Navigating the Storms of the Mind
The first time my four-month-old daughter Cedar spasmed, I had no idea I was witnessing a seizure. I had seen seizures in adults before, but this looked entirely different. Babies do strange stuff all the time, I thought, and this had been a brief thing. I dismissed the possibility that anything was wrong. But my wife Julia knew immediately what we had witnessed—a rare type of seizure called an infantile spasm. Sure enough, an hour later Cedar repeated the same motion of clenching her fists, raising her arms as if starting a hug, and tucking her head down like she was starting a sit up. We called an ambulance, and she and Julia were off to Children’s National Hospital.
Since that moment, I’ve learned that there are many kinds of seizures. Neurologists and epileptologists detect and distinguish them using an electroencephalogram (EEG). At Children’s, Cedar’s head was covered in a jellylike goop and capped with a cloth hat attached with more than a dozen electrodes and wires. She wore the EEG for over twelve hours, and I found myself in the surreal position of hoping for more seizures so they would be captured by the EEG and help our doctors to give us some answers. Watching Cedar spasm and hoping in those twelve hours that anything that could go wrong, would go wrong, was the most helpless I have ever felt in my entire life.
The doctors confirmed that not only was Cedar having infantile spasms, but she also had another type of seizure called a focal seizure. She was diagnosed with epilepsy, a neurological disorder. Simply put, seizures are when the neurons in the brain exhibit unusual activity, misfiring at the wrong time or intensity or in an abnormal pattern, and sometimes overloading the brain with too much electrical activity.
As I learned from our team of doctors, not everyone who has a seizure has epilepsy, another rare condition. A diagnosis of epilepsy means that the person has had more than one seizure not caused by an infection, injury, or some other insult. Just over one percent of people living in the United States (approximately three point four million) have active epilepsy, of which about four hundred and seventy-five thousand are children.
There are numerous nomenclatures and categorizations used to describe the different types of seizures someone may have. It’s incredibly difficult to assuredly label a seizure type based purely on the outward presentation of body movements or cognitive behavior exhibited during a seizure. Classification of a seizure is based on what an EEG shows. EEGs will show whether the seizure starts in both sides of the brain (called a generalized seizure) or on one side (focal seizures). Sometimes, a seizure may start as a focal and it morphs into a generalized.
To complicate matters, because EEGs are measuring electrical currents emanating from all over the brain simultaneously, parsing out the start of a seizure from background activity, especially if that brain isn’t functioning normally to start with, can be incredibly difficult. Imagine hiking through a forest and listening for the call of a specific rare bird. When there are dozens of other birds and animals singing and calling out, and with no warning when your bird may speak up, you can see how it could be easy to miss it or mistake it for something else.
Like any neurological condition, epilepsy occurs across a broad spectrum of ages and severity. It commonly develops during childhood, and in this case is often linked with physical or cognitive developmental delay. Some individuals are able to prevent their seizures with medication and live relatively unaffected lives. Those who cannot achieve complete control of their seizures need to make adjustments in their daily life, the degree of which depends on whether their seizures are predictable. However, some people have no warning that a seizure is about to begin, which can be a serious risk to their personal safety. Depending on the type of seizure and how much of their brain is involved, the individual seizing may be completely unaware of what’s happening.
The infantile spasms (IS) that Julia and I saw (and still see) in Cedar are very rare—only two to three thousand children are diagnosed with IS in the US each year. They are thought to be a result of miscommunication between the cortex and the brain stem. The first step is to identify the cause (if any), as this can influence the treatment plan and prognosis.
IS can also occur with no identifiable cause. In this case, the spasms may eventually stop and some of those children may grow up relatively unaffected. IS can occur due to a short-term cause (e.g., injury, fever, low blood sugar), and they may resolve when the underlying cause is addressed. However, the majority of children with IS have a structural abnormality in the brain and/or an underlying genetic disorder. These children tend to have a poor prognosis. Cedar was developing relatively on track until her spasms began, so we hoped that she would fall into the group of children with no identifiable cause.
The large majority of children who have IS also exhibit something called hypsarrhythmia. Hypsarrhythmia is a type of abnormal brain activity presenting as disjointed, irregular, and high-amplitude slow brain waves. When you introduce hypsarrhythmia to that forest of bird calls we imagined earlier, it can significantly complicate the ability to find your bird (or interpret an EEG). Imagine you’re back in that forest, straining to hear the call of that rare bird. However, now you’re standing next to a large waterfall. The roar of that waterfall makes it even harder to hear your bird, or may even drown out the sound. This is why a good epileptologist is critical to getting an accurate diagnosis using an EEG, particularly in a patient with hypsarrhythmia.
Cedar’s EEG confirmed the presence of hypsarrhythmia and led her team of neurologists to investigate the central underlying cause of her spasms and hypsarrhythmia. There is a very small chance that a child that has spasms and hypsarrhythmia may still develop normally as they grow, but it all depends on the cause. If no cause can be found, that glimmer of hope remains, so parents are always rooting for negative test results.
Generally, an identified cause is linked with poor prognosis. Identifying the cause also needs to happen quickly, as different medications may be more or less effective for some underlying genetic disorders. The longer that spasms and hypsarrhythmia occur, the greater the likelihood of developmental delays. Stopping, or at least reducing, both is critical. Cedar quickly underwent extensive testing: MRIs, eye exams, blood tests, X-rays, and ultrasounds in order to identify any underlying conditions.
Tuberous sclerosis complex (TSC) is the most common single cause of IS. TSC is a rare genetic disease caused by mutations in one of two genes, TSC Complex Subunit 1 (TSC1) or Subunit 2 (TSC2). It is an autosomal dominant condition, meaning the genes are found on nonsex chromosomes and only one of the two genes needs to be mutated for the disease to occur. Knocking out the function of either gene causes benign tumors to grow in the brain, heart, and other tissues. Often, these tumors disrupt neuronal activity in the brain and cause IS. Patients with TSC respond to one medication far better than patients without TSC, so this diagnosis can lead to faster and more effective treatment of IS.
In Cedar’s case, genetic testing for TSC was not necessary. Her MRI showed significant structural abnormalities in her brain not associated with TSC: thinning/shortening of her corpus callosum (the structure that connects the two halves of her brain); disruptions in major sensory pathways; neurons that migrated to the wrong area of the brain (known as heterotopia); the presence of cysts; and polymicrogyria, a developmental problem where the brain has more folds than usual, but they are not very deep.
The presence of just one of these problems can predispose individuals to seizures. Many neurodevelopmental and seizure disorders are linked to thinning of the corpus callosum, though curiously, some individuals can live relatively normal lives with no corpus callosum at all. However, most structural abnormalities indicate an underlying genetic mutation.
Seizures have been linked to variants and mutations within dozens of genes. Many of these genes have roles governing brain development, establishing connectivity between brain regions, or how specific subsets of neurons electrochemically signal one another. One classic seizure-related gene is the sodium channel, voltage-gated, type I, alpha subunit (SCN1A). SCN1A codes for a part of a sodium ion channel. The channel forms a gateway in the cell membrane that allows for sodium ions to pass in and out of the cell.
Controlling the amount of sodium both inside and outside of neurons is a critical part of maintaining a specific electrochemical charge within the cell that allows the neuron to fire an action potential and signal to downstream neurons. Over nine hundred mutations in this one gene have been found to be linked with a variety of seizure disorders and syndromes.
Some children with seizures may undergo genetic testing when imaging and blood work uncover no obvious causes in order to find additional clues to their condition. For Cedar, the constellation of structural problems in her brain, along with abnormalities in her eyes, led to a diagnosis of Aicardi Syndrome without the need for genetic testing.
Aicardi Syndrome is an ultrarare genetic syndrome. Best estimates are that there are only a few thousand patients worldwide. As with most neurological conditions, Aicardi has a spectrum of possible systemic physical and cognitive outcomes. Unfortunately, for most with Aicardi, the spectrum is severe. These patients have such profound phenotypes that all have a significantly shortened life span and developmental delay. Most will exhibit profound cognitive impairment and will never gain complete control over their seizures.
The diagnosis is devastating to all parents, regardless of their background. Julia and I were formally trained in neuroscience and genetics, respectively. But while we quickly understood the lingo and consequences of what the tests had uncovered, our training offered no solace for our tears and grief. We were fortunate to live close to Children’s National Hospital and the incredible pediatric neurology team there. Our doctors and nurses helped us remain human and focus on our family during the five days we lived in the hospital. They stayed late to hug us and cry with us as we tried to understand this new reality for our daughter. They were, and will forever be, our heroes.
Within hours of Cedar’s diagnosis, Julia and I read most of the available literature on Aicardi Syndrome, which was unnervingly scant. The lack of known genetic causes for conditions like Aicardi is frustrating. As a scientist, I understand that funding is limited for rare genetic conditions. As a parent, it makes me want to punch a wall.
No specific genes have been conclusively linked to Aicardi, but the syndrome is believed to be caused by a de novo mutation on the X chromosome. De novo mutations occur in the genome of the egg or sperm cell, or very early on in the development of the fertilized egg. They are random and nearly impossible to catch unless you are genetically screening for a particular condition. It’s believed to be X-linked because there are only a few reported cases of Aicardi Syndrome ever reported in males. Every male patient with Aicardi also has Klinefelter syndrome, a condition in which they have an additional X chromosome and an XXY genotype.
Researchers speculate Aicardi is a result of a de novo mutation within the genetic sequence of a regulatory region responsible for the expression of several genes. Unfortunately, in conditions with mutations that impact the structure of the brain so profoundly, there will be no cure. However, advances in seizure treatment have led to better seizure control with fewer negative side effects. Continued advances in this area could reduce the developmental regression seen in patients with these rare disorders due to damage from seizures and hypsarrhythmia. Currently, studies on treatments for IS have been difficult to interpret and compare due to the small number of patients and variations in the study designs and methods.
The first line of treatment for IS is a drug called Acthar, which is a purified form of adrenocorticotropic hormone. Acthar is a gel formulation that needs to be injected twice daily into the muscles of the thigh. In addition to the burning sensation of the Acthar, the drug has a wide array of miserable side effects including extreme irritability in most babies. Injecting Cedar was awful, as any parent with experience with this drug will tell you. But Acthar is thought to offer the best hope for treating IS and hypsarrhythmia.
With Cedar’s first injection, Julia and I began the treatment kaleidoscope that most families with epilepsy and IS experience. Just as every individual with epilepsy will have unique presentations of seizures, triggers, and underlying causes—the response to treatment is equally unique. In Cedar’s case, Acthar did reduce her spasms and hypsarrhythmia, but didn’t eliminate either. She’s now on a cocktail of three other antiseizure medications and still has spasms, other types of seizures, and hypsarrhythmia. For children like her, with the panoply of brain abnormalities, it’s likely her seizures will never be fully under control.
Another challenge for patients and families is that while there are many different types of antiseizure medications, all come with their own list of efficacies and side effects. As well, there are a limited numbers of specialists who may be able to effectively develop appropriate and personalized care plans. Cost and access also remain significant barriers for successful and timely treatment.
For rare conditions like Cedar’s, the lack of data and definitive answers are hard realities to accept. Thankfully, research is advancing for rare genetic syndromes and epilepsy. There’s an iron will within the clinic, support communities, and families to advocate and push forward. But the reality is that for those waiting for the boundary of knowledge to inch forward, advances will always feel too slow. While we wait for progress, my job will always focus on helping Cedar and others like her experience as much of the beauty in this world as possible.