How does serotonin impact epilepsy? This is the question I have been asking lately, as I continue to look at how and why pyidoxine affects children with epilepsy. Since pyridoxine can indirectly affect serotonin (in conjunction with 5HTP or tryptophan) it only seems logical that serotonin itself might be something to consider for Mira. The question I have is whetherer pyridoxine is simply a catalyst in this process and is not directly involved in her irritable disposition when she isn't taking it.
If you simply Google 'serotonin and epilepsy', one of the first hits put you directly into PubMed territory, which I am all too familiar with. So, I read this article today and discovered some very interesting concepts that researchers in this study were asking almost 15 years ago. The idea behind this particular article was to find a connection between serotonin receptors and how they impact the onset and latency of seizures. This goes under the premise that there have been previous studies indicating that certain SSRIs (Selective Serotonin Reuptake Inhibitors) have shown to act as neuroprotectants. A few SSRIs, including fluoxetine, which Mira is currently taking, have shown to posses anticonvulsant properties, by supposedly altering the course of serotonin breakdown in the body, allowing it to more readily available to the brain and central nervous system. The irony with SSRIs in general, is that while the assumed mechanism of action is to block the reuptake of serotonin, it ultimately cannot be proven, and the exact method of how SSRIs actually function, is unknown. The assumed targets are 5-HT receptors. In terms of depression and anxiety, which is what SSRIs are most commonly prescribed for, they are clinically ineffective in 40-60% who use them, depending on what study you are reading.
One of the more interesting abstracts I have read that implicates serotonin in epilepsy, is this one. It analyzed the changes in spinal fluid on a small group of children, before and after ACTH treatment for Infantile Spasms (IS), which is Mira's original diagnosis. In the United States, ACTH is the typically the first line of defense in trying to control IS and it many cases, it is successful in stopping the spasms and improving the EEG pattern (hypsarrhythmia) of those who complete the round of treatment. In Japan, pyridoxine is the first line of treatment. If the assumption that both ACTH and pyridoxine indirectly target serotonin receptors, then the main thing to take away from this abstract is:
'These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms.'
Can some cases of Infantile Spasms be the result of a faulty serotonin production or metabolism? Since it has been proven that tryptophan and/or 5-HTP can both effectively raise serotonin levels, it raises another question. If one of the mechanisms of action ACTH promotes, is to somehow alter the course of tryptophan metabolism and ultimately affecting the serotonin pathway, can simply providing supplementation of serotonin-altering agents be used instead of ACTH to treat IS? Those children who have certain disrupted serotonin receptors and their responsiveness to ACTH are discussed briefly in this abstract, which basically states that there is a relationship between the two, when it comes to Infantile Spasms. There is a much more in-depth analysis of the relationship of ACTH and IS here. It accentuates the point that there is a strong need to understand the importance of neurochemistry and how it impacts epilepsy, as it is complex. On a soapbox level, this article calls into question just how many neurologists need to fully recognize the importance of the neuroscience behind some of the basic neurotransmitters.
I am simplifying this relationship of the serotonin pathway and epeilepsy tremendously, but the fact that serotonin itself it synthesized from tryptophan, and the fact that serotonin deficiency is implicated so much in epilepsy and autism, it seems reasonable to think that one of the many possible causes of epilepsy could stem from either a disruption in the serotonin or kynurenine pathway, or a simple issue of having low serotonin levels. As I continued to dig further into this, it turns out that this connection has been seriously questioned for the last 30+ years. In terms of autism, the idea that serotonin has been implicated in rampant through the research, as in this article, that states:
'Serotonin, as a monoamine neurotransmitter and hormone, plays numerous roles and is a critical modulator of neuronal interaction that supports diverse behaviors and physiological processes, and acts via different specific transporters, receptors, and intracellular signaling pathways. Multiple lines of evidence implicate abnormal serotonergic signaling in psychiatric and neuro-developmental pathogenesis. However, the entire serotonin system is poorly defined and is far from a complete understanding. Laboratory analyses of cerebrospinal fluid (CSF) describe a frequency of up to 20% of patients with altered serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in neurological disorders, including subjects with ASD.'
Another study located here, looked at MRI changes during tryptophan depletion and ultimately came to this conclusion:
'Our results also add to existing evidence that serotonin may play a key role in the pathophysiology of autism. The brain areas that we found to be differentially modulated by ATD (acute tryptophan depletion) form part of a fronto-striato-thalamo-cerebellar network of inhibitory control that develops progressively with age (Rubia et al., 2007), and has intermediate-to-high levels of serotonin receptors and transporters (Pazos et al., 1987; Varnäs et al., 2004) in healthy populations. Further, it has previously been reported by ourselves and others that in these regions, subjects with ASD have significant differences from controls in serotonin synthesis (Chugani et al., 1997), transporters (Nakamura et al., 2010) and 2A receptors (Murphy et al., 2006).'
When Mira was first diagnosed with Infantile Spasms back in 2005, one of the names that kept surfacing in all of the parent support groups at the time, was Dr. Harry Chugani, who is now the Chief of Neurology at the Nemours Neuroscience Center in Delaware. Back in 2005, he was with the Children's Hospital in Detroit and her was looked upon as one of the leading experts in the country in Infantile Spasms. Part of his protocol for the treatment approach for children with IS, involved a PET scan, which would look at the overall metabolism in the brain. Based on the information from the scan, medical history, EEG data, and I am assuming, an extensive clinical analysis, Dr, Chugani would often determine whether or not the child would be a surgical candidate, which at the time, was a very frightening prospect for us.
Seeing Dr. Chugani's name buried in one of the references in the article was not surprising, especially when this particular article has to do with an MRI/PET analysis. Back in 2009, we had started to make arrangements for Mira to be seen in the clinic in Detroit with Dr. Chugani, but we decided not to go through with it. After talking with parents and additional email correspondence with Dr. Chugani himself, we abandoned the idea of taking Mira to Detroit and subjecting her to such extensive testing. In hindsight, I think it was the best decision, as we had already seen 4-5 neurologists at that point and the overwhelming message with Mira was the same from everyone - she is not a surgical candidate, as her seizures involve her entire brain and are not isolated to one particular area, based on all the EEGs and MRIs she had had to that point. It didn't seem logical to do a PET scan with her at the time, based on what we knew.
Anyway, as it turns out, Dr. Chugani, along with numerous other neurologists and researchers, have been using PET scans and other methods, to further understand the connection between serotonin and epilepsy. I plan on reading this article, that Dr. Chugani and his wife, Dr. Diane Chugani, published back in 2005 and will report back on it soon in Part 2.