the territory defined by a particular arterial distribution.

Small vessel CNS vasculitis affects vessels smaller than those seen by magnetic resonance angiography and conventional angiography. Therefore, by definition, this condition has negative angiography findings.[9] Lesions can be multifocal and bilateral and tend not to conform to a distinct vascular distribution. The diagnosis is confirmed by brain biopsy findings.

Large-medium vessel disease has been further subdivided into progressive and nonprogressive groups, which are defined by evidence of disease progression on angiography findings 3 months after diagnosis. Nonprogressive large-medium vessel vasculitis shares many similarities with both postvaricella angiopathy and transient cerebral arteriopathy of childhood. A significant overlap in the presentation and imaging findings among these conditions is often observed. Studies are needed to define the differences in pathophysiology and treatment requirements for each clinical disorder and to determine whether these are, in fact, distinct disease entities.

Children with progressive large-medium vessel disease typically have neurocognitive dysfunction at presentation, multifocal lesions on MRI, and evidence of distal stenosis on angiography.[8]

The risk of progression in terms of new vascular lesions is considered to be low when the presentation consists of an isolated stroke and imaging reveals evidence of unilateral, proximal vessel stenosis.[8] However, the risk of recurrent stroke due to the initial vascular injury in the same distribution is thought to be significant. Decreasing the subsequent stroke risk is the rationale for treating these patients with immunosuppressive therapy.[10]

Frequency

International

Because of the small of number of cases that have been described to date, estimating the frequency is not possible. As recognition of this condition increases, the number of cases that are diagnosed and treated appropriately also increases.

Mortality/Morbidity

A small number of case reports have described fatalities resulting from this disease.[11] However, although the neurological compromise observed at initial presentation may be very grave and even life-threatening, most children survive. In the past, this condition may have gone unrecognized, meaning severe, refractory, and even fatal cases of status epilepticus or stroke in the pediatric population may have been attributable to undiagnosed primary CNS vasculitis. Practice guidelines to aid in the diagnosis of status epilepticus have been established.[12]

Morbidity is not uncommon, and includes a wide variety of diffuse and focal neurological deficits. Expectations for neurological improvement should be guided by the principal that although brain inflammation is reversible, ischemia is not. With early recognition and prompt treatment, including immunosuppression and anticoagulation when appropriate, the morbidity related to this disease can be greatly decreased. In current studies, good neurological outcome has been reported in 45% of patients with progressive large-medium vessel disease, in 31% of patients with nonprogressive large-medium vessel disease, and in 69% of patients with small vessel disease.[8, 13] Tools such as the Pediatric Stroke Outcome Measure can be used to quantify neurological deficits on serial clinical assessments.

Race

No race predilection has yet been identified.

Sex

Currently, no evidence suggests that one sex is affected more frequently than the other.

Age

This disease has been described in children as young as infancy and as old as adolescence. No peak in age distribution has been identified.

A broad spectrum of clinical presentation in patients with primary CNS vasculitis of childhood is observed, ranging from an insidious onset of headache,[14] cognitive decline, behavior changes or psychosis, an acute stroke, seizures, or status epilepticus. Optic neuritis (in particular bilateral) and cranial nerve palsies have also been seen. The presentation may be affected by the type of vascular lesion (large-medium vs small vessel), as well as the location of discrete lesions seen on MRI and angiography.

• Large-medium vessel disease frequently presents with focal deficits, including acute hemiparesis, hemisensory deficit, or fine motor deficit. Diffuse deficits are also seen in this condition and may include headache, concentration and cognitive deficits, behavior and personality changes, and seizures. Neurocognitive dysfunction and headaches are reportedly more frequent in progressive large-medium vessel disease, whereas hemiparesis is a more common presentation in nonprogressive large-medium vessel disease.[8]

• Small vessel disease also has a wide variety of presentations, including seizures (either acute onset or a chronic seizure disorder), headache, neurocognitive deficits, and psychiatric symptoms, including psychosis. Focal deficits that involve gross motor skills, fine motor skills, and sensory function are also seen.[9, 15]

• Constitutional symptoms are uncommon in patients with large-medium vessel disease but can be present in a minority of patients with small vessel disease. These may include fever, fatigue, and flulike symptoms. In general, such systemic symptoms should prompt investigation for infection or other secondary cause of CNS vasculitis.

• Eliciting features of systemic inflammatory disease that exclude the diagnosis of primary CNS vasculitis is important. These may include rashes, arthritis, respiratory symptoms, urinary abnormalities, and GI symptoms among others.

The physical examination findings generally reflect the neurological symptoms that are present, as well as any constitutional features that are part of the patient's disease. Most importantly, as with the history, signs of systemic inflammatory disease that may indicate secondary rather than primary CNS vasculitis should be sought.

• A full neurological examination that includes cranial nerve, fine and gross motor, sensory, cerebellar, and reflex testing is essential.

• Assessment of neurocognitive deficits is important and may include objective tools such as the Pediatric Stroke Outcome Measure.

• Some patients may be able to compensate to a certain degree for long-standing cognitive impairment; as such, deficits may not be readily apparent on informal testing. A formal assessment completed by a neuropsychologist or other professional with expertise in this field is often helpful in fully delineating the degree of dysfunction.

• The systemic examination should be thorough because findings such as oral ulcers, alopecia, lymphadenopathy, hepatosplenomegaly, rash, arthritis, or respiratory abnormalities may indicate an underlying systemic disease responsible for the neurological symptoms.

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• The cause of primary CNS vasculitis of childhood is unknown. Given the commonalities noted between CNS vasculitis and postvaricella angiopathy, an infectious trigger may be responsible; however, none has been identified to date.

• By definition, any case of CNS vasculitis caused by an underlying systemic disease is not primary CNS vasculitis.

The goal of the workup in patients with suspected primary CNS vasculitis of childhood should be to rule out other causes of secondary CNS vasculitis and to look for markers of inflammation. Inflammatory changes in the blood are often not present; however, this does not exclude the diagnosis. If the clinical suspicion is high, investigation beyond simple laboratory tests is still indicated.

• CBC count and differential may reveal mild anemia and elevated WBC count.[9, 16]

• Erythrocyte sedimentation rate, C-reactive protein levels, and von Willebrand factor antigen levels may be elevated.[9, 16] Nonspecific markers of inflammation may also include elevated complement and immunoglobulin levels.

• Creatinine and BUN levels should be measured and urine microscopy should be performed to rule out evidence of systemic inflammatory disease that involves the kidney.

• No specific autoantibody pattern has been identified in isolated CNS vasculitis. However, autoantibody testing should be considered to investigate for underlying connective tissue or systemic vasculitic disease.

• Infectious and prothrombophilic studies may be indicated to rule out CNS vasculitis secondary to infection or thromboembolic stroke unrelated to inflammatory brain disease. The role of anticardiolipin and lupus anticoagulant have not yet been elucidated in primary CNS vasculitis.

Brain imaging is a crucial stage in investigation of suspected isolated CNS vasculitis. Brain MRI is the first step. MRI sequences in investigation of CNS vasculitis should include the following:

• Sagittal T1

• Axial T2, fluid-attenuated inversion recovery (FLAIR), which may reveal areas of signal hyperintensity in both large-medium and small vessel disease

• Diffusion weighted imaging (DWI), which can identify areas of ischemia in large-medium vessel disease

• Coronal T2

• Magnetic resonance angiography to delineate large-medium vessel abnormalities[17]

• Magnetic resonance venography

• Postcontrast axial 3-dimensional spoiled gradient recalled (SPGR) and coronal T1 spin echo (T1SE) to reveal abnormal enhancement (if abnormalities are identified on the sequences mentioned above and no contraindications to contrast are noted)

Postcontrast techniques to evaluate vessel wall inflammation are currently under investigation and may prove to be of significant use in identifying active vascular inflammation in large-medium vessel disease.

Conventional angiography is performed in most children with large-medium vessel disease to confirm and further delineate abnormalities seen on magnetic resonance angiography. Conventional angiography may be more sensitive than magnetic resonance angiography in identifying distal lesions that affect small caliber vessels. In patients with suspected small vessel disease, angiography is performed to confirm that no demonstrable large-medium vessel abnormalities are present. By definition, small vessel disease has negative angiography findings.

In large-medium vessel disease, brain MRI classically reveals areas of acute ischemia in a vascular distribution.[18, 19] These lesions may be unilateral in nonprogressive disease and are typically multifocal in progressive disease.[8] They may involve gray and white matter. Magnetic resonance angiography and conventional angiography provide detailed assessment of the vasculature and characteristically reveal beading, tortuosity, stenosis, and occlusion of the vessels.[20]

In small vessel disease, brain MRI reveals lesions that may be bilateral or unilateral, multifocal, and involve both gray and white matter.[9] Unlike the lesions seen in large-medium vessel disease, these lesions do not usually conform to a vascular distribution. Meningeal enhancement can be seen, which may help differentiate this condition from other inflammatory brain diseases such as multiple sclerosis. As mentioned above, by definition, conventional angiography findings are negative.

Lumbar puncture is an essential part of the diagnostic workup. The results often reveal elevated opening pressure, mildly elevated white cell count, and elevated protein.[8, 15, 21] However, as with serum markers of inflammation, the findings may be within the reference range.

Assessment by an ophthalmologist to look for retinal vasculitis, signs of underlying infection, or signs of other inflammatory disease is important.

Brain biopsy for confirmation of the diagnosis of CNS vasculitis in the case of negative conventional angiography findings has been a useful tool and should be considered in all suspected cases of small vessel disease.[22] Performing a biopsy of a lesion seen on neuroimaging, with tissue samples that capture the leptomeninges, cortex, and white matter, is preferable. Nonlesional biopsy should be considered when the clinical suspicion is high and the lesions identified on imaging are not easily accessible.

Ideally, a biopsy of a peripheral lesion identified on MRI should be performed prior to or at the onset of treatment with corticosteroids. A prolonged course of steroids decreases the sensitivity of the biopsy findings and can lead to indeterminate histology.

A brain biopsy is typically performed to aid in the diagnosis of CNS vasculitis with negative angiography findings, as opposed to large-medium vessel disease, in which confirmation is made using imaging modalities. The biopsy findings characteristically reveal segmental, nongranulomatous, intramural infiltration of arteries, arterioles, capillaries, or venules.[9, 15]

The predominant inflammatory cells involved are T cells. Calcification and pallor of myelin staining may also be observed in the surrounding tissue. Gliosis can be seen in long-standing disease.

No controlled trials have described treatment protocols for primary CNS vasculitis of childhood. The treatment of progressive large-medium vessel disease and small vessel disease consists of immunosuppression in induction and maintenance phases, with anticoagulation as appropriate.[13]

• Induction immunosuppression occurs over a 6-month period and includes 7 pulses of intravenous cyclophosphamide administered every 4 weeks, as well as high-dose corticosteroids.[23] Prophylaxis against Pneumocystis jirovecipneumonia (formerly Pneumocystis carinii pneumonia) with a medication such as cotrimoxazole is important while receiving cyclophosphamide.

• Following the completion of induction with cyclophosphamide, maintenance therapy that consists of oral azathioprine or mycophenolate mofetil continues for 18 months, with weaning doses of oral corticosteroids to continue administration of immunosuppressive therapy.

• In adults, rituximab, a monoclonal antibody that depletes B cells, is challenging the role of cyclophosphamide. However in pediatric systemic vasculitis, its role is limited to those patients who have disease refractory to current conventional therapy.

• Low molecular weight heparin administered for a brief period at presentation, followed by an antiplatelet agent, is frequently used in progressive large-medium vessel disease.

• The treatment of nonprogressive large-medium vessel disease is controversial but often consists of a 3-month course of high-dose corticosteroids and an antiplatelet agent.

• Control of symptoms such as seizures and psychosis is of paramount importance and may require anticonvulsants, psychiatric medications, or other medications.

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• A multidisciplinary approach that involves a rheumatologist, neurologist, radiologist, physiotherapist, occupational therapist, and social worker is required.

• Involving a psychiatrist, speech and language pathologist, or neuropsychologist for both assessment and treatment of this condition may be appropriate.

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• A healthy diet with low fat and sodium intake is appropriate when a patient begins corticosteroid treatment.

• Adequate intake of calcium and vitamin D, with supplementation when necessary, is essential when children are treated with corticosteroids.

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• Activity restrictions should be based on symptoms. For example, this may include support with ambulation if instability is present during the initial stages or restrictions on driving if seizures are part of the disease.

Class Summary

Induction immunosuppression occurs over a 6-month period with cyclophosphamide, followed by 18 months of maintenance therapy with azathioprine or mycophenolate mofetil. An oral corticosteroid is administered with cyclophosphamide before a slow, controlled taper during maintenance therapy.

Cyclophosphamide (Cytoxan)

Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.

When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T-cell functions.

Azathioprine (Imuran)

Imidazolyl derivative of 6-mercaptopurine. Many of biological effects are similar to those of parent compound. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after taken.

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Mechanism whereby azathioprine affects autoimmune diseases is unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. As many as 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/mL or lymphocyte count to drop below 1000/mL.

Available in tablet form for PO administration or in 100-mg vials for IV injection.

Mycophenolate mofetil (CellCept)

Inhibits inosine monophosphate dehydrogenase and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Class Summary

An oral corticosteroid is administered with cyclophosphamide. Attempt a slow, controlled downward dosage taper during maintenance therapy.

Prednisone (Deltasone, Prednisone Intensol Concentrate)

Used to control acute symptoms and laboratory evidence of inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Class Summary

Low molecular weight heparin is administered for a brief period at presentation and is followed by an antiplatelet agent; this is frequently administered in progressive large-medium vessel disease.

Enoxaparin (Lovenox)

Produced by partial chemical or enzymatic depolymerization of UFH. Binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).

Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared to UFH.

Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications, or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.

Used to treat DVT or PE in conjunction with warfarin for inpatient treatment of acute DVT with or without PE or for outpatient treatment of acute DVT without PE.

No use in checking aPTT (drug has wide therapeutic window and aPTT does not correlate with anticoagulant effect). Titrate dosing based on enoxaparin levels. Average duration of treatment is 7-14 d.

Aspirin (Bayer)

Odorless white powdery substance available in 81 mg, 325 mg, and 500 mg for PO administration. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids.

Stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. Acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero order pharmacokinetics.

Irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for life of cell (approximately 10 d).

May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Reduces likelihood of myocardial infarction. Also very effective in reducing risk of stroke. Early administration of aspirin in patients with AMI may reduce cardiac mortality in first mo.

Ongoing close follow-up with a multidisciplinary team is important in primary CNS vasculitis of childhood. The particular needs of each patient should be identified and addressed as they arise during treatment. These may include educational support for reintegration in school, adequate seizure control, and emotional support of the family, among others.

• In both small vessel disease and large-medium vessel disease, MRI should be repeated at 3 months and 6 months following disease onset to study the changes in parenchymal brain lesions. In large-medium vessel disease, little improvement in the vessel anatomy may be observed until 6 months after diagnosis, at which time conventional angiography should be performed. Of course, should clinical symptoms change or disease progression be suspected, early imaging is appropriate.

• Once a diagnosis of small vessel disease is confirmed by biopsy findings, further biopsies do not need to be performed.

• The involvement of psychiatrists to assist with behavioral symptoms secondary to inflammatory brain disease is often necessary; psychiatric medication may be needed.

• Serial cognitive assessments with the Pediatric Stroke Outcome Measure are a useful way to quantify deficits.

• Annual neuropsychological assessments for evaluation of cognitive deficits and identification of assistance needed in school should be performed.

• Structured quality-of-life assessments using standardized questionnaires can provide insight into the impact of disease on a child's daily life.

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• Complications are mostly related to the immunosuppression and anticoagulation that constitute therapy for the different varieties of primary CNS vasculitis. Side effects of prednisone, such as weight gain, susceptibility to infection, hypertension, and osteopenia, can be seen with the prolonged course of corticosteroids that are a mainstay of treatment.

• Complications related to disease, such as ongoing seizure disorder, may be noted. Flare of the disease is possible even while receiving therapy. The neurological signs that accompany this may be subtle, and repeating neuroimaging to ascertain the presence of new lesions on MRI or conventional angiography is often necessary. This may require increasing current immunosuppression or the institution of a different immunosuppressive medication to induce remission.

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• With early recognition and prompt treatment, prognosis can be excellent.[24] Neurological recovery may take place over months, during which time physical therapy, occupational therapy, speech language therapy, appropriate schooling, and seizure control should be continued. Families of patients affected with primary CNS vasculitis should be prepared for a prolonged rehabilitation period.

• Although many patients exhibit complete neurological recovery, deficits may remain after completion of treatment. This may include focal and diffuse neurological deficits and behavioral and cognitive symptoms.