Both diagnosis and treatment of epilepsy pose huge issues in interpretation of “big data” sources

In the current era, “big data” is considered to be a way to find out things that studies run on small populations cannot derive. It has been used specifically to address comparative evaluation of new interventions, and assessment of cost versus quality in care. These approaches are very appropriate when 1) both the disease and the outcome are relatively straightforward, 2) there is no clear bias in where or how the patient presents and 3) the codes used to capture both diagnosis and outcomes are representative of what actually occurs. An example might be myocardial infarction, where the majority of patients come to the ER, they get a correct diagnosis, and their outcome may be recovery or death.

Unfortunately, both diagnosis and treatment of epilepsy pose huge issues in interpretation of “big data” sources. Epilepsy is an extremely heterogeneous disease, that may be benign or deadly. It is difficult to diagnose.  It may be diagnosed in the ER, in an outpatient clinic, or during a hospitalization. Patients may come to a neurologist for assessment of symptoms, or may be referred because they are felt to need more comprehensive care. The diagnostic codes are not applied properly, and many associated diseases may be caught in the epilepsy net. A non-neurologist may apply an epilepsy diagnosis to cases that do not have epilepsy, or may use an intractability code inappropriately.

The outcomes, as noted by Hill and colleagues, are also not well captured. If people do not end up in the ER or with an injury, does that mean that they are “OK”? are they employed? Are they able to function and lead a normal life? Are they able to drive? Unfortunately, we have found time and time again that “big data” does not necessarily provide a clear picture of what happens with epilepsy care.

These very interesting results once again highlight that where epilepsy is concerned, “the devil is in the detail”. It would be fascinating to be able to dig more deeply into these cases, to find out how they are similar, and how they differ. Without such an ability, unfortunately, we will have to continue to ponder how to interpret these results, and others based on diagnosis codes alone.

  1. Hill, CE, Lin CC, Burke JF, et al. Claims Data Analyses Unable to Properly Characterize the Value of Neurologists in Epilepsy Care. Neurology Epub 2019 Jan 23

Back to Bedside Initiative

Eight with a known patient, 10 to 24 with a new patient: these are the average amount of minutes medicine interns spend with patients in inpatient services.1 In the outpatient setting, direct patient care time only amounts to half of the time spent working in the EMR.2

Are you are a resident/fellow who has an idea of how to improve physician time with patients? If so, you could have the opportunity to lead a local research project funded by the ACGME.

The ACGME launched its Back to Bedside initiative in 2017 in order to encourage residents and fellows to create novel ways to spend more time with patients. The second call for applications is now in process, and proposals are due March 15, 2019. A total of 32 projects will be funded, and awards range from $5,000 to $15,000 for each project.  Should a project be chosen, members of the team are expected to attend up to three collaborative meetings with other awardees in Chicago, IL and will also be expected to attend the 2021 ACGME Annual Education Conference in Nashville, TN.

During the first application period in 2017, the ACGME planned to fund five one-year projects, however 223 applications were received and the ACGME expanded the program to fund 30 projects over a two-year period. Funded projects included a program allowing residents to spend a pager-free lunch once a week with a patient, a program to post photos with brief bios of residents in patient rooms to encourage exchange of non-medical conversation between patients and residents, and a project changed the electronic medical record system to improve note writing efficiency. These projects successfully created more meaningful patient interactions, leading the ACGME to call for another round of projects.

Neurology residents and fellows need to spend considerable time with patients elucidating complex histories and performing detailed neurologic exams. This requirement has likely already prompted innovative solutions and methods by which to circumvent time constraints in several neurology training programs. The Back to Bedside program is the perfect place to share such ideas and launch a new project.

More details can be found at https://www.acgme.org/Residents-and-Fellows/Back-to-Bedside

  1. Block, L., Habicht, R., Wu, A.W., Desai, S.V., Wang, K., Silva, K.N., …Feldman, L. (2013). In the Wake of the 2003 and 2011 Duty Hours Regulations, How Do Internal Medicine Interns Spend Their Time?. Journal of General Internal Medicine, 28 (8), 1042-1047. doi: 10.1007/s11606-013-2376-6
  2. Sinksy, C., Colligan, L., Li, L., Prgomet, M., Reynolds, S., Goeders, L., …Blike, G. (2016). Allocation of Physician Time in Ambulatory Practice: A Time and Motion Study in 4 Specialties, 165 (11), 753-760. doi: 10.7326/M16-0961

A promising technique for clearly diagnosing ALS earlier

Amyotrophic Lateral Sclerosis (ALS) is commonly referred to as “diagnosis of exclusion”: A combination of clinical findings indicating lower and upper motor neuron dysfunction which cannot be explained by some other disease mechanism.  This process of exclusion can result in delayed diagnosis, poor clinical trial enrollment and emotional distress for patients.

As indicated by the authors, the true promise of this technique will be determined by the utility of TMS outside of the hands of Dr. Geevasinga and colleagues. The authors have spent more than a decade developing transcranial magnetic stimulation (TMS) techniques to distinguish ALS from ALS mimics. Much of the literature cited in the manuscript reflects their own previous work and I suspect many of the patients included in this work were part of the development of their knowledge base with TMS. While TMS has been used by several other groups it would be most interesting to see the ALSDI validated externally. If this could be done it is likely that the ALSDI could be a powerful tool in the diagnosis of ALS in patients who do not meet Awaji criteria.  

In their manuscript “Amyotrophic Lateral Sclerosis Diagnostic Index: Towards a Personalized Diagnosis of ALS” Geevasinga et al. describe the development of a diagnostic score that incorporates “clinical, conventional neurophysiological and [Transcranial Magnetic Stimulation] parameters” to determine an ALS diagnosis.1  After training on cohort of patients with ALS or ALS mimics they designated weighted values to ALS risk factors including:  Age > 50 (1), Bulbar Onset (2), Median CMAP amplitude < 5.0 (1), Cortical Silent Period (CSP) duration < 160 (3), CSP 160-220 ms (1), Short Interval Intracortical Inhibition (SICI) 0 (20), 0.1-6.0 (2).  An ALS diagnostic index (ALSDI) score of ≥ 4 had a sensitivity of 83% and specificity of 84%. The reference standard Awaji criteria had a similar sensitivity (85%) but somewhat worse specificity (72%). Notably there was no statistically significant difference between the area under the curve (AUC) between the Awaji criteria and ALSDI. As the Awaji criteria rely on standard clinical testing and do not require the specialized technique and additional costs of TMS, ALSDI may be of limited utility in patients who meet Awaji criteria for an ALS diagnosis. However, the authors found that an ASLTDI Score ≥ 4 was able to successfully distinguish patients who did not initially meet Awaji diagnostic criteria and/or had primarily lower or upper motor neuron disease.  These findings suggest a promising technique for clearly diagnosing ALS earlier even with upper or lower motor neuron predominant disease.  As these patients commonly experience delayed diagnosis or exclusion from trials, this could be an important finding.

  1. Geevasinga N, Howells J, Menon P, et al. Amyotrophic lateral sclerosis diagnostic index: Toward a personalized diagnosis of ALS. Neurology 2019;92:e536-e547

Based on recent study by Xu et al, should neurologists consider OCT testing for the diagnosis of a prior unilateral optic neuritis?

Optical coherence tomography (OCT) is a diagnostic tool used primarily by eye care providers to quickly and non-invasively image the front and back of the eye. A recent article by Xu, et al explored the sensitivity of OCT in detecting prior unilateral optic neuritis in adults by comparing the average retinal nerve fiber layer (RNFL) thickness and ganglion cell inner plexiform layer (GCIPL) thickness between affected and unaffected eyes. Additionally, affected eyes were compared to age matched controls. OCT was highly sensitive (96%) when using both the GCIPL and RNFL to compare between the affected and unaffected eyes. OCT was less sensitive (78%) when compared to age-matched controls using a threshold below the 1st percentile, which is not surprising as people have varying thicknesses of both the GCIPL and RNFL.

Based on this study, should neurologists consider OCT testing for the diagnosis of a prior unilateral optic neuritis? The answer at this point is: no. First, careful history and an eye exam are typically enough to make the diagnosis of prior unilateral optic neuritis. The most objective bedside test, the afferent pupillary defect typically remains, even in those patients with recovered visual acuity and visual fields. Optic disc pallor is also frequently present allowing a diagnosis to be established without any ancillary testing. Second, OCT testing should not be used by a neurologist without an accompanying eye examination. As the authors rightly point out, any optic neuropathy (eg. ischemia or compression) and even some retinal events (eg. retinal artery occlusion) can lead to thinning of the RNFL and GCIPL. Therefore, it is important that an OCT is read by someone with experience interpreting the test within the context of the history and examination. Lastly, this study has only taken the first of many steps necessary to establish the utility of a new diagnostic test. All that we can conclude from this study is that more work is needed. The next steps should address whether OCT can be used to correctly identify patients with unilateral optic neuritis when the clinical history and examination is only suggestive, not definite. If so, then it will also be important to investigate whether the small number of patients who need OCT because their diagnosis cannot be established based on history and examination alone, fare better than those patients whose diagnosis may be less certain. The study by Xu, et al has taken the first of many steps necessary to demonstrate that OCT may have a role in the diagnosis of prior unilateral optic neuritis, but that role is likely to be very limited and OCT currently should not be part of a routine assessment for prior unilateral optic neuritis.

  1. Xu SC, Kardon RH, Leavitt JA et al. Optical coherence tomography is highly sensitive in detecting prior optic neuritis. Neurology Epub 2019 Jan 23

“Palatucci Advocacy Leadership Forum”—An Important Opportunity for Professional Development in Leadership and Advocacy that is now open to non-US applicants!

Program Overview

Effective leadership and advocacy are critical across the globe and in all disciplines. But there are often limited opportunities for formal professional development on this front and the routine training track undertaken by neurologists simply doesn’t prepare one for major leadership and advocacy roles. In the US, the Palatucci Forum has long served as an incubator of young talent and as developed some of our finest leaders. This year, they are expanding this opportunity to non-US neurologists. Applications are due March 4, 2019. Global Neurology needs global leaders. Apply now or forward this on to someone you think this would help develop.

The Palatucci Advocacy Leadership Forum teaches neurologists the following skills:

Action Planning: Create an effective plan that identifies your issue and resolves the problem

Media Relations: Sharpen your on-camera interview skills, work with reporters, and improve your confidence

Grassroots Advocacy: Get an inside look at how governments work and how to get results

Understanding HIV’s complex interplay with other health conditions in tropical settings

In a recent issue of Neuroimmunology & Neuroinflammation, work by Kamtchum-Tatuene et al’s Blantyre-Liverpool collaboration further reinforce existing concerns that even with excellent access to antiretroviral medications in sub-Saharan Africa, there will be a public price to pay in comorbid health conditions exacerbated by HIV infection1. The researchers accessed biobanked samples from Dr. Laura Benjamin’s previously completed START study—a case-control study designed to identify risk factors for stroke in Malawi2. Taking advantage of the ~10% HIV prevalence in the population, they evaluated traditional serum markers for endothelial activation and injury among stroke vs. non-stroke patients stratified by HIV status. Surprisingly, despite relatively small numbers for analysis, they found an odds ratio of 3.6 (CI 1.3-10.6) for higher plasma levels of ICAM-1 (a biomarker of endothelial activation) among HIV-infected individuals regardless of their stroke status and even when they were on HIV treatments with good viral suppression. Chronic endothelial activation might be expected to increase all cardiovascular risks in the long run for HIV infected individuals who are otherwise doing well in terms of their infection. Additional concerns would be for increased risks of vascular dementia and peripheral neuropathies associated with diabetes or other metabolic problems. Further evaluations are also needed to determine how HIV-associated endothelial activation might impact the risks and neurologic injuries associated with severe malaria, whose effects are largely mediated by endovascular dysfunction.

  1. Kamtchum-Tatuene J, Mwandumba H, Al-Bayati Z et al. HIV is associated with endothelial activation despite ART, in a sub-Saharan African setting. Neurology 2018 Dec 21
  2. Benjamin LA, Allain, TJ,  Mzinganjira H, et al. The Role of Human Immunodeficiency Virus–Associated Vasculopathy in the Etiology of Stroke. The Journal of Infectious Diseases 2017;216:545-553

Use of continuous EEG in the ICU leads to favorable outcomes

by Nathalie Jetté, MD, MSc, FRCPC and Churl-Su Kwon, MD, MPH

The use of continuous EEG (cEEG) in the Intensive Care Unitis increasing. As indicated by the American Clinical Neurophysiology Society, current indications for this non-invasive tool include: monitoring/diagnosis of seizures and/or status epilepticus, detecting cerebral ischemia, measuring sedation, providing post-arrest prognostication1. However, research has been rather sparse in the past decade regarding specific use of cEEG and clinical outcomes in the critically ill.

With the variability in cEEG practices seen across health systems (timing, length, when to start ensuing treatment) and the fact that it is resource intense, there is much need to define its optimal use. This will diminish inconsistencies in cEEG application as well as curtail avoidable costs, especially with health in the USA experiencing much policy transformation with linkage of traditional health-care services to value-based care and highlighting population health and novel mechanisms of health-care delivery.

The authors used 2004-2013 data from the National Inpatient Sample which is the largest cross-sectional, all-payer inpatient healthcare nationwide database, consisting of information on patient and hospital level factors for more than seven million hospital discharges annually2. In this study, mechanically-ventilated adults in intensive care units were sampled and patients who underwent cEEG were compared to those who did not. cEEG use was associated with lower in-hospital deaths, as were larger bed size and urban teaching hospitals. Subgroup analysis showed similar results in patients who had subarachnoid/intracerebral hemorrhage and altered consciousness unless they had seizures/status epilepticus likely due to a disease severity confounding effect. Proportions of critically ill patients who underwent cEEG varied across hospitals, suggesting discrepancies in hospital resources and expertise. Longer hospital stays and total hospitalization costs were associated with cEEG utilization, but justifiable in the setting of decreased mortality of nearly 20%.

This study has many strengths, including the large population and adjustment for important confounders such as comorbidity. Though it is carefully designed and the authors are to be congratulated for this important work, this study is not without limitations, most of which are highlighted by the authors. These include issues related to the validity of diagnostic coding which is lacking for NIS-specific data, low sensitivity of ICD coding for mechanical ventilation, under-ascertainment of cEEG use and lack of cost-effectiveness data.

This study highlights that cEEG use for critically ill patients is associated with lower in-hospital deaths and suggests possible under-utilization of cEEG (0.3% of critically ill, though utilization increased more than tenfold from 0.06% in 2004 to 0.8% in 2013). Although these data may warrant continued expansion of cEEG use, explicit cost-analysis quantifying the value of cEEG in the critically ill is essential in future studies to elicit cost-effective strategies. Since survival is seen to differ across diagnoses, rigorous investigation is necessary to develop cEEG evidence-based practices to improve outcomes, decrease variability in care and enhanced cost-benefit frameworks across different populations.  

  1. Herman ST, Abend NS, Bleck TP, et al. Consensus Statement onContinuous EEG in Critically Ill Adults and Children, Part I. J ClinNeurophysiol. 2015;32:87–95.
  2. Hill CE, Blank LJ, Thibault D, et al. Continuous EEG is associated with favorable hospitalization outcomes for critically ill patients. Neurology Epub 2018 November 30.

Without Borders Latest Interview: Dr. Benjamin Warf and Practice in Africa

Advances in Neurosurgical Capacity and Practice in Africa are improving options for patients while also informing care and offering training opportunities for neurosurgeons in the US. To learn more, listen to our interview with Dr. Benjamin Warf. Dr. Warf is the Director of the Neonatal and Congenital Anomaly Neurosurgery and Professor of Neurosurgery at Harvard Medical School. Early in his career, he moved his family to Uganda to direct a neurosurgical hospital for children funded by CURE. In 2012, he was awarded a MacArthur (‘genius’) Fellowship.

Resident & Fellow Section Author Guides

Scientific writing is a critical part of medical training.  We use case reports, clinical trials, and basic research to advance the practice of medicine and to share new ideas across the field of neurology.  However, writing a manuscript can be a daunting task and a novice writer may not know where to start.  For a resident or fellow, the first manuscript is often a case report which means the first step is to find a great case.  What makes a great case?  Atypical presentations of common illnesses are worth publishing so that all clinicians can recognize the full spectrum of the diagnosis.  For similar reasons, rare entities, particularly if there is a new genetic diagnosis, should be published.  Case reports that include a series of patients are more impactful and can often be accompanied by an analysis of trends or varied responses to treatment. When trying to decide if your patient case should be considered for publication, it is important to review existing literature.  How many case reports have already been published on that disease?  How is your case different from previously published cases?

Continue Reading “Resident & Fellow Section Author Guides”

Fumbled Priorities and Lost Perspectives: Epilepsy in LMICs Today

Three cheers for Dr. Mamta Bhushan Singh whose candid editorial in the November issue of Seizure really sums up the problems of epilepsy research and care in the developing world today. 1  Such a maddening paradox—70% of epilepsy cases would respond to basic treatment, if provided. And rather than expending efforts to assure we put systems in place to roll out sustainable care to the masses, we in the global epilepsy arena continue to focus most of our attention and resources on the 30% of patients with treatment resistant epilepsy. This approach might make sense in developed settings, but certainly not in low and middle income settings where the treatment gap really hasn’t budged in more than two decades.

Continue Reading “Fumbled Priorities and Lost Perspectives: Epilepsy in LMICs Today”