MINCEP’s View on Current Issues in Seizure Disorders Fall 2013 MINCEP® Epilepsy Reports

Lennox Gastaut Syndrome and its Variants: Outpatient services provided at: Persistence Often Pays Off University of Minnesota Physicians MINCEP® Epilepsy Care Thaddeus S. Walczak, MD 5775 Wayzata Blvd., Suite 255 AN INTERESTING CASE: A 38 year old woman presented to our MINCEP St. Louis Park, MN 55416 clinic with the following history. Seizures started at around age 3 and mild developmental delay appeared at this point as well. As she grew older tonic, University of Minnesota tonic-clonic and atypical absence seizures appeared. Family did not remember Medical Center, Fairview laughter being a component of her seizures at any point. Treatment with a Phillips-Wangensteen Bldg. variety of anticonvulsants was unsuccessful. During mid teen years a high Neurology/Epilepsy Clinic, 1A resolution MRI at another epilepsy center demonstrated a hypothalamic 516 Delaware St. SE hamartoma. Resective surgery succeeded in removing about 80% of the Minneapolis, MN 55455 lesion. Unfortunately seizures did not improve and she was left with significant Physicians impairment in the formation of new memories and mild SIADH. Tonic, atypical Miguel Fiol, MD absence and tonic-clonic seizures persisted at the rate of 10 per month or Robert Gumnit, MD more with frequent injuries. A vagus nerve stimulator was implanted, didn’t Thomas R. Henry, MD help and was turned off after several years. Ilo E. Leppik, MD A 3 Tesla MRI found an approximately 1cm diameter persistent hamartoma Sima I. Patel, MD in the left anterior medial hypothalamus. Video-EEG monitoring revealed Zhiyi Sha, MD, PhD subtle nocturnal tonic seizures, occasional daytime tonic seizures and several Minoo Shams, MD atypical absence seizures per day. Interictal record showed diffuse slowing, Thaddeus S. Walczak, MD and 2 Hz generalized spike wave. Compulsive review of old pharmacy records by our Pharmacology team revealed she had not yet been treated with Inpatient/Emergency oxcarbazepine, felbamate, zonisamide, rufinamide or clobazam. We suggested services provided at: ablating remaining hamartoma with focused radiotherapy (gamma knife). University of Minnesota However, family refused because of concern that this would worsen cognitive Medical Center, Fairview and neuroendocrine symptoms. An aggressive trial of felbamate didn’t result Emergency Department - East Bank in substantial improvement. Zonisamide at 600 mg per day significantly 500 Harvard Street improved seizures and stopped injuries; however cognitive abilities worsened Minneapolis, MN 55455 to the point that she was unable to care for herself. Rufinamide gradually 612-672-7575 increased to 60 mg/kg did not help. Clobazam was added and gradually increased to 20 mg QHS. Remarkably, the seizures decreased significantly and then stopped. Neither patient nor caregivers were aware of any seizures for Call 24/7 for a consultation or one year when she last seen several months ago. Felbamate and rufinamide to schedule an appointment: were gradually discontinued during this period of time but she continues 952-525-4500 or 800-359-4477 treatment with divalproex. Memory has not improved but she is able to live in her own apartment with caregivers assisting with medication administration. Now available at MINCEP COMMENT: Lennox Gastaut Syndrome often elicits despair in the treating Evening hours on Mondays and physician. Patients afflicted with this syndrome often present with severe Thursdays. Expert care delivered epilepsy in spite of multiple anticonvulsant medications and medication related conveniently for your patients. toxicity. Emergency room visits due to seizure related falls and other traumas are common. Caregivers demand additional treatment; unfortunately this often means adding additional medications that worsen toxicity. Fortunately, in the last ten years, several medications have been found to be effective in this specific epilepsy syndrome allowing a rational treatment approach.

The diagnosis of Lennox Gastaut Syndrome traditionally required three criteria: 1) developmental delay, 2) multiple intractable seizure types including at least tonic or atonic seizures, and 3) EEG findings including slowed background and generalized spike wave at the rate of less than 2.5 Hz. In practice variations

umphysicians.org/epilepsy of this classical triad respond to similar treatment approaches Response of Seizures in Lennox Gastaut Syndrome and are often referred to as “symptomatic generalized” or to Various Antiepileptic Drugs “symptomatic generalized/symptomatic multifocal” epilepsy. Not all people with this diagnosis are developmentally Effective, Probably Effective, May Worsen Has FDA Indication Does Not Have FDA Indication Seizures delayed though the great majority are. Seizure types include Felbamate Valproate Tiagabine myoclonic, atypical absence, complex partial and generalized Lamotrigine Zonisamide Gabapentin tonic-clonic seizures. Typical EEG findings often include runs Topiramate Ethotoin Pregabalin of generalized paroxysmal fast activity, especially during sleep. Rufinamide Phenobarbital Multiple etiologies are associated; most involve bilateral Clobazam brain damage and occur in early childhood. About one third present with infantile spasms (West Syndrome). Focal or Making the syndromic diagnosis is important because patients diffuse cortical dysplasia is not unusual and a well defined with Lennox Gastuat Syndrome clearly respond better to some course of progressive encephalopathy associated with medications than others. The table lists medications that are intractable seizures has been described in patients with FDA approved for this syndrome and additional medications hypothalamic hamartoma. A variation of this was seen in that are probably effective but that have not been rigorously the case described here. evaluated with contemporary methodology. Detailed

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comments are worthwhile. Felbamate remains underutilized associated with major motor seizures but this surgery does but should generally be avoided in people with liver disease, not help with atypical absence or complex partial seizures. autoimmune disease or bone marrow disease. A thorough discussion regarding the rare but severe complications of A comprehensive and systematic approach is critical. This aplastic anemia and hepatitis is needed. Zonisamide and starts with a thorough review of previous treatments and topiramate are often helpful but may further impair cognitive gradual elimination of medications known to be ineffective. status as occurred in our case. Interactions between rufinamide As illustrated in the case report, systematically using and valproate or felbamate should be watched for though medications known to be effective in this syndrome often we have not found them problematic. Very recently the FDA leads to significant improvements in seizure control and has released a warning regarding 6 cases of Stevens-Johnson overall quality of life. However, experience with these Syndrome tentatively associated with clobazam. The frequency medications and a careful documentation of response with which this severe complication occurs is unclear; it is to various trials are needed. It is important not to change interesting that Stevens-Johnson Syndrome was not associated medication regimens too quickly; the treatment chosen with clobazam use in Europe during the last 25 years. must be given a chance to work and this requires counseling and support so that appropriate expectations are set. If Vagus nerve stimulation reduces seizures by 50% in 30 – 50% progress is not made, referral to a center such as UMP of patients but has not been evaluated in rigorous trials. In well MINCEP is appropriate. There is more hope for patients with selected cases, corpus callosotomy reduces falls and traumas Lennox Gastaut syndrome than ever before but specialized knowledge and a persistent and gradual approach are needed.