Nodding Syndrome May Be Only the Ears of the Hippo.

Abstract

Nodding Syndrome (NS) is a neurological disorder of unknown etiology and pathogenesis, reported to occur mainly in the Western Equatoria State in South Sudan, in several districts in northern Uganda, and in Mahenge district in Tanzania [1]. The characteristic clinical feature of NS is a paroxysmal spell where the head nods forward repeatedly, 5–20 times per minute, in a seemingly unresponsive affected child. These nodding episodes represent an atonic form of epilepsy during which generalized electrodecrement is seen on electroencephalography and paraspinal dropout on electromyography [2]. During these episodes, children exhibit differing levels of decreased awareness, confusion, and unresponsiveness to commands [1]. Children with NS develop varying degrees of mental retardation, and in some, there is considerable stunting of growth and failure to develop secondary sexual characteristics. The syndrome generally appears between the ages of five and 18. Affected children are generally reported to be healthy until the nodding episodes begin. The natural history is not well known but has been described as starting with nodding and often progressing to generalized tonic-clonic seizures with accumulated sequelae. No proven effective specific treatment is available, and many children have died as a result of uncontrolled seizures that led to drowning or burning [1]. Recent studies, however, show that children with NS who receive adequate care—including anti-epileptic treatment, nutritional and emotional support, and physical rehabilitation—may substantially improve clinically [3]. NS is characterized by temporal, geographical, and familial clustering in villages in some onchocerciasis-endemic areas. The extent of the outbreaks in South Sudan and northern Uganda has made NS a major public health problem in these countries. In contrast, in Tanzania, the prevalence of NS is low and stable [4]. NS, like other forms of epilepsy, is associated with social stigma and can have severe socioeconomic consequences for families and communities. Various infectious, toxic, nutritional, psychosocial, and genetic causes for NS have been proposed, but none have been confirmed [5]. Cerebrospinal fluid (CSF) total protein, cells, and glucose are generally normal [2]. In a study in Uganda of 19 patients with NS, brain MRIs without contrast, performed using a 0.5 Tesla machine, showed different degrees of cortical and cerebral atrophy but no focal changes [6]. However, in a study of 12 patients with NS in Tanzania, using an MRI machine with better resolution (1.5 Tesla), five had gliotic lesions and five had changes in the hippocampus [7]. A weak association between Onchocerca volvulus (OV) skin PCR positivity and lesions on MRI was reported [7]. No autopsy or brain biopsy data for NS patients has been published. Epidemiological studies suggest a strong association between NS and onchocerciasis [8]. NS is only known to occur in onchocerciasis-endemic areas, and case-control studies have demonstrated a statistically significant higher prevalence of onchocerciasis in individuals with NS than in controls [7,9,10]. It is, however, unclear how onchocerciasis might cause NS because microfilariae (mf) and adult OV worms are not generally considered able to invade the central nervous system. In 1976, Duke et al., however, noted the presence of small numbers of OV microfilariae in the CSF ( 100 mf/mg skin) onchocerciasis patients. During diethylcarbamazine treatment, in 10 of 11 heavily infected patients presenting with an ocular form of onchocerciasis, the numbers of OV microfilariae in the CSF increased even up to 8–31 mf/ml [11]. However, more recently, a Tanzanian study of patients with onchocerciasis and epilepsy did not have microfilariae in the CSF, and PCR of CSF of patients with NS failed to identify OV DNA [7,10,12]. The latter results are difficult to interpret, as it was unclear how many participants had been previously treated with ivermectin and how frequently [13]. Most of the patients (60.8%) had visible microfilariae on microscopic examination of the skin biopsies, but the mean microfilariae density was low, 3.6 mf/mg, potentially because of prior ivermectin treatment [12].