Epilepsy and Autism: From a Stress Perspective

In a previous post, “What is a Stress Perspective“, I hypothesize that we can use a Stress Model to see patterns in most disorders. Here is a quick exercise on epilepsy (consider this a starting model for a work in progress).

Epilepsy’s connection to autism is yet unknown. It is presumed that both being conditions of a dysfunctional nervous system accounts for the overlap. More individuals with autism have intractable epilepsy and there is a greater risk of death for those on the spectrum with epilepsy. About 20-30% of those one the spectrum are suggested to have epilepsy (AutismSpeaks, WebMD, Spence 2009)

A Quick example of Epilepsy plugged into a “Stress Model”. Looking at genetic susceptibility and environmental influences that create stress and programming overlaps and conditions.

  • Genetics: “novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation and regulation of the mammalian target of rapamycin (mTOR) protein in the etiology of epilepsy” (Meyers 2015). Variation of gene response to medication is an important consideration (Balestrini 2017) and pleiotropy of genes (Berkovic 2015)

    1. Genes associated with dopamine, serotonin, MOATXNRD1, Nrf2 and mTOR signalling.
  • Epigenetics
    1. The importance of gene-environment interactions in epilepsy . The dynamics of epigenetic mechanisms (e.g. DNA methylation, histone modifications, chromatin remodelling, and non-coding RNAs) provide likely explanations for common features in epilepsy and other complex diseases. (Kobow 2017) New findings based on biochemical manipulation of the DNA methylome suggest that: (i) epigenetic mechanisms play a functional role in epileptogenesis; and (ii) therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy. (Boison 2016)
    2. Early Life Stress (ELS) Exposures (Koe 2009) and its involvement in epilepsy, as well as ELS and sexual-dimorphic vulnerability (Desgent 2012)
  • Nutrients, Medications and “Lifestyle” Factors  (these create greater susceptibility when deficient and *may* be involved in some level of treatment protocols.)

    1. Antioxidants and Oxidative Stress Channels (Martinec 2012, Shin 2011)
      1. Melatonin (Ni 2015Malhotra 2004) and disruption of circadian rhythms (Xiang 2017),  Glutamate Toxicity, Oxidative Stress and Melatonin in Epilepsy (Vishnoi 2016)
      2. Study: “Alleviation of Oxidative Damage and Involvement of Nrf2-ARE Pathway in Mesodopaminergic System and Hippocampus of Status Epilepticus Rats Pretreated by Intranasal Pentoxifylline” (Kang 2017)
      3. Study: Effect of Oxidative Stress on ABC Transporters: Contribution to Epilepsy Pharmacoresistance (Grewal 2017)
      4. Study: “The effects of quercetin on the gene expression of the GABAA receptor α5 subunit gene in a mouse model of kainic acid-induced seizure” (Moghbelinejad 2017)
      5. Study: “Comparative studies on the effects of clinically used anticonvulsants on the oxidative stress biomarkers in pentylenetetrazole-induced kindling model of epileptogenesis in mice.” (Mazhar 2017)
      6. Study: “Maternal methyl-enriched diet in rat reduced the audiogenic seizure proneness in progeny.” (Poletaeva 2014)
    2. FAT– Early life susceptibility with n-3 deficiency (Sun 2010).  The use of high fat diet as treatment with Ketogenic diet. Inflammation/NAFLD associated with seizures (Aksoy 2014). Explanation of Ketogenic Diet by Practitioners (“Eat to Beat Seizures” Coeli 2015)
    3. GERMS– Microbiota levels
      1. Case Study of Fecal Implant and reversal of seizures (He 2017)
      2. Ketogenic diet alters microbiota (Tagliabue 2017) , Microbiota alters Th17 (Wu 2016) and Mast Cells (Girolamo 2017).
    4. SUNLIGHT – Benefits of sunlight: vitamin D deficiency might increase the risk of sudden unexpected death in epilepsy. (Scorza 2010)
      Vitamin D3 for the Treatment of Epilepsy: Basic Mechanisms, Animal Models, and Clinical Trials: There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D3 is actively under investigation as a potential intervention for epilepsy. Vitamin D3 is fat-soluble steroid, which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D3 may reduce seizures, and animal data support the efficacy of Vitamin D3 in rat and mouse models of epilepsy. Very little clinical data exist to support the treatment of human epilepsy with Vitamin D3, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D3 as a treatment for human epilepsy. (Pendo 2016) Review Vitamin D and Epilepsy (Hollo 2014)
  • Social Stress: HPA axis (Maguire 2013), stress in childhood seizures (van Campen 2015), Macquire also discusss gene-environment and early life programming in “Primed for Problems: Stress Confers Vulnerability to Epilepsy and Associated Comorbidities” (Mcguire 2015)
  • Exercise: Physical stress is a stress that can help build stress resiliency and will therefore be found associated with stress-related disorders such as Epilepsy. As an interesting history, because exercise induced stress and therefore seizures it was discouraged. That thinking is beginning to change as we realize exercise, if applied and supported properly, can also be beneficial. (Pimental 2015, Iqbal 2017, )

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