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Discussion
The clinical features described in this 56-year-old man fit the diagnosis of NORSE, although there were some unusual features. Notably, our patient had a single left temporal lesion resembling a low-grade neoplasm, while in most cases brain abnormalities on MRI and epileptiform activity on EEG tend to be multifocal. However, histopathology revealed inflammatory changes without any evidence of tumor. There have been several conditions described in the literature that share features with NORSE, including fever-induced refractory epileptic encephalopathy and others (reviewed by Ismail and Kossoff), but these affect younger populations (mostly children, rarely young adults) and a febrile illness is almost unanimously present before disease onset. In all of these conditions, abolition of status epilepticus is difficult, mortality is high, and neurocognitive outcome is often devastating. Surgical treatment is usually not considered due to the multifocal abnormalities. In contrast, our patient underwent emergency surgery and recovered with complete cessation of seizures and minimal neurological symptoms.
The AMT-PET findings played an important role in the diagnosis and management of our patient. AMT is a PET tracer, originally developed for mapping cerebral serotonin synthesis, which is not a substrate of the enzymes involved in protein synthesis. Subsequent studies in patients with partial epilepsy have suggested that AMT may accumulate in epileptic cortex and in epileptogenic lesions as a result of increased metabolism via the inflammatory kynurenine pathway. This pathway plays a limited role in the normal brain but can be significant under inflammatory conditions, mostly via upregulation of IDO. In the presented case, increased AMT accumulation extended considerably beyond the nonenhancing MRI-defined lesion, mostly into the posterior temporal cortex (Fig. 1). While most low-grade gliomas accumulate AMT, increased tracer uptake usually does not extend far beyond the lesion; thus, this PET finding made presence of a low-grade glioma less likely. Rather, increased AMT uptake around nonneoplastic lesions is highly suspicious for epileptic cortex, as it has been seen in perituberal cortex in children with tuberous sclerosis complex. The advantage of AMT over 2-deoxy-2[F] fluoro-D-glucose as a PET radiotracer is its high specificity to detect epileptic cortex via focal radiotracer accumulation in the interictal state. Therefore, the relatively extensive temporal cortical AMT-PET abnormality, together with the electroclinical symptoms in our patient, prompted us to map the ictal onset zone with long-term subdural EEG monitoring before resection of a large portion of the left temporal lobe, which helped to maximize the chance of seizure freedom. This strategy was indeed successful, as the patient has remained seizure free over a 3-year follow-up period.
Histopathology of the resected epileptic tissue showed reactive gliosis and inflammation, which was present specifically in the AMT-accumulating tissue. High expression of IDO in the specimen suggested activation of the inflammatory kynurenine pathway and increased conversion of tryptophan to kynurenine metabolites as a result. Proinflammatory cytokines, such as IL-1β or tumor necrosis factor-α, can potentiate induction of IDO. IL-1β, along with other cytokines, plays an important role in the mechanisms of hyperexcitability involved in experimental seizure models. Cortical tubers resected to alleviate seizures showed signs of a chronic inflammatory response, including expression of a variety of markers such as IL-1β and its signaling receptor IL-1R1, components of the complement cascade, CD68-reactive macrophage infiltration, and expression of molecules (such as tumor necrosis factor-α) involved in cytokine signaling. Epileptogenic focal cortical dysplasia Type II (but not Type I) also showed prominent expression of IL-1β, components of the complement cascade, and perivascular and parenchymal CD3+ T lymphocytes (with a predominance of CD8+ cytotoxic/suppressor T cells), thus supporting involvement of different inflammatory pathways in these developmental lesions. This expression pattern appears to coincide with the pattern of increased AMT uptake seen in focal cortical dysplasia subtypes. Expression of IL-1β and IL-1R1 was also seen in specimens obtained from epileptogenic glioneuronal tumors, with widespread expression in multiple cell types including neurons, astrocytes, and microglia. Seizure-induced brain inflammation and IL-1β release are also associated with transient blood-brain barrier impairment. Therefore, increase of AMT uptake and trapping in epileptic tissue may be related to increased tryptophan transport (due to blood-brain barrier defect) and metabolism of tryptophan to L-kynurenine (due to IDO activity), respectively. Coexpression of IL-1β, IL-1R1, and IDO in AMT-accumulating cortex in specimens obtained from our patient is consistent with the notion that increased AMT uptake shown by PET imaging of the epileptic brain may serve as a biomarker of immune activation. Comparison of the intracranial EEG and PET findings also suggested that the inflammatory changes extended beyond the epileptogenic region. Postsurgical reversal of increased AMT uptake in nonresected cortex in the posterior temporal region (which was not involved in seizure onset) suggests that some of the AMT-PET abnormalities were either seizure induced or represented reversible inflammation not inducing epileptogenesis.
The etiology of seizures in this patient remains unknown, as is the case with most patients with NORSE. However, there is an increasing body of evidence demonstrating that release of IL-1β and other proinflammatory cytokines can be both a cause and a consequence of severe seizures, thus playing a central role in inflammation-mediated seizures and status epilepticus. Since status epilepticus in NORSE is resistant to standard antiepileptic treatment and the incidence of mortality is especially high in adults, there is an urgent need for novel therapeutic approaches. Our case demonstrates that surgery is an option when neuroimaging and electrophysiological data indicate a relatively limited unilateral brain abnormality. In cases with multifocal abnormalities, pharmacological approaches might be the only option. The results with wide-spectrum immunomodulatory treatment regimens have been disappointing; therefore, exploration of new antiinflammatory strategies is warranted. Molecular imaging with AMT, or other imaging approaches targeting molecular mechanisms associated with neuroinflammation, can offer a noninvasive way to assess presence, severity, and extent of seizure-associated inflammatory changes in the epileptic brain. These modalities could be instrumental not only when surgery is being considered but also in clinical trials as biomarkers when testing novel antiinflammatory approaches.
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