Epilepsia Partialis Continua: Acute Disseminated Encephalomyelitis or Rasmussen’s Encephalitis? Vijay Ramaswamy, BSc, D. Barry Sinclair, MD, B. Matt Wheatley, MD, PhD, Lawrence Richer, MD, and Thomas Snyder, PhD This report describes a 15-year-old male presenting with headaches and seizures after a viral illness progressing to intractable seizures of the right hand and face. This patient presented with diffuse white matter lesions on magnetic resonance imaging which disappeared with treatment. A relapse 6 months later involving the left temporal and insular regions produced epilepsia partialis continua involving the right face and hand. The relevant literature is reviewed with an emphasis on possible etiologies, including both acute disseminated encephalomyelitis and Rasmussen’s encephalitis. © 2005 by Elsevier Inc. All rights reserved. Ramaswamy V, Sinclair D, Wheatley B, Richer L, Snyder T. Epilepsia Partialis Continua: Acute Disseminated Encephalomyelitis or Rasmussen’s Encephalitis? Pediatr Neurol 2005;32:341-345. Introduction Acute disseminated encephalomyelitis is a demyelinating disorder of the central nervous system which may From the Comprehensive Epilepsy Program, University of Alberta, Edmonton, Alberta, Canada. © 2005 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2005.01.001 ● 0887-8994/05/$—see front matter occur after vaccination or viral infection. The pathogenesis of acute disseminated encephalomyelitis is thought to be autoimmune, and standard treatment consists of high-dose steroids. This disorder is characterized primarily by diffuse neurologic symptoms and altered cognition. Approximately 30% of cases present with seizures, the remainder presenting with symptoms such as ataxia, cranial nerve palsies, fever, headache, and language disturbance [1,2]. White matter signal abnormalities on magnetic resonance imaging are a ubiquitous finding in acute disseminated encephalomyelitis, with half of all cases presenting with some gray matter abnormalities in the basal nuclei [3]. Most cases are monophasic although some multiphasic cases have been reported, all of which respond to steroids. To date, no cases of chronic intractable acute disseminated encephalomyelitis presenting as seizures have been reported. This study describes a case with an initial presentation of acute disseminated encephalomyelitis progressing to epilepsia continua partialis with clinical and radiographic features of chronic focal (Rasmussen’s) encephalitis. Case Report The patient is a 15-year-old, right-handed male without any history of disease. A month before initial presentation in January 2003, the patient began to experience headaches and unusual seizures occurring several times per day consisting of left- or right-sided facial twitching, facial flushing, and confusion lasting minutes. A few weeks before the onset of these episodes, he suffered a viral illness. At initial presentation, the patient had a normal neurologic examination. Magnetic resonance imaging revealed bilateral lesions involving the right mesial temporal structures, left perisylvian fissure, and the left frontal gyrus (Fig 1). A diagnosis of postviral acute disseminated encephalomyelitis was made. The patient was admitted to the Pediatric Epilepsy Monitoring Unit and was treated with methylprednisolone 1 gm/day for 5 days. The seizures resolved, and he was discharged on carbamazepine 400 mg twice daily. The patient presented 12 weeks later with worsening seizures consisting of twitching of the left face and eye, confusion, flushing, and increased heart rate occurring many times per day. These episodes lasted less than 1 minute. In addition, he had declining memory and cognitive status. Repeat magnetic resonance imaging indicated resolution of the previously observed lesions and was reported as normal. Laboratory tests for infectious etiologies accounting for his presentation were negative. The patient was again treated with methylprednisolone 1 gm/day for 5 days, and clobazam 30 mg/day was added to the carbamazepine therapy. The patient’s seizures resolved, and he remained seizure-free for 3 months. He then began experiencing a severe decline in short-term memory and increasing confusion. Clobazam was increased to 50 mg/day, and carbamazepine was increased to 600 mg twice a day. The seizures involving his right arm and hand increased in frequency until his Communications should be addressed to: Dr. Sinclair; Director, Division of Pediatric Neurology; University of Alberta; Edmonton, AB, T6G 2B7, Canada. Received October 19, 2004; accepted January 4, 2005. Ramaswamy et al: Epilepsia Partialis Continua 341 Figure 1. Magnetic resonance imaging axial T2-weighted fluid-attenuated inversion-recovery images (TR/TE: 8500/112),(A) at diagnosis revealing a lesion involving the right mesial temporal structures, and (B) a lesion involving the left perisylvian fissure and the left frontal gyrus. hand began to twitch continuously, with occasional twitching of the right eye. He was readmitted to the Pediatric Epilepsy Monitoring Unit where electroencephalographic monitoring revealed continuous left anterior temporal epileptic discharge and slowing. A repeat magnetic resonance imaging scan documented resolution of the white matter lesions observed on the initial scan, with a residual abnormal signal of the left insular cortex. The patient was treated with intravenous phenytoin and intravenous methylprednisolone 1 gm/day for 10 days with no response. In October 2003, a course of intravenous immunoglobulin 75 grams intravenously per day for 3 days was given as one course each month for 3 months. The patient failed to respond and continued to deteriorate. In December 2003, prednisolone 40 mg/day and phenytoin 800 mg twice daily was added to the regimen without improvement. A repeat electroencephalogram again revealed focal slowing and continuous epileptic discharge from the left fronto-temporal region (Fig 2). A repeat magnetic resonance imaging scan in January 2004 disclosed reappearance of the left insular hyperintensity (Fig 3). The patient was then referred to the Montreal Neurological Institute in March 2004, where primidone therapy (500 mg/day) was initiated with deterioration in cognition and no improvement in seizure control. He went for surgery at the University of Alberta in June 2004, where he underwent intraoperative cortical mapping, brain biopsy, and multiple subpial transections of the lower central area of the left hemisphere. The intraoperative electrocorticography revealed a small horizontal strip of hyperemic cortex with continuous epileptic discharge. Postoperative electrocorticography in the operating room demonstrated successful disruption of the focal epileptic discharge. Although there was transient improvement postoperatively, the patient continues to have simple and complex partial seizures involving the right side of his face, arm, and hand. He has recently undergone a large central resection of the face and 342 PEDIATRIC NEUROLOGY Vol. 32 No. 5 hand area of the motor cortex and is presently seizure-free but hemiplegic. Pathologic studies revealed the presence of focal perivascular cuffing mainly by T-lymphocytes, presence of microglial nodules, and reactive astrogliosis with neuronal loss. These histologic changes are consistent with Rasmussen’s encephalitis. Comprehensive neuropsychological testing was conducted at the time of initial hospitalization, with three follow-up assessments conducted during the ensuing year for monitoring treatment outcome. Premorbid functioning was average to superior according to his achievement in school and the results of academic and intellectual testing. Before initial treatment with intravenous methylprednisolone, he manifested normal perception, normal language skills, mildly impaired capacity to sustain attention, and in general his memory for figural information was poorer than for verbal information, a difference suggestive of more right mesial temporal disease. Reassessment after 3 months of treatment indicated probable gains in memory but not complete normalization. Subsequent assessments at 8 and 12 months after the first assessment revealed new deficits of expressive language, worsening of memory for verbal information, and the emergence of symptoms of anxiety and depression associated with general psychosocial decline. These results are consistent with widespread cerebral dysfunction prominently affecting frontotemporal regions and progression of disease on the left temporal lobe. The worsening of neuropsychological changes is consistent with the progression of lesions observed on magnetic resonance imaging. Discussion When this patient first presented to us in January 2003, a diagnosis of acute disseminated encephalomyelitis was Figure 2. Electroencephalogram depicting focal slowing and epileptic discharges over the left fronto-temporal region (F7-T3). suspected based on the findings of multifocal hyperintense lesions on T2-weighted magnetic resonance imaging, acute symptoms after a viral illness, and the resolution of his symptoms and neuroimaging abnormalities with intravenous steroid therapy [1,3]. Although the patient suffered a relapse 3 months after initial presentation, multiphasic cases of acute disseminated encephalomyelitis have been reported, and this diagnosis was further supported by the resolution of white matter changes on magnetic resonance imaging within 6 months of presentation [4]. However, the clinical course over the 18 months after initial presentation is atypical for acute disseminated encephalomyelitis. The symptoms returned with changes in imaging findings, and the patient went on to develop epilepsia partialis continua and cognitive decline. A study characterizing the clinical and neuroradiologic presentation of acute disseminated encephalomyelitis in children reported that 8 of 84 children in their cohort with acute disseminated encephalomyelitis had definite relapses [1]. Similar to our patient, these 8 patients manifested new lesions on magnetic resonance imaging; however, they all responded to high-dose steroid treatment without further relapses. A similar study describing a cohort of 18 children with acute disseminated encephalomyelitis reports one patient with a relapse presenting as continuous seizures [2]. The patient in that report manifested new lesions in the contralateral subcortical white matter on magnetic resonance imaging with atrophy of the previously involved hemisphere 18 months after initial presentation, and responded to antiepileptic therapy. Because the patient in the present study developed epilepsia partialis continua, a diagnosis of Rasmussen’s encephalitis was suspected. Although the magnetic reso- nance imaging signal abnormalities and initial presentation are consistent with acute disseminated encephalomyelitis, his intractable seizures, cognitive decline, and inflammatory changes in the temporal and insular regions on magnetic resonance imaging are consistent with Rasmussen’s encephalitis [5]. Although he initially presented with bilateral hyperintense signals on magnetic resonance imaging in the temporoinsular region, seizures were confined strictly to one hemisphere as were the electroencephalographic findings. A study comparing the utility of positron emission tomography and magnetic resonance imaging in localizing the affected hemisphere in Rasmussen’s encephalitis reported that 9 of 10 patients had bilateral foci of T2 hyperintense signal on magnetic resonance imaging, of whom two had asymmetric findings that did not correlate with the clinical presentation [6]. In these nine patients with bilateral imaging findings, only the affected side of the body displayed hypometabolism, as observed on positron emission tomography. This finding supports our diagnosis of Rasmussen’s encephalitis involving only the left hemisphere despite bilateral signal changes documented on magnetic resonance imaging. There is some evidence that suggests that acute disseminated encephalomyelitis and Rasmussen’s encephalitis may have similar pathogenic mechanisms. Both conditions have an autoimmune pathogenesis, and although Rasmussen’s encephalitis has been classically considered a humoral immune response, recent evidence suggests that both conditions are cell-mediated [7,8]. In support of this, two reports analyzing pathologic samples from patients with both acute disseminated encephalomyelitis and Rasmussen’s encephalitis reveals similar expression of cytokines [9,10]. In par- Ramaswamy et al: Epilepsia Partialis Continua 343 Figure 3. Magnetic resonance imaging axial T2-weighted fluid-attenuated inversion-recovery (TR/TE: 8500 ms/112 ms) with reappearance of a hyperintense lesion in the left insula. ticular, they both share substantial upregulation of interleukin-1␤ and tumor necrosis factor alpha, two major mediators of inflammatory and immune response, suggesting that the pathogenesis of both conditions shares some components of a common molecular pathway of neuronal damage. In support of this hypothesis, a recent neuropathologic study of 45 hemispherectomies revealed that the distribution of lesions in Rasmussen’s encephalitis resembles those evident in acute disseminated encephalomyelitis and multiple sclerosis [11]. Treatment options for acute disseminated encephalomyelitis and Rasmussen’s encephalitis in childhood are similar, and both involve immunomodulatory therapy [1,12]. In both conditions, high-dose intravenous steroid therapy is the most efficacious treatment, with some patients requiring maintenance oral steroid therapy. In addition, intravenous immunoglobulin therapy has been demonstrated to be a useful adjunctive therapy should steroids and antiepileptics fail. Functional hemispherectomy is an effective treatment for Rasmussen’s encephalitis but may carry a significant morbidity in the language dominant hemisphere [13]. Resection of affected areas of the motor cortex, similar to the procedure that our patient underwent, may be a viable option once medical options have been 344 PEDIATRIC NEUROLOGY Vol. 32 No. 5 exhausted. Multiple subpial transections have been attempted in patients with Rasmussen’s encephalitis; however, the results are usually temporary [14]. We have performed multiple subpial transactions in two patients with Rasmussen’s encephalitis, and both had only temporary improvement. The patient in the present report failed high-dose steroid therapy, multiple antiepileptics, intravenous immunoglobulin therapy, and combination therapy involving all three modalities, suggesting that trials of newer and more specific immunomodulatory therapy such as the T-cell specific immunosuppressant, tacrolimus may prove to be beneficial [15]. The patient began a trial of tacrolimus after his initial surgery with an encouraging initial response. Although this patient appears to have developed chronic focal (Rasmussen’s) encephalitis, his original presentation was consistent with that of acute disseminated encephalomyelitis. Both disorders are thought to have an immunologic basis and share similar clinical features, neuroimaging appearance, and treatment options. It can be speculated from this case study and from the literature that both acute disseminated encephalomyelitis and Rasmussen’s encephalitis share elements of a common etiology, and perhaps these two conditions are part of a spectrum of autoimmune diseases of the central nervous system. This observation supports a hypothesis whereby the clinical entity responsible for our patient’s presentation is consistent with both acute disseminated encephalomyelitis and Rasmussen’s encephalitis. Further immunologic study of these overlapping conditions is planned. References [1] Tenenbaum S, Chamoles N, Fejerman N. 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