Germain B, Maria BL. Epileptic Encephalopathies. J Child Neurol. 2017 Jan 1:883073817697846. doi: 10.1177/0883073817697846. [Epub ahead of print]
Epileptic encephalopathies encompass a heterogeneous group of epilepsy syndromes that manifest with cognitive, behavioral, and neurologic deficits, seizures that are often intractable and multiform, aggressive electroencephalographic paroxysmal activity, and sometimes early death. As more is learned about the etiologies and manifestations of epileptic encephalopathies, progress has been made toward better treatment options. However, there is still a great need for further randomized controlled trials and research to help create clinically effective therapies. The 2015 Neurobiology of Disease in Children symposium, held in conjunction with the 44th annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of epileptic encephalopathy, (3) discuss clinical management and therapies for epileptic encephalopathy, and (4) define future directions of research. This article summarizes the presentations and includes an edited transcript of question-and-answer sessions.
From the manuscript
As far as current treatment for spasms is concerned, there is no clear consensus as to what treatment regimen is best. Seventy percent of providers are seeing fewer than 10 patients per year with new-onset spasms, which stresses the importance of having a consortium to identify treatment options. The aim of treatment is to stop clinical spasms and hypsarrhythmia, which in turn will help prevent future developmental regression. Most first-line medications, such as adrenocorticotropic hormone and vigabatrin, will stop spasms fairly quickly. Adrenocorticotropic hormone can stop spasms within a week and vigabatrin sometimes within a month. The relapse rate is about a quarter to a third of patients with spasms…
Oral prednisolone is also thought to help, but there is really no consensus as to whether adrenocorticotropic hormone or oral prednisolone is more effective. Several studies have looked at this, but have drawn different conclusions. The Pediatric Epilepsy Research Consortium protocol for adrenocorticotropic hormone is based on a study done by Baram in 1996 in which she looked at 29 infants randomly assigned to receive adrenocorticotropic hormone or prednisone. Of those treated with adrenocorticotropic hormone, 87% responded, compared with 29% who received prednisone. The protocol is a high dose of adrenocorticotropic hormone at 150 µg/m2 divided twice a day for the first 2 weeks and then tapered quickly. However, adrenocorticotropic hormone is very expensive. Each vial costs $28,000. In addition, parents must be taught to administer it by intramuscular injection, and it is typically given in an inpatient setting because the child was just diagnosed with spasms through an EEG or MRI…
Dr Koh concluded by providing current data collected by the Pediatric Epilepsy Research Consortium on spasms. The consortium of 38 pediatric epilepsy centers has enrolled about 230 patients with new-onset infantile spasms under the age of 2. The main goal is to identify numbers of children with the presenting information, etiologies, and short-term outcomes to provide baseline data for a larger comparative effectiveness trial. The etiologies found are similar to those identified by the UKISS group, in that about 64% of their patients did have a known etiology. The most common etiologies found were genetic or metabolic issues such as trisomy 21 and hypoxic-ischemic encephalopathy.
After 3 months of freedom from spasms, it seemed that the adrenocorticotropic hormone group had a much better response rate, especially compared with participants who received second-line medications, which were associated with a very low response rate. Those who had no developmental problems prior to spasms or those with mild developmental delay seemed to do better than those who had moderate or severe developmental delay prior to onset of spasms. In terms of etiology, those who had cryptogenic or unknown neurologic issues or etiologies with genetic or metabolic issues such as trisomy 21 did much better compared with those who had cortical dysplasia, who did not do as well. Those who had high-dose adrenocorticotropic hormone had a better response rate than those who had a low-dose form.
Ninety-three percent were diagnosed with Lennox-Gastaut syndrome within 1 year of seizure onset; 59% had normal development prior to seizure onset, with 11 patients having normal posterior rhythm on EEG. Only 11.8% had prior West syndrome. A detailed genetic analysis was performed, and it was found that de novo mutations were enriched in specific gene sets, including genes regulated by the fragile X protein. However, it was found that clinical phenotype could not predict a responsible gene. Because various genetic pathways resulted in epileptic encephalopathy, researchers explored the interrelationship between these mutations. They found that about three-fourths of the genetic defects in the cryptogenic group were associated with a protein involved in synaptic regulation, which will hopefully help to further progression of treatment methods.
First-line evaluation of Lennox-Gastaut syndrome, following clinical history and physical examination, includes brain MRI, EEG, and routine laboratory studies. If there are no abnormalities consistent with etiology, a chromosomal microarray may be done, which has a 12% to 13% yield. Urine organic acids, amino acids, and metabolic screening may yield an etiology in only about 1 in 50 to 100 patients. Targeted next-generation sequencing of epileptic encephalopathy panels has a high yield of about 12% to 13%. The Epilepsy Phenome/Genome Project is then suggesting whole exome sequencing be performed in those remaining…
ESES in Landau-Kl3effner
Dr Hirsch reviewed previous studies of electrical status epilepticus in sleep, including studies of sleep homeostasis and genetic studies. It has been demonstrated that the role of sleep was disturbed, mostly in the down-scale of the slow activity usually observed during sleep related to spike-and-wave activity. In genetic studies, a relation between this group of diseases and autism has been shown. In a study conducted by Dr Hirsch and colleagues in 2010, 10% to 50% of these patients had a mutation of GRIN2A, which is related to cortical oscillation and maturation and can be attributed to acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction, as well as idiopathic focal epilepsy with rolandic spikes.
With regard to treatment, studies have proven efficacy of benzodiazepines, steroids, and immunoglobulins. Use of personalized therapy with memantine in patients with GRIN2A mutation and early-onset epileptic encephalopathy has also been demonstrated and showed while there was no effect on the EEG, there was an effect on seizures. In a study by Downes and colleagues in 2015, subpial transections had no effect on patients with Landau-Kleffner syndrome.
In conclusion, studies reveal that pediatric forms of autoimmune encephalitis are generally similar to those seen in adults. Encephalopathy, seizures, and cognitive and behavioral changes are common, and children are often apyrexic at presentation. They do not always have high cerebrospinal fluid cell counts, and not all of them have MRI abnormalities, making these features less helpful. They can be diagnosed by specific antibody, although lack of known antibody should not rule out a high suspicion of an autoimmune form and the appropriate treatment. Coexisting or previous infections are becoming quite common, and they do not rule out an autoimmune etiology for the patient’s present symptoms. Also, some antibodies, such as the voltage-gated potassium channel-complex antibodies, are not always directly pathogenic and may be a biomarker for inflammatory, potentially treatable, disease.
To summarize, the cannabinoid system has significant representation in multiple brain regions, making it a promising target for therapeutics, but mechanisms are complex. Clinical data are available for some indications but data for epilepsy are still sparse and often poorly conducted; more research is needed. Extensive literature on potential toxicity highlights the need for safety monitoring, especially in children and adolescents. Regulatory measures are inconsistent and evolving, with differences at the state and federal level. Increased use of complementary and alternative medicine indicates an unmet therapeutic need and highlights the need to ask patients and families about this subject. Lastly, if patients and families are choosing to use complementary and alternative medicines, a standardized approach to assess safety and efficacy should be developed.