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Nodding syndrome is an uncommon epileptic disorder of childhood onset, which appears winkler conscious dating occur exclusively in clusters in sub-Saharan Africa.

It was first reported in the s, in what is now southern Tanzania, then in Liberia, winkler conscious dating later winkler conscious dating South Sudan and northern Uganda, with both epidemic and winkler conscious dating patterns described. The cause remains unknown. Here we describe the background and development of descriptions of the disorder, review its clinical features and summarize current theories and studies concerning its cause, outlining the principal remaining research questions relating to this highly unusual winkler conscious dating. Nodding winkler conscious dating NS is a childhood-onset epileptic disorder occurring in clusters in sub-Saharan Africa.

Attacks could be triggered by presentation with food. Later, impaired cognitive and physical development was common, and death not infrequently occurred from burns or drowning. Several instances of multiple affected siblings occurred; Jilek-Aall described considerable therapeutic success with phenobarbitone Luminal.

Louise Mathilde Aall-Jilek. Fuller descriptions followed a decade later. Finally so farcases were reported in Uganda: in the west in peer-reviewed description only appearing much later; Kaiser et al.

Geographical distribution of nodding syndrome in sub-Saharan Africa. Winkler conscious dating more definitive description of NS, confirming its primarily epileptic nature, appeared inbased on Tanzanian cases Winkler et al. Proposed case definitions for nodding syndrome Winkler conscious dating, Reported head nodding in a previously normal person.

Head nodding is defined as repetitive, involuntary drops of the head to the chest on two or more occasions. Plus a documented nodding episode that is: Observed by trained healthcare worker, or. Curiously, while the original Tanzania and Liberia cases appeared endemic Jilek-Aall, ; van der Waals et al.

Currently, NS appears to be found in southern Tanzania and in northern Uganda and the adjacent southern and central states of South Sudan. In northern Uganda, no new cases are occurring; new cases are reported by non-governmental organizations though not yet in the peer-reviewed literature in South Sudan; whether this is true of Tanzania is uncertain. The current scale of the problem is also uncertain, with no detailed epidemiological prevalence studies.

A careful Uganda Ministry of Health survey documented cases in northern Uganda Aceng, The disorder is characterized by repetitive head nodding, 5—20 nods per minute, resulting from momentary but repeated loss of neck extensor tone. Occasionally, an associated loss of tone in the upper trunk and shoulders occurs. Remarkably, being presented with food commonly provoked nodding Jilek-Aall, ; Winkler et al. Cold weather could also trigger attacks Winkler et al.

In some cases, nodding was associated with impaired awareness; other affected individuals continued eating and interacting between nods during episodes Sejvar et al.

In most cases, after a period of months to a year or more, focal onset to bilateral tonic-clonic fits follow. Focal impaired awareness seizures, tonic-clonic and atypical absence seizures are all reported. Photosensitivity may be seen Jilek-Aall, ; van der Waals et al. Failure of cognitive development and physical winkler conscious dating retardation are common Idro et al.

Whether the frequently reported psychological and psychiatric manifestations, including mood changes, sleep disturbances, major depression, aggressive outbursts and episodes of wandering Spencer et al. Reports of catatonia strongly suggest primary psychiatric disorder Kakooza-Mwesige et al.

The natural history of NS also remains unclear. Some authors describe a prodromal phase, with dizziness and lethargy but no explicit mention of seizures Idro et al.

Most, but not all sufferers progress from nodding attacks to other seizure types. Also uncertain is whether such individuals, who appear to have progressed through recognizable if overlapping stages Idro et al. Early anecdotal reports of NS described a rapidly progressive course from the onset of nodding, with increasing neurological and cognitive disabilities, then progressive deterioration of consciousness and death Lacey, ; Wasswa, ; Idro et al.

No studies report any instance of spontaneous recovery. EEGs winkler conscious dating 10 patients were normal in four, non-specifically abnormal including winkler conscious dating slowing in four, and showed more clearly epileptic interictal activity in two, with intermittent generalized slowing and sharp wave activity Winkler et al. Later studies differed, reporting interictal changes in the great majority of cases Tumwine et al.

In one, epileptiform activity comprised frequent runs of generalized, 2. Others, however, found no consistent frequency to spikes or sharp waves Idro et al. None of the studies sought EEG-photosensitivity. The clinical and electrophysiological picture is therefore complex: multiple seizure types occur. Later, tonic-clonic, myoclonic and atypical absence winkler conscious dating, with both focal and generalized onset, are seen, with abnormal interictal EEG including slow spikewave and polyspike-and-wave activity Idro et al.

MRI reports, including 48 NS children in total, describe no disease-specific changes and no aetiological clues. Others reported no such cortical lesions, and normal hippocampi Idro et al.

CSF examination has been similarly uninformative: most report normal cell counts and winkler conscious dating. Oligoclonal bands were not sought in either of the principal studies Winkler et al. One study published only in abstract form, studying three siblings, reported isolated oligoclonal bands in one; Soldatos et al. Other studies report performing spinal fluid tests, but included no results in their accounts Tumwine et al. The difficulties of conducting such analyses given the often very remote location of patients Fig.

Nodding syndrome in Uganda. The great majority live in remote rural settings, presenting practical challenges in particular to neurological investigations right. In these settings, most anti-epileptic drugs are unavailable, unaffordable or both. Phenytoin, carbamazepine and sodium valproate are accessible; phenobarbital is also used.

There have been no randomized controlled treatment trials, but retrospective assessments of therapeutic responsivity are reported. NS in Liberia appeared less responsive van der Waals et al.

The Ugandan Ministry of Health winkler conscious dating management response included a formal set of treatment guidelines Idro et al. Sadly, a very recent later follow-up found low levels of implementation of and adherence to these guidelines, mostly because of financial constraints Abbo et al.

Perhaps unsurprisingly, the general benefits of targeted dietary supplementation in NS children winkler conscious dating clear Gazda and Kitara, Furthermore, management of behavioural and emotional difficulties, nutritional therapy and physical rehabilitation significantly improved levels of independence in basic self-care, school enrolment and behavioural and emotional symptomatology Idro et al.

Many hypothetical causes of NS have been advanced, some rather speculative, others with more persuasive supporting evidence, but none proven. Prions, climate change Donnelly,antibody-mediated channel blockade, monkey meat consumption Lacey,toxic residue from munitions Lacey,mitochondrial dysfunction, toxic traditional medicines, forms of autism Spencer et al. Jilek-Aall herself postulated unspecified nutritional deficiency. Two studies have reported B6 hypovitaminosis Donnelly, ; Obol et al.

Others reported no reduction in vitamin B6 levels in NS cases Kyu et al. Alternative diet-associated possibilities have included food-related toxins. No other dietary components, including red sorghum grain, a major dietary component previously anecdotally implicated, were associated. A later case-control study in the same area differed, finding no link to cassava.

Rather, an association with the consumption of World Food Programme emergency food was winkler conscious dating, particularly maize that had become mouldy Spencer et al.

However, a subsequent comprehensive exploration of mycotoxins in a range of grains found no evidence to associate NS with consumption of mycotoxins in maize or any other contaminated food. The levels of aflatoxin and ochratoxin in maize were no different to those in any of the grain types tested; and there was no correlation between the total concentration of any of the various types of mycotoxin with the presence of children with NS in households Echodu et al. Mycotoxins are widespread in core food products throughout Africa, including maize, spices and groundnuts Darwish et al.

Also related to IDP camps—and more specifically, conflict—is an alternative neurotoxin hypothesis, namely that munitions-related chemical or biological agents are implicated. Winkler conscious dating elegant epidemiological study explored the relationship between the emergence of NS in northern Uganda and conflict. A case-control study of Ugandan children suggested that self-reported exposure to munitions was associated with NS Foltz et al.

Winkler conscious dating absence of NS in other theatres of war in Africa or elsewhereand the occurrence of NS as an endemic disease in non-warfare situations, both also strongly weigh against this possibility.

In particular, the description of NS with an onset in Spencer et al. Infectious—or infection-related—causes for NS have also been implicated, principally onchocerciasis river blindness. Neither original report from Tanzania or Liberia mention river blindness, but both winkler conscious dating the extremely common co-incidence of various infections in nodding-affected children Winkler conscious dating, ; van der Waals et al. Other, later case-control studies reported a positive link with onchocercal infection Tumwine et al.

Others assert that O. An alternative onchocerciasis-based hypothesis proposes that, rather than direct infection, the organism triggers auto-immune winkler conscious dating by generating cross-reactive antibodies. Leiomodin-1 was expressed in human neurons in vitro winkler conscious dating and, at least in the rodent, is also expressed in CNS neuronal populations in vivo Takebayashi et al. This hypothesis is arguably winkler conscious dating indirectly by the suggestion that onchocerciasis causes river blindness by comparable mechanisms—not directly infecting the eye, but eliciting a secondary inflammatory response to some of its antigens McKechnie et al.

The problem, however, remains that river blindness is seen globally, wherever ochocerciasis occurs, in stark contrast to NS. In addition, almost half of NS patients have no leiomodin antibodies, while a third of normal controls do have winkler conscious dating. Leiomodin is also strongly expressed in muscle, which appears unaffected in NS.

Concerning the related if less exotic immunological possibility of ion channel-mediated autoimmunity, no evidence of circulating anti- N -methyl- d -aspartate NMDA or voltage gated potassium channel-complex VGKC antibodies were found winkler conscious dating NS Dietmann et al.

Finally, autoimmune suggestions receive no support from the limited number of published autopsy studies, which winkler conscious dating none of the inflammatory changes seen in ion channel antibody-mediated encephalitis Winkler et al. Measles virus has also been implicated, with NS suggested as a post-measles complication in malnourished children, based partly on the anecdotal but likely incorrect hypothesis that the clinical features and course of NS—an inevitable progression to death—were comparable to sub-acute sclerosing panencephalitis Spencer et al.

A case-control study in northern Uganda reported a significant association of NS with prior measles infection Spencer et al. However, other NS studies, in south Sudan and in the same area of northern Uganda, found no measles relationship Tumwine et al. Autopsy studies also showed no evidence of viral or other infection Winkler et al. Finally on the infectious front, one South Sudan study reported a link with Mansonella perstans infection a midge-borne filarial nematode; Tumwine et al.

Confirmation has not winkler conscious dating forthcoming, and the incidence of Mansonella perstans-related disease in numerous areas where NS is not seen, together with the absence of evidence of parasite infection in autopsy studies Pollanen et al. Autopsy studies are often invaluable in elucidating disease origins, and a significant advance appeared possible from the first major study in NS, which proposed that the disorder was winkler conscious dating novel tauopathy Pollanen et al.

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