Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
What’s New, What’s Hot: The 2015 AES Hot Topics Symposium Emily L. Johnson, MD Johns Hopkins School of Medicine, Baltimore, Maryland A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY © 2016 Direct One Communications, Inc. All rights reserved. 1 Importance of Genetics in Epilepsy A growing body of evidence is emerging for the importance of genetics in epilepsy: » Results of twin studies have shown that monozygotic twins » » » have a higher rate of concordance than do dizygotic twins. Family studies have shown that the risk of generalized epilepsy is 10% in siblings of a patient with the same condition, and the risk of focal epilepsy is 5% in siblings of patients with focal epilepsy. Phenotypic studies have identified families with inherited epilepsy syndromes, such as generalized epilepsy with febrile seizures plus (GEFS+). Genetic studies of these families using copy-number variants, linkage analysis, and positional cloning have produced discoveries of associated genes. Vadlamudi L et al. Neurology. 2014;83:1042; Hartmann C et al. Epilepsia. 2015;56:e26–e32. © 2016 Direct One Communications, Inc. All rights reserved. 2 History of Epilepsy Genetics Discoveries related to epilepsy genetics have increased exponentially over the past few years: © 2016 Direct One Communications, Inc. All rights reserved. 3 History of Epilepsy Genetics continued Before 2001, the “channelopathy era” saw the discovery of specific channel mutations. From 2001 to 2009 (the “dark ages” of epilepsy genetics) more than 100 association studies yielded negative or irreproducible results. Since 2009, the study of microdeletions, microduplications, and next-generation sequencing has led to an exponential increase in epilepsy genetics. » Example: a recent study of 805 children with epilepsy found that 40 patients (5%) had microdeletions or microduplications that explained the patient’s epilepsy phenotype. Olson H et al. Ann Neurol. 2014;75:943 © 2016 Direct One Communications, Inc. All rights reserved. 4 Patterns of Genetic Epilepsy Patterns of genetic epilepsy include inherited genes, de novo mutations, and de novo postzygotic mutations. Inherited genes may be autosomal dominant or autosomal recessive. In genome-wide association studies of patients with infantile spasms or Lennox-Gastaut syndrome (LGS) and their parents, de novo causative mutations can be identified; increasing the size of these studies allows better identification of enriched de novo mutations in patients with epileptic encephalopathy when compared with the general population. Poduri A, Lowenstein D. Curr Opin Genet Dev. 2011;21:325; EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, and Epi4K Consortium. Nature. 2013;501:217; Am J Hum Genet. 2014;95:360. © 2016 Direct One Communications, Inc. All rights reserved. 5 Which Patients Should Be Tested? Genetic testing should be undertaken when diagnostic certainty and prognosis are important; identifying genetic causes of epilepsy can help to improve patient care by leading to clinically relevant models, preclinical trials, and precise treatment: » For example, a 6-month-old boy with new-onset infantile spasms and hypsarrhythmia (with negative MRI findings) who has a specific mutation in a gene associated with epilepsy or infantile spasms could forgo further workup (eg, metabolic testing, lumbar puncture). » Likewise, a teenage patient with a history of juvenile myoclonic epilepsy and a family history of generalized seizures can be reassured that the disease is benign and nonprogressive after genetic test results are gathered. © 2016 Direct One Communications, Inc. All rights reserved. 6 Which Patients Should Be Tested? continued Another reason to perform genetic testing is when information on specific genes can guide specific treatments to pursue or avoid, such as mutations in the following genes: » SCN1A, in which lamotrigine and phenytoin should be avoided; » SCN2A, in which high-dose phenytoin therapy may be helpful; » SLC2A1, in which the ketogenic diet may be useful; » ALDH7A1, in which response to pyridoxine may be expected; and » PNPO, in which patients may respond to pyridoxal-5phosphate. © 2016 Direct One Communications, Inc. All rights reserved. 7 Which Patients Should Be Tested? continued Other mutations may be related to promising off-label use of specific treatments, although more information is needed; they include mutations of: » KCNQ2, in which ezogabine therapy could be considered; » KCNT1, in which quinidine use could be helpful; and » GRIN2A, in which memantine could be prescribed. For patients with epilepsy and tuberous sclerosis, treatment with everolimus could be considered. © 2016 Direct One Communications, Inc. All rights reserved. 8 Which Patients Should Be Tested? continued Patients with “epilepsy plus” syndromes—the combination of epilepsy with dysmorphic features, intellectual disability, infantile spasms, or autism— also should undergo genetic testing. The clinical picture may suggest a classic syndrome associated with a single gene: » For example, Down syndrome suggests trisomy 21 (verified with a karyotype); » Dravet syndrome suggests a SCN1A mutation (tested with SCN1A sequencing for deletion or duplication); and » Rett syndrome suggests a MECP2 mutation (which can be sequenced for deletion or duplication). © 2016 Direct One Communications, Inc. All rights reserved. 9 Which Patients Should Be Tested? continued Patients with refractory epilepsy that affects treatment should also be tested, particularly if surgery is considered. Examples are patients with early-onset epileptic encephalopathy, patients < 4 years of age with earlyonset absence seizures, and patients with familial focal epilepsy. In refractory cases, an identifiable genetic cause may influence the consideration of surgical treatment. © 2016 Direct One Communications, Inc. All rights reserved. 10 Options for Genetic Testing Available options for genetic testing include: » Chromosomal microarray analysis; » Single-gene testing (sequencing, duplication, deletion testing); » Panel testing, including an “epilepsy panel” or “autism panel”; and » Whole-exome sequencing. When a phenotype highly suggests the diagnosis of a specific syndrome, testing for that syndrome should be performed. » For example, when pyridoxine-related epilepsy is suspected, testing for a mutation in ALDH7A1 should be done. © 2016 Direct One Communications, Inc. All rights reserved. 11 Options for Genetic Testing continued A patient with a history and examination suggesting Angelman syndrome should undergo chromosomal microarray analysis. » If the results of UBE3A sequencing are negative, an epilepsy panel for Angelman-like genes should be considered. » If all results are negative, whole-exome sequencing should be performed, since the syndrome is highly likely to be genetic. For early-onset absence seizures that occur before the age of 4 years, the SLC2A1 gene should be tested, and determination of glucose levels in cerebrospinal fluid (CSF) can be considered. © 2016 Direct One Communications, Inc. All rights reserved. 12 Options for Genetic Testing continued For patients with “epilepsy plus” or early-onset refractory epilepsy, a chromosomal microarray analysis and epilepsy gene panel are recommended, with progression to whole-exome sequencing if initial tests are negative. If the results of all genetic tests are negative, patients can be referred to a registry of people with specific genetic epilepsies (eg, Dravet syndrome), individual research studies, the Rare Epilepsy Network (https://ren.rti.org/), or the Epilepsy Genetics Initiative (http://www.cureepilepsy.org/egi/). © 2016 Direct One Communications, Inc. All rights reserved. 13 Autoimmune Epilepsy Immune epilepsy is said to be present when there is evidence of autoimmune-mediated inflammation of the central nervous system (CNS), according to the International League Against Epilepsy. » Examples of immune-mediated epilepsy include anti-LGI1 encephalitis and anti-NMDA receptor encephalitis. Similarly, autoimmune epilepsy is autoimmune encephalitis with a predominant epileptic phenotype. Approximately 80% of people with autoimmune encephalitis have epilepsy or seizures, and some 2% of all epilepsies have an autoimmune etiology. International League Against Epilepsy. ILAE Revised Terminology for Organization of Seizures and Epilepsies, 2011–2013; Irani SR et al. Curr Opin Neurol. 2011;24:146 © 2016 Direct One Communications, Inc. All rights reserved. 14 Autoimmune Epilepsy continued Antibodies causing autoimmune epilepsy are immunoglobulin-G (IgG) complexes directed against extracellular or intracellular central nervous system (CNS) antigens. Extracellular antigens include AChR (GlyR), NMDAR, LGI1, and CASPR2. Intracellular antibodies include GAD65 and VGKC. Rates of association with systemic malignancies vary, depending on the autoantibody. Vincent A et al. Lancet Neurol. 2011;10:759 © 2016 Direct One Communications, Inc. All rights reserved. 15 Autoimmune Epilepsy continued In a study of 300 patients, epilepsy was the second most common cause of autoantibody testing (22%) after encephalitis or encephalopathy (42%). Autoantibodies were less often tested for in patients with cognitive or psychiatric disorders (9%) or peripheral neurologic disorders (4%). The frequency of positive antibodies identified in that laboratory was 4.7% (out of 6,893 patients). The most commonly detected antibody was GAD65 (27.9%); the next most common were NMDAR (23.4%) and LGI1 (18.1%). Dogan Onugoren M et al. J Neurol Neurosurg Psychiatry. 2015;86:965 © 2016 Direct One Communications, Inc. All rights reserved. 16 Suggestive Clinical Features Specific syndromes, including limbic encephalitis, faciobrachial dystonic seizures, and encephalopathy, raise the possibility of autoimmune epilepsy. Young women with epilepsy and patients with other autoimmune diseases also are at increased risk. Other seizure types and patterns that raise the possibility of autoimmune epilepsy include: » Pilomotor seizures; » Unexplained new-onset epilepsy in adult life; and » New-onset epilepsy with status epilepticus or with a very high frequency of seizures. © 2016 Direct One Communications, Inc. All rights reserved. 17 Suggestive Diagnostic Features The presence of an “extreme delta brush” (which has been associated with NMDAR encephalitis) on an electroencephalogram (EEG) An elevated cell count in the CSF Unmatched oligoclonal bands in the CSF but not in the serum Encephalitic lesions on MRI, especially in the mediotemporal areas Histopathology showing “chronic encephalitis” Dogan Onugoren M et al. J Neurol Neurosurg Psychiatry. 2015;86:965; Bien CG. Epilepsia. 2013;54(Suppl 2):48; Schmitt SE et al. Neurology. 2012;79:1094 © 2016 Direct One Communications, Inc. All rights reserved. 18 Incidence of Autoimmune Epilepsy The incidence of antibody-confirmed autoimmune epilepsy may be surprisingly high. In one study of 19 women (age, 15–45 years) with new-onset epilepsy and no obvious preceding cause or syndrome, 5 (26%) had NMDAR antibodies. » Of those five women, four (80%) had prominent psychiatric symptoms. In a series of 13 patients with new-onset status epilepticus, 8 (62%) had NMDAR antibodies; 9 (69%) had oligoclonal bands in the CSF; and additional patients had GAD65, Ri, and neuropil antibodies. Niehusmann P et al. Arch Neurol. 2009;66:458; Holzer FJ et al. Eur Neurol. 2012;68:310 © 2016 Direct One Communications, Inc. All rights reserved. 19 Which Tests Should Be Ordered? Although CSF-only antibodies are found in < 25% of cases, antibody testing of the CSF is more sensitive than serum testing for NMDAR antibodies. In a study of 250 patients with confirmed NMDAR encephalitis, CSF antibodies were detected in all 250 patients, but serum antibodies were detected in only 214 patients on both immunohistochemical and cellbased assays. Serum-only LGI1 and ampiphysin antibodies are common. Consequently, paired CSF and serum specimens should be sent to the laboratory whenever possible. Gresa-Arribas N et al. Lancet Neurol. 2014;13:167 © 2016 Direct One Communications, Inc. All rights reserved. 20 Significance of Antibody Testing Positive antibody test results must be compared with the clinical response of patients. The specificity of some tests are not confirmed (eg, the significance of NMDAR antibodies in serum only; CASPR2 at < 1:200; VGKC complex antibodies other than those directed to LGI1/CASPR2). Positive findings on nonspecific tests should be treated with caution. Non-IgG antibodies have no proven clinical significance. © 2016 Direct One Communications, Inc. All rights reserved. 21 Treatment of Autoimmune Epilepsy If the presence of autoantibodies is confirmed by testing, a suggested treatment approach using several drugs off label may be tried. Bien CG, Bien C. Z Epileptol. 2015;28:201; Dalmau J et al. Lancet Neurol. 2011;10:63 © 2016 Direct One Communications, Inc. All rights reserved. 22 Treatment of Autoimmune Epilepsy continued If the antibody test is not confirmatory (“gray cases”), 80 mg/d of prednisolone for 4 weeks can be tried, followed by tapering the dosage by 10 mg/d each week to 10 mg/d. If no clinical improvement is noted after 3 months, discontinue prednisolone. If the patient shows partial improvement, increase the dosage of prednisolone or switch to rituximab and/or cyclophosphamide. If the patient has had a clinical remission, continue giving 5 mg/d of prednisolone for 6 months. Bien CG, Bien C. Z Epileptol. 2015;28:201 © 2016 Direct One Communications, Inc. All rights reserved. 23 Treatment of Autoimmune Epilepsy continued Treatment responses to immunotherapy can be high. One study of 30 patients with autoimmune epilepsy, including 21 patients (69%) with daily seizures, who had been treated with monthly methylprednisolone or intravenous immunoglobulin found that 62% of the patients had a 50% reduction in seizure frequency, including 10 patients (33%) who were seizure-free. Toledano M et al. Neurology. 2014;82:1578 © 2016 Direct One Communications, Inc. All rights reserved. 24 Valproate Safety in Women The European Medicines Agency in 2014 advised doctors in the EU not to prescribe valproate “for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant, or in girls unless other treatments are ineffective or not tolerated.” This followed a drug safety announcement issued by the FDA in 2013 stating that “valproate products should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable…. All non-pregnant women of childbearing age taking valproate products should use effective birth control.” © 2016 Direct One Communications, Inc. All rights reserved. 25 Valproate Safety in Women continued However, many providers in the epilepsy community are concerned that the alternatives to valproate in treating generalized idiopathic/genetic epilepsies may not be as effective. The risk of uncontrolled seizures is not considered, and women may be encouraged to rapidly discontinue valproate during pregnancy, with potentially serious consequences. In a recent study, epilepsy-related deaths, mainly sudden unexplained death in epilepsy patients (SUDEP), accounted for 4%–7% of maternal deaths— 10-fold higher than expected—in the United Kingdom. Edey S et al. Epilepsia. 2014;55:e72 © 2016 Direct One Communications, Inc. All rights reserved. 26 Risks of Taking Valproate The risk of major congenital malformations (MCMs) among pregnant women taking valproate is higher than that associated with other antiepileptic drugs (AEDs) and is dose dependent. Tomson T et al. Lancet Neurol. 2011;10:609; Hernandez-Diaz S et al. Neurology. 2012;78:1692; Tomson T, Battino D. Lancet Neurol. 2012;11:803 © 2016 Direct One Communications, Inc. All rights reserved. 27 Risks of Taking Valproate continued Adding other AEDs to valproate has no major impact on the frequency of MCMs. In utero exposure to valproate negatively impacts neurodevelopmental/cognitive outcomes and IQ when measured at 3 and 6 years of age. These cognitive findings are also most significant when high doses of valproate (> 800 mg/d) are used. In addition, there is an increased absolute risk of autism spectrum disorder after valproate exposure in utero. Tomson T et al. Neurology. 2015;85:866; Meador K et al. N Engl J Med. 2009;360:1597; Meador K et al. Lancet Neurol. 2013;12:244; Baker GA et al. Neurology. 2015;84:283; Wood AG et al. Epilepsia. 2015;56:1047 © 2016 Direct One Communications, Inc. All rights reserved. 28 Task Force Recommendations In 2015, the ILAE Commission on European Affairs and the European Academy of Neurology jointly recommended that “whenever possible, valproate should be avoided in the treatment of girls and women of childbearing potential.” The task force recommended that women with epilepsy be informed about the teratogenic risks of valproate, and the drug should not be used to treat focal epilepsy; if valproate is used in women of childbearing potential, it should be given at the lowest effective dose, and women not planning pregnancy should use effective birth control. Tomson T et al. Epilepsia. 2015;56:1006 © 2016 Direct One Communications, Inc. All rights reserved. 29 Task Force Recommendations continued In cases of newly diagnosed generalized epilepsies, the risks and benefits of valproate versus those of alternative therapies should be carefully weighed. Valproate is a reasonable choice provided that the woman is fully informed about its risks and benefits and is not planning pregnancy. Valproate is also appropriate therapy for girls with epilepsy when there is a high likelihood of seizure remission and AED discontinuation before puberty. Valproate treatment also may be considered in patients with severe or disabling epilepsies for whom the likelihood of pregnancy is extremely low. Tomson T et al. Epilepsia. 2015;56:1006 © 2016 Direct One Communications, Inc. All rights reserved. 30 Task Force Recommendations continued For women already taking valproate who are not planning pregnancy, use of a different AED should be considered if seizure control is suboptimal. For women with seizures that did not respond to other AEDs before valproate therapy was started, continuation of valproate is reasonable. If seizures are controlled, valproate withdrawal or a change in therapy should be considered if the risk of relapse is acceptable to the patient. Because the risk of major congenital malformations is dose dependent, total daily doses should be reduced to below 600 mg if valproate is continued. Tomson T et al. Epilepsia. 2015;56:1006 © 2016 Direct One Communications, Inc. All rights reserved. 31 Task Force Recommendations continued In patients with generalized genetic epilepsies, patients and clinicians together may agree that continuing valproate is reasonable after carefully weighing the risks and benefits. When possible, the lowest effective dose of valproate should be established before conception. If seizures are well controlled on low doses of valproate (< 600 mg/d), and if the patient considers the risk of withdrawal or switching to another AED unacceptable, continued low-dose valproate therapy may be considered. Tomson T et al. Epilepsia. 2015;56:1006 © 2016 Direct One Communications, Inc. All rights reserved. 32 Task Force Recommendations continued Women already on valproate who become pregnant should try to reduce their dose below 600 mg/d if the risk is acceptable to the patient (usually when the history suggests that the patient does not need a high dose for seizure control). Pregnant women with epilepsy should consider withdrawing from valproate therapy if they agree that they do not need the drug for seizure control or are willing to switch to another AED. Tomson T et al. Epilepsia. 2015;56:1006 © 2016 Direct One Communications, Inc. All rights reserved. 33 Cannibinoids: Preclinical Studies Tetrahydrocannabinol demonstrated anticonvulsant effects in a majority of preclinical studies and proconvulsive effects in a minority of those studies. Cannabidiol (CBD), by comparison, demonstrated anticonvulsant effects in the majority of studies and no proconvulsant effects. CBD has multiple molecular targets, including ion channels and enzymes; many of these targets have been demonstrated only in vitro. Animal studies of cannabinoids have shown promise in protecting mice and rats from cocaine- and kainic acid-induced seizures. Fezza F et al. Mol Cell Neurosci. 2014;62:1; Whalley B. American Herbal Pharmacopoeia. 2014; Ibeas Bih C et al. Neurotherapeutics. 2015;12:699; Vilela LR et al. Toxicol Appl Pharmacol. 2015;286:178 © 2016 Direct One Communications, Inc. All rights reserved. 34 Cannibinoids: Clinical Studies In a survey of families with children taking CBD for infantile spasms, LennoxGastaut syndrome (LGS), and severe myoclonic epilepsy of infancy (Dravet syndrome), the majority of families reported a decrease in seizure frequncy. Hussain SA et al. Epilepsy Behav. 2015;47:138 © 2016 Direct One Communications, Inc. All rights reserved. 35 Cannibinoids: Clinical Studies continued In a retrospective study of 75 patients in Colorado (mean age, 7 years), one third of the families reported at least a 50% decrease in seizures, and two families reported seizure freedom in their children. Families that had children with LGS reported the highest decrease in seizures. Eleven families (15%) discontinued CBD, mostly due to inefficacy. Although 44% of families reported adverse effects of CBD, 33% of families reported seeing improved alertness or behavior, and 11% saw improvements in motor and language skills. Press CA et al. Epilepsy Behav. 2015;45:49 © 2016 Direct One Communications, Inc. All rights reserved. 36 Cannibinoids: Clinical Studies continued Efficacy and safety data from 261 patients treated for 3 months in a CBD expanded-access program showed a mean decrease in seizure frequency of 45%, while patients with Dravet syndrome experienced a decrease of 62.7% in seizure frequency and those with LGS, a drop of 71.1%. Seizure freedom was achieved by 9% of the patients. Somnolence and diarrhea were the most common side effects of CBD (23%), and serious side effects occurred in 106 patients, including death in seven gravely ill patients. Devinsky O et al. AES 2015, Poster 3.397 © 2016 Direct One Communications, Inc. All rights reserved. 37