Tag: Ethiopia

Recommendation for Valproic Acid Restricted Use in Ethiopia

prenatal ultrasound of myelomeningocoel
Prenatal ultrasound showing fetus with lumbar myelomeningocoel

Given the already highest incidence of neural tube defects measured globally present in Ethiopia it would seem exceedingly urgent to immediately call for the cessation of use of Valproic acid, which has been shown to cause neural tube defects,  in women of child bearing age in Ethiopia except for special circumstances.

History of Valproic Acid

Valproic acid was first produced in 1882. At that time its discoverer did not imagine that would be any therapeutic use because it was thought to have no pharmacological value. Then in the 1960s it was begun to be used in France and then in the late 1970s was approved for use in the United States as a primary drug for first epilepsy and then also for migraine headaches as well as mood disorders.

Over the next thirty years, however, concerns began to be raised about the potential relationship of the drug and birth defects.  Both a joint European study and a separate French study showed that women of child bearing age taking appropriate therapeutic doses of 1000 mg a day or more had a high incidence of neural tube defects and other malformations up to seven times higher than the control population.

Valproic Acid Use in Ethiopia

The use of Valproic acid is relatively new in Ethiopia in just the last few years. A review of the treatment of epilepsy from Gondar University showed that 4.84 % of patients were using it. In addition it is being used to treat mood disorders and migraine headache to an unknown extent. The prescription of this medicine is relatively unrestricted and can be done by general practitioners and even non-physician health care providers. Unfortunately the official formulary for Ethiopia briefly mentions that pregnancy is a contraindication and suggests consideration for folic acid supplementation should be given to reduce the risks of birth defects. However a recent animal model study using chick embryos showed that supplemental folic acid for neural tube defects caused by valproic acid was not effective in prevention.

Neural Tube Defects in Ethiopia

Our research at Mekelle University looking at the incidence of neural tube defects in the Tigray region of Northern Ethiopia suggested an over all incidence of at least 130 per 10,000 births but with some locals reporting close to 300 per 10,000 births. We know from studies done by the Ethiopian Institute of Public Health that 28% of women of children bearing age throughout Ethiopia have a significant folic acid deficiency which is likely the strongest contributing factor to the high incidence of neural tube defects

Recommendations for Valproic Acid Restriction in Ethiopia

1.Given the already highest incidence of neural tube defects measured globally present in Ethiopia it would seem exceedingly urgent to call for the immediate cessation of use of Valproic acid in women of child bearing age except for situations where no other drug can be used and the patient is receiving implantable or injectable forms of birth control.

2. Prescription of Valproic acid should only be done by physician sub-specialists in neurology, neurosurgery, or psychiatry and should require extensive counseling to the patient.

3.The formulary of Ethiopia should be modified and vigorously amended to warn of the risks. Although consideration for folic supplementation is appropriate it should be clearly stated that such supplementation may not be effective in preventing birth defects.

 

Should Surgeons other than Neurosurgeons Treat Hydrocephalus in Africa?

An illustration of a ventricular peritoneal shunt

Traditionally surgery for hydrocephalus has been performed by neurosurgeons who undergo vigorous neuroscience basic training and supervised surgical experience of at least 5 years in length (longer in developed countries) after medical school. Recently there has been some discussion as to whether in African and other undeveloped countries general surgeons should be taught to perform ventriculoperitoneal shunts to treat hydrocephalus. The treatment of hydrocephalus should remain under the direction and in the hands of neurosurgeons.

Hydrocephalus as a medical condition has been recognized since the time of the ancient Greeks. The concept of surgery to treat hydrocephalus by diverting the flow of cerebrospinal fluid began in  1949, when Nulsen and Spitz implanted a shunt successfully into the caval vein with a ball valve. Between 1955 and 1960, four independent groups invented distal slit, proximal slit, and diaphragm valves almost simultaneously.

An estimated 750,000 people have hydrocephalus, and 160,000 ventricular peritoneal shunts are implanted each year worldwide almost always by neurosurgeons. About 56,600 children and adolescents younger than age 18 years have a shunt in place.

The incidence of hydrocephalus in Africa is estimated to be 145 per 100,000 which is three times higher than in the developed world. Thousands of these children will need surgical intervention, either ventricular peritoneal shunt or the newer, but still not clearly accepted as superior, endoscopic procedures. 

A survey conducted among African neurosurgeons in 1998 showed that there were 500 neurosurgeons in Africa; that is, one neurosurgeon for 1,350,000 inhabitants, and 70,000 km2. That number is significantly increased now but the exact current number is unknown. Worldwide the average is 1 neurosurgeon per 230,000 but in Africa it can be as low 1 per 9 million people. It is believed there are 700 neurosurgeons currently or about 1 per 1,238,000  people which is an improvement but still not nearly enough. Ethiopia currently has about 30 practicing neurosurgeons and will soon be graduating about 30 newly trained neurosurgeons per year. This means Ethiopia will need about 450 functioning neurosurgeons taking into account expected population growth. 

Although the training of neurosurgeons in performing ventriculoperitoneal shunts has become somewhat standardized via the World Federation of Neurosurgical Societies as well as international neurosurgical groups, the training of general surgeons to do this procedure has not been rigorously studied. There are very few publications about the results of general surgeons performing ventriculoperitoneal shunts but an a study from Kenya done in 2010 showed a significantly high complication rate of 65% with an infection rate of 9.1% and shunt malfunction rate of 11.1%. This was much different than reported by Dr. Warf , an American trained neurosurgeon who created a specialized center in Uganda, with a malfunction rate of 4%.

More recently endoscopic procedure to open the third ventricle to the cistern and coagulate the choroid plexus are gaining ground but not totally proven yet. These procedures clearly require specialized training and knowledge of anatomy of the caliber of a neurosurgeon and not a general surgeon.

The real issue was not really the shortage of surgeons but the bottleneck was lack of hospitals, operating rooms, and clinics. Additionally transportation to get healthcare is a real issue. Now Ethiopia has seen the light and has  three training programs for neurosurgery in Ethiopia and are graduating about 30 per year. Again the problem is we have more surgeons than facilities to operate in.

African governments will see the idea of adding shunt placement to general surgery as an easy fix. In reality they are already overworked. I have taught medical students and general surgery residents. Many people think ventriculoperitoneal shunts are the easiest procedure but I always tell my neurosurgery residents and fellows it is not. Decisions about when to shunt, is the shunt working, is it infected? require experience and training. Academic following of outcomes, techniques, epidemiology requires an academic neurosurgery program take the lead.

Unfortunately there is no shortcut to capacity building. We are now training neurosurgeons for other African countries as well as Ethiopia. Eventually we will need more than 450 which will take time.

Finally I would say that our approach to hydrocephalus is changing rapidly. For us and the Uganda group we are consistently reducing the number of shunts we are doing each year. Whereas in the past we did nearly two hundred it is now going to be less than 100 even though we cover 20 million plus population with the highest myelomeningocoel rate in the world. We now recognize that many neural tube defect newborns have low grade infections which require antibiotics sometimes over 21 days until the csf is clear. Many times their hydrocephalus stabilizes after a few fontanelle taps. Although the post infectious group is rising ( we are in the infamous meningitis belt of Africa) similar we have avoided shunting by similar close follow-up. Our shunt infection rate is currently 3% because we identify these chronic low grade infections. I shutter to think what would happen if general surgeons with little experience are let loose upon this situation.

 

 

Finely Controlled Hypotension during Brain Surgery in Ethiopia

Brain surgery being done with controlled hypotension at Ayder Comprehensive Specialized Hospital

At Ayder Comprehensive Specialized Hospital, the university medical center for Mekelle University in Ethiopia, our experience with finely controlled hypotension during brain surgery for both adults and children has reduced the need for blood transfusion by half. 

In many underdeveloped African countries the surgical treatment of brain tumors is often very late in the course of the disease due to delay in the patient seeking treatment, having a diagnostic study to find the tumor, and being scheduled for surgery as many university centers have long waiting lists. Such is the situation we are in Ethiopia. These large brain tumors, often 10 centimeters or more in diameter, can require massive transfusion during the surgery to remove or reduce them. 

Large meningioma which has risk for high blood loss during surgery

The Department of Neurosurgery in the School of Medicine at Mekelle University in a close partnership with our Department of Anesthesia has been working on creating sustainable safe controlled hypotension techniques to reduce our blood loss during brain tumor surgery in adults and children at Ayder Comprehensive Specialized Hospital.  Thanks to the donation of a high quality intravenous perfuser by a diaspora American anesthesiologist and the cooperation of the university to gain stocks of Isoflurane  inhalation agent and Propofol intravenous agent as well as in house training together we have significantly reduced blood loss leading to much less transfusion during brain surgery. End tidal CO2 is kept at 4.5 to 5% and mean arterial blood pressure maintained at 65-70 mm/Hg.

brain surgery under controlled hypotension

Food and Salt Fortification to Prevent Neural Tube Defects in Ethiopia

A joint study by the Departments of Neurosurgery and Nutrition (School of Public Health) of Mekelle University and the Department of Epidemiology of Emory University has concluded that thousands of newborn deaths and lifelong disability from neural tube defects could be prevented by fortifying food and possibly salt with folic acid to significantly reduce the epidemic currently occurring in Ethiopia.

“High potential for reducing folic acid‐preventable spina bifida and anencephaly, and related stillbirth and child mortality, in Ethiopia” is being published in Birth Defects Research.

 

The Need for Physician-Scientists in Ethiopia

Discussing multidisciplinary research at Mekelle University

Ethiopia is now at a point where non-communicable disease is overtaking the classic major infectious and malnutrition disorders which dominated the major morbidity and mortality for the country. Now more than ever with scant resources and unique cultural situations there is a need for effective clinically related medical research at the top universities in Ethiopia.  Effective clinically related medical research in Ethiopia requires that academic medical centers begin to train physician-scientists.

Unfortunately the model of how to do medical research and by whom it should be directed and/or overseen is outdated. Because medical schools lagged behind the development of fields like Public Health and Nursing these entities dominated the university structure. At the beginning there were no specialists and very physicians who were so overworked they really had no time for training in methods of research let alone doing it.

Today over 50% of the needs of Ethiopian doctors require specialist training. Additionally the experiments such as occurred in British National Health Service of relying on mostly non-physician scientists to direct and oversee medical research backfired. In the current system almost no funds are directed to physician directed medical research yet Ethiopia desperately needs physician-scientists to lead the way into dealing the health care needs of a growing population of over 100 million people.

We are currently advocating changing this system at Mekelle University. Similar changes are already occurring at St. Pauls Millenium and Addis Ababa University in Addis Ababa, Ethiopia.

The Alliance for Academic Internal Medicine has published these recommendations for training physician-scientists which I think should be strongly considered for adoption wholly or least substantially in Ethiopian university training centers.

Summary of Best Practice Recommendations for Physician-Scientist
(The American Journal of Medicine, Vol 131, No 5, May 2018)
Physician-Scientist Training Programs (PSTPs)
Curriculum and Infrastructure
A. Providing combined residency and subspecialty fellowship training is an attractive feature.
B. PSTPs should include training in study design, biostatistics, team science, ethics, scientific regulatory requirements,
institutional review board application, grant writing, time management, leadership, work/life balance, and mentor/mentee
relations.
C. Directors of PSTPs would benefit from organizing a formal alliance and meeting regularly.
Recruitment and Selection of Trainees
A. Candidates for PSTPs most likely to translate their training into successful careers as well-established physician-scientists
are those who have significant research experience and can demonstrate a balanced commitment to both science and
medicine.
B. PSTPs should make increasing diversity among its trainees a stated goal, with active efforts to recruit qualified women and
members of underrepresented minority populations.
C. Initiatives to recruit qualified international medical graduates as trainees should be increased and additional sources of
funding for international medical graduates trainees should be pursued.
Mentorship Practices
A. Mentoring teams are essential for PSTP trainees and should be carefully crafted.
B. Mentors need to be formally trained in mentoring, and they need to be recognized for their contributions.
4. Funding of PSTPs and Their Trainees
A. The success of PSTPs and their trainees is highly dependent on strong institutional support.
B. The success of PSTPs and their trainees is also highly dependent on adequate levels of external funding including the
successful receipt of individual career development awards.
Tracking Success of PSTPs and Their Graduates
A. Success factors of PSTPs and their graduates should be tracked.
B. Tracked data should be coordinated with other PSTPs and shared in a national data base.
6. Sustaining PSTPs and Employing Continuous Improvement Practices
A. Sustainability is contingent on institutional support and an adequate census of qualified applicants.
B. Sustainability is also impacted by the percentage of trainees who successfully complete their training.

New Recommended Action Plan for Prevention of Neural Tube Defects in Ethiopia

Over the past year in response to the Mekelle University Multidisciplinary Research team publications on neural tube defects in Tigray we have been interacting with the Ministry of Health, Maternal and Child, and the Ethiopian Public Health Institute. Two months ago Dr. Afework Mulugeta and myself as well as invited international experts gave a scientific advisory of this problem to the EPHI.

Yesterday a brief was given by the EPHI which was mostly based upon our research and recommendation as well as their review of available evidence.

Officially now the Ethiopian government recognizes “that there is an alarmingly high rate of neural tube defects and folate acid deficiency in Ethiopia”. The following recommendations were made to the higher ministry officials for approval
1. Periconceptional oral folate supplementation for all women of reproductive age as an immediate solution. Low cost imported folic acid is available for the public to purchase.
2. Making the first visit for pregnancy earlier instead of the current 16 weeks
3. Promoting the consumption of folic-rich foods.
4.Implementing mandatory wheat-flour food fortification.
5.Considering salt fortification with folic acid after doing a pilot study in Tigray
6.Establishing a surveillance system for NTDs throughout Ethiopia
7. Awareness creation for all recommended interventions strategies for the prevention of NTDs
Further studies will be done on community basis and on salt
Monitoring of food fortification measures to evaluate effectiveness

Difficulties in Preventing Neural Tube Defects in Ethiopia

Ethiopian mother hold her child with lumbar myelomeningocoel

The Mekelle University Multidisciplinary Research Group for Neural Tube Defects has just published its first research paper in Brain & Development Journal July 2018, “Maternal Risk Factors Associated with Neural Tube Defects in the Tigray Region of Ethiopia”. This being the first major prospective study done on neural tube defects in Ethiopia confirmed our worst fears of a very high incidence, significantly higher than the 75 per 10,000 births seen in most of Sub-Saharan Africa. There a many challenges in how this problem can be addressed involving cultural beliefs and practices, poverty, diet diversity, supplementation, and fortification.  Unfortunately, applying a Western style solution for Ethiopia will not be so easy or likely to succeed as well.

For the past decade the development of neurosurgery in Ethiopia has witnessed the high incidence of neural tube defects including myelomeningocoel and anencephaly coming to their clinics first in Addis Ababa but now also in Mekelle, Gondar, Bahir Dar, and Oromia. Previous published reports noted incidences first of greater than 160 per 10,000 births in Addis with a more recent report of 191 per 10,000 births in Addis Ababa. The reports of up 300 per 10,000 in some areas of Tigray are higher than those reported in any other developing countries.

Research replicated in nine countries in the 1960s and 1970s showed that neural tube defects were somewhat but no totally related to lack of folic acid in the diet and that adding folic acid would significantly reduce the incidence of neural tube defects. At first attempts were made with prescribing supplementation for women of childbearing age but this did not have the desired result. The incidence really came down in Europe and the United States when the government mandated the fortification of folic acid in food staples like bread and cereals

One of the factors we identified was that a lack of diet diversity increased the risk for NTDS while increased diversity reduced it. About 65% of the diet of most Ethiopians is enjera bread made at home from teff and boiled chick peas called shiro.   Although a serving of raw chick peas has about 1000 micrograms of folic acid its likely that boiling them reduces the folic acid to basically nothing.   A similar situation exists for spinach which is often boiled and eaten during the rainy season.

Traditionally, Ethiopians avoid eating fresh vegetables and fruits as documented in our study and many previous others. In fact a study of the one hundred most elite Ethiopian runners showed that 20% had a significant folic acid deficiency which correlated with lack of dietary diversity (avoiding greens and fruit). In the countryside where the women may spend many hours a day just to get 5 gallons of water, there is not much water to spare for cleaning produce. The population fears getting diarrheal illness from such produce.

Our study showed that of more than 13,000 women interviewed who were pregnant essentially none of them had any knowledge of preconceptional nutritional needs or about neural tube defects. 

Convincing Ethiopians to take medication for invisible illness such as hypertension has proved difficult. Research in many parts of Ethiopia has shown for example that as few as 50% of those prescribed medication for hypertension actually take it. There exists underlying fears of addiction to “un-natural” substances. Will Ethiopian women be convinced to take supplementation?

Ethiopians especially the 88% who live in country side rarely buy food staples like bread but instead make their own enjera from stored teff. Currently there is only one factory in the country capable of making fortified bread but it is not functioning.

The cost of a months supply of folic acid 4 milligrams per day is about 80 birr or about $2.40 US for a single woman. Given the fact that the average family makes about 250 birr per month to support a family of six, there is little room to allow payment of this expense. There are no current domestic producers of folic acid so considerable hard foreign currency would need to be mobilized to import stock. For the government to provide this for every women of child bearing age would cost tens of millions of dollars to be added to the budget of a country which currently spends the equivalent of about $13 per capita for the 100 million population.

Ultimately addressing the issue of the high incidence of neural tube defects in Ethiopia will be requiring taking into account cultural norms and practices in such a way that changes are seen as consistent with Ethiopian culture.  Widespread public education and a major investment in folic acid purchases by the government will be necessary. This begins with the clear realization that there is a problem.

 

Research:Neural Tube Defects in Tigray Ethiopia

Recent research we have done at Mekelle University soon to be published has confirmed that there is a high rate of neural tube defects affecting the brain and spinal cord in Tigray. Experience suggests this is also the case in other parts of Ethiopia as well. At least 131 out of every 10,000 births is affected with some areas having almost twice that number. Defects result in death at birth for about 77% of the pregnancies affected, usually with anencephaly, while the 23% born alive usually have severe paralysis of the lower extremities and often need a operations to close the open spine, closure of myelomeningocoel,  and to control pressure in the brain, ventricular peritoneal shunt, for lumbar and thoracic myelomeningocoel associated with an Arnold Chiari II malformation causing hydrocephalus. Lesser numbers of encephalocoel often requiring closure were encountered as well.

Ethiopian mother hold her child with lumbar myelomeningocoel

The most likely significant cause is lack of diversity in the diet and especially failing to consume foods with the vitamin folic acid. This is usually found in green and leafy vegetables as well as fresh fruits. Cooking foods such as chick peas which may contain folic acid will destroy much of it.

Around the world these birth defects have been reduced about 75% by encouraging women to plan their pregnancy and take 4 milligrams of folic acid daily starting before conception. We are working with our research group at Mekelle University to help the Tigray Regional Health Bureau and the Ethiopian Ministry of Health come up with programs to reduce these defects but this will take time.

In the meantime we encourage all women in Ethiopia to plan their pregnancy, starting folic acid supplementation before they conceive, and practice dietary diversity. They should try to wait one year between pregnancies, and understand that breast feeding increases their need for folic acid. Very young and older women are more susceptible to having children with these defects. Other factors may be involved besides folic acid deficiency but the good news is that folic acid supplementation will likely still reduce these defects.