Catastrophic Epilepsy

The word catastrophic tends to evoke a lot of different emotions, but usually carries with it a negative connotation, as we commonly hear the word in conjunction with some sort of natural disaster or an economic collapse. Prior to have a child with significant special needs, I would have never to thought to use the word in the same sentence as my child's name. I remember first hearing the term being used in the context of epilepsy, from one of Mira's neurologists about 10 years ago, and the word has stuck with me ever since. Little did I know that the word had long ago been adopted by the epilepsy community. Epilepsy can be catastrophic, especially in the developing brain, when it is basically in a state of constant plasticity for the first several years. Infantile Spasms can be catastrophic, if the seizures become uncontrollable, and morph into Lennox-Gastaut Syndrome or some other syndrome, as they did with Mira. The seizures themselves often become intertwined with a myriad of other symptoms, affecting numerous systems in the body, from the brain, to the central nervous system, to the endocrine system.

There is a great overview of the catastrophic epilepsies, written by a pediatric neurologist from UCLA (at the time of publication) that can be downloaded here. It is a brief synopsis of the more 'common' syndromes, including West Syndrome (WS or more commonly referred to as Infantile Spasms or IS), Lennox-Gastaut Syndrome (LGS), and Dravet Syndrome (often referred to as Severe Myoclonic Epilepsy in Infancy or SMEI) and a few lesser know syndromes. Ironically, Mira has been diagnosed with all three of the syndromes, each at different times, by a different neurologist. All are very similar in nature, but are often defined by age of onset, seizure type, EEG pattern, and sometimes, etiology.

Mira has never truly had seizure control, thus her epilepsy has evolved into different seizure types, including infantile spasms, myoclonics, tonic-clonics, and any combination thereof. Infantile spasms ultimately progressed into full-blown tonic-clonics around 2 or 3 years old and what came with that, was a diagnosis of LGS/SMEI at the time. At one point, one of her neurologists swore that she had Angelman's Syndrome, yet a genetic screen, which would have identified the deletion, mutation, or mosaicism of the gene UBE3A, ruled that out quickly. At another point, Mira seemed to be a strong candidate for Rett Syndrome (RS), which is one of the more common genetic issues that effects only girls. Despite not finding the recognizable genetic markers through the CDKL5 and MECP2 genes, Mira still has nearly all of the characteristics and symptoms of RS. One of her former neurologists had gone so far as to say she has Atypical Rett Syndrome. No definitive genetic marker, yet all of the symptoms.

However, through a whole exome screen, there was a mutation found with one of Mira's genes, called TPP1, which is a gene responsible for making an enzyme called tripeptidyl peptidase 1. Mutations and issues with the TPP1 gene are often associated with Neuronal-Ceroid Lipofuscinosis (NCL). Since Mira's mutation is a heterozygous mutation, meaning she still has one functioning gene, the theory is that it may or may not be the cause of her condition. However, in reading extensively on NCL, I have found that both homozygous and heterozygous mutations can be responsible for the dysfunction in the TPP1 gene. I haven't really read a convincing explanation that fully explains NCL, as the diagnosis can be clinical, not simply based on genetics. Mira meets all of the criteria and symptoms for NCL, only a skin biopsy, performed in 2016, failed to reveal the typical skin/storage marker(s) for NCL. Clinically, she meets all of the criteria for NCL, including severe myopia (-10.00 in both eyes, she is extremely nearsighted), seizures, ataxia, motor function impairment, and myoclonus, but the biopsy states otherwise.

With all of the advancements in genetics and testing, it is still very difficult to pinpoint the cause or etiology of any one of these catastrophic syndromes, as it often tends to be much more complex puzzle. While some syndromes can be traced back to a non-functioning gene, others are the result of a series of different bodily systems that are not working in unison or are simplistically put, imbalanced. Such is the case of autism and Autism Spectrum Disorders (ASD). Some children who are diagnosed with epilepsy are often given a secondary diagnosis of ASD, based on overlapping symptoms. There is a very general and rudimentary introduction to those coexisting conditions explained here, through the Epilepsy Foundation. For a more exhaustive and historical read on epilepsy and autism, you can find that here. Autism in itself can be catastrophic and when combined with the damaging effects of epilepsy, it can be truly devastating.