Autoimmune epilepsy: The roles of APE2 and RITE2 scores

BY BRUCE JANCIN


Up to 20% of new focal-onset epilepsy in adults may have an autoimmune cause. But narrowing down the population of these patients to those most suitable for costly autoantibody testing has been a diagnostic challenge. And “a nonselective approach to testing epilepsy patients for neural autoantibodies is ill advised,” Jeffrey W. Britton, MD, cautioned during a presentation at the International Epilepsy Congress in Bangkok.

“In your clinic, if you tested everybody, anywhere from 5% to even as many as 20% may have an autoantibody. It’s unclear in some cases if it’s relevant. You might stumble upon a GAD65 antibody in a patient with run-of-the-mill epilepsy and not know what to do. You need some criteria for testing,” according to Dr. Britton, professor of neurology and chair of the division of epilepsy at the Mayo Clinic in Rochester, Minn.

 

Dr. Jeffrey W. Britton
 The widely cited criteria (Lancet Neurol. 2016 Apr;15[4]:391-404) developed by Josep O. Dalmau, MD, of the University of Barcelona and colleagues for the diagnosis of autoimmune encephalitis – not autoimmune epilepsy – do not place much emphasis upon seizures.

“In the clinic, when you’re seeing a patient presenting mainly with seizures, the Dalmau criteria aren’t completely applicable to that population,” Dr. Britton said.

Fortunately, making the decision to perform autoantibody testing is becoming more straightforward as a result of recent refinements in clinical scoring systems, he said.


credit: Dr. Jeffrey W. Britton / Mayo Clinic

Enter APE2

At the congress, which was sponsored by the International League Against Epilepsy, Dr. Britton described three modifications to the Antibody Prevalence in Epilepsy and Encephalopathy (APE) score. With these changes, a score of 4 or higher on the new variation of APE, called APE2, is still 98% sensitive but the specificity for predicting neural autoantibody positivity improves from 78% to 84%.

So an epilepsy patient with an APE2 score of 4 or more warrants neural autoantibody testing. And a score of 7 or higher has a 100% sensitivity, he said. 

Neural autoantibodies commonly associated with autoimmune epilepsy include GAD65 (glutamic acid decarboxylase 65 IgG), LGI1 (leucine-rich glio-ma-inactivated protein 1), and NMDA-R (N-methyl-D-aspartate receptor).

The APE2 is based largely upon clinical characteristics. This screening test awards points based on the presence of 10 relevant clinical characteristics (see graphic). Compared with APE, the criteria for evaluation of brain MRI were changed to include additional abnormalities recognized as consistent with auto-immune encephalitis such as T2 or FLAIR (fluid-attenuated inversion recovery) hyperintensity largely restricted to one or both medial temporal lobes, or multifocal abnormalities involving gray matter, white matter, or both compatible with demyelination or inflammation. Additionally, only cancers diagnosed within 5 years of seizure or the onset of cognitive dysfunction are scored in APE2. The third change to APE was an increase in the score assigned to faciobrachial dystonic seizure (FBDS), which is an independent predictor of LGI1 IgG positivity.

Dr. Britton also described another screening test called Response to Immunotherapy in Epilepsy and Encephalopathy (RITE). That test was modified (RITE2) to include additional points for the presence of neural-specific cell surface autoantibodies and an interval of less than 6 months from seizure onset to starting immunotherapy.

The RITE2 score is determined by adding the accrued points from the components of APE2 plus the presence of a plasma membrane–specific autoantibody and initiation of immunotherapy within 6 months of symptom onset. A RITE2 score of 7 or more has 88% sensitivity and 84% specificity of a favorable seizure outcome, defined as at least a 50% reduction in seizure frequency, following initiation of immunotherapy (Epilepsia. 2019 Feb;60[2]:367-369). 




Fluorodeoxyglucose positron emission tomography scan of a 62-year-old woman experiencing frequent focal seizures and severe memory disturbance. Marked hypermetabolism is visible in both hippocampi (arrow). The patient was found to have high titers of anti-GAD 65 antibody.
credit: Dr. Jeffrey W. Britton / Mayo Clinic


MRI scans of a 62-year-old woman experiencing frequent focal seizures and severe memory disturbance. A. Coronal fluid-attenuated inversion recovery (FLAIR) imaging before treatment shows hyperintensity involving the bilateral orbitofrontal (bracket), right hypothalamic (white arrow) and bilateral hippocampal (yellow arrow) regions. B. Four months after treatment, orbitofrontal and hypothalamic abnormalities are shown to be resolved; however, both hippocampi show significant hyperintensity (yellow arrow).
credit: Dr. Jeffrey W. Britton / Mayo Clinic

APE2 in action: a case report

Dr. Britton shared the case of a middle-aged attorney who was found in an alley endlessly repeating the word “ball.” He had a 1-month history of illness. And he was having 50 seizures per day.

“High seizure frequency is a big red flag,” the neurologist commented.

Using the APE2 criteria, the man had a total score of 8 points: 1 point each for the recent-onset of his seizures, another for irritability and memory loss, plus 2 points for being refractory to three antiepileptic drugs, another 2 points for an elevated CSF WBC, and 2 points for having MRI abnormalities. Thus, he was a clearcut candidate for neural autoantibody testing.

The test came back positive for LGI1. The patient was placed on IV methylprednisolone while in the Mayo Clinic EEG monitoring unit and promptly went from 50 seizures per day to zero seizures by day 3 of treatment. He relapsed after transitioning to oral prednisone, prompting initiation of intravenous immunoglobulin (IVIg) in conjunction with continued oral prednisone. In response, he regained remission and was then placed on mycophenolate.

“Five years later, he’s still on mycophenolate and one antiseizure medication, and he’s doing very well, working full time as an attorney. He has rare aura, so I’m very hesitant to fully stop his medications,” Dr. Britton explained.

He reported having no financial conflicts regarding his presentation.

Suggested Reading

Brown LW et al. The neurologist’s role in supporting transition to adult health care: A consensus statement. Neurology. 2016;87(8):835-40.

Camfield P et al. Transition from pediatric to adult epilepsy care: A difficult process marked by medical and social crisis. Epilepsy Curr. 2012;12(Suppl 3):13-21.