Rudolph's Pediatrics, 22nd Ed.

CHAPTER 556. Immune- and Inflammatory-Mediated Central Nervous System Syndromes

Mark P. Gorman

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, multiple 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. Myelin is composed of a lipid bilayer of cholesterol, phospholipids, and glycolipids along with membrane-associated proteins, such as proteolipid protein and myelin basic protein.1,2 In the CNS, oligodendrocytes produce myelin, which surrounds axons with periodic interruptions at nodes of Ranvier. The main functions of myelin are to speed the conduction of action potentials along axons and to support the development and maintenance of axons.

Myelin can be injured by many different mechanisms, such as hypoxia, metabolic derangements, and toxic insults. The disorders discussed in this chapter are considered to have an autoimmune etiology, with loss of tolerance resulting in an aberrant, self-reactive inflammatory process directed against CNS myelin.

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.3 Demyelination can also lead to secondary axonal loss, which leads to permanent disability.4

FIRST ATTACK OF DEMYELINATION

DEFINITIONS, TERMINOLOGY, AND CLASSIFICATION

In the past, variable terminology and lack of consistent definitions in the literature hampered our understanding of pediatric CNS demyelinating disorders. In April 2007, diagnostic definitions were proposed by the International Pediatric Multiple Sclerosis (MS) Study Group.5 Although they have not yet been prospectively validated, these definitions provide a very useful framework both for clinical and research purposes.

With a first presentation of a CNS demyelinating disorder, determining whether mental status changes are present or absent serves as the initial step in classification (Fig. 556-1). When present and accompanied by multifocal symptoms, the appropriate diagnosis is acute disseminated encephalomyelitis (ADEM), which can be confirmed with magnetic resonance imaging (MRI). When the patient’s mental status is normal, first-time acute demyelinating events are collectively referred to as clinically isolated syndromes (CIS). Clinically isolated syndromes can be subdivided based on whether the symptoms and signs are focal or multifocal. Common locations for focal CIS include the optic nerve (optic neuritis), spinal cord (transverse myelitis), brain stem, and cerebellum. If multiple CNS locations are involved simultaneously but the mental status is normal, the appropriate diagnosis is a polysymptomatic CIS.

FIGURE 556-1. Algorithm for the classification of a first central nervous system (CNS) demyelinating attack. ADEM, acute disseminated encephalomyelitis, CIS, clinically isolated syndrome.

A patient with a CIS may have evidence of demyelination on MRI in numerous CNS sites without accompanying clinical symptoms and signs. Although such an MRI finding is important for the patient’s prognosis for the development of MS, it does not alter the diagnosis, which is based on clinical findings. For example, a patient with optic neuritis, normal mental status, and multiple, asymptomatic brain and spine MRI lesions should be classified as having optic neuritis, not ADEM, and is at high risk to develop MS.

Demyelination of the spinal cord (myelitis) can be partial with mild, asymmetric motor and sensory symptoms, or complete with severe, symmetric motor, sensory, and autonomic symptoms. Partial myelitis is a type of CIS and carries a high risk for the development of MS, and the complete form poses little risk of recurrence in the pediatric population. The term acute transverse myelitis (ATM) should be reserved for the complete form. Definitions of ATM have varied significantly in the literature. In 2002, the Transverse Myelitis Consortium Working Group published useful diagnostic criteria.6

GENERAL ASPECTS OF THE DIFFERENTIAL DIAGNOSIS

Although the differential diagnosis varies somewhat based on the site of CNS demyelination, general principles can be applied to all of the disorders. There are many conditions that 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 but it has recently been reviewed.7 In common practice, one will obtain laboratory tests including erythrocyte sedimentation rate, C reactive protein, serum Lyme titers, antinuclear antibody, and vitamin B12 level in all patients with CNS demyelinating disorders, with additional testing if necessary as guided by the history and examination. In general, the differential diagnosis and subsequent workup should be expanded in patients with younger onset, progressive decline in function, poor response to immunomodulation, and extra-CNS organ system involvement. The main disease categories that should be considered are infectious diseases, rheumatological disorders, metabolic disorders, and neoplastic conditions.

Regarding infectious diseases, microorganisms can directly infect the CNS (Fig. 556-2A) or can infect peripheral organs and secondarily trigger an autoimmune response. If there is any clinical concern for CNS infection in a patient with suspected CNS demyelination, cerebrospinal fluid (CSF) should be examined for common infections, such as enterovirus, and serious, treatable infections, such as herpes simplex virus, with polymerase chain reaction testing. Additional infectious disease testing can be tailored based on the season of the year and the patient’s geographic region, exposures, and immunocompetence, with strong consideration given to testing for Borrelia burgdoferi, Mycoplasma pneumoniae, and Epstein-Barr virus.

Many rheumatological disorders such as systemic lupus erythematosus (SLE) have been associated with CNS complications, which may be partially mediated by inflammatory demyelination (Fig. 556-2B).  Primary and secondary CNS vasculitis can also mimic demyelination and should be considered, particularly when headaches are a prominent symptom, symptoms recur during steroid withdrawal, or MRI reveals significant cortical involvement (Fig. 556-2C).

Leukodystrophies are genetic and metabolic disorders that preferentially affect the white matter and therefore mimic CNS demyelination. In patients with a subacute to chronic course, progressive degeneration, and symmetric white matter involvement on MRI, metabolic testing should be considered, with specific tests based on the patient’s age, presentation, and MRI findings (Fig. 556-2D). These disorders are discussed in Chapter 576.

FIGURE 556-2. A: Axial fluid attenuated inversion recovery (FLAIR) magnetic resonance image (MRI) with hyperintense signal mainly in the right frontal cortex and deep gray matter of a 6-year-old boy who presented with fever, left-sided weakness and left-sided focal motor seizures. Cerebrospinal fluid polymerase chain reaction testing was positive for Epstein-Barr virus. B: Axial FLAIR MRI showing discrete hyperintensities in the subcortical white matter bilaterally in a 12-year-old girl who presented with chorea and hematuria. Workup revealed positive antinuclear antibody, and she was diagnosed with systemic lupus erythematosus (SLE). C: Axial FLAIR MRI with bilateral hyperintense signal in the subcortical white matter and cortex diffusely in a 5-year-old boy who presented with seizures and encephalopathy. Brain biopsy was consistent with primary CNS vasculitis. D: Axial FLAIR MRI showing bilateral symmetric hyperintense signal involving all of the cerebral white matter with sparing of the immediate subcortical region in a 7-year-old boy who presented with a 2-year history of progressive cognitive decline followed by ataxia. Biochemical and genetic testing was consistent with metachromatic leukodystrophy. E: Axial T2-weighted MRI showing a large heterogeneous lesion in the deep white matter of the left temporal-parietal region with extensive surrounding edema mimicking a tumor in an 8-year-old girl who presented with headaches, diplopia, and seizures. Biopsy of the lesion revealed perivascular lymphocytic and monocytic infiltration with patchy demyelination. F: Axial FLAIR MRI showing discrete, ovoid hyperintense lesions involving the periventricular more than the subcortical white matter in a 17-year-old boy who presented with right-sided numbness. His diagnostic workup and subsequent course was consistent with relapsing-remitting multiple sclerosis.

Neoplasms can be confused with demyelination, particularly when there is a large, focal inflammatory lesion (ie, tumefactive demyelination) (Fig. 556-2E). MRI of the entire neuroaxis to look for multifocal involvement and cytological examination of the CSF should be obtained in such circumstances. Rarely, biopsy of the lesion is needed to make a definitive diagnosis.

GENERAL ASPECTS OF ACUTE TREATMENT

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. 556-3). High-dose intravenous (IV) corticosteroids are the first-line treatment.

Although not formally tested in pediatric patients, high-dose IV corticosteroids are used for the initial treatment of acute attacks of demyelination. The most commonly used protocol consists of methylprednisolone 20 to 30 mg/kg/dose (maximum 1 gram) intravenously once a day for 3 to 5 days. During use of this steroid, pulse, vital signs, especially blood pressure, and glucose control should be monitored. Ulcer prophylaxis should be used. Common adverse side effects include insomnia and mood changes.

The use of oral steroid tapers following intravenous treatment is controversial. Patients who have complete or nearly complete symptom resolution may not need tapers, but those with incomplete recovery may benefit from a 2- to 3-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 intravenous immunoglobulin (IVIg) and plasma exchange. Based on case reports, IVIg 0.4 grams/kg for 5 days or 1 gram/kg for 2 days can be used as second-line treatment.11,12 The mechanism of action of IVIg is uncertain, but likely involves decreased production of autoantibodies.13

If IVIg is ineffective, plasma exchange administered every other day for a total of 5 exchanges can be considered. This regimen has been used successfully in 1 case series of 6 pediatric patients with ADEM who did not respond adequately to steroids and IVIg.14

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)

EPIDEMIOLOGY

Acute disseminated encephalomyelitis (ADEM) is defined as an acute or subacute inflammatory demyelinating event affecting multifocal areas of the CNS with multiple accompanying symptoms, which must include encephalopathy.5 The incidence of ADEM is approximately 4 cases per 1 million persons under the age 20 per year.18 It is more common in children than adolescents and adults, with a mean age of onset between 5 and 8 years of age.

PATHOPHYSIOLOGY

Although the pathophysiology of ADEM is likely autoimmune mediated, the precise mechanisms remain uncertain. Indirect evidence implicating the immune system includes the frequent association with a preceding viral infection or, less commonly, a vaccination, 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.

Both B and T lymphocytes appear to play a role in ADEM. Regarding B cells, autoantibodies to myelin oligodendrocyte glycoprotein were found in 20% of patients with ADEM.20 Antimyelin autoreactive T cells have also been found in the serum of a small group of patients with ADEM.21 Additional work is needed to clarify the immune and genetic mechanisms of ADEM.

Although biopsies are rarely needed to establish the diagnosis of ADEM, those that are performed provide more direct evidence of the role of the immune system. Biopsy specimens typically show perivenous infiltrates of lymphocytes and macrophages with accompanying demyelination and relative axonal sparing (Fig. 556-4).

FIGURE 556-3. Algorithm for the treatment of an acute central nervous system (CNS) demyelinating attack. IVIg, intravenous immunoglobulin.

CLINICAL PRESENTATION

Children with ADEM present with a combination of nonspecific symptoms and signs suggestive of meningoencephalitis, as well as focal neurologic deficits. Approximately 70% of cases follow a viral illness or vaccination, usually occurring 7 to 14 days prior to the onset of neurological symptoms. The most common associated infection is a nonspecific upper respiratory tract infection. Pooled data from nine case series totaling 411 patients 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%).18,22-29 Thus, a typical clinical scenario is that of a previously healthy child who develops a nonspecific infection, fully recovers, and then develops acute encephalopathy and multifocal neurological symptoms and signs.

DIFFERENTIAL DIAGNOSIS

As suggested by these symptoms, the presentation of ADEM can be indistinguishable from meningoencephalitis. Thus, direct CNS infection should be ruled out with lumbar puncture and appropriate studies in all patients with suspected ADEM. 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.18,22-29Thus, basic CSF studies may not distinguish ADEM from encephalitis, and testing for specific causes of viral encephalitis should be performed. Additional testing should be guided by clues in the history, examination, or neuroimaging as described above.

DIAGNOSTIC EVALUATION

All patients with acute disseminated encephalomyelitis (ADEM) should undergo contrastenhanced MRI of the brain and spine. Although patients with ADEM may initially require computerized tomography (CT) of the head to rule out other emergent conditions, CT has a poor sensitivity of approximately 40% when compared to MRI in patients with ADEM.18,22-29 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 rather than periventricular regions. However, cortical, deep grey nuclei, brain stem, cerebellar, and spinal cord lesions are also seen (Fig. 556-5). Lesions tend to be large with ill-defined borders and lack contrast enhancement.

TREATMENT

The initial treatment of ADEM is similar to that used for all acute attacks of CNS demyelination (see above). In addition to immunomodulation, supportive care during the acute attack may include airway management in patients with depressed mental status, anticonvulsants in patients with seizures, and pain management. As ADEM is a terrifying event for patients and their families, psychosocial support should also be given. By definition, ADEM is a monophasic disorder and does not require chronic immunomodulation. However, patients with ADEM are at risk for long-term sequelae (see below) and therefore should be followed by a pediatric neurologist with treatment of cognitive deficits, physical handicaps, and epilepsy, as appropriate.

PROGNOSIS

Approximately 80% of patients with ADEM make a full recovery.18,22-29 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.18,22-29 Cognitive sequelae may be more common than previously appreciated, as suggested by 2 recent studies that demonstrated a high percentage of cognitive deficits with formal neuropsychological testing, particularly in patients with the onset of ADEM at less than 6 years of age.30,31 Thus, children with ADEM should be followed closely for declines in cognition or school performance following the acute illness.

FIGURE 556-4. Autopsy specimen of the subcortical white matter from an 18-year-old boy who presented with lethargy, seizures, and ataxia following a viral infection. Despite treatment, the patient developed brain herniation and died. The specimen shows intense perivenular mononuclear cell infiltration (round, purple cells) with associated demyelination indicated by absence of Luxol fast blue staining in the perivenular white matter. The remainder of the white matter is relatively spared. (Source: Courtesy of Hart Lidov, MD, Department of Pathology, Children’s Hospital, Boston.)

FIGURE 556-5. 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.

Approximately 80% of patients with ADEM experience a single event without recurrences.18,22-29 Based on the expert opinion of the International Pediatric MS Study Group, symptoms occurring within 3 months of the initial onset of ADEM can be considered part of the initial event.5

The reemergence of the initial symptoms after 3 months has been designated recurrent ADEM. If the symptoms are different than the initial presentation, the term multiphasic ADEM can be used5 (Fig. 556-6). Both recurrent and multiphasic ADEM require that the relapses be accompanied by mental status changes. Multiphasic ADEM is less common than recurrent ADEM, occurring in less than 5% of patients overall.18,22-29 Given the relative rarity of recurrent and multiphasic ADEM, a broad differential diagnosis should be reconsidered before making these diagnoses. Patients with recurrent or multiphasic ADEM do not generally require chronic immunomodulation, but it could be considered for unusual patients with frequent or severe attacks. If mental status changes are not present during the second event following ADEM, it will most likely represent a CIS-type event (ie, optic neuritis).

The percentage of patients with an initial diagnosis of ADEM who later develop MS is uncertain. Estimates of this risk have ranged from 0%26 to as high as 18%32 in the existing literature, with a pooled average of approximately 10%.18,22-29 Although there are no highly predictive risk factors, optic nerve involvement with ADEM, family history of CNS demyelination, and MRI features suggestive of MS may increase the risk of developing MS following ADEM.32

FIGURE 556-6. Algorithm for classifying recurrent demyelinating events following an initial presentation of acute disseminated encephalomyelitis (ADEM).

ACUTE TRANSVERSE MYELITIS

EPIDEMIOLOGY

Idiopathic, complete acute transverse myelitis (ATM) affects approximately 1.34 persons per million per year.33 In the pediatric age group, patients present at a mean age of 8 years with an equal gender ratio.34-40 Approximately 280 cases of ATM occur in pediatric patients in the United States per year.41,42

PATHOPHYSIOLOGY

Although the pathophysiology of ATM is uncertain, the frequent association with preceding infections and accumulating immunological data support an inflammatory cause for the disorder.33,34,43,44Approximately 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.33,34,39,41 Some cases of ATM are associated with recent vaccination.

CLINICAL PRESENTATION

Pooled data from 7 published case series (n = 205) of pediatric ATM patients reveal common symptoms.34-39,41 Patients with ATM universally report acute to subacute, bilateral leg weakness. Arm involvement occurs in about 40% of patients. Approximately 90% complain of bowel and bladder dysfunction and sensory symptoms, including parasthesias 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.33 Back pain and fever afflict nearly 50% of patients. These symptoms develop rapidly, peaking at an average of 2 to 5 days.34,41

DIFFERENTIAL DIAGNOSIS

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,46 spinal epidural hematomas,47 and tumors,48 are neurosurgical emergencies that must be diagnosed rapidly for effective treatment. Intramedullary lesions that can mimic ATM include primary spinal cord tumors (most commonly astrocytomas and ependymomas),49-51 radiation injury,52 spinal cord infarction, and vascular malformations.53 Direct infections of the spinal cord, typically viral in etiology, can also occur. Acute transverse myelitis can also be secondary to a variety of systemic autoimmune disorders.

The initial clinical presentation of ATM can be similar to that of Guillain Barre syndrome. Both can present with back pain, paraparesis, and sensory abnormalities. However, the presence of a spinal cord sensory level and bowel and bladder involvement is highly suggestive of ATM.

Some patients may present with spinal cord dysfunction, as well as symptoms or signs referable to other parts of the CNS. The presence of mental status changes and cerebral white matter magnetic resonance imaging (MRI) abnormalities suggest ADEM as the correct diagnosis. Mild, asymmetric spinal cord symptoms, previous episodes of transient neurological symptoms attributable to locations other than the spinal cord, and subclinical brain MRI lesions point toward MS.54 Concurrent or preceding optic neuritis suggests neuromyelitis optica (NMO) as a possible diagnosis.55

DIAGNOSTIC EVALUATION

Every patient with suspected ATM should undergo emergent gadolinium-enhanced MRI of the entire spine in order 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 segments34 and may involve the entire spine56 (Fig. 556-7). Spinal cord swelling with effacement of the surrounding cerebrospinal fluid spaces may be present in severe cases. Contrast enhancement is present in as many as 74% of patients.41 In some patients with very suggestive clinical features, the initial spine MRI may be normal, and it should be repeated several days later.34,35,37

Unless a specific contraindication exists, all patients with ATM should undergo lumbar puncture. Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance.41 Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, are also detected in about 50% of patients.41 Glucose concentration is typically normal. A normal CSF profile does not rule out ATM, as it occurs in approximately 25% of patients. In addition to MRI and lumbar puncture (LP), further testing should be guided by clues in the history, examination, or neuroimaging as described above.

FIGURE 556-7. Sagittal T2-weighted magnetic resonance image (MRI) of the spine of a 16-year-old boy who presented with bilateral leg parasthesias 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.

TREATMENT

The initial treatment of ATM is similar to that used for all acute attacks of CNS demyelination (see above). There have been no randomized, controlled trials in ATM to support this approach. However, case reports and series have suggested a beneficial effect of high-dose corticosteroids.36,57,58 For patients who do not improve adequately with intravenous steroids, intravenous immunoglobulins12 or plasmapharesis can be considered. Additional treatment includes pain management, urinary bladder catheterization, bowel regimens, peptic ulcer and deep venous thrombosis prophylaxis, physical therapy, and psychosocial support. Mechanical ventilation is required in approximately 5% of patients.

PROGNOSIS

Although limited by variable definitions in the literature, the prognosis for pediatric patients with ATM is generally favorable.59 Paine and Byers’ recovery categories have been the most widely reported outcome scale.39 Based on this scale, approximately 80% of pediatric patients who receive high-dose IV steroids achieve full or good recovery, and 20% have a fair or poor outcome.36,57 Among patients not treated with highdose IV steroids, 60% have a full or good recovery, and 40% have a fair or poor outcome.39 Higher rostral levels and number of overall spinal segments on spine MRI predicts worse outcome.41

One large, quaternary-referral, center-based study of 47 children with ATM, of whom 70% were treated with IV steroids, has cast doubt on the favorable prognosis of the disorder in childhood.41 In this study, approximately 40% of patients were nonambulatory and 50% required bladder catheterization at a median follow-up of 3.2 years. However, these results may have been influenced by referral bias, as well as a higher percentage of patients less than age 3 years and patients with cervical involvement compared to other studies.

During recovery, motor function returns first, with an average time to independent ambulation of 56 days in one study34 and 25 days in a group of patients treated with high-dose IV steroids.36 Bowel and bladder control recovers more slowly with an average time to recovery of normal urinary function of 7 months in those patients with complete recovery.34

The overwhelming majority of pediatric patients with idiopathic, complete ATM have a monophasic course. In a series of 24 pediatric patients with complete ATM with a mean follow-up of 7 years, there were no recurrences.34 In another study of children with a variety of initial acute demyelinating events, only 2 of 29 (7%) patients with transverse myelitis had a later demyelinating event.22,60 As opposed to complete ATM, partial ATM carries a much higher risk of MS (Fig. 556-8).

Patients who have complete ATM followed by subsequent attacks of optic neuritis or complete ATM may have neuromyelitis optica (NMO). NMO is a distinct CNS demyelinating disorder that can be diagnosed in patients with optic neuritis, transverse myelitis, and at least 2 of 3 supportive criteria: spinal cord MRI lesion extending ≥ 3 vertebral segments, brain MRI not consistent with MS, and detection of serum NMO-IgG.55 NMO-IgG is an autoantibody that targets the predominant CNS water channel protein aquaporin-4 which is concentrated in astrocytic foot processes in the blood-brain barrier. It has been detected in 78% of pediatric patients with relapsing NMO.61 The ideal management of NMO is uncertain. For acute attacks, initial treatment consists of high-dose IV corticosteroids. However, given the likely pathogenic role of the NMO-IgG, patients who do not respond to corticosteroids should be promptly treated with plasma exchange. Chronic treatment with the goal of preventing relapses may include chronic low-dose oral prednisone, azathioprine,62 IVIg, or rituximab.63

FIGURE 556-8. Sagittal T2-weighted magnetic resonance image (MRI) showing discrete, ovoid hyperintense lesions, individually involving less than 1 vertebral body segment, in a 16-year-old girl who presented with mild right arm and leg weakness and numbness sparing her face. Brain MRI revealed additional, asymptomatic lesions. Two months later, she developed left optic neuritis and was diagnosed with relapsing-remitting multiple sclerosis (MS).

OPTIC NEURITIS

EPIDEMIOLOGY AND PATHOPHYSIOLOGY

The incidence of optic neuritis in children is unclear. Data from 4 case series (n = 170) suggest a mean age of onset from 9 to 12 years of age and an approximate 1.5:1 female to male ratio.64-67

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.64-67 Due to the high risk of complications and the availability of noninvasive diagnostic techniques, biopsy of the optic nerve in patients with suspected optic neuritis is rarely performed. Direct pathological data are therefore limited. However, the frequent association of optic neuritis with more diffuse disorders such as acute disseminated encephalomyelitis (ADEM) or multiple sclerosis (MS) suggests common autoimmune mechanisms.

CLINICAL FEATURES

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 patients64-67; bilateral involvement occurs in 50%.64-67 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.64-67 In addition, a normal fundoscopic exam is seen in 30% of patients and does not rule out the diagnosis.64-67 Examination may also reveal an afferent pupillary defect and poor color vision.

DIFFERENTIAL DIAGNOSIS AND EVALUATION

The differential diagnosis of optic neuritis is extensive and reviewed elsewhere.68 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. Isolated optic neuritis can be confused with Leber’s hereditary optic neuropathy, especially when pain with eye movements is absent. Family history, brain MRI, and mitochondrial DNA mutation analysis can be used to distinguish these conditions. Optic neuritis can also be confused with an optic nerve glioma, although the latter usually presents more slowly and is frequently associated with neurofibromatosis type I. 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 magnetic resonance imaging (MRI) with thin cuts through the orbits should be obtained in all patients with optic neuritis. Spine MRI should also be considered to define the extent of demyelination. Lumbar puncture should be performed if direct CNS infection cannot be ruled out clinically. Following appropriate neuroimaging to rule out mass lesions, lumbar puncture with measurement of opening pressure is also required if idiopathic intracranial hypertension is suspected. All patients with optic neuritis should be evaluated by an ophthalmologist with formal visual field testing. Additional testing should be guided by clues in the history, examination, or neuroimaging.

TREATMENT AND PROGNOSIS

Similar to other acute CNS demyelinating syndromes, patients with optic neuritis are often treated with high-dose intravenous methylprednisolone. In the Optic Neuritis Treatment Trial in adults, a 3-day course of intravenous methylprednisolone sped the rate of recovery in patients with visual acuity less than 20/40 but did not affect the long-term visual outcome.10 Experience with IVIG and plasma exchange is limited.  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.64-67 However, patients with optic neuritis frequently report subjective changes in vision, even when visual acuity returns to 20/20; this may only be detected with specialized techniques.

Despite the favorable prognosis for functional recovery, a significant minority of patients later develop MS. In a study of 79 patients with a median follow-up of 19.4 years, 26% of patients were estimated to develop MS by 40 years.64 The risk of MS was even higher in a study of 36 children with optic neuritis, with 36% of patients developing MS within 2 years.67

MULTIPLE SCLEROSIS

In children with recurrent CNS demyelination, the most likely diagnosis is pediatric-onset multiple sclerosis (MS). The International Pediatric MS Study Group defined pediatric-onset as occurring prior to the 18th birthday.5Pediatric-specific criteria for the diagnosis of MS are based on the adult MS diagnostic criteria,74 with minor revisions,5 and incorporate both clinical and MRI findings. Following an initial CIS, patients can satisfy diagnostic criteria for MS with either a second attack or new MRI lesions affecting a different part of the CNS (“dissemination in space”). The second attack or new MRI lesions must occur at least 30 days beyond the initial event (“dissemination in time”).

EPIDEMIOLOGY

The exact incidence of pediatric MS is uncertain. Overall, between 2.7% and 10.5% of patients with MS develop their first symptoms prior to 18 years of age.75,76 With approximately 400,000 patients with MS in the United States, these figures would yield about 20,000 pediatric patients with MS. The vast majority of pediatric patients develop their first symptoms after age 10, with a steady increase in incidence during the teenage years and into adulthood.75,77-79 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 2:1.75,79 This change in gender ratios around the onset of puberty likely reflects the influence of sex hormones on MS susceptibility.

PATHOPHYSIOLOGY

The pathological hallmark of acute MS is the inflammatory plaque, with demyelination and variable degrees of axonal loss.3 Although many different types of immune cells participate in this process, perivascular lymphocytes and macrophages are the main cells in biopsy specimens.3 Helper CD4+ T cells with a Th1 phenotype, which produce proinflammatory cytokines such as interleukin 2 and tumor necrosis factor, play a central role. However, cytotoxic CD8+ T cells and antigen-presenting and auto-antibody-producing B cells also contribute to the pathogenesis of MS.

In general, with increasing disease duration, MS lesions change from an active to a chronic state, with inflammation becoming less apparent and axonal loss becoming more prominent.3

Both genetic and environmental factors contribute to the autoimmune response in MS. The higher incidence of MS in relatives of patients with MS (3–5%) compared to adopted relatives and the general population (0.2%) supports the role of genetics in the development of MS.85,86 Linkage studies in patients with MS suggest the involvement of many genes, with a complex inheritance pattern.87 The major histocompatibility complex on chromosome 6, particularly the HLA DB1*1501 allele, carries the strongest genetic association with the development of MS, but many other genes are involved.86 Single-nucleotide polymorphisms in the interleukin-2 receptor alpha gene and the interleukin-7 receptor alpha gene also contribute to the genetic risk of MS.88

Environmental factors also clearly play a role in MS pathogenesis. There is a positive correlation between the incidence of MS and distance from the equator, with viral infections and sunlight exposure partly explaining this phenomenon. Among the many viruses that have been studied, Epstein-Barr virus (EBV) appears to be the most important. A significantly higher percentage of children and adolescents with MS have been previously infected with EBV, but not other common viruses, compared to age-matched controls.89,90

In addition to viral infections, sunlight exposure may also partially explain the latitude effect in MS; the effect could be related to vitamin D levels. In adults, higher circulating levels of vitamin D have been associated with a lower risk of the development of MS.92

CLINICAL FEATURES

Pediatric patients with MS typically present with an acute to subacute attack of neurological symptoms, with the specific symptoms dependent on the affected CNS location. Data can be pooled from 8 series of pediatric-onset MS patients (n = 592) to yield common clinical features.75-77,93-97 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 acute disseminated encephalomyelitis (ADEM), although the percentage is uncertain. ADEM may be a more common presentation in patients with disease onset younger than 10 years. Seizures also appear to be more common in this subgroup.98,99 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 pediatric-onset MS patients follow a relapsing-remitting course,100 with discrete attacks followed by complete or nearly complete recovery with intervening attack-free periods. Many patients will later enter the secondary progressive phase, during which acute attacks decline and eventually stop, but disability gradually accumulates. The percentage of patients who ultimately enter this phase is unclear, but increases with longer follow-up.100Primary progressive MS, in which a steady decline in function occurs from disease onset without discrete attacks, is rare in children. This diagnosis should be made with caution and only after extensive evaluation for genetic and metabolic leukodystrophies.

DIFFERENTIAL DIAGNOSIS AND EVALUATION

As described above and reviewed in detail elsewhere,7 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.5

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 (Fig. 556-9). A characteristic pattern involves such lesions oriented perpendicularly to the corpus callosum called “Dawson’s fingers,” which is shown especially well on sagittal FLAIR sequences (Fig. 556-10). When applied to children, adult MRI diagnostic criteria for MS appear to be less sensitive, reflecting an overall lower disease burden in the younger patients.101

Most patients with suspected pediatric-onset MS should undergo lumbar puncture for routine studies, as well as testing for cerebrospinal fluid (CSF) oligoclonal bands and IgG index.  When isoelectric focusing followed by immunoblot testing is used, more than 90% of patients with pediatric-onset MS have CSF oligoclonal bands.18,22-29,102 as compared with less than 10% of patients with ADE.18,22-29 In addition to oligoclonal bands, 66% of pediatric-onset MS patients have an elevated CSF white blood cell count, typically less than 50 cells/mm3 with a lymphocytic predominance.102 A mildly elevated total protein level may also be present. In addition to MRI and LP, additional testing should be performed to rule out diagnoses that can mimic MS (see above and reviewed in detail elsewhere).7

TREATMENT AND PROGNOSIS

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).

FIGURE 556-9. Axial fluid attenuated inversion recovery magnetic resonance image showing an ovoid, periventricular hyperintense lesion in a 15-year-old boy with relapsing-remitting multiple sclerosis.

FIGURE 556-10. Sagittal axial fluid attenuated inversion recovery magnetic resonance image (FLAIR MRI) showing hyperintense lesions radiating perpendicularly to the corpus callosum in a 12-year-old boy with relapsing-remitting multiple sclerosis (MS).

Once the diagnosis of MS in children is made, prophylactic treatment should be offered. In adult patients with MS, large-scale randomized controlled trials of the beta interferons and glatiramer acetate have shown that these medications effectively reduce relapse rates by approximately 35%, which led to US Food and Drug Administration (FDA) approval for this indication.103-106 Although the effect of these medications on long-term disability is less clear, emerging studies suggest that they prolong the time to secondary progression and permanent disability.108

The interferons used in MS are once-weekly intramuscular interferon beta-1a (Avonex), every other day subcutaneous interferon beta-1b (Betaseron), and thrice weekly subcutaneous interferon beta-1a (Rebif). The most common side effects are flu-like symptoms, including fever, chills, and myalgias, which typically occur within 24 hours of administration. Preinjection ibuprofen or acetaminophen can be used to decrease these side effects and can be taken as needed following the injections. The flu-like side effects tend to be most prominent when first starting therapy and gradually diminish over time. Asymptomatic leukopenia and liver function test abnormalities are also common and may require dose adjustments.109 Baseline complete blood counts and liver function tests should be obtained monthly for 3 months and then approximately every 3 to 6 months. Rarely, interferons can also cause depression and should be used with caution in patients with preexisting mood disorders.

Glatiramer acetate (Copaxone) is administered subcutaneously once a day. The most common side effects are injection site reactions, with redness and swelling, which can be managed with application of ice or antihistamine creams. Rarely, patients experience a panic-attack-like reaction immediately after the injection. Although frightening, it is not dangerous and typically lasts less than 30 minutes. Routine laboratory monitoring is not needed with glatiramer acetate.

None of these medications have been tested in randomized controlled trials in pediatric patients. However, open-label studies of beta interferons and glatiramer acetate in children have shown comparable levels of efficacy and tolerability compared to the adult data.97,109-111

There are no clear guidelines in determining whether or not these medications have been successful in an individual patient. However, increases in relapse rates or the appearance of new MRI lesions, especially gadolinium-enhancing lesions, should prompt consideration of a change in therapy. If a patient is failing treatment on an interferon, although very controversial, it may be reasonable to check neutralizing antibodies to interferon, which may decrease their effectiveness.114 Patients failing on low-dose interferon (Avonex) who are antibody negative can be switched to high-dose interferon (Betaseron or Rebif) or glatiramer acetate, with the latter a probable better choice in antibody-positive patients. Glatiramer acetate can also be considered for patients failing on high-dose interferon.

Some patients may require treatment beyond the interferons and glatiramer acetate. There is minimal published data on second- or third-line treatments in pediatric MS. Cyclophosphamide has been extensively used in adult MS115and pediatric lupus patients, but has rarely been reported in pediatric MS.116 There is very little experience with mitoxantrone in pediatric MS and concerns regarding cardiotoxicity limit its use. Monoclonal antibodies, such as natalizumab, rituximab, and daclizumab, are used in adult MS but have not been reported in pediatric MS.

In addition to disease-modifying therapies, symptomatic treatment may be needed. Fatigue is present in up to 50% of pediatric MS patients121 and may require treatment with amantadine, modafanil, or stimulant medications. Mood disorders are also common121 and may require both pharmacologic as well as psychologic approaches. Bladder dysfunction is present in some patients and can be addressed with behavioral techniques, as well as anticholinergic agents. Spasticity is an uncommon symptom in pediatric MS patients, especially early in the disease course, but can be treated with baclofen if needed. Physical and occupational therapy may also be useful for some patients.

In addition to pharmacologic therapy, pediatric MS patients and their families benefit from a comprehensive treatment approach. Cognitive dysfunction, particularly affecting executive function and attention, has been detected in approximately 35% of patients.121 This cognitive dysfunction, in addition to school disruption caused by acute relapses and medical appointments, can cause significant educational problems. Therefore, neuropsychological testing should be obtained in most, if not all, patients. Individualized education plans to address the student’s identified deficits may be needed. Patients and families should also be offered psychological counseling to help address the psychosocial stresses encountered in the course of a chronic disease like MS.

Compared to adult patients, children with MS appear to have more frequent acute relapses.122 Despite higher relapse rates, they have slower rates of disability accumulation compared to adults.76,77,123Pediatric MS patients enter the secondary progressive phase in about 20 years as compared with about 10 years in adults.76,77,123


IMMUNE-MEDIATED CEREBELLAR SYNDROMES


ACUTE CEREBELLAR ATAXIA

The incidence of acute cerebellar ataxia (ACA) is uncertain, but it is a common cause of acute ataxia in children less than 5 years.124 The pathophysiology is also not defined, but the frequent association with a preceding infection and the mild CSF inflammatory changes have suggested an autoimmune mechanism.125,126 Varicella zoster virus (VZV) is a common precipitating infection, observed in approximately 25% of cases.125,126 The role of VZV is likely to wane in vaccinated populations. Epstein-Barr virus has also been reported as a common cause of ACA. The detection of autoantibodies to cerebellar antigens in postvaricella127 and post-EBV128 ACA also supports the autoimmune hypothesis.

Patients with ACA typically present with an explosive onset of gait ataxia 1 to 2 weeks after an infection. Truncal ataxia and dysmetria are the most common findings, affecting about 70% of patients, while nystagmus is surprisingly uncommon (10–20%).125 The diagnostic workup for suspected ACA should include neuroimaging and lumbar puncture to confirm the diagnosis and rule out other causes. Additional testing should be guided by the history and examination, with all patients undergoing toxicology screening. Brain MRI is usually normal but can reveal mild changes suggestive of inflammation.125 Lumbar puncture usually reveals a mild pleocytosis with a mean white blood cell (WBC) count of 10 cells/μL with normal or mildly elevated total protein.125

The differential diagnosis is broad, including primary CNS infections, metabolic disorders, and cerebellar tumors, with toxic ingestions being the main consideration.124 Regarding immune-mediated causes, the most important alternative diagnoses are ADEM and opsoclonus-myoclonus-ataxia syndrome. In addition, ACA should be differentiated from acute cerebellitis, in which there are more severe symptoms and prominent MRI findings.

The prognosis is very favorable, with 90% to 100% of patients showing complete recovery over 1 to 2 months.125,126 However, some may have chronic neurological sequelae including behavioral and learning difficulties.125

OPSOCLONUS-MYCOLONUSATAXIA SYNDROME

Patients with presumed ACA who do not follow the typical, self-resolving course or who develop opsoclonus should be suspected of having opsoclonus-myoclonus-ataxia syndrome (OMS). The incidence of OMS is unknown. Patients present at a mean age between 18 and 22 months with an approximately equal gender ratio.129-138

Approximately 50% of patients with OMS have a detectable neuroblastoma, and 2% to 3% of patients with neuroblastoma have OMS.138,139 In keeping with other paraneoplastic syndromes, patients with neuroblastoma and OMS have lower tumor grades and higher survival rates compared to patients with neuroblastoma without OMS.133,135 Onconeural antigens present in these tumors which mimic CNS proteins likely induce an autoimmune response in affected patients. Many of the remaining patients are reported to have an infection preceding the onset of OMS, most frequently a nonspecific viral infection.

Opsoclonus is the most characteristic symptom, consisting of random, conjugate, chaotic eye movements. Unlike nystagmus, these movements do not have a fast and a slow phase. Although the classic triad includes opsoclonus, myoclonus, and ataxia, not all patients have all of these features. Many also have prominent behavioral changes, with marked irritability and sleep disturbance. Diagnostic criteria require the presence of 3 of the following 4 features: opsoclonus, myoclonus/ataxia, behavioral change/sleep disturbance, or neuroblastoma.139

Any patient presenting with these features should be thoroughly investigated for a neuroblastoma. Initial screening can include abdominal ultrasound and urine catecholamines. However, normal results on these tests do not rule out a neuroblastoma, especially in patients with OMS, as they typically have smaller tumors that appear to secrete less catecholamines than non-OMS neuroblastomas. Thus, MRI of the neck through pelvis with thin cuts through the adrenals, as well as an iodine meta-iodobenzylguanidine (MIBG) scan, should be obtained in patients with OMS. Patients should also undergo MRI of the brain to rule out other causes of ataxia and lumbar puncture to assess for inflammatory changes.

There are no randomized, controlled trials in the treatment of OMS. Tumor resection may improve the acute symptoms, but most patients still require immunotherapy. Steroid therapy, in the form of intramuscular adrenocorticotropin hormone (ACTH) or oral prednisolone, is the usual treatment. Other treatments, alone or in combination with steroids, have included IVIg, rituximab, and cyclophosphamide.133,136,144 Patients frequently require chronic treatment with immunotherapy for months to years.

The prognosis of OMS is poor. At least 75% of patients have a chronic, relapsing course, and a similar percentage have permanent neurologic sequelae.129-138 Symptoms often reemerge in the setting of viral infections or medication weans. Although opsoclonus and myoclonus often resolve, many patients are left with residual ataxia, cognitive dysfunction, and behavioral disorders.136,137


CNS VASCULITIS


Inflammation of the CNS blood vessels can be restricted to the CNS (primary) or associated with a number of systemic conditions (secondary). Primary CNS vasculitis of childhood can be diagnosed based on the following criteria: newly acquired neurologic deficit, conventional or magnetic resonance (MR) angiographic or histologic evidence of CNS vasculitis, and no identifiable associated systemic condition.145Secondary CNS vasculitis can be associated with CNS infections or systemic autoimmune disorders. The differential diagnosis also includes noninflammatory conditions such as moyamoya disease, sickle cell disease, and arterial dissection. This section will focus on primary CNS vasculitis of childhood. The incidence of this disorder is unknown, but there are an estimated 150 to 200 new cases per year in North America with a median age of presentation of 7 years.145,146

The pathogenesis of primary CNS vasculitis is uncertain. In some patients, reactivation of varicella zoster virus (VZV) may play a role, as suggested by similarities with the associated VZV-related conditions of postvaricella angiopathy and transient cerebral arteriopathy.146 Biopsies in pediatric patients with CNS vasculitis show lymphocytic infiltration of the blood vessel walls.

Common presenting symptoms of CNS vasculitis include severe headaches, strokes, and cognitive dysfunction. Specific symptoms appear to correlate with angiographic findings, being abnormal (positive) or normal (negative) (eFig. 556.1 ). The angiography-positive group is subdivided into progressive (30%) and nonprogressive (70%) forms.145 Patients within the progressive group present with focal and diffuse neurological symptoms, multifocal MRI lesions, and involvement of the proximal and distal CNS vasculature. Nonprogressive patients typically present with strokes, focal MRI lesions, and proximal vessel involvement on angiography. Patients with normal angiograms are diagnosed on the basis of meningeal or brain biopsy and have diffuse symptoms and multifocal MRI parenchymal abnormalities.146

Laboratory tests for systemic inflammation should be checked, but normal results do not exclude the diagnosis, as ESR and CRP are elevated in 50% and 75% of cases, respectively.145 All patients should also undergo lumbar puncture and gadolinium-enhanced MRI of the brain and spinal cord. CSF is abnormal in only 40%,145 but brain MRI is abnormal in virtually all patients with CNS vasculitis (see Fig. 556-2C). The CNS vessels should be imaged initially with MR or CT angiography. MRA has a sensitivity of approximately 70% compared to conventional angiography, frequently missing small vessel abnormalities.147 Therefore, if the noninvasive angiography is unrevealing, conventional angiography should be performed. In some patients, brain biopsy is needed to confirm the diagnosis.

There have been no controlled treatment trials in pediatric CNS vasculitis. A commonly used regimen for progressive 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 such as azathioprine or mycophene-late mofetil.146 The optimal treatment of nonprogressive vasculitis is even less clear but may include acyclovir and corticosteroids. Low-dose aspirin should be considered for all patients to prevent secondary strokes. The prognosis of pediatric CNS vasculitis is guarded, with only 34% of patients achieving a full long-term neurologic recovery.145