Hiroki Nariai, Susan Duberstein, Shlomo Shinnar. Treatment of Epileptic Encephalopathies. Journal of Child Neurology. In press.
Childhood epileptic encephalopathies are age-dependent disorders of the brain whose hallmarks include loss of neurologic function over time, abnormal electroencephalographic findings, and seizures. Ictal and interictal electrographic activity are conjointly thought to be at the root of the often devastating neuropsychological deterioration, which is specific to the maturing brain. The goals of treatment are not only to control seizures, but also to prevent or reverse neurologic loss of function. In general, time is of the essence in diagnosis, and experienced specialists should promptly design a treatment plan. Hormonal and immune therapies are at the forefront of treatment in many cases, with traditional antiepileptic drugs and surgery (when an identifiable lesion is present) playing a limited role. However, gold standard evidence for treatment of epileptic encephalopathies remains limited. Ongoing clinical and basic research may lead to better understanding of these catastrophic conditions and to better and more effective therapies.
From the article
The shared clinical feature of the epileptic encephalopathies is that they are associated with loss of neurologic function over time. This loss can be rapid, as in the case of infantile spasms or Landau-Kleffner syndrome, or very gradual over years, as is the case with Lennox-Gastaut syndrome. The neurologic change is clearly separate from the seizures themselves. Although Lennox-Gastaut syndrome is generally associated with intractable seizures, syndromes such as electrical status epilepticus in sleep and Landau-Kleffner syndrome do not even always have associated clinical seizures and, when present, they are usually not difficult to control. In infantile spasms, the seizures themselves are brief, self-limited, and not very dramatic, but the loss of neurologic function can be profound, leading to Dr Shields’s famous dictum, “little seizures, big consequences.” Conceptually, the term epileptic encephalopathy embodies the notion that “the epileptic activity itself may contribute to severe cognitive and behavioral impairments.” This is, therefore, one of the few settings where treating electroencephalographic (EEG) abnormalities even when seizures are fully controlled or absent may be important, as we assume that the electrical epileptic activity itself is contributing to progressive disturbance of cerebral functions (especially in infantile spasms and electrical status epilepticus in sleep). Thus, the goal of treatment is not simply to control seizures but also to eliminate the underlying EEG abnormality, with the hope of preventing loss of neurologic function. Ideally, one also hopes to restore lost function, though that is always more difficult.
Given these goals of treatment, there are major differences between the treatment of epileptic encephalopathies and other epilepsies. Perhaps most significantly, for most epilepsies, our treatments are considered “antiseizure” in the sense that they suppress clinical seizures but are not disease-modifying. For epileptic encephalopathies, the true goal is to modify the disease. Thus, when we give high-dose adrenocorticotropic hormone (ACTH) for 2 weeks to children with infantile spasms, especially to those with infantile spasms of unknown etiology, the expectation is that we abolish both the clinical seizures and the hypsarrhythmia, and that this effect will continue when medication is withdrawn. This would not be the case when prescribing carbamazepine for localization-related epilepsy.
The second major difference is the need for early treatment. Because in most epilepsies, the treatments are not disease-modifying and the disorder is not progressive, the data are pretty clear that delay in treatment does not alter long-term prognosis. These data are what allow us to not immediately treat children with, for example, a single first unprovoked seizure. Where the clinical picture and the electrographic evidence speak to the presence of a childhood epilepsy syndrome, early treatment may indeed be recommended. It is also increasingly clear that even in the cases of “benign” childhood epilepsy syndromes such as childhood absence epilepsy and benign epilepsy with centrotemporal spikes (BECTS), neuro-psychological deficits and academic difficulties are frequently present. However, it is not clear that treatment, however beneficial from the perspective of reducing the number of seizures or reduction of parental anxieties, changes these sequelae. These neurologic comorbidities are, further, usually present at baseline and do not worsen over time.
This is decidedly not the case for epileptic encephalopathies. Here, the best evidence is from studies of infantile spasms, where there are compelling data that early treatment is associated with both better seizure control and cognitive outcomes. Although infantile spasms has the most data, other epileptic encephalopathies fall into the same category. For example, it is believed that treating electrical status epilepticus in sleep and other syndromes prior to major loss of function will result in better outcomes. Again, considering the goals of treatment for epileptic encephalopathies, it should come as no surprise that our conventional antiepileptic drugs are of limited benefit when used as sole therapy. They are actually reasonably effective in controlling clinical seizures in many of the described syndromes, and some medications, such as valproate, may even help normalize the EEG. But because seizure control here is secondary to the dual goals of treating the underlying EEG and preventing/reversing loss of neurologic function, other drugs are the mainstays of therapy. These include hormonal therapy (steroids and ACTH) and immune modulators (steroids, intravenous immunoglobulin, rituximab). Vigabatrin occupies a unique role in treatment of infantile spasms associated with tuberous sclerosis complex. We present an overview of the current state of the art in the treatment of selected epileptic encephalopathies…
Although epileptic encephalopathies are a small proportion of all childhood epilepsies, given the potentially devastating developmental outcomes, they account for a disproportionate effect on cognition, quality of life, and economic burden on families. Current understanding of these syndromes limits clinicians striving to achieve the ultimate primary goal of treatment, which is to improve overall neurologic outcomes. In most cases, conventional antiepileptic drugs are not effective in achieving this outcome, which has led to a shift in treatment focus to steroids and other immunomodulatory therapies. Given the success of using these modalities even in conditions where there is no clear immunologic component, as we better understand the etiology and genetics of these conditions, it may become clear that there is a larger autoimmune component to many of these disorders than previously realized. Genetic discoveries may also eventually guide novel and directed therapies in some cases. Clinicians are in need of effective and evidence-based guidelines to better shape treatment of the epileptic encephalopathies. Given the relative rarity of the conditions, this will likely require multicenter and/or multinational studies.