Nodding syndrome (NS) is an enigmatic recurrent epidemic neurological disease that affects children in East Africa. The illness begins with nodding of the head and grand mal seizures that may lead to death after several years. The most recent outbreaks of NS occurred in northern Uganda and South Sudan. We describe the clinicopathologic spectrum of NS in Uganda. Ten children or young adults with NS were studied at autopsy and the neuropathological findings correlated with the onset, duration and progression of their neurological illness. All cases had epilepsy with grand mal seizures. Three cases had a clinical course that was predominantly characterized by epilepsy. Seven patients had progressive frontotemporal dementia. Two of the patients with dementia also had progressive quadriparesis. In all cases, the brain revealed tau pathology. In cases with an epilepsy-predominate course, the tau pathology was largely limited to the anterior frontal lobes but cases with dementia had more widespread cortical and subcortical tau pathology. In some cases, the histologic pattern was reminiscent of progressive supranuclear palsy. There are some interesting parallels between NS and the amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC). The similarities are the presence of geographical isolates of disease manifesting in indigenous populations with familial clusters but no clear heritability. Both disorders appear to be related to an unknown environmental factor and both diseases appear to be fading over time in the respective geographical locations. One of the major open questions is whether ALS occurs in NS. This question will be addressed in future clinical studies and postmortem examination of the spinal cord. We propose that NS is a unique epilepsy-dementia complex in East Africa.