Risk of Unnatural Mortality in People With Epilepsy

Key Points

Question  What is the risk and medication contribution to cause-specific unnatural mortality in people with epilepsy?

Findings  In this population-based cohort study, more than 50 000 people with epilepsy and 1 million matched individuals without epilepsy were identified in 2 data sets from the general populations of England and Wales. People with epilepsy had a 3-fold increased risk of any unnatural mortality and a 5-fold increased risk of unintentional medication poisoning; psychotropic and opioid, but not antiepileptic, drugs were most commonly used in poisoning.

Meaning  Clinicians should provide advice on unintentional injury and poisoning and suicide prevention and consider the toxicity of concomitant medication when prescribing drugs for people with epilepsy.


Importance  People with epilepsy are at increased risk of mortality, but, to date, the cause-specific risks of all unnatural causes have not been reported.

Objective  To estimate cause-specific unnatural mortality risks in people with epilepsy and to identify the medication types involved in poisoning deaths.

Design, Setting, and Participants  This population-based cohort study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014). Each person with epilepsy was matched on age (within 2 years), sex, and general practice with up to 20 individuals without epilepsy. Unnatural mortality was determined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes V01 through Y98 in the Office for National Statistics mortality records. Hazard ratios (HRs) were estimated in each data set using a stratified Cox proportional hazards model, and meta-analyses were conducted using DerSimonian and Laird random-effects models. The analysis was performed from January 5, 2016, to November 16, 2017.

Exposures  People with epilepsy were identified using primary care epilepsy diagnoses and associated antiepileptic drug prescriptions.

Main Outcomes and Measures  Hazard ratios (HRs) for unnatural mortality and the frequency of each involved medication type estimated as a percentage of all medication poisoning deaths.

Results  In total, 44 678 individuals in the CPRD and 14 051 individuals in the SAIL Databank were identified in the prevalent epilepsy cohorts, and 891 429 (CPRD) and 279 365 (SAIL) individuals were identified in the comparison cohorts. In both data sets, 51% of the epilepsy and comparison cohorts were male, and the median age at entry was 40 years (interquartile range, 25-60 years) in the CPRD cohorts and 43 years (interquartile range, 24-64 years) in the SAIL cohorts. People with epilepsy were significantly more likely to die of any unnatural cause (HR, 2.77; 95% CI, 2.43-3.16), unintentional injury or poisoning (HR, 2.97; 95% CI, 2.54-3.48) or suicide (HR, 2.15; 95% CI, 1.51-3.07) than people in the comparison cohort. Particularly large risk increases were observed in the epilepsy cohorts for unintentional medication poisoning (HR, 4.99; 95% CI, 3.22-7.74) and intentional self-poisoning with medication (HR, 3.55; 95% CI, 1.01-12.53). Opioids (56.5% [95% CI, 43.3%-69.0%]) and psychotropic medication (32.3% [95% CI, 20.9%-45.3%)] were more commonly involved than antiepileptic drugs (9.7% [95% CI, 3.6%-19.9%]) in poisoning deaths in people with epilepsy.

Conclusions and Relevance  Compared with people without epilepsy, people with epilepsy are at increased risk of unnatural death and thus should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts, and behaviors. The suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions.



Vitamin and Mineral Supplements

Dietary supplementation is approximately a $30 billion industry in the United States, with more than 90 000 products on the market. In recent national surveys, 52% of US adults reported use of at least 1 supplement product, and 10% reported use of at least 4 such products.1 Vitamins and minerals are among the most popular supplements and are taken by 48% and 39% of adults, respectively, typically to maintain health and prevent disease.

Despite this enthusiasm, most randomized clinical trials of vitamin and mineral supplements have not demonstrated clear benefits for primary or secondary prevention of chronic diseases not related to nutritional deficiency. Indeed, some trials suggest that micronutrient supplementation in amounts that exceed the recommended dietary allowance (RDA)—eg, high doses of beta carotene, folic acid, vitamin E, or selenium—may have harmful effects, including increased mortality, cancer, and hemorrhagic stroke.2

In this Viewpoint, we provide information to help clinicians address frequently asked questions about micronutrient supplements from patients, as well as promote appropriate use and curb inappropriate use of such supplements among generally healthy individuals. Importantly, clinicians should counsel their patients that such supplementation is not a substitute for a healthful and balanced diet and, in most cases, provides little if any benefit beyond that conferred by such a diet.

Clinicians should also highlight the many advantages of obtaining vitamins and minerals from food instead of from supplements. Micronutrients in food are typically better absorbed by the body and are associated with fewer potential adverse effects.2,3 A healthful diet provides an array of nutritionally important substances in biologically optimal ratios as opposed to isolated compounds in highly concentrated form. Indeed, research shows that positive health outcomes are more strongly related to dietary patterns and specific food types than to individual micronutrient or nutrient intakes.3

Although routine micronutrient supplementation is not recommended for the general population, targeted supplementation may be warranted in high-risk groups for whom nutritional requirements may not be met through diet alone, including people at certain life stages and those with specific risk factors (discussed in the next 3 sections and in the Box).


Key Points on Vitamin and Mineral Supplements

General Guidance for Supplementation in a Healthy Population by Life Stage
  • Pregnancy: folic acid, prenatal vitamins

  • Infants and children: for breastfed infants, vitamin D until weaning and iron from age 4-6 mo

  • Midlife and older adults: some may benefit from supplemental vitamin B12, vitamin D, and/or calcium

Guidance for Supplementation in High-Risk Subgroups
  • Medical conditions that interfere with nutrient absorption or metabolism:

    • Bariatric surgery: fat-soluble vitamins, B vitamins, iron, calcium, zinc, copper, multivitamins/multiminerals

    • Pernicious anemia: vitamin B12 (1-2 mg/d orally or 0.1-1 mg/mo intramuscularly)

    • Crohn disease, other inflammatory bowel disease, celiac disease: iron, B vitamins, vitamin D, zinc, magnesium

  • Osteoporosis or other bone health issues: vitamin D, calcium, magnesiuma

  • Age-related macular degeneration: specific formulation of antioxidant vitamins, zinc, copper

  • Medications (long-term use):

    • Proton pump inhibitorsa: vitamin B12, calcium, magnesium

    • Metformina: vitamin B12

  • Restricted or suboptimal eating patterns: multivitamins/multiminerals, vitamin B12, calcium, vitamin D, magnesium

a Inconsistent evidence.


The evidence is clear that women who may become pregnant or who are in the first trimester of pregnancy should be advised to consume adequate folic acid (0.4-0.8 mg/d) to prevent neural tube defects. Folic acid is one of the few micronutrients more bioavailable in synthetic form from supplements or fortified foods than in the naturally occurring dietary form (folate).2 Prenatal multivitamin/multimineral supplements will provide folic acid as well as vitamin D and many other essential micronutrients during pregnancy. Pregnant women should also be advised to eat an iron-rich diet. Although it may also be prudent to prescribe supplemental iron for pregnant women with low levels of hemoglobin or ferritin to prevent and treat iron-deficiency anemia, the benefit-risk balance of screening for anemia and routine iron supplementation during pregnancy is not well characterized.2

Supplemental calcium may reduce the risk of gestational hypertension and preeclampsia, but confirmatory large trials are needed.2 Use of high-dose vitamin D supplements during pregnancy also warrants further study.2 The American College of Obstetricians and Gynecologists has developed a useful patient handout on micronutrient nutrition during pregnancy.4

Infants and Children

The American Academy of Pediatrics recommends that exclusively or partially breastfed infants receive (1) supplemental vitamin D (400 IU/d) starting soon after birth and continuing until weaning to vitamin D–fortified whole milk (≥1 L/d) and (2) supplemental iron (1 mg/kg/d) from 4 months until the introduction of iron-containing foods, usually at 6 months.5 Infants who receive formula, which is fortified with vitamin D and (often) iron, do not typically require additional supplementation. All children should be screened at 1 year for iron deficiency and iron-deficiency anemia.

Healthy children consuming a well-balanced diet do not need multivitamin/multimineral supplements, and they should avoid those containing micronutrient doses that exceed the RDA. In recent years, ω-3 fatty acid supplementation has been viewed as a potential strategy for reducing the risk of autism spectrum disorder or attention-deficit/hyperactivity disorder in children, but evidence from large randomized trials is lacking.2

Midlife and Older Adults

With respect to vitamin B12, adults aged 50 years and older may not adequately absorb the naturally occurring, protein-bound form of this nutrient and thus should be advised to meet the RDA (2.4 μg/d) with synthetic B12 found in fortified foods or supplements.6 Patients with pernicious anemia will require higher doses (Box).

Regarding vitamin D, currently recommended intakes (from food or supplements) to maintain bone health are 600 IU/d for adults up to age 70 years and 800 IU/d for those aged older than 70 years.7 Some professional organizations recommend 1000 to 2000 IU/d, but it has been widely debated whether doses above the RDA offer additional benefits. Ongoing large-scale randomized trials (NCT01169259 and ACTRN12613000743763) should help to resolve continuing uncertainties soon.

With respect to calcium, current RDAs are 1000 mg/d for men aged 51 to 70 years and 1200 mg/d for women aged 51 to 70 years and for all adults aged older than 70 years.7 Given recent concerns that calcium supplements may increase the risk for kidney stones and possibly cardiovascular disease, patients should aim to meet this recommendation primarily by eating a calcium-rich diet and take calcium supplements only if needed to reach the RDA goal (often only about 500 mg/d in supplements is required).2 A recent meta-analysis suggested that supplementation with moderate-dose calcium (<1000 mg/d) plus vitamin D (≥800 IU/d) might reduce the risk of fractures and loss of bone mass density among postmenopausal women and men aged 65 years and older.2

Multivitamin/multimineral supplementation is not recommended for generally healthy adults.8 One large trial in US men found a modest lowering of cancer risk,9 but the results require replication in large trials that include women and allow for analysis by baseline nutrient status, a potentially important modifier of the treatment effect. An ongoing large-scale 4-year trial (NCT02422745) is expected to clarify the benefit-risk balance of multivitamin/multimineral supplements taken for primary prevention of cancer and cardiovascular disease.

Other Key Points

When reviewing medications with patients, clinicians should ask about use of micronutrient (and botanical or other dietary) supplements in counseling about potential interactions. For example, supplemental vitamin K can decrease the effectiveness of warfarin, and biotin (vitamin B7) can interfere with the accuracy of cardiac troponin and other laboratory tests. Patient-friendly interaction checkers are available free of charge online (search for interaction checkers on drugs.com, WebMD, or pharmacy websites).

Clinicians and patients should also be aware that the US Food and Drug Administration is not authorized to review dietary supplements for safety and efficacy prior to marketing. Although supplement makers are required to adhere to the agency’s Good Manufacturing Practice regulations, compliance monitoring is less than optimal. Thus, clinicians may wish to favor prescription products, when available, or advise patients to consider selecting a supplement that has been certified by independent testers (ConsumerLab.com, US Pharmacopeia, NSF International, or UL) to contain the labeled dose(s) of the active ingredient(s) and not to contain microbes, heavy metals, or other toxins. Clinicians (or patients) should report suspected supplement-related adverse effects to the Food and Drug Administration via MedWatch, the online safety reporting portal. An excellent source of information on micronutrient and other dietary supplements for both clinicians and patients is the website of the Office of Dietary Supplements of the National Institutes of Health.

Clinicians have an opportunity to promote appropriate use and to curb inappropriate use of micronutrient supplements, and these efforts are likely to improve public health.

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Article Information

Corresponding Author: JoAnn E. Manson, MD, DrPH, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215 (jmanson@rics.bwh.harvard.edu).

Published Online: February 5, 2018. doi:10.1001/jama.2017.21012

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Manson and Bassuk reported that their research division conducts randomized clinical trials of several vitamins and minerals. The Vitamin D and Omega-3 Trial (VITAL) is sponsored by the National Institutes of Health but the vitamin D is donated by Pharmavite. In COSMOS, the multivitamins are donated by Pfizer. Both authors collaborate on these studies.


Kantor  ED, Rehm  CD, Du  M, White  E, Giovannucci  EL.  Trends in dietary supplement use among US adults from 1999-2012.  JAMA. 2016;316(14):1464-1474.PubMedGoogle ScholarCrossref

Rautiainen  S, Manson  JE, Lichtenstein  AH, Sesso  HD.  Dietary supplements and disease prevention: a global overview.  Nat Rev Endocrinol. 2016;12(7):407-420.PubMedGoogle ScholarCrossref

Marra  MV, Boyar  AP.  Position of the American Dietetic Association: nutrient supplementation.  J Am Diet Assoc. 2009;109(12):2073-2085.PubMedGoogle ScholarCrossref

American College of Obstetricians and Gynecologists. Nutrition during pregnancy. https://www.acog.org/Patients/FAQs/Nutrition-During-Pregnancy. Published April 2015. Accessed November 20, 2017.

American Academy of Pediatrics. Vitamin D & iron supplements for babies: AAP recommendations. HealthyChildren.org. https://www.healthychildren.org/English/ages-stages/baby/feeding-nutrition/Pages/Vitamin-Iron-Supplements.aspx. Updated May 27, 2016. Accessed November 20, 2017.

Institute of Medicine.  Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998.

Institute of Medicine.  Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011.

Moyer  VA; US Preventive Services Task Force.  Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: US Preventive Services Task Force recommendation statement.  Ann Intern Med. 2014;160(8):558-564.PubMedGoogle ScholarCrossref

Gaziano  JM, Sesso  HD, Christen  WG,  et al.  Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial.  JAMA. 2012;308(18):1871-1880.PubMedGoogle ScholarCrossref

I Solemnly Share

When I was a little girl, my mom or dad would tuck me in at night. I would make each parent complete the ritual of saying goodnight to my stuffed animals and dolls. There was a giant stuffed bunny whose name now escapes me and a multitude of Beanie Babies. There was my Raggedy Ann doll, and there were two plump handmade dolls named Peppermint and Tom. To me, it was essential that each of these entities be kissed and greeted every night, as a reminder that he or she was loved. I was certain the toys would feel terribly sad if neglected. Looking back, I’m sure my parents found this repetitive behavior tiresome, but they tolerated it out of love. This was the first time I remember feeling responsible for the well-being of someone else. “Goodnight, Peppermint,” we would say together. “Goodnight, Tom. Goodnight, Raggedy Ann.”

Twenty years later, I was well into my second year of medical school. I had weathered the storm of the first year of basic sciences and was now struggling to understand neuropathology. I had scored very poorly on the first week’s quiz, so I needed a much higher mark on the second quiz if I wanted to pass the neuroscience sequence.

The night before the second quiz, I remember scrolling through what seemed like an endless series of lecture slides on movement disorders. Each slide presented testable information on the signs, symptoms, genetics, and pathology of different diseases. Like almost everything else in medical school, digesting and memorizing this mass of information felt like an impossible task. Historically, I had outperformed my own expectations, managing a passing grade on each weekly quiz. There was evidence to suggest that I could do this, and yet viscerally, I knew that I could not—not this time.

Something happened within me in the previous months, though I lacked the language to describe it. The chronic anxiety and sleeplessness of the previous year and a half had begun to wear on me. The daily struggle to get by had dominated my focus for so long that I could no longer recall the basic love of science that had pushed me toward medicine. As with every prior test of my endurance, I challenged myself to dig deeper and find the strength to keep going. Yet when I searched, I could not locate a reservoir of resolve and I emerged empty-handed and exhausted. As I scrolled to a histological image of Alzheimer disease, I was startled by a droplet of fluid that splashed onto my iPad screen. I picked up the device in earnest and watched the salty tear slide tortuously through tau protein accumulations and neurofibrillary tangles.

I failed the neuroscience sequence. There were other life developments that concurrently clawed at my confidence, but this failure was the main precipitant of my fall. I am tempted to make an elaborate case for the depression that subsequently took me over. I am compelled to defend my feelings with logical reasoning and to list all the reasons I was justified in feeling the way that I did. But depression didn’t proceed logically. I was already low and failure brought me lower still so that like an opportunistic infection, depression took advantage of the chance to devastate me. In the weeks that followed, I began to see myself as incompetent, unlovable, negligent. I interpreted each bump in the road as evidence that these were accurate judgments. I remember breaking down when I received an email stating that I was late on my monthly cable payment. Then, afterward, hating myself for being so insufferably unstable.

Once—and I have never shared this before—I stepped into the street on my walk home from the library. I knew that the bus hurtling through the night would not have time to stop before colliding with my darkly dressed frame, fracturing my bones and scattering my belongings. I imagined my head hitting the asphalt and my brain banging around inside of my skull, bruising irreparably with each impact. I imagined the bus driver’s horror as he turned off the ignition with shaking hands and leapt out of the vehicle to locate my body. It would be a catastrophe that the trauma surgeons could not salvage. I would die.

“Goodnight, Peppermint. Goodnight, Tom. Goodnight, Raggedy Ann.”

These words emerged from somewhere in the depths of my consciousness, and I stepped out almost as quickly as I had stepped in. The warmly begrudging faces of my parents invaded the violent scene in my mind. They believed in my ability to take care of other creatures. I did not have it in me to take that away from them.

I realized after that moment that I needed to ask for help. After almost a year of medications and therapy and taking time off school, I am grateful to feel like a stronger, more grounded version of myself. For the first six months of treatment, I stayed extremely private about the state of my health, confiding only in my family and a few very close friends. Yet as time went on, other people approached me with their problems. I willed myself to be more open about my own struggles. It is amazing what you learn when you open up to your fellow medical students. Depression and its vestiges are everywhere.

Practicing physicians and physicians in training often write about their patients and use writing to make sense of their clinical experiences. But in a profession in which subjective evaluation is constant and for which we are expected to be pillars of strength and beacons of empathy at once, it is less popular to use writing to publicly deconstruct ourselves and our own emotions. Writing about our own struggles with natural elements of human experience, like sadness and loss, is painful and risks affecting one’s professional image. When physicians’ mental health is discussed, it is often done so through an academic lens, with particular attention to trends and statistics. Rarely is the voice of any specific individual emphasized. Paradoxically, the way this topic is presented can make depression seem like a standard emergent property of medical training. An underlying suggestion is that depression is simply something that physicians experience—it is something that physicians handle.

Yet I think we do people a disservice anytime we attempt to preserve the belief that medical professionals, stewards of good health, need less help coping with psychiatric disease than do their patients. Depression leaves massive economic and health care costs, and a growing body of evidence suggests that it has a penchant for painful interference in the lives of physicians1 and medical students.2 We contribute to the stigmatization of mental illness, furthering the notion that dealing with depression is something to be ashamed of, something that should be kept quiet. A recent study estimates the costs associated with physician turnover, decreased productivity, and decreased patient satisfaction due to self-reported symptoms consistent with burnout, noting that system-level change addressing the drivers of burnout, including institutional culture, is both ethically and financially responsible, with an enormous measurable return on investment.3

Depression is not weakness, though depression is a disease that may make you feel weak. Depression is neither laziness, nor apathy, nor a lack of professional fortitude. It is an expression of an underlying neurobiological pathology about which researchers still have many questions. It is a pathology that, like a many-tentacled octopus, grasps at our emotional stability, our cognition, our sleep, our patience with people, and our will to go on. Depression can obscure our personhood, so that it is hard for others—and for ourselves—to see us for who we really are. Admitting to depression is not weakness but rather is further confirmation of an insidious, life-threatening epidemic in the medical profession. On a very simple level, it constitutes an admission of humanness.

Even as I pen these words, a great fear swells and rises in my throat, threatening to take me over. At least for me, shame has never quite relinquished its grip on vulnerability, and vulnerability is deeply uncomfortable. As an aspiring physician, I may be committing professional self-sabotage by telling my story. My prospective employers may judge me to be unstable and unfit to care for patients. But the tears of my colleagues, the tales of deferred suicide attempts my classmates have confided in me, and the tragic deaths of bright minds around the country lend strength to my conviction to write about my experience.

I admit openly that I am just as vulnerable to the elements of life as are my future patients, hoping that others will do the same. I do so in the hopes that the culture of the medical profession will evolve to value imperfection as a harbinger of humanity, and that this value will be exemplified by the way we judge our students and residents. If I have learned anything after spending most of my short life in pursuit of academic distinction, it is that the appeal of the dividends—good grades, high praise, awards—is as ephemeral as the warm glow felt on their receipt. Not so with the call to protect human life; that’s something truly worth living for.


Effect of Oral Administration of a Mixture of Probiotic Strains on SCORAD Index and Use of Topical Steroids in Young Patients With Moderate Atopic Dermatitis

Key Points

Question  Can treatment with an oral probiotic reduce the SCORAD index and the use of topical steroids in children with moderate atopic dermatitis?

Findings  This randomized clinical trial of 50 children treated with a mixture of probiotics or placebo for 12 weeks found that SCORAD and topical steroid use decreased significantly in the probiotic group compared with the placebo group.

Meaning  This probiotic is an effective and safe coadjuvant treatment to reduce the SCORAD index and topical steroid use in children with moderate atopic dermatitis.


Importance  Oral intake of new probiotic formulations may improve the course of atopic dermatitis (AD) in a young population.

Objective  To determine whether a mixture of oral probiotics is safe and effective in the treatment of AD symptoms and to evaluate its influence on the use of topical steroids in a young population.

Design, Setting, and Participants  A 12-week randomized, double-blind, placebo-controlled intervention trial, from March to June 2016, at the outpatient hospital Centro Dermatológico Estético de Alicante, Alicante, Spain. Observers were blinded to patient groupings. Participants were children aged 4 to 17 years with moderate atopic dermatitis. The groups were stratified and block randomized according to sex, age, and age of onset. Patients were ineligible if they had used systemic immunosuppressive drugs in the previous 3 months or antibiotics in the previous 2 weeks or had a concomitant diagnosis of intestinal bowel disease or signs of bacterial infection.

Interventions  Twelve weeks with a daily capsule containing freeze-dried powder with 109 total colony-forming units of the probiotic strains Bifidobacterium lactis CECT 8145, B longum CECT 7347, and Lactobacillus casei CECT 9104 and maltodextrin as a carrier, or placebo (maltodextrin-only capsules).

Main Outcomes and Measures  SCORAD index score and days of topical steroid use were analyzed.

Results  Fifty children (26 [50%] female; mean [SD] age, 9.2 [3.7] years) participated. After 12 weeks of follow-up, the mean reduction in the SCORAD index in the probiotic group was 19.2 points greater than in the control group (mean difference, −19.2; 95% CI, −15.0 to −23.4). In relative terms, we observed a change of −83% (95% CI, −95% to −70%) in the probiotic group and −24% (95% CI, −36% to −11%) in the placebo group (P < .001). We found a significant reduction in the use of topical steroids to treat flares in the probiotic arm (161 of 2084 patient-days [7.7%]) compared with the control arm (220 of 2032 patient-days [10.8%]; odds ratio, 0.63; 95% CI, 0.51 to 0.78).

Conclusions and Relevance  The mixture of probiotics was effective in reducing SCORAD index and reducing the use of topical steroids in patients with moderate AD.