In this case-control study in a southern Han Chinese population, HLA-A* 24:02 was identified as a risk factor for Stevens-Johnson Syndrome (SJS) from exposure to antiepileptic drugs including carbamazepine, lamotrigine, and phenytoin. HLA-B* 15:02 polymorphisms in this population were an already recognized risk factor for SJS after similar exposures. The prevalence of the HLA-A* 24:02 polymorphism in this population remains unknown making it difficult to determine if routine screening is indicated.
We learned in January perhaps something that many of us already instinctly knew—burnout among U.S. neurologists is a real and probably growing problem1. This week in Neurology, U.S. Neurologists may be comforted somewhat to find they are not alone. A survey of the China Neurologist Association conducted by Zhou and colleagues found that 53% (compared to 41% in the US) of neurologists suffer from burn out and many of the associated factors such as longer work hours, more patients, and more night call coverage were shared risks of burn out in both the U.S. and Chinese respondents. There are some unique challenges in the Chinese healthcare sector that might be contributing to burnout including rising violence against physicians, possibly because of patient concerns that physician are enriching themselves at patient expense by inappropriate prescribing patterns2,3. Although there have been a number of recent reports on burnout among Chinese physicians 4-8, we don’t know whether neurologists there are disproportionately affected by burnout as they appear to be in the US. This would seem to be an important question to ask since if such a global phenomenon is occurring it may be telling us something important.
1. Busis NA, Shanafelt TD, Keran CM, et al. Burnout, career satisfaction, and well-being among US neurologists in 2016. Neurology 2017;88:797-808.
2. Burki T. China faces challenges to fix its pharmaceutical system. Lancet 2017;389:353-354.
3. Beam C. Why Chinese patients are turning against their doctors. The New Yorker 2014.
4. Ding Y, Qu J, Yu X, Wang S. The mediating effects of burnout on the relationship between anxiety symptoms and occupational stress among community healthcare workers in China: a cross-sectional study. PLoS One 2014;9:e107130.
5. Gong Y, Han T, Chen W, et al. Prevalence of anxiety and depressive symptoms and related risk factors among physicians in China: a cross-sectional study. PLoS One 2014;9:e103242.
6. Jin WM, Zhang Y, Wang XP. Job burnout and organizational justice among medical interns in Shanghai, People's Republic of China. Adv Med Educ Pract 2015;6:539-544.
7. Wen J, Cheng Y, Hu X, Yuan P, Hao T, Shi Y. Workload, burnout, and medical mistakes among physicians in China: A cross-sectional study. Biosci Trends 2016;10:27-33.
8. Xiao Y, Wang J, Chen S, et al. Psychological distress, burnout level and job satisfaction in emergency medicine: A cross-sectional study of physicians in China. Emerg Med Australas 2014;26:538-542.
We invite you to listen to our latest podcast covering global public health activities that address neurological disorders. Dr. Kiran T. Thakur interviews Dr. Tarun Dua, Medical Officer at the World Health Organization working on the Program for Neurological Diseases and Neuroscience, Management of Mental and Brain Disorders in the Department of Mental Health and Substance Abuse.
“We are not focusing on the basic science part or any of the clinical aspects, because we feel there are many centers, many organizations, and institutions involved in doing that work. The focus of our work is on public health, meaning understanding: what’s the problem, and what kind of resources or services are available at country-level? Thinking in terms of simple guidance, and prevention and management of neurological disorders in non-specialized settings.” - Dr. Tarun Dua
One of the daily pleasures of neurology is ‘solving the mystery’ of a patient’s complaints and/or deficits, integrating the pathophysiology of the condition through localization and pattern recognition sometimes armed only with our own minds and a reflex hammer. Less often, we have the opportunity to watch as researchers begin to unravel the mystery of a neurologic disorders that has remained unsolved for more than a century. Few neurologic conditions have frustrated modern medicine’s efforts to elucidate its underlying cause more than Nodding Syndrome (NS), but in a February article published in Science Translational Medicine efforts led by NIH’s Intramural Director for Infections of the Nervous System, Dr. Avi Nath and team detail a rather convincing series of experiments indicating that NS may be an epilepsy syndrome caused by autoimmune-medicated brain injury triggered, at least in some victims, by infection with O. volvulus with subsequent molecular mimicry1.
NS is an acquired, often progressive, neurodevelopmental disorder that affects children and is characterized by seizures manifesting as head nodding attacks with associated neurodevelopmental delays and/or regression. ‘Outbreaks’ of NS have popped up periodically for at least the past century, often in regions affected by war and/or mass displacement of populations. The most recent outbreak began in Uganda in 2008, seems to have subsided around 2013 and is thought to have affected more than 2000 children. Ecologic and epidemiological associations between O. volvulus (the filarial parasite carried by biting black flies that causes River blindness) have been known for some time but the absence of a clear pathophysiologic causal mechanism remained a major frustration. In a series of experiments, they identified the leiomodin-1 autoantibody in the population of interest and then found higher rates among NS patients compared to village control. They then went on to identified these autoantibodies in CSF, showed leiomodin-1 to be expressed in human neurons in vitro and using mouse brain localized this to the hippocampus, cerebellar Purkinje cells and cortical neurons. Finally, they went on to demonstrate neurotoxicity of leiomodin-1 in vitro and cross-reactivity between leiomodin-1 autoantibodies in NS patients with O. volvulus antigens. The elegant series of experiments conducted is a good read. Not everyone with NS has evidence of O. volvulus infection and not all outbreaks have occurred in regions subject to river blindness, but this represents a major leap in our understanding of a monstrously devastating condition. The Ugandan government is to be commended for acting on epidemiologic data alone when they instituted massive ivermectin distribution in response to the 2008 epidemic2. Ivermectin and supportive therapy with valproic acid provides some improvement for many.3 Will immunomodulatory therapies will be readily available to affected populations? Can the injury be reversed to any significant extent?
In a parallel and fascinating story in PLos Neglected Tropical Diseases, Foger at al. do some sleuthing through the literature and provide links between Nakalanga and NS4. Nakalanga Syndrome is a childhood onset condition of growth retardation, various skeletal physical deformities and endocrine dysfunction often with associated epilepsy and cognitive regression or impairment reported from many of the same geographic regions where NS outbreaks have occurred.
1. Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med 2017;9,
2. Idro R, Musubire KA, Byamah Mutamba B, et al. Proposed guidelines for the management of nodding syndrome. Afr Health Sci 2013;13:219-232.
3. Idro R, Namusoke H, Abbo C, et al. Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study. BMJ Open 2014;4:e006476.
4. Foger K, Gora-Stahlberg G, Sejvar J, et al. Nakalanga Syndrome: Clinical Characteristics, Potential Causes, and Its Relationship with Recently Described Nodding Syndrome. PLoS Negl Trop Dis 2017;11:e0005201.
The Conference on Retroviruses and Opportunistic Infections (CROI) is an annual scientific meeting devoted to the science around the pathophysiology, prevention, and treatment of Human Immunodeficiency Virus (HIV) and opportunistic infections in patients living with HIV. Given that patients with HIV are living longer and are less likely to develop opportunistic infections, there has been growing interest in non-communicable disorders associated with HIV, such as HIV-associated Neurocognitive Disorders (HAND) and HIV-associated stroke. This year at CROI (held February 13-16 in Seattle), the primary emphasis was on the possibility of HIV cure, but there were a number of interesting presentations related to CNS complications of HIV.
There were several epidemiologic studies demonstrating that cognitive complications of HIV remain a major issue, even in the era of combined antiretroviral therapy (cART). In IMPAACT P1104s, longitudinal neurocognitive testing was performed in cART-treated children with HIV ages 5-11 in 6 countries in Sub-Saharan Africa. Children with HIV demonstrated significantly worse neurocognitive performance compared to controls, and longitudinal testing demonstrated that these differences persisted or worsened over time. One exciting aspect of CROI this year was that we are beginning to see results from treatment studies. For example, The SABES study randomized patients with very early HIV infection to immediate vs. deferred treatment, and found significant improvements in cognition with early treatment. There were also two interesting studies presented looking at a treatment intensification strategy for treatment of HAND. The first, using the CCR5 antagonist maraviroc, failed to meet the primary endpoint of decreased CSF inflammatory markers, but did show a statistically significant improvement in executive function. The second trial, using the novel CCR5/CCR2 antagonist cenicriviroc, demonstrated a significant improvement in global cognitive function as well as a decrease in CSF inflammatory markers. Both studies were small, open label, uncontrolled trials, and so should be viewed with some skepticism, but treatment intensification appears to be a promising strategy for treatment of cognitive complications of HIV.
In Global Perspectives, Expanding medicines for neurological disorders on the WHO Model List, Rimmer and colleagues successfully argue that treatments for neurologic conditions are under-represented in the Essential Medicines List (EML) compiled by WHO each year relative to burden and evidence base for treatment. They conclude that “The low rate of Essential Medicines List inclusion for neurological medications is likely influenced by a relative paucity of application submissions and inadequate neurological or neuropharmacological expertise on the Expert Committee.” They provide details on how application can be submitted, but what individuals or entities should take the lead? And how can applications receive an adequate review of the ‘Expert Committee’ doesn’t include adequate representation from neurologists?
As detailed by Rimmer and colleagues, treatment for neurologic disorders are undoubtedly neglected today in terms of the Essential Medicines Lists (EML) used globally and the reasons for this are complex. In Global Perspectives, they successfully argue that treatments for neurologic conditions are under-represented in the EML compiled by WHO each year relative to burden and evidence base for treatment. They conclude that “The low rate of Essential Medicines List inclusion for neurological medications is likely influenced by a relative paucity of application submissions and inadequate neurological or neuropharmacological expertise on the Expert Committee.” They provide details on how application can be submitted, but what individuals or entities should take the lead? And how can applications receive an adequate review of the ‘Expert Committee’ doesn’t include adequate representation from neurologists? The openness of the process of applying for a medication to be added to the EML, which allows virtually any individual or entity to make an application to the World Health Organization for a drug to be included in the EML, has the downside of not clearly delineating whose responsibility it is to do this. Dr. Rimmer’s paper can be viewed as a “call to arms” for neurologists working in and engaged with activities in resource-limited settings to organize themselves into action to begin to prepare appropriate applications to WHO to improve the situation.
This is clearly a timely topic. A Lancet Commission on Essential Medicines for Universal Health coverage offers additional insights into the problems of an EML that provides care for all1. A concerned word of caution though to urge those who take up the Commission’s advice to be aware of the risk of unintended consequences.
Epilepsy is among the commonest chronic neurologic conditions globally2. In 2006, the World Bank ranked epilepsy among the most cost effective conditions to treat3. Phenobarbitone, a medication on virtually all Essential Medicines Lists, is an inexpensive, easy-to-use, effective antiepileptic drug4—or at least it was until WHO capacity building activities with Pharmaceutical Regulatory Authorities in LMICs led to enhanced requirements for handling controlled substances. Despite a clinical profile making it highly unlikely to be a drug of abuse, the chemical structure of phenobarbitone is such that it falls under the regulatory conditions imposed for controlled drugs. As a result, the handling of phenobarbitone has become costly in terms of personnel time, the requirement to have special locked facilities to secure the drug, documentation of drug distribution and maintenance of this documentation in case of audit. Given the low profit margin of this cheap drug as well as the potential of significant fines and even criminal prosecution one might be exposed to for failing to adhere to the regulations, many pharmacists in LMICS have simply stopped carrying phenobarbitone. Even management of it within the public health sector has been abdicated by many primary care facilities to higher levels of care5. Attempts to get phenobarbitone removed from the list of controlled substances have been ineffective6.
Phenobarbitone is not an isolated example. During a study of antiretroviral (ARV) adherence 7,8, we identified poorer adherence in one catchment and discovered the pharmacies serving this area were providing only 1-2 weeks’ supply of ARVs at a time rather than dispensing the 2-3 months’ supply prescribed. Paradoxically, this problem arose only from pharmacies that had participated in capacity building activities that included additional training of persons responsible for drug purchasing. The take home message from the training was that the purchaser’s responsibility was to assure that drugs did not run out of stock AND drugs did not expire on the shelf. Giving shorter courses of ARVs helped assure that the drug purchasers met job performance evaluations, but clearly the overall outcome here was not as intended. In pursuing the Commission’s recommendations and as neurologist globally contemplate efforts to expand the EMLs to better cover neurologic needs, unexpected consequences need to be anticipated and evidence for them actively sought. And mid-stream policy changes need to be made when negative effects are identified.
1. Wirtz VJ, Hogerzeil HV, Gray AL, et al. Essential medicines for universal health coverage. Lancet 2017; 389(10067): 403-76.
2. WHO. EpilepsyUpdated Feb 2017, 2017. http://www.who.int/mediacentre/factsheets/fs999/en/ (accessed 14Feb17).
3. World Bank. Disease Control Priorities in Developing Countries. New York, NY: Oxford University Press & THe World Bank; 2006.
4. Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy and its future. Epilepsia 2012; 53 Suppl 8: 40-6.
5. Chomba EN, Haworth A, Mbewe E, et al. The current availability of antiepileptic drugs in Zambia: implications for the ILAE/WHO "out of the shadows" campaign. Am J Trop Med Hyg 2010; 83(3): 571-4.
6. Bhalla D, Aziz H, Bergen D, et al. Undue regulatory control on phenobarbital--an important yet overlooked reason for the epilepsy treatment gap. Epilepsia 2015; 56(4): 659-62.
7. Birbeck GL, Chomba E, Kvalsund M, et al. Antiretroviral adherence in rural Zambia: the first year of treatment availability. Am J Trop Med Hyg 2009; 80(4): 669-74.
8. Birbeck GL, Kvalsund MP, Byers PA, et al. Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia. Am J Trop Med Hyg 2011; 85(4): 782-9.
Disclaimer: Blogs constitute the opinion of the author and do not reflect the views of the AAN or of Neurology ®
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Neurology mini-sites: New content and re-use of previously published Neurology content
Patricia K. Baskin, MS, Executive Editor and Robert A. Gross, MD, PhD, FAAN, Editor-in-Chief
Near the time this editorial is published, online readers of Neurology® will be able to access 2 new subspecialty satellite or mini-sites, which will carry articles in a particular topic area. These sites, which can be reached by links from the Neurology home page, will focus on health services topics (Innovations in Clinical Neurology) or global neurology (Without Borders). Both topics ... Full Text