Immunotherapy in Rasmussen’s encephalitis: when should it be taken into account?

Abstract

A pathogenic role of immunity in epilepsies has long been suggested based on observations of efficacy of immunomodulating treatments (steroids and immunoglobulin) and, more recently, by the findings of markers of inflammation (i.e., IL-6, IL-1b and IL-1ra, TGF-b) [1] and autoantibodies (i.e., GluR3, anti-NMDA, anti-GAD, VGCC-Ab, VGKC-Ab, anti-D2-glycoprotein) in some epileptic disorders [2]. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy [3]. Recently, the role of immunomodulatory therapy in the treatment of Rasmussen’s encephalitis (RE) has been emphasized [4–6]. Rasmussen encephalitis is a degenerative disorder characterized by intractable epilepsy and progressive loss of motor/cognitive functions, due to unilateral brain atrophy. Although the exact pathophysiology remains mysterious, both cellular inflammation and epilepsy triggered by nonspecific infection and generating cell necrosis might probably be involved [3]. Recently we have reported a 9-year-old girl with RE, who had been early treated with immunomodulatory and antiepileptic drugs [6]. In this patient, the disease started with few partial motor seizures well responding to conventional antiepileptic drugs (topiramate). Her first magnetic resonance imaging (MRI) study of the brain was normal. She was seizure free and developed normally over the following 2 years, after that, those seizures restarted and became refractory to antiepileptic drugs (AEDs) (topiramate, levetiracetam). The girl gradually developed epilepsia partialis continua (EPC) with continuous myoclonic jerks of the left limb, occurring over hours/days. She had no deficits of high cortical function, cranial nerves and sensory functions. A second MRI performed in this phase showed a focal hyperintense lesion in FLAIR signal and T2-weighted images at the right fronto-parietal region that was interpreted as focal cortical dysplasia without signs of atrophy. However, as a consequence of persistent drugresistant EPC and the presence of glutamate receptor antibodies (GluR3Ab) in cerebrospinal fluid, the hypothesis of RE was still considered and immunotherapy with corticosteroids and IgIV associated with phenytoin was started, obtaining good clinical results. However, 2 years after the cessation of immunotherapy there was a rapid worsening of the epileptic activity and the onset of progressive hemiparesis. A 7T-MRI performed at the age of 8 years revealed diffuse atrophic change of the brain that confirmed the diagnosis of RE [7]. The peculiarity of this case was the slow progression of the acute phase that may result from the early association of antiepileptic and immunomodulating therapies. This association led to reduction of both epileptic activity and inflammation, improving the blood–brain barrier damage. This strategy contrasted the vicious circle in which the humoral compounds and epileptic activity seem to contribute to the neuronal loss and cortical atrophy in RE. Consequently, the signs of atrophy in MRI were evident only 4 years after the onset of the acute phase. This initially led to interpretation of the hyperintense area as a cortical dysplasia. The slow progression of the disease in the first stages may have also contributed to the initial success of the therapy in this patient. To date hemispherectomy is still considered the gold standard for the treatment of RE, providing remarkable results in terms of seizure outcome [4]. However, in a L. Papetti A. Spalice (&) F. Nicita F. Ursitti P. Iannetti Child Neurology Division, Department of Pediatrics, ‘‘Sapienza’’ University of Rome, Viale Regina Elena 324, 00161 Rome, Italy e-mail: childneurology.sapienzaroma@live.it