Parasitic Worm May Cause Childhood Seizure Disorder

Pauline Anderson

February 16, 2017

New research confirms that a parasitic worm may trigger the onset of nodding syndrome (NS), an incurable childhood seizure disorder.

The study results, published online February 15 in Science Translational Medicine, imply that NS is the result of an inappropriate immune response to an infection by the parasitic worm Onchocerca volvulus.

The research "provides insight into the pathophysiological mechanisms that contribute to the development of nodding syndrome," the authors conclude. "This syndrome can now be added to a growing list of autoimmune epilepsies."

Clinicians who suspect a patient's epilepsy might have an infectious component should try to identify the culprit agent by taking samples very early in the disease course, said study author Avindra Nath, MD, chief, Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Dr Avindra Nath

"As neurologists, we oftentimes just look at the spinal fluid and do MRI scans; we don't think about other things," he told Medscape Medical News.

The first case of NS, a progressive and often fatal type of epilepsy that afflicts children aged 5 to 15 years, was documented in the United Republic of Tanzania in the 1960s. Since then, cases have also been described in Uganda and the Republic of South Sudan.

There are now reports of a growing epidemic. A 2012–2013 survey estimated that there were about 2000 cases in Northern Uganda alone.

Head-Dropping Motion

Children with NS have atonic seizures that are characterized by a head-dropping motion. They may also develop clonic-tonic seizures; atypical absence seizures; cognitive impairment; and cerebellar, cerebral, and hippocampal atrophy.

Extensive research carried out on the disorder has uncovered no clear cause or therapy. Children with NS are typically treated with standard antiepileptic medications.

However, research has shown an association between NS and O volvulus, an organism that is known to cause river blindness and is spread by black flies. Because there's no evidence that the mature parasite invades the brain or cerebrospinal fluid (CSF), it was thought that an immune-mediated mechanism may be involved.

Researchers had serum samples from 19 children with NS in a single remote region of Uganda, as well as from 19 age-matched (within 5 years) unaffected controls in the same village. They also had samples from a second cohort of 36 patients with NS from South Sudan and 36 unaffected village controls, for a total of 55 patients (mean age, 11.8 years) and 55 controls (mean age, 10.8 years).

Researchers also had CSF samples from 16 patients with NS. It was not considered appropriate to obtain CSF from unaffected village controls.

With pooled sera from patients and from controls, researchers carried out immune-typing for autoreactive antibodies using a protein chip with thousands of proteins. The top two signals were from autoantibodies to leiomodin-1 (increased 33,000-fold) and autoantibodies to DJ-1 (increased 750-fold). However, only antibodies to leiomodin-1 — and not to DJ-1 — were detected in the CSF of patients with NS.

The study showed leiomodin-1 antibodies were more frequently detected in patients with NS than in unaffected village controls: 29 of 55 (52.7%) vs 17 of 55 (30.9%) (P = .024; matched odds ratio, 2.7; 95% confidence interval [CI], 1.1 - 6.5).

In patients with NS, there was a higher percentage of O volvulus–positive status in leiomodin-1 antibody–positive cases than in leiomodin-1 antibody–negative cases. The same did not hold true for unaffected village controls.

Researchers compared the CSF from the 16 patients with NS in East Africa with 8 patients in the United States with epilepsy. Half (8 of 16) of the patients with NS showed antibodies to leiomodin-1 in the CSF vs none (0 of 8) of the US patients with epilepsy (P = .022).

The researchers also confirmed that leiomodin-1 is expressed in the human brain. They detected leiomodin-1 messenger RNA in human brain tissue extracts, human neuronal stem cells, and cultured neurons.

It was previously thought that leiomodin-1 was present primarily in muscle.

"We tried to see if we could find the protein in the brain and, lo and behold, it's actually present in the brain, and present in large amounts in the brain," commented Dr Nath.

The investigators also determined that antibodies to leiomodin-1 cause neuronal dysfunction. Neurons treated with sera from a patient with NS with detectable leiomodin-1 antibodies demonstrated neurotoxicity.

"The neurotoxicity induced by autoantibodies to leiomodin-1 from patients with nodding syndrome in conjunction with the expression of leiomodin-1 in the CNS suggests that antibodies directed against leiomodin-1 may play a role in nodding syndrome disease pathogenesis," the authors write.

They also demonstrated that leiomodin-1 is expressed in neurons in distinct regions of the mouse brain, including the cerebral cortex and areas of the hippocampus and cerebellum. These areas, said the authors, correspond with those thought to be associated with the clinical manifestation of NS, such as cerebral atrophy and cognitive abnormalities.

According to the authors, autoreactive T cells may be the main mediators of the immunopathology of NS, with the production of leiomodin-1 autoantibodies a consequence of this T cell activation. It's also possible that antibodies to leiomodin-1 are directly contributing to the disease.

Why Children?

It's not clear why NS affects only children. Their developing immune system, or ongoing brain development, may make children more vulnerable to the condition, and, because some patients also have delayed sexual development, pituitary-hypothalamic dysfunction may be involved, said the authors.

Although the study found a statistically significant association between leiomodin-1 antibodies and NS, Dr Nath pointed out that a third of unaffected village controls also had detectable antibodies. He also noted that Onchocerca is much more prevalent in areas of Africa other than the regions with an epidemic of NS.

"It's possible that it takes time to develop the syndrome," said Dr Nath. "Maybe there's a second component that's necessary and that just having the antibodies alone is not sufficient. Maybe you need a genetic background that makes you more susceptible."

Dr Nath likened the situation to the annual flu outbreak in North America, where everyone develops antibodies but people react differently to the infection. "Some people fall really sick and others have mild symptoms, but it's the exact same infection."

The study results suggest that children with NS may benefit from immunomodulatory therapies, especially before developing cognitive impairment. "Once neurons are damaged, the immunotherapy is not going to do much," stressed Dr Nath.

However, in remote areas such as those where NS is found, administering immunotherapy "is not an easy task," and neither is monitoring patients for side effects, he said.

It's possible, too, said the authors, that the immune responses may cause monophasic neurotoxicity, in which case immunotherapy may not be beneficial.

Dr Nath believes that the best approach to the problem is prevention — getting rid of Onchocerca altogether. He noted that the Ministry of Health in Uganda has started treating the entire population with an antiparasitic agent, and the incidence of NS has already gone down.

This new research is important because it suggests that other epilepsy syndromes may also be triggered by infectious processes, said Dr Nath.

Reached for a comment, Shaun Hussain, MD, director, assistant professor of pediatrics, Division of Pediatric Neurology,?David Geffen School of Medicine, University of California, Los Angeles, called the new work "exciting," as NS is a "very new" form of epilepsy and "truly unique" in its limited geographic distribution.

"This is the first real evidence supporting the idea that Onchocerca exposure actually causes nodding syndrome, and that the association isn't just a coincidence."

But while he's hopeful that this discovery will facilitate new treatments for epilepsy, "I am only modestly enthusiastic," said Dr Hussain. "Most of us in the West view nodding syndrome as a curiosity and conceptualize it as a special case, with limited generalizability."

However, he added, "this finding at least opens the door for immune modulation as a potential means to dramatically alter the often grim course of nodding syndrome."

The new research "is an important incremental step" in unravelling the "mysteries" surrounding the ways in which the brain and immune system interact, a field "still in its infancy," said Dr Hussain.

This research was supported by the Intramural Research Programs of the National Institutes of Health and Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.

Sci Transl Med. Published online February 15, 2017. Abstract

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