Published in UAB Insight, Summer 2007

Comprehensive Care Center At UAB

Mimickers of
Demyelinating Diseases

Lymphoma, medulloblastoma, or other malignancies of the brain or spinal cord. Inflammatory disorders: systemic lupus erythematosus, vasculitis, sarcoidosis, Behçet’s disease, antiphospholipid syndrome. Leukodystrophies: metachromatic leukodystrophy, Alexander’s disease, childhood ataxia with cerebral hypomyelination. Genetic and metabolic disorders: aminoaciduria, Fabry’s disorder, mitochondrial diseases. Nutritional deficiencies, such as vitamin B12 or folate deficiency. Migraine Stroke and vascular disorders including moyamoya syndrome, arterial venous malformation, carotid dissection. Infections: herpes virus infections or other viral infections, Lyme disease, HIV, human T-lymphotropic virus type 1 or 2, progressive multifocal encephalopathy.

Acute onset demyelination of the central nervous system (CNS) is rare in childhood, and diagnosis and management of such diseases can be difficult. The spectrum ranges from monophasic focal diseases (optic neuritis and transverse myelitis) to diffuse involvement (acute disseminated encephalomyelitis [ADEM]). Recurrent demyelination poses a greater challenge as it may represent a recurrence of ADEM or multiple sclerosis (MS). Lack of validated diagnostic criteria in the pediatric population and the possibility of significant clinical and magnetic resonance imaging (MRI) findings that overlap with other childhood-onset diseases further complicate the diagnosis of demyelinating diseases. “It is important that clinicians recognize the symptoms of a demyelinating disease in their pediatric patients, consider the possibility of MS, and refer patients to specialists to determine the correct diagnosis,” says Jayne M. Ness, MD, PhD, assistant professor of pediatric neurology and director of the UAB Center for Pediatric Onset Demyelinating Disease (CPODD).

Is It MS?
“It is imperative to distinguish between pediatric MS and other childhood CNS inflammatory demyelinating disorders such as ADEM,” Ness says. Several recent studies have found that early initiation of disease modifying therapies improves the underlying disease course in adults (J Neurol. 2004;251:1329-1339) and (Ann Neurol. 2007;61:300-306). “Starting these treatments early may benefit children as well,” Ness says. “Neurocognitive deficits are common in pediatric MS and can impair both academic and psychosocial function at a critical juncture in a young person’s life.” At CPODD a pediatric neurologist and an adult MS specialist evaluate each child’s symptoms, MRI findings, and laboratory and spinal fluid results to differentiate among several demyelinating diseases that can mimic each other.

An initial episode of CNS demyelinating symptoms is characterized by the location of demyelination and whether or not behavioral changes are present. Clinically isolated syndromes (CIS) occur in the absence of encephalopathy and may involve demyelination of the brain, optic nerves, spinal cord, or, less commonly, isolated large lesions. “Among patients at our center, more than 50% of those presenting with CIS have developed MS,” Ness says, “and the risk is increased further if discrete T2 or gadolinium-enhancing lesions are present on brain MRI.”

In contrast, ADEM is a monophasic inflammatory demyelinating event with multifocal neurological deficits associated with persistent behavioral changes (altered consciousness, lethargy, and irritability) and fever. MRI studies in ADEM usually demonstrate large lesions involving both gray and white matter. ADEM often occurs in postinfectious, parainfectious, or postvaccinal settings and usually follows a monophasic course. However, the first episode may be followed by one or more attacks involving the CNS that may represent either recurrent ADEM or development of MS. “Recurrent demyelination in children does not necessarily indicate MS. It can be difficult to differentiate,” Ness says. “About 10% of ADEM cases at our center progress to MS. While early diagnosis of pediatric MS may optimize treatment, we must avoid overdiagnosing and starting unnecessary medications.”

According to the National Multiple Sclerosis Society, an estimated 2% to 5% of MS patients experience their first symptoms before age 18 years. This translates into 8000 to 10,000 children in the United States with MS and another 10,000 to 15,000 with symptoms suggestive of ADEM or MS. Clinical features that suggest demyelination of the brain, spinal cord, or optic nerves include numbness or weakness that is either unilateral or bilateral, dizziness, double vision, loss of vision, facial weakness or numbness, bladder problems, or a band-like sensation around the trunk that patients may mistake as stomach pain. Symptoms typically last longer than 24 hours; frequently from days to weeks. No single diagnostic test exists to confirm the presence of MS or to rule it out definitively. At a minimum, diagnosis requires a clinical episode consistent with CIS along with either a follow-up MRI study that shows new lesions or a second episode at least 30 days after the initial clinical event that involves a different region of the CNS. If ADEM was the initial presentation, great care must be taken in differentiating recurrent forms of ADEM from MS.

Ness participated in a recent international study group that developed consensus definitions of major CNS inflammatory demyelinating disorders of children and adolescents. The group noted further research is needed to determine the validity and utility of proposed diagnostic categories (Neurology. 2007;68:S7-S12).

“Many pediatricians are not familiar with MS, which is commonly thought to be an adult disease,” Ness says. Diagnosing MS in children is more difficult than in adults because the clinical and MRI findings frequently overlap with ADEM and other childhood-onset diseases, increasing diagnostic ambiguity. Subjective and transitory symptoms often are overlooked or incompletely investigated, and children often do not report symptoms such as vision loss in one eye or numbness on one side of the body if they are otherwise feeling well. An accurate sensory examination may be impossible, especially in a preschooler.

Ness and colleagues have structured UAB’s CPODD to address every aspect of care. “We have an outstanding multidisciplinary model of care drawing on the expertise of UAB neurologists, neuro-ophthalmologists, neuropsychologists, psychiatrists, urologists, radiologists, school counselors, and physical and occupational therapists,” she says.

UAB CPODD
UAB’s CPODD provides comprehensive care and support for children, teenagers, and families living with CNS demyelinating diseases. It is one of six Pediatric Multiple Sclerosis Centers of Excellence in the country. “The centers collaborate to establish diagnosis and treatment guidelines that can improve disease management strategies for this population,” says center Co-Director Khurram Bashir, MD, MPH, who directs UAB’s adult Multiple Sclerosis Center.

CPODD is building a multiethnic research cohort of children and teenagers with demyelinating diseases from around the country to study the pediatric patient population with respect to clinical presentation, neuroimaging, laboratory findings, treatment regimens, neurocognitive functioning, quality-of-life measures, and long-term outcomes.

CPODD offers resources to families (including funding for transportation and psychological testing not covered by insurance) to help cope with the challenges such diseases pose to daily living, including medication monitoring, physical therapy, cognitive and educational evaluation and intervention, and psychosocial support. As cognitive problems take a greater toll on school-aged patients, and academic performance diminishes, Ness and colleagues offer support to teachers, guidance counselors, and school nurses, and even tackle issues such as career options.

“In adults lifelong treatment is recommended after the first demyelinating episode in the setting of specific MRI criteria,” Ness says, “but no controlled trials have evaluated immunomodulatory treatment specifically in children.” Medications approved for demyelinating diseases in adults are prescribed off-label for the pediatric population. “We know disease-modifying therapies such as interferon beta and glatiramer acetate can prevent relapses, slow accumulation of disability, and reduce disease burden [as assessed by MRI], but we do not know yet what long-term impact these treatments may have when used in children,” Ness says.

Further research is needed to describe disease course, determine underlying biological and epidemiological factors that contribute to early onset, delineate the differences between demyelinating diseases, and identify consensus treatment guidelines. “We must advance our understanding of disease pathophysiology and improve long-term outcomes in these children,” Ness says.

For more information:
Dr. Jayne Ness
Dr. Khurram Bashir
www.uab.edu/cpodd
205.996.7633
cpodd@uab.edu