Nodding syndrome

Nodding syndrome also called nodding disease or nodding head syndrome, is a rare unexplained neurological condition that is characterized by episodes of repetitive dropping forward of the head (head nodding), often accompanied by other seizure-like activity, such as convulsions or staring spells, often in association with progressive neurocognitive impairment and physical decline ¹. Recent studies have concluded that the head nods are due to atonic seizures ². Nodding syndrome was first documented in the United Republic of Tanzania in the 1960s, then later in the Republic of South Sudan in the 1990s, in northern Uganda in 2007 and southern Tanzania ³. Jilek et al ⁴ first described several children with attacks of “head nodding” in Mahenge, a region in United Republic of Tanzania. Nodding syndrome predominantly affects children between the ages of 5 and 15 years old, causing progressive cognitive dysfunction, neurological deterioration, stunted growth and a characteristic nodding of the head. The age of onset in the vast majority of cases ranges between 5 and 15 years old, but cases have been reported in children as young as 2 years old and in adults up to 32 years old. There is no observed significant difference in the proportion of males to females among the affected, nor is there an observed seasonal variation. Despite numerous and extensive investigations in all three countries, very little is known about the cause of the disease. No underlying cause or cure has been established ⁵.

Nodding syndrome is known to occur in the southern region of the United Republic of Tanzania (Mahenge mountains, Ulanga District), South Sudan (Western Equatoria State, Eastern Equatoria State, Central Equatoria State, and Lakes State) and northern Uganda (Pader, Kitgum and Lamwo districts, with new cases starting to present in Gulu, Amuru, Oyam and Lira districts) ³.

Samaritan Purse, a local NGO, described observations of head nodding among several children in southern Sudan in the Lui and Amadi villages of East Mundri County in the mid-1990s. A physician from Samaritan Purse reported the outbreak to World Health Organization (WHO) in 1997 ³. The 2001-2002 investigations by WHO and partners estimated the prevalence of Nodding syndrome at 4.6% among a small population in Western Equatoria State, which appeared to have the highest burden of the illness. By 2003, an estimated 300 cases had been reported from this region ³. The Ministry of Health of South Sudan estimates the current burden of Nodding syndrome at between six and seven thousand cases, but no systematic large-scale prevalence study has been conducted. The Mundri region in the northeast of Western Equatoria is the presumed epicenter for the disease.

In 2008 and 2009, an illness consistent with Nodding syndrome was reported from Kitgum and Pader Districts in northern Uganda. As of February 2012, Uganda has reported over 3 000 cases of Nodding syndrome from the three districts of Kitgum, Lamwo and Pader. A community survey is underway in Uganda to determine the real burden of Nodding syndrome in the affected districts. Kaiser et al ⁶ referred to a phenomenon of head nodding observed in the Kabarole District in Western Uganda as possibly constituting a feature of an epileptic syndrome caused by Onchocerca volvulus (onchocerciasis or river blindness). Today there is overwhelming evidence that Nodding syndrome, together with the Nakalanga syndrome is one of the clinical presentations of onchocerciasis-associated epilepsy ⁷.

The prevalence of both onchocerciasis and epilepsy in the areas affected by Nodding syndrome is high. The affected populations are impoverished and experience regular and prolonged periods of severe food shortages. In South Sudan and in northern Uganda, affected populations have a history of internal displacement and living in internally displaced persons camps.

Familial clustering has been observed in some families with Nodding syndrome patients, with more than one sibling with Nodding syndrome and/or siblings or relatives with other forms of epilepsy.

Nodding syndrome causes

Nodding syndrome has been discovered to be a special seizure called an atonic seizure of unknown cause ⁵. Associations of Nodding syndrome with malnutrition and with onchocerciasis (Onchocerca volvulus infection or river blindness) have been documented, but remain inconclusive. Extensive investigation of environmental neurotoxins, nutritional deficiencies, genetic disorders, or infectious organisms has been unrevealing ⁸. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. A high prevalence of epilepsy has also been reported in many onchocerciasis meso- and hyper-endemic regions particularly where transmission is poorly controlled ⁹. A study in an onchocerciasis-endemic region in the Mbam valley in Cameroon showed that the risk of developing epilepsy increased with increasing Onchocerca volvulus microfilarial density ¹⁰. Johnson et al ¹¹ hypothesized that Nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, they detected autoantibodies to leiomodin-1 more abundantly in patients with Nodding syndrome compared to unaffected controls from the same village ¹¹. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with Nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with Nodding syndrome ¹¹. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with Onchocerca volvulus antigens. This study ¹¹ provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with Onchocerca volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.

Nodding syndrome symptoms

Nodding syndrome is characterized by episodes of repetitive dropping forward of the head, often accompanied by other seizure-like activity, such as convulsions or staring spells, often in association with progressive cognitive dysfunction, neurological deterioration and stunted growth ¹. The age of onset in the vast majority of cases ranges between 5 and 15 years old, but cases have been reported in children as young as 2 years old and in adults up to 32 years old. There is no observed significant difference in the proportion of males to females among the affected, nor is there an observed seasonal variation.

Five clinical stages with deteriorating seizures, neuro-cognitive, physical and psychiatric disability can be identified in Ugandan patients. These include a prodrome; development of head nodding and cognitive impairment; other seizure types; multiple complications and, severe disability.

Nodding episodes occur several times a week to many times per day, and episodes have been observed by investigators, recorded videographically, and documented by video–EEG ¹². Often triggered by eating or cold weather, the head drops repeatedly toward the chest in cycles of 5–20 nods/min for several minutes. Nodding may be accompanied by automatisms or other seizure-like activity, and the child is either unaware of his or her surroundings or has a decreased ability to continue an activity (e.g., eating) or respond to questions or external stimuli.

Simultaneous recording of 2 episodes by EEG, videography, electromyography, and electrocardiography documented that the nodding episodes are manifestations of atonic seizures. In these case-patients, head nodding was associated with generalized electrodecrement, followed by generalized sharply contoured rhythmic theta activity, dropping of the chin, and paraspinal electromyographic abnormalities ¹². Other EEG recordings in ≥61 patients reported or observed to have nodding syndrome have consistently identified interictal abnormalities and various electrographic seizure types ¹². In the Sudan patient series, which included 32 patients at various stages of disease, worsening or more severe clinical disease was associated with more severe EEG findings, as shown by progressively more abnormal background activity, ultimately resulting in diffuse subcontinuous nonreacting delta–theta activity and loss of normal cerebral electrical architecture ¹³. Biphasic or triphasic periodic sharp waves of the type frequently seen in human prion diseases or metabolic disorders were not observed in any of these assessments, and there were no periodic lateralizing epileptiform discharges suggestive of encephalitis from herpesvirus or other viruses.

Nodding syndrome diagnosis

The causes of Nodding syndrome are currently unknown. More recently, scientists have found evidence to suggest that Nodding syndrome is caused by an inappropriate immune response to Onchocerca volvulus parasitic worm.  Johnson et al ¹¹ hypothesized that Nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, they detected autoantibodies to leiomodin-1 more abundantly in patients with Nodding syndrome compared to unaffected controls from the same village ¹¹. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with Nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with Nodding syndrome ¹¹. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with Onchocerca volvulus antigens. This study ¹¹ provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with Onchocerca volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.

Essential investigations include thick and thin blood smears for malaria parasites, blood glucose, complete blood count, peripheral blood film and ESR, blood chemistry for liver and renal function and electrolytes and creatine kinase ¹⁴. In addition, a diagnostic electroencephalogram (EEG) recording and a skin snip (for a diagnosis of Onchocerca volvulus and Mansonella perstans) should be obtained in all patients. Blood cultures, lumbar puncture for cerebrospinal fluid and brain imaging with brain MRI and/or CT scan should be performed as indicated. Lumber puncture is indicated in patients with features suggestive of meningitis or trypanosomiasis. In the case of repeated uncontrolled seizures and maybe new neurological signs/symptoms one should envisage serology for Taenia solium cysticercosis. Skull and limb X-rays to exclude fractures from injuries, chest X-rays for evidence of chest infection and X-rays of the wrist to determine bone age may also be performed.

Nodding syndrome treatment

There is currently no cure for Nodding syndrome and its management is not standardized and there is no established definitive treatment ¹⁵. Antiepileptic drugs (phenobarbitone, sodium valproate) and ivermectin, which have had various outcomes with patients, are the main drugs currently used for treatment. There are no clinical trials that have examined antiepileptic medications in Nodding syndrome. Anecdotal reports among patients with head nodding from Tanzania suggest a decrease in seizure frequency whe nthey used phenytoin and phenobarbitone either individually or in combination ¹⁶. These two are the most common antiepileptic drugs in the affected communities. In developing the guidelines, carbamazepine was not considered because of risk of precipitating myoclonic jerks ¹⁷. Instead, the types of seizures in these patients suggested sodium valproate may be a better option ¹⁸. Sodium valproate is also active against some behavioral difficulties like aggression and impulsive behavior ¹⁹. It is suggested to start with 10 mg/kg/day in two divided doses and increase the dose by 5 mg/kg/day increments until seizure control is achieved orthe maximum dose is reached. Idro et al ¹⁴ suggest amaximum dose of 40mg/kg/day in children. Preferably, a single brand should be used consistently as absorption characteristics may differ among brands. The pre-treatment liver function should be determined before initiation of therapy and used inmonitoring treatment toxicity

Ivermectin kills the Onchocerca volvulus larvae and prevents them from causing damage but it does not kill the adults. There is a promising treatment using doxycycline that kills the adult worms by killing the Wolbachia bacteria on which the adult worms depend in order to survive. If you are infected, it is possible that your doctor will want to treat you both with ivermectin and with doxycycline.

Futhermore, medical centers in Uganda have shown that treatment with adequate nutrition, and psychosocial support can improve the long-term outlook of the condition ²⁰.

References

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