Germain B, Maria BL. Epileptic Encephalopathies. J Child
Neurol. 2017 Jan 1:883073817697846. doi: 10.1177/0883073817697846. [Epub
ahead of print]
Abstract
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.
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From the manuscript
Infantile spasms
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.
Lennox-Gastaut
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.
Autoimmune encephalopathies
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.
Cannabinoids
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.
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