Multiple sclerosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Multiple Sclerosis? What are the typical findings for this disease?

A first attack of neurological symptoms in children with central nervous system (CNS) demyelination may represent a monophasic illness or be the first presentation of a chronic relapsing disorder such as multiple sclerosis (MS), a condition that is increasingly being recognized and diagnosed in childhood. Cranial, and possible spinal imaging, and lumbar puncture are key diagnostic tests.

Acute management of demyelination usually involves initiation of corticosteroid therapy with IVIG, with plasma exchange required in severe cases. Once the diagnosis of MS is confirmed, immunomodulatory treatment should be initiated with the goal of reducing relapse rates and disability accrual. Safety and tolerability data support the use of these MS immunomodulatory therapies in pediatric MS.

Acute Central Nervous System Demyelination

Neurological symptoms attributable to demyelination commonly include the following:

  1. Unilateral or bilateral visual loss (optic neuritis)

  2. Motor, sensory or urological deficits localizing to the spinal cord (transverse myelitis)

  3. Ataxia

  4. Brainstem deficits (typically internuclear ophthalmoplegia or INO)

  5. Other monofocal or polyfocal neurological deficits

  6. Polyfocal neurological deficits with encephalopathy (acute disseminated encephalomyelitis or ADEM)

Optic Neuritis

Optic neuritis should be considered in any child presenting with subacute monocular or binocular visual loss (see Figure 1). Ophthalmological features of optic neuritis typically include:

  • Reduced visual acuity

  • Central visual field defect

  • Pain with extraocular eye movements

  • Relative afferent pupillary defect (RAPD)

  • Red color desaturation

Figure 1.

Selected differential diagnosis of optic neuropathy.

Optic disc edema is sometimes seen, but may be absent in retrobulbar optic neuritis. Neurological abnormalities outside of the optic nerve may also be present. Neuroimaging, usually brain magnetic resonance imaging (MRI) with contrast, reveals optic nerve thickening and/or enhancement in approximately 55% of children (see Figure 2) and visual evoked potentials are abnormal in up to 88% of children. Optical coherence tomography (OCT), a non-invasive technique for measuring retinal nerve fiber thickness, may aid in diagnosis.

Figure 2.

Axial T1 MRI with contrast shows left optic nerve thickening and enhancement in a child with optic neuritis.

Transverse Myelitis

Transverse myelitis should be considered in any child presenting with subacute onset of weakness and sensory deficits localizing to the spinal cord (see Figure 3). Typical symptoms of transverse myelitis include:

  • Bilateral (may be asymmetric) lower extremity weakness

  • Sensory paresthesias or hyperesthesias with a spinal sensory level

  • L'Hermitte's symptom (pain with forward neck flexion) indicating cervical spinal involvement

  • Bowel or bladder dysfunction (lesions above the sacral cord cause urinary retention and constipation)

Figure 3.

Axial FLAIR MRI shows diffuse bilateral gray and white matter lesions in a child with ADEM.

While many children will experience partial TM, others may have complete cross-sectional cord involvement with clinical features of flaccid paresis with hyporeflexia and later hyperreflexia. Longitudinally-extensive transverse myelitis (spanning > 3 spinal segments) or transverse myelitis with concurrent or rapidly sequential optic neuritis should prompt consideration of neuromyelitis optica (see Figure 2). Of note, approximately 10% of children with MS have longitudinally-extensive spinal cord lesions.

Somatosensory evoked potentials (SSEPs) may be useful to confirm a spinal cord localization.

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is defined by the presence of polyfocal neurological symptoms and signs with encephalopathy (either behavioral change or alteration in consciousness). Symptoms of ADEM are often preceded by a febrile illness or viral prodrome. ADEM may be the clinical manifestation of age-dependent demyelination as the majority of individuals with ADEM are under the age of 10 years. While ADEM is most commonly a monophasic illness, relapsing and multiphasic forms have been described. International consensus definitions for monophasic and relapsing forms of ADEM describe the clinical features and time course in detail. Typical brain MRI findings of ADEM are shown in Figure 4.

Figure 4.

Sagittal T2 weighted MRI shows a) longitudinally extensive lesion typical for NMO and b) short-segment spinal lesion typical for MS.

Other Monofocal and Polyfocal Presentations

Other presentations of acute demyelination include:

  • Isolated motor impairment

  • Isolated sensory impairment

  • Isolated cerebellar deficits (ex: ataxia)

  • Internuclear ophthalmoplegia (INO)

  • Polyfocal neurological deficits without encephalopathy

MS Diagnosis

The cornerstone of MS diagnosis is demonstration of demyelination that is disseminated in both space and time. Specific consensus definitions have been proposed for childhood-onset MS requiring either (i) two discrete demyelinating attacks separated by at least 30 days and involving two separate areas of the CNS; (ii) one attack consistent with demyelination and MRI evidence of new lesions meeting criteria for dissemination in time (see below); or (iii) two non-ADEM attacks in a child with an initial ADEM presentation.

As in adult-onset MS, MRI may be used as a surrogate marker for dissemination in space and time, facilitating earlier disease diagnosis. Specifically, new criteria proposed by Polman et al (2010) require that dissemination in space on MRI be defined as involvement of greater than or equal to one T2 lesion in at least two of the following four areas: i. periventricular ii. juxtacortical iii. infratentorial and iv. spinal cord with symptomatic brainstem or spinal cord symptoms not contributing towards the total lesion count. Dissemination in time may be fulfilled by demonstration of either: i. new T2 and/or gadolinium-enhancing spinal cord lesion(s) on follow-up MRI (irrespective of timing of baseline MRI) or ii. simultaneous presence of gadolinium-enhancing and non-enhancing lesions.

Disease course

More than 95% of children with multiple sclerosis initially experience a relapsing-remitting disease course with reported relapse rates between 0.38 and 1.2 per year. Primary progressive disease (neurological deterioration in the absence of discrete relapses) is rare in the pediatric age group. Children with MS appear to experience more frequent relapses as compared to adult-onset MS patients in the first several years following diagnosis. The time from a first attack to a second neurological event is highly variable and may be greater in younger children. Childhood-onset MS patients may enter a secondary progressive phase, defined by disability progression in the absence of clear relapses, between 15 to 20 years following first attack.

What other disease/condition shares some of these symptoms?

Acutely, it is important to exclude central nervous system infection especially if neurological symptoms are accompanied by fever, encephalopathy, meningismus or other systemic signs. The combination of brain and/or spinal cord white matter abnormalities with multiple cranial neuropathies should raise suspicion of central nervous system Lyme disease (neuroborreliosis), especially if there has been recent travel to an endemic area or if a tick bite is recalled.

While rare, malignancy, such as central nervous system lymphoma, should also be considered, particularly if MRI features are atypical for demyelination, or if spinal fluid examination reveals atypical cells.

A history of persistent or increasingly frequent headache, seizures, or lumbar puncture evidence of an elevated opening pressure should prompt consideration of isolated CNS vasculitis or CNS vasculitis associated with systemic disease (such as systemic lupus erythematosus). Children with CNS vaculitis usually respond to steroid therapy and experience an exacerbation of symptoms as steroids are tapered. Distinguishing vasculitis from MS has important therapeutic implications as vasculitis management requires long-term immunosuppression with medications such as cyclophosphamide.

Neurological symptoms associated with renal or liver impairment, fever, lymphadenopathy and disseminated intravascular coagulation should prompt consideration of macrophage activation syndrome. High serum ferritin and fasting triglycerides, unexpectedly low ESR, and the presence of hemophaocytic cells in a bone marrow aspirate or CSF are diagnostic.

Repeated attacks of optic neuritis and transverse myelitis should raise suspicion of the diagnosis of neuromyelitis optica (NMO). The diagnosis of NMO is aided by testing for antibodies directed against Aquaporin 4. NMO is important to consider as the disease often has an aggressive course with rapid disability progression, requiring potent immunosuppressive agents to maintain disease control. See Figure 6.

Figure 6.

Selected differential diagnosis of transverse myelitis.

What caused this disease to develop at this time?

MS is thought to be a disease influenced by both genetic predisposing factors and environmental triggers of aberrant CNS directed autoimmunity. It is increasingly believed that MS predisposition is established during childhood, as evidenced by studies of immigrants to areas of high MS prevalence who acquire the MS risk of their new community only if they immigrated prior to age 15 years.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There is no laboratory test that can confirm MS diagnosis. The majority of laboratory evaluations are performed to exclude other conditions - a requirement prior to considering MS as the etiology of a patient's clinical symptoms. However, several investigations are helpful in supporting an MS diagnosis.

Cerebrospinal Fluid Examination

Cerebrospinal fluid (CSF) examination is important in confirming the presence of CNS demyelination and for excluding other diagnoses. At first presentation, more that 50% of children with MS will have an elevated CSF leukocyte count, typically below 30 cells/microliter with a lymphocytic predominance. A higher leukocyte count or neutrophilic predominance should prompt consideration of CNS vasculitis, CNS infection, or NMO. CNS vasculitis is also often associated with an elevated opening pressure.

CSF oligoclonal bands (OCBs) in CSF, but not detected in serum, may be found in up to 90% of childhood-onset MS patients at first presentation as compared to approximately 10% of children with ADEM or NMO. Isoelectric focusing methods have the highest diagnostic yield. It should be noted that MS patients may initially have undetectable CSF OCBs, but may develop them later in the disease course.

Multimodal Evoked Potentials

Testing of visual, brainstem auditory, and visual evoked potentials is often useful for confirming the clinical demyelinating syndrome and for documenting subclinical disease. Almost 50% of children with MS in one study demonstrated subclinical abnormalities in at least one of these evoked potential pathways, most commonly visual. Visual evoked potentials are abnormal in over 85% of children with clinical optic neuritis.

Would imaging studies be helpful? If so, which ones?

Neuroimaging, especially brain and/or spinal MRI with contrast, is valuable in confirming the presence of inflammatory CNS lesions and in excluding other possible diagnoses. Lesion characteristics of younger children may differ from older children, with younger MS patients being more likely to have ill-defined brain MRI lesions and grey matter involvement. Large lesions with indistinct borders are typical for ADEM.

One recent study suggested that the presence of two of the following MRI features may aid in distinguishing children with MS from those with ADEM with 81% sensitivity and 95% specificity: i. presence of T1 black holes ii. absence of diffuse bilateral pattern iii. presence of two or more periventricular lesions. MRI has now been incorporated into the diagnostic criteria for MS in children and adults and allows a diagnosis of MS even at first presentation if there is the simultaneous presence of gadolinium-enhancing and non-enhancing lesions suggesting disease dissemination in time.

Confirming the diagnosis

Classification of Childhood Demyelinating Syndromes

An algorithmic approach to the classification of childhood demyelination has been published (Banwell, Lancet Neurol 2007) and Yeh (Nature Reviews Neurol 2009 ).

If you are able to confirm that the patient has Multiple Sclerosis, what treatment should be initiated?

The care of children with MS revolves around management of acute relapses and longer-term immunomodulation with the goal of reducing relapse rates and disability accrual.

Acute Management

The acute management of a first attack of demyelination or MS relapse usually relies on initiation of corticosteroid therapy. Doses in the range of 20-30 mg/kg IV per day (maximum 1 g per dose) for 3 to 5 days are typically used. Mild relapses that are not distressing to the patient and do not impair functioning may require supportive management, but not pharmacological therapy. Serum glucose, urine glucose, and blood pressure should be monitored during corticosteroid treatment. If children improve, with this initial course but have an incomplete resolution of symptoms, an oral prednisone taper starting at 1 mg/kg/day for 2-3 weeks could be considered.

If children do not significantly improve or clinically worsen during the course of steroid therapy, evidence from published case series suggest that IVIG may be of benefit with a typical dose of 2 g/kg administered over 2 to 5 days.

If symptoms of demyelination are severe and potentially life-threatening (for example, severe encephalopathy or respiratory depression), there is class I evidence in adult MS patients for the use of plasma exchange (PLEX), which is typically administered as 5 to 8 exchanges over 10 days.

Chronic Management

First-Line Agents:

Class I evidence in adult-onset MS exists for the following therapies: interferon beta 1a, interferon beta 1b, and glatiramer acetate. Route of administration, doses, potential adverse effects, and associated laboratory abnormalities are summarized in Figure 5. While there have been no formal randomized-controlled trials of interferons or glatiramer acetate in children with MS, available case-series level evidence suggest that these treatments are safe and well-tolerated in childhood.

Figure 5.

First-line treatments for childhood MS.

Children who are receiving interferon treatments should have serum white blood cell counts and liver enzymes monitored monthly for the first 6 months and every 3 months thereafter. Thyroid function should be monitored yearly. Sexually active patients should be counselled regarding contraceptive use due to potential teratogenicity of some of these agents.

Second-line therapies

Second-line therapies are offered to families if frequent relapses occur despite treatment with one of the first-line agents, or if treatment with these agents causes intolerable side effects. Cyclophosphamide, mitoxantrone, azahtioprine all have case-series level evidence to support their use in childhood MS. Case series have also recently been published reporting natalizumab use in pediatric MS patients.

Fingolimod (FTY 720) has recently been licensed for use in adult-onset MS patients and increased efficacy and convenience of oral administration may make this an attractive therapeutic option for pediatric MS patients. The safety of this medication in children for whom the immune system is still maturing has not yet been definitively established and fingolimod does not have regulatory approval for use in children.

Emerging therapies including cladribine, rituximab, alemtuzumab, dacluzumab, laquinimod and ocrelizumab also have the potential for improved efficacy and tolerabiltiy as compared to interferons or glatiramer acetate but the risks of life-threatening infection and malignancy must be carefully considered, especially for pediatric MS patients.

What are the adverse effects associated with each treatment option?

Corticosteroid therapy may be associated with the development of hypertension and hyperglycemia. Many children experience gastrointestinal irritation that can be reduced with use of H2 blocking agents. Agitation, mood disturbances, sleep disruption and personality changes are common in patients on high doses of corticosteroids, but typically resolve as doses are reduced. Longer-term use may be associated with osteopenia, weight gain, and adrenal suppression. Given that long-term (ie: more than 3 weeks) of corticosteroid therapy is not recommended and repeated monthly intravenous corticosteroids failed as a model for MS disease modulation, corticosteroids are reserved for acute relapse therapy.

IVIG infusion may be associated with headache, nausea, flushing, back pain, and hyptotension. If any of these occurs during an infusion, the infusion rate may be slowed or the medication discontinued. Premedication with antihistamines or corticosteroids may be useful in preventing these symptoms. Rarely, IVIG may be associated with acute renal failure, cardiac failure, or thrombosis. Severe anaphylactic reactions have been described in patients with IgA deficiency. Aseptic meningitis is a well-described complication of IVIG administration. As in treatment with other blood products, transmission of infectious agents is possible.

Treatment with PLEX may be associated with hypotension, pulmonary edema, metabolic alkalosis and electrolyte abnormalities (ex: hypocalcemia or hypokalemia) and therefore requires administration by a trained team of individuals and close monitoring. Anaphalaxis is rare but can occur as can significant hemorrhage (from heparin-induced thrombocytopenia) and infection.

Side effects of commonly used first-line immunomodulatory therapies are summarized in Figure 5.

What are the possible outcomes of Multiple Sclerosis?

Almost 95% of children with MS experience a relapsing remitting course with attacks consisting of subacute onset of neurological symptoms separated by periods of relative disease quiescence. While recovery after an acute relapse is expected, residual deficits often perist. Persistent neurological deficits may significantly affect daily functioning. After a period of between 15 to 20 years, childhood-onset MS patients may enter a secondary progressive phase where there is disability accrual in the absence of discrete relapses.

The goal of immunomodulatory treatment is to reduce relapse rate and long-term disabilty. The available first-line therapeutic agents have a similar efficacy in reducing relapse rates by approximately 18-30%. Medications differ in terms of route of administration, frequency of administration, and side effect profiles and therefore treatment choice must be individualized.

Other clinical considerations

Fatigue significant enough to limit daily activities and to affect school performance is experienced by up to 40% of children with MS. Non-pharmacological measures such as scheduling key activities for early in the day, and brief daytime napping may be sufficient for some MS patients, but pharmacological therapy is often required. Modafinil prescribed at a starting dose of 50 mg once daily and increased as needed up to 100 mg twice daily is often an effective pharmacological therapy.

Childhood MS occurs during key academic years and ongoing CNS inflammation may interfere with learning and memory. Between 50- 70% of children with MS demonstrate evidence of cognitive impairment with formal testing. Cognitive impairment has been associated with younger age at first attack and longer disease duration. Impaired learning and scholastic difficulties have longer-term implications for global functioning and vocational choices.

Children with MS may experience bowel and/or bladder dysfunction as well as sexual dysfunction. Mood disorders, most commonly depression, are often identified in pediatric MS patients. Health care practioners should be comfortable discussing these issues with adolescent patients.

What causes this disease and how frequent is it?

Childhood MS is being increasingly recognized and diagnosed. While the true incidence of pediatric MS remains to be precisely defined, it is estimated that 3-10% of all MS patients experience their first symptoms prior to the age of 18 years.

Geography and Migration

Multiple sclerosis in both children and adults has been reported in many countries worldwide, but there is marked regional variation in MS prevalence.

  • There is a well-described latitude gradient in MS, with greatest MS prevalence reported in countries further away (in either direction) from the equator.

  • Early life place of residence appears to correlate with MS risk. A study of adult-onset MS patients demonstrated that immigration from areas of low reported MS prevalence (India and Pakistan) prior to the age of 15 years was associated with higher risk of being later diagnosed with MS as compared to immigration after age 15.

  • A single center Canadian study of adult and childhood-onset MS patients showed that the two groups shared the common experience of having spent most of the childhood years in Canada, irrespective of self-reported familial ancestry.

Vitamin D

One of the factors that may explain regional variations in MS risk and especially the latitude gradient is sunlight exposure and consequent serum vitamin D status.

  • Studies in adults have shown that MS risk is inversely related to daily oral vitamin D intake and serum 25-hydroxyvitamin D [25(OH)D] levels.

  • A study of twins discordant for MS diagnosis showed that co-twins who reported higher sunlight exposure were less likely to subsequently develop MS.

  • Risk of adult-onset MS is higher for individuals born in the spring as compared to the fall, suggesting that maternal vitamin D status during pregnancy may be an important determinant of MS risk.

  • Both retrospective and prospective studies in children have shown that low serum 25(OH)D levels at first presentation are correlated with increased risk of MS diagnosis.

Epstein-Barr Virus (EBV)

Epstein-Barr Virus (EBV) infection has been implicated as a contributing factor to MS development in both children and adults.

  • Three case-control studies in children have shown that children with MS more commonly demonstrate remote EBV seropositivity as compared to matched controls.

  • One prospective Canadian study has shown EBV seropositivity at first attack of CNS demyelination to be more common in children later diagnosed with MS as compared to those individuals remaining monophasic.

  • In seropositive individuals, antibody titres are also higher in children with MS as compared to controls.


MS is more common in first-degree relatives of MS patients, as compared to the general population, and MS has a higher prevalence in monozygotic as opposed to dizygotic twins, suggesting that there may a genetic contribution to MS risk.

  • The HLA DRB1 allele has been associated with increased risk of adult-onset MS in numerous studies.

  • A recent prospective study in Canadian children with a first attack of central nervous system demyelination demonstrated that the HLA DRB1*15 allele was more common in those children later diagnosed with MS as opposed to children who remained monophasic.

  • Several genome-wide studies have implicated other immune-related genes in MS, but all are felt to have a very low contribution to individual MS risk.

What complications might you expect from the disease or treatment of the disease?

Fatigue, cognitive impairment, and persistent neurological disability are all possible complications of MS in children (see above).

Treatment-related side effects are discussed in the section describing therapies.

Are additional laboratory studies available; even some that are not widely available?

Optical coherence tomography (OCT) is a new non-invasive technique that enables measurement of retinal nerve fibre thickness. As significant numbers of axons are found in the retina, OCT is emerging as a potentially valuable tool in measuring the degree of axonal degeneration in MS. Applications of OCT in MS include estimation of visual prognosis after optic neuritis, demonstration of degree of axonal degeneration in MS patients without optic neuritis, and use as a surrogate outcome marker in MS treatment trials.

How can Multiple Sclerosis be prevented?

To date, there is no known intervention that will prevent MS development. There is increasing evidence that vitamin D deficiency at first presentation of neurological symptoms increases risk of subsequent attacks and is associated with relapse rate in individuals with established MS. Future studies exploring the role of vitamin D supplementation are of considerable interest.

What is the evidence?

The following are recommended references:

Krupp, LB. "Consensus definitions proposed for pediatric multiple sclerosis and related disorders". Neurology. vol. 68. 2007. pp. S7-12.

(This article proposes consensus definitions for childhood MS, ADEM, recurrent ADEM, multiphasic ADEM, and NMO.)

Polman, CH. "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"". Ann Neurol. vol. 58. 2005. pp. 840-6.

Polman, CH. "Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria". Ann Neurol. vol. 69. 2011. pp. 292-302.

(The above two articles summarize current diagnostic criteria for multiple sclerosis.)

Banwell, B. "Multiple sclerosis in children: clinical diagnosis, therapeutic strategies and future directions". Lancet Neurol. vol. 6. 2007. pp. 887-902.

Yeh, EA. "Pediatric multiple sclerosis". Nat Rev Neurol. vol. 5. 2009. pp. 621-31.

(The above two articles each provide a comprehensive overview of the clinical features, epidemiology, approach to diagnosis, and treatment of childhood MS.)

Dale, RC. "Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica and multiple sclerosis". Curr Opin Neurol. vol. 22. 2009. pp. 233-40.

(This article reviews the consensus definitions for childhood demyelinating syndromes published by Krupp et al, examines long-term outcomes of pediatric demyelination, and discusses available therapies for childhood-onset MS.)

Pohl, D. "CSF characteristics in early-onset multiple sclerosis". Neurology. vol. 63. 2004. pp. 1966-7.

(This study describes the CSF profile of a group of childhood-onset MS patients.)

Pohl, D. "Pediatric multiple sclerosis: detection of clinically silent lesions by multimodal evoked potentials". J Pediatr. vol. 149. 2006. pp. 125-7.

(This study examines the utility of evoked potential testing for detecting clinically-silent lesions in children with MS.)

Kuntz, NL. "Treatment of multiple sclerosis in children and adolescents". Expert Opin Pharmacother. vol. 11. 2010. pp. 505-20.

(This review evaluates the literature pertaining to the pharmacological treatment of MS in both adults and children.)

Banwell, B. "Therapies for multiple sclerosis: considerations in the pediatric patient". Nat Rev Neurol. vol. 7. 2011. pp. 774-80.

(This article evaluates current and emerging MS therapies, with a focus on the treatment of children with MS, and provides algorithmic approaches to therapy using different treatment models.)

Resources:MS Society of Canada: National MS Society:

Ongoing controversies regarding etiology, diagnosis, treatment

There is still considerable debate about definitions for many childhood demyelinating syndromes, especially recurrent and multiphasic forms of ADEM. It remains unclear whether these forms of ADEM represent discrete diagnostic entities with a favourable prognosis, or if these forms of ADEM represent an age-related early manifestation of MS.

Treatment algorithms for childhood MS are largely derived from randomized controlled trials conducted in adults. There is a paucity of clinical trials that include pediatric participants. Inclusion of children with MS in large scale therapy trials will be increasingly important in the near future with the introduction of new potent immunosuppressive/immunomodulatory treatments for whom the effects on the developing immune system have yet to be defined.

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