Authors: ^*Peter S. Spencer, PhD, FANA, FRCPath., *Valerie S. Palmer, BS
^Department of Neurology, School of Medicine; ^Center for Research on Occupational and Environmental Health; and *Global Health Center, Oregon Health and Science University, Portland, Oregon 97239, USA

Internal displacement, severe food shortages, vermiform infection, notably Onchocerca volvulus (OV), and lack of medicine and immunization, are common to populations affected by Nodding Syndrome (NS) in Uganda, South Sudan, and Tanzania, where records indicate cases as early as 1934 [1]. Children with NS are born normally and undergo unremarkable perinatal development before growth slows and the child becomes physically and mentally stunted coincident with periodic head nodding and convulsions triggered by sensory stimuli, such as food or cold. MRI reveals hippocampal pathology and gliosis in some, but cerebrospinal fluid is free of OV by polymerase chain reaction [2,3]. While NS is always associated with OV, the reverse is not true, which suggests additional etiologic factors, notably those associated with poor food quality. Sorghum, an imported red variety of which was statistically associated with NS in South Sudan [4], is prone to spoilage by Fusarium verticillioides; this fungus elaborates fumonisin B1, which blocks sphingolipid synthesis and causes leukoencephalomalacia in horses and hippocampal lesions in laboratory species [5]. Other common food molds include Aspergillus ochraceus and Penicillium verrusosum that elaborate ochratoxin A, a mitochondrial toxin with renal and neurotoxic potential [6,7]. Ochratoxin and other mycotoxins generated by Aspergillus spp. (aflatoxin B1) and Fusarium spp. (trichothecenes) inhibit RNA and/or protein synthesis [8], an absolute requirement for growth and development. Several other grass-related tremorgenic mycotoxins (aflatrem, tremortin) induce tremulousness in cattle by perturbing neurotransmitter function, and ergot-related alkaloids elaborated by Claviceps spp. induce hallucinations, irrational behavior and convulsions in humans [9]. Additionally, in immunocompromised hosts, inhalation of certain food molds (Aspergillus, Penicillium) causes systemic mycoses, including seizure-prone cerebral aspergillosis [10]. Importantly, nematodes such as OV and several mycotoxins suppress host immune function, which raises the possibility of opportunistic fungal infections, as occurs in HIV. Systemic exposure to certain neurotoxic fungal metabolites would explain the cold extremities of children with NS [3], the metabolic acidosis [11], and low pyridoxine levels [12], since ergot is vasconstrictive, ochratoxin induces acidosis, and L-penicillamine from Penicillium spp. acts as an antivitamin B6. The foregoing raises the possibility that systemic mycotoxins in the presence or absence of an occult mycosis perturb childhood development and create a pro-convulsive state, such that a variety of sensory stimuli (food, cold) can trigger seizure activity in the NS subject. Fungicides as well as anticonvulsants and vermifuges (including Ivermectin for OV) would be indicated for the treatment of such a previously unrecognized neurological mycosis.

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