Unraveling the Mysteries of a Seizure Disorder Called New-onset Refractory Status Epilepticus

When Daniel Wong was overcome by seizures that struck out of the blue only two months after he graduated from Stanford in 2013, his doctors were alarmed. They could find no triggering event, no history of epilepsy, no explanation for his sudden prolonged seizures. Doctors placed the 22-year-old Daniel in a drug-induced coma to protect his brain and tried numerous therapies to control his seizures. All treatments failed. Less than three months later, Daniel died without regaining consciousness.

The Mysterious Seizure Disorder Has a Name

At the suggestion of one of his doctors, Daniel’s parents, Nora and Raymond Wong (both graduates of Yale College) met with Yale School of Medicine (YSM) neurologists Lawrence J. Hirsch, MD '91; Emily J. Gilmore, MD; and Nicolas Gaspard, PhD, at Yale New Haven Hospital in August 2014. The clinicians were planning a multinational, multicenter study to include patients like Daniel—who was thought to have a syndrome referred to as new-onset refractory status epilepticus or NORSE.

NORSE is described as a clinical presentation of prolonged seizures that are uncontrolled by at least two antiseizure medications, with the cause of the seizures remaining unidentifiable for 72 hours. NORSE tends to affect primarily healthy young adults and children with no previous history of epilepsy. The consequences of the disorder are devastating. There is significant short-term mortality (as high as 27%) and morbidity. Patients often survive with significant brain damage and develop chronic epilepsy. The Wongs created the Daniel Raymond Wong Neurology Research Fund at YSM to support this prospective observational study that collects clinical data from NORSE patients and their biospecimens, both of which are banked at Yale.

Raising Awareness of New-onset Refractory Status Epilepticus

With Hirsch and Gaspard as co-chairs of her medical advisory board, Nora Wong established the NORSE Institute (norseinstitute.org), a collaboration of NORSE families, clinicians, and basic scientists. Since its inception, the NORSE Institute has worked to raise awareness of this rare disorder. At Nora’s request, Hirsch and Gaspard wrote the first description of NORSE issued on the rare disease websites hosted by the National Institutes of Health’s Genetic and Rare Diseases Information Center (GARD), the National Organization for Rare Disorders (NORD), and the Epilepsy Foundation.

To build a common language for the disorder, Hirsch assembled a group of international experts to develop consensus definitions of NORSE and a related syndrome termed FIRES (febrile infection-related epilepsy syndrome). “So far the NORSE Institute has developed, posted, and published a recommended diagnostic evaluation for specialists, readily available through the NORSE Institute website,” said Hirsch. “One of the first challenges for a new disease is creating a name and consistent definition for it. The next is awareness—making sure everyone knows about the disease or the condition’s definition.” The NORSE Institute has been very successful in addressing these issues.

“NORSE shares some attributes with FIRES, now defined as a subset of NORSE, in which the patient has a prior infection with fever, usually a mild one,” said Hirsch. He added that although FIRES has traditionally been associated with children, it occurs in adults as well.

Through the Wongs’ support, the NORSE Institute sponsored the first international conference on NORSE in Salzburg, Austria, in 2017, where Hirsch and his group of experts met and later presented the consensus definitions. The definitions were published in Epilepsia in 2018 and are accepted as standard definitions worldwide. A roadmap of NORSE research was published in Neurology by Hirsch, Gaspard, and other members of the NORSE Institute medical advisory board.

The institute sponsored multiple roundtable workshops with international researchers discussing the immunologic, genetic, and clinical aspects of NORSE, including ways to determine the best treatments. And in December 2019, the NORSE Family Registry was launched. This registry allows families to provide retrospective information about NORSE patients; it is intended to complement the ongoing prospective study of acutely ill NORSE patients. The NORSE family registry is supported through a gift to Yale by the family of Robert N. Kohn, who also died of NORSE.

Originally published Winter 2020; updated May 11, 2022.