- Email: [email protected]
Acquired Disorders Affecting the White Matter
100 Acquired Disorders Affecting the White Matter Naila Makhani, J. Nicholas Brenton, and Brenda Banwell
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Demyelination of the central nervous system (CNS) may occur as a monophasic illness or may represent the first attack of chronic inflammatory diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). Herein, we review the clinical and neuroimaging features of childhood acquired CNS demyelinating disorders.
ACUTE CENTRAL NERVOUS SYSTEM DEMYELINATION Children with an acquired demyelinating syndrome (ADS) may present either with neurologic signs and symptoms attributable to a single CNS location (monofocal ADS) or with signs attributable to multiple CNS sites (polyfocal ADS), with or without encephalopathy (Krupp et al., 2013).
OPTIC NEURITIS Optic neuritis (ON) should be considered in any child presenting with acute or subacute visual loss (Fig. 100-1). Demyelinating ON is typically clinically characterized by reduced visual acuity, a central visual field deficit, pain with eye movements, and red color desaturation. Optic disc edema is sometimes seen, but may be absent in retrobulbar ON. Although some studies suggest that childhood ON is more commonly bilateral, others have reported that ON is more commonly unilateral. In one study of 36 children with ON, neuroimaging studies of the optic nerve were abnormal in 55%, and 88% had abnormal visual-evoked potentials (typically a P100 latency delay). Optical coherence tomography (OCT) utilizes near-infrared light to measure the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), yielding a quantitative measure of axonal and neuronal loss. RNFL and GCL thinning have been demonstrated in children with isolated ON and MS and may provide quantifiable information about retinal integrity. Following ON, 80% to 85% of children achieve full visual recovery. Children with ON have a 30% risk of a subsequent MS diagnosis. Magnetic resonance imaging (MRI) evidence of one or more T2-weighted lesions apart from the optic nerve is strongly predictive of MS, with up to 68% of such patients being diagnosed with MS within 2 years. Concurrent or rapidly sequential transverse myelitis, MRI features of brainstem or diencephalic involvement in a pattern atypical for MS, and serum antibodies against aquaporin-4 suggest a diagnosis of NMO.
Transverse Myelitis Demyelination of the spinal cord is termed transverse myelitis (TM). Typical features of TM include subacute bilateral lower extremity weakness, a spinal sensory level, and impaired bowel/bladder control. L’Hermitte’s symptom (pain with
forward neck flexion) suggests a cervical cord lesion. Paresis is often initially flaccid with hyporeflexia, and later hyperreflexia develops below the lesion level. These features help distinguish TM from other spinal cord pathologies (Fig. 100-2). A review of 47 pediatric TM patients reported that, at the time of maximal deficit, 89% either were unable to walk and/ or required ventilator assistance. After 3 years, 43% were unable to ambulate more than 30 feet, and 21% required an ambulatory aid; in addition, 68% had residual bladder symptoms. Younger age at TM, complete paraplegia, sphincter dysfunction, and less than 24 hours to maximal deficit are associated with poorer functional outcomes. MS risk following TM is 2% to 8%. Less than 24 hours to symptom nadir and abnormal baseline brain MRI were strong predictors of relapse in one study. Longitudinally extensive TM (LETM) (≥ 3 spinal segments), recurrent TM, and TM with ON should prompt consideration of NMO.
Polyfocal Demyelination Neurologic symptoms suggesting multiple CNS areas of involvement may occur +/–encephalopathy (Fig. 100-3). When encephalopathy (behavioral change or alteration in level of consciousness) is present, the clinical syndrome is acute disseminated encephalomyelitis (ADEM). ADEM occurs in younger patients (especially < 10 years). Fever and a recent history of infection are often present. ADEM generally carries a favorable prognosis, but 11% to 17% of children experience residual motor deficits. Cognitive deficits may also persist. ADEM is typically monophasic. However, approximately 5% to 29% of children will go on to have additional demyelinating attacks characteristic of MS. Rarely, ADEM represents the first attack of NMO. ADEM may also precede or follow a diagnosis of anti-NMDA receptor encephalitis.
Other Clinical Presentations Children with ADS may also present with intranuclear ophthalmoplegia (INO), focal motor deficits, sensory loss/ paresthesias, or isolated cerebellar deficits.
Investigation of a Child with Acute Demyelination Laboratory Investigations Cerebrospinal fluid (CSF) analysis is important for excluding other diseases, including infection and malignancy. CSF leukocyte counts in children with MS are elevated (>4 cells/µL) in 66% (typically < 30 cells/µL). Higher leukocyte counts are more consistent with infection, vasculitis, or NMO. A study of 107 children with MS reported that those younger than 11 years of age had a higher percentage of CSF neutrophils and
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PART XI White Matter Disorders Polyfocal presentation
With encephalopathy
Without encephalopathy
ADEM
Polyfocal ADS Slow progressive deficits Hearing loss Family history of neurodegenerative disease
Brain MRI
Multifocal lesions involving WM and GM
WM pattern atypical for acquired demyelination
Leukodystrophy Mitochondrial disease Metabolic disease Nutritional deficiency
CSF examination
↑ CSF WBC* Fever, systemic illness CNS infection
↑ CSF opening pressure Persistent headache or malaise Vasculitis
Normal or minimal ↑ WBC
Positive CSF OCBs
Inflammatory demyelination
Figure 100-3. Approach to polyfocal neurologic symptoms. ADEM, acute disseminated encephalomyelitis; ADS, acquired demyelinating syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; GM, gray matter; MRI, magnetic resonance imaging; OCBs, oligoclonal bands; WBC, white blood cell count; WM, white matter.
a lower percentage of monocytes and were less likely to have an elevated IgG index than children older than 11 years of age. Elevated protein (typically 100–720 mg/L) may be seen, indicating disruption of the blood–CSF barrier. CSF oligoclonal bands (OCBs) are detected at diagnosis of ADS in up to 90% of children subsequently diagnosed with MS, which is lower than the reported rate of 98% in adult MS. Isoelectric focusing methods have the highest yield for OCB detection. CSF OCBs are detected in less than 10% of children with either ADEM or NMO. CSF immunoglobulin G synthesis can occur later in the disease course, and OCBs may therefore only be detected over time. Evoked potential testing in the visual-evoked potential, brainstem auditory-evoked potential, and somatosensoryevoked potential pathways is useful for confirming the presence of demyelination and for detecting clinically silent disease. In one study, almost 50% of 85 children with MS demonstrated clinically silent abnormalities in at least one of the evoked potential pathways, most commonly the visual pathway.
Magnetic Resonance Imaging MRI is a valuable tool to illustrate inflammatory demyelination and to exclude other diagnoses. The MRI appearance of MS in children younger than 10 years of age is similar to that of adults (Figure 100-4). MS lesions are typically ovoid and
are often seen in the periventricular or juxtacortical region, brainstem, and/or spinal cord. Periventricular lesions are often oriented 90 degrees perpendicular to the long axis of the corpus callosum. Infratentorial lesions and large, ill-defined lesions are more common in children than in adults. The presence of one periventricular lesion and one “black hole” (a T1 iso- or hypo-intense lesion relative to cortical gray matter) on imaging obtained at ADS identifies children with MS with 84% sensitivity and 93% specificity. Large lesions, ill-defined lesions, and lesions in gray and white matter commonly occur in younger children, especially those with ADEM. Lesions located predominantly in the diencephalon or periaqueductal gray matter, longitudinally extensive spinal cord lesions, and bilateral or extensive optic nerve lesions characterize NMO.
Management of Acute Demyelination Acute demyelination is generally treated with corticosteroids if symptoms are severe enough to interfere with daily functioning (Fig. 100-5). Typically 20 to 30 mg/kg/day of intravenous methylprednisolone (maximum 1 g) is given as a single daily dose for 3 to 5 days. If there is a significant improvement in symptoms, no further treatment is required. If there is an incomplete response to treatment but residual symptoms are relatively mild, a tapering course of oral steroids (starting at
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A
B
C
D
E
F
Figure 100-4. MRI in childhood ADS and MS. A, Axial T1-weighted image with gadolinium of a child with optic neuritis shows optic nerve thickening and enhancement (arrow). B, T2-weighted hyperintense spinal lesion (arrow) in a child with transverse myelitis. C, Axial fluid-attenuated inversion-recovery (FLAIR) image demonstrates diffuse bilateral deep gray- and white-matter lesions in a child with acute disseminated encephalomyelitis. D, Axial FLAIR image demonstrates multiple lesions in a child with multiple sclerosis. E, Several of the lesions observed in panel D enhance following gadolinium administration. F, Multiple nonenhancing T1 “black holes” are present in the same child, suggesting chronic disease.
1 mg/kg/day and tapering over 14–21 days) is often considered. If children have significant residual symptoms after intravenous steroid treatment, a second 3- to 5-day course may be given. Alternatively, treatment with intravenous immunoglobulin (IVIg; 2 g/kg over 2–5 days) may be of benefit (class IV evidence). Profound encephalopathy and respiratory depression may occur with brainstem/upper cervical spinal cord involvement and may be a life-threatening condition. Plasma exchange may be useful in this situation (class I evidence in adult-onset MS). A typical regimen of plasma exchange treatment is 5 to 8 exchanges in 10 days.
RELAPSING DEMYELINATING DISORDERS Multiple Sclerosis MS, a chronic inflammatory and degenerative disorder of the CNS, is being increasingly diagnosed in children.
Epidemiology of Pediatric Multiple Sclerosis Childhood-onset MS has been reported in many countries. Although the exact incidence remains unknown, 3% to 10% of MS patients experience their first symptoms at younger than 18 years of age. Gender differences in pediatric MS are related to age. In children younger than 10 years of age, the female-to-male ratio is approximately 1 : 1. After age 10, this ratio increases to 3 : 1. A family history of MS is reported in 5% to 15% of children, slightly lower than the 20% to 30% of adult MS patients who report MS in at least one first-degree relative.
Diagnostic Criteria for Pediatric Multiple Sclerosis MS diagnosis requires demonstration of CNS demyelination separated in both space and in time (Fig. 100-6). A child with two separate characteristic attacks meets the clinical criteria for dissemination in space (DIS) and time (DIT). MRI may
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PART XI White Matter Disorders ADEM with partial or complete clinical recovery
New neurological symptoms < 90 days of initial illness
Polyfocal symptoms with encephalopathy > 90 days from initial illness with new or re-emergent clinical and MRI features
Two or more nonADEM attacks involving different CNS area separated by at least 30 days OR one non-ADEM attack > 90 days from initial ADEM and MRI meeting DIS* and DIT † criteria
Protracted initial ADEM illness
Multiphasic ADEM
Multiple Sclerosis
A First attack of demyelination without encephalopathy
Clinical evidence of one CNS lesion (monofocal presentation)
Clinical evidence of two or more CNS lesions (polysymptomatic presentation)
Dissemination in space as demonstrated by: • MRI* or • Second clinical attack involving a new CNS area AND Dissemination in time as demonstrated by: • MRI† or • Second clinical attack
Dissemination in time as demonstrated by: • MRI† or • Second clinical attack
Multiple Sclerosis
B Figure 100-6. Classification of further attacks of demyelination. A, Approach to further attacks of demyelination in the child initially presenting with acute disseminated encephalomyelitis (ADEM). B, Approach to further attacks of demyelination in the child presenting with a monofocal or polyfocal neurologic syndrome without encephalopathy. *MRI criteria for dissemination in space require the presence of at least one lesion in the following locations: periventricular, juxtacortical, infratentorial, and spinal cord. †MRI criteria for dissemination in time require either new T2 lesions on serial scans or the simultaneous presence of a clinically silent gadolinium-enhancing and nonenhancing lesion on a single baseline scan (Polman, Reingold et al., 2011).
also be used to demonstrate DIS or DIT (Polman et al. 2011). Specifically, MRI evidence of DIS requires at least one T2-hyperintense lesion in two of four CNS areas: periventricular, juxtacortical, infratentorial, and/or spinal cord. MRI DIT criteria require new T2 or gadolinium-enhancing lesions over time (≥30 days from a baseline scan) or at the time of initial presentation, provided the baseline scan shows the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions. McDonald 2010 MS criteria have a positive predictive value of 76% and a negative predictive value of 100% when applied to children with ADS; however, these criteria are less
predictive in younger children and cannot be reliably applied in ADEM.
Clinical Course of Pediatric Multiple Sclerosis MS is relapsing-remitting in more than 95% of children. A study of 21 pediatric and 110 adult patients demonstrated that, compared with adults, children with MS experience more frequent relapses in the first few years following diagnosis (annualized relapse rate of 1.13 versus 0.4, p < 0.01). A German study showed that relapse rates decreased between year 1 and year 5 following diagnosis in both patients younger than 11
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years of age (relapse rate of 2.1 versus 0.79) and patients between 14 and 16 years of age (1.8 versus 0.42). Secondary disease progression, when accrual of disability occurs in the absence of discrete relapses, typically begins after 15 years of age. Because of their younger age at onset, pediatric MS patients accrue disability approximately 10 years earlier than do adult patients.
Magnetic Resonance Imaging Features of Pediatric Multiple Sclerosis Imaging studies have shown that pediatric-onset MS is associated with a global reduction in brain volume, especially in the thalami, and a reduction in age-expected head size. Both T1and T2-weighted lesion volume is higher in pediatric-onset MS patients compared with adults, with a greater lesion burden located infratentorially in children. The long-term effects of this extensive pathology on cognitive, physical, psychiatric, and socioeconomic functioning have yet to be defined. Complex imaging modalities, including diffusion-tensor imaging (DTI), magnetization transfer ratio (MTR) imaging, and functional MRI (fMRI), hold great promise as tools to link structural and functional parameters.
Pathobiological Insights Into Pediatric Multiple Sclerosis The greatest genetic contributor to MS risk in children and adults is associated with the HLA DRB1*1501 haplotype. Over 100 non-HLA risk SNPs have been identified as contributors to adult-onset MS risk. Early studies indicate that similar non-HLA risk SNPs also contribute to pediatric-onset MS risk. Several environmental risk factors have been shown to contribute to pediatric MS risk (reviewed in Waldman et al., 2014), including: 1. Low serum 25-hydroxyvitamin D levels 2. Remote Epstein–Barr virus (EBV) infection 3. Earlier age at menarche 4. Secondhand smoke exposure 5. Increased body mass index (BMI)
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Case-control studies suggest that cytomegalovirus infection may be associated with reduced pediatric MS risk. A Canadian study of children with ADS found a higher risk of later MS diagnosis in children who had (a) low serum 25-hydroxyvitamin D level (<75 nmol/L), (b) evidence of remote EBV infection, and (c) at least one HLA DRB1*1501 allele compared with those children who had none of these risk factors at presentation (hazard ratio [HR] = 5.27, 95% confidence interval [CI] = 1.23–22.6) (Banwell et al., 2011). Children with demyelination may display antibodies against MOG, aquaporin-4, NMDA receptors, voltage-gated potassium channels, and glycine receptors. Defining the range of autoantibodies present in children with demyelination and their associated clinical phenotypes will be of considerable future interest. The cerebrospinal fluid (CSF) of children with ADS appears to be enriched in components of the axoglial apparatus, including neurofascin, contactins, and contactin-associated proteins, suggesting that axoglial apparatus disruption may be involved in MS pathobiology. Altered cellular immune responses are associated with pediatric-onset MS. Both T-cell repertoire (proportions of naïve versus memory T-cells) and functional T-cell responses to myelin and nonmyelin antigens appear to be disrupted in children with MS.
Immunomodulatory Therapy in Pediatric Multiple Sclerosis Principles of Immunomodulatory Therapy. There are now 12 MS therapies approved by the U.S. Food and Drug Administration (FDA) available in the United States. In children, first-line treatment is usually with interferons (beta 1a or 1b), or glatiramer acetate (GA) (Table 100-1). These agents reduce relapse rates by approximately one third in adult MS patients and also reduce the number of T2 brain MRI lesions. Interferons and GA are generally considered safe and well tolerated in children with MS. Transaminitis is the most frequent laboratory abnormality in children treated with interferons and is possibly reduced by a gradual dose titration starting at one fourth of the usual adult dose. GA is utilized at full dose.
TABLE 100-1 Immunomodulatory Therapies for Pediatric Multiple Sclerosis Drug
Dosing Regimen
Common Side Effects
Potential Laboratory Abnormalities
Interferon beta 1a (Avonex®)
30 µg IM weekly
Flu-like myalgia and headache Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Interferon beta 1a (Rebif®)
22–44 µg SC weekly
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Pegylated Interferon beta 1a (Plegridy®)
125 µg SC every 14 days
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Interferon beta 1b (Betaseron®)
0.25 mg SC every 2 days
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Glatiramer acetate (Copaxone®)
20 mg SC daily or 40 mg SC 3 times a week
Injection-site reaction (redness, pain, and induration) Immediate postinjection reaction (flushing, tachycardia, and chest pain)
No significant effect on liver or hematological function
IM, intramuscular; SC, subcutaneous.
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White blood cell counts and liver function tests should be monitored monthly for 6 months and then every 3 months thereafter during interferon treatment. Thyroid function should be monitored yearly. Sexually active patients should receive counseling regarding contraceptive use. Second-Line Therapies. Immunosuppressive therapy is offered when frequent relapses occur despite compliance with interferon or GA. Proposed definitions for inadequate treatment response require full compliance for at least 6 months and at least one of the following: (a) increased or stable relapse rate or new T2- or contrast-enhancing lesions compared with pretreatment baseline or (b) at least two clinical or MRI attacks within 12 months (Chitnis et al., 2012). Therapeutic options for children experiencing an inadequate treatment response include switching between first-line therapies or escalating to a second-line agent. Children with frequent relapses on interferon therapy should be checked for neutralizing antibodies. Cyclophosphamide, azathioprine, methotrexate, mitoxantrone, and rituximab have all been utilized in isolated cases or small case series of pediatric MS patients. There are increasing numbers of reports of natalizumab use in pediatriconset MS. A study of 55 children with MS treated with natalizumab reported that the annualized relapse rate (ARR) decreased from 2.4 +/– 1.6 to 0.1 +/– 0.2 (p < 0.001). Mild transient hematological abnormalities were observed in 7 out of 55 patients, and no serious adverse events were reported. Natalizumab is associated with increased risk of progressive multifocal leukoencephalopathy, especially in patients seropositive for JC virus (particularly with an index value > 1.5), patients previously treated with other immunosuppressive agents, and those treated for more than 24 months. Several oral agents (e.g., dimethyl fumarate, fingolimod, and teriflunomide) and infusion-based therapies (e.g., alemtuzumab) are now approved for use in adult-onset MS. Clinical trials for some of these agents are ongoing in pediatric MS, and future trials are expected.
General Care Issues The care of children with MS requires a multidisciplinary team that often includes a neurologist, nurse, occupational therapist, physiotherapist, psychologist, dietician, and social worker. An MS diagnosis has important implications for social functioning, family functioning, and overall psychosocial well-being.
Multiphasic Acute Disseminated Encephalomyelitis MS diagnosis in a child with initial ADEM requires either two subsequent non-ADEM attacks or one subsequent clinical attack not accompanied by encephalopathy at least 3 months from the initial ADEM associated with MRI findings meeting current definitions for DIS and DIT (Krupp, Tardieu et al., 2013). Recurrence of ADEM more than 3 months after an initial ADEM episode is termed multiphasic ADEM (Krupp et al., 2013), which is treated in the same manner as an acute demyelinating attack.
Neuromyelitis Optica NMO is a severe, inflammatory CNS demyelinating disorder with unique clinical, laboratory, and MRI features. The identification of a biomarker for NMO (NMO-IgG) has resulted in improved diagnostic accuracy (Lennon et al., 2004).
Epidemiology of Pediatric Neuromyelitis Optica The exact incidence of NMO in childhood is unknown. In children and adults, NMO has a marked female predominance, with some studies reporting a female-to-male ratio as high as 9 : 1. There is an overrepresentation of children reporting non-Caucasian ethnicity compared with other demyelinating diseases. In one U.S. study, 42 out of 58 NMO-IgG–seropositive children (73%) with available ethnicity data were non-Caucasian.
Clinical Features of Pediatric Neuromyelitis Optica NMO is characterized by severe ON (visual acuity typically 20/200 or worse) and TM, occurring either simultaneously or sequentially. When sequential, ON and TM may be separated by months or even years. Approximately 53% to 100% of pediatric NMO patients experience a relapsing (as opposed to monophasic) course. Predictors of a relapsing course in one study of adult NMO patients included female gender, older age at onset, and evidence of systemic autoimmunity. NMO-IgG–seropositive patients appear more likely to experience a relapsing course compared with seronegative individuals. In a retrospective analysis of 20 children with NMO, mean time to relapse was shorter in seropositive patients compared with seronegative patients (0.76 versus 2.4 years, p = 0.03). Serum NMO-IgG titers correlated with disease severity in one study. NMO is typically characterized by severe attacks with poor recovery, leading to rapid disability accrual. In a study of adults with NMO, 31 out of 66 (47%) were functionally blind (visual acuity of 20/200 or worse) in at least one eye, and 32 out of 71 (45%) exhibited permanent monoplegia or paraplegia, after a mean follow up of 16.9 years in relapsing patients and 7.7 years in monophasic patients. Respiratory failure was observed in one third of relapsing patients. One pediatric study reported that after a median of 12 months of follow up, 54% of NMO patients had permanent visual impairment, and 44% had limb weakness severe enough to affect mobility.
Symptomatic Brain Involvement in Neuromyelitis Optica Brain MRI lesions in NMO typically follow the distribution of aquaporin-4 water channel expression, including the diencephalon and brainstem periaqueductal gray matter. Brain lesions are symptomatic in 35% to 45% of children. Brainstem involvement may present as hiccups, nausea/vomiting, ophthalmoplegia, and, in severe cases, respiratory failure or death. Symptoms of diencephalic involvement may include hypersomnolence, narcolepsy, inappropriate antidiuretic hormone secretion, or menstrual irregularities. Large multifocal lesions have been associated with encephalopathy and an ADEM-like phenotype.
Diagnostic Criteria for Pediatric Neuromyelitis Optica Revised pediatric consensus criteria for NMO require the presence of ON and TM with at least two of the following supportive features (Krupp et al., 2013): 1. MRI evidence of a contiguous spinal lesion at least three spinal segments in length 2. Brain MRI not meeting diagnostic criteria for MS 3. NMO-IgG seropositivity The presence of two of the three supportive criteria has 99% sensitivity and 90% specificity in distinguishing adults with NMO from those with MS (Wingerchuk, Lennon, Pittock,
Lucchinetti, and Weinshenker, 2006). Children may present with recurrent ON or TM associated with serum NMO-IgG; such cases are considered NMO spectrum disorders (Krupp et al., 2013).
Systemic Autoimmunity in Neuromyelitis Optica There is a high frequency of coexisting systemic autoimmunity in NMO. In one pediatric cohort, 16 out of 38 patients (42%) met the criteria for clinical diagnosis of another autoimmune condition, including systemic lupus erythematosus, type 1 diabetes, juvenile rheumatoid arthritis, and Graves disease. Some children with NMO harbor other autoantibodies without meeting formal diagnostic criteria for another autoimmune disorder. Some children with anti-NMDA receptor encephalitis display NMO-IgG in the absence of clinical NMO symptoms. The relevance of incidentally detected NMO-IgG in children with other CNS autoimmune conditions is unclear.
Laboratory Features of Neuromyelitis Optica The CSF in NMO patients typically demonstrates a marked pleocytosis (>50 leukocytes/µL), with a neutrophilic or lymphocytic predominance. This is in contrast to the moderate lymphocytic pleocytosis (<25 leukocytes/µL) typical of pediatric MS. One study of lumbar punctures in 89 pediatric and adult NMO patients found that pleocytosis (>5 leukocytes/µL) occurred in 50% of samples, with a median white blood cell count of 15 leukocytes/µL (range = 6–380). The median number of white blood cells and percentage of samples containing neutrophils were higher during relapses compared with periods of clinical quiescence. CSF OCBs are detected in less than 10% of children with NMO. In one pediatric study, OCBs were more commonly detected in seropositive (2/10) compared with seronegative (0/7) NMO patients. Visual-evoked potentials are frequently abnormal in NMO patients and typically display a prolongation or absence of the P100 response. In adults with NMO, markedly abnormal or absent visual-evoked potential responses at baseline are associated with worse long-term visual outcomes. Delayed P100 responses have been observed in the absence of a clear history of ON, suggesting that optic nerve involvement may be subclinical. OCT-based studies have demonstrated that RNFL thinning is frequently seen in NMO patients, and that RNFL thinning after an episode of ON is more severe in patients with NMO compared with those with MS. NMO-IgG is directed against the aquaporin-4 water channel located on astrocytic end feet. This serum biomarker has a sensitivity of 73% and a specificity of 91% in differentiating NMO from other demyelinating disorders, including MS, in adult patients (Lennon et al., 2004) and is detected in up to 78% of children with relapsing NMO. NMO-IgG has also been detected in children with NMO spectrum disorders. A proportion of individuals with clinical NMO will repeatedly test negative for NMO-IgG, even when sensitive cell-based assays are employed. A subset of these NMO-IgG– seronegative patients displays serum anti-MOG antibodies. Studies suggest that NMO patients with anti-MOG antibodies (without NMO-IgG) have an increased likelihood of being male, are slightly younger, have better recovery from attacks, are less likely to experience a relapsing course, and, in one study, were more likely to present with simultaneous/ sequential ON and TM. In three reported children with clinical NMO and anti-MOG antibodies, there was an initial relapsing course, with a beneficial response to longer-term immunotherapy (azathioprine or monthly IVIg). Two children displayed deep gray-matter involvement on MRI.
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Magnetic Resonance Imaging in Neuromyelitis Optica As in MS, MRI during an acute ON attack in NMO typically reveals optic nerve thickening and an increased signal on fatsuppressed T2-weighted images. Fat-suppressed postcontrast T1-weighted images show optic nerve enhancement in 94% of patients. To date, there are no MRI features that reliably distinguish ON in NMO from that in MS, although a trend toward more extensive and greater posterior optic nerve involvement in NMO has been noted. Brain MRI lesions are common in children with NMO, with 53% to 100% of children demonstrating brain abnormalities distinct from the optic nerves at presentation. In NMO, brain MRI lesions typically occur in areas of aquaporin4 water channel expression, including (a) lesions surrounding the ventricular system (e.g., diencephalic lesions around the third ventricle, dorsal brainstem lesions adjacent to the fourth ventricle, and peri-ependymal lesions surrounding the lateral ventricles); (b) hemispheric lesions that may be large (>3 cm diameter); (c) lesions involving the corticospinal tracts; and (d) small, nonspecific, deep white-matter lesions (most common lesion type) (Fig. 100-7) (Kim et al., 2015). Enhancing lesions may demonstrate a patchy, diffuse, “cloudlike” enhancement pattern. As discussed earlier, brain lesions may be symptomatic. Lesions that are perpendicular to ventricles, S-shaped U-fiber lesions, lesions along the inferior aspect of the lateral ventricles, temporal lobe lesions, and lesions that have an ovoid or open-ring enhancement pattern are more characteristic of MS (Kim et al., 2015). Acute spinal MRI in NMO typically reveals lesions spanning at least three contiguous spinal segments that are hyperintense on T2-weighted images (Fig. 100-7A) and hypointense on T1-weighted images. It is important to note, however, that LETM is frequently seen in children with idiopathic TM, in TM with ADEM, and in up to 25% of TM cases associated with an MS attack. NMO patients occasionally present with short-segment spinal lesions. Partial cord lesions in NMO often localize to the cervical and upper thoracic cord. Acutely, lesions typically affect central cord gray and white matter, with diffuse gadolinium uptake within the lesion core. Bilateral and symmetric anterior horn cell signal abnormalities resembling anterior cord infarction have been described. Over time, the development of spinal cord atrophy is associated with an increased likelihood of persistent neurologic deficits.
Treatment of Pediatric Neuromyelitis Optica Acute attacks are usually treated with intravenous corticosteroids. If symptoms progress despite steroid therapy, IVIg and/ or plasmapheresis is usually administered. Longer-term immunosuppression is generally used to prevent relapses and disability accrual given the aggressive nature of this disease. Azathioprine (+/– oral prednisone), repeated IVIg or plasmapheresis, rituximab, cyclophosphamide, mycophenolate mofetil, and ofatumumab have all been used in children with NMO.
CONCLUSIONS Acquired demyelination of the CNS, including transient forms and pediatric-onset MS and NMO, is being increasingly recognized and diagnosed worldwide. This has been aided by the development of consensus diagnostic criteria, evolving MRI criteria, and the discovery of the NMO-IgG biomarker. The current and emerging armamentarium of increasingly powerful medications for adult-onset MS will require vigilant and
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A
B
Figure 100-7. MRI in childhood neuromyelitis optica. A, Sagittal T2-weighted MRI image shows a longitudinally extensive intramedullary spinal lesion. B, Axial fluid-attenuated inversion-recovery (FLAIR) MRI from a different child shows bilateral hyperintense diencephalic lesions.
thoughtful use in children. Collaboration between clinicians and scientists, such as that fostered by the International Pediatric MS Study Group and other organizations, is essential to optimize care. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. RESOURCES National Multiple Sclerosis Society (United States). .nationalmssociety.org>. Multiple Sclerosis Society of Canada..
SELECTED REFERENCES Banwell, B., Bar-Or, A., Arnold, D.L., et al., 2011. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol. 10 (5), 436–445. Chitnis, T., Tenembaum, S., Banwell, B., et al., 2012. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult. Scler. 18 (1), 116–127. Kim, H.J., Paul, F., Lana-Peixoto, M.A., et al., 2015. MRI characteristics of neuromyelitis optica spectrum disorder: An international update. Neurology. Krupp, L.B., Tardieu, M., Amato, M.P., et al., 2013. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple
sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult. Scler. Lennon, V.A., Wingerchuk, D.M., Kryzer, T.J., et al., 2004. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364 (9451), 2106–2112. Polman, C.H., Reingold, S.C., Banwell, B., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69 (2), 292–302. Waldman, A., Ghezzi, A., Bar-Or, A., et al., 2014. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 13 (9), 936–948. Wingerchuk, D.M., Lennon, V.A., Pittock, S.J., et al., 2006. Revised diagnostic criteria for neuromyelitis optica. Neurology 66 (10), 1485–1489.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 100-1 Approach to visual loss. Fig. 100-2 Approach to symptoms localizing to the spinal cord. Fig. 100-5 Approach to the management of acute demyelination in childhood.
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Demyelination of the central nervous system (CNS) may occur as a monophasic illness or may represent the first attack of chronic inflammatory diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). Herein, we review the clinical and neuroimaging features of childhood acquired CNS demyelinating disorders.
ACUTE CENTRAL NERVOUS SYSTEM DEMYELINATION Children with an acquired demyelinating syndrome (ADS) may present either with neurologic signs and symptoms attributable to a single CNS location (monofocal ADS) or with signs attributable to multiple CNS sites (polyfocal ADS), with or without encephalopathy (Krupp et al., 2013).
OPTIC NEURITIS Optic neuritis (ON) should be considered in any child presenting with acute or subacute visual loss (Fig. 100-1). Demyelinating ON is typically clinically characterized by reduced visual acuity, a central visual field deficit, pain with eye movements, and red color desaturation. Optic disc edema is sometimes seen, but may be absent in retrobulbar ON. Although some studies suggest that childhood ON is more commonly bilateral, others have reported that ON is more commonly unilateral. In one study of 36 children with ON, neuroimaging studies of the optic nerve were abnormal in 55%, and 88% had abnormal visual-evoked potentials (typically a P100 latency delay). Optical coherence tomography (OCT) utilizes near-infrared light to measure the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), yielding a quantitative measure of axonal and neuronal loss. RNFL and GCL thinning have been demonstrated in children with isolated ON and MS and may provide quantifiable information about retinal integrity. Following ON, 80% to 85% of children achieve full visual recovery. Children with ON have a 30% risk of a subsequent MS diagnosis. Magnetic resonance imaging (MRI) evidence of one or more T2-weighted lesions apart from the optic nerve is strongly predictive of MS, with up to 68% of such patients being diagnosed with MS within 2 years. Concurrent or rapidly sequential transverse myelitis, MRI features of brainstem or diencephalic involvement in a pattern atypical for MS, and serum antibodies against aquaporin-4 suggest a diagnosis of NMO.
Transverse Myelitis Demyelination of the spinal cord is termed transverse myelitis (TM). Typical features of TM include subacute bilateral lower extremity weakness, a spinal sensory level, and impaired bowel/bladder control. L’Hermitte’s symptom (pain with
forward neck flexion) suggests a cervical cord lesion. Paresis is often initially flaccid with hyporeflexia, and later hyperreflexia develops below the lesion level. These features help distinguish TM from other spinal cord pathologies (Fig. 100-2). A review of 47 pediatric TM patients reported that, at the time of maximal deficit, 89% either were unable to walk and/ or required ventilator assistance. After 3 years, 43% were unable to ambulate more than 30 feet, and 21% required an ambulatory aid; in addition, 68% had residual bladder symptoms. Younger age at TM, complete paraplegia, sphincter dysfunction, and less than 24 hours to maximal deficit are associated with poorer functional outcomes. MS risk following TM is 2% to 8%. Less than 24 hours to symptom nadir and abnormal baseline brain MRI were strong predictors of relapse in one study. Longitudinally extensive TM (LETM) (≥ 3 spinal segments), recurrent TM, and TM with ON should prompt consideration of NMO.
Polyfocal Demyelination Neurologic symptoms suggesting multiple CNS areas of involvement may occur +/–encephalopathy (Fig. 100-3). When encephalopathy (behavioral change or alteration in level of consciousness) is present, the clinical syndrome is acute disseminated encephalomyelitis (ADEM). ADEM occurs in younger patients (especially < 10 years). Fever and a recent history of infection are often present. ADEM generally carries a favorable prognosis, but 11% to 17% of children experience residual motor deficits. Cognitive deficits may also persist. ADEM is typically monophasic. However, approximately 5% to 29% of children will go on to have additional demyelinating attacks characteristic of MS. Rarely, ADEM represents the first attack of NMO. ADEM may also precede or follow a diagnosis of anti-NMDA receptor encephalitis.
Other Clinical Presentations Children with ADS may also present with intranuclear ophthalmoplegia (INO), focal motor deficits, sensory loss/ paresthesias, or isolated cerebellar deficits.
Investigation of a Child with Acute Demyelination Laboratory Investigations Cerebrospinal fluid (CSF) analysis is important for excluding other diseases, including infection and malignancy. CSF leukocyte counts in children with MS are elevated (>4 cells/µL) in 66% (typically < 30 cells/µL). Higher leukocyte counts are more consistent with infection, vasculitis, or NMO. A study of 107 children with MS reported that those younger than 11 years of age had a higher percentage of CSF neutrophils and
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PART XI White Matter Disorders Polyfocal presentation
With encephalopathy
Without encephalopathy
ADEM
Polyfocal ADS Slow progressive deficits Hearing loss Family history of neurodegenerative disease
Brain MRI
Multifocal lesions involving WM and GM
WM pattern atypical for acquired demyelination
Leukodystrophy Mitochondrial disease Metabolic disease Nutritional deficiency
CSF examination
↑ CSF WBC* Fever, systemic illness CNS infection
↑ CSF opening pressure Persistent headache or malaise Vasculitis
Normal or minimal ↑ WBC
Positive CSF OCBs
Inflammatory demyelination
Figure 100-3. Approach to polyfocal neurologic symptoms. ADEM, acute disseminated encephalomyelitis; ADS, acquired demyelinating syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; GM, gray matter; MRI, magnetic resonance imaging; OCBs, oligoclonal bands; WBC, white blood cell count; WM, white matter.
a lower percentage of monocytes and were less likely to have an elevated IgG index than children older than 11 years of age. Elevated protein (typically 100–720 mg/L) may be seen, indicating disruption of the blood–CSF barrier. CSF oligoclonal bands (OCBs) are detected at diagnosis of ADS in up to 90% of children subsequently diagnosed with MS, which is lower than the reported rate of 98% in adult MS. Isoelectric focusing methods have the highest yield for OCB detection. CSF OCBs are detected in less than 10% of children with either ADEM or NMO. CSF immunoglobulin G synthesis can occur later in the disease course, and OCBs may therefore only be detected over time. Evoked potential testing in the visual-evoked potential, brainstem auditory-evoked potential, and somatosensoryevoked potential pathways is useful for confirming the presence of demyelination and for detecting clinically silent disease. In one study, almost 50% of 85 children with MS demonstrated clinically silent abnormalities in at least one of the evoked potential pathways, most commonly the visual pathway.
Magnetic Resonance Imaging MRI is a valuable tool to illustrate inflammatory demyelination and to exclude other diagnoses. The MRI appearance of MS in children younger than 10 years of age is similar to that of adults (Figure 100-4). MS lesions are typically ovoid and
are often seen in the periventricular or juxtacortical region, brainstem, and/or spinal cord. Periventricular lesions are often oriented 90 degrees perpendicular to the long axis of the corpus callosum. Infratentorial lesions and large, ill-defined lesions are more common in children than in adults. The presence of one periventricular lesion and one “black hole” (a T1 iso- or hypo-intense lesion relative to cortical gray matter) on imaging obtained at ADS identifies children with MS with 84% sensitivity and 93% specificity. Large lesions, ill-defined lesions, and lesions in gray and white matter commonly occur in younger children, especially those with ADEM. Lesions located predominantly in the diencephalon or periaqueductal gray matter, longitudinally extensive spinal cord lesions, and bilateral or extensive optic nerve lesions characterize NMO.
Management of Acute Demyelination Acute demyelination is generally treated with corticosteroids if symptoms are severe enough to interfere with daily functioning (Fig. 100-5). Typically 20 to 30 mg/kg/day of intravenous methylprednisolone (maximum 1 g) is given as a single daily dose for 3 to 5 days. If there is a significant improvement in symptoms, no further treatment is required. If there is an incomplete response to treatment but residual symptoms are relatively mild, a tapering course of oral steroids (starting at
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A
B
C
D
E
F
Figure 100-4. MRI in childhood ADS and MS. A, Axial T1-weighted image with gadolinium of a child with optic neuritis shows optic nerve thickening and enhancement (arrow). B, T2-weighted hyperintense spinal lesion (arrow) in a child with transverse myelitis. C, Axial fluid-attenuated inversion-recovery (FLAIR) image demonstrates diffuse bilateral deep gray- and white-matter lesions in a child with acute disseminated encephalomyelitis. D, Axial FLAIR image demonstrates multiple lesions in a child with multiple sclerosis. E, Several of the lesions observed in panel D enhance following gadolinium administration. F, Multiple nonenhancing T1 “black holes” are present in the same child, suggesting chronic disease.
1 mg/kg/day and tapering over 14–21 days) is often considered. If children have significant residual symptoms after intravenous steroid treatment, a second 3- to 5-day course may be given. Alternatively, treatment with intravenous immunoglobulin (IVIg; 2 g/kg over 2–5 days) may be of benefit (class IV evidence). Profound encephalopathy and respiratory depression may occur with brainstem/upper cervical spinal cord involvement and may be a life-threatening condition. Plasma exchange may be useful in this situation (class I evidence in adult-onset MS). A typical regimen of plasma exchange treatment is 5 to 8 exchanges in 10 days.
RELAPSING DEMYELINATING DISORDERS Multiple Sclerosis MS, a chronic inflammatory and degenerative disorder of the CNS, is being increasingly diagnosed in children.
Epidemiology of Pediatric Multiple Sclerosis Childhood-onset MS has been reported in many countries. Although the exact incidence remains unknown, 3% to 10% of MS patients experience their first symptoms at younger than 18 years of age. Gender differences in pediatric MS are related to age. In children younger than 10 years of age, the female-to-male ratio is approximately 1 : 1. After age 10, this ratio increases to 3 : 1. A family history of MS is reported in 5% to 15% of children, slightly lower than the 20% to 30% of adult MS patients who report MS in at least one first-degree relative.
Diagnostic Criteria for Pediatric Multiple Sclerosis MS diagnosis requires demonstration of CNS demyelination separated in both space and in time (Fig. 100-6). A child with two separate characteristic attacks meets the clinical criteria for dissemination in space (DIS) and time (DIT). MRI may
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PART XI White Matter Disorders ADEM with partial or complete clinical recovery
New neurological symptoms < 90 days of initial illness
Polyfocal symptoms with encephalopathy > 90 days from initial illness with new or re-emergent clinical and MRI features
Two or more nonADEM attacks involving different CNS area separated by at least 30 days OR one non-ADEM attack > 90 days from initial ADEM and MRI meeting DIS* and DIT † criteria
Protracted initial ADEM illness
Multiphasic ADEM
Multiple Sclerosis
A First attack of demyelination without encephalopathy
Clinical evidence of one CNS lesion (monofocal presentation)
Clinical evidence of two or more CNS lesions (polysymptomatic presentation)
Dissemination in space as demonstrated by: • MRI* or • Second clinical attack involving a new CNS area AND Dissemination in time as demonstrated by: • MRI† or • Second clinical attack
Dissemination in time as demonstrated by: • MRI† or • Second clinical attack
Multiple Sclerosis
B Figure 100-6. Classification of further attacks of demyelination. A, Approach to further attacks of demyelination in the child initially presenting with acute disseminated encephalomyelitis (ADEM). B, Approach to further attacks of demyelination in the child presenting with a monofocal or polyfocal neurologic syndrome without encephalopathy. *MRI criteria for dissemination in space require the presence of at least one lesion in the following locations: periventricular, juxtacortical, infratentorial, and spinal cord. †MRI criteria for dissemination in time require either new T2 lesions on serial scans or the simultaneous presence of a clinically silent gadolinium-enhancing and nonenhancing lesion on a single baseline scan (Polman, Reingold et al., 2011).
also be used to demonstrate DIS or DIT (Polman et al. 2011). Specifically, MRI evidence of DIS requires at least one T2-hyperintense lesion in two of four CNS areas: periventricular, juxtacortical, infratentorial, and/or spinal cord. MRI DIT criteria require new T2 or gadolinium-enhancing lesions over time (≥30 days from a baseline scan) or at the time of initial presentation, provided the baseline scan shows the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions. McDonald 2010 MS criteria have a positive predictive value of 76% and a negative predictive value of 100% when applied to children with ADS; however, these criteria are less
predictive in younger children and cannot be reliably applied in ADEM.
Clinical Course of Pediatric Multiple Sclerosis MS is relapsing-remitting in more than 95% of children. A study of 21 pediatric and 110 adult patients demonstrated that, compared with adults, children with MS experience more frequent relapses in the first few years following diagnosis (annualized relapse rate of 1.13 versus 0.4, p < 0.01). A German study showed that relapse rates decreased between year 1 and year 5 following diagnosis in both patients younger than 11
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years of age (relapse rate of 2.1 versus 0.79) and patients between 14 and 16 years of age (1.8 versus 0.42). Secondary disease progression, when accrual of disability occurs in the absence of discrete relapses, typically begins after 15 years of age. Because of their younger age at onset, pediatric MS patients accrue disability approximately 10 years earlier than do adult patients.
Magnetic Resonance Imaging Features of Pediatric Multiple Sclerosis Imaging studies have shown that pediatric-onset MS is associated with a global reduction in brain volume, especially in the thalami, and a reduction in age-expected head size. Both T1and T2-weighted lesion volume is higher in pediatric-onset MS patients compared with adults, with a greater lesion burden located infratentorially in children. The long-term effects of this extensive pathology on cognitive, physical, psychiatric, and socioeconomic functioning have yet to be defined. Complex imaging modalities, including diffusion-tensor imaging (DTI), magnetization transfer ratio (MTR) imaging, and functional MRI (fMRI), hold great promise as tools to link structural and functional parameters.
Pathobiological Insights Into Pediatric Multiple Sclerosis The greatest genetic contributor to MS risk in children and adults is associated with the HLA DRB1*1501 haplotype. Over 100 non-HLA risk SNPs have been identified as contributors to adult-onset MS risk. Early studies indicate that similar non-HLA risk SNPs also contribute to pediatric-onset MS risk. Several environmental risk factors have been shown to contribute to pediatric MS risk (reviewed in Waldman et al., 2014), including: 1. Low serum 25-hydroxyvitamin D levels 2. Remote Epstein–Barr virus (EBV) infection 3. Earlier age at menarche 4. Secondhand smoke exposure 5. Increased body mass index (BMI)
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Case-control studies suggest that cytomegalovirus infection may be associated with reduced pediatric MS risk. A Canadian study of children with ADS found a higher risk of later MS diagnosis in children who had (a) low serum 25-hydroxyvitamin D level (<75 nmol/L), (b) evidence of remote EBV infection, and (c) at least one HLA DRB1*1501 allele compared with those children who had none of these risk factors at presentation (hazard ratio [HR] = 5.27, 95% confidence interval [CI] = 1.23–22.6) (Banwell et al., 2011). Children with demyelination may display antibodies against MOG, aquaporin-4, NMDA receptors, voltage-gated potassium channels, and glycine receptors. Defining the range of autoantibodies present in children with demyelination and their associated clinical phenotypes will be of considerable future interest. The cerebrospinal fluid (CSF) of children with ADS appears to be enriched in components of the axoglial apparatus, including neurofascin, contactins, and contactin-associated proteins, suggesting that axoglial apparatus disruption may be involved in MS pathobiology. Altered cellular immune responses are associated with pediatric-onset MS. Both T-cell repertoire (proportions of naïve versus memory T-cells) and functional T-cell responses to myelin and nonmyelin antigens appear to be disrupted in children with MS.
Immunomodulatory Therapy in Pediatric Multiple Sclerosis Principles of Immunomodulatory Therapy. There are now 12 MS therapies approved by the U.S. Food and Drug Administration (FDA) available in the United States. In children, first-line treatment is usually with interferons (beta 1a or 1b), or glatiramer acetate (GA) (Table 100-1). These agents reduce relapse rates by approximately one third in adult MS patients and also reduce the number of T2 brain MRI lesions. Interferons and GA are generally considered safe and well tolerated in children with MS. Transaminitis is the most frequent laboratory abnormality in children treated with interferons and is possibly reduced by a gradual dose titration starting at one fourth of the usual adult dose. GA is utilized at full dose.
TABLE 100-1 Immunomodulatory Therapies for Pediatric Multiple Sclerosis Drug
Dosing Regimen
Common Side Effects
Potential Laboratory Abnormalities
Interferon beta 1a (Avonex®)
30 µg IM weekly
Flu-like myalgia and headache Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Interferon beta 1a (Rebif®)
22–44 µg SC weekly
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Pegylated Interferon beta 1a (Plegridy®)
125 µg SC every 14 days
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Interferon beta 1b (Betaseron®)
0.25 mg SC every 2 days
Flu-like myalgia and headache Injection-site reaction (redness, pain, and induration) Depression
Transaminitis (typically 2- to 3-fold elevation of transaminases) Rarely, fulminant liver failure
Glatiramer acetate (Copaxone®)
20 mg SC daily or 40 mg SC 3 times a week
Injection-site reaction (redness, pain, and induration) Immediate postinjection reaction (flushing, tachycardia, and chest pain)
No significant effect on liver or hematological function
IM, intramuscular; SC, subcutaneous.
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White blood cell counts and liver function tests should be monitored monthly for 6 months and then every 3 months thereafter during interferon treatment. Thyroid function should be monitored yearly. Sexually active patients should receive counseling regarding contraceptive use. Second-Line Therapies. Immunosuppressive therapy is offered when frequent relapses occur despite compliance with interferon or GA. Proposed definitions for inadequate treatment response require full compliance for at least 6 months and at least one of the following: (a) increased or stable relapse rate or new T2- or contrast-enhancing lesions compared with pretreatment baseline or (b) at least two clinical or MRI attacks within 12 months (Chitnis et al., 2012). Therapeutic options for children experiencing an inadequate treatment response include switching between first-line therapies or escalating to a second-line agent. Children with frequent relapses on interferon therapy should be checked for neutralizing antibodies. Cyclophosphamide, azathioprine, methotrexate, mitoxantrone, and rituximab have all been utilized in isolated cases or small case series of pediatric MS patients. There are increasing numbers of reports of natalizumab use in pediatriconset MS. A study of 55 children with MS treated with natalizumab reported that the annualized relapse rate (ARR) decreased from 2.4 +/– 1.6 to 0.1 +/– 0.2 (p < 0.001). Mild transient hematological abnormalities were observed in 7 out of 55 patients, and no serious adverse events were reported. Natalizumab is associated with increased risk of progressive multifocal leukoencephalopathy, especially in patients seropositive for JC virus (particularly with an index value > 1.5), patients previously treated with other immunosuppressive agents, and those treated for more than 24 months. Several oral agents (e.g., dimethyl fumarate, fingolimod, and teriflunomide) and infusion-based therapies (e.g., alemtuzumab) are now approved for use in adult-onset MS. Clinical trials for some of these agents are ongoing in pediatric MS, and future trials are expected.
General Care Issues The care of children with MS requires a multidisciplinary team that often includes a neurologist, nurse, occupational therapist, physiotherapist, psychologist, dietician, and social worker. An MS diagnosis has important implications for social functioning, family functioning, and overall psychosocial well-being.
Multiphasic Acute Disseminated Encephalomyelitis MS diagnosis in a child with initial ADEM requires either two subsequent non-ADEM attacks or one subsequent clinical attack not accompanied by encephalopathy at least 3 months from the initial ADEM associated with MRI findings meeting current definitions for DIS and DIT (Krupp, Tardieu et al., 2013). Recurrence of ADEM more than 3 months after an initial ADEM episode is termed multiphasic ADEM (Krupp et al., 2013), which is treated in the same manner as an acute demyelinating attack.
Neuromyelitis Optica NMO is a severe, inflammatory CNS demyelinating disorder with unique clinical, laboratory, and MRI features. The identification of a biomarker for NMO (NMO-IgG) has resulted in improved diagnostic accuracy (Lennon et al., 2004).
Epidemiology of Pediatric Neuromyelitis Optica The exact incidence of NMO in childhood is unknown. In children and adults, NMO has a marked female predominance, with some studies reporting a female-to-male ratio as high as 9 : 1. There is an overrepresentation of children reporting non-Caucasian ethnicity compared with other demyelinating diseases. In one U.S. study, 42 out of 58 NMO-IgG–seropositive children (73%) with available ethnicity data were non-Caucasian.
Clinical Features of Pediatric Neuromyelitis Optica NMO is characterized by severe ON (visual acuity typically 20/200 or worse) and TM, occurring either simultaneously or sequentially. When sequential, ON and TM may be separated by months or even years. Approximately 53% to 100% of pediatric NMO patients experience a relapsing (as opposed to monophasic) course. Predictors of a relapsing course in one study of adult NMO patients included female gender, older age at onset, and evidence of systemic autoimmunity. NMO-IgG–seropositive patients appear more likely to experience a relapsing course compared with seronegative individuals. In a retrospective analysis of 20 children with NMO, mean time to relapse was shorter in seropositive patients compared with seronegative patients (0.76 versus 2.4 years, p = 0.03). Serum NMO-IgG titers correlated with disease severity in one study. NMO is typically characterized by severe attacks with poor recovery, leading to rapid disability accrual. In a study of adults with NMO, 31 out of 66 (47%) were functionally blind (visual acuity of 20/200 or worse) in at least one eye, and 32 out of 71 (45%) exhibited permanent monoplegia or paraplegia, after a mean follow up of 16.9 years in relapsing patients and 7.7 years in monophasic patients. Respiratory failure was observed in one third of relapsing patients. One pediatric study reported that after a median of 12 months of follow up, 54% of NMO patients had permanent visual impairment, and 44% had limb weakness severe enough to affect mobility.
Symptomatic Brain Involvement in Neuromyelitis Optica Brain MRI lesions in NMO typically follow the distribution of aquaporin-4 water channel expression, including the diencephalon and brainstem periaqueductal gray matter. Brain lesions are symptomatic in 35% to 45% of children. Brainstem involvement may present as hiccups, nausea/vomiting, ophthalmoplegia, and, in severe cases, respiratory failure or death. Symptoms of diencephalic involvement may include hypersomnolence, narcolepsy, inappropriate antidiuretic hormone secretion, or menstrual irregularities. Large multifocal lesions have been associated with encephalopathy and an ADEM-like phenotype.
Diagnostic Criteria for Pediatric Neuromyelitis Optica Revised pediatric consensus criteria for NMO require the presence of ON and TM with at least two of the following supportive features (Krupp et al., 2013): 1. MRI evidence of a contiguous spinal lesion at least three spinal segments in length 2. Brain MRI not meeting diagnostic criteria for MS 3. NMO-IgG seropositivity The presence of two of the three supportive criteria has 99% sensitivity and 90% specificity in distinguishing adults with NMO from those with MS (Wingerchuk, Lennon, Pittock,
Lucchinetti, and Weinshenker, 2006). Children may present with recurrent ON or TM associated with serum NMO-IgG; such cases are considered NMO spectrum disorders (Krupp et al., 2013).
Systemic Autoimmunity in Neuromyelitis Optica There is a high frequency of coexisting systemic autoimmunity in NMO. In one pediatric cohort, 16 out of 38 patients (42%) met the criteria for clinical diagnosis of another autoimmune condition, including systemic lupus erythematosus, type 1 diabetes, juvenile rheumatoid arthritis, and Graves disease. Some children with NMO harbor other autoantibodies without meeting formal diagnostic criteria for another autoimmune disorder. Some children with anti-NMDA receptor encephalitis display NMO-IgG in the absence of clinical NMO symptoms. The relevance of incidentally detected NMO-IgG in children with other CNS autoimmune conditions is unclear.
Laboratory Features of Neuromyelitis Optica The CSF in NMO patients typically demonstrates a marked pleocytosis (>50 leukocytes/µL), with a neutrophilic or lymphocytic predominance. This is in contrast to the moderate lymphocytic pleocytosis (<25 leukocytes/µL) typical of pediatric MS. One study of lumbar punctures in 89 pediatric and adult NMO patients found that pleocytosis (>5 leukocytes/µL) occurred in 50% of samples, with a median white blood cell count of 15 leukocytes/µL (range = 6–380). The median number of white blood cells and percentage of samples containing neutrophils were higher during relapses compared with periods of clinical quiescence. CSF OCBs are detected in less than 10% of children with NMO. In one pediatric study, OCBs were more commonly detected in seropositive (2/10) compared with seronegative (0/7) NMO patients. Visual-evoked potentials are frequently abnormal in NMO patients and typically display a prolongation or absence of the P100 response. In adults with NMO, markedly abnormal or absent visual-evoked potential responses at baseline are associated with worse long-term visual outcomes. Delayed P100 responses have been observed in the absence of a clear history of ON, suggesting that optic nerve involvement may be subclinical. OCT-based studies have demonstrated that RNFL thinning is frequently seen in NMO patients, and that RNFL thinning after an episode of ON is more severe in patients with NMO compared with those with MS. NMO-IgG is directed against the aquaporin-4 water channel located on astrocytic end feet. This serum biomarker has a sensitivity of 73% and a specificity of 91% in differentiating NMO from other demyelinating disorders, including MS, in adult patients (Lennon et al., 2004) and is detected in up to 78% of children with relapsing NMO. NMO-IgG has also been detected in children with NMO spectrum disorders. A proportion of individuals with clinical NMO will repeatedly test negative for NMO-IgG, even when sensitive cell-based assays are employed. A subset of these NMO-IgG– seronegative patients displays serum anti-MOG antibodies. Studies suggest that NMO patients with anti-MOG antibodies (without NMO-IgG) have an increased likelihood of being male, are slightly younger, have better recovery from attacks, are less likely to experience a relapsing course, and, in one study, were more likely to present with simultaneous/ sequential ON and TM. In three reported children with clinical NMO and anti-MOG antibodies, there was an initial relapsing course, with a beneficial response to longer-term immunotherapy (azathioprine or monthly IVIg). Two children displayed deep gray-matter involvement on MRI.
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Magnetic Resonance Imaging in Neuromyelitis Optica As in MS, MRI during an acute ON attack in NMO typically reveals optic nerve thickening and an increased signal on fatsuppressed T2-weighted images. Fat-suppressed postcontrast T1-weighted images show optic nerve enhancement in 94% of patients. To date, there are no MRI features that reliably distinguish ON in NMO from that in MS, although a trend toward more extensive and greater posterior optic nerve involvement in NMO has been noted. Brain MRI lesions are common in children with NMO, with 53% to 100% of children demonstrating brain abnormalities distinct from the optic nerves at presentation. In NMO, brain MRI lesions typically occur in areas of aquaporin4 water channel expression, including (a) lesions surrounding the ventricular system (e.g., diencephalic lesions around the third ventricle, dorsal brainstem lesions adjacent to the fourth ventricle, and peri-ependymal lesions surrounding the lateral ventricles); (b) hemispheric lesions that may be large (>3 cm diameter); (c) lesions involving the corticospinal tracts; and (d) small, nonspecific, deep white-matter lesions (most common lesion type) (Fig. 100-7) (Kim et al., 2015). Enhancing lesions may demonstrate a patchy, diffuse, “cloudlike” enhancement pattern. As discussed earlier, brain lesions may be symptomatic. Lesions that are perpendicular to ventricles, S-shaped U-fiber lesions, lesions along the inferior aspect of the lateral ventricles, temporal lobe lesions, and lesions that have an ovoid or open-ring enhancement pattern are more characteristic of MS (Kim et al., 2015). Acute spinal MRI in NMO typically reveals lesions spanning at least three contiguous spinal segments that are hyperintense on T2-weighted images (Fig. 100-7A) and hypointense on T1-weighted images. It is important to note, however, that LETM is frequently seen in children with idiopathic TM, in TM with ADEM, and in up to 25% of TM cases associated with an MS attack. NMO patients occasionally present with short-segment spinal lesions. Partial cord lesions in NMO often localize to the cervical and upper thoracic cord. Acutely, lesions typically affect central cord gray and white matter, with diffuse gadolinium uptake within the lesion core. Bilateral and symmetric anterior horn cell signal abnormalities resembling anterior cord infarction have been described. Over time, the development of spinal cord atrophy is associated with an increased likelihood of persistent neurologic deficits.
Treatment of Pediatric Neuromyelitis Optica Acute attacks are usually treated with intravenous corticosteroids. If symptoms progress despite steroid therapy, IVIg and/ or plasmapheresis is usually administered. Longer-term immunosuppression is generally used to prevent relapses and disability accrual given the aggressive nature of this disease. Azathioprine (+/– oral prednisone), repeated IVIg or plasmapheresis, rituximab, cyclophosphamide, mycophenolate mofetil, and ofatumumab have all been used in children with NMO.
CONCLUSIONS Acquired demyelination of the CNS, including transient forms and pediatric-onset MS and NMO, is being increasingly recognized and diagnosed worldwide. This has been aided by the development of consensus diagnostic criteria, evolving MRI criteria, and the discovery of the NMO-IgG biomarker. The current and emerging armamentarium of increasingly powerful medications for adult-onset MS will require vigilant and
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A
B
Figure 100-7. MRI in childhood neuromyelitis optica. A, Sagittal T2-weighted MRI image shows a longitudinally extensive intramedullary spinal lesion. B, Axial fluid-attenuated inversion-recovery (FLAIR) MRI from a different child shows bilateral hyperintense diencephalic lesions.
thoughtful use in children. Collaboration between clinicians and scientists, such as that fostered by the International Pediatric MS Study Group and other organizations, is essential to optimize care. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. RESOURCES National Multiple Sclerosis Society (United States). .nationalmssociety.org>. Multiple Sclerosis Society of Canada.
SELECTED REFERENCES Banwell, B., Bar-Or, A., Arnold, D.L., et al., 2011. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol. 10 (5), 436–445. Chitnis, T., Tenembaum, S., Banwell, B., et al., 2012. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult. Scler. 18 (1), 116–127. Kim, H.J., Paul, F., Lana-Peixoto, M.A., et al., 2015. MRI characteristics of neuromyelitis optica spectrum disorder: An international update. Neurology. Krupp, L.B., Tardieu, M., Amato, M.P., et al., 2013. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple
sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult. Scler. Lennon, V.A., Wingerchuk, D.M., Kryzer, T.J., et al., 2004. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364 (9451), 2106–2112. Polman, C.H., Reingold, S.C., Banwell, B., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69 (2), 292–302. Waldman, A., Ghezzi, A., Bar-Or, A., et al., 2014. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 13 (9), 936–948. Wingerchuk, D.M., Lennon, V.A., Pittock, S.J., et al., 2006. Revised diagnostic criteria for neuromyelitis optica. Neurology 66 (10), 1485–1489.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 100-1 Approach to visual loss. Fig. 100-2 Approach to symptoms localizing to the spinal cord. Fig. 100-5 Approach to the management of acute demyelination in childhood.