Day: April 4, 2016

What Genetics are Associated with Multiple Sclerosis?

Patient Presentation
A 5-year-old female came to clinic for her health supervision visit. She was well and her mother had no concerns. During the interview the mother offered that she had been diagnosed with multiple sclerosis after having some fatigue and numbness with problems walking and some visual changes. She was taking medication and was in remission. The family history was positive for thyroid disease, diabetes, and stroke. There were no other neurological problems.

The pertinent physical exam showed a healthy female with normal vital signs and growth parameters around the 15-25%. Her examination, including her neurological examination, was normal. The diagnosis of a healthy 5 year old was made. The mother remarked that she was doing well but did worry about her daughter getting multiple sclerosis. “They don’t know what causes it but they do know somethings like it can be genetic, so we’re just going to have to keep monitoring her as she grows,” her mother said.

Discussion
Multiple sclerosis (MS) is “a chronic degenerative, often episodic disease of the central nervous system marked by patchy destruction of the myelin that surrounds and insulates nerve fibers, usually appearing in young adulthood and manifested by one or more mild to severe neural and muscular impairments, as spastic weakness in one or more limbs, local sensory losses, bladder dysfunction, or visual disturbances.”

It is a chronic disease and therefore symptoms must occur more than once. The first episode is called an acute demyelinating attack. Fifteen to forty-five percent of children with their first attack will go on to have others and therefore later be diagnosed with MS. Because pediatric patients have high relapse rates, diagnosis often is within a year of the initial clinical event. Historically the diagnosis required multiple attacks or evidence of new MRI lesions in different parts of the CNS. The 2010 revised MacDonald criteria can be used to diagnose MS with the first attack if specific criteria are met. The keys to the diagnosis of MS are that there needs to be evidence of inflammatory disease that is occurring in multiple CNS brain regions and overtime is disseminated.

“About 2-10% of patients with multiple sclerosis (MS) will have their first symptom before the age of 18 years. The majority of children presenting with the acute demyelination of the central nervous system manifest with acute visual loss (optic neuritis), limb weakness and bladder impairment (transverse myelitis), brainstem symptoms, or with a syndrome characterized by polyfocal deficits associated with encephalopathy (acute disseminated encephalomyelitis[ADEM]).” Children may have a difficult time describing their symptoms including sensory or visual changes and so it can be hard to diagnosis the initial event.

MS and ADEM are not the same but have some overlapping characteristics. “[MS] is a chronic inflammatory disease of the central nervous system (CNS) characterized by immune-mediated myelin loss with variable degrees of axonal injury. It is characterized by recurrent attacks of neurological dysfunction. Acute disseminated encephalitis (ADEM) is typically known as a monophasic inflammatory demyelinating disorder of the CNS usually following a viral infection. Complete recovery from ADEM is reported at 57 to 89%.”

Pediatric patients with MS tend to have cognitive deficits at the time of diagnosis which worsens over time. They tend not to have as many physical disabilities at onset, and actually have physical disabilities that are delayed about 20 years. However, the onset of physical disabilities is ~10 years before patients who are adults at onset. Pediatric patients also have high lesion volumes and high relapse rates.

There are several options for treatment of MS. For acute attacks, some children are just monitored closely. Others may receive intravenous steroid therapy and for those that have severe impairment, plasma exchange is considered. First line therapy is usually with interferon beta or glatiramer acetate. Unfortunately both are injectable and many children will not tolerate them. If patients do not respond or do not tolerate them, natalizumab or cyclophosphamide are considered. Teriflunomide and fingolimod are oral medications that are currently in clinical trials which include pediatric patients.

For healthy children of parents who have MS, a systemic review found conflicting data but several studies showed the children exhibited negative psychosocial traits when compared to children living with healthy parents. They also found that adolescents often necessarily had increased family responsibilities which were linked to higher stress and poorer social relationships. However these children and adolescents also had higher personal competence.

Learning Point
The cause of MS is unknown but certain genetic factors appear to be related although familial aggregation is not strong. Children with at least 1 HLA-DRB15 allele (one of the major histocompatability genes) have an increased risk of being diagnosed with MS. Some single nucleotide polymorphisms (SNPs) have also been associated. Vitamin D deficiency and exposure to different viruses also have been implicated. Epstein Barr virus serology from previous remote infection is found in 85-88% of pediatric MS patients. Cytomegalovirus exposure has a negative predictive association. Herpes simplex virus exposure does not increase risk, but in patients who are the HLA-DRB15 allele positive the risk increases.

Questions for Further Discussion
1. What are criteria for an acute demyelinating attack?
2. What are indications for brain imaging using computed tomography vs magnetic resonance imaging or positron emission tomography?
3. What are indications for consultation with a neurologist?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Multiple Sclerosis and Neuromuscular Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Alper G, Heyman R, Wang L. Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features. Developmental medicine and child neurology. 2009;51(6):480-486. doi:10.1111/j.1469-8749.2008.03136.x.


Kornek B. Treatment of pediatric multiple sclerosis. Neuropediatrics. 2013 Dec;44(6):309-13.

Razaz N, Nourian R, Marrie RA, Boyce WT, Tremlett H. Children and adolescents adjustment to parental multiple sclerosis: a systematic review. BMC Neurol. 2014 May 19;14:107.

Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014 Sep;13(9):936-48.

Online Mendelian Inheritance in Man. #142860 Major Histocompatibility Complex Class II, DR Alpha; HLA-DRA. Available from the Internet at http://omim.org/entry/142860 (rev. 12/11/14, cited 1/12/16).

Online Mendelian Inheritance in Man. #126200 Multiple Sclerosis, Susceptibility to; MS. Available from the Internet at http://omim.org/entry/126200 (rev. 11/18/14, cited 1/12/16).
Narula S, Banwell B. Treatment of multiple sclerosis in children and its challenges. Presse Med. 2015 Apr;44(4 Pt 2):e153-8.

Dictionary.com.
Available from the Internet at http://dictionary.reference.com/browse/multiple-sclerosis?s=t (cited 1/12/16).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital