Thursday, January 19, 2017

Biotinidase Deficiency

Very similar to Pyridoxine Deficiency (PD) there is another very treatable cause of epilepsy in children, called Biotinidase Deficiency (BD). As children with PD require extremely high dosages of vitamin B6, infants and children with BD require large doses of biotin (vitamin H) typically in the 5-10mg a day range. The recommended daily intake for biotin is 5mcg, thus a dosage for someone diagnosed with BD is 5,000-10,000 times the RDI for the vitamin. Once a child has been diagnosed with the deficiency, they must stay on this high dosage of biotin for life - the lack of this enzyme requires a consistent high dosage to maintain proper levels in the body. All of the symptoms for BD are very similar to Pyridoxine Deficiency, including hypotonia, ataxia, seizures, developmental delay, eczema, and hearing loss. The enormously wide spectrum of epilepsy can have many causes - Biotinidase Deficiency can be one of those causes and has a very simple treatment. Early recognition of BD is critical, as delays in diagnosis can lead to developmental delay and can sometimes have permanent damaging effects.

Back in 2005, when Mira was born, Kansas had not adopted newborn testing for BD, thus Mira was not actually tested at birth. I happened to stumble on BD in all of my readings soon after her diagnosis and brought it up to her neurologist who thought it would be a good idea to have her tested. A simple blood draw ruled it out - her levels were normal, but she obviously had many of the symptoms of BD. Prior to the testing, we went ahead and put her on a large dosage of biotin for a few days until the results came in, but it did nothing for her seizures. We ruled out BD very early on in Mira's journey with epilepsy, nonetheless, I was glad to have found this very treatable cause of epilepsy as a potential cause, early on.

Wednesday, January 18, 2017

The Ketogenic Diet

The Ketogenic Diet (KD) is a specfically designed diet for the treatment of epilepsy, developed nearly a century ago, in the Mayo Clinic. It was a popular and successful treatment option for epilepsy, especially in children and young adults, but it fell out of favor in the 1940's, as AEDs began to flood the pharmaceutical market. It is still used today, typically started through the direction of a medical professional in a hospital, requiring a fair amount of monitoring to initiate. Equally as difficult is continual compliance with the diet, because of its strict guidelines on the fat to carbohydrate ratio. The KD can be very difficult on the body as well, with many children stopping it due to kidney stones, diarrhea, severe constipation, and/or the inability to tolerate the limited food choices the diet has to offer in general.

How does the diet work? Once the diet is initiated, the body eventually goes into a state of ketosis, where the primary source of fuel for the body is fat and protein, which in turn, affects how the brain functions, in a very simplistic sense. The traditional KD uses little to no carbohydrates as a source of energy, instead uses fat to break down into ketone bodies. The Modified Atkins Diet (MAD) is similar in structure, yet allows more carbohydrates into the overall ratio of caloric intake. It could be referred to as the 'Ketogenic Diet Light' in a sense. The typical KD however, is fairly rigorous, with the ratio of fat to protein and carbohydrates being in the range of 4:1 to 1:1 (4:1 being obviously the most aggressive and rigorous end of the diet) in order to try and gain seizure control. On a 1,000 calorie diet, only 8 grams of carbs would be allowed on a 4:1 ratio, which makes it very difficult to meal plan around such a limited amount of carbohydrates.

If you consider the foods that have zero or nearly zero carbs, you won't get a hand cramp writing them down: eggs, heavy cream, butter, most meats, most cheeses, mayonnaise, coconut oil, and MCT oil. There are a host of vegetables that have low carbs, including spinach, cauliflower, and even broccoli, but they still contain some carbs, so the ability to weave them into the diet is challenging. When you are limited to 8 grams of carbs a day, it makes meal planning very difficult, yet very predictable. Again, there are less strict ratios for the diet, but the basic idea is that you are substituting a large percentage of your typical intake of carbohydrates and protein, with fat and calories.

We tried the MAD with Mira years ago and it was very difficult on her. We initially tried to have her admitted to try the traditional KD, but her labs were so far off the charts, that the clinic felt she would not be a good candidate for the diet. Before she was even considered being admitted to the hospital, she had very elevated BHB (beta hydroxybutyrate) levels for some reason, indicating that she was already in some level of ketosis. She also had very high cholesterol levels, which no one felt comfortable starting her on the diet at that point. We agreed to start her on the MAD instead, thinking that she might tolerate the ratio better that the KD. If we saw some seizure reduction with the MAD, we could increase the ratio as we went along. Unfortunately, Mira did not tolerate the diet well - there was a lot of irritability, constipation, vomiting, and continued elevated cholesterol after several months, that we slowly abandoned the diet after 4 or 5 months. She never really could stay in a solid state of ketosis either and with all of the complications just on the MAD, going to the full-fledged KD would have been brutal for Mira. We never saw any change in seizures in that time as well, in fact, if my memory serves me well, her seizures actually worsened.

Clearly, the diet does not work for everyone, but it has helped a lot of kids with seizure control. The Charlie Foundation was developed over 20 years ago as a resource for the KD, as a result of the diet being hugely successful for a child named Charlie Abrahams, who was battling epilepsy at the time. It is a fantastic point of departure to find out information on the diet, find support, and to see other therapeutic applications the KD has to offer.

Tuesday, January 17, 2017

Back at School

Mira was back at school today, after an extended 4-day weekend. She must have sensed something was happening this morning, since she was kicking her feet 100 miles and hour, making it a wrestling match to try and get her dressed and ready. She wanted nothing but to be in her chair and moving. Based on her teacher's report, she had a solid morning, but wanted to eat lunch early - not a surprise, since her M.O. the past few mornings has been to eat a mediocre breakfast (a half-bottle as opposed top her usual 2 full bottles). She was moving so much this morning before the bus, that it made it difficult to get her to drink anything, since she just wouldn't stay still or interested long enough to finish a bottle. She was quiet this afternoon after school and during dinner, probably worn out from getting back into the school rhythm.


The amino acid taurine was a subject of interest of mine for awhile. It is one of those supplements that is mentioned repeatedly in medical abstracts as a potential source of epilepsy relief, usually in the context of it being a 'complimentary' treatment option.

I first started investigating the basic pharmacokinetics of taurine, which were studied here, which ultimately led me to how they potentially could impact seizures, either in conjunction with mainstream AEDs or by itself. Since taurine has the ability to cross the blood-brain-barrier (BBB) and it is widely recognized as being a neuroprotectant, I figured I would be able to find some significant epilepsy studies on it. However, like vinpocetine, I couldn't track down many that involved the effects of taurine on seizures that weren't animal studies, other than a lone clinical trial, that I could not find results on. I did find some interesting facts on neurotransmission and the impact taurine has on the central nervous system, which can be located here.

Taurine acts as a membrane stabilizer, particularly with voltage-gated calcium channels (VGCCs) - the article goes into great technical depth with and explanation, which I can only digest and interpret so much of before my eyes glaze over. One of the main takeaways I read in the article, was how taurine's inhibition or monitoring of VGCCs, was also the assumed mechanism of action of Lyrica. Since MIra has been on Lyrica (pregabalin) for years now, I found it necessary to explore the potential relevance. Based on this connection alone, I kept traveling down the taurine rabbit hole. Ultimately, I found a ton of information of what taurine supposedly does, in the articles listed below, but again, not a lot of direct, conclusive studies:

Based on this article, there seemed to be a lot of interest in taurine and an anti-seizure medication, back in the 1970's. All of the references for studies were all done prior to 1979. I lost interest in reading about taurine, as I found more research in animal studies, and even more studies for taurine in relation to canine epilepsy. While I found taurine as being a simple amino acid, its relevance to cell membrane functioning was complex and confusing. Based on what I read, it had a wide range of influential activity, but not really much specific to epilepsy and/or seizure control. Please email me or post links if you can find some conclusive studies or additional information.

Sunday, January 15, 2017

Quality Toy Time

Mira has been been getting her share of quality toy time today. She has been up and down most of the day and getting the toy in front of her has been a great redirection. On most occasions, she wouldn't last more than 15-20 minutes with it, but late this afternoon, she was playing with it for a solid 45 minutes, just smacking those bulbs., over and over. It's funny how we have tuned out the noise of it over the years - we sat and watched the end of the Dallas/Green Bay game with Mira sitting with us, with her just relentlessly banging on that toy. The sounds it makes just become background noise. It's no wonder those toys don't seem to last very long, as she wears them out quickly by hitting them so much. She ended up throwing it on the floor twice today - the first time, she shoved it so forcefully that she snapped the Theraband off of her tray and it went crashing to the floor. The second time, I just couldn't catch it in time as she pushed it and it twisted off of her easel. The 'major ice storm' we were supposed to get today was pretty uneventful, yet we had no chance to get outside, thus we ended up doing some walking in the house. That kept Mira entertained for awhile, but we needed the toy as well. The kids will finish up their 4 day weekend tomorrow and head back to school on Tuesday.

Saturday, January 14, 2017

New Bibs

Mira has been pretty irritable today and hasn't had interest in doing much. We have give her an ample amount of time with her toy, but she quickly loses interest in it. She also hasn't cared much for racing around the house either. Her appetite has been strong, but her fussiness level has been stronger. Just one of those days where we have a lot of fans running in the house. On a side note, Mira tends to drool a lot, especially when she is really getting into playing her toy. She keeps her mouth open when she is staring at it, which often leaves a puddle by the time she is finished playing. A good friend of ours made a series of colorful bibs for Mira, so she doesn't end up drenching her shirts. Thank you, Tisha!


I only stumbled across the potential for vinpocetine as an anticonvulsant back in mid-2016. I'm not sure how a came across it, but it was intriguing enough to research it for a bit. Vinpocetine is a chemical extract from the lesser periwinkle plant and is sold as a dietary supplement in the U.S. and actually a prescribed medication in other countries. It is known for potentially increasing blood flow in the brain and offers neuroprotective properties, based on some initial animal studies. There aren't a ton of human studies on vinpocetine, but there are a few that conclude that it did reduce cerebral inflammation, as well as decrease ion channel permeability, which ultimately affects seizure potential(s). There was another animal based study here and another one here, proving its effectiveness in halting chemically-induced EEG patterns. The supposed mechanism of action is through the reduction of calcium and sodium channel permeability. In terms of human clinical trials, there was one study completed a few years ago, but no results were formally posted.

Again, vinpocetine is widely available as a supplement, but at the end of the day, I didn't see enough evidence to warrant pursuing it as an option for Mira. I didn't see enough human trials or support that prove it might be beneficial, beyond anecdotal trials that involved chemically-provoked seizures to measure its effectiveness. If anyone had some hard data on it, I would pursue it further as a potential relief option for Mira. In the meantime, I will continue to look into it.

Friday, January 13, 2017

Coping Mechanisms

Epilepsy affects everyone in our family. Of course, the only one who suffers from actual seizures is Mira, but the path that she has been traveling on for the last 11+ years has taken our entire family down a very tumultuous road at times. We still have our joyous and happy moments as a family, but having a child with a catastrophic epileptic syndrome is often very difficult to deal with, day in and day out. Sarah, Eli, Jonah, and myself all have our individual coping mechanisms when days get rough with Mira. Trying to develop and exercise those coping skills is very important in trying to maintain balance.

Mira cries and some days, she cries a lot. In many ways, she functions at about a 2-3 month old level, which can be exhausting, when you area trying to raise a child that never really progresses beyond this stage of development. It has been the equivalent of raising an infant, for 11 years. In other ways, she does make minor progress -  progress that isn't necessarily measurable on a neutotypical development scale. Her patterns of irritability are unpredictable and you have to do your best to take them in stride. When we are noticing an uptick in her fussiness level, we typically start asking why or investigate what has changed (if anything) in her patterns, which ultimately leaves everyone frustrated, because there usually isn't an answer that we can pinpoint. There is no 'why'. There only 'is'. Mira cries and 95% of the time, we have no idea why. Eli and Jonah both ask the question, nearly every time she gets upset and I never have a tactical response that helps ease their anxiety and often, their frustrations with her.

Like Sarah and I, the boys become exhausted at times with her, which is totally understandable. We live in a small, 1,700 square foot house, that only has so many rooms to try and create distance from Mira's crying. Thus, one of our major coping mechanisms is a box fan. Ironically, box fans have had a significant impact on Mira's sleeping patterns. (You can read this very brief post to understand what I mean). Mira has been sleeping with a box fan in her room for the last 10 years, and nearly every single room in our house, has a box fan. Whenever Mira gets irritable and we have run out of options, she ends up in her bed, with a box fan going for white noise, but again, since our house is so small, the boys will revert to the kitchen or their respective rooms, and turn on their box fans. I think our family coat of arms or crest would involve a box fan. The noise is wonderful tactic to help create some background noise to help us all cope with the crying, when it happens.

Granted, when the weather is nice and time permitting, Mira loves to go on walks outside, and I am always happy to take her out for a stroll. Getting outside for a change of scenery and some fresh air, tends to help Mira's irritable disposition. However, when we can't get out, we try to do 'laps' in the house in her chair, which is the near equivalent of going for a walk outside, minus the scenery, the fresh air, and changes in elevation. Ok, it's a mediocre consolation, but at least she is in a constant state of movement, which is what she is typically craving. Since we have hardwood floors throughout the house, we developed a walking 'track' through all of the rooms, in large figure-8 pattern, from the living room, through the foyer, into the kitchen/dining room, and back again. In the thousands of laps we have walked in this pattern, I've only managed to gouge the kitchen base cabinets with her chair, on two occasions. That's a pretty solid track record, every pun intended.

Coping mechanisms can take on any number of forms in our house and they don't just revolve around Mira's irritability. Transferring, bathing, meal preparation, and diaper changing - the routines that Sarah and I do with Mira, often multiple times a day, are exhausting in itself. We often tire from the physical labor that is required of us on a daily basis, and by the time dinner is over and the kitchen is clean, we are looking for some down time just for ourselves. There tends to be a fair amount of physical coping, whether it's laying on the couch and squeezing in a nap in the middle of the day (a method I have perfected on the weekends) or just vegging out on the computer for a half-hour. It can be something simple.

When it comes to coping mechanisms in general, my attitude is this: whatever works to help maintain your physical, spiritual, and mental health, in being able to get up the next day and prepare to do it all again. Raising a child, with special needs or not, is challenging. Add to it the physical and emotional demands of a child (or children) with debilitating issues, you recognize and openly invite, those seemingly minor moments throughout the day, that keeps everything in balance, and helps maintain perspective.

Wednesday, January 11, 2017

Rett Syndrome

Being one of the more recognizable genetic manifestations in the world of epilepsy, Rett Syndrome (RTT) is often diagnosed through one of two associated genes, MECP2 and CDKL5. Mutations in the FOXG1 gene often fall under the same in the genetic diagnosis umbrella. One of the most surprising facts about the syndrome is that is primarily only affects girls, although there is inclusion criteria that can affect boys. All of the inclusion criteria for typical classic RTT are listed here, typically involving a period of normal development, that regress to a complete loss of language, purposeful hand movements, and a myriad of other neurological issues. Repetitive hand gestures often take the form of hand-wringing, clapping, or hand-rubbing. Unfortunately, seizures are quite common, thus Rett Syndrome is often synonymous with epilepsy.

Monica Coenraads, who is the executive director of the Rett Syndrome Research Trust, works tirelessly to generate research funding to drive the development of potential treatments. Her daughter Chelsea was diagnosed with Rett Syndrome. Most of the research targeted for RTT revolve around alleviating the symptoms, not necessarily focusing on a cure per se, since the genetic mutation(s) associated with Rett's are obviously permanent in nature. However, there have been clinical trials performed to help combat the symptoms, which include creatine therapy, IGF-1, and a few experimental drugs, including EPI-743, which targets specific mitochondrial functions. There is much promise in some of the ongoing studies, as some symptoms have actually been reversed in mice models.

At certain points through Mira's journey with epilepsy (back in the days of single-gene testing) several neurologists were highly suspicious that Mira had Rett Syndrome. Despite the inability to pinpoint any genetic specifics, with Mira (nothing related to MECP2, CDKL5, or FOXG1) she does have many of the hallmark features.

Tuesday, January 10, 2017

The MOAs of AEDs

One of the many questions that always came up every time one of Mira's neurologists recommended a new AED (anti-epileptic drug) was how does it actually work chemically and neurologically in helping control seizures? What is the mechanism of action (MOA) and how is going to potentially impact my child's seizures? Mira has tried many different medications, unsuccessfully, so many of the details have escaped me over the years. I can however, remember the sedating ones like ethosuximide, the horrible ones, like felbamate, and the rest simply by name, but overall, medications overall have done nothing for Mira in terms of seizure control. Researching the MOAs of these medications has been eyeopening. Simply reading through the medication product literature of many popular AEDs, the overwhelming majority of them read very similarly, and in the case of Lyrica, which Mira is currently taking, it states:

 'The exact mechanism of action of Lyrica (pregabalin) has not been fully elucidated. The current findings are based on preclinical animal models. The clinical significance in humans is unknown.'

Not exactly the sentence you want to read as you are signing your child up for one of these medications. As I have said many times before, I am certainly not anti-pharmaceuticals, as there are many out there that provide effective relief for many suffering from epilepsy. There is the right medication or combination of meds that works for that particular individual and it's refreshing to hear those stories. However, there are some meds that can have harmful, damaging, and often permanent side-effects. This list of these side effects are typically listed with the medication pamphlet, along with the MOAs. I would encourage everyone in becoming familiar with the side effects at a minimum - recognizing these effects is critical. For instance, when Mira was prescribed Lamictal (lamotrigine) we were warned by her neurologist at the time, that in rare cases, users can have a potentially fatal skin reaction called Stevens-Johnson Syndrome or in the case of Sabril (vigabatrin), there is the looming threat of permanent retinal toxicity - basically it can cause you to go blind.

Buried with all of the side-effect warnings, clinical trial data, and other relevant user information, usually is an explanation of the supposed MOA(s) of the medication. Most pharmaceutical MOAs revolve around the following actions or potentials:

GABA receptors
Voltage-gated calcium channels (VGCC)
Voltage-gated potassium channels (VGPC)
Voltage-gated sodium channels (VGSC)
NMDA receptors
Glutamate receptors

There is a decent article that can be accessed here, that offers a charted breakdown of 20+ AEDs and their assumed MOA. The only medication Mira has ever had a positive reaction to is Lyrica, thus it is part of the reason she is still on it and has continued to take it for the last 8+ years. Mira's seizures subsided for almost 6 months, within a week after starting Lyrica in 2007, which was miraculous at the time. We attributed her seizure freedom to Lyrica, but the reality is, her EEG never improved in that 6 months and eventually, the seizures came back in full force and have stayed ever since, despite numerous dosage increases and modifications. Nonetheless, I went on a research endeavor back then, trying to dig up as much information on the MOA and history of Lyrica, going so far as to contact the person who actually 'invented' the chemistry behind the drug. I emailed with him numerous times and found the process and method in which a formula ultimately reaches the end user, disconcerting. It is fairly easy to discover the supposed MOA for Lyrica is assumed to be through voltage-gated calcium channels (VGCCs), a claim which is buried in the 55 pages of prescribing information, that can be found here. The MOA and pharmacology can be located in section 12.1.

Every single medication that enters the marketplace should be offering this information to the consumer and of course, the health care professional who is prescribing it. It may seem exhausting to read, but I can assure you, the publicly available information regarding pharmaceuticals will be nothing but enlightening, if not frightening. For a more exhaustive article of the MOAs and the neuropharmacology of commonly prescribed AEDs, can be accessed here, through one of my favorite resources, the NCBI Bookshelf.

Monday, January 9, 2017

Thank You, Variety KC!

Over the past 2 years or so, we have been coming to the conclusion that we are going to need to buy an adapted van. Considering that we are currently driving an 11 year Odyssey with 100,000 miles on it, we know that our next new vehicle must be an adapted van. We started looking at vans several years ago and were completely astounded at the price. New side-entry vans start in the $45,000 range and run upwards of $65,000, which is incredibly expensive, but this is the financial reality we are dealing with. Knowing then (and now) that we could not afford the cost of a new van, we have been pursuing other options, the least expensive option being to get a lightweight adaptive stroller for the van. With her current chair weighing over 75 lbs, the strain and exertion that Sarah and I have been putting on our backs, trying to lift her chair into the back of the van by ourselves, has taken its toll. It is a task that we can no longer do with one person.

To make a long story short, I ended up throwing my back out this past summer lifting it into the van, ending up in the ER taking some serious painkillers for the next week to recover. Because of the weight of her chair, it has made it very difficult for Sarah or I to take Mira anywhere by ourselves, unless Eli comes along with one of us to help lift her chair. The idea behind the lightweight stroller was that we could use the it, instead of her regular chair, whenever just one of us has to run errands or just get around town with Mira. The stroller we picked only weighs less than 30 pounds, which can be more easily lifted by one person into the van.

So, I received some fantastic news this afternoon, from Variety KC, saying that they were going to purchase a new stroller for Mira! Variety is a fantastic charitable organization here in Kansas City, led by Executive Director Deborah Wiebrecht, who is the tireless force behind this wonderful group. We met Deborah about 6 or 7 years ago, in of all places, Costco. Mira at the time was about 5 or 6 years old when introduced herself to all of us, asking if we needed any help financially with any durable medical equipment. Ironically, we were in the process of getting Mira a new wheelchair and Deborah was incredibly helpful in getting Mira's chair paid for through Variety! We were floored by her generosity and the compassion she has, in working with children and families with special needs. She is an amazing person and we cannot thank her and Variety in helping Mira again!

Serotonin - Part 2

As I continue down the pyridoxine-tryptophan-serotonin rabbit hole, I am finding that there is a lot of prior research in this area, in regards to not only epilepsy, but also depression, autism, and a host of other neurological manifestations. There are countless articles that reiterate the connection between pyridoxine and serotonin.

One of the first articles I came across had to do with the kynurenine pathway (KP). By simulating a sort of mock-pyridoxine deficiency, this study successfully showed that tryptophan metabolism occurs almost exclusively through the KP and that a significant decrease in pyridoxine in the brain (among other areas), created an increased dumping of metabolites, including kynurenric acid, which has known anticonvulsant properties. A simple explanation would be that a pyridoxine deficiency leads to an increased susceptibility to seizures in people that have an issue somewhere along this pathway. Does pyridoxine deficiency ultimately lead to a decrease in tryptophan metabolism, which leads to a decrease in serotonin levels? Much of the research that exists indicates yes. Does this reduction in available serotonin lead to some epileptic syndromes? Again, some of the research that exists indicates yes as well. Children with Infantile Spasms (IS) have been shown to have low serotonin levels. Trying to understand exactly how, why, and where this breakdown along the pathway occurs, is the question that keeps being asked.

There was another interesting abstract I found, having to do with the Ketogenic Diet (KD), which is a century old rigorous diet used to treat children with refractory epilepsy, and its relevance to serotonin levels, before and after initiating the diet. The abstract, which can be read here, says this:

'Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5-HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action.'

So, there is a legitimate connection between the epilepsy, autism, and depression (read this article) all of which point to a dysfunction of the kynurenine pathway. Investigating this pathway led to me obscure syndromes that I had never heard of, including hydroxykynurinuria. I am certainly not saying that this is particularly relevant to Mira (as the basis around the diagnosis involved a homozygous mutation of the KYNU gene), yet the dysfunction of the kynurenine pathway is interesting. However, in reading the health conditions related to this syndrome, many of them are very relevant.

In looking into just the subject of epilepsy and serotonin levels, there just seems to be a massive amount of literature on the KP and how it ultimately impacts serotonin and other neurotransmitters in the body - it is difficult to get my arms fully around it. If you are interested in reading more on any of this, you can simply do a search through Google Scholar for 'kynurenine pathway dysfunction and epilepsy' and your will get over 2,500 hits. For now, in trying to bring some closure to my last few posts on serotonin, I would recommend reading this article, scrolling down especially to the section entitled 'Brain 5-HT Concentration and Epilepsy'. The downloadable PDF can be found here. It is a good overview of all of the studies in the last 20+ years in regards to serotonin and epilepsy, with endless references at the end to make your head spin.