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NEURODEGENERATIVE AND DEMYELINATING DISEASES AND OTHER CNS DISORDERS

Amy Houtrow

This chapter covers numerous conditions that pediatric rehabilitation medicine physicians may encounter during their training and career. Because data contained in other chapters of this book are particularly relevant to the conditions presented here, the reader will be guided back to other chapters from time to time. This chapter will address pediatric demyelinating diseases of the central nervous system (CNS) and acquired brain injury from encephalitis (including anti-N-methyl-D-aspartate receptor [NMDAR] encephalitis), pediatric brain tumors, and seizure focus resection.

PEDIATRIC DEMYELINATING DISEASES

In this section of this chapter, the following pediatric demyelinating diseases of the CNS will be described: multiple sclerosis (MS), transverse myelitis, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM). Together, these conditions have incidence in children of 1.66 per 100,000 person-years (1). They are more common among Whites and Blacks and less common among Hispanics and Asians (2). Acute inflammatory demyelinating polyradiculoneuropathy (Guillain–Barré syndrome), a peripheral process, is described in Chapter 18. Generally, demyelinating diseases are described as monophasic or polyphasic and monofocal or polyfocal. Monophasic disease is also often referred to as a clinically isolated syndrome (3). Some children with monophasic disease go on to develop chronic demyelinating conditions such as MS or NMO. And it is important to note that there is considerable clinical overlap between these conditions (4).

PEDIATRIC MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease characterized by demyelination and axonal degeneration. Approximately 5% of the total population of individuals with MS are children (5). In 2007, the International Pediatric Multiple Sclerosis Study Group proposed provisional definitions for CNS demyelinating disorders for children that were updated in 2012 and published in 2013 (6). The diagnosis requires the presence of CNS inflammatory disease that is disseminated in time and space. Pediatric MS can be diagnosed when any one of the following exists:

EPIDEMIOLOGY OF PEDIATRIC MS

While 1.7% to 5.6% of the total MS population is under the age of 18, diagnosis under the age of 10 is very rare. The incidence of pediatric MS worldwide is not known, but in California, the reported incidence is 0.51/100,000 person-years (1). There is greater racial/ethnic diversity among children with MS compared to adults, among whom most are non-Hispanic Whites (5). The remote history of Epstein–Barr virus is associated with pediatric MS and many studies have supported the geneviral environment hypothesis (7). The exact mechanisms that lead to MS are not understood and ongoing research is being conducted to identify triggers and the pathophysiology.

TABLE 19.1 2010 MCDONALD MRI CRITERIA FOR THE DIAGNOSIS OF MULTIPLE SCLEROSIS

When MS is suspected, a complete neurologic exam is necessary as is MRI with gadolinium of the brain and spinal cord. MRI findings consistent with MS include ovoid T2 lesions, and fluid-attenuated inversion recovery (FLAIR) hyperintensities in the periventricular white matter are typical. Cortical lesions are less common in children with MS compared to adults (9). See Figure 19.1 for an MRI of a teenaged girl with MS.

FIGURE 19.1 The sagittal (A) and axial (B) views of the MRI of a teenaged girl with MS demonstrate T2-FLAIR hyperintensities separated in space. The arrows point to the lesions.

Source: Images courtesy of Guilio Zuccoli, MD, Associate Professor of Radiology, University of Pittsburgh.

Recommended blood work includes a complete blood count (CBC) with differential, C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, angiotensin-converting enzyme, folate, B-12, and thyroid-stimulating hormone (3). Depending on the clinical presentation, a fundoscopic exam and MRI of the orbits may be indicated. A lumbar puncture with opening pressure may be performed especially if the presentation is atypical. Cerebral spinal fluid examination often reveals a lymphocytic predominance, normal glucose, and elevated protein levels (5). The differential diagnosis of pediatric MS includes other autoimmune conditions, vascular disorders, space-occupying lesions (tumors), metabolic disorders including nutritional deficiencies, mitochondrial disorders, and leukodystrophies (3). It is important to evaluate for the stigmata of neurofibromatosis (NF) and tuberous sclerosis (TS). Complicated migraines and CNS vasculitis may mimic MS and should also be on the differential when headaches are the predominant presenting symptom (6).

Since the 1980s, the Expanded Disability Status Scale (EDSS) and the Functional Systems Score (FSS) have been used to track MS-related disability (18). The systems in the FSS are: pyramidal functions, cerebellar functions, brainstem functions, sensory function, bowel and bladder function, visual function, and cerebral (mental) functions (18). See Table 19.2 for the FSS.

The scores on the EDSS range from 0 (normal neurologic exam) to 10 (death due to MS) and focus on mobility skills and FSS dysfunction. See Table 19.3 for the complete EDSS.

The EDSS does not map well to functional assessment tools typically used in pediatric rehabilitation such as the Functional Independence Measure for Children (WeeFIM), Pediatric Evaluation of Disability Inventory (PEDI), and Functional Rehabilitation Evaluation of Sensori-Neurologic Outcomes (FRESNO) (19–21). Nonetheless, the EDSS is used in most research related to the clinical management of MS and is important for the rehabilitation physician to understand. Developmentally speaking, EDSS is not appropriate for children who would not be expected to be ambulatory or independent with their self-care. This is rarely a problem because MS is extremely uncommon among very young children.

The rehabilitation interventions depend on the functional impairments, activity limitations, and participation restrictions experienced by the child with MS. Common impairments include: weakness, spasticity, neurogenic bladder, neurogenic bowel, pain, fatigue, and depression. Although physical and occupational therapy are the primary way weakness is addressed, potassium channel blockade has been shown to improve ambulation due to the improved conduction in demyelinated fibers (22). Because of the narrow therapeutic window, it is not recommended for use in children. When considering an antispasticity agent such as baclofen, it is important to evaluate if the spasticity is benefiting function such as for ambulation when spasticity in the lower extremities is compensating for weakness (23). It is also important to consider the side effect of fatigue because fatigue is a common symptom of MS and may be made worse with the initiation of an antispasticity agent. For intractable spasticity, intrathecal baclofen pump placement may be a consideration. For more localized spasticity, botulinum toxin injection should be considered (24). Botulinum is also used for neurogenic detrusor overactivity (25). But the first-line management remains anticholinergic agents such as oxybutynin (23).

Symptomatic neurogenic bladder impacts about 80% of all patients with MS with detrusor hyperactivity and detrusor-sphincter dyssynergia as the most common diagnoses (23). There is little consensus about when to start intermittent straight catheterizations (26), but issues regarding continence should be discussed both from the medical and social perspectives. For the adolescent with MS, discussions about sexual functioning should occur. Management of neurogenic bowel and constipation follows the recommendations for management of upper motor neuron bowel (see Chapter 16 for details). Neuropathic pain and musculoskeletal pain are common. Antiepileptic medications play an important role in the genic bladder impacts about 80% of all patients with MS with detrusor hyperactivity and detrusor-sphincter dyssynergia as the most common diagnoses (23). There is little consensus about when to start intermittent straight catheterizations (26), but issues regarding continence should be discussed both from the medical and social perspectives. For the adolescent with MS, discussions about sexual functioning should occur. Management of neurogenic bowel and constipation follows the recommendations for management of upper motor neuron bowel (see Chapter 16 for details). Neuropathic pain and musculoskeletal pain are common. Antiepileptic medications play an important role in the modulation of neuropathic pain and traditional analgesics are helpful in musculoskeletal pain (7). In adults, the use of cannabis extract has been used with success in the management of painful spasticity refractory to other interventions (27). When a child presents with debilitating fatigue, a close examination of the medications should be conducted to determine whether they are contributing to the fatigue. A sleep hygiene regime may be initiated and medications modafinil and amantadine may be considered, but their efficacy is limited (23). Mood disorders are frequent among individuals with MS and likely under-recognized in children. Psychological interventions, including cognitive behavioral therapy have been shown to be helpful (23). Medications to address mood may be considered.

TABLE 19.2 KURTZKE FUNCTIONAL SYSTEMS SCORES

TABLE 19.3 THE EXPANDED DISABILITY STATUS SCALE

To address activity limitations and participation restrictions, the rehabilitation program should be family-centered and goal-directed. The child and the family should be actively involved in goal setting. These goals should include skill attainment/reacquisition/refinement, enhancement of endurance, and adaptations to the environment as necessary (23). Occasionally, the child with MS will present for comprehensive inpatient rehabilitation, but more commonly, the child will be engaged in outpatient services. It is important to coordinate care between the treating therapists, the neurologist, and the rehabilitation physician. Regular re-evaluation is essential because MS is not a static disease. Close attention to the cognitive sequelae of MS is necessary because school programming frequently needs to be adapted. Some children may do well with a 504 plan and others may require an Individualized Education Program (IEP). Neuropsychological testing can help guide cognitive therapy and classroom adaptations. For older adolescents, vocational rehabilitation may be an adjunct to their therapeutic program. Additionally, structured drivers’ education may be necessary.

Transverse myelitis, also called acute transverse myelitis, is an acute monophasic or clinically isolated syndrome of the spinal cord (4). Transverse myelitis may also be associated with polyphasic condition such as neuromyelitis optica, MS, or systemic lupus erythematosus (SLE) (28). The diagnosis relies on the exclusion of other causes of myelitis and spinal cord compression. Once other etiologies are excluded, the diagnosis depends on meeting the inclusion criteria listed in Table 19.4 (29).

When working up myelopathy, there are three priorities (30):

Epidemiology of Transverse Myelitis

Transverse myelitis is a rare condition but one that often requires comprehensive inpatient rehabilitation. Approximately 20% of the 1,400 new cases in the United States each year are children (31). Children with transverse myelitis tend to be older at the age of diagnosis compared to children with ADEM (1). There appears to be a bimodal distribution with peaks in early childhood and a board peak between school-age and older children/adolescents (32). A considerable percentage of children with transverse myelitis go on to be diagnosed with a polyphasic demyelinating disorder such as MS (33).

TABLE 19.4 THE DIAGNOSTIC CRITERIA FOR TRANSVERSE MYELITIS

Development of dysfunction attributable to the spinal cord

Bilateral signs and symptoms (not necessarily symmetric)

Inflammation of the spinal cord evidenced by:

Abbreviation: CSF, cerebrospinal fluid.

Source: Adapted from Ref. (29). Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59(4):499–505.

Clinical Course and Diagnosis of Transverse Myelitis

If there is clinical concern for transverse myelitis, a thorough history should be gathered to document time course and extent of the symptoms, as well as any recent illness or prodromal symptoms (29). A recent mild illness is reported in a vast majority of cases; less frequently the patient may report a vaccine or allergy shot (28). The location of the lesion is most commonly the thoracic spine, but any and all segments may be involved (3,32). Therefore, a majority of patients present with complaints of lower extremity weakness. Rarely conus medullaris syndrome presentation may occur (32). In cases of posterior column involvement, fine motor discoordination and ataxic gait may mimic cerebellar disease (28). Children with posterior cord syndrome should be worked up for B₁₂ and copper deficiency (33). In addition to weakness, most children present with constipation and bladder dysfunction consistent with neurogenic bowel and bladder, respectively. Children often also present with sensory disturbances such as allodynia and paresthesias (28,32). Horner syndrome, in lesions above T2, has also been reported (28).

A full neurologic exam is warranted with delineation of motor and sensory levels. The child’s neurologic level of the injury should be determined to the best of the examiner’s ability recognizing the challenges of conducting a comprehensive spinal cord examination on a very young child. The neurologic level is the most caudal segment with normal sensation and antigravity motor function bilaterally (34). The American Spinal Injury Association impairment scale classifies the completeness of the injury based on sacral sparing, which is the presence of motor or sensory function in the most caudal sacral segments (34). The grading of the degree of impairment is important not only to anticipate function, but also because partial transverse myelitis is associated with a higher likelihood of future diagnosis of a polyphasic demyelinating disorder (31,33). In the very early phases of the disease, the child may be in spinal shock and have absent reflexes. Guillain–Barré Syndrome can present similarly with diminished reflexes, dysautonomia, and bowel and bladder dysfunction, but usually is quickly distinguished from transverse myelitis (28). See Table 19.5 for the differential diagnosis of myelitis (28,30,33,34).

TABLE 19.5 THE DIFFERENTIAL DIAGNOSIS OF TRANSVERSE MYELITIS

FIGURE 19.2 This sagittal view MRI demonstrates diffuse alteration of the signal intensity of the cord from C2 downward. Multilevel cord expansion is also noted.

A gadolinium-enhanced MRI of the spine should be conducted as soon as possible. Depending on the timing, a brain MRI can be conducted simultaneously or at a later time. If a compressive myelopathy is identified, then urgent surgical referral is warranted and steroids may be considered (29). The MRI of transverse myelitis usually reveals T1-isointense and T2-hyperintense signals over multiple contiguous segments (3,33). The entire cord may be involved and there can be substantial swelling with effacement (3). See Figure 19.2 for the MRI of a child with tetraplegia from transverse myelitis.

Children with transverse myelitis tend to have more severe presentations than adults (30). Complete recovery can occur, but occurs in a minority of children (30). A number of factors have been identified as poor prognostic indicators, including: rapidity to nadir (in some studies), need for ventilator support, higher lesion level, larger number of segments involved, and spinal shock (28,30,32). Symptom nadir tends to occur within a week of presentation. Around that time, children with transverse myelitis may experience autonomic instability with fluctuations in heart rate, temperature, and respirations (28). Recovery is most rapid during the first 6 months after onset, but improvements have been documented years after the disease (30). As mentioned previously, some children, especially those with partial lesions will go on to develop a polyphasic demyelinating condition despite good recovery from the first lesion.

Treatment for Transverse Myelitis

High-dose steroids given for 5 to 7 days are the mainstay of treatment for transverse myelitis (3), although there is insufficient evidence to determine the efficacy of steroids (31). In fulminant disease, plasmapheresis and intravenous immunoglobulin (IVIg) may be considered (3,31). Many children present with pain and sensory changes, which may persist long-term. Medications to manage spasticity and pain are commonly needed. Children with cervical lesions may need ventilatory support.

Rehabilitation for Transverse Myelitis

The rehabilitation management of the child with transverse myelitis is similar to the management of children with spinal cord injuries of other etiologies (see Chapter 16). Consultations with therapies and pediatric rehabilitation medicine should occur early in the acute period to help maximize recovery (28). As with other children with spinal cord injury, children should receive interdisciplinary, family-centered, goal-directed rehabilitation that focuses on recovery of lost function and making adaptations when function does not return. Depending on the timing of admission to rehabilitation and the capabilities of the rehabilitation unit, some children with transverse myelitis may still be receiving steroids, IVIg, or plasmapheresis for disease management. If a child is transitioned to rehabilitation early in the disease course, vigilance is required to monitor for worsening symptomatology because the time to reach nadir is variable (28). The child with cervical transverse myelitis is at particular risk for decompensation and should be monitored closely for changes in respiratory status due to disease progression. If the lesion is cervical or thoracic, the aggressive pulmonary toilet is recommended. Children with tetraplegia may need cough assist; therefore families should be trained to assist with “quad coughing.” Later in their rehabilitation course, children with transverse myelitis lesions above T6 are at risk for autonomic dysreflexia (see Chapter 16) (28).

Chronic sensory changes have been noted in nearly half of patients (32). If bothersome, long-term antiepileptic mediation should be considered. Amitriptyline may also be used in the management of pain (28). A desensitization program may be considered for the child experiencing allodynia or dysesthesia that is interfering with activities. During the acute rehabilitation phase and long term, children with transverse myelitis are at risk for skin breakdown due to limited sensory input and limited mobility. Prevention of skin breakdown is the most effective management and requires keen attention to at risk areas. The patient and family need to be educated extensively and equipment that minimizes risk should be provided.

NMO is a polyfocal and often polymodal demyelinating condition characterized by optic neuritis and transverse myelitis (3,33). A relapsing course of NMO, previously known as Devic disease, is more common than a monophasic course (37). NMO used to be considered a rare variant of MS but is now understood to be a separate disease (38). The key to diagnosing NMO includes ensuring that the child’s presentation is not more consistent with MS. This is important because management differs, NMO is less responsive to treatment, and it has a poorer prognosis than MS (38,39). Seropositivity for NMO-IgG is not required for the diagnosis but is highly indicative. Children are seropositive less frequently than adults (3). The binding of NMO-IgG (aquaporin-4-IgG) to aquaporin-4 results in a biological cascade that results in inflammation and demyelination characteristic of the disease (37). The understanding of NMO has expanded exponentially in the past decade and consensus has been reached regarding the diagnosis (40). Table 19.6 details the diagnostic criteria for NMO (41).

TABLE 19.6 THE DIAGNOSTIC CRITERIA FOR PEDIATRIC NEUROMYELITIS OPTICA

Optic neuritis

Acute myelitis

Two of the following:

NMO spectrum disorders are those disorders that do not meet diagnostic criteria for NMO and include recurrent optic neuritis and recurrent transverse myelitis, with seropositivity (6,40). The child with an NMO spectrum disorder may go on to meet the criteria for NMO. Because of this, children with NMO spectrum disorders need to be monitored very closely for disease progression. Children who have relapsing optic neuritis without evidence of other neurologic deficits or systemic disease have chronic relapsing optic neuropathy (CRION), which is often bilateral and steroid dependent (42). These children also have to be closely monitored for progression.

Epidemiology of NMO

NMO is exceptionally rare; for every individual with NMO, there are 50 to 100 individuals with MS (38). NMO can affect children and adults of any age, but children tend to present in late childhood or adolescence (3). There is a strong female predominance, even stronger than the female predominance for MS (37,39). NMO is more common among those of Asian and African descents (33). NMO tends to occur sporadically but familial cases have been identified (40). A large majority of patients with NMO have serologic evidence of autoimmunity (37). Children with NMO are often seropositive for antinuclear, SS-A, antiacetylcholine receptor, or double stranded DNA antibodies (38). Autoimmune conditions such as SLE, Sjogren syndrome, juvenile idiopathic arthritis, and Graves disease may coexist or precede NMO (37).

The hallmarks of NMO are transverse myelitis (see preceding section) and optic neuritis. Children with optic neuritis can present with unilateral or bilateral blurry vision, a black spot in the central visual field, or visual acuity loss (43). Compared to adults, vision loss is more severe in children. Children may also report pain with ocular movement (3). If the diagnosis of optic neuritis is suspected, the child should be seen by an ophthalmologist or neuro-ophthalmologist, if one is available. A normal fundoscopic exam does not rule out the diagnosis as some cases are due to retrobulbar inflammation. Visual acuity, visual field, low contrast sensitivity, and color vision should all be assessed. The neuro-ophthalmologist may also perform visual evoked potentials and may recommend optical coherence tomography and an orbital MRI (3). Figure 19.3 demonstrates active optic neuritis.

The differential diagnosis list for optic neuritis includes vitamin B₁₂ deficiency, adrenoleukodystrophy, Leber hereditary optic neuropathy (usually pain is absent but a family history is often present), and optic glioma. Additionally, sarcoidosis may present with cranial nerve defects and optic neuritis (3).

FIGURE 19.3 This coronal view MRI demonstrates left-sided optic neuritis in a child with NMO.

Source: Image courtesy of Guilio Zuccoli, MD, Associate Professor of Radiology, University of Pittsburgh.

The treatment of isolated optic neuritis is high-dose steroids (3,44). Refractory cases may be treated with IVIg or plasmapheresis (3). Children tend to recover well from optic neuritis with a majority achieving at least 20/40 vision at follow-up (43,45). Children with bilateral optic neuritis have an increased likelihood of developing MS, as are children who are older (45,46). Children with relapsing optic neuritis may go on to develop either MS or NMO. The case of seropositivity and relapsing optic neuritis without other signs of NMO is NMO spectrum disease. Because children with optic neuritis can later develop MS or NMO, the workup should include a gadolinium-enhanced MRI of the brain and spinal cord and a lumbar puncture with opening pressure (3). Because NMO can occur concurrently with other autoimmune conditions, additional serologies should also be ordered.

Similar to other pediatric demyelinating conditions, children often present after a prodromal flu-like illness (37). The child with NMO tends to present with complete transverse myelitis. This is in contrast to MS in which children tend to present with partial lesions (37). Occasionally, though, central cord syndrome may be the presentation of transverse myelitis in NMO (33). A careful and thorough neurologic examination is necessary to delineate the findings of NMO. While transverse myelitis and optic neuritis are the hallmarks of the condition, children with NMO may also have signs and symptoms of intracranial pathology. The MRI of the brain typically demonstrates lesions in the areas of the brain that are aquaporin-4 rich such as the hypothalamus, subcortical white matter, and the periventricular gray matter (3). Brain lesions are more common in pediatric NMO than adult NMO (37). In addition to the typical MRI findings, “cloud-like” enhancements, linear lesions extending from the brainstem to the spinal cord, and posterior reversible encephalopathy syndrome (PRES)-like lesions may be seen (40). Necrosis can occur in the areas of the brain with severe antibody-mediated inflammation and demyelination (37). Children with NMO may also present with encephalopathy and can therefore resemble ADEM. The MRI lesions may be quite large and be radiographically difficult to distinguish from ADEM (3,37,40). In patients with MRI findings in the area postrema, the clinical presentation often includes weeks to months of intractable emesis (37).

Treatment of NMO

The treatment of NMO includes management of acute episodes, prevention of relapses, symptom management, and rehabilitation (40). The medical management for pediatric NMO is based on the treatment recommendations for adults. First-line treatment is IV methylprednisolone 30 mg/kg/day for 5 days. Plasmapheresis and IVIg are also treatment options in the acute period (37,40). Plasmapheresis is considered a first- or second-line agent and may be given concurrently with steroids or instead of steroids if the child does not tolerate steroid treatment. Five exchanges scheduled every other day is the typical administration and can lower NMO titers (3). IVIg at a total dose of 2 g/kg given over 2 to 5 days is a third-line agent (3). Long-term immunosuppression is the standard of care but is associated with significant side effects about which the patient and parents should be educated (40). Children should be treated with calcium and vitamin D to promote bone health, and they need surveillance because of the risk of bone demineralization (37).

The rehabilitation management of NMO includes the management of transverse myelitis as described in the previous section and in Chapter 16. Additionally, children with brain lesions should receive appropriate brain injury rehabilitation. The rehabilitation program should be interdisciplinary, family-centered, and goal-directed. Neuropsychological testing may be conducted after the acute recovery period to guide classroom adaptations. Like the other polymodal pediatric demyelinating conditions, periodic neuropsychological screening is warranted and repeat testing is often indicated. Unlike the other pediatric demyelinating conditions, except occasionally pediatric MS, low vision rehabilitation may need to be incorporated into the rehabilitation program.

Optimally, low vision rehabilitation is a multidisciplinary endeavor that provides assessments, adaptive techniques and strategies, and training (47). Functional vision assessment is the measurement of how well patients use their existing vision to conduct day-to-day activities (47,48). The ophthalmologic assessment should include measurement of visual acuity, contrast sensitivity, perimetry, light characteristics, refractory errors, oculomotor functions, and cortical visual integration (47). Based on the findings, optical assistive devices may be prescribed. Occupational therapists with specialized low vision rehabilitation training teach patients how to use the assistive devices in everyday activities and help patients strategize compensatory strategies (49).

Community reentry, including return to school, may be particularly complicated for the child with NMO because of the combination of motor, cognitive, and vision deficits. Environmental assessments and adaptations of the home and school can help improve participation and quality of life by assuring a safe environment for optimal functioning (48,49).

While the prognosis remains relatively poor for NMO, advances in the management will hopefully lead to improvements in prognosis in the next several years (40). Actively employing rehabilitation strategies to maximize function in conjunction with immunosuppression and careful multidisciplinary surveillance should improve clinical outcomes and the quality of life of children with NMO.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

ADEM is a polyfocal demyelinating disease more commonly diagnosed in children than adults (3). To be diagnosed with ADEM, the encephalopathy (behavioral change or altered consciousness) cannot be explained by fever, an infectious process, or a postictal state (6). Additionally, the presentation must be the first demyelinating illness for that child, the MRI must be abnormal in the acute phase (first 3 months), and new findings cannot emerge after the acute phase (6). The typical brain MRI findings in ADEM are diffuse, large white matter lesions with poor demarcation. There may also be focal punctate lesions, bithalamic or basal ganglia lesions, or more rarely, hemorrhagic lesions consistent with hemorrhagic leukoencephalopathy (50).

Epidemiology of ADEM

The estimated incidence of ADEM is 0.4/100,000/year (51), making it a rare disease. Children commonly present between the ages of 5 and 8 years old and are more often affected than adults. Some cases of ADEM can be linked to preceding viral illness or vaccine administration (Semple rabies vaccine, small pox vaccine, and older measles vaccines), but most are not linked to a specific pathogen (3,52,53).

Clinical Course of ADEM and Diagnosis

When ADEM is suspected, a full neurologic examination is warranted. An MRI of the brain and spinal cord should be ordered—lesions may or may not enhance with gadolinium. The MRI images in Figure 19.4 demonstrate multifocal lesions associated with ADEM in a young boy.

Rapid determination of a potential viral etiology such as herpes simplex virus (HSV) is essential. Empiric treatment with acyclovir is warranted if a viral etiology is suspected. Cerebral spinal fluid and serologic studies should be collected to help rule out an infectious etiology. Bacterial, viral, and fungal cultures, as well as assays for HSV, Epstein–Barr virus, enterovirus, West Nile virus, and varicella zoster virus (VZV) should be sent (54,55). If anti-NMDAR encephalitis is suspected, then titers should be drawn. Collecting extra cerebrospinal fluid (CSF) for additional studies is wise as it may eliminate the need for a repeat lumbar puncture. The cerebral spinal fluid of ADEM is characterized by normal opening pressure, normal glucose, and moderately elevated cell count and protein (3). Rarely children will experience severe decompensation with increased intracranial pressure warranting surgical intervention (3). Approximately 2% of children with ADEM experience fulminant hemorrhagic demyelination with cerebral edema (50). This condition, called acute hemorrhagic leukoencephalitis is often fatal (55).

Treatment for ADEM

The first-line treatment for ADEM is corticosteroids intravenously, usually given as 1 g/day for 5 days in children over 40 kg or 20 to 30 mg/kg/day for smaller children. In addition to acyclovir, antibiotic coverage may also be started (3). IVIg is a second-line treatment which can be used in refractory cases or in situations where steroid treatment is not tolerated (3,55). The typical dose of IVIg is 2 g/kg over 2 to 5 days. Plasmapheresis with three to five exchanges may also be used in refractory cases (56). Cyclophosphamide has been used in some cases (55). In the acute period, supportive interventions in the intensive care setting may be necessary to maintain adequate ventilation in cases of respiratory failure, to control blood sugars, and to manage nutrition. After the nadir is reached and the child is stable from a respiratory standpoint, they may be transferred to an acute floor or directly to comprehensive inpatient rehabilitation if it is warranted.

FIGURE 19.4 These two axial MRI FLAIR views of the brain demonstrate multiple lesions with increased diffusivity consistent with ADEM. The two largest lesions on each view are indicated with arrows.

Source: Images courtesy of Guilio Zuccoli, MD, Associate Professor of Radiology, University of Pittsburgh.

Recovery from ADEM is variable. Children with a history of viral illness may have worse outcomes (57). Poorer outcomes are seen with higher lesion load (58). Usually after improvement with treatment in the acute period, children make gradual improvements over time (weeks to months) (3,58). Although some researchers consider ADEM to be a relatively benign condition (50), children may be left with neurocognitive and behavioral consequences (59). Neurocognitive findings may persist after lesions are fully resolved on imaging (59,60). Children with a history of ADEM are at risk for recurrent disease. Approximately 10% of children with an initial diagnosis of ADEM have another demyelinating episode (50). Children with two ADEM episodes separated by at least 3 months and not associated with additional demyelinating episodes are considered to have multiphasic ADEM (6). Pediatric ADEM may be the first manifestation of MS or NMO. Periventricular lesions can occur in ADEM, but if present, raise suspicion for the possibility of an MS diagnosis in the future. Similarly, hypodense white matter lesions that persist are predictive of MS (6). The presence of a positive anti-aquaporin-4 IgG titer with ADEM is strongly suspicious for a subsequent NMO diagnosis.

The typical presentation for encephalitis is prodromal “flu-like” illness followed by changes in behavior or consciousness, headaches, and nausea and vomiting. Children may also present with focal neurologic signs and/or seizures (54). Some presentations are more likely to be associated with particular types of encephalitis. For example, children with ADEM often have multifocal neurologic signs, HSV is often characterized by temporal lobe seizures, and arboviruses typically present with fever and early obtundation (64). Important aspects of the history taking at the time of presentation include detailing potential exposures, recent illnesses and vaccines, history of autoimmune disorders, and immunosuppression status (64). In addition to a detailed physical with a complete neurologic examination, neuroimaging and CSF and serum studies are necessary. Blood work should include a culture, CBC with differential, renal, liver, and coagulation studies (54,64). The CSF usually shows lymphocytic pleocytosis, normal glucose, and elevated protein. Oligoclonal IgG bands are rarely seen. Serum and CSF IgM antibodies and/or rising IgG may help the identification of specific viral etiologies (54). CSF viral detection by polymerase chain reaction (PCR) amplification should also be sought to identify specific viral etiologies (54). Samples of both blood and CSF should be stored for future study and a repeat lumbar puncture may be needed when an etiology is not readily identified. Because of the challenges and expense associated with determining a specific etiology, investigations should be directed toward determining if the encephalitis is caused by an autoimmune process versus a viral process to help guide treatment (65). MRI findings vary with etiology. Figure 19.5 demonstrates several small lesions in a child with encephalitis.

For the child with suspected seizures, an EEG should be ordered. Nonspecific findings of diffuse high-amplitude slow waves are often seen (54). Although not pathognomonic for HSV encephalitis, temporal lobe periodic lateralizing epileptiform discharges are highly suggestive (54,64). The clinical course is variable depending on the etiology. Some children may require prolonged care in the intensive care setting and may have long-lasting consequences of their disease.

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