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 multiple sclerosis (POMS) and transverse myelitis (TM). Included in these processes is a component of axonal loss and neurodegeneration as seen in multiple sclerosis (MS). 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.
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.1
Recently, LETM has been related to refers to a spectrum relapsing remitting 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; Multiple sclerosis has been associated to LETM in up to 14% of children with MS.
Epidemiology including risk factors and primary prevention
According to current studies, the incidence of POMS ranges between 0.66 and 1.66 per 100,000.2 It has been shown that about 10% of all individuals with MS experience their first attack before 18 years of age. . 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.3 Acute TM is reported in 2 cases per million people in the U.S. with 20% of these cases occurring in children.1 No risk factors have been identified for TM.
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 apopotosis or death. In TM, the inflammation is associated with T cell and monocyte infiltration. Molecular mimicry, superantigen effect, humoral-based dysregulation, interleukin-mediated toxicity, and elevated immunoglobuin levels are mechanisms thought to lead to inflammatory infiltration of the spinal cord.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- New onset: Typically presents with focal deficits such as unilateral weakness, numbness and paresthesias. Other common forms of presentation include optic neuritis, monofocal brainstem, or polyfocal neurologic deficits. Subacute: Pediatric MS follows a relapsing-remitting course; greater than 75% of children with MS will experience a second attack in the first two years after the initial attack and risk remains high during the first five years. Children are on average 10 years younger at the time of evolution to secondary progressive MS, compared to adults.4
- 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.
- New onset: Presents with complaints of pain, sensory loss in a band-like distribution, and bowel/bladder dysfunction.
- 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.
- Chronic/Stable: 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/bladder/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.
2. ESSENTIALS OF ASSESSMENT
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 more than half of the cases are preceded by a mild febrile illness 3 weeks before onset of symptoms.
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.
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.5 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.6 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.
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.
In all disease presentations, MRI of the brain and spinal cord should be obtained, including the use of gadolinium in order to accurately assess for active demyelinating lesions, such as in MS, inflammation, infection, and possible tumor presence. Current diagnostic criteria for MS allows for specific findings on brain MRI to substitute for diagnosing relapses based on clinical presentation and therefore allow a diagnosis of MS with a first clinical attack, if lesions are disseminated in time and space. If MRI evidence is not met, diagnosis can be made with evidence of new lesion on follow up imaging. Spine lesions in MS typically are small areas of patchy hyperintense T2 signals spanning fewer than 3 spinal segments and involving only a portion of the transverse diameter of the cord,
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.1 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.10
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 also 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
Most pediatric patients with MS recover well from these early relapses, and cumulative physical disability is rare in the first 10 years of disease. Brainstem attacks, poor recovery from a single attack, and a higher frequency of attacks portend a greater likelihood of future disability.
Poorer prognosis in MS is associated with increased relapse rate in the first 2 years of disease, onset in the very young, and severity of initial events. 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.1
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 SCI 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.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Current treatment of pediatric onset Multiple Sclerosis (POMS) follows adult onset Multiple Sclerosis recommendations and guidelines. 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 treatment11. 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.11 The first line agents include injectable therapies such as beta interferons and glatiramer acetate, as supported by treatment of adult onset MS and observational POMS studies. Up to date, there is still a lack of randomized controlled trials performed with DMT in the pediatric MS patients, which continues to limit their use with this population. A 2018 United States’ Network of Pediatric MS Center’s database review showed a change in first line DMT pattern used in pediatric patients. Natalizumab, rituximab, fingolimod, daclizumab and teriflunomide showed higher efficacy according to the latter. Glatiramer Acetate is currently the only DMT FDA approved for pediatric MS patients.11 Acute relapses are treated with IV methylprednisolone of 20-30 mg/kg/day over 3-5 days. If symptoms recur or there is a worsening of symptoms after discontinuation of IV steroids, an oral taper can be added. If the relapse is severe or there is incomplete recovery after high dose steroids, a second pulse of IV steroids can be given, intravenous immunoglobulin (IVIG) 2g/kg over 2-5 days can be trialed, and/or plasma exchange can be used.
Acute management of transverse myelitis has been informed primarily in case series and expert opinion and no randomized controlled trials have been performed yet. 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. If there is no clinical improvement within 24-48 hours IVIG can be given at 2g/kg divided over 2-5 days. Children with TM usually do not need additional treatment aimed at their disease after the acute phase. 1,7,8,9
LETM treatment is directed at the underlying cause. As with Transverse Myelitis, high dose corticosteroids in the acute inflammatory presentation is 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
|New onset/acute||-Proper medical management|
-Evaluate for bowel/bladder dysfunction. Start appropriate programs with intermittent catherization or bowel program.
-Initiate PT, OT, SLP to maintain range of motion, prevent contractures, orthotic evaluation, assess cognition and swallow.
|Same as MS||Same 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.||-Course may be relapsing remitting, similar to MS|
|Chronic/stable||As 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|
|Temporal progression has yet to be fully described and detailed..|
|Pre-terminal or end of life care||Assure 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. Specific deficits will determine the medical specialties involved.
Patient & family education
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.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
New oral medications target the immune system and the immunopathologic process of MS: those tested in adults include Cladribine, Fingolimod, Teriflunomide, Fumarate, and Laquinimod. They have been shown to decrease MRI activity and/or decrease relapse rates. Monoclonal antibodies targeting the immunopathologic process include Rituximab, Daclizumab, and Alentuzumab, which have shown promise in decreasing MRI and disease activity as well.8
The trial of fingolimod versus interferon B-1a in POMS is the first double blind, active comparator trial completed in POMS showing superior efficacy of fingolimod over interferon B-1a in reducing relapses in children and adolescents 12 to 18 years old.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
To date, there is one completed randomized controlled clinical trial in POMS confirming the efficacy and safety of fingolimod. Nonetheless, there are ongoing clinical trials with other disease modifying treatments testing their efficiency in this particular population.11
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Original Version of the Topic
Linda E. Krach, MD, Stacy Stibb, DO. Multiple sclerosis (including transverse myelitis). 09/20/2013.
Edwardo Ramos, MD
Nothing to Disclose
Ana Ortiz-Santiago, MD
Nothing to Disclose
Nanichi Ramos-Roldan, MD
Nothing to Disclose
Jose Vives-Alvarado, MD
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