The central role of the immune system in several pediatric central nervous system (CNS) disorders has been increasingly appreciated in recent years. Although relatively rare as individual diseases, collectively, they constitute a sizable proportion of pediatric neurology practice. The acute, severe symptoms associated with these disorders usually lead to inpatient hospitalization. Due to the broad differential diagnoses associated with these conditions, numerous other pediatric subspecialists, such as infectious disease and rheumatology physicians, are often asked to evaluate affected patients. Last, because of the potential long-term sequelae of both the monophasic and recurrent immune-mediated CNS disorders, all aspects of a patient’s medical and psychosocial care can be affected. Thus, these disorders have relevance to general pediatricians and pediatric subspecialists in both the inpatient and outpatient settings.
CNS IMMUNE-MEDIATED DEMYELINATING DISORDERS
Demyelinating disorders comprise the largest subgroup within CNS immune-mediated disorders. Demyelination leads to slowing or blockade of action potential propagation, with resulting symptoms referable to the affected CNS areas. Although remyelination can occur in the CNS, the thickness of the original myelin sheath is never reachieved. Demyelination can also lead to secondary axonal loss, which leads to permanent disability.
THE FIRST EPISODE OF DEMYELINATION
DEFINITIONS, TERMINOLOGY, AND CLASSIFICATION
With a first presentation of a CNS demyelinating disorder, determining whether the symptoms and signs are focal or multifocal serves as the initial step in classification (Fig. 548-1). Common locations for focal presentations include the optic nerve (optic neuritis), spinal cord (transverse myelitis), brain stem, and cerebellum, which collectively are termed clinically isolated syndromes (CIS). When multifocal symptoms and signs are present and accompanied by encephalopathy, the appropriate diagnosis is acute disseminated encephalomyelitis (ADEM), which can be further supported with magnetic resonance imaging (MRI). If multiple CNS locations are involved simultaneously but the mental status is normal, the appropriate diagnosis is a polysymptomatic CIS.
Algorithm for the classification of a first central nervous system (CNS) demyelinating attack. ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome.
In 2010, the McDonald criteria for the diagnosis of multiple sclerosis (MS) in adults were revised and have since been adopted for the diagnosis of pediatric MS. For the first time, these criteria allowed for the diagnosis of MS at the time of the first clinical attack, provided that specific MRI features were present that showed dissemination in space and time. Although this approach appropriately allows for an earlier diagnosis of MS and initiation of prophylactic treatment, given the implications of a diagnosis of MS, these criteria should be applied only by clinicians with the requisite expertise. With these newer criteria, some pediatric patients with a CIS will meet criteria for MS.
Although the differential diagnosis varies somewhat based on the site of CNS demyelination, general principles can be applied to all of the disorders. Many conditions can mimic and be mimicked by pediatric CNS demyelinating disorders. In addition, as there are no absolutely definitive diagnostic tests for CNS demyelinating disorders, a broad differential diagnosis must be considered. A complete discussion of the entire differential diagnosis is beyond the scope of this chapter. The main disease categories that should be considered are infectious diseases, rheumatologic disorders, metabolic disorders, and neoplastic conditions.
The treatment of pediatric CNS demyelinating disorders can be generally divided into acute and prophylactic phases. Acutely, attacks of demyelination are treated similarly, regardless of etiology (Fig. 548-2). High-dose intravenous (IV) corticosteroids are the first-line treatment to speed the recovery. The most commonly used protocol consists of IV methylprednisolone 30 mg/kg/dose (maximum 1 g) once a day for 3 to 5 days.
Algorithm for the treatment of an acute central nervous system (CNS) demyelinating attack. IVIg, intravenous immunoglobulin.
The use of oral steroid tapers following IV treatment is controversial. Patients who have complete or nearly complete resolution of symptoms, particularly those with MS, may not need tapers, but those with incomplete recovery may benefit from a 4-week taper. Due to the adverse effects of chronic corticosteroid use and the availability of other immunomodulatory agents, prolonged courses of oral steroids for the treatment of CNS demyelinating disorders is not recommended.
If significant functional disability remains after several days of observation following high-dose steroid treatment, additional options include plasma exchange and IV immunoglobulin (IVIg). IVIg is given as 0.4 g/kg/dose for 5 days or 1 g/kg for 2 days. The mechanism of action of IVIg is uncertain, but likely involves decreased production of autoantibodies. Plasma exchange may work via the removal of pathogenic autoantibodies from the circulation and usually is performed through the exchange of 1 plasma volume every other day for a total of 5 to 7 exchanges. The proposed algorithm (see Fig. 548-2) has been useful in practice but requires further study.
ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)
Acute disseminated encephalomyelitis (ADEM) is defined as an acute or subacute inflammatory demyelinating event affecting multifocal areas of the CNS with several accompanying symptoms, which must include encephalopathy. The incidence of ADEM is approximately 4 cases per 1 million persons younger than the age 20 per year. ADEM more commonly affects younger children than adolescents and adults, with a mean age of onset between 5 and 8 years of age.
Although the pathophysiology of ADEM is thought to be autoimmune-mediated, the precise mechanisms remain uncertain. Indirect evidence implicating the immune system includes the frequent association with a preceding viral infection as well as the apparent effectiveness of immunomodulation. The former point suggests that molecular mimicry, whereby epitopes on microorganisms mimic those found in CNS myelin and thus provoke an autoimmune response, may play a role in the pathophysiology of ADEM. As most of the infections reported to act as triggers for ADEM are very common, additional host susceptibility factors must be present in patients with ADEM but are largely undefined.
Children with ADEM present with a combination of nonspecific symptoms and signs suggestive of meningoencephalitis, as well as focal neurologic deficits. Approximately 65% of cases follow a viral illness usually occurring 7 to 14 days prior to the onset of neurologic symptoms. By definition, all patients with ADEM have altered mental status, with approximately 50% having reduced level of consciousness and 50% having less severe alterations in their mood and behavior. Pooled data from case series yield the following estimates for presenting symptoms and signs: motor (60%), fever (50%), headache (40%), vomiting (40%), ataxia (40%), cranial nerve deficits (40%), seizures (25%), and vision loss (15%).
CNS infection should be ruled out with lumbar puncture. Cerebrospinal fluid (CSF) analysis is abnormal in approximately 60% of patients with ADEM, with the most common findings being lymphocytic pleocytosis or elevated protein concentration, or both. Thus, basic CSF studies may not distinguish ADEM from encephalitis, and testing for specific causes of viral encephalitis should be performed.
Patients with a likely diagnosis of ADEM should undergo contrast-enhanced MRI of the brain and spine. MRI typically shows bilateral, asymmetric, multifocal hyperintense lesions on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. The lesions predominantly affect the cerebral white matter, more so in subcortical than periventricular regions. However, cortical, deep gray nuclei, brain stem, cerebellar, and spinal cord lesions are also seen (Fig. 548-3). Lesions tend to be large with ill-defined borders and lack contrast enhancement.
Axial fluid-attenuated inversion recovery magnetic resonance image (MRI) showing multifocal, large, ill-defined hyperintense lesions in the subcortical white matter, basal ganglia, and cortex in a 9-year-old girl with acute disseminated encephalomyelitis (ADEM) who presented with fever, headaches, encephalopathy, and weakness following a viral infection. Following steroid treatment, the symptoms and MRI findings resolved.
The initial treatment of ADEM is similar to that used for all acute attacks of CNS demyelination (see above). ADEM does not require chronic immunomodulation.
Approximately 80% of patients with ADEM make a full recovery. Most show significant improvement prior to hospital discharge, with the remainder of the recovery occurring gradually over several months. However, some patients are left with motor (10–15%), cognitive or behavioral (10%), epileptic (5–10%), or visual (5%) sequelae.
Approximately 80% of patients with ADEM experience a single event without recurrences. Based on the expert opinion of the International Pediatric MS Study Group (IPMSSG), symptoms occurring within 3 months of the initial onset of ADEM can be considered part of the initial event.
If a patient has a second episode of ADEM, the term multiphasic ADEM is used. Given the rarity of multiphasic ADEM, a broad differential diagnosis should be reconsidered before making this diagnosis. Patients with multiphasic ADEM do not generally require chronic immunomodulation.
The percentage of patients with an initial diagnosis of ADEM who later develop MS is uncertain. Estimates of this risk have ranged from 0% to as high as 18% in the existing literature, with a pooled average of approximately 10%.
ACUTE TRANSVERSE MYELITIS
Idiopathic, complete acute transverse myelitis (ATM) affects approximately 1.34 persons per million per year. In the pediatric age group, patients present at a mean age of 8 years, with an equal gender ratio.
Although the pathophysiology of ATM is uncertain, the frequent association with preceding infections and accumulating immunologic data support an inflammatory cause for the disorder. Approximately 50% of patients report a preceding infection, typically a nonspecific upper respiratory tract infection, with an intervening symptom-free interval of 5 to 11 days.
Patients with ATM universally report acute to subacute, bilateral leg weakness. Arm involvement occurs in approximately 40% of patients. Approximately 90% complain of bowel and bladder dysfunction and sensory symptoms, including paresthesias and numbness. A spinal cord sensory level is usually located in the thoracic region (80%) and, less commonly, in the cervical (10%) or lumbar (10%) area. A definite sensory level may be difficult to detect in young children. Back pain and fever afflict nearly 50% of patients. These symptoms develop rapidly, peaking at an average of 2 to 5 days.
Numerous disorders can affect the spinal cord and produce identical symptoms and signs that mimic idiopathic ATM. Such conditions must be ruled out through a combination of history, physical examination, neuroimaging, and laboratory evaluation. In patients with acute, isolated spinal cord dysfunction, extramedullary compressive lesions, including spinal epidural abscesses, spinal epidural hematomas, and tumors, are neurosurgical emergencies that must be diagnosed rapidly for effective treatment.
The initial clinical presentation of ATM can be similar to that of Guillain-Barré syndrome. Both can present with back pain, paraparesis, and sensory abnormalities. However, the presence of spinal cord sensory level and bowel and bladder involvement is highly suggestive of ATM.
Mild, asymmetric spinal cord symptoms, previous episodes of transient neurologic symptoms attributable to locations other than the spinal cord, and subclinical brain MRI lesions point toward MS. Concurrent or preceding optic neuritis, as well as other findings such as intractable vomiting or hiccups, suggests neuromyelitis optica (NMO) as a possible diagnosis.
Every patient with suspected ATM should undergo emergent gadolinium-enhanced MRI of the entire spine to confirm the diagnosis and rule out alternative diagnoses, particularly compressive lesions. All patients with ATM should also undergo gadolinium-enhanced MRI of the brain to assess for additional demyelinating lesions suggestive of ADEM or MS. Spinal MRI in ATM typically reveals T1 isointense and T2 hyperintense signal over several contiguous spinal cord segments and may involve the entire spine (Fig. 548-4). Contrast enhancement is present in as many as 74% of patients.
Sagittal T2-weighted magnetic resonance image (MRI) of the spine of a 16-year-old boy who presented with bilateral leg paresthesias that progressed to paraplegia and urinary and bowel retention. MRI demonstrates diffuse T2 hyperintense signal extending from C4 through the thoracic region to the conus medullaris. His symptoms resolved with high-dose steroids.
Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance. Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, are present in approximately 50% of patients. CSF glucose concentration is typically normal. A normal CSF profile does not rule out ATM, as it occurs in approximately 25% of patients.
The initial treatment of ATM is similar to that used for all acute attacks of CNS demyelination (see above). Case series have suggested a beneficial effect on ambulation and overall recovery of high-dose corticosteroids. For patients who do not improve adequately with IV steroids, IVIg or plasmapheresis can be considered.
As many as 80% of pediatric patients with ATM who receive high-dose IV steroids achieve full or good recovery, but some patients will remain nonambulatory and/or require bladder catheterization. During recovery, motor function typically returns first with return to independent ambulation over the course of 1 to 2 months, with slower recovery of bowel and bladder function. More than 90% of pediatric patients with idiopathic, complete ATM have a monophasic course. As opposed to complete ATM, partial ATM carries a much higher risk of developing MS.
Neuromyelitis optica (NMO) is a distinct CNS demyelinating disorder that typically includes attacks of transverse myelitis and can be diagnosed in patients meeting specific diagnostic criteria. Patients who have complete ATM preceded or followed by subsequent attacks of optic neuritis and/or other characteristic presentations (diencephalic syndrome, brain stem syndrome, area postrema syndrome) may have NMO. NMO IgG, an autoantibody that targets the predominant CNS water channel protein aquaporin-4, has been detected in approximately 70% of pediatric patients with NMO.
The incidence of optic neuritis in children is unclear. Data from case series suggest a mean age of onset from 9 to 12 years of age and an approximate 1.5:1 female-to-male ratio.
Similar to the other CNS demyelinating disorders, indirect evidence suggests that autoimmune mechanisms are involved in the pathogenesis of optic neuritis. Approximately 35% of patients report a viral infection.
The major presenting symptom of optic neuritis is vision loss, which typically affects the central visual field more than the periphery. In children, the vision loss is usually severe, with visual acuity of 20/200 or worse in approximately 75% of patients. Bilateral involvement occurs in 50%. Although highly suggestive of optic neuritis when present, pain with eye movements is not required for the diagnosis, as only 40% of pediatric patients report this symptom. In addition, a normal fundoscopic exam is seen in 30% of patients and does not rule out the diagnosis. Examination may also reveal an afferent pupillary defect and poor color vision.
Optic neuritis can be isolated or associated with more widespread involvement of the CNS, as in ADEM, MS, or NMO. It can also be associated with a variety of systemic autoimmune disorders. Although papilledema from increased intracranial pressure can appear the same as swelling of the optic discs from bilateral optic neuritis, the former typically presents more slowly, is not usually associated with severe vision loss (especially early in the course), and is not associated with an afferent pupillary defect.
Brain MRI with orbital sequences should be obtained in all patients with optic neuritis. Spine MRI should also be considered to define the extent of demyelination. Lumbar puncture with measurement of opening pressure should be performed. All patients with optic neuritis should be evaluated by an ophthalmologist with formal visual field testing.
Similar to patients with other acute CNS demyelinating syndromes, patients with optic neuritis are often treated with high-dose IV methylprednisolone. IVIg and plasma exchange can be considered for patients with steroid-refractory optic neuritis.
Despite the initially severe symptoms, most pediatric patients recover well from optic neuritis, with approximately 75% having visual acuity of 20/40 or better at follow-up. However, patients with optic neuritis frequently report subjective changes in vision, even when visual acuity returns to 20/20; this may be detected only with specialized techniques.
Despite the favorable prognosis for functional recovery, approximately 40% of pediatric patients with optic neuritis have or will develop MS. Older age of onset within the pediatric age range and asymptomatic brain MRI lesions significantly increase the risk of MS. Using the current criteria, some pediatric patients with optic neuritis will meet criteria for the diagnosis of MS at their initial presentation.
In children with recurrent CNS demyelination, the most likely diagnosis is pediatric-onset MS. Pediatric-specific criteria for the diagnosis of MS are based on the adult MS diagnostic criteria, with minor revisions, and incorporate both clinical and MRI findings.
The incidence of pediatric MS in the United States is approximately 0.5 per 100,000 children per year. Overall, between 3% and 10% of patients with MS develop their first symptoms prior to reaching 18 years of age. Approximately 80% of pediatric patients develop their first symptoms after age 10, with a steady increase in incidence during the teenage years and into adulthood. Overall, the mean age of onset within the pediatric MS population is between 11 and 14 years of age. Prior to age 10 to 12 years, the ratio of girls to boys affected is approximately 1:1; after this age, the ratio assumes the adult figure of approximately 2:1 to 3:1. This change in gender ratios around the onset of puberty likely reflects the influence of sex hormones on susceptibility to developing MS.
The pathologic hallmark of acute MS is the inflammatory plaque, with demyelination and variable degrees of axonal loss. Although many different types of immune cells participate in this process, perivascular lymphocytes and macrophages are the main cells in biopsy specimens. Both genetic and environmental factors contribute to the autoimmune response in MS.
Pediatric patients with MS typically present with an acute to subacute attack of neurologic symptoms, with the specific symptoms dependent on the affected CNS location. Pooled data from series of patients with pediatric-onset MS reveal that the presenting symptoms are similar to adult patients with MS with minor differences and include the following: sensory (25%), optic neuritis (20–25%), brain stem (20–25%), motor (20%), cerebellar (10–15%), and bowel/bladder (0–5%). Patients with pediatric-onset MS may initially present with ADEM, although the percentage is uncertain. ADEM may be a more common presentation in patients with disease onset younger than 10 years. Subsequent attacks involve similar symptoms as above, but recovery from attacks may be slower or less complete as disease duration progresses.
More than 95% of patients with pediatric-onset MS follow a relapsing-remitting course, with discrete attacks followed by complete or nearly complete recovery with intervening attack-free periods.
DIFFERENTIAL DIAGNOSIS AND EVALUATION
As described above and reviewed in detail elsewhere, there is an extensive differential diagnosis to consider when making the diagnosis of pediatric-onset MS. Despite the broad differential, the diagnosis of MS can be made with confidence and with focused testing in the overwhelming majority of patients, with adherence to the recommended criteria.
All patients with suspected MS should undergo gadolinium-enhanced MRI of the brain and spine. MRI shows discrete, ovoid T2 and FLAIR hyperintensities involving the white matter, with a predilection for the periventricular regions. A characteristic pattern involves such lesions oriented perpendicularly to the corpus callosum called “Dawson’s fingers,” which are shown especially well on sagittal FLAIR sequences (Fig. 548-5).
Sagittal fluid-attenuated inversion recovery magnetic resonance image showing hyperintense lesions radiating perpendicularly to the corpus callosum in a 12-year-old boy with relapsing-remitting multiple sclerosis.
Although the diagnosis of MS can be made without CSF data, many patients with suspected pediatric-onset MS undergo lumbar puncture for routine studies, as well as testing for CSF oligoclonal bands and IgG index.
The treatment of MS includes pharmacologic and nonpharmacologic approaches. The treatment of acute attacks is similar to that for other acute CNS demyelination (see above). The majority of attacks are likely to be treated with high-dose IV steroids, with the goal of speeding symptom resolution. However, because steroids do not significantly alter the long-term prognosis, mild attacks that do not impair function can be treated supportively.
Once the diagnosis of MS in children is made, prophylactic treatment should be offered so as to reduce the frequency of attacks and prevent long-term disability. There are 14 US Food and Drug Administration–approved treatments for MS in adults. None of these medications have been tested in randomized controlled trials in pediatric patients. A detailed discussion of these agents is beyond the scope of this text, and a physician experienced in the treatment of MS should prescribe and manage these medications. First-line treatment in pediatric MS is typically an intramuscular or subcutaneously injected β-interferon or glatiramer acetate. Children who cannot tolerate these treatments or who demonstrate breakthrough disease are considered for second-line agents, which include newer oral medications. More aggressive disease can require the use of IV agents, such as natalizumab (Tysabri). There is a trade-off in higher adverse event risk for greater drug efficacy with more aggressive treatments. Natalizumab has been associated with the development of JC virus–related progressive multifocal encephalitis (PML) in some adult MS patients.
Autoimmune encephalitis/encephalopathy (AE) encompasses a spectrum of immune-mediated brain disorders that cause severe neuropsychiatric manifestations due to autoantibody-driven disruption of normal synaptic communication. The true prevalence and incidence of childhood and adult AE subtypes is unknown. The prototype and most prevalent of the autoimmune encephalitides is N-methyl-D-aspartate (NMDA) receptor antibody encephalitis (NMDAR AE). Per a recent encephalitis registry study, NMDAR AE may be more prevalent in children and young adults than are certain viral encephalitides. Children with AE are still often misdiagnosed as having a CNS infection or a primary psychiatric condition and may seek care from multiple providers prior to getting a definitive AE diagnosis.
In adults, various forms of AE have a high association with occult neoplasms. However, children with AE have a lower incidence of occult tumors. In addition, pediatric AE as a manifestation of a paraneoplastic process is exceptionally rare outside of NMDAR AE. Approximately 40% of girls ages 12 to 18 years old with NMDAR AE may have an associated ovarian teratoma (often benign). It is exceptionally uncommon to have tumors found in pediatric males. The exact pathophysiology underlying most cases of pediatric AE is still unclear and may relate to an inappropriate immune response after an infection.
Manifestations of AE may include an acute or subacute (< 3 months) presentation of encephalopathy (confusion, altered sensorium, and/or reduced level of consciousness), seizures, cognitive dysfunction, psychiatric disease (mostly psychosis), and/or abnormal movements (eg, chorea and myoclonus). Infants and toddlers with AE may present with irritability and acute regression in speech and behavior. Signs of AE may not all present at once, and behavioral and psychiatric signs may often precede development of encephalopathy, seizures, and abnormal movements.
The presentation of AE is similar to that encountered in the setting of infectious meningoencephalitis, to include herpes encephalitis. It is appropriate to initiate empiric antibiotic and antiviral treatment until an underlying infection is ruled out. Acquired demyelinating conditions, such as ADEM, can present with altered mentation, seizures, and multifocal neurologic deficits. However, abnormal MRI findings are more common in ADEM than in most autoimmune encephalitides, which helps to distinguish such conditions. Rheumatologic diseases, including neuropsychiatric lupus, will more often have other constitutional signs and symptoms of systemic inflammatory disease. Specific antibody testing for rheumatologic conditions will also help to differentiate conditions. Primary psychiatric diseases that first develop in adolescence, such as schizophrenia, may be considered in the absence of other neurologic manifestations, and consultation with a pediatric psychiatrist can help to identify such conditions.
A significant majority of children with AE have CSF abnormalities (presence of CSF autoantibodies, elevated protein, pleocytosis, and/or oligoclonal bands). Electroencephalogram studies are abnormal in most children and reveal diffuse slowing (indicative of encephalopathy) and epileptogenic foci in children with seizures. Brain MRIs may be normal but may reveal subtle or transient inflammatory changes in any brain region. Unlike in systemic autoimmune or rheumatic conditions, acute phase response indicators (complete blood count [CBC], erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) may be lacking. Given the association of occult teratoma in NMDAR AE, a pelvic ultrasound or other imaging modality should be completed to look for an ovarian mass in older girls.
Serum and CSF antibody tests are clinically available for NMDAR AE as well as other less common forms of AE, such as those related to antibodies directed against potassium channels (VGKCs) or glutamic acid decarboxylase (GAD). The identification of a pathogenic antibody confirms the diagnosis of seropositive AE.
Immunomodulation and immune suppression with a combination of agents are often needed to improve symptoms and induce remission of disease. Combinations of corticosteroids, IVIg, plasmapheresis, rituximab, and/or cyclophosphamide are mainstays of many treatment regimens. In addition, resection of an identified teratoma will dampen propagation of the paraneoplastic immune response. Treatment is certainly indicated for confirmed seropositive AE. Many children with a clinical presentation suspicious for AE will not have an identified antibody. In the absence of an alternate diagnosis, a positive response of symptom improvement to initial empiric treatment with corticosteroids may provide support for the diagnosis of AE and guide further management decisions. Optimal care of children with AE requires the collaboration of multiple disciplines (neurology, hospitalists, psychiatry, rehabilitation, and rheumatology).
AE leads to protracted hospital stays with complex neurocognitive rehabilitation needs and may pose significant psychosocial strains on families and caregivers. Length of stays in NMDAR AE may be greater than 2 months and may include an intensive care unit component. The recovery period in NMDAR AE may last up to 18 to 24 months before psychiatric and cognitive deficits diminish. A good outcome (with no more than slight neurologic deficits) for both children and adults was seen in as many as 81% of NMDAR AE patients, according to 1 large cohort study assessing therapy and outcomes. Outcomes for children with non–NMDAR AE subtypes remain unknown.
Although rare, CNS vasculitis is increasingly recognized as a cause of acute and sustained neurologic deficit in children. Due to the invasive nature of diagnosis via biopsy, especially for angiographic-negative small vessel disease, it is likely underreported, and the exact incidence and prevalence are not known.
The pathogenesis of primary CNS vasculitis is uncertain. In some patients (especially with a nonprogressive focal process), reactivation of varicella-zoster virus (VZV) may play a role, as suggested by similarities with the associated post-varicella angiopathy and transient cerebral arteriopathy. Brain biopsies in pediatric patients with CNS vasculitis show lymphocytic infiltration of the blood vessel walls and not the predominant granulomatous patterns seen in adults with vasculitis.
Common presenting symptoms of CNS vasculitis include severe headaches, strokes, cognitive dysfunction, seizures, and, at times, constitutional complaints. Clinical features relate to the caliber and distribution of vessels that are involved, and disease can be either monophasic (nonprogressive) or relapsing (progressive). Patients within the progressive group present with both focal and diffuse neurologic symptoms, frequent multifocal MRI lesions, and involvement of the proximal and distal CNS vasculature. Diffuse symptoms such as headaches and behavioral changes may precede a child’s stroke in this subtype. Nonprogressive patients typically have a monophasic disease process and present with strokes, focal MRI lesions, and proximal vessel involvement on angiography. The nonprogressive subtype is usually characterized by a unilateral arteriopathy of a carotid or cerebral vessel. A characteristic difference between progressive and nonprogressive forms is that the former demonstrates multivessel involvement at presentation and radiographic disease progression on imaging performed 3 months after the initial presentation.
Inflammation of the CNS blood vessels can be restricted to the CNS (primary) or associated with a systemic inflammatory vascular process (termed secondary vasculitis). A secondary CNS vasculitis may be related to an underlying infection or a systemic rheumatic condition such as systemic lupus erythematosus (SLE) or systemic vasculitides (such as antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis) or a systemic vasculopathic process (such as Behçet syndrome). Although primary CNS vasculitis occurs in the absence of systemic disease, the differential diagnosis also includes noninflammatory vascular conditions such as moyamoya disease, sickle cell disease, and arterial dissection.
Primary CNS vasculitis of childhood can be diagnosed based on the following criteria: newly acquired and otherwise unexplained neurologic or psychiatric deficit, conventional or magnetic resonance (MR) angiographic or histologic evidence of CNS vasculitis, and no identifiable associated systemic condition. All patients should undergo gadolinium-enhanced MRI of the brain and spinal cord. Brain MRI is abnormal in virtually all patients with CNS vasculitis. Laboratory tests for systemic inflammation (such as an ESR and CRP) should be checked, but normal results do not exclude the diagnosis. Lumbar puncture should be performed, and CSF abnormalities may include an elevated opening pressure, increased protein, pleocytosis, and even oligoclonal bands in a small percentage of children.
The CNS vessels should be imaged initially with MR or computed tomography (CT) angiography. Whether or not conventional angiography provides additional sensitivity beyond MR or CT angiography on a per-patient basis is controversial. Patients with an angiography-positive presentation do not need a brain biopsy as their diagnosis is confirmed by vascular imaging and their inflammatory disease may be patchy and missed by tissue histology. Patients whose neurologic presentation is consistent with CNS vasculitis yet who have a normal cerebral angiogram will require a brain biopsy to confirm the diagnosis and to rule out potential noninflammatory mimics (such as a CNS infection or rarely a malignancy). The utility of a brain biopsy is dependent on obtaining all 3 layers of brain tissue and on being performed early in the diagnostic period (before more than 1 week of anti-inflammatory therapy). Lesional biopsies often are preferred to increase diagnostic yield. Positive biopsies reveal a lymphocytic small- vessel inflammatory process.
There have been no controlled treatment trials in pediatric CNS vasculitis. A commonly used regimen for progressive angiography-positive and small-vessel subgroups consists of high-dose corticosteroids and monthly cyclophosphamide for 6 months, followed by maintenance therapy with tapering dose of oral steroids and an oral immunosuppressant (predominantly azathioprine or mycophenolate mofetil). The optimal treatment of nonprogressive angiography-positive CNS vasculitis is even less clear but may include acyclovir (if there is a concern for VZV), corticosteroids, and antithrombotic therapy (often for 3 months). Low-dose aspirin should be considered in all patients to prevent secondary strokes. The prognosis of pediatric CNS vasculitis is guarded, with apparent better outcomes than in adult forms. With better recognition and earlier aggressive immunosuppression, it is thought that only 20% to 30% of children with primary CNS vasculitis will have persistent neurologic deficits.
NEUROLOGIC COMPLICATIONS OF RHEUMATOLOGIC DISEASE
Neurologic manifestations may complicate a host of underlying primary rheumatic conditions that are otherwise characterized by constitutional signs and symptoms. These conditions include autoimmune conditions such as SLE and lupus spectrum disorders (such as Sjögren and antiphospholipid antibody syndrome). Neurologic involvement may also complicate systemic inflammatory conditions such as sarcoidosis, Behçet syndrome, and systemic vasculitides (Takayasu, polyarteritis nodosa, and ANCA-associated vasculitides). Finally, novel autoinflammatory conditions such as the periodic fever syndromes may have associated neuroinflammatory signs and symptoms.
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE is the most prevalent rheumatic disorder in children that affects the nervous system. It only rarely affects the nervous system without affecting other organs. Other commonly affected organs include joints, skin, kidneys, and the bone marrow (cytopenias). Among pediatric patients with SLE, the true prevalence of neuropsychiatric involvement is debated, but it may affect a majority of children often during the first 2 years of their disease.
The pathogenesis of neuropsychiatric SLE (NPSLE) is uncertain but most often involves vascular abnormalities (predominantly vasculopathy and thrombosis that may lead to stroke or transient ischemic attack), as well as primary parenchymal brain disease mediated by autoantibody, complement, and cytokine-mediated damage.
At the time of neurologic dysfunction, a child with SLE may have arthritis, photosensitivity reactions, proteinuria, renal insufficiency, and/or cytopenias. Manifestations can be broadly divided into CNS, peripheral nervous system, and psychiatric signs and symptoms. The most common neurologic symptoms are headache, seizures, stroke, and affective disorders.
When a child with SLE presents with neurologic symptoms, it is important to rule out other causes. If a child is on immunosuppressive agents, CNS infections are to be ruled out promptly as the cause of neurologic dysfunction. Active renal disease and high-dose corticosteroids in SLE may lead to hypertension and metabolic derangements, which may impair neurologic function, as in hypertensive-mediated encephalopathy.
All children with systemic rheumatic disorders with neurologic manifestations should undergo gadolinium-enhanced MRI of the brain with MR angiography to assess for both parenchymal and vascular abnormalities. Lumbar puncture should be performed to rule out infection and assess for signs of neuroinflammation. Antiphospholipid antibodies, which are prevalent in a majority of children with SLE, play an important role in abnormal coagulation in cerebral blood vessels (vasculopathy) and must be checked in all patients with NPSLE.
The optimal treatment of pediatric NPSLE has yet to be studied in a controlled fashion. Mild symptoms such as headaches may be treated symptomatically with changes in corticosteroid dosing. Yet, more severe symptoms such as seizures, stroke, acute confusional state (altered sensorium), or transverse myelitis typically require immunosuppression with high-dose steroids and often monthly cyclophosphamide and/or B-cell depletion with rituximab. If thrombotic mechanisms are thought to play a role, anticoagulation (low-molecular-weight heparin or warfarin) may be added to anti-inflammatory regimens. Second-line immunomodulators for rheumatic conditions that affect the brain may target the specific immune pathway that is dysregulated (eg, tumor necrosis factor-α or interleukin-1).
The prognosis of pediatric NPSLE is variable and depends largely on the type and severity of the initial symptoms. In general, the presence of childhood NPSLE increases overall morbidity and is rarely a source of mortality.
et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics
et al. Clinical features of neuromyelitis optica in children. Neurology
et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known CNS autoantigens. J Neurol Neurosurg Psychiatry
et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler
et al. Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders. Neurology
. 2016;87(9, S2):S28–S37.
NF, Von Scheven
S. Neurologic manifestations of rheumatic disorders of childhood. In: Swaiman
KF, ed. Swaiman’s Pediatric Neurology. 5th ed. New York, NY: Elsevier Saunders; 2012:1437–1632.
et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–165.
SM. The spectrum of CNS vasculitis in children and adults. Nat Rev Rheumatol. 2012;8:97–107.
et al. Pediatric optic neuritis. Neurology
. 2016;87(9, S2):S53–S58.