Neuroinflammation and Not Tauopathy Is a Predominant Pathological Signature of Nodding Syndrome

Abstract

Nodding syndrome (NS) is an epileptic disorder occurring in children in African onchocerciasis endemic regions. Here, we describe the pathological changes in 9 individuals from northern Uganda who died with NS (n = 5) or other forms of onchocerciasis-associated epilepsy (OAE) (n = 4). Postmortem examinations were performed and clinical information was obtained. Formalin-fixed brain samples were stained by hematoxylin and eosin and immunohistochemistry was used to stain astrocytes (GFAP), macrophages (CD68), ubiquitin, α-synuclein, p62, TDP-43, amyloid β, and tau (AT8). The cerebellum showed atrophy and loss of Purkinje cells with hyperplasia of the Bergmann glia. Gliosis and features of past ventriculitis and/or meningitis were observed in all but 1 participant. CD68-positive macrophage clusters were observed in all cases in various degrees. Immunohistochemistry for amyloid β, α-synuclein, or TDP-43 was negative. Mild to sparse AT8-positive neurofibrillary tangle-like structures and threads were observed in 4/5 NS and 2/4 OAE cases, preferentially in the frontal and parietal cortex, thalamic- and hypothalamic regions, mesencephalon and corpus callosum. Persons who died with NS and other forms of OAE presented similar pathological changes but no generalized tauopathy, suggesting that NS and other forms of OAE are different clinical presentations of a same disease with a common etiology.

Prevalence and incidence of nodding syndrome and other forms of epilepsy in onchocerciasis-endemic areas in northern Uganda after the implementation of onchocerciasis control measures

“…Indeed, we carried out another post-mortem study in the same area, among five persons with NS and four persons with another type of OAE. This study revealed similar neuroinflammatory histopathological changes with mild to sparse deposits of tau-immunoreactive neurofibrillary tangles in 4/5 persons with NS and 2/4 persons with another form of OAE, suggesting that NS and other forms of OAE are caused by a similar phenomenon [38]. The tau deposits most likely are induced by repetitive seizures [39] with seizure-associated hypoxia [40] and possibly repeated head injuries [41].…”

Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove

“…Nodding syndrome (NS) is a devastating childhood epilepsy, characterized by severe attacks of nodding of the head, progressive cognitive dysfunction, neurological deterioration, stunted growth and additional pathological neurological features [1][2][3][4][5][6][7][8][9][10].…”

OV16 Seroprevalence among Persons with Epilepsy in Onchocerciasis Endemic Regions: A Multi-Country Study

“…The level O. volvulus microfilarial load in children was shown to be a predictor for developing OAE later in life [ 3 , 4 ]; however, the pathophysiological mechanism on how the O. volvulus parasite causes the seizures remains unknown. No parasites or O. volvulus DNA and no Wolbachia DNA (an O. volvulus endosymbiont) were found in cerebrospinal fluid [ 28 ] or in brain tissue of persons who had died of OAE [ 29 ]. An auto-immune mechanism induced by neurotoxic O. volvulus cross-reacting antibodies was proposed [ 30 ], but this hypothesis still needs to be confirmed.…”