Clinical/Scientific Notes J.G. Boyd, MD, PhD S. Taylor, MSc, MD J.P. Rossiter, MB BCh, PhD O. Islam, MD A. Spiller, MD, PhD D.G. Brunet, MD NEW-ONSET REFRACTORY STATUS EPILEPTICUS WITH RESTRICTED DWI AND NEURONOPHAGIA IN THE PULVINAR New-onset refractory status epilepticus (NORSE) is a recently defined clinical entity which describes pa- tients who present with severe generalized seizures of unclear etiology that occur in the context of a preced- ing febrile illness. 1-3 These seizures are typically unre- sponsive to antiepileptic medications. Case report. A 26-year-old otherwise healthy right- handed man presented with generalized tonic-clonic seizures after a 1-week history of headache, fever, and myalgias. He was admitted to our intensive care unit for treatment and underwent continuous EEG mon- itoring for 77 days. On admission to our intensive care unit, the CSF contained 92  10 6 white blood cells (96% lymphocytes). Consistent with previous reports of NORSE, an exhaustive structural, infec- tious, toxic/metabolic, autoimmune, neoplastic, and paraneoplastic workup did not identify a clear underly- ing etiology (figure, A). IV infusions of propofol or thiopental were used to maintain the patient in either an electrographic burst suppression pattern or electro- graphic silence, while enteral antiepileptic medications were titrated to therapeutic doses (e.g., phenytoin, val- proic acid, clobazam, topiramate, vigabatrin, phenobar- bital, and levetiracetam) (figure, B). Attempts to wean IV antiepileptic drugs were met with recurrence of elec- trographic multifocal sharp transients, originating from either temporal lobe, which evolved into clinical and electrographic seizures. The patient had 4 MRIs throughout his clinical course that showed restricted diffusion in the distribu- tion bilateral medial temporal lobes, insular cortex, with extension posteriorly into the pulvinar nuclei of the thalamus (figure, C). The MRIs also showed progres- sive increase in T2 signal intensity and progressive atro- phy of the hippocampi bilaterally, consistent with the radiologic diagnosis of mesial temporal sclerosis. The patient died 77 days after admission from septic perito- nitis secondary to a perforated jejunal ulcer. The general autopsy did not demonstrate any sys- temic neoplasm. The key neuropathologic findings were the profound loss of pyramidal neurons in the bilateral hippocampi, occasional microscopic foci of perivascular white matter ischemic injury, and con- spicuous neuronophagia of neurons within the pulv- inar nuclei (figure, D and E). Importantly, there was no evidence of underlying cerebral neoplasm, vascu- litis, or infectious process. Discussion. This is the first case to demonstrate re- stricted diffusion in the bilateral pulvinar nuclei and neuronophagia in a patient with NORSE. In hu- mans, the pulvinar nucleus has extensive reciprocal connections with most cortical regions, including temporal, parietal, and insular cortices. 4 Further- more, intraoperative recordings during epilepsy sur- gery have shown that neurons within the pulvinar nucleus have ictal changes in response to temporal lobe seizures. 5 The same study showed that temporal lobe seizures associated with ictal changes in the pulvinar nucleus were more likely to spread beyond the onset zone, suggesting that the pulvinar nucleus might participate in the propagation of these sei- zures. A study has recently demonstrated that some patients (30%) with partial-onset status epilepticus have areas of restricted diffusion involving the pulvi- nar nucleus, ipsilateral to the seizure focus. 6 Com- pared to patients without thalamic restricted diffusion, these patients also demonstrated restricted diffusion in the cerebral cortex ipsilateral to the sei- zure focus, particularly in the posterior regions. There was a broad spectrum of etiologies underlying the seizures, including mass lesions, ischemic stroke, and sagittal sinus thrombosis. However, nearly half did not have any structural etiology for their seizures. The pathophysiologic basis for the restricted dif- fusion along cortico-pulvinar circuits remains un- clear, but it may be related to bioenergetic failure of the neurons involved in sustained seizure activity. In support of this hypothesis, intracerebral microdialy- sis studies have shown that critically ill patients with electrographic seizures have elevated lactate/pyruvate ratios, compared to those without seizures. 7 In our patient, the surface EEG showed essentially electro- graphic silence for the majority of the 77 days of recording, not continuous electrographic discharges. Nonetheless, we cannot exclude seizure discharges from the deeper cortical structures and thalamic re- gions. The presence of active neuronophagia within this Neurology 74 March 23, 2010 1003