The Growing Infant Meningitis Crisis in Ethiopia

 

MRI of infant with meningits
Infant with meningitis seen on MRI to have hydrocephalus and meningeal enhancement

Ethiopia is facing a growing crisis in infant meningitis compounded by a false reliance on the power of antibiotics to treat the problem without definitive diagnosis and follow up.

A growing problem
As you may know north eastern Africa including Ethiopia is part of the so-called “meningitis belt” with the highest rates of bacterial meningitis in the world. Just a couple a months ago I was attending a meeting with Ministry of Health with the new five pediatric neurosurgery centers of excellence in Ethiopia where a new growing epidemic of chronic meningitis seen throughout the country was discussed. Over the past year we are seeing more and more cases of infants on an almost daily basis presenting with progressive hydrocephalus who have diagnostic cerebrospinal fluid consistent with chronic meningitis. Our average census is 5 to 8 in hospital all the time whereas a few years ago it was only one or two. Many of these children have hospitalizations of 12 weeks or more. Many have died and many are left with significant cerebral disability which could have been prevented by earlier intervention and appropriate treatment lengths.

Systemic deficiencies
While this epidemic seems to be worsening, Dr. Abreha (Head of Pediatrics and Pediatric Neurologist at Mekelle University) and myself are concerned that deficiencies in facilities and procedures within the medical system may be contributing to it. Unfortunately throughout Ethiopia almost no lumbar punctures are now done to diagnose meningitis. A sample inquiry of pediatric residents and interns found that 75% of them had never done a lumbar puncture. Additionally many clinics and hospitals do not even have lumbar puncture trays. A false sense of security exists that powerful antibiotics given a short period time can will solve the problem

Secondly, the lack of ability to process or even receive an CSF specimen for analysis beyond 5 PM forces the treating physicians to start treatment without first obtaining a culture which is against world wide standard of culture first then start treatment. This seems very contrarian to the frequent theme of the pharmacy and laboratory professionals in Ethiopia that there is abuse of antibiotics.

A key analysis is determining the glucose, protein, and cell count in cerebrospinal fluid. Dr. Abreha recently gave a sample of tap water to the laboratory to be tested on the automated machine and it diagnosed multiple WBC consistent with meningitis. The equipment supplied to Ethiopian hospital is not capable of accurate diagnosis. Technicians can do manual counts but these are time consuming and labor intensive. This inaccuracy has greatly impaired our ability to determine if patients are infection free which they must be before they can undergo definitive treatment for hydrocephalus which is a ventriculoperitoneal shunt.

Thirdly, around the world there is much controversy about for how long antibiotic treatment should be given ranging from 10 days to 21 days. The problem is that partially treated meningitis patients who have not been cleared from the infection often do not have fever, meningeal signs, or other clinical findings except hydrocephalus. Many infants are briefly seen for nonspecific fever and receive short courses of antibiotics in Ethiopia without specific diagnosis being made and without adequate follow up. Many of these children we believe are harboring these low grade chronic infections leading to their late appearance at Ayder  Comprehensive Specialized Hospital. This creates a great dilemma as these children often require treatment of intravenous powerful expensive antibiotics from 21 days to in excess of six weeks or more until the infection is cleared by the demonstration of two negative cultures off antibiotics and normal cell counts. In addition in order for the shunt to work the protein has to be less than 150 mg/dl. Failure to diagnose an active residual infection before a shunt placement will only aggravate the infection leading to shunt removal and complications.

The treasure and future of Ethiopia is in her children. Meningitis appropriately treated early and followed can have a very low morbidity and disability outcome. The current situation if not acted upon will result in increasing medical costs, increasing disability, and increasing infant death which could be prevented with simple directed community and institutional action. 

Recommended Course of Action
1. Immediate upgrade of laboratory ability in hospitals to receive CSF specimens 24 hours a day for culture, gram stain, sensitivity.
2. Training of interns and residents in performing lumbar puncture and making sets available
3. Institute an Ethiopian wide policy of obtaining CSF before starting antibiotics. Children with seizures, lethargy, focal deficit, or signs of increased intracranial pressure would be emergently sent to a referral hospital for CT Scan or if possible if they have an  open fontanelle undergo an head ultrasound locally to rule out mass before lumbar puncture.
4. Make sure all children treated for meningitis undergo follow-up and that a repeat lumbar puncture is done after treatment. This may seem over kill but given the crisis happening it is the only way to prevent these chronic cases.
5. Funding of community service, public education, and research projects on this vital issue in cooperation with the regional health bureaus.
6. Training of health officers, nurses, and general practitioners in proper diagnosis, evaluation, treatment, and referral of children with meningitis and hydrocephalus.

Reflections on the Age of Limits in Healthcare Resources

The academic new year at Mekelle University for residents (doctors who have graduated from medical school and now will undertake several years of specialty training) is just a few weeks away. They will transform from the theoretical and observing from the sideline to actually being involved in medical care to improve the quality and longevity of their patients. A part of the new experience will be their discovery that there is a limit of resources even in the richest countries and of course more severe in the developing countries. This same thing is happening not just in Mekelle, not just in Ethiopia, but around the world in all the teaching hospitals.

Although we like to pretend otherwise there is no escaping the inevitable fact that we are mortal and will at some point suffer significant illness followed by death. An Ethiopian diaspora calculated based upon the year 2000 that the per capita lifetime medical expenses where $316,000 in the state of Michigan (USA). Most of the cost occurs in the first year of life and after age 50. Women were more than men because they live longer. About one third occurs in middle age and about one half in the senior year of life.
It is hard to put a measure on the value of human life.

When discussions occurred about the use of dialysis as to whether should be payed for by government, analysts determined that spending $50,000 to give an additional year of quality life was worthwhile. This same measure was applied by several governments world wide. The actuarial value of a human life in developed countries is put somewhere between $ 500,000 and ten million dollars by actuarial experts. It is much less in developing countries where the economic output of an individual is much lower often less than a few hundred dollars a year.

The most recent budget for healthcare in Ethiopia was 1.4 billion dollar equivalents which cames out to about $14 per person for the approximately 100 million Ethiopian population. If you count out of pocket expenses it increases to about $24 per capita. This is of course much less than than the $4000-$5000 you see in European countries and the almost $10,000 in the United States. Yet even in these rich countries there are cries that funding is insufficient.

This means that physicians and the policy makers whom they advise have to learn to do more with less. They have to spend resources where they will have most impact. How are these decisions made? Medical ethicists talk about years of productive life as a reasonable way to compare, for example, spending money to help newborns versus the elderly. But not all cultures would agree with this concept totally. There is often a belief that older citizens should be rewarded for their service to society. Note the creation of Medicare and Social Security and its equivalents in the United States and many other developed countries.

Good medical care even in this age of limits is possible. It requires a sound knowledge of likely outcomes, compassion, and realistic communications with the patients and the community at large in both developing and developed countries. The inevitable consequences of our mortality and economic reality of limits leaves no room for anything other than truthful sincerity.

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.

 

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

Interpersonal Violence and Head Injury in Tigray:Public Health Issue

The head injury problem especially that due to interpersonal violence in Tigray is a growing and significant problem which requires a public health approach.

3d CT scan of man suffering depressed fracture of skull from stone injury

Research published by Fasika et al showed that 24.8% of head injury admissions came from interpersonal violence from 2011 to 2014 which was before neurosurgery was permanently established at Ayder Comprehensive Specialized Hospital. Currently we are seeing about 10 patients a day and operating on 2 to 3 every day. Most of the surgeries we do are for depressed fractures caused by stone injury received in interpersonal violence. The age range of these injuries ranges from preschool to the eighth decade of life. We know there is a cultural proclivity to this type of injury but it is not well studied.

The hospital burden of head injury includes about 19% of adult ICU admissions and bedspace and 25% of pediatric ICU admissions and bed space. Our average daily census on the adult ward is 5 for head injury and on the pediatric ward also 5. The length of stay can vary from 24 hours to months with most of the surgical patients requiring a least a 5 days stay in the hospital.This burden acts to limit the care those suffering from other maladies can receive.

At the current time there is no public health or government plan to try to prevent these injuries.The World Health Organization has created a Violence Prevention Alliance which sees interpersonal violence as requiring a public health approach.

This public health approach to violence prevention seeks to improve the health and safety of all individuals by addressing underlying risk factors that increase the likelihood that an individual will become a victim or a perpetrator of violence.

The approach consists of four steps:

1 To define the problem through the systematic collection of information about the magnitude, scope, characteristics and consequences of violence.
2 To establish why violence occurs using research to determine the causes and correlates of violence, the factors that increase or decrease the risk for violence, and the factors that could be modified through interventions.
3 To find out what works to prevent violence by designing, implementing and evaluating interventions.
4 To implement effective and promising interventions in a wide range of settings. The effects of these interventions on risk factors and the target outcome should be monitored, and their impact and cost-effectiveness should be evaluated.

 

Diagram of WHO prevention plan

By definition, public health aims to provide the maximum benefit for the largest number of people. Programs for the primary prevention of violence based on the public health approach are designed to expose a broad segment of a population to prevention measures and to reduce and prevent violence at a population-level.

I propose that Mekelle University put together a multidisciplinary team consisting of not only physicians but also social scientists, public health professionals, police and prosecutors ( this was previously discussed with the head of the Tigray police who was interested), and government stakeholders. This type of investigation and policy development is exactly the type of activity which the University with all its resources and knowledge base should be tackling.

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.