Helen Yates, Chief Executive of MSRC, commenting on this paper said; "Whilst we are always saddened to hear of MS in the very young, it is very important that the medical profession is becoming increasingly aware that the condition DOES exist in children. MSRC is working to provide as many resources as possible for young people with MS and their families"

Introduction

Multiple sclerosis (MS) in children is being recognized with increasing frequency. The first descriptions of MS in children were published by Charcot between 1829 and 1849, though it was not for another 50 years that MS in children was again described in the literature (Hanefeld, 2007). There are now several national programs focused on the research and clinical management of children with MS. Recently, an International Pediatric Multiple Sclerosis Study group was constituted with the goal of fostering collaborative efforts (for more information, email: info@ipmssg.org).

Demographics and Epidemiology of Pediatric Multiple Sclerosis
How common is MS in children?

Analysis suggests that 2% to 5% of all patients with MS are diagnosed before their 16th birthday (Ness et al., 2007). These estimates, however, are based on retrospective review of established adult MS populations and may underestimate the true prevalence of the disease in the pediatric population. The annual average incidence of a first demyelinating event in Canadian children is 0.9/100,000, but has been reported as lower in other parts of the world (Banwell et al., 2007; Pohl, 2008). The incidence of MS diagnosis following an acute demyelinating event is the subject of ongoing research.

Genetics of MS

Genetic factors clearly influence the risk of developing MS, as MS can "run" in families. The risk of developing MS is approximately 30% if you have an identical twin with MS, 5% if you have a first degree relative (parent or non-twin) with MS, but only 0.1% if no one in the family has MS (Sadovnick, Dircks, & Ebers, 1999). Furthermore, carefully documented family histories reveal that approximately 20% of people with MS will have at least one first degree or distant relative with MS (Sadnovnick, Baird, & Ward, 1988). Family history data obtained from a large international study of MS demonstrated that 6% to 8% have a positive history of MS (Banwell et al., 2007). It is important to remember that the first degree relatives of pediatric patients with MS are still young, and may still be at risk to develop MS in the future.

A female preponderance in MS is well-established in the adult MS population. In children, however, the F:M ratio varies depending on age at first presentation. Males outnumber females when MS onset occurs prior to 10 years of age (F:M ratio, 0.7) (Simone et al., 2002; Ruggieri, Polizzi, Pavone, & Grimaldi, 1999). A female preponderance is pronounced in adolescence-onset MS (F:M ratio, 2.7 - 4.7) (Ghezzi et al., 2002). Hormonal contributions to pediatric MS risk in females after puberty require further study.

Immunological Studies

In order for the immune system to "attack", it must first recognize the "target." Scientists are very interested in learning what is initially targeted in MS. Complicating this search, however, is the fact that once the immune system is active, it will not only attack the initial target, but over time will also attack the injured tissue in the brain/spinal cord as well.

We found that children with MS harbor T-cell populations that proliferate when exposed to myelin proteins (Banwell et al., 2008). These T-cell findings may reflect the injured tissue response, rather than a primary immune aspect of MS and they represent one of several abnormalities in immune cell regulation in MS (Bar-Or, 2008).

Environmental Triggers

Infectious Triggers

Children with MS have been shown to have a significantly increased likelihood, relative to healthy age-matched peers, of being previously infected with Epstein-Barr virus (EBV) (Alotaibi et al., 2004). EBV infection leads to persistent B-cell infection, and B-cells are known to play a role in MS. Study of children enrolled from geographical regions has confirmed that the association of EBV with MS, suggesting that the association of EBV with MS is common among multiple world regions (Banwell, Krupp et al., 2007). Immunological studies specifically exploring T- and B-cell behavior in EBV-positive MS patients, may provide insights into how EBV infection influences the immune system in people with MS (Ascherio et al., 2007).

Sunlight Exposure, Vitamin D, and MS

The increased prevalence of MS in temperate regions has prompted consideration of the role of vitamin D and sunlight exposure as potential non-infectious environmental risk factors for MS. Exposure to sunlight is the primary source of vitamin D, and as such, in the winter months very little, if any, cutaneous vitamin D synthesis occurs. Individuals with MS have been shown to have lower vitamin D levels as compared to age-matched healthy controls (Nieves et al., 1994), although this finding is confounded by the potential limit in outdoor activity of patients with MS. An inverse relationship has also been demonstrated between serum concentrations of 25-hydroxyvitamin D obtained from young adults entering the military and their risk of MS diagnosis in mid-adulthood (Munger et al., 2006). The potential role for vitamin D supplementation in the primary prevention, or amelioration, of MS is an exciting area of ongoing research.

Clinical Features of Acute Demyelination in Children

The First Attack

MS in both children and adults is characterized by multiple episodes of neurological dysfunction secondary to inflammatory demyelination of the central nervous system (CNS). Just as in adults, however, not all children who experience an initial acute demyelinating syndrome (ADS) will develop MS. The term "clinically isolated syndrome or CIS" has also been applied to persons experiencing a first demyelinating event, although many authors restrict the term CIS to patients with an initial demyelinating event at high risk for future diagnosis of MS. As such, the term "CIS" is not universally applied across the entire spectrum of ADS events, particularly those considered to have a low risk of relapses.

An ADS is classified as "monofocal" if the clinical features were referable to a single CNS lesion, such as optic neuritis, transverse myelitis, or brainstem, cerebellar, or hemispheric dysfunction; and as polyfocal if the clinical features are localized to more than one CNS location. This is based on the physician's clinical examination, rather than MRI findings (which could show asymptomatic lesions). "Polyfocal" features refer to more than one CNS lesion and when accompanied by problems with thinking, is termed, acute disseminated encephalomyelitis (ADEM) (Krupp, Banwell, & Tenembaum, 2007).

Specific ADS presentations include:

Transverse Myelitis: Transverse myelitis (TM), or attack of the immune cells on the spinal cord, leads to loss of strength and sensation of the limbs and difficulty with bowel and bladder control. TM was the presenting feature of MS in only 14% of children enrolled in a multinational pediatric MS Study (Banwell, Teller et al., 2005).

Optic Neuritis: Optic neuritis (ON), an attack of the immune system on the optic nerve from the eye, results in reduced vision, pain with eye movements, and difficulty seeing color. It has been thought that bilateral ON is more common in children and unilateral ON more common in adults. This may simply reflect, however, that young children may not notice or report loss of vision in one eye. In one study of childhood ON, in which some patients were followed for 40 years, 26% were ultimately diagnosed with MS (Lucchinetti et al. 1997). In a review of ON at SickKids (www.sickkidsfoundation.com), bilateral ON was more common than monocular ON, and was associated with a greater likelihood of MS diagnosis (Wilejto et al., 2006). Of the 36 children enrolled, 13 (36%) were diagnosed with MS within the two years of ON, an outcome that was highly correlated with MRI evidence of white matter lesions in the brain.

Acute Disseminated Encephalomyelitis (ADEM): For a diagnosis of ADEM, there must be a multiple neurological symptoms plus trouble thinking (encephalopathy). The demyelinating event in some children may be accompanied by fever, drowsiness or even coma, and neck stiffness.

What happens to children with ADS:

In a review of 296 children with acquired demyelination in France, 57% were diagnosed with MS, while the remaining 43% appeared to have a monophasic illness (Mikaeloff, Suissa et al., 2004). The children in this study were followed for a mean of 2.9 years (range 0.5- 14.9 years). Since patients can develop their second MS-defining attack years after their first attack, it is possible that the percentage of children in the French study ultimately diagnosed with MS will increase as the duration of follow-up lengthens.

Recurrent Attacks: Diagnosis of MS

Pediatric MS requires multiple episodes of CNS demyelination separated in time (by four weeks or more) and space (involving new areas of the CNS) just as is specified for adults. MRI evidence of new lesions in new CNS locations can be used to meet the requirement for disease dissemination in time (Polman et al., 2005).

Approximately 95% of pediatric patients with MS have recurrent attacks followed by periods of clinical recovery or stability (Banwell, Ghezzi et al., 2007; Boiko et al., 2002). This form of MS is known as relapsing-remitting MS (RRMS). Over time, children with RRMS may enter a phase of the disease in which they show increasing physical disability even in the absence of attacks (secondary progressive MS, SPMS). Primary progressive MS (PPMS), in which neurological disability worsens over time in the absence of clear attacks, appears to be exceptionally rare in children. Figure 1 illustrates the typical MRI features of MS in children.

How do children with MS do?

The time from the initial acute attack to the second, MS-defining event is highly variable. Younger children tend to have a longer interval from first to second attack (median 6 years), in contrast to most adolescent patients with MS who typically have their second attack within 12 months. The annual relapse rate reported in retrospective studies with long observation periods range from 0.38 per year to 1.0 per year (Simone et al., 2002).

In a multinational study of 137 children with MS, 13% of children with MS showed fixed neurological deficits that limited their ambulation (EDSS >4.0) after a mean disease duration of 5 years. Mikaeloff and colleagues, (Mikaeloff et al., 2006) documented EDSS scores of 4 or higher in 15% of children with MS enrolled in the French KIDSEP study after a median observation of 4.8 years (from second demyelinating event).

While physical disability may occur relatively infrequently in the first decade in pediatric-onset MS, cognitive impairment may be a significant clinical concern (Banwell & Anderson, 2005). Formal neurocognitive assessments are required to fairly appreciate the breadth of cognitive impairments, as review of academic performance, however, many underestimate the deleterious effects of MS on cognitive capacity and academic potential. Cognitive impairments in attention and memory have been reported in approximately 60% of adults with MS (Rao, 1986), and emerging evidence suggests that impaired cognitive performance occurs in at least 30% to 40% of pediatric patients with MS. Deficits are most notable in attention, working memory, information processing, speed, and understanding of more complex sequential tasks.

MS Disease Course

In a study reviewing the disease course of 116 patients with MS onset under age 16 years, 53% of the 116 patients ultimately progressed to SPMS at 23 years post-MS diagnosis. In comparison to studies in adult MS, pediatric-onset MS patients progress more slowly and take a longer period of time to develop disability (Boiko et al., 2002). It is important to consider, however, that a 10 year-old child with MS will only be about 30 to 40 years of age when he/she is at risk for SPMS-and thus, actually younger than the typical age of onset of disability in adult-onset patients with MS. Children with more disability early in the disease are at greater risk of severe disability over time.

Symptoms of MS in Children

Many symptoms may accompany an MS relapse, which by definition, lasts at least 24 hours.

Sensory symptoms: The most common sensory symptoms are numbness and paresthesias (tingling) in one or more limbs. The sensory symptoms can be due to a myelopathy, which can produce a spinal sensory level. Sensory deficits that arise from lesions in the sensory cortex or the supraspinal pathways lead to numbness. Patients may also have radicular symptoms due to a lesion at the dorsal root entry zone of the spinal cord or the brainstem, although this is very rare. Patients with sensory deficits involving the dorsal column pathways subserving vibration and propioception, can experience a "useless hand syndrome" in which motor movement is preserved, but the ability to manipulate the arm in space is impaired (El-Moslimany & Lublin, 2008).

Motor symptoms: Weakness can occur in any extremity, singly or in combination. The most dramatic of the acute motor syndromes is an acute transverse myelitis. In most children with MS, TM manifests as a partial cord syndrome. Longitudinally extensive lesions that traverse the cross-sectional diameter of the cord are more typical of isolated TM or NMO (Pidcock et al., 2007).

Spasticity: Spasticity or stiffness of the limbs during attempted limb movement occurs in patients following severe relapses associated with residual damage to motor pathways, and occurs as a core component of the progressive disability seen in the secondary progressive phase of MS. As such, it is relatively rare as a major symptom in children with RRMS. When present, spasticity is disabling, causes disruption of sleep, and contributes to pain.

Bladder and sexual function: Lesions of the distal spinal cord can impair both bladder and sexual function. While such deficits are rarely reported in children and adolescents with MS, recognition of these issues is critical. Impaired bladder emptying can lead to retention of urine, infection, and potential life-threatening sepsis. Impaired sexual function is a socially and psychologically devastating issue for sexually-active adolescents--and an issue that few are comfortable discussing unless a strong rapport and level of trust have been established between the pediatric MS care provider and the patient. Clinical interviews with parents out of the room are essential for these discussions.

Bladder impairment most commonly results from overactivity of the detrusor muscle of the bladder. This produces the sensation or urgency despite low bladder volume. Urge incontinence occurs if high intravesical pressure results in the loss of some urine.

Detrusor-sphincter dyssynergia is characterized by contraction of the internal urethral sphincter during an involuntary detrusor contraction. This is due to the loss of synchronization between the detrusor and internal urethral sphincter leading to incomplete bladder emptying and hesitancy (El-Moslimany et al., 2008).

Fatigue: Fatigue or a "sense of physical tiredness and lack of energy, distinct from sadness or weakness," is reported by approximately 40% of children and adolescents with MS. (Banwell, Ghezzi et al., 2007). Fatigue of sufficient severity to compromise participation normal activities, such as sports, social events, or completion of academic tasks is considered worthy of treatment.

Dysarthria: Children with MS can have different forms of dysarthria or impaired speech production. Dysarthria of the cerebellar type results in scanning speech which is characterized as monotonous speech interspersed with explosive consonants, resulting in irregular volume and indistinct articulation tremor of the voice. As cerebellar involvement occurs relatively commonly in pediatric-onset MS, speech impairment is also a notable feature of some children. Pseudobulbar dysarthria is caused by spastic vocal cords, which causes a high-pitched low-volume speech with slurred consonants- this is rarely seen in children. The precise frequency and severity of speech disorders in pediatric MS have not been described.

Tremors and other movement disorders: Tremors in MS are usually most notable when the child is reaching for an object or attempting to perform purposeful movements of the upper limbs. Tremor in MS is associated with greater impairment and functional disability due to impairments in hand-writing, self-care, and fine motor tasks. Transient tremor is a common feature of corticosteroid therapy, and patients and parents should be made aware of this in order to avoid concern over what they may perceive to be a new neurological deficit.

Pain: A significant number of adults with MS, and a lesser proportion of pediatric patients with MS, experience pain, which may be due to many factors. Patients can have musculoskeletal pain due to weakness, spasticity, imbalance, osteoporosis, compression fractures or osteoarthritis. All these processes are due to the disease or to immobility secondary to MS. Pain, and particularly back pain, reported by any child that has been exposed to prolonged or repeated corticosteroid therapy should prompt a careful evaluation for pathological fractures of the spine, ribs, or long bones associated with osteopenia.

Burning pain or " dysesthetic pain" is reported in some patients with MS. While the cause of this type of pain is not entirely clear, the mechanism could be spontaneous activity in the deafferented neurons, ephaptic transmission, or sympathetic activation (El-Moslimany & Lublin, 2008). Transmission of abnormal electrical discharges laterally across a demyelinated plaque might produce painful symptoms.

L'Hermitte's phenomeno: This is a specific sensory symptom seen in patients with spinal cord lesions. It is defined as a sensation of electric shock in the back and legs of patients brought on by neck flexion. The symptom usually remits quickly, but also can persist. Younger children describe this as "an elastic band feeling" or a "cell phone going off my spine." The presence of L'Hermitte's symptom should prompt imaging of the spinal cord.

Depression: Mood disturbances are a common feature of MS, and depression is a significant health issue that warrants recognition in pediatric patients with MS. Reactive depression, initiated often by diagnosis or by a severe relapse, is not surprising in children and adolescents facing an uncertain future with an unpredictable illness. Counseling sessions with a mental health care professional may be sufficient to address the issue.

Paroxysmal symptoms: While an attack has been defined as a period of neurological dysfunction lasting for 24 hours, patients with MS can have brief episodes of numbness, tingling, visual loss, sensory, speech or balance problems , occur frequently (from 1-2 times per day to hundreds of times a day).

Seizures: Seizures occur in about 5% of children with MS (Boiko et al., 2002). Seizures and headache are particularly prominent features in children with tumefactive demyelination, a demyelinating phenotype characterized by one or more large areas of demyelination, perilesional edema with mass effect, and often ring-enhancement (McAdam, Blaser, & Banwell, 2002).

MRI Findings in MS

Magnetic resonance imaging (MRI) is a useful tool for supporting the diagnosis of MS in adults and children. The MRI appearance of pediatric MS, however, is not entirely similar to that of adult-onset MS, particularly in younger children. The increasing recognition and treatment with MS underscores the urgent need for pediatric-specific MRI diagnostic criteria. Mikaeloff and colleagues have demonstrated that the sole presence of well-defined lesions, as well as lesions perpendicular to the corpus callosum are highly specific for MS in children, although these criteria are only met by approximately 30% of pediatric MS patients (Mikaeloff et al., 2004). Using standardized scoring methods, Callen and colleagues have proposed pediatric-specific modifications to the currently accepted MRI criteria that are more sensitive and specific for the diagnosis of MS in children. (Callen et al, Neurology in press) These criteria required two of the following: (1) 5 or more lesions; (2) 2 or more periventricular lesions; and (3) 1 brainstem lesion. The validity of these proposed criteria predictive of MS outcome in children experiencing an initial demyelinating attack is currently being evaluated.

Figure 2 depicts the varied appearance of MS in children, including the diffuse, ill-defined lesion appearance that may be seen early in the MS disease course of very young children. In children with ADEM, despite a rather dramatic MRI appearance, MRI resolution of initial lesions typically occurs. The capacity for lesion resolution suggests either that the neuroimaging features represent a greater contribution of swelling (edema) rather than demyelination or tissue injury, or that children have an enhanced capacity for rapid lesion repair. More advanced imaging techniques, such as magnetization transfer imaging, are required to explore this possibility. Longitudinal MRI studies are required to evaluate the rate of lesion accrual, and the progression of brain shrinkage or atrophy, and to determine whether these measures correlate with physical and cognitive outcomes of MS in children.

Laboratory Studies

More than 90% of children with MS will have oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) - obtained by performing a lumbar puncture or spinal tap- provided that sensitive techniques such as isoelectric focusing are used (Pohl et al., 2007). Although OCBs may be present transiently in children with monophasic ADEM, CNS lupus, and in patients with primary CNS infections, the presence of OCBs is strongly supportive of MS. Electrical tests called evoked potential testing can confirm the involvement of or detect clinically silent problems in the visual system, the auditory system, or in the sensory system.

Differential Diagnosis of Pediatric MS

The diagnosis of MS requires that other possible diagnoses be excluded. Acute infections of the brain (i.e., viral, lyme, West Nile virus), deficiency of vitamin B12, inflammation of the brain with other autoimmune diseases (i.e., systemic lupus erythematosus, vasculitis, sarcoidosis), acute stroke or trauma, tumors, and metabolic diseases (i.e., mitochondrial or leukodystrophies) must be considered.

Treatment of Pediatric MS

The care of children with MS is optimized by a multidisciplinary team comprised of pediatric or adult neurologists with expertise in pediatric MS, nurses, physiotherapists, occupational therapists, social workers, psychologists, and psychiatrists. Compliance with medication, especially among adolescent patients, rests on a strong relationship between medical teams, patients, and parents.

Treatment of pediatric MS can be divided into: (1) treatment of acute attacks; (2) treatments to reduce the number of attacks and attack severity; (3) treatment of intermittent or persistent MS symptoms. Most care models for pediatric MS are based on protocols optimized in adults. Randomized control trials in pediatric MS are challenged by the relative rarity of MS in children, and by the fact that pivotal studies of MS therapies are restricted to patients over age 18 years of age.

Acute MS Relapses

Corticosteroids. These agents are very effective at reducing the inflammation (swelling, brain irritation) associated with acute MS attack, and are associated with a more rapid recovery from an acute MS relapse. While it remains to be proven that therapy for acute relapses alters the long-term course of MS, hastening of recovery from an attack leads to reduced school absenteeism and enhanced quality of life. Acute MS attacks in our pediatric MS population are managed with intravenous methylprednisolone (Solumedrol) 20 to 30 mg/kg/day (maximum of 1 gram) as a single dose for 3 to 5 days. Children with complete resolution of symptoms receive no further corticosteroids. Children with incomplete clinical recovery following the intravenous treatment are prescribed oral prednisone tablets starting at 1 mg/kg/day, followed by a tapering schedule with reduction by 5 mg every 2 to 3 days.

The most frequent side effects of high dose glucocorticoids are facial flushing, sleep difficulties, irritability, mild tremor, and increased appetite. In children, growth retardation is an additional concern, and is related to the cumulative dose. Every effort should be made to keep the total duration of corticosteroid exposure to a minimum. In our program, the total duration of tapering dosing is restricted to 21 days. Hypertension and hyperglycemia are rare, but important corticosteroid related toxicities, and thus all patients should be monitored closely with regular evaluation of blood pressure, glucose, and electrolytes. Many patients experience gastrointestinal irritation during corticosteroid therapy, and administration of gastric protection is suggested.

Intravenous Immunoglobulins. Some children do not experience sufficient clinical recovery with corticosteroids (steroid-resistant) or develop recurrent symptoms during the prednisone taper (steroid-dependent). Treatment with intravenous immunoglobulin (IVIg) can be helpful in these patients. Case-report level evidence supports efficacy for IVIg (in a dose of 2 gms/kg over 2-5 days) in children with acute demyelinating attacks (Nishikawa et al., 1999).

Plasma Exchange. Level 1 evidence exists for plasma exchange to treat severe relapses in adult patients with MS when they fail to recover after treatment with high-dose glucocorticoids (Keegan et al., 2002). Five exchanges over 8 to 10 days is generally recommended.

Treatment to Reduce Number of Attacks

Immunomodulatory therapy. Both glatiramer acetate (GA) and interferon beta (IFNB) are immunomodulators, and decrease the relapse rate and MRI accrual of new lesions in adults with MS (IFNB Multiple Sclerosis Study Group 1993; Jacobs et al., 1996; PRISMS 2000; Comi, Filippi, & Wolinsky, 2001). Overall, these medications reduce the frequency of clinical relapse by 29% to 34%.

Interferon beta - 1b (Betaseron/Betaferon®). A retrospective review of safety and tolerability in a cohort of 43 children and adolescents with MS was reported by an international working group (Banwell et al., 2006). Given the variable size and weight of children, many pediatric MS specialists initiate therapy at one quarter of the adult dose, and increase monthly by quarter dose increments provided that tolerability is acceptable. In particular, it is critical to observe liver function, as some younger patients may demonstrate elevation in liver transaminases. Typically, the elevation in transaminases resolves if the interferon dose is reduced, and the escalation phase is performed over a longer period of months. Most common adverse effects (AE) included flu-like symptoms (35%), abnormal liver function test (LFT) (26%), and injection site reactions (21%) (Pohl et al., 2007).

Interferon beta - 1a IM (Avonex®). Data on the tolerability of weekly IM IFNB - 1a for treatment of RRMS in 9 children younger than 16 years of age was reported in a retrospective study (Pohl et al., 2007). Adverse effects included flu-like symptoms (44%), headaches (44%), fever (22%), and injection site soreness (11%). A reduction of annualized relapse rate from 3.1 (pre-treatment) to 0.3 and stable EDSS were reported. However, in the absence of a randomized double-blind control design, efficacy data must be considered with caution.

Interferon beta - 1a (Rebif®). In a cohort of 46 patients with pediatric MS, 22 µg SC of IFNB - 1a treatment was initiated three times weekly (Pohl et al., 2005). In five additional patients with very active disease, treatment was started at 44 µg three times weekly. Side effects were similar to those described for adult patients: injection site reaction (71%); flu-like symptoms (65%); gastrointestinal symptoms (10%); and blood count (39%) and liver function abnormalities (35%).

Glatiramer acetate (Copaxone®). Glatiramer acetate appeared to be safe and well-tolerated in seven children with RRMS at the daily dose of 20 mg daily administered SQ for 24 months (Kornek et al., 2003). Reported adverse reactions included injection site pain or induration and a short lived whole body reactions such as facial flushing and fast heart rate. After a mean treatment duration of 14.7 months, there was a reduced relapse rate from a baseline of 2.5 to 0.1 on drug and stable EDSS were reported. Again, efficacy cannot truly be evaluated in retrospective reviews of small groups of children.

Immunosuppressive therapy. Oral azathioprine has been used in MS to prevent exacerbations by some clinicians, although little has been reported regarding safety or efficacy. Azathioprine is not used commonly in adults with MS, as efficacy is considered limited. Side effects include cytopenia, gastrointestinal intolerance, liver toxicity, and skin rashes. The cost of azathioprine makes it an attractive therapy for patients or countries unable to afford the high cost of the immunomodulatory therapies. Efficacy, however, requires evaluation. Close monitoring of the complete blood count (CBC) and LFTs is recommended.

Disease-modifying Therapy

Initiation. The International Pediatric MS Study Group agreed that immunomodulatory treatment should be started in children and adolescents with active relapsing-remitting disease (defined clinically or by MRI scans) after MS diagnosis. In patients with a recent clinical exacerbation, any MRI change or enhancement on a follow-up brain MRI 3 to 6 months after the exacerbation would suggest disease activity.

Choice of medication. Treatment selection should occur after discussions with the child and parents focused on issues related to compliance, efficacy, and tolerability. The initial IFNB therapy is often initiated at 25% to 50% of the recommended full dose for adults with MS, followed by a stepwise escalation every 2 to 4 weeks up to full or highest tolerated dose. Use of acetaminophen or ibuprofen at the time of injections and, if necessary, 4 to 6 hours thereafter will lessen frequency and severity of flu-like symptoms during the first months of therapy. Glatiramer acetate regimen in children and adolescents is similar to adult regimen. No dose escalation is necessary.

Interferon therapy requires laboratory monitoring, monthly for six months and then three-to six-monthly thereafter.

One approach to evaluate treatment efficacy in an individual patient is to perform neurological examinations at treatment initiation and at 1, 3, and 6 months, and every 6 months thereafter. A repeat brain MRI scan with gadolinium should be obtained around the time of treatment initiation, and again after a period of therapy (typically at 6 or 12 months). These suggestions are based on the clinical model followed in our pediatric MS clinic - formal protocols have not been evaluated.

Change of DMT should be considered in the presence of severe side effects, poor compliance, or in patients who appear to be poor responders. Again, while a standardized definition of treatment failure has yet to be adopted, most clinicians consider a patient to be failing a specific therapy if the child experiences more than two relapses in 12 months, or it the MRI demonstrates accrual of numerous lesions.

Symptomatic Therapy

Spasticity. The goal of spasticity treatment is to improve mobility, reduce pain, and control painful muscle spasms. In severely affected patients, care involves positioning in order to prevent contractures and pressure sores. The treatments offered to reduce spasticity in children with MS are very similar to methods used in children with severe spastic cerebral palsy. Initial management utilizes daily stretching and physical therapy, with particular focus on range-of-motion exercises. If these are insufficient, baclofen, a GABA agonist, is the drug of choice for monotherapy. Tizanadine, a central alpha-adrenergic agonist, can be considered as monotherapy for patients who do not tolerate baclofen. Selective botolinum toxin type A injections can be considered if the above-mentioned therapies are not effective. It has successfully relieved severe leg adductor spasticity in some patients.

Fatigue. Many patients with MS complain of fatigue that is sufficiently severe to interfere with school performance or social activities. Amantidine is an NMDA receptor antagonist with antiviral, neuroprotective, and anti-parkinsonian effects. If amantidine is not effective, modafinil, should be considered. Modafinil (Provigil®) has been shown to be efficacious in adults with MS.

Tremor and ataxia. Occupational therapy and physical therapy can be helpful in providing adaptive equipment for safe walking and other daily activities. Clonazepam (Rivotril®) is one of the most effective treatments for MS intention tremor. Primidone can also be considered.

Urologic and bowel disorders. A urinary tract infection should be excluded in all patients with bladder dysfunction and treated accordingly with appropriate antibiotics. Detrusor-sphincter dyssynergia responds to combination of anticholinergic agents with intermittent straight catheterization. Formal urological assessment is highly recommended.

Coping With the Diagnosis of MS

The diagnosis of a chronic illness such as MS leads to significant impact not only on the child, but on the entire family. Some children/teenagers will require psychiatric support, and we recommend that all children/teenagers be offered a psychiatry or social work referral. Many pediatric MS patients adopt an "invincible" attitude, a common coping mechanism for this age (Boyd et al., 2005). Psychiatric support for these patients may be delayed until such time as they are willing to participate in these discussions. Parents of pediatric MS patients, on the other hand, typically seek support immediately. The Canadian and US National MS Societies provide several resources for children with MS and their families, including a parent handbook.

Conclusion

Although recognition of pediatric MS is increasing, there remains a great deal to learn. Optimal care paradigms remain to be decided, and collaborative efforts are required to meaningfully develop such care plans. Research initiatives are also critical as understanding gained through the exploration of MS in the youngest patients may unveil clues involved in the beginning of the MS disease process.

Jean Marie B. Ahorro, MD-The Hospital for Sick Children, Toronto, Ontario Canada; Brenda L. Banwell, MD-Director, Pediatric Multiple Sclerosis Clinic The Hospital for Sick Children, Toronto, Ontario Canada

MSRC