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Disease/ Disorder

Definition

Immune mediated diseases resulting in inflammation and demyelination of the central nervous system have been described in the pediatric and adult population, including the previously denominated pediatric-onset multiple sclerosis (POMS) and transverse myelitis (TM). Acquired demyelinating syndromes are acute illnesses characterized by neurological deficits persisting for at least 24 hours and involve the optic nerve, brain, or spinal cord, associated with regional areas of increased T2 signal on MRI.1 Included in these processes is a component of axonal loss and neurodegeneration as seen in multiple sclerosis (MS). TM is an immune mediated disorder causing demyelination with the spinal cord that is characterized by motor, sensory, and autonomic dysfunction.2,3 A variant of TM is acute flaccid myelitis, where a patient presents with flaccid weakness in at least one limb and MRI changes predominate in the grey matter.2 Longitudinally extensive transverse myelitis (LETM) is an inflammatory spinal manifestation, which has been related to neuromyelitis optica (NMO) disorders. It refers to the ­­­rapidly progressive spinal cord hyperintensity spanning at least three continuous vertebral segments on T2 weighted sagittal magnetic resonance imaging. It most often involves the cervical and thoracic segments.3

Etiology

The exact etiology of these diseases is unknown. In MS, autoimmune, genetic, and environmental factors are thought to contribute to the disease. TM and LETM can be idiopathic, or disease associated. In children, idiopathic TM accounts for 89% of the cases, with the child having a mild illness, a recent vaccine, allergy injections, or sustaining mild trauma prior to onset of symptoms. Disease-associated TM is secondary to an underlying autoimmune disorder such as MS, acute disseminated encephalomyelitis, or systemic lupus erythematosus.3-5 LETM can also develop secondary to inflammatory, metabolic, vascular, degenerative disorders, spinal cord infarct, dural arteriovenous fistula, and systemic malignancies.3,5

LETM refers to severe inflammatory disease of the central nervous system stratified according to the presence of the serum aquaporin-4 (APQ4) antibody. It has been associated with various non-specific viral illnesses, ischemia, rheumatologic disorders, sarcoidosis, NMO and MS; NMO is the most common cause of LETM.3 The clinical course of LETM is characterized by single or multiple attacks.3

Epidemiology including risk factors and primary prevention

According to current studies, the incidence of POMS ranges between 0.05 and 2.85 per 100,000 children.6 It has been shown that about 10% of all individuals with MS experience their first attack before 18 years of age. The female-male ratio of children under 12 years of age is 1.2:1; though the ratio increases to 2.8:1 in children 12 and older (probably due to hormonal factors).1,6 Risk factors include female gender, if diagnosed post-pubertal, low vitamin D concentration, cumulative dose of cigarette smoke exposure, remote Epstein Barr virus infection, the HLA-DRB1 gene, and a family history of MS.1,7

Acute TM is reported in 2 cases per million people in the U.S. with 20% of these cases occurring in children.4,5 is a slight male predominance (1.1-1.6:1) in prepubertal children, while a female predominance is seen following puberty.5 A preceding illness has been noted in two-thirds of cases in TM.5

Patho-anatomy/physiology

Active demyelinating lesions demonstrate a component of perivascular inflammation combined with lipid laden macrophages and large reactive astrocytes. In MS, there is heterogeneity regarding the pattern of inflammation, with two patterns involving T cell and macrophage inflammation and another two demonstrating oligodendrocyte apoptosis or death. The inflammation leads to autoimmune attacks against protein constituents with the myelin sheath, causing axonal damage and neurodegeneration.6 Additionally, there has been increasing evidence on the significant role of B cells in MS pathogenesis, possibly contributing to both MS relapses and disease progression.6 Since autoreactive T cells and autoantibodies have been reported in patients with MS, myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein have been suggested as auto-antigens involved in the pathogenesis of MS.6 Three distinct neuroimmune conditions can be distinguished, MS, myelin oligodendrocyte antibody-associated disease (MOGAD), and aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (AQP4-NMOSD).6

In TM, the pathogenesis is unknown, though T-cell mediated autoimmunity (perivascular lymphocytic infiltrates, necrosis, and demyelination) has been implicated.3

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Multiple Sclerosis:

  • New onset: POMS presents similarly to adult-onset multiple sclerosis (AOMS), though tends to have a more aggressive onset and a more active course of the disease, with higher relapse rates and greater white and grey matter damage.6 Common presentations include optic neuritis, transverse myelitis, sensory loss, and bladder dysfunction. Approximately half to two-thirds of patients with POMS have a polysymptomatic presentation with the most commons symptoms being sensory, cerebellar, visual, brainstem, and pyramidal.1 
  • Subacute: Pediatric MS follows a relapsing-remitting course (98.5%)6; approximately 80% of children with POMS will relapse in the first year.1 Children are on average 10 years younger at the time of evolution to secondary progressive MS, compared to adults.1,8
  • Chronic/stable: Between attacks of relapsing-remitting MS, children return to their baseline function but once they evolve into secondary progressive MS, they will experience a slow continual deterioration of function. Due to neuroplasticity, the progression of POMS seems to be slower than that of AOMS, however, it results in worse long-term physical and cognitive outcomes that can lead to severe compromise regarding quality of life.6 In regard to cognition, the domains affected are similar to those with AMOS, and include memory, information processing speed, executive function, and attention.1 The increased susceptibility to cognitive impairment may be due to the vulnerability of the developing brain to even a single episode of demyelination, which may impair subsequent maturation of white matter pathways involved in cognitive functioning. Disease onset during early formative years may disrupt the acquisition of basic building blocks crucial for future learning.1

Transverse Myelitis:

  • New onset: Presents with complaints of pain, typically low back pain, followed para- or tetraparesis, sensory loss in a band-like distribution, and bowel/bladder dysfunction that develop within hours or days.3
  • Subacute: Recovery typically starts 4-6 days after onset, with resolution of pain symptoms first, followed by improvement in motor deficits, but symptoms can persist for months.3
  • Chronic/Stable: Clinical course is variable. Some individuals have persistent motor and/or bladder deficits. Patients may also develop persistent flaccid motor weakness. Rarely do children experience a repeat episode of TM.

Longitudinally Extensive Transverse Myelitis:

  • New onset: presentation is similar to Transverse Myelitis with neurosensory disturbances, including bowel and bladder dysfunction.
  • Subacute/Chronic/Stable: studies have yet to demonstrate long term progression of patients with LETM.

Specific secondary or associated conditions and complications

Children with MS can experience spasticity, bowel and bladder dysfunction, sexual dysfunction, pain, cognitive and functional impairments. There is a risk for developing depression and significant fatigue; fatigue is reported in 20-50% of patients. Children with TM and LETM can demonstrate a range of outcomes, from no residual neurological deficit to complete paralysis with neurogenic bowel and bladder, as well as ongoing pain. Approximately 25% require walking aids or are non-ambulatory and about 10-20% never regain mobility or bladder function.

Essentials of Assessment

History

History-taking is an important component of evaluation of demyelinating diseases. Some symptoms include motor weakness, sensory disturbances, pain, bladder or bowel dysfunction. History of previous attacks, progression of symptoms, recent illness or sick contact, vaccinations, travel, medical history, social history, family medical history, surgical history, and review of systems should be collected.

In the pediatric population, a febrile illness preceded the presentation of TM in two-thirds of reported cases.5

Physical examination

A full neurologic and functional assessment should be performed. Examination should include evaluation of tone, cognition, cranial nerves, reflexes (including abdominal and bulbocavernosus reflexes), and gait. A thorough assessment to determine a spinal motor or sensory level, including a rectal exam, as well as determination regarding a partial or complete level is appropriate. Ophthalmological examination is warranted to determine if subclinical optic neuritis exists. Serial examinations will help to assess for changes or progression of disease. Depression screening is appropriate. Skin evaluation for pressure ulcers, especially over sensitive areas and bony prominences such as the occiput, sacrum, ischia, and heels.

Functional assessment

The Functional Independence Measure for Children (WeeFIM) can be used to assess functional independence in children ages 6 months to 7 years. It rates 18 items within the 3 categories of self-care, mobility, and cognition.9 The Kurtzke Expanded Disability Scale can be used in MS to assess and follow function. It contains 8 functional systems: visual, pyramidal, brainstem, cerebellar, sensory, bowel and bladder, cerebral, and other, which are each rated from 0-5, representing limited to severe impairment.10 Although the Kurtzke Expanded Disability Scale has been used for over 30 years, there is no literature describing specific psychometric properties. It has been used in children as well as adults, since the clinical manifestations of MS are similar in the two populations.

Laboratory studies

The diagnosis of multiple sclerosis requires evidence of dissemination of the CNS inflammatory activity distributed in more than one CNS location and recurrent disease over time. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-A antibodies (AQP4-Ab) has led to a shift in the classification of relapsing demyelinating syndromes; and therefor a need for different first-line treatments in MOGAD compared with MS.1 In children with acquired demyelinating syndromes, it is important to eliminate both inflammatory and non-inflammatory mimics. The most common differential diagnoses are the antibody-mediated disorders (MOG-Ab and AQP4-Ab), acute infections of the CNS (EBV, mycoplasma, and enteroviruses), inherited leukodystrophies, and inflammatory vasculopathies. AQP4-Ab are rarely seen in children, occurring in 0.7% to 4.5% of children with acquired demyelinating disorders. One-third of children who present with acquired demyelinating disorders have MOG-Ab, and approximately half of the patients with MOG-Ab have a relapsing disease course.1 Of note, these antibodies have been identified in nearly all children with multiphasic disseminated encephalomyelitis and acute disseminated encephalomyelitis followed by optic neuritis.1 Patients who are MOG-Ab positive are less likely than those with MS to have intrathecal oligoclonal bands and may have cerebrospinal fluid pleocytosis.1 Of note, many patients diagnosed with POMS have been reclassified as having MOG-Ab-associated demyelination in recent years.1 Why is this important? Because MOG-Ab-associated demyelination does not respond to first-line disease modifying therapies used in POMS.1 Earlier studies done on POMS, where the patients were diagnosed with POMS, may have actually had MOG-Ab-associated demyelination.

Cerebrospinal fluid should be sent for viral and bacterial culture as well as evaluation for cellular profiles, oligoclonal bands, and IgG. Vitamin D level, evaluation for previous Epstein Barr virus, and HLA-DRB1 can be assessed, as they are associated with increased risk of MS. Since TM can be idiopathic or secondary to an underlying autoimmune disease, serum evaluation should be directed to assess for underlying pathology.

There is limited laboratory workup that may provide sensitive or specific information regarding initial LETM presentation, as AQP4 antibody results may take weeks to return. CSF examination may aid in distinguishing between MS and NMO associated LETM. Pleocytosis is frequent and marked in NMO, while uncommon in MS.  Oligoclonal bands are persistent in MS.

Imaging

In all disease presentations, MRI of the brain and spinal cord should be obtained, including the use of gadolinium to accurately assess for active demyelinating lesions, such as in MS, inflammation, infection, and possible tumor presence. Younger children are more likely to present with many supratentorial brain lesions, whereas older children and adults commonly present with optic neuritis.1 An MRI confirms dissemination of inflammatory activity in more than one CNS location to coincide with two clinical attacks, each lasting more than 24 hours and being more than 20 days apart. The diagnosis of MS is based on clinical findings supported by MRI, cerebrospinal fluid analysis, and other laboratory results. The criteria for the diagnosis of MS was updated in 2017 with the following changes to the 2010 McDonald criteria: 1) the presence of intrathecal oligoclonal bands to substitute for recurrent disease over time in patients presenting with a clinically isolated syndrome who fulfil the requirements for dissemination of inflammatory activity; 2) the inclusion of a symptomatic lesion as evidence of dissemination of inflammatory activity  or recurrent disease over time; and 3) the inclusion of cortical gray matter lesions in dissemination of inflammatory activity now considered in combination with juxtacortical lesions.1 Dissemination of inflammatory activity can be demonstrated by one or more T2 lesions that are characteristic of MS in at least two of the following areas: periventricular; juxtacortical, or cortical; infratentorial; or spina cord.1 Recurrent disease over time can be confirmed by simultaneous presence of gadolinium-enhancing lesions on a single MRI scan, or by a new T2 and/or gadolinium-enhancing lesion on a follow-up scan.1 Spinal cord lesions occur preferentially in the cervical region.1

In TM it is imperative to rule out any compressive etiology within the spine that could present with similar symptoms and findings of cord inflammation and warrant emergent neurosurgical intervention.  MRI findings in TM are different to those found in MS as the pattern is symmetric, uniform, spanning 3 or more consecutive vertebral levels, and can involve the entire diameter of the cord.4 Lumbar puncture and evaluation of CSF must be performed, which would be remarkable for pleocytosis or increased IgG index. These findings are accompanied by time of maximal disability of more than 4 hours, but less than 21 hours. Longitudinally extensive transverse myelitis can be diagnosed when a hyperintense spinal cord lesion extends 3 or more levels on spinal MRI.

Magnetic resonance imaging plays a key role in identifying LETM, regardless of its etiology (infectious, idiopathic, infarction, NMOSD, viral myelitis, among others. Brain MRI of an NMO patient should be normal or with non-specific changes; around 50% of MRIs are normal at presentation. Spinal cord bright spotty lesions on axial T2W images have been the most distinctive finding of NMO related LETM. Features associated with AQP4 positive antibody include cervicomedullary junction involvement, cord expansion in the acute stage, presence of bright spotty lesions, and female sex.11

Supplemental assessment tools

Urodynamic studies can be performed to further assess bladder function. Ophthalmologic examination, including visual evoked potentials and ocular coherence tomography, can be used to assess for optic neuritis in young children who cannot describe visual changes, and to assess for subclinical optic neuritis. Neuropsychological testing can assess for cognitive abnormalities in memory, problem solving, attention, and executive function, all of which can often be found in MS patients.

Early predictions of outcomes

Prognostic factors are hard to define in POMS. One recent study found that starting treatment at an age younger than 12 years is the only factor in multivariate analyses to positively affect outcome; however, in other studies this has not been the case.1 Another study found that a time of less than 1 year between the first and second attack to be a negative prognostic factor; however, 80% of patients with POMS will relapse within the first year.1

Severity of initial demyelination events was found to be worse in non-whites, as well as initial localization within the optic nerve or cerebral hemispheres. Poorer prognosis in TM has been associated with idiopathic TM, severe motor weakness at nadir, high anatomic rostral border of sensory level, longitudinal extension of cord lesion, need for ventilatory support, and younger age at onset.4

Environmental

Obtaining information and assessment of the patient’s home, school, or work environment are necessary to make use of proper modifications, adaptive devices and equipment to allow the child to be as independent as possible. Depending on the degree of impairment, environmental modifications may be needed for wheelchair use at home and work/school, use of ramps and door width adjustments to ensure safe mobility. Attendants/aids, bath and toilet equipment, assistive and adaptive devices, and technology can be adjunctive support for people with MS and TM to promote as much functional independence as possible.

Social role and social support system

A comprehensive approach is vital to address the needs of the patient and family. This includes quality of life, long-term treatment, social and school support, lifestyle assessment and modification as needed, symptom management, and mental health assessment and treatment. Inquiring about the child’s support system should address whether there are family members, friends, community groups, etc. available that can lend physical and emotional support.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Current treatment of POMS follows AOMS recommendations and guidelines. Early recognition of POMS is crucial to initiate early and appropriate treatment to minimize and prevent long-term disability and cognitive impairment. Recent reviews have stated a comprehensive approach to address the needs of the patient and family regarding long term disease modifying agents, social support and mental health assessment are crucial to start treatment.12 After a diagnosis of MS, children are started on disease-modifying treatments (DMT). The process of choosing a disease modifying agents should focus on the collective goals and risk tolerance. Long term risk of disability, dosing, monitoring, cost, and safety of medication should be carefully taken into consideration. Delaying treatment may lead to worsening disability due to ongoing inflammation and subsequent damage while awaiting treatment initiation.12 The first line agents include injectable therapies such as interferon-beta, glatiramer acetate, dimethyl fumarate, and teriflunomide, as supported by treatment of AOMS and observational POMS studies. Second line agents include fingolimod, cyclophosphamide, natalizumab, alemtuzumab, and anti CD20 cell depleting therapies including rituximab, ocrelizumab, and ofatumumab.6

To date, there are few data-driven POMS therapies available for children, mostly derived from observational studies.6 Several studies have demonstrated the safety and efficacy of using interferon-beta and glatiramer acetate in the pediatric population.6 There is a phase III, double-blinded, placebo-controlled, three-arm randomized controlled trial (CONNECT) that is currently recruiting patients to evaluate the safety and efficiency of dimethyl fumarate compared with placebo and pegylated interferon-beta.6 There is another study (FOCUS) looking at the effect of dimethyl fumarate on MRI lesions and pharmacokinetics in POMS with relapsing-remitting MS.1 Preliminary reports on a phase III trial (TERIKIDS) evaluating the efficacy, safety, and pharmacokinetics of teriflunomide in children with relapsing-remitting MS aged 10 to 17 years showed a lower risk of clinical relapses and disability progression then delayed initiation of teriflunomide after placebo. It was well tolerated and had a manageable safety profile.6 As a result, teriflunomide was approved for the pediatric population of at least 10 years of age in 2021 by the European Medicines Agency.6 Fingolimod was approved by the FDA in 2018 for relapsing-remitting POMS following the PARADIGMS trial. The PARADIGMS trial was a randomized, double-blind, active-controlled, parallel-group, multi-center study which compared the effects of oral fingolimod and intramuscular interferon-beta in a cohort of 215 children aged 10-17 years, randomly treated with either one or the other drug. It showed the superior efficacy and comparable safety of fingolimod versus interferon-beta and was associated with a significant reduction of an annualized rate of relapse.6 Natalizumab is considered one of the most efficacious treatments among the newer DMTs used in MS, though progressive multifocal leukoencephalopathy (PML) is a documented complication associated with treatment. Although there have been no reported pediatric cases of natalizumab-related PML, routine monitoring with John Cunningham virus antibody titers and brain MRIs are strongly recommended.6 There are two ongoing studies of natalizumab in the pediatric population, one is a phase I study of natalizumab in 13 POMS patients and the second one is a large observational study involving 400 POMS patients.6 There is an ongoing clinical trial (LemKids) with 50 patients (aged 10 – <18 years) with relapsing-remitting POMS who have failed at least two DMTs to evaluate the efficacy, safety, and tolerability of alemtuzumab. It is set to be completed in 2026.6 Targeted anti-CD20 therapies have been shown to be effective in treating POMS, as well as other immune-mediated inflammatory disorders of the central nervous system, such as NMOSD and relapsing MOGAD. Specifically, rituximab has shown a reduction in gadolinium-enhancing lesion load on MRI and clinical relapses in POMS.6 There is currently a randomized controlled trial evaluating the pharmacokinetic/pharmacodynamic effects of Ocrelizumab in children and adolescents (aged 10 – <18 years) with relapsing-remitting POMS is currently in progress.

Recent studies are supporting the widespread opinion that newer DMTs, especially the infusions, are superior to injectables in controlling clinical and radiologic disease activity.6 This may lead to a change in first line agents. Of note, currently, the only FDA approved DMTs in the pediatric population are interferon-beta (> 2 years of age), glatiramer acetate (> 12 years of age), teriflunomide (> 10 years of age), and fingolimod (> 10 years of age). Other medications are used off label.

As stated previously, it is imperative to get an accurate diagnosis, as MOG-Ab-associated demyelination does not respond to first line DMTs (interferon-beta and glatiramer acetate); however, azathioprine, mycophenolate mofetil, rituximab, and intravenous immunoglobin have been associated with a reduction in relapse frequency to varying effect.1

Traditionally, acute relapses were treated with intravenous (IV) methylprednisolone of 20-30 mg/kg/day over 3-5 days or oral methylprednisolone at a dose of 500mg for 5 days.1 A recent multicenter randomized controlled trial and a meta-analysis have shown oral methylprednisolone to be equally effective as IV methylprednisolone so there has been a shift in clinical practice.1

Monitoring of patients with POMS during treatment is crucial. This consists of clinical evaluation every 3 to 6 months and an MRI every 6 to 12 months to monitor response to treatment and to assess accrual of asymptomatic lesions. The International Pediatric Multiple Sclerosis Study Group Guidelines propose 6-monthly scans (preferably both brain and spinal cord) and scan 6 months after initiation of any new therapy to avoid prematurely defining treatment failure.1 Treatment failure is defined by ongoing clinical activity (relapses) and MRI activity (new T2 lesions) in patients who are fully compliant and on full-dose treatment for a period that is sufficient for the drug to be effective. Second line therapies may be considered if there is treatment failure. Although second line DMTs are more efficacious, they are associated with more significant side effects. Up to 60% of patients with POMS will require escalation to more effective therapy. The decision of which treatment to use depends on the severity and frequency of relapses, the route and mechanism of action of proposed therapy, and the side effect profile of the proposed treatment.1

Acute management of transverse myelitis has been informed primarily in case series and expert opinion and no randomized controlled trials have been performed yet.5 First line treatment for noninfectious immune-mediated TM includes IV methylprednisolone at 30mg/kg/day for 5-7 days with a maximum dose of 1g/day followed by an oral corticosteroid taper of 1mg/kg/day for 3-4 weeks.3 If there is no clinical improvement or symptoms worsen within 24-48 hours IVIG can be given at 2g/kg divided over 2-5 days or plasmapheresis can be given.3 Children with TM usually do not need additional treatment aimed at their disease after the acute phase. 4,13-15 Two-thirds of patients are at moderate or severe risk of sequalae. For this reason, some medical centers are recommending the use of IVIG or plasmapheresis therapy simultaneously with steroids for patients with severe motor or respiratory dysfunction. However, to date, there is no adequate evidence to support the efficacy of these treatments alone or in combination.3

LETM treatment is directed at the underlying cause. As with Transverse Myelitis, high dose corticosteroids in the acute inflammatory presentation are recommended. Plasma exchange should be considered for severe attacks.  In NMO and idiopathic LETM, early plasma exchange with concomitant steroid administration has shown to reduce disability compared to corticosteroids alone. In patients with severe LETM and administration of plasma exchange is contraindicated, IVIGs may be attempted, although efficacy has not been studied.

At different disease stages

StageMSTMLETM
New onset/acute-Proper medical management
-Evaluate for bowel/bladder dysfunction. Start appropriate programs with intermittent catheterization or bowel program.
-Initiate PT, OT, SLP to maintain range of motion, prevent contractures, orthotic evaluation, assess cognition and swallow.
Same as MSSame as MS
Subacute-Course is relapsing-remitting, so child should return to baseline between episodes.
-Encourage continued physical activity, especially aerobic exercise to fend against fatigue and depression.
-Continued cognitive exercises focusing on memory and processing speed.
Ongoing deficits may exist most frequently with bladder dysfunction and pain. Address these deficits with proper medications and bladder programs as well as early involvement in a pain program if necessary.Same as TM
Chronic/stableAs the child evolves into a secondary progressive disease, care should focus on symptom management for spasticity, pain, bowel/bladder/sexual dysfunction, fatigue, sleep hygiene, and depression. Continue to evaluate child on a regular basis as their disease progresses for changes in cognitive and functional status and obtain new equipment or initiate therapy as appropriate.Not a chronic disease, though deficits may persist long-term  Deficits may persist long-term, high morbidity rate
Pre-terminal or end of life careAssure patient is comfortable and that patient has the emotional and physical support necessary.  

Coordination of care

It is imperative to have open communication between the medical personnel involved (physiatry, neurology, psychology, psychiatry, urology, ophthalmology), therapists (PT, OT, SLP), social work, as well as the child’s school and family members throughout their disease course. Treatment concerns regarding long term disease modifying therapy use and safety, are neurodevelopmental stage, pediatric pharmacokinetics, and pharmacodynamics and cognitive function. Cognitive needs to be addressed early in the Multiple Sclerosis population as it may result in disabling outcomes. A young age at disease onset is the strongest risk factor for these impairments, which may be due to the effect of inflammatory demyelination and neurodegeneration on the developing central nervous system and neural networks in children.

Children affected by TM may require inpatient rehabilitation to address deficits in mobility and ADLs, as well as equipment assessment, depending on their residual deficits. Some children with MS may initially need outpatient services since after starting treatment they should return to their baseline function as their disease progresses more intensive therapy may be warranted. Up to 40% of children with TM will have residual deficits.5 Specific deficits will determine the medical specialties involved.

Patient & family education

N/A

Emerging/unique interventions

The WeeFIM can be used to assess function over time. The Kurtzke Expanded Disability Status Scale can be used in individuals with MS to assess function. The Modified Ashworth Scale can be used to assess spasticity pre- and post-treatment. There are various fatigue, depression, and quality of life scales that can be used in children and adolescents to follow their symptoms over time.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Periodic follow-up is advised to assess the child’s function and help address any deficits early.

Cutting Edge/ Emerging and Unique Concepts and Practice

Future goals for research in POMS need to focus around making early, accurate diagnosis and ensuring safe remission of inflammation. Neuroimaging-derived biomarkers may be used for diagnostic accuracy and monitoring for remission, for example the use of central vein sign and grey matter lesion topology, to differentiate between MS and NMO spectrum disorders. Magnetization transfer ratio and positron emission tomography markers of remyelination, chronic inflammation, and microglial activation could be used as more sensitive markers of disease progression. Atrophy of the brain, particularly the thalamus, and spinal cord, measured longitudinally, has been shown to correlate with disability and impaired cognition, and could be used as an outcome measure in future studies. Optical coherence tomography can also be used as an objective measure of neuroaxonal loss in children with optic neuritis. There has been increasing debate amongst experts on the importance of induction vs escalation therapy. As stated previously, the current treatment approach for POMS involves initiation of first line DMTs (safer but less efficacious), followed by more-efficacious (worse side effect profile) second line DMTs for escalation, or treatment failure. The goal being to lessen permanent disability or loss of cognitive function while waiting to be changed to a more efficacious DMT.1

Gaps in the Evidence-Based Knowledge

To date, there are several ongoing studies on DMTs in POMS to test their efficacy and safety in the pediatric population.

References

  1. Duignan, S., Brownlee, W., Wassmer. E., et al. Paediatric Multiple Sclerosis: a New Era in Diagnosis and Treatment. Developmental Medicine & Child Neurology. 2019; 61: 1039-1049. doi: 10.1111/dmcn.14212.
  2. Greenberg, B., Plumb, P., Cutter, G., Dean, J., et al. Acute Flaccid Myelitis: long-term outcomes recorded in the CAPTURE study compared with paediatric transverse myelitis. BMJ Neurol Open.2021; 3:e000127. doi:10.1136/bmjno-2021-000127
  3. Celik, H., Aksoy, E., Oztroprak, U., Ceylan, N., et al. Longitudinally extensive transverse myelitis in childhood: clinical features, treatment approaches, and long-term neurological outcomes. Clinical Neurology and Neurosurgery. 2021; 207: 106764. doi:10.1016/j.clineuro.2021.106764
  4. Wolf VL, Lupo PJ, Lotze TE. Pediatric acute transverse myelitis overview and differential diagnosis. Journal of Child Neurology. 2012; 27(11): 1426–1436.
  5. Wang, C., & Greenberg, B. Clinical Approach to Pediatric Transverse Myelitis, Neuromyelitis Optica Spectrum Disorder and Acute Flaccid Myelitis. Children. 2019; 6(5): 70. doi:10.3390/children6050070
  6. Nicotera, A., Spoto, G., Saia, M., et al. Treatment of Multiple Sclerosis in Children: A Brief Overview.  Clinical Immunology. 2022; 237:108947. doi:10.1016/j.clim.2022.108947
  7. Bigi S, Banwell B. Pediatric multiple sclerosis. Journal of Child Neurology. 2012; 27(11): 1378–1383.
  8. Otallah, S., & Banwell, B. Pediatric Multiple Sclerosis: an Update. Current Neurology and Neuroscience Reports. 2018; 18:76.
  9. http://www.udsmr.org/Documents/WeeFIM/WeeFIM_II_System.pdf
  10. Thomas T, Branson HM, Verhey LH, et al. The demographic, clinical, and magnetic resonance imaging (MRI) features of transverse myelitis in children. Journal of Child Neurology. 2012; 27(1): 11–21.
  11. Chee, C., Park, K., Lee, J., Ahn, H., Lee, E., Kang, Y., & Kang, H. . MRI Features of Aquaporin-4 Antibody–Positive Longitudinally Extensive Transverse Myelitis: Insights into the Diagnosis of Neuromyelitis Optica Spectrum Disorders. American Journal of Neuroradiology. 2018; 39(4): 782-787. doi:10.3174/ajnr.a5551
  12. Rensel, M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children. 2019; 6(6): 73. doi:10.3390/children6060073
  13. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Multiple Sclerosis. (Houndmills, Basingstoke, England). 2012; 18(1): 116–127.
  14. Ghezzi A. Therapeutic strategies in childhood multiple sclerosis. Therapeutic Advances in Neurological Disorders. 2010; 3(4): 217–228.
  15. Yeh EA. Management of children with multiple sclerosis. Paediatric Drugs. 2012; 14(3): 165–177.

Original Version of the Topic

Linda E. Krach, MD, Stacy Stibb, DO. Multiple sclerosis (including transverse myelitis). 9/20/2013.

Previous Revision(s) of the Topic

Linda E. Krach, MD, Stacy Stibb, DO. Multiple Sclerosis and Transverse Myelitis in Children. 10/25/2019.

Author Disclosure

Clarice Sinn, MD, MHA
Nothing to Disclose