In July 2010, a 53-year-old woman with no significant neurologic history experienced a single convulsion. Four months later, she experienced two similar convulsions, quickly progressing to status epilepticus. She was treated at an outside institution and recovered full function and returned to work. Initial MR imaging at that time was reported as normal. However, despite AED treatment, she continued to have focal seizures, characterized by clonic jerks of the right face. Over the next year, her seizures progressed in both frequency as well as semiology, involving the right arm as well as language. Admission to an outside epilepsy monitoring unit (EMU) revealed both electroclinical (semiology of right face/arm movements) and purely electrographic seizures arising from the left frontal region in the context of minimal responsiveness, consistent with focal status epilepticus. She was again treated for status epilepticus and discharged on AED polytherapy: phenytoin, valproic acid, levetiracetam, and oxcarbazepine.\nAs her epilepsy became more refractory, a very extensive etiologic work-up was performed at an outside institution, approximately 2 years from epilepsy onset. MRI demonstrated a left parietal FLAIR hyperintensity with mild associated volume loss (Figure ). CT imaging of the chest, abdomen, and pelvis did not reveal malignancy. Extensive serum and CSF studies, notably paraneoplastic and autoimmune encephalitis antibody testing (including AMPA-R, GABA B-R, ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, amphiphysin, CRMP-5, VGKC, NMDA-R) as well as genetic testing for CADASIL and MELAS were also negative.\nIn addition to a known left frontoparietal epileptic focus, the patient then developed a second focus in the ipsilateral occipital quadrant, first observed in May 2013 (Figure ). Brain PET imaging performed showed overall left hemisphere hypometabolism, with areas of increased metabolism in the left frontal, parietal, and occipital regions, thought to represent ictal changes. Treatment broadened to include rescue doses of benzodiazepines and implantation of a vagal nerve stimulator, approximately 3 years from epilepsy onset. After whole body FDG PET imaging did not reveal occult malignancy, an autoimmune etiology of her epilepsy was presumed and immune therapy was initiated. Single trials of high dose intravenous methylprednisolone (1000 mg × 5 days, March 2014), plasma exchange treatments (5 treatments over 10-day period, May 2015), as well as an induction dose of Rituximab (1000 mg, May 2015) had no clinical effect. During these immunotherapy trials, the patient also underwent brain biopsy targeting the left frontal lobe. The biopsy showed only mild gliosis and rare T lymphocytes, without evidence of vasculitis, microglial nodules, or viral cytopathic changes. Concurrent AED therapy included trials of vigabatrin, zonisamide, and clobazam, with only the last having a meaningful impact on seizure frequency, albeit at a high dose (40 mg daily).\nAt this point, approximately 4 years from first clinical manifestation, the patient presented to our institution. At the time, the patient was having roughly 20 clinical seizures per day and her AED regimen was as follows: lacosamide, levetiracetam, carbamazepine, zonisamide, clonazepam, and clobazam. Her clinical exam was notable for a moderate mixed aphasia and a mild right hemiparesis. She was admitted to the EMU and found to be in epilepsia partialis continua with near continuous right face and arm twitching. After loading doses of levetiracetam and fosphenytoin, the patient began having distinct episodes of right arm and face movements coupled with mutism. The electrical correlate on EEG monitoring was frequent, brief (average duration of 30 s) left frontal seizures (Figure ). AEDS were further adjusted, with the addition of perampanel and prn dosing of lorazepam having the greatest effect on seizure frequency reduction. Based on progressive hemiatrophy on imaging (Figure ), medically refractory epilepsy, static neurologic deficits (right hemiparesis and mixed aphasia), and the extensive serum and CSF sampling, the diagnoses of RE, while conjectured in the past, was finally established. The patient was treated with regular dosing of IVIG. A dose interval of 3 weeks was determined based on the patient family’s impression of when seizure frequency began to increase after the last dose of IVIG. Despite regular IVIG dosing for approximately 6 months as well as concomitant AED therapy, the patient’s epilepsy remained refractory. Currently, the patient is under the care of another institution and IVIG therapy has been discontinued at the behest of the family and her AED regimen was adjusted to include felbamate, lacosamide, levetiracetam, phenobarbital, and lorazepam. Presently, she has a dense right hemiparesis and severe global aphasia.
In March 2007, a 47-year-old woman with a history of bilateral optic neuritis at age 35 experienced her first seizure. One month later, she experienced a second seizure and was started on lamotrigine. She presented to our institution as an elective admission to the EMU 6 months after seizure onset. Many right temporal seizures (clinical semiology of paresthesias over left face and arm) were observed and the interictal EEG was notable for right periodic lateralized discharges (PLDs; Figure ). MRI showed abnormal T2 signal in the right frontal cortex, right thalamus as well as a small area of contrast enhancement in the right temporal uncus. MR SPECT showed normal choline:creatinine ratio. Serum studies were notable for the following normal/negative studies: ANA, ACE, anti-TPO, Lyme, paraneoplastic antibody (ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, CRMP-5, VGKC). CSF evaluation was significant for a mild lymphocytic pleocytosis, negative HSV and CMV PCR, and cytology negative for malignant cells. Ultimately, after trials of several AEDs including lamotrigine, levetiracetam, and carbamazepine, oxcarbazepine and phenytoin were utilized for seizure control.\nOver the next 3 years, the patient had several admissions to our institution for breakthrough seizures. Her seizure semiologies over this time frame were isolated left face and arm paresthesias, focal motor seizures involving left face and arm as well as secondarily generalized tonic/clonic seizures. A static mild left hemiparesis, most affecting the left hand, was also noted during this time. Further diagnostic work-up over one of these later admissions was notable for normal CSF cell counts, a CT scan of the chest, abdomen, and pelvis negative for malignancy, and repeat negative paraneoplastic panel evaluation. At this point, the patient was lost to follow-up.\nShe re-presented to our institution 5 years later after she experienced a generalized convulsion. Collateral history indicated that she had become unable to live at home unassisted and often had confusional and agitated episodes. Since last seen at our institution, her AED regimen had been changed to levetiracetam and valproic acid. In addition, a third lumbar puncture was performed and notably NMDA-R antibody testing was negative. The patient was found to be in non-convulsive status epilepticus and treated with benzodiazepines and augmented doses of her AEDs. CT imaging done on this admission revealed marked right hemisphere atrophy. Continuous EEG monitoring showed both right frontal and temporal spikes and left temporal slowing. Clinical exam was significant for perseverative speech, inability to follow complex commands and a moderate left hemiparesis. Given the patient’s marked hemiatrophy, refractory epilepsy, and static neurologic deficits, she was diagnosed with RE and monthly IVIG was initiated.\nMR imaging performed showed marked right hemisphere volume loss, affecting both gray and white mater (Figure ). Despite the marked asymmetry on imaging findings, EEG monitoring during this advanced stage of disease revealed bihemispheric electrographic pathology; in addition to PLDs in the right posterior quadrant, PLDs and spikes were observed over the left temporal region as well as bilateral independent frontal spikes (Figure ). By family and caregiver report, patient’s overall seizure frequency decreased over the 5-month period she was treated with immunotherapy. As there was no significant change in the patient’s overall neurologic functional status, decision was made by family to discontinue IVIG infusions and pursue hospice.\nWritten informed consent was obtained from patients or next of kin for publication of these three case reports.