INTRODUCTION

Our recent August 2019 epilepsy outreach mission to Liberia, West Africa highlights three salient observations which deserves academic attention and by extension, plans for further clinical engagement and interventions. ie: a) public health; b) biophysical and c) biochemical.

Public Health

The absolute location of Liberia is latitudes 40 20’ and 80 30’ north of the equator and longitudes 7o 18’ and 11o 20’ west of the prime meridian. Liberia covers an area of 111,370 sq. km. 15,050 sq. km is water and the remaining 96,320 sq. km is land. The relief systems of Liberia is sub-divided into four relief belts parallel to the coast rising in steps, the Coastal Belt (50 ft, 15 meters ); Rolling Hills belt (300 ft, 100 meters), the Dissected Plateau belt (1000 feet, 300 meters) and the Northern Highlands belt (6000 feet, 1800 meters) above sea level respectively. Most of the country comprises of forest except a narrow strip along the coast where mangrove vegetation alternate with coastal savanna. The climate conditions in the entire country allow the vegetation to develop into a tropical rainforest.

The country is resource rich but due to gross ineptitude, poor leadership and lack of national vision, all economic and health indices are essentially moribund and primitive. The health sector is faring no better.

We chose to focus on epilepsy this year (Ref. 1,video) due to prior reports including the seminal work by Gadjusek et al (Ref 5) in 1983 about the epilepsy epidemic and epilepsy belt in Liberia, making Liberia with the second highest incidence of epilepsy on the African continent according to WHO statistics. Since that seminal report there has been no noticeable effort in Liberia to address this report and its findings.

Even in 2019 we noted that Liberian national policy makers do not even treat epilepsy with the national urgency that it deserves. To make matters worse, there is a serious lack of common anticonvulsants (the only commonly available AEDs , albeit inconsistently available, were carbamazepine and Phenobarbital). The costs associated with these medications are sometimes prohibitive for a large segment of affected individuals. A truly serious inhibitory factor is the dearth of neurologist in Liberia.

As per WHO and WFN data, the ratio of neurologists per country in Africa is 0.03 neurologists per 100,000 population (contrast with Europe where it is 4.84 neurologists per country) (4). This means that Liberia should have at least 1 locally available neurologist. The reality is there is no local neurologist in Liberia and this is true for 23 African countries as per recent World Federation of Neurology followup data. The fact is that since its independence in 1847, Liberia has not had produced any neurologist locally. Your humble servant is the only neurologist trained from that country since its inception in 1847 (certainly mighty thanks to Hungary).

Many epidemiology, etiologic and management studies of epilepsy in sub Saharan Africa especially door to door studies estimate that the prevalence of epilepsy is double that in Asia, Europe and North America. Incidence of epilepsy is stated as 81.7 per 100 000 in less developed countries vs 45 per 100 000 in more developed countries. Mortality from epilepsy in Western countries is two to three times than the average population, that is several times higher in Africa. From western studies, men are more affected than women and that trends seems to hold true to Africa as well. (6, Diop et al) . Cases of epilepsy in Africa tend to be more severe due to lack of proper treatment and stigmatization.

The implicated risk factors are CNS infections (bilharzia, cerebral malaria, cysticercosis, meningitis), birth trauma and traumatic brain injury. Public health measures are urgently needed to address several of the risk factors that can be impacted: eg. Use of the berries of Phytolacca dodecandra which produces a carboxylic acid saponification agent (called lemmatoxin) which can be used to eradicate the bilharzia or Schistosomiasis (mansoni, haematobium, japonicum) parasite and its intermediate host, Bulinus snails , which is prevalent in central Liberia and is a significant causative agent of neuroschistosomiasis and seizures.

Public health awareness of traffic accidents prevention and the mandatory use of helmets by the riders of motorcycles, a very prominent mode of transport in Liberia as well as prenatal health services and skilled midwifery especially in the rural areas. In endemic areas, the annual widespread use of praziquantel (40 mg /kg) in endemic area is proposed as a proactive mitigation effort. Serious effort for the institution of CT scan head national protocol for all seizure patients (at present less than 0.05% get CT scans). A look at home schooling efforts for those kids who because of prevailing stigmatization are at least 6 grade levels behind their peers until national seizure education becomes effective. (See videos 1 and 1a). Serious strategies to prevent epilepsy, to reduce stigma and treatment gaps and home schooling for school kids excluded from attending school due to prevailing population ignorance about epilepsy are of utmost public health priorities.

Biophysical and Circalunar rhythms

In the coastal city of Buchanan, where we examined and treated 125 patients about one third gave a clear convincing history of increased seizure frequency during the full moons ie the perigee syzygy of the lunar phase. This raises an interesting question about astronomy and seizure occurrence. Several of these patients use this phenomenon in a practical way: ie. During the full moon, many skip work and other such activities staying home as preemptive measures to avoid much of the prevailing public stigma associated with seizures in Liberia. Another 15 to 20% of affected patients report a predominant nocturnal occurrence of their seizures without relevant family history of seizures. Further investigations show that the magnetic intensity of the moon is minimal on small bodies contrary to the effect of the moon on high and low tides. Other researches postulate that possible sleep deprivation during full moon periods might be explanatory. The phenomenon of moonstruck is at best controversial at present. Further observations are surely warranted.

Further, the Circadian Output Locomotor Cycles Kaput gene encoding CLOCK, a transcription factor critically important in the generation of circadian rhythms has been shown from surgically resected specimen in epilepsy patients who underwent therapeutic resections, that its deletion in excitatory neurons (but not in inhibitory neurons) decreases seizure threshold and increases spontaneous seizures. BMAL 1 is the other half of the two master heterodimeric transcription factor. It is further reported that 25% of patients report seizures in their sleep-adding some relevance to this history obtained from these patients we examined and treated in Buchanan, Grand Bassa County (2,3,7)..

Biochemical

A prevailing notion among the Liberian doctors we encountered was the cyanide hypothesis. They postulate that cassava , the commonly prepared and eaten in Liberia has a significant biochemical role in epileptogenesis. There is very little scientific or anthropologic evidence to support this hypothesis. There is a serious scientific need to prove or disprove this notion as it seems to be accepted as a foregone conclusion over there. The common used method to prepare cassava tuber in Liberia detoxifies and eradicate the cyanide content of cassava leaves and tubers. The use of this tuber is so wide spread that if this hypothesis were true, a significantly higher incidence of seizures, much higher than the already high incidence and prevalence would be the case.

Cassava roots, peels and leaves contain two cyanogenic glycosides: linamarin and lotaustralin, which are decomposed by linamarase, a naturally occurring enzyme in cassava, which when in contact with either will liberate hydrogen cyanide (HCN). In all parts of Liberia, cassava roots and leaves are used in many national dishes.. Cassava peels are uniformly disposed off by all without any consumption. Uniformly sweet (not bitter) cassava is consumed by all.. Sweet cassava contains less than 50 mg cyanide per kg hydrogen cyanide vs bitter variety, 400 mg per kg on fresh weight basis of hydrogen cyanide. Methods such as grating, soaking, fermenting, rasping, boiling etc are methods used by the locals and this is responsible for about 90% cyanogen removal.

Cyanide poisons the mitochondrial electron transport chain within cells specifically binding to the a3 portion (complex IV) of cytochrome oxidase, preventing cells from deriving energy, ATP from oxygen, causing rapid death. The early signs of cyanide poisoning include headache, dizziness, rapid heart rate, shortness of breath and then progresses to seizures, slow heart rate, hypotension, and then cardiac arrest. Symptoms usually start in a few minutes. If patients survive then neurologic complications are seen. This sequence of events was not reported by any of the nearly 500 patients examined and treated. Thus making the cyanide hypothesis widely held in Liberia less tenable.

Methods

Over a period of 2.5 weeks in August 2019, as part of an annual medical mission, 493 neurologically afflicted patients were seen in the tropical nation of Liberia, a resource rich but infrastructure and health sector poor nation. Out of the total number, 89% had epilepsy(skewed because of epilepsy focused radio broadcasts) and of this number about 35 % were children , age 15 months to 18 years. Due to unavailability or poor access to anticonvulsants, there was a very high seizure recurrence rate with severe. attendant sequelae and complications including premature deaths, SUDEP, psychomotor retardation, intellectual regression and profound disability.

The unavailability of common anticonvulsants as well as the total lack of trained neurologist in the entire country (0.03 neurologists per 100,000 population in Africa vs 4.84 neurologists per 100,000 population in Europe) also posed a real challenge for all patients. An informal assessment of depression (due to limitation of time) was done. A prevalence 25 to 30% of depression as comorbid factor in the epilepsy patients was estimated.. Data on suicides, attempted or completed was not obtainable due to time restricted but certainly it needs to be fully documented so intervention strategies can be devised and implemented.

Results

Severe debilitating social stigmatization of epileptic patients and consequent forced isolation made their lives even more unbearable. Rate of depression, suicide and other psychological disorders remain a very real concern in the country especially in this patient cohort. Clustering of patients in a particular geographic region due to stigmatization, mystification of the disease, and ostracization of affected individuals was commonly observed. Many epileptic pediatric patients were at least 6 grade levels behind their peers due to the common practice of essentially frequent customary suspension of these afflicted school goers (based on the local widely held erroneous belief of the contagiousness of epilepsy) until they achieve relatively long seizure free periods.

Conclusions

In this presentation, the state of epilepsy diagnosis and management as well as its public health, and socioeconomic implications and the interesting phenomena of the circalunar rhythms of seizure patterns are discussed. Further possible biochemical and biophysical mechanisms of chronic untreated seizures including the potential role of the core circadian rhythm genes of CLOCK and BMAL 1 affecting seizure threshold, rhythmic occurrence and neuronal excitability are presented and discussed. Further directions for pathomechanism and etiogenesis research as well as strategies for disease burden reduction and socioeconomic steps are suggested.

https://www.youtube.com/watch?v=PZYZIU5PEWU&t=1s (from time 16:47)

Thanks you for your attention!

REFERENCES

ACKNOWLEDGEMENTS

Our greatest appreciation to Dr. Sodey Lake, RN, PhD (mission coordinator), Janet Zumo (mission financer), Tomah Tilo (patient’s advocate), Martina Zumo, RN (nurse specialist), Malaika Zumo (asst technician), Samson Davis (videographer), Serina Johnson(West point burrough coordinator), Augustine Tambah (mechanic and driver), Drs. Szabo and Parvizi(mission advocates), Karen and Otis Stroup, Joe DiMaggio &Donna Selsor (ophthalmology section advocates), Magdalene Harris & Janjay Village of Hope Team (Buchanan sector support group), Mr and Mrs Eddie and Eliane Dunn, mission hosts; Save Haven Community Health Services staff and the rest of the support team that made our work possible despite challenges.