One of the daily pleasures of neurology is ‘solving the mystery’ of a patient’s complaints and/or deficits, integrating the pathophysiology of the condition through localization and pattern recognition sometimes armed only with our own minds and a reflex hammer. Less often, we have the opportunity to watch as researchers begin to unravel the mystery of a neurologic disorders that has remained unsolved for more than a century.
Few neurologic conditions have frustrated modern medicine’s efforts to elucidate its underlying cause more than Nodding Syndrome (NS), but in a February article published in Science Translational Medicine efforts led by NIH’s Intramural Director for Infections of the Nervous System, Dr. Avi Nath and team detail a rather convincing series of experiments indicating that NS may be an epilepsy syndrome caused by autoimmune-medicated brain injury triggered, at least in some victims, by infection with O. volvulus with subsequent molecular mimicry1.
NS is an acquired, often progressive, neurodevelopmental disorder that affects children and is characterized by seizures manifesting as head nodding attacks with associated neurodevelopmental delays and/or regression. ‘Outbreaks’ of NS have popped up periodically for at least the past century, often in regions affected by war and/or mass displacement of populations. The most recent outbreak began in Uganda in 2008, seems to have subsided around 2013 and is thought to have affected more than 2000 children. Ecologic and epidemiological associations between O. volvulus (the filarial parasite carried by biting black flies that causes River blindness) have been known for some time but the absence of a clear pathophysiologic causal mechanism remained a major frustration. In a series of experiments, they identified the leiomodin-1 autoantibody in the population of interest and then found higher rates among NS patients compared to village control. They then went on to identified these autoantibodies in CSF, showed leiomodin-1 to be expressed in human neurons in vitro and using mouse brain localized this to the hippocampus, cerebellar Purkinje cells and cortical neurons. Finally, they went on to demonstrate neurotoxicity of leiomodin-1 in vitro and cross-reactivity between leiomodin-1 autoantibodies in NS patients with O. volvulus antigens. The elegant series of experiments conducted is a good read. Not everyone with NS has evidence of O. volvulus infection and not all outbreaks have occurred in regions subject to river blindness, but this represents a major leap in our understanding of a monstrously devastating condition. The Ugandan government is to be commended for acting on epidemiologic data alone when they instituted massive ivermectin distribution in response to the 2008 epidemic2. Ivermectin and supportive therapy with valproic acid provides some improvement for many.3 Will immunomodulatory therapies will be readily available to affected populations? Can the injury be reversed to any significant extent?
In a parallel and fascinating story in PLos Neglected Tropical Diseases, Foger at al. do some sleuthing through the literature and provide links between Nakalanga and NS4. Nakalanga Syndrome is a childhood onset condition of growth retardation, various skeletal physical deformities and endocrine dysfunction often with associated epilepsy and cognitive regression or impairment reported from many of the same geographic regions where NS outbreaks have occurred.
- Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med 2017;9,
- Idro R, Musubire KA, Byamah Mutamba B, et al. Proposed guidelines for the management of nodding syndrome. Afr Health Sci 2013;13:219-232.
- Idro R, Namusoke H, Abbo C, et al. Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study. BMJ Open 2014;4:e006476.
- Foger K, Gora-Stahlberg G, Sejvar J, et al. Nakalanga Syndrome: Clinical Characteristics, Potential Causes, and Its Relationship with Recently Described Nodding Syndrome. PLoS Negl Trop Dis 2017;11:e0005201.