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Guide for Physicians

PEDIATRIC MULTIPLE SCLEROSIS

Lauren B. Krupp, MD
Professor of Neurology
Director of the Lourie Center for Pediatric MS
Stony Brook University Medical Center

Multiple sclerosis (MS) is an immune mediated inflammatory demyelinating disorder ofthe central nervous system (CNS). Children and adolescents can develop MS although less commonly than adults. An estimated 2-3 % of patients with MS are under age 18.[1, 2].

DEFINITION

To facilitate clinical research and establish uniform criteria for the diagnosis, an operational and consensus based definition for pediatric MS was developed.[3]. The criteria for the diagnosis require:

1) Multiple episodes of CNS demyelination disseminated in time and space with no lower age limit

2) MRI findings can be applied to meet dissemination in space criteria if they show three of the following four features – 1) nine or more white matter lesions or one gadolinium enhancing lesion, 2) three or more periventricular lesions 3) one juxtacortical lesion, 4) an infratentorial or spinal cord lesion

3) The combination of an abnormal cerebral spinal fluid (CSF) and two lesions on the MRI, of which one must be in the brain, can also be used to meet dissemination in space criteria; the CSF must show either oligoclonal bands (OCB) or an elevated IgG index

4) MRI can be used to satisfy criteria for dissemination in time following the initial clinical event, even in the absence of a new clinical demyelinating event. A new gadolinium enhancing lesion or new T2 lesion 3 months after the clinical event can be a surrogate for another clinical event.

This definition is distinguished from self-limited demyelinating disorders such as acute disseminated encephalomyelitis (ADEM) which in contrast to pediatric MS is associated with encephalopathy and typically shows large ( 1 – 2 cm or more) lesions of the white matter as well as the deep grey matter within the brain.

DEMOGRAPHIC FEATURES OF PEDIATRIC MS

The disease usually begins with a mean age of onset between 8- 14 years of age, depending on whether the cohort has a cut off below 16 or 18.[1, 2, 4]

The distribution of boys and girls varies according to age. For children equal to or above age 10, girls outnumber boys by approximately 2.5:1.[1, 2, 5, 6]For children below age 10 the ratio of girls and boys is approximately 0.5:1.[7, 8] . These demographic features suggest sex hormones play a role in MS pathogenesis which is also suggested from data in adult MS.[9]

CLINICAL FINDINGS

Symptoms and Signs

Presenting symptoms of MS often depend on the location of the white matter lesions. Initial symptoms can include optic neuritis (unilateral or bilateral), motor weakness, balance problems, sensory disturbance, loss of coordination, bladder dysfunction, or problems related to brainstem involvement (facial numbness, diplopia).[10] A polysymptomatic onset occurs in 8-67% of the patients. [1, 2, 5, 10]

At presentation, children tend to have more brainstem and cerebellar symptoms, encephalopathy, or optic neuritis than do adults.[11, 12] Among those under six, seizures, marked alteration in consciousness, a polysymptomatic onset, and atypical MRIs are more frequent.[7, 11]

MRI findings

Lesions predominantly involve the white matter. In contrast, cortical or central gray involvement is uncommon.[4] In figure 1, an MRI from a typical patient with MS is shown. The lesions tend to be discrete, often associated with gadolinium enhancement, and are usually periventricular in location. [5] However, some children lack typical MRI findings of MS and have either large tumefactive lesions associated with edema or deep grey matter involvement. [13]

Figure 1: 15 year old with MS and typical white matter lesions

Disease course

In over 93% - 98% of cases[10] the disease course at onset is characterized by relapses and remissions. A progressive course without relapses in pediatric MS usually suggests an alternative diagnosis.

Adults usually transition to secondary progressive MS, 7-10 years after diagnosis, In contrast children transition more slowly, approximately 20 years following the diagnosis.[6, 11, 12]

PROGNOSTIC FACTORS

Features at the time of a child’s first demyelinating event, increase the likelihood of a subsequent event include the presentation ofoptic neuritis or if the child is older than 10 years.[14]A decreased risk for a second event is noted in children presenting with spinal cord symptoms or alteration in mental status.[14]

Negative prognostic factors regarding disease course have been identified for both children and adults. These include a progressive course at onset[11, 12, 15], poor clinical recovery from an event, numerous attacks in the first 2 – 5 years after diagnosis [16], short interval between the first and second attack, symptoms of sphincter dysfunction, and absence of encephalopathy. [11, 12, 15, 17]

PSYCHOSOCIAL ISSUES

Pediatric MS, like other chronic illnesses, poses psychosocialchallenges to families. Behavioral problems include denial, difficulty with family and peers, and non-compliance with therapy.[18] A further concern is that perceived stress can increase the probability of increased disease activity. [19]

Young people with MS may be at a particular high risk for additional psychological problems due to the effects of the disease on the CNS.[20]. For example, among adults with MS, depression is associated with an increased lesion burden in the inferior – medial frontal-temporal areas.[21]

In our experience at our Center approximately 46% of children have some form of affective disorder. More information is available on the psychiatric complications of adults with MS.[22] Over 25% of adults with MS from community samples [23] have depression. In clinical populations the life time prevalence of major depression is 40-50%. [24, 25] and the frequency of anxiety disorders ranges from 25 – 34%. [22]

Cognitive and academic functioning

Over one third of children with MS have cognitive deficits attributed to the disease. The must vulnerable areas are memory, perceptual and visual motor skills, executive functioning, cognitive processing speed, and global IQ.[18, 26-29] A similar range of deficits are also observed in adults. The rate of progression of cognitive loss is not known. Fortunately, declines in academic functioning can be mitigated by educating school personnel, providing special accommodations, such as reduced work load due to fatigue and teaching compensatory strategies to assist memory loss.[18, 26-30]

PATHOLOGY AND PATHOGENESIS

Both genetic and environmental factors contribute to MS. Examples ofthe environmental influences include the increasedprevalence of MS at greater distances from the equator[31], season of birth[32]and exposure to sunlight during childhood.[33]The association between low sunlight exposure and increased MS risk may be mediated via Vitamin D levels. which have been shown to be low in CaucasianMS patients.[34]Migration studies suggest that place of residence during childhood may also be associated with MS risk.[35, 36]While there is clearly a role for environmental effects on MS pathogenesis, genetics also contributes.[10]

A monozygotic twin sibling of an MS patient has a 20-30% risk for the disease in contrast to the reduced risk of a dyzygotic twin of an individual with MS. The gene most closely associated with MS risk is HLA DR1B. This genetic marker shows an increased frequency in adults as well as children with the disease.[10, 37] Recently, an association of the genes coding for the receptors of the cytokines IL-7 and IL-2 have been identified in adult MS.[38, 39]These cytokines play a role in T and B cell development. Both T and B cells contribute to the pathogenesis of MS. However, the exact role of the cytokines is still under investigation.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of MS is large and includes other inflammatory disorders of the white matter, infections, neoplasms, vasculitis, hereditary disorders of the white matter, metabolic disorders, mitochondrial disorders, and vitamin deficiencies.[40]Examples of several entities within each category are listed below.

ADEMis another inflammatory and demyelinating disorder of the CNS which unlike MS is self limited. While the two disorders can overlap in presentation certain features as shown in Table 1 are more typical of ADEM than MS.[41]

Typical clinical features of ADEM not usually found in MS are fever and encephalopathy (manifested by stupor, severe lethargy, seizures, confusion, and rarely coma). Focal and multifocal signs of cerebral white matter dysfunction which mimic MS include optic neuritis (bilateral or unilateral), pyramidal signs (hemiparesis, paraparesis, or monoparesis), sensory loss, or brainstem and cerebellar signs. The MRI in ADEM in contrast to MS, typically shows large poorly defined lesions which involve the white matter but can also affect deep grey structures such as the basal ganglia. Positive OCB are present in 25% or less of ADEM cases.[5, 30, 41, 42]which is a lowerfrequency of positive OCB in MS which ranges from 55 - 95%.[11, 43]The clearest distinction between MS and ADEM is the ultimate disease course. While rarely ADEM may relapse over time, these relapses do eventually stop and the MRI resolves partially or fully.

Table 1 Clinical differences between ADEM and MS

Features

ADEM

MS

Typical age group

< 10 years

>10 years

Encephalopathy

Required in definition

Rare

Seizures

Occasional

Rare

Grey matter involvement on MRI

Often

Rare

CSF pleocytosis greater than 50 mm/ml

Often

Rare

OCB

Occasional

Often

Infectionsmust always need to be excluded and include entities such as meningitis, encephalitis, brain abscess,[40]Lyme disease, and HIV.

Neoplasmsenter the differential diagnosis among patients with single tumefactive lesions which can resemblea primary CNS neoplasm or lymphoma. Most often grey matter involvement will lead to an alternative diagnosis than MS but occasionally biopsy is needed.

Vasculitiscan include neurological complications which can be mistaken for MS. Among the disorders to exclude are systemic lupus erythematosus, Bechet’s disease, sarcoidosis, CNS vasculitis, or Sjogren’s syndrome.

Neurogenetic leukoencephalopathiesinvolve the cerebral white matter and occasionally can have an MRI appearance that resembles MS. However these conditions can be distinguished from MS by their progressive course, the presence of developmental delay, and the onset during infancy. This group of disorders includes but is not limited to:adrenoleukodystrophy (ALD) metachromatic leukodystrophy (MLD); Pelizaeus-Merzbacher Disease; Refusm’sdisease; leukoencephalopathy with vanishing white matter;childhood ataxia with cerebral hypomyelination of the brain stem and spinal cord;adult and juvenile onset Alexander’s disease; and cerebral autosomal dominant arteriography (CADASIL).

Mitochondrial Disordersare also included in the differential. For the patient with optic neuritis, Leber’s Hereditary Optic Neuritis must be considered. Other conditions which rarely may be confused for MS include Leigh’s disease, Kearns-Sayne syndrome, and Mitochondrial Encephalopathy with Lactic Acidosis and Stroke like episodes as well as other mitochondrial disorders.

Vitamin deficienciesthat can have symptoms which overlap with those of MS includeB12, folate, and vitamin E.

TREATMENT

Treatment of relapses

Management of acute relapses includes neurological evaluation and initiation of steroid therapy for relapses which affect daily functioning. The goal is to decrease the duration of the relapse and enhance the rate of recovery.[44, 45] Since no clinical trials for relapse management have been done in pediatric MS the treatment follows the approach used for adults. High doses of parenteral methyprednisolone (typically one gram) appear more effective than lower oral doses. [46] Treatment regimens vary from 3 to 5 days. In our experience children respond to doses ranging from 20 to 30 mg per kilogram. In adults, high doses of oral methyprednisolone have been substituted for parenteral therapy.[47]Complications can develop with steroid therapy and include gastrointestinal upset, irritability, insomnia, and at their most extreme – psychosis. It is not easy to predict which individuals will be at greatest risk for behavior related side effects

On occasion, children with MS treated with high doses of steroids and followed by an oral taper, develop steroid dependence (inability to wean off therapy due to reoccurrence of symptoms.) Patients may also fail to respond to steroid therapy.In the event of steroid dependence or steroid failure pulse intravenous immunoglobulin therapy (.4mg/kg per day x 5 days) can be tried.Alternatively, patients failing to improve with steroids may respond to plasmapheresis.[48]

Disease modifying therapies

Disease modifying therapies (DMT) constitute the principal approach to altering the disease course. These treatments have only been shown to be useful in relapsing remitting MS or in adults with a single relapse who are at high risk for a subsequent event. The medications are most effective in decreasing the frequency and severity of relapses. To a lesser degree they lessen the accumulation of neurological impairments or disability. As shown in table 2, the most commonly used agents (in order of their timing of FDA approval) are interferons beta 1bSQ (Betaseron) at a dose of 250 ug every other day; interferon beta 1a intramuscular (Avonex) at a dose of 30 ug once a week; glatiramer acetate (Copaxone) SQ at a dose of 20mg daily; and interferon beta 1a SQ)(Rebif) at a dose of 44 ug three time a week. The interferons and glatiramer acetate affect the immune system by slightly different mechanisms. However, each of these therapies has their own advantages and disadvantages, largely based on adverse event profile, convenience, and relative effect on MRI. Psychiatric complications have been anecdotally associated with the interferon therapies. However, in the pivotal clinical trials, in including the most recent, the frequency of mood disorder was not significantly different than placebo.[49]

Natilizumab (Tysabri), mitoxantrone (Novantrone), and cyclophosphamide (Cytoxan) are second line therapies which are given intravenously. They are usually prescribed when first line agents fail but their use as induction therapies is being studied

Table 2Current Disease Modifying Therapies used in MS

First Line Treatments

Dose and frequency

Interferon beta 1b (Avonex)

30 mg once a week

Interferon beta 1aintramuscular (Rebif)

44 micrograms three times a week

Glatiramer acetate (Betaseron)

250 micrograms every other day

Interferon beta 1a subcutaneous (Copaxone)

20 mg daily

Second Line Treatments

 

Natilizumab (Tysabri)

300mg in normal saline, monthly infusions

Novantrone (Mitoxantrone)

12 mg/kg IV every three months to a maximum of 144mg/kg

Cyclophosphamide (Cytoxan)

600- 800 mg/kg monthly x 3-6 months followed by biannual pulses

Symptomatic therapy

A major principle of therapy is symptomatic management.[44, 50] Problems to treat include mood disturbance, spasticity, fatigue, bladder and bowel dysfunction, and pain. If mood related problems are not treated they tend to worsen. Treatment studies of depression in MS support the use of antidepressant therapy and cognitive behavioral therapy.[22]

Spasticity and painful spasms can be managed very well with exercise and physical therapy either with or without medications. Medications which treat spasticity unresponsive to exercise or stretching include baclofen, a GABA agonist, tizanidine, a central alpha-adrenergic agonist, and benzodiazepams such as clonazepam. These agents can be effectiveas monotherapy or in combination.

Pain, such as trigeminal neuralgia, responds best to carbamazepam or other anti-convulsants. Non-neuropathic pain syndromes can be managed with exercise, physical therapy as well as analgesics such as non-steroidal anti-inflammatory agents. Another very frequent problem is fatigue. Fatigue is both intrinsic to MS as well as a consequence of the depression, sleep disturbance, and pain associated with the disease. Management includes steps to conserve energy, exercise and medication. Medications considered effective and well tolerated in children include amantadine, an NMDA receptor antagonist and modafinil.[44] Methyphenidate- HCL has also been used, albeit infrequently.

Other MS related problems include bladder dysfunction where both a hyperactive bladder and hypotonic bladder can be the problem. Oxybutrin and tolterodine are among several medications available to control urgency. Both are available in a slow release formulation.

Ideally the management of children with MS is multidisciplinary. A recreational program for teens with MS is also available through the Teen Adventure Program. This activity helps teens meet others their age in a pleasant non-medical setting.

As progress in the management of MS growsindividuals can expect better and more convenient treatment options.

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