Chapter XVIII.8. Multiple Sclerosis
Nicole M. Baca, MD
Roshan Raja, DO
May 2015

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Lori S. Maruyama. This current second edition chapter is a revision and update of the original author's work.

A 13 year old female, who is otherwise healthy, presents to the clinic with complaints of a one-week history of blurred vision in the right eye with loss of color recognition and pain with eye movement. On examination, she has decreased visual acuity of 20/40 in the right eye, reduced color perception, and an afferent pupillary defect pupil (poor response of the pupil to light stimulation as compared to the other eye during a swinging light test). There is no visible swelling of the optic disk or pallor of the optic nerve on funduscopy. The rest of her physical examination is unremarkable. Upon further questioning, she reports that a few months ago, she had double vision for a few hours.

She is hospitalized for further evaluation. A visual evoked potentials (VEP) test shows increased latencies and reduced amplitudes of wave forms. A lumbar puncture is performed which shows oligoclonal banding proteins in the CSF fluid. A brain MRI shows multiple 3 mm oval lesions with poorly defined margins in the periventricular areas of the white matter.

She is treated with high dose corticosteroids that results in gradual but complete remission of her symptoms. Over the next few years she continued to have neurological symptoms intermittently including ataxia, focal sensory loss, and episodes of optic neuritis. She has responded to corticosteroids with each neurological exacerbation and returns to her baseline.


Multiple sclerosis (MS) is a challenging diagnosis to make in children, especially those who are prepubertal, because of the atypical clinical, biological, and MRI presentations (1). Typically MS is diagnosed in adults between 20 to 40 years old (2). Childhood onset, defined as occurring before 16 years of age, is seen only in 2% to 10% of MS patients (1). MS is present in approximately 0.1% of the U.S. population (most of whom are adults) (3).

Approximately 20% of pediatric MS patients are diagnosed prior to age 10. The female to male ratio is 0.8:1 in children less than 6 years of age. As children age, the female to male ratio changes from 1.6:1 at age 6, to 2.1:1 at age 10, and finally to 3:1 in adolescents (1). There is a greater ethnic diversity in pediatric MS than in adult MS. Studies have shown that pediatric MS is seen more often in those of Caribbean, Asian, or Middle-Eastern ancestry unlike in adults where most patients are of European ancestry. It is likely a combination of genetic and environmental influences, but exact causes are unknown (1).


T-cells play a key role in the pathophysiology of MS. Current models of disease indicate that activated T-cells cross the blood-brain barrier causing inflammatory reactions within the CNS (central nervous system) (1). A study has shown that children with CNS inflammatory demyelination, type 1 diabetes, and other CNS injury had heightened peripheral T-cell responses to a wide variety of self-antigens as compared to their healthy counterparts (1). Myelin oligodendrocyte glycoprotein (MOG) is expressed on the outer myelin membrane and may be one of the targets of antibodies in MS. This study also showed that 38% of patients diagnosed at younger than 10 years of age were found to have MOG antibodies, whereas only 15% of patients diagnosed between 10 and 18 years old had MOG antibodies (1).

Risk Factors for Pediatric MS susceptibility:

There appears to be both environmental and genetic factors playing a role in MS (3). There are higher rates of MS in the northern regions of Europe, Southern Australia, and the middle part of North America (3). There is an increase in the frequency of MS in specific ethnic populations as they migrate into higher prevalence geographies, which suggests that there is an environmental influence (3). Vitamin D has a proposed role in MS. Lower serum 25-hydroxyvitamin D(3) levels are associated with a substantially increased subsequent relapse rate in pediatric-onset multiple sclerosis (4).

As for a genetic factor, the concordance rate among monozygotic twins is approximately six times the rate compared to dizygotic twins (3). The absolute risk for a first degree relative to develop MS is less than 5%; however, the chance to develop MS is about 20 to 40 times greater than the general population (3). There is a higher risk in patients with the HLA-DRB1 allele (1,3). Despite a clear genetic risk, no specific genes have been identified.

Studies have looked for a correlation between viral seropositivity and MS. Pediatric MS patients are three times more likely to be seropositive for Epstein-Barr virus (EBV) compared to the general pediatric population (1). There was no difference in the seropositivity of cytomegalovirus, herpes simplex virus type 1, varicella-zoster virus, or parvovirus B19 (1). There is also evidence that MS patients are more than twice as likely to have been exposed to second-hand cigarette smoke compared to a control group (1). There have been concerns whether the use of vaccinations, specifically the hepatitis B vaccine, contributes to MS. There is conflicting data and it is a source of ongoing investigation (1).

Clinical Presentation:

Pediatric MS patients can present with hemiparesis, paraparesis, unilateral or bilateral optic neuritis, focal sensory loss, ataxia, diplopia, dysarthria, and bowel or bladder dysfunction (5). In younger patients, several studies have shown that encephalopathy or neuromyelitis optica may also occur with the first episode (1). In young children, the presence of encephalopathy may be related to the immature brain and immune system rather than being helpful in differentiating between MS and acute disseminated encephalomyelitis (ADEM) as it is in adults (1). Young children may not be able to articulate some of the symptoms that they are having, such as diplopia, which can make MS more difficult to diagnose.

Diagnosis and Differential Diagnosis:

Like adult MS, pediatric MS patients can be diagnosed following two demyelinating episodes localizing to distinct CNS regions that last more than 24 hours, are separated by greater than 30 days, and no other plausible explanations exists (5). The diagnosis of MS may also be made with one attack who have objective clinical evidence of two or more lesions on MRI (6). Diseases to consider in the differential diagnosis include acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO) (5). There are also other diseases to consider if specific signs or symptoms are present as follows:

. . . Consider a systemic inflammatory disorder if other organ systems are involved, such as joints, kidney, lungs or skin (1).

. . . Consider CNS infections or lymphoma if fever, constitutional symptoms or enhancing lesions (including leptomeningeal enhancement) are present (1).

. . . Consider vasculitis if focal neurologic symptoms with headache are present.

. . . Consider leukodystrophies if there are symmetric changes on MRI and possible peripheral nervous system involvement.

. . . Consider mitochondrial diseases if the course is progressive and fluctuating with myopathy, optic neuropathy or strokes.

Diagnostic Testing:

The CSF analysis in childhood-onset MS can vary by age. Typically the white blood count ranges from 0 to 50 cells per microliter with a lymphocytic predominance (1). There are more neutrophils in the CSF of children younger than 11 years (1). Half or more of the children with MS have oligoclonal bands (OCB) found in the CSF. One study reports that 92% of children with MS had OCB whereas another study found OCBs were less frequent in younger children (43%) than in adolescents (63%) (1). The term "oligoclonal bands" means that there are finite number of distinct clones of proteins being produced indicating that there are a finite number of immunoglobulin producing cell clone lines that are producing the proteins found in the CSF that are associated with MS.

Brain MRI exhibits discrete T2 lesions in the cerebral white matter, especially in the brainstem, cerebellum, juxtacortical, and deep gray matter (5). Children with MS have a higher lesion burden on their initial brain MRI scans than adults. Brain lesions in children less than 11 years old are large, with poorly defined borders and are frequently confluent at disease onset (1). These bright T2 foci may vanish on repeat scans, unlike in teenagers or adults, which suggest that the disease process, including the immune response, may be different in the developing brains of young patients.

Vision testing can be difficult in younger children as they may not be able to express their difficulties with vision. Low-contrast letter acuity charts (Sloan charts) have been proven to be a sensitive and reliable visual acuity test in the pediatric population. Optical coherence tomography, originally used in patients with glaucoma, has been used for pediatric MS patients and is able to provide sensitive evaluation of the retinal nerve fiber layer thickness, which correlates to optic atrophy (1). Demyelination of the afferent visual pathways can be seen in visual evoked potentials (VEP) by abnormal findings including increased latencies and reduced amplitudes of waveforms, and are seen in 65% of patients with optic neuritis (7).

Visual evoked potentials have shown that almost half of all childhood MS patients have increased visual latencies, which reveal a second focus of demyelination before a second clinical attack (1,7).


First line therapy for pediatric MS patients experiencing functional disability includes methylprednisolone. Disease modifying therapies (DMT) have been used in the pediatric population even though they do not all have FDA approval (1,5). Currently there is little data regarding IM DMTs (1,5). The most commonly used DMTs are natalizumab and mitoxantrone. Natalizumab has been used in pediatric MS populations and appears to be well tolerated with fewer clinical relapses (1,5). Natalizumab therapy has been associated with the risk of developing progressive multifocal encephalopathy, which is a CNS infection with human polyomavirus JC; however, there are no documented cases of this occurring in the pediatric population (1,5). Mitoxantrone has been used in some U.S. pediatric centers of excellence; however, there are reported side effects of leukemia and cardiomyopathy with this drug (5). Interferon-beta and glatiramer acetate also appear to be well tolerated in children. Other DMTs include rituximab, cyclophosphamide, fingolimod, and cladribine, but there is less data in pediatric populations with these therapies (1,5).

Clinical Course:

87% to 100% of pediatric MS patients have a relapsing and remitting course, which is higher than in the adult MS population (1). 62% of patients with relapsing-remitting MS (RRMS) will have complete recoveries. Some patients will develop a more insidious progression of disability with or without superimposed exacerbations, which is known as secondary progression, in associated with the RRMS. One study showed that pediatric MS patients had a higher relapse rate during the first few years of their disease than adults; however, their relapses are shorter with more complete recovery than in adults.

The mean estimated time to second progression in pediatric MS patients is 28 years and the median age of conversion to secondary progression is 41 years (2). It takes patients with pediatric-onset MS longer to progress to states of irreversible disability; however, they still do so at a younger age than in patients with adult-onset MS (2).


1. You have a 16 year old female patient who was diagnosed with multiple sclerosis about two years ago. The patient has had several exacerbations of her MS and has had complete remissions with corticosteroids. Her family has come for a follow up appointment and has questions about her long-term prognosis. Which of the following is the most accurate statement about pediatric MS?
. . . . . a. Pediatric MS is not as serious as adult onset MS and she will likely not have permanent neurological deficits.
. . . . . b. She appears to have relapsing-remitting MS. On average pediatric patients reach the irreversible state of the disease, known as secondary progression, at a younger age than patients who are diagnosed as adults.
. . . . . c. Pediatric MS patients do not have bilateral neurological deficits
. . . . . d. Pediatric MS patients have fewer exacerbations during the first few years of their diagnosis as compared to adult patients, but they have less than complete responses to treatment.

2. You are seeing a 4 year old boy for a health maintenance exam. He was recently diagnosed with MS. His parents ask you to explain if it is unusual that a boy of his age has been diagnosed with MS. The most appropriate response is:
. . . . . a. MS is less commonly diagnosed in young children than in adolescents or adults. In patients less than 6 years of age, boys are diagnosed slightly more often than girls.
. . . . . b. MS is most often diagnosed in children less than 10 years of age. It is uncommonly diagnosed in adolescents and adults.
. . . . . c. MS is less commonly diagnosed in children than in adolescents or adults. It is more common in females than in males in all age groups.
. . . . . d. MS is less commonly diagnosed in children than in adolescents or adults. MS is more common in males of all ages.

3. What is first line treatment for pediatric MS patients?
. . . . . a. methylprednisolone
. . . . . b. natalizumab
. . . . . c. mitoxantrone
. . . . . d. cyclophosphamide

4. Which one of the following patients meets the diagnostic criteria for MS?
. . . . . a. A 12 year old female, who has had an episode of blurry vision that lasted less than 24 hours and was associated with a headache.
. . . . . b. A 6 year old male, who has had ataxia for several weeks that is progressively getting worse. A space-occupying lesion was found on head CT.
. . . . . c. A 14 year old female, who had ataxia about eight months ago which completely resolved. Two weeks ago, she was referred to an ophthalmologist, who diagnosed her with bilateral optic neuritis.
. . . . . d. A 1 year old female, who presented to a clinic with ataxia and swelling of her right knee.

5. You are giving a lecture to medical students and explaining the risk factors of developing MS. Which is the most accurate statement?
. . . . . a. Environmental factors play a role in MS. Patients living in northern latitudes have higher rates of MS than those living closer to the equator. As populations move to higher frequency areas, the new immigrants have increased rates of MS.
. . . . . b. There is an increased risk of MS when a family member has MS.
. . . . . c. Pediatric patients who are exposed to second-hand smoke have a higher risk of developing MS as compared to peers who are not exposed to second-hand smoke.
. . . . . d. Pediatric MS patients are more likely to be seropositive for Epstein-Barr virus (EBV) than the general pediatric population.
. . . . . e. All of the above


1. Chitnis T, et al. Pediatric Multiple Sclerosis. Neurological Clinicals 2011;29:481-505.

2. Renoux C, et al. Natural History of Multiple Sclerosis with Childhood Onset. New England Journal of Medicine 2007;356(25):2603-2613.

3. Noseworthy JH, et al. Multiple Sclerosis. New England Journal of Medicine 2000;343:938-952.

4.Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67(5):618-624.

5. Ness J. Chapter 593: Demyelinating Disorders of the CNS. In: Kliegman RM, et al (eds). Nelson Textbook of Pediatrics, 19th Edition. 2011, Philadelphia. pp.2076-2077.

6. Polman CH, Reingold SC, Banwell B, et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Ann Neurol 2011;69(2):292-302.

7. Balcer LJ. Optic Neuritis. New England Journal of Medicine. 2006;354(12):1273-1280.

Answers to questions

1. B. The majority of pediatric patients have RRMS (relapsing-remitting MS). Pediatric patients take longer to progress to secondary progression; however, because they are diagnosed at a younger age they also reach secondary progression at a younger age (on average in their early 40s). Pediatric patients are not immune to permanent neurological damage. MS is a known cause of bilateral neurological deficits. As compared to adult patients, pediatric patients often have more exacerbations in the first few years of the disease; however, they also tend to have better responses to treatment.

2. A. Pediatric MS, defined as being diagnosed prior to age 16 years old, only makes up about 0.4-10.5% of MS patients. Interestingly, in the patients who are less than 6 years old, the female to male ratio is 0.8:1. This is the only age group in which males outnumber females.

3. A. Corticosteroids, such as methylprednisolone, are the first line treatment for pediatric MS. Disease modifying treatments are also used; however, some of them do not have FDA approval in pediatric patients. Natalizumab has been associated with the risk of developing progressive multifocal encephalopathy, which is a CNS infection with human polyomavirus JC; however, there are no documented cases in the pediatric population. Mitoxantrone has been used at some centers; however, there are reported side effects of leukemia and cardiomyopathy. Cyclophosphamide has not been studied well in pediatric MS patients and is not commonly used.

4. C. Pediatric MS patients are diagnosed by having at least two demyelinating episodes localizing to distinct CNS regions that last more than 24 hours, are separated by greater than 30 days, and that no other plausible explanations exist. Patient A had only one episode that lasted less than 24 hours and was associated with a headache. Patient A did not meet the minimum requirements because she has only had one episode and it lasted less than 24 hours. Also, she had a headache during the episode so there may be another plausible cause, such as a vasculitis. Patient B does not meet the criteria because he only had one episode and because he has a space-occupying lesion on head CT, he likely has another explanation for his neurological symptoms. Patient D also only presented with one episode and she has swelling of a joint, which may lead to another cause of her ataxia, such as a systemic inflammatory disorder.

5. E. The risk of developing MS is multifactorial and all of the answer choices are known risks.

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