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

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, experien

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