The spectrum of disease and tau pathology of nodding syndrome in Uganda.

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.

Nodding syndrome in Uganda is a tauopathy.

Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. We conclude that nodding syndrome is a tauopathy and may represent a newly recognized neurodegenerative disease.

Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus.

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.