Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT01730313 |
| Other study ID # |
CDC-CGH-6318 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 2016 |
| Est. completion date |
July 2017 |
Study information
| Verified date |
May 2022 |
| Source |
Centers for Disease Control and Prevention |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Nodding Syndrome (NS) is a novel form of epilepsy seen predominantly among children aged 5-15
years and characterized by head nodding, progressively worsening seizures, and cognitive
impairment. To date, the cause of NS remains unclear. A recent assessment by the Uganda
Ministry of Health (MOH), World Health Organization (WHO), and US CDC conducted in Kitgum
District in northern Uganda documented that the nodding episodes themselves resulted from
atonic seizures, and that the children also exhibit multiple different seizure types, both
clinically and electrographically. The investigation also found that there was significantly
greater sero-positivity for onchocerciasis among children with NS compared with control
children, and demonstrated low serum concentrations of vitamin B6 (pyridoxine) among both
cases and controls. Vitamin B6 is involved in neurotransmission and has been an effective
treatment of seizures for certain rare type of epileptic syndrome. Children with nodding
syndrome in Kitgum have been episodically treated with multivitamins, ivermectin, and
anti-epileptic medications including phenobarbital, phenytoin, carbamazepine, and valproate,
but the possible beneficial or harmful effects of any of these medications for nodding
syndrome has not been systematically assessed, and reports from parents and guardians about
apparent effectiveness are varied.
The investigators propose a randomized blinded four group clinical trial with crossover
design to study the effect and response to therapeutic doses of oral pyridoxine (vitamin B6)
and treatment with currently used conventional anti-epileptics including phenytoin and sodium
valproate, among children with nodding syndrome.
Description:
Nodding Syndrome (NS) is described as an epileptic seizure disorder and has been documented
in various geographic areas of sub-Saharan Africa. Jilek et al, 1962, first described several
children with attacks of 'nodding head' in Mahenge, a region in southern Tanzania (1,2,3). A
missionary doctor described children in southern Sudan in the mid-1990s, where it was first
noted in the Lui and Amadi villages of East Mundri county and the Lui region of western
Equatoria; a medical NGO then reported the condition to WHO in 1997. An estimated 300 cases
were reported in 2003 from this region (4, 5). Winkler et al., using data from Tanzania
provided a clinical classification of seizures, semiology and socio-cultural aspects
suggesting it was a syndrome (referred to as "head-nodding syndrome") and a form of epilepsy
(6, 7). In 2008 and 2009, reports of an illness consistent with NS were reported in Kitgum
and Pader districts, northern Uganda. Kaiser et al, in 2009, referred to the phenomenon of
head nodding as possibly constituting a feature of an epileptic syndrome caused by O.
volvulus (8).
Descriptions of the features of NS appear similar between reports (Appendix A). Nodding is
frequently described as occurring in response to some stimulus, frequently being the presence
of food or exposure to cold (4, 5, 6, 7). The nodding consists of repetitive bobbing or
nodding of the head, sometimes associated with loss of muscle tone in the trunk and upper
extremities (6, 7). Consciousness may or may not be impaired during the nodding episodes. The
syndrome has been described to be progressive, with gradual neurological deterioration and
development of additional seizure types, developmental regression, cognitive decline, and
sometimes reportedly resulting in serious injuries or death both due to accidental falls into
fires or wells during seizure episodes. Treatment with conventional antiepileptic medications
has anecdotally been reported to result in some symptomatic improvement of both nodding and
other seizure types. Health workers in southern Sudan report that children who start
treatment early and on regular basis have seizures less frequently (9).
The cause of NS is unknown. Various factors and exposures have been postulated to cause NS,
including exposure to munitions, prior history of measles infection, consumption of baboon
meat and sorghum, and others. Two recent case-control investigations, one conducted among
children with NS in Uganda during 2009 - 2010 and another conducted in S. Sudan in 2011
(below) have not supported these associations. One risk factor that appears to consistently
demonstrate an association with NS is evidence of infection, past or present, with the
microfilarial parasite Onchocerca volvulus, or a similar microfilarial parasite that is
serologically cross-reactive with Onchocerca. O. volvulus is transmitted by black flies.
Clinical manifestation of onchocerciasis is mainly ocular, with resultant vision loss due to
inflammatory keratitis ("River Blindness"). A significant association of NS with detection of
O. volvulus microfilariae in skin snips was observed in a case-control investigation in Sudan
in 2001 - 2002, and in an assessment in Tanzania (84% of 62 children with NS had
microfilariae or O. volvulus nucleic acid in skin snips). Various studies and reviews have
identified an association between onchocerciasis and epilepsy in general (5, 10, 11, 12, 13,
14, 15, 16, 17, 44, 46). A high prevalence of seizure disorders in onchocerciasis endemic
areas was noted in Western Equatoria in 1946.
In the WHO investigations conducted in southern Sudan in late 2001, skin snip positivity and
higher microfilaria loads of O. volvulus were found in children with NS when compared to
children without the condition, consistent with similar observations of a possible
association between seizures and onchocerciasis from other studies (5, 10, 11, 12, 13, 14,
15, 16, 17, 44, 46). These, and subsequent investigations in 2002 by WHO could not identify
any environmental pollutants, chemical agents or food toxins, nor several infectious agents,
as possible causes for the seizures. EEG among 31 children assessed showed progressive
epileptic encephalopathy.
In December 2009, a team from the US Centers for Disease Control and Prevention (CDC)
assisted the Uganda Ministry of Health and the WHO in the investigation of the occurrence of
NS in Kitgum / Pader regions of northern Uganda. A total of 51 cases with reported NS, and 93
household or friend controls were identified for the case control investigation and
additionally, 23 subjects with reported NS were enrolled in a case series that underwent
thorough medical and neurological assessments.
Unpublished data from the assessment demonstrated that NS is a seizure disorder, and that the
nodding episodes are due to atonic seizures resulting in loss of tone associated with changes
on electroencephalography (EEG) including multiple other clinical and subclinical seizure
types. The surveillance data showed that the prevalence of NS in parts of Kitgum region is
many-fold higher than what would be expected for comparable forms of epilepsy, based upon
data from North America and Europe.
In the case-control investigation, while skin snip positivity for the presence of O. volvulus
microfilariae was not associated with NS cases, seropositivity for antibodies to O. volvulus
was, with 95% of cases positive for onchocerciasis serology compared with 54% of controls
(p=0.03). The investigation also showed low serum vitamin B6 (pyridoxine) levels (<20) among
the population of children between the ages of 5 and 15 in the region as a whole, both cases
and controls. Deficiencies in vitamin A, selenium, and zinc, among both cases and controls
were also noted.
The Ministry of Health, Government of Southern Sudan (MoH-GoSS), further investigated for NS
in the Witto internally displaced persons (IDP) camp in Witto Payam in western Equatoria in
September 2010. A total of 96 cases were registered, most aged between 5-20 years (highest in
the age group 10-15 years). Head nodding, tonic-clonic partial seizures with secondary
generalization and generalized seizures were reported. Based on the past two investigations,
and available data, it was concluded that NS is a form of epilepsy with causes remaining
obscure (9).
In May and June of 2011, a team from the CDC assisted the South Sudan Ministry of Health and
the WHO with an investigation of NS in Western Equatoria State in South Sudan. A total of 38
case-control pairs matched by age- and village- were identified for the case control
investigation and separately, 25 subjects with reported NS were enrolled in a case series and
underwent thorough medical and neurological evaluations (17). The findings from this
investigation were consistent with the unpublished findings from investigations in Uganda in
2009-10, with the cause of Nodding syndrome continuing to remain unknown.
Currently, parents and caregivers of children with NS report that children respond to locally
available anti-epileptic drugs (AEDs) differently; some reporting that there is a response
and others not. These locally available AEDs include carbamazepine, phenytoin,
phenobarbitone, and valproate. However, this information is anecdotal and it remains unclear
whether children receive medications on a regular basis, what doses are administered or
adhered to, or whether they achieve therapeutic levels of AEDs. The investigators therefore
additionally propose two AED treatment arms with conventional anti-epileptic therapy
including sodium valproate and phenytoin, in order to validate the reported response to
conventional anti-epileptic drugs.
Based on investigations done so far, children with NS appear to suffer from multiple clinical
and electrographic seizure types, including generalized tonic-clonic, partial complex,
atypical absence, and atonic seizures. Seizures are classified as partial generalized, and
unclassified based on the clinical features and associated electroencephalographic findings
(Appendix Y). There are many causes for seizures, including infectious, metabolic, drugs,
genetic, nutritional, endocrinal, and trauma. In some cases, an etiology is not known, and
the seizures are referred to as idiopathic or cryptogenic. Currently, because an etiology for
NS has not been identified, the children suffer from multiple different seizure types, and
many children demonstrate cognitive impairment, NS could be considered a form of cryptogenic
epileptic encephalopathy. This is important because such epilepsies can be very difficult to
control with standard AEDs, and in some cases, may be exacerbated with certain AEDs (e.g.,
carbamazepine) (18, 19, 20, 21, 22). Thus, a formal assessment of the effects of AEDs on
children with NS is important.
The finding of low pyridoxine levels among children assessed, in the population of Kitgum
District as well as in the children assessed in Western Equatoria in South Sudan is notable,
in the light of a condition known as pyridoxine-dependent seizures (PDS) and
pyridoxine-responsive seizures. Hunt et al, (1954) first described pyridoxine dependent
seizures (PDS) (23) with an autosomal recessive inheritance. PDS is due to defective binding
of pyridoxine to its apoenzyme, glutamate decarboxylase, which catalyzes the conversion of
glutamic acid, a critical nutrient, into gamma-aminobutyric acid (GABA), an inhibitory
central nervous system neurotransmitter. The resultant reduced levels of GABA lower the
seizure threshold, leading to intractable seizures (24, 25,26, 27, appendix Z).
PDS commonly manifests among infants as intractable seizures, generally beginning within
hours of birth. Classically multiple types of clinical and electrographic seizures are
described among individuals with PDS (24, 28, 29, 30). Prolonged seizures and recurrent
episodes of status epilepticus are typical, also reported are recurrent self-limited events
including partial seizures, generalized seizures, atonic seizures, myoclonic events, and
infantile spasms (27, 30, 31).
Commonly seen in neonates and infants, atypical presentations are known to occur with seizure
onset later in childhood including report in a child of 6 years (26, 27, 32, 33, 34).
PDS is a diagnostic consideration in such instances among infants when the seizures are
intractable and may not be controlled with conventional anticonvulsants but that respond both
clinically and electrographically to pharmacologic doses of pyridoxine (27, 35).
A trial of therapeutic doses of B6 (administration of 100 mg or more of pyridoxine) is
indicated in infants / children with intractable seizures unresponsive to standard
anti-epileptic drug (AED) treatment (24, 25, 26, 35, 36, 37, 38). Intravenous or
intramuscular administration is recommended in infants with ongoing seizures or status
epilepticus, in order to achieve immediate resolution of seizures and clinical seizures
generally cease over several minutes to hours (29). If responsive, oral maintenance dose of
2-500mg/day PO (15-18mg/kg/day optimally and sometimes as high as 680mg initially and 200
mg/day subsequently) has to be followed indefinitely (33, 35). Clinical seizures generally
cease over several minutes to hours. Recommended daily allowance (RDA) for pyridoxine is 0.5
mg for infants and 2.0 mg for adults or 50-100 mg of pyridoxine per day (38, 39, 40) with
dosage adjustment for age, intercurrent illnesses and to allow greatest intellectual
performance but not exceeding 500 mg/day (27, 28, 36, 38, 41). The chance to identify
specificity is lost if pyridoxine is given together with or after, many anticonvulsant drugs
(27). Daily supplementation with pharmacologic doses of pyridoxine is the accepted treatment
for this disorder.
The seizures as reported to occur among children with NS appear to share several features
with PDS, namely multiple seizure types. However, NS does not represent PDS in its typical
form; any relationship between NS and pyridoxine deficiency is only suspected in light of the
presence of the deficiency in the population. However, unpublished findings from two
investigations undertaken separately in Uganda (2010) and South Sudan (2011) show that
deficiency of B6 has been noticed among this population of children (both cases and controls)
raises the possibility of a contributory role of B6 deficiency in NS. Since the entire
population, including both children with and without NS, appears to be pyridoxine-deficient,
the illness cannot be attributed to B6 deficiency alone; however, the possibility that low B6
levels may be a contributory factor remains and therefore a treatment trial with pyridoxine
is proposed because PDS is a therapeutic diagnostic consideration in such settings. Because
the seizures in children with NS appear to have a gradual onset, and are intermittent with
significant interictal periods, intravenous administration of pyridoxine is not necessary and
oral supplementation will be most appropriate. B6 treatment is safe. There are few reports of
significant side effects of B6 treatment. Apnea, lethargy and hypotonia among infants soon
after starting B6 have been reported (3 out of 5 infants by Mikati, et al), but these are
rare (29).
Since the diagnosis of PDS is based upon a response to the therapeutic intervention and
requires a trial of the treatment, and such replacement may provide a safe, efficacious
treatment for PDS, we propose to assess the possible efficacy of B6 supplementation for NS in
the form of oral pyridoxine treatment to evaluate the response and efficacy on the cessation
or reduction of seizures. Dosing for pyridoxine is 30 - 50 mg/kg/day in a single daily dose.
In summary, there appears to be growing data that NS is a seizure disorder and some of the
various current treatment approaches have focused on use of antiepileptic medications. For
most Ugandan children with this disorder, the current standard is no treatment or episodic
treatment with multivitamins and/or antiepileptic medications, which are typically
administered by psychiatric nurses with no or limited physician oversight. Information about
the effectiveness of this treatment approach is based on anecdotal reports, and there are no
reliable systematically collected data about dosage or frequency of medication use. In
addition to the lack of scientific data on the effectiveness of these treatment approaches,
there are important questions that need to be addressed regarding possible adverse effects of
use of antiepileptic medications in children with NS. Anecdotal reports from caregivers and
local treating physicians suggest that NS seizures appear to respond variably to locally
available anti-epileptic drugs; however, for the reasons outlined above, this has not been
clearly demonstrated. In addition, several aspects of treatment remain undetermined
including, whether children are given medications on a regular basis, are given appropriate
doses of antiepileptic drugs per weight, or are achieving therapeutic doses of drug.
In addition, it is not clear whether the children with NS are obtaining clinical benefit or
are being harmed from AED treatment. Given the knowledge on the nature of the seizure types
seen in NS, it is possible that NS will be difficult to manage with conventional AED
approaches. In fact, certain antiepileptic medications may in some cases paradoxically
exacerbate certain seizure conditions (18, 19, 20, 21, 22). Such exacerbation is particularly
true in epileptic encephalopathies. For children with cryptogenic generalized epileptic
disorders, the AED sodium valproate (valproic acid) has been found to be often effective, has
fewer side effects than many other AEDs, and is considered the drug of choice (42). Valproic
acid is currently listed as a recommended AED by WHO. The investigators therefore propose a
simultaneous assessment of pyridoxine, valproic acid, as well as an AED that is currently
being utilized in the community for children with NS (phenytoin) and compare them with
response if any to a placebo controlled intervention group.
