Neurosurgery in East Africa
See 2013 article and radio piece at Voice of America
House Foreign Relations Subcommittee on Africa, Global Health, and Human Rights hearings August 2, 2011
Congressional Hearing Book with Testimony on Hydrocephalus
CSPAN Coverage of Hydrocephalus Hearings August 2, 2011
See Fall 2010 article in Engineering Penn State Magazine
I am devoting increasing effort towards addressing problems affecting children in the developing world. The following projects address hydrocephalus, epilepsy and malaria, and the intersection of the potential infectious underpinnings of these conditions, as well as new technological approaches to diagnosis and treatment.
In treating epilepsy in the industrialized countries, MRI technology is the mainstay of the structural diagnosis of the scarring and shrinking of the deep parts of the temporal lobes of the brain in such patients. Such asymmetric scarring, when consistent with the clinical signs and scalp EEG characteristics of a deep temporal lobe epilepsy focus, carries high prognostic value that a surgical resection of the deep temporal structures will have a significant benefit to reduce seizures and improve the quality of life. The risk to benefit evaluation of the medical versus surgical treatment of such illnesses, in parts of the world where drug maintenance and pharmacological laboratory monitoring are often impractical, may be different from the industrialized countries. Despite the substantial literature supporting the use of MRI for volume measurements of the deep structures of the temporal lobe, there appears to be no previous work using CT for this diagnosis. Although MRI is generally not available in the developing world, the less expensive CT is now becoming increasingly prevalent.
One needs to ask why the incidence of epilepsy in malarial prone regions of Africa can be upwards of 5 times the indigence in the industrialized countries. There is a known relationship between cerebral malaria, which is especially dangerous to children, and post-malarial epilepsy in the survivors have been reported between 5-10%.
Neonatal infections kill over a million newborn infants each year worldwide, with the vast majority of these deaths occurring in sub-Saharan Africa and southern Asia. A related issue for sub-Saharan Africa is post-infectious hydrocephalus in early childhood. Serious neonatal infections within the first month of life, known as sepsis, appear to account for the majority of hydrocephalus cases seen in East Africa. Maintaining shunt hardware, and managing the early postoperative complications, and the late emergent shunt obstructions in children who become shunt dependent, weakens the risk-benefit balance for shunt insertions. A growing effort to use endoscopic fluid diversions, especially third ventriculostomy, is being applied by surgical centers in sub-Saharan Africa such as the CURE Children’s Hospital of Uganda in Mbale, Uganda. Nevertheless, the question of whether these children so treated do as well as children treated with shunts remains unanswered. In addition, as our technological approaches to hydrocephalus treatment increase in sophistication, one must ask whether the organisms causing post-infectious hydrocephalus can be identified and prevented. We know from recent literature that cerebral malaria seems not to be an active agent with such obstructive hydrocephalus, and that HIV seropositivity is below 5% in such infants. A hunt for the causative organisms is long overdue.
Motivated by the above, we have several collaborative projects currently underway:
First, we have an effort to develop the image analysis strategies to use the more sustainable CT as a substitute for MRI in patients with temporal lobe epilepsy. Our first efforts are to use landmarks to measure volume in regions of the brain that we can clearly outline on CT, rather than the small grey matter structures, such as the hippocampus, which can only be visualized well on MRI. Our basic strategies including standard volumetric image analysis - using contours on stacks of CT scans (planimetry) or surface area estimation (Cavalieri method) on such images. Yet in a broader sense, we know that even ‘unilateral’ temporal lobe epilepsy is often a more widespread disease - if you damage part of the brain, everything connected to that damaged part will be affected. We suspect that the more widespread are the abnormalities in the brain of such patients, the more likely that the epileptic seizures can and do arise from more than one structure, and the less likely that surgical resection of a small affected part (such as the hippocampus) will significantly help with the patient’s seizures. So in addition to our standard volumetric analysis, we are exploring whether the symmetries within the brain, between left and right temporal lobes, and between the hemispheres, might be a more sensitive indicator of seizure focus localization as well as a gauge of potential surgical outcome.
A related imaging project involves the evaluation of hydrocephalus. We are developing methods of breaking an image up, whether CT or MRI, into volumes of brain and fluid. We presently use head circumference to quantify the magnitude and outcome of treatment of children with hydrocephalus. But this is not the metric that would best reflect the results of the disease or its treatment. We are developing two new growth curves - one for brain, and one for fluid within the head. Such growth curves, based on populations of normal children, will provide a more sensitive and direct measure of the effect of hydrocephalus treatment - demonstrating that the brain is re-acquiring a more normal growth curve. This is critical if, for instance, following internal fluid diversion the majority of the fluid is not drained out as is typical following shunt insertion. The NIH Fogarty Internation Center, in partnership with the National Institute of Neurological Disorders and Stroke, have teamed up to fund a new Phase III Randomized Controlled Clinical Trial in Uganda comparing shunt with endoscopic treatment. In this study, whose PIs are Drs Warf (Harvard), Schiff (Penn State), and Kulkarni (Toronto), where volumetric analysis techniques are being used in a prospective fashion to learn how to better treat and predictively manage such patients.
We have two clinical trials underway to further explore the microbial origins of postinfectious hydrocephalus in East Africa. The majority of the hydrocephalus in this part of the world appears postinfectious, but the identification of the causative organisms has remained elusive. We have recently completed a study of the bacterial DNA fragments within the fluid sampled from the brain at the time of surgery for such postinfectious hydrocephalus at the CURE Children’s Hospital of Uganda, subjected another cohort to extensive bacterial culture, and performed environmental sampling from the villages where these infants were born. We found bacterial DNA in almost all of these infants, and matched the sequences to environmental samples. A publication describing our microbial findings has appeared as a Cover Article in the January 2011 issue of the Journal of Neurosurgery: Pediatrics.
With funding from a Clinical Translational Sciences Institute grant from Penn State University for 2009-2010, and now with funding from the Pennsylvania Department of Health, Commonwealth Universal Research Enhancement (CURE) Program, we are now conducting two further clinical trials. In Mbarara, in collaboration with colleagues at the Mbarara University of Science and Technology, we are studying the microbial origins of neonates with sepsis, as well as screening their mothers as mother-infant pairs. At Mbale, we are comparing the fluid from children with postinfectious and non-postinfectious hydrocephalus.
We have fused climate data with our patient case data, since our findings point to the possibility that as with other infectious diseases, the season of the year may affect case presentation. We have recently published a surprising finding that rainfall, measured by satellite, is strongly associated with the case numbers of these postinfectious hydrocephalic infants, appearing as a Cover Article in the September 2012 issue of the Journal of Neurosurgery: Pediatrics .
These projects have a range of implications. We suspect that the high incidence of both infantile hydrocephalus, as well as temporal lobe epilepsy later in childhood, are both related to prior infections in this part of the developing world. The disease spectrum and living conditions in rural East Africa do not respect political borders, and we anticipate that our findings will have applicability to countries beyond Uganda. In terms of image analysis, the strategy of using less detailed and fuzzy images to make more accurate diagnosis and treatment decisions is a universally applicable strategy. Image technology, whether MRI or CT, is expensive, and requiring less expensive hardware by improving analysis serves as a model for containing costs in both developing or industrialized societies.
Most recently, we have been awarded a grant from Citizen’s United for Research in Epilepsy to pursue further development of therapies capable of preventing post-malarial epilepsy in children with cerebral malaria. We are exploring with advanced EEG analysis, multiphoton optical imaging, and immune system modulation, how to uncover mechanisms that can be brought to clinical trial to help reduce this high incidence of childhood epilepsy in malaria prone regions of Africa.
These projects are a collaborative effort between faculty and trainees across Penn State, as well as our colleagues at other universities and at medical centers, including:
Penn State University Park: Department of Biology, and Veterinary and Biomedical Science (Dr. Mary Poss, Dr. Vivek Kapur), Department of Engineering Science and Mechanics (Drs. Bruce Gluckman, Corina Drapaca, and Patrick Drew), and Department of Aerospace Engineering (Jacob Langelaan).
Penn State Hershey Medical Center: Department of Neurosurgery (Drs. Steven Schiff, Robert Harbaugh, James McInerney, Kenneth Hill), and Department of Radiology (Drs. Dan Nguyen, Kevin Moser).
And beyond Penn State: Dr. Benjamin Warf (Harvard University), Abhaya Kulkarni (University of Toronto), Dr. Andrew Webb (University of Leiden), Dr. Warren Boling (University of West Virginia), Dr. John Mugamba, Dr. Peter Ssenyonga, and Derek Johnson (CURE Children’s Hospital of Uganda), and Drs. Julius Kiwanuka, Juliet Mwanga, and Joel Bazira (Mbarara University of Science and Technology).