Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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Nodding syndrome is a newly discovered tau-associated neurologic disorder with poorly understood etiology and is clinically characterized by seizures, which present as nodding of the head, global developmental delay, and neuropsychiatric dysfunctions. It affects previously healthy children between 3 and 18 years of age. It was first documented in the United Republic of Tanzania in the 1960s, but mainly came to public attention when epidemic outbreaks were reported in what is now the Republic of South Sudan in the 1990s and in northern Uganda in the late 2000s. In this article, available data from different case series and case-control studies are reviewed.
• Nodding syndrome is a novel tau-associated neurologic disorder with poorly understood etiology and is clinically characterized by seizures, which present as nodding of the head, global developmental delay, and neuropsychiatric dysfunctions. It usually affects previously healthy children between 3 and 18 years of age.
• It was first documented in the United Republic of Tanzania in the 1960s, but mainly came to public attention when epidemic outbreaks were reported in what is now the Republic of South Sudan in the 1990s and in northern Uganda in the 2000s.
• Case series described clinical features and performed investigations of cerebrospinal fluid, electroencephalography, neuroimaging (magnetic resonance imaging), and pathology.
• Case-control studies assessed risk factors and tested for infectious pathogens, toxin exposures, and nutritional deficiencies. Of significance are the epidemiological associations with exposure to Onchocerca volvulus and Mansonella spp, possible vitamin B6 deficiency, and a prior history of measles infection.
In the 1990s, nodding syndrome was reported in what is now the Republic of South Sudan and northern Uganda as a distinct novel entity characterized by repetitive head nodding, neurologic and cognitive impairment, delayed puberty, and growth retardation variably associated with other seizures. During 2001 to 2002, the disease subsequently reached the attention of local authorities, the World Health Organization (WHO), and media. However, in retrospect, similar cases of children with head nodding, cognitive impairment, and abnormal growth and development were previously described in Tanzania, Liberia, and western Uganda (02; 50; 18). Regarding the Mahenge region in Tanzania, records from 1960 to 1971 have documented the presence of the disease for at least 80 years (01; 02; 45).
Definition. The First International Scientific Meeting on Nodding Syndrome held in Kampala, Uganda, in 2012 approved the first standardized case definition for nodding syndrome (55). Nevertheless, this case definition is intended to be reviewed and modified as new data become available (15). Additionally, consensus was reached to denominate the combination of signs and symptoms as nodding syndrome and replace the terms “nodding disease” and “head nodding disease.”
• Head nodding is reported in a previously normal person.
Probable case. Suspected case plus both of the following major criteria:
• Age at onset of nodding between 3 and 18 years old
And at least 1 of the following minor criteria:
• Other neurologic abnormalities (cognitive decline, school dropout due to cognitive/behavioral problems, other seizures or neurologic abnormalities)
Confirmed case. Probable case plus a documented nodding episode observed by a trained healthcare worker, or videotaped, or on EEG/EMG.
In 2008, Winkler and colleagues proposed and established a classification system that separates patients into subgroups with head nodding episodes only (HN only) or with further forms of epileptic seizures (HN plus) (51). A Ugandan study on the neuropsychiatric aspects of nodding syndrome proposed to classify the syndrome into “neurologic nodding syndrome,” “psychiatric nodding syndrome,” and “mixed nodding syndrome” (31).
Nevertheless, reports about the clinical features and course of nodding syndrome may differ, and it remains uncertain whether the reports about nodding syndrome all refer to the same disorder. In the long-term course, physical and cognitive decline may differ in the different regions. Compared to reports from Uganda and Sudan, children with nodding syndrome in Tanzania seem to be less severely affected, and, hence, prognosis may be better (51; 52; 54). Current evidence and surveillance data suggest that death mainly results from secondary causes, like drowning or burns from fire, due to seizures or malnutrition (Ugandan Ministry of Health, unpublished).
EEG and semiology. Nodding syndrome is most likely an epileptic encephalopathy (47; Winkler et al 2012; 54; 41; 05). However, there is significant heterogeneity in the underlying ictal and interictal neurophysiological findings. Tumwine and colleagues described a series of repetitive, involuntary dropping of the head, lasting 2 to 5 minutes with a frequency of 10 to 20 per minute (47). The episodes were noted especially in the morning or while eating. Although some children were unresponsive to commands along with absently staring, consciousness was not impaired in others as they continued to eat and follow commands to rise, walk, or turn. Sometimes such nodding episodes evolved into generalized tonic or tonic-clonic seizures; in others, episodes of sudden shouting, screaming, jumping up, and running in circles were reported by caretakers. Tumwine and colleagues described another patient in whom head nodding with remaining responsiveness could reliably be induced by local food prepared from maize (ugali), although it was not observed when the patient ate a Western candy bar (47). Similar semiologic descriptions have been also reported by others (51; 13; 41).
To date, several studies have reported heterogenous ictal and interictal findings on EEG. Idro and colleagues reported abnormal routine EEGs in 20 of 22 children, with abnormal slow background activity as well as generalized and focal epileptiform discharges, and they suggested symptomatic generalized and symptomatic focal epilepsy (13). No long-term EEGs or overnight recordings were performed and ictal findings were not reported. Routine video-EEGs in a study by Sejvar and colleagues showed abnormal interictal activity in 10 of 12 children with frequent 2.5 to 3 Hz generalized spike-and-wave discharges, multifocal spikes, and polyspikes (41). Complex partial seizures were recorded in 2 children; in 1 of the children, the seizure was preceded by drinking a cold beverage. Nodding episodes were recorded in 2 children, showing a generalized electrodecrement with subsequent generalized sharply contoured rhythmic theta activity assessed as atonic seizures. Tumwine and colleagues described routine EEGs of 32 subjects with nodding syndrome showing universal recurrent paroxysmal pathological discharges (47). In 3 cases, nodding episodes were recorded showing paroxysmal slow-wave rhythms “followed by a brief and small fast discharge.” This activity was observed in a pseudo-periodical manner for several minutes.
In contrast, Winkler and colleagues reported unremarkable routine EEGs in 4 (40%) of 10 patients with head nodding (one with HN plus); abnormal background activity and intermittent sharp slow-wave activity were reported in 2 patients each (51). Seizures or nodding episodes were not recorded. In their follow-up study, Winkler and colleagues reported abnormal background activity in 11 (44%) of 25 patients (54). Generalized ictal 2.5 Hz spike-wave activity was recorded in 2 patients (8%), and interictal bursts of 1.5 to 2 Hz spike-wave rhythms were observed in 4 of 25 (16%) patients.
de Polo and colleagues reported abnormal EEG findings in 20 of 21 children with nodding syndrome from South Sudan (05). Interictally, background activity in majority of the children was found in the delta and theta range. Eighty-five percent of the children showed bilateral 2 to 3.5 Hz spike and wave epileptiform discharges over the fronto-temporal or fronto-centro-temporal regions (75%) and fronto-parietal-temporal region (10%) that were often intermingled with sharp waves. Ictal EEG in 3 children with nodding syndrome showed a high-amplitude, bi- or triphasic slow wave with inverse phases reversal over the vertex region. These slow waves were occasionally followed by an electrodecrement with diffuse fast activity for 2 to 4 seconds. The ictal activity repeated every 3 to 10 seconds and often occurred in clusters, correlating clinically, with nodding episodes (05).
Although there is a general consensus that head nodding spells are seizures, authors have often disagreed about the interpretation of the neurophysiological data and characterization of the head nodding episodes. Although Sejvar and colleagues classified the nodding episodes as atonic seizures (41), Winkler and colleagues have characterized them as atypical absence seizures (54). Furthermore, de Polo and colleagues have made a strong case for describing these head nodding spells as late-onset epileptic spasms (05). Given the inconsistency and the heterogeneity of the neurophysiological data, EEG is not yet considered an essential criterion for diagnosis of nodding syndrome (55).
Clinical course. In a large retrospective study of 210 children with nodding syndrome in Uganda, Idro and colleagues identified 5 overlapping clinical stages with deteriorating epilepsy, cognitive impairment, and functional and psychiatric abnormalities (14).
Prodromal stage. An initial prodrome with “dizziness” and loss of attention, sleepiness, lethargy, and staring was reported in 4 patients up to 6 weeks prior to the first head nodding episodes.
Head nodding. This stage was found to be the pathognomonic feature of the syndrome. The mean age of head nodding was 7.5 years. Characteristic dorso-ventral head drops were noted with frequency of 5 to 20 Hz lasting several minutes. With progression of disease there is development of other types of seizures including atypical absences and myoclonic jerks.
Convulsive seizures. Within 6 months to 3 years, children with nodding syndrome develop convulsive seizures, cognitive dysfunction, and psychosis.
Functional impairments. Around 2 to 5 years after head nodding spells appear there is significant functional impairment. During this time there is gradual deterioration in behavior, motor skills, speech, cognition, and psychiatric symptoms. Some patients developed skeletal abnormalities such as kyphosis and limb and pectus deformities. The children who were still active and mobile, wandered around or ran away, and were prone to getting lost.
Severe disability. Children lose their mobility and appear severely wasted and apathic, with flat affect, limited speech, and poor appetite; some develop limb deformities.
Reliable long-term data are not available, and whether wasting (stage V) is obligatory in the course is still controversial and only infrequently seen in Tanzania (54). Sejvar and colleagues followed 12 of 23 children for 8 months without seeing improvements in nodding or seizure frequency (41). Over a period of 4 years, Winkler and colleagues followed 53 of 62 patients, most of them on antiepileptic drugs (54). Among the 23 patients initially classified as HN only, 10 remained HN only and 5 deteriorated towards HN plus with additional generalized tonic-clonic seizures. Head nodding ceased in 2 patients, and they developed no further seizure types. In 6 of the original HN only patients, head nodding stopped although they developed other seizures. Among the 30 initial HN plus patients, 9 remained HN plus with head nodding and other seizures. In 15 patients, head nodding ceased although the other seizures persisted; 4 patients with HN plus changed to HN only, and head nodding and generalized tonic-clonic seizures in 2 patients had stopped on follow-up.
Overall, head nodding stopped in 25 of 53 (47.2%) interviewed patients, with a median head nodding duration of 5 years at a median age of 15 years, although 21 patients (84%) developed other epileptic seizures, mainly generalized tonic-clonic seizures, and 20 of the 25 (80%) in whom head nodding had stopped were still on antiepileptic drugs. Four of 53 (7.6%) patients (2 previously classified as HN plus) were seizure free, and the head nodding seizures had stopped at a median age of 13 years; 2 were still on antiepileptic drug treatment.
Cognitive impairment. Severe cognitive impairment has been consistently noted, although standardized neuropsychological assessment has been infrequently performed in the rural setting in Africa. Mental retardation was reported in 15% of nodding syndrome patients in Sudan and 40% of Tanzanian patients, although the tests were not specified or the patients were graded according to the parents’ assessments (52; 47). In Uganda, Sejvar and colleagues performed a brief self-designed, 5-item test and Mini Mental Status Examination (MMSE) to asses 65 children with nodding syndrome (41). Compared to age- and village-matched controls, the patients displayed a reduced ability to copy simple and complex shapes, list animal names, and recapitulate a series of sequential numbers and finger tapping of the dominant hand. Anecdotally, the cognitive impairment seems to be progressive, although there was no long-term observation performed (47; 41). Idro and colleagues described cognitive impairment and school dropout within 2 to 4 years after the onset of head nodding in 22 children (13). Cognition was assessed in 3 children between 13 and 15 years of age using the KABC-II (Kaufman Assessment Battery for Children) test 2 weeks after beginning treatment with sodium valproate. The study demonstrated severe cognitive impairment. (Working memory, planning, learning, visual spatial, and knowledge domains demonstrated abilities of children 5 years or younger.)
Psychiatric abnormalities. Children with nodding syndrome often show psychiatric abnormalities. Idro and colleagues reported 4 children with paroxysmal episodes of fear, panic, and visual hallucinations, with 1 child shouting and running at the onset of hallucinations and a fourth seeing a person with knives trying “to kill her” (13). Tumwine and colleagues also cited caretakers reporting similar episodes of sudden shouting or screaming, jumping up and running in circles, as well as agitation, weakness, daytime sleepiness, and fluctuating mental abilities (47).
Previously, nodding syndrome was regarded as invariably fatal by local caretakers, although available data do not support such reports. During their 2012 census study, the Ugandan Ministry of Health reported 19 deaths among 767 patients with probable nodding syndrome (2.5%), although they provided no time reference or details (15).
At present, only 1 long-term study is available; Winkler and colleagues followed up with 53 of their original 62 patients after 4 years (53). Two patients (3.5%) had died, 1 during a prolonged status epilepticus and 1 from traumatic brain injury, and 7 patients were lost to follow-up. Additionally, there is significant socioeconomic cost for affected households (25).
The etiology of nodding syndrome remains uncertain, although the disorder emerged in areas of extreme poverty, recent food shortages, armed conflicts, and population displacement (47; 07; 44). Several observational case series and case-control studies demonstrated wasting and stunting in patients with nodding syndrome, but failed to consistently identify associations with consumption of several distinct foods, micronutrient malnutrition (cobalamin, folate, retinol, or selenium), or ingestion of toxic substances (mercury, homocysteine, thiocyanates, copper, lead, arsenic, pesticides, pesticides, or mycotoxins) (47; 07; 09; 13; 41; 46; 08). In Sudan, Tumwine and colleagues reported consumption of red sorghum, consumption of baboon brain, and absence of a previous measles infection as being associated with nodding syndrome, although Foltz and colleagues failed to reproduce these observations (47; 09). In Uganda, Spencer and colleagues reported an epidemiological association of nodding syndrome with prior history of measles infection; however, serological or histopathological data are lacking (44). Regarding infections, malaria, trypanosomiasis, cysticercosis, prion disease, hepatitis E, and polymerase chain reaction for various known viral infections could not depict any associations in Uganda (07; 09). Considering inflammatory markers, Ogwang and colleagues found elevated C-reactive protein (CRP) and C5/C5A in the sera and CSF, respectively, of subjects with nodding syndrome as compared to controls (35). The authors concluded this finding to be suggestive of a nonspecific inflammatory state of still undetermined origin that is possibly infectious, postinfectious, or autoimmune mediated. Of significance are the persistent epidemiological associations with the microscopic helminthic parasites Onchocerca volvulus and Mansonella spp, whereas other filariae such as Loa loa and lymphatic filariasis do not seem to be related to nodding syndrome (47; 07; 09; 46).
Onchocerciasis and nodding syndrome. Epidemiological associations between onchocerciasis and epilepsy in general are reported in several studies (37; 19). Similarly, compared to children without nodding syndrome, a higher prevalence of onchocerciasis was consistently demonstrated in children with nodding syndrome by skin snip microscopy and OV16- and OvFAR/OvMSA-based serology (47; 07; 09; 46). Studies from Tanzania did not find evidence for either the presence of O volvulus in CSF by polymerase chain reaction, nor evidence of O volvulus infection in the CNS by detection of IgM or IgG antibodies against the parasite in CSF, despite O volvulus antibody positivity in serum in 81% of the tested patients with epilepsy (22). This led to the possibility that nodding syndrome is an autoimmune-mediated disease caused by molecular mimicry with O volvulus antigens (17).
Autoimmunity and nodding syndrome. Johnson and colleagues used unbiased protein chip methodology and detected autoantibodies to leiomodin-1, a neuronal cytoplasmic protein that is cross-reactive with O volvulus antigens in the sera and CSF of cases with nodding syndrome from Uganda (17). The authors found leimodin-1 antibody more commonly in the sera of nodding syndrome cases than in sera of the unaffected controls from the same community. Furthermore, the authors were able show that the antibodies to leiomodin-1 were neurotoxic in vitro. However, the same study reported the presence of leimodin-1 antibodies among the unaffected individuals from the same community who were O volvulus positive, and it remains unclear why these individuals do not show symptoms of nodding syndrome. A more perplexing issue was that only 50% of cases with nodding syndrome showed antibodies to leimodin-1 in the CSF. Although this study provided initial evidence to establish nodding syndrome as an immune-mediated epileptic encephalopathy, a causal relationship remains to be established. Conversely, Hotterbeekx and colleagues analyzed the sera of individuals with onchocerciasis-associated epilepsy including nodding syndrome versus healthy controls via a cell mediated and Western blot assay, and no association was found between Onchocerca volvulus infection or epilepsy status and the presence of leiomodin-1 autoantibodies (11). However, only 27% of the affected subjects had nodding seizures, the rest having onchocerciasis-associated epilepsy without nodding seizures. This is in contrast to Johnson and colleagues whose study population only consisted of children with nodding syndrome (17).
Levite and colleagues studied 30 individuals with nodding syndrome and healthy controls from South Sudan and found that a significantly higher proportion subjects with nodding syndrome have antibodies to 3 extracellular peptides of glutamate receptors: anti-AMPA-GluR3B (86%), anti-NMDA-NR1 (77%), and anti-NMDA-NR2 (87%) (27). The same study also found that purified IgGs from subjects with nodding syndrome, particularly subject’s anti-GluR3B antibodies, killed both human neural cells and T cells. Furthermore, the authors were able to induce seizures in vivo after infusing IgG from subjects with nodding syndrome into the brains of normal mice. These experimental findings led the authors to conclude that nodding syndrome is modulated by autoantibodies to the GluR3B receptors that expressed on both neural and T cells, and these glutamate antibodies bind and injure both cell types. A dual-hit on the immune and the nervous system subsequently results in nodding syndrome and overall deterioration of general health due to an external environmental trigger such as Onchocerca volvulus.
Another study investigated the role of antineuronal antibodies against N-methyl-D-aspartate and voltage gated potassium channel receptors in pathogenesis of nodding syndrome in a Tanzanian cohort but did not find any association (06). The difference in the findings among the 3 cohorts from Uganda, Tanzania, and South Sudan needs to be further evaluated.
Genetic aspects. The high familial occurrence and clustering within circumscribed villages and tribes may suggest a hereditary nature of nodding syndrome, as well as of the associated generalized epilepsy and its specific genetic traits. Regarding the area around Mahenge in Tanzania where nodding syndrome seems endemic rather than epidemic, extraordinarily high epilepsy rates in adults and children have been reported--up to 37 per 1000 inhabitants (02; 40; 32; 29). Clusters of people with epilepsy were found in distinct tribes and villages, and within families, whereas other tribes and villages were hardly or not affected (47; 13; 41; 46). Patients with nodding syndrome often have first-degree relatives with epilepsy, and siblings are frequently affected (51). There is a paucity of detailed workup for genetic disorders, although exome sequencing in a child from Uganda and another from South Sudan has not revealed any disease-related changes (07).
Benedek and colleagues evaluated the role of human leukocyte antigen (HLA) class I and II molecules in the pathogenesis of nodding syndrome (03). In 48 subjects with nodding syndrome and 51 health controls from South Sudan, the authors examined 7 human leukocyte antigen loci by next-generation sequencing or sequence-specific oligonucleotide probes. The study found both protective and susceptible haplotypes. Particularly, HLA-B*15:31, HLAB*35:01, HLA -C*01:05, and HLA-DPB1*11:01 were associated with susceptibility, although this was not statistically significant due to small cohort size. The authors concluded that human leukocyte antigen haplotype might affect immunity and promote an autoimmune process leading to the pathogenesis of nodding syndrome in the South Sudanese children. Larger immunogenetic studies, particularly among other affected populations, are needed to further validate the findings of this study.
Metabolic aspects. Inborn errors of metabolism, though infrequent in populations, may frequently result in epilepsy, especially in newborns and infants. However, there are no specific features of nodding syndrome that specifically point toward errors of metabolism. At present, a single study described a metabolic acidosis and diminished vitamin B6 levels in patients with nodding syndrome; further investigations are lacking (07; 09; 21).
Pathology. Pollanen and colleagues reported neuropathological findings in 5 cases of nodding syndrome who were 13 to 18 years of age at death (38). Pathological examination showed tau-immunoreactive neuronal neurofibrillary tangles, pretangles, neuropil threads, and dot-like lesions affecting the cerebral cortex. The tau pathology preferentially affected the frontal and temporal lobes in a patchy distribution. In addition, subcortical nuclei and brainstem were also noted to be involved. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus showed globes neurofibrillary tangles and thread (38).
In another independent study from Uganda, Hotterbeekx and colleagues described pathological changes in 5 individuals with nodding syndrome (10). The authors found inflammatory gliotic changes in several cortical regions and the mesencephalon. The authors also reported CD-68 positive macrophage cluster, primarily in the dentate nucleus, cerebellar vermis, medulla oblangata, and frontal cortex. Similar to the previously reported findings, Hotterbeekx and colleagues also noted presence of Tau-immunoreactive neurofibrillatory tangles in the cortical regions (temporal, frontal, and parietal lobes and the sulcus calcarinus), mesencephalon, thalamic, and basal nucleus.
Population-based studies from 3 independent sites in sub-Saharan Africa--South Sudan, northern Uganda, and southern Tanzania--have been widely published (02; 18; 24; 51; 52; 53; 54; 22; 34; 47; 09; 13; 45; 46; 15). Elsewhere, van der Waals and colleagues reported a few cases of “seizure disorders with dorsoventral movements of the head” in Liberia, and Prischich and colleagues described 4 patients in Cameroon with complex partial seizures characterized by “repeated head movements” and impaired responsiveness lasting a few seconds to several minutes (50; 39). Additionally, a larger epidemiological study confirmed the findings of the smaller case series and found head nodding seizures in Cameroon (42). In Central African Republic, 5 cases of nodding syndrome were described in a cross-sectional survey of over 6000 individuals residing along the Ubangui river (30). Nodding syndrome appears to be “epidemic” in South Sudan and northern Uganda, although it seems rather endemic in Tanzania, with reports dating back to the 1960s (01; 02).
Uganda. In Uganda, the first cases of nodding syndrome were reported in 1997, and between 2000 and 2009 the numbers increased in an epidemic fashion, especially in the northern districts of Kitgum, Lamwo, and Pader (09). As of February 2012, the Ugandan Ministry of Health reported a total of 3097 suspected cases and 170 deaths (case fatality rate: 5.4%) from the 3 northern districts of Kitgum, Lamwo, and Pader; however, a decline in overall and newly diagnosed nodding syndrome cases was noted from mid-2012 onwards (36). Within the first 15 weeks of 2014, the Ministry of Health reported no new cases in Uganda. During the same period in 2013, 25 new cases were reported (49).
Using the newly developed consensus case definition, the U.S. Centers for Disease Control and Prevention and the Ugandan Ministry of Health performed a first systematic prevalence study in March 2013. In the 3 northern Uganda districts, 1687 probable nodding syndrome cases were registered, reflecting a prevalence of 6.8 probable nodding syndrome cases per 1000 children aged 5 to 18 years with a male to female ratio of 1.1 (15). It was noted that the cases were located in proximity to the fast-flowing rivers Pager and Aswa and breeding sites of Simulium flies; the term “river epilepsy” was suggested in accordance to “river blindness” (37; Ugandan Ministry of Health 2011).
South Sudan. In Mundri County, in then southern Sudan, nodding syndrome emerged around 1991 and was reported around 1992 (46). This was prior to the large-scale displacement in the Jambo area noted in Lui, the later epicenter of nodding syndrome, around 1995 (24; 34). Increasing numbers were reported to the WHO in 1997, although incidence stabilized after 2000 with 300 cases being described by 2003 (23). Another increase in incidence of nodding syndrome was confirmed in 2010 (04). Most of the cases were reported from the town of Lui and the village of Amadi in Mundri County, Western Equatoria, with prevalence rates of 2.3% (41 of 1783) and 6.7% (57 of 854) in 2001, respectively, and a female to male ratio of 1.2 (47). The age at onset ranged from 2 to 18 years, with a mean duration of 3.0 years. Further cases were reported from Central Equatoria and Lakes State. In 2012, the overall number of cases was estimated by the Ministry of Health and WHO to be about 6000 to 8000 cases (43). As in Uganda, nodding syndrome is mainly seen in areas endemic for onchocerciasis and around the breeding sites of Simulium flies. It has only been reported in the sessile Moru tribe and not in the itinerant Dinka tribe (46).
Tanzania. Winkler and colleagues reported 62 patients with nodding syndrome with a median age of 14 years and a 3 to 2 female predominance (51). Detailed epidemiologic data from Tanzania are not available; so far, it has only been described in the Wapogoro tribe.
The literature often links nodding syndrome to Nakalanga syndrome, a form of endemic dwarfism described in Uganda, Ethiopia, Burundi, and Rwanda (28; 16; 26; 20; 33). The children present with arrested growth in early or mid-childhood, delayed maturity and sexual development, wasting, muscle atrophy, and skeletal abnormalities (kyphoscoliosis, pectus carinatum, shortened neck, prognathism). The clinical findings have been attributed to endocrine dysfunction as histologic abnormalities in the adenohypophysis, thyroid, adrenal gland, and testis have been found. The children are often described as gentle, docile, and apathic; cognitive impairment and epilepsy are frequently associated, although not compulsory findings. The disorder was first described in areas hyperendemic for onchocerciasis, with a prevalence of up to 1.7 %. Virtually all patients suffered from onchocerciasis, and reports of the disorder ceased with eradication of Simulium vectors in the affected areas. Nevertheless, epileptic seizures seem to be only an additional finding in Nakalanga syndrome, although they are noted (16; 26; 20; 33). Stereotyped body movements such as nodding of the head or body rocking are observed in several neurologic and psychiatric disorders, such as Rett syndrome, autisms, and posttraumatic stress disorders. Many of the children, especially in Uganda and South Sudan are traumatized by displacement, violence, abuse and war crimes, orphanages, poverty, starvation, and lack of appropriate care, and their general appearance may resemble children from Romanian orphanages with anaclitic depression as reported in the ‘90s.
At present, the diagnosis of nodding syndrome remains based on the epidemiological clinical case definition established at the First International Scientific Meeting on Nodding Syndrome and according to the level of evidence; suspected, probable, and confirmed cases are distinguished (55). There are no distinct serological, cerebrospinal fluid, imaging, or electrophysiological studies to diagnose nodding syndrome. However, nutritional and micronutrient deficiencies have been commonly reported in case of nodding syndrome and need to be evaluated. Iron deficiency, anemia, metabolic acidosis, and vitamin B6 deficiency are described, although they are likely secondary to the marked wasting. Kitara and colleagues described endocrine parameters such as thyroid-stimulating hormone, thyroxin (T4), T3, prolactin, vitamin D3, and parathyroid hormone in 10 patients without major abnormalities, but with no control group; the significance of these findings is unclear (21).
MRI studies performed by Idro and colleagues showed different degrees of cortical and cerebellar atrophy in 19 of 22 patients without focal cerebral cortical or hippocampal changes (12). Sejvar and colleagues performed MRI investigations in 5 children with nodding syndrome, 4 of whom showed varying degrees of generalized cortical and cerebellar atrophy most prominent in the parieto-occipital and anterior temporal areas and in the cerebellum (41). Hippocampal atrophy was noted in 2 children, and the MRI for 1 child revealed encephalomalacia with a large calcified cystic lesion of the right parietal lobe most likely due to a previous cerebral infection. Winkler and colleagues performed MRI studies in 12 patients (53). Four of 7 patients with HN only had a normal scan. In the other 3 patients, hippocampus pathologies were seen: 2 had additional gliotic lesions. None of the 5 patients with HN plus had a normal MRI; all showed either gliotic lesions or hippocampus pathologies.
As the etiology and pathophysiology of nodding syndrome remains uncertain, there are no specific or definitive therapies available. Nevertheless, Idro and colleagues proposed guidelines for the management of nodding syndrome and presented a manual to guide and train health workers (12). Including data from Uganda, Tanzania, and South Sudan, they provide recommendations on symptomatic supportive care for emergency, inpatient, outpatient, and community-based settings and advise on diagnostics, follow-up care surveillance, documentation, and community education. Recommendations on seizure control, management of malnutrition, behavioral and psychiatric problems, nursing, wound care, infections, as well as nutritional, physical, and cognitive rehabilitation are given. Regarding seizure control, few data are available. Drugs were mainly chosen due to their availability, and, hence, their use differs at the various sites. At present, sodium valproate, phenobarbital, carbamazepine, and phenytoin have been described.
Within their guidelines, Idro and colleagues recommend valproate up to 40 mg/kg/day and suggest lamotrigine and levetiracetam as second-line medication, although both drugs have not been used in nodding syndrome so far (12). Recommendations on the duration of treatment have not been given.
Applying these guidelines in a cohort of 22 children previously treated with low doses of phenytoin, phenobarbital, and carbamazepine, Idro and colleagues reported a 57% reduction of seizure frequency (nodding and generalized tonic-clonic seizures) under valproate 15 to 25 mg/kg/day within 2 to 3 weeks (13).
Winkler and colleagues reported on the long-term outcome of 53 Tanzanian patients with nodding syndrome, 46 (86.8%) of whom were on antiepileptic medication (54). Of the 32 patients treated with phenobarbital, head nodding stopped in 15 patients, although 13 (86.7%) had ongoing generalized tonic-clonic seizures. Head nodding frequency decreased in 11 children, remained unchanged in 4, and increased in 2. In 3 of 7 patients treated with carbamazepine alone, head nodding stopped, although the patients continued to have generalized tonic-clonic seizures. Head nodding seizures decreased in another 3 patients, whereas they increased in 1 patient.
With the findings of possible autoantibody-mediated pathogenesis of nodding syndrome caused by molecular mimicry with O volvulus, patients may benefit from immunomodulatory therapies (17). However, this hypothesis is yet to be studied.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.See Profile
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