Long-term outcome after limited cortical resections in two cases of adult-onset Rasmussen encephalitis

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1 BRIEF COMMUNICATION Long-term outcome after limited cortical resections in two cases of adult-onset Rasmussen encephalitis *Flavio Villani, *Giuseppe Didato, *Francesco Deleo, Giovanni Tringali, *Rita Garbelli, Tiziana Granata, Carlo Efisio Marras, Roberto Cordella, and *Roberto Spreafico SUMMARY Flavio Villani is a Senior Neurologist in the Epilepsy & Sleep Disorders Monitoring Unit of the Epilepsy Surgery Center at the Foundation IRCCS Neurological Institute Carlo Besta, in Milan, Italy. Rasmussen encephalitis (RE) is a progressive inflammatory disorder characterized by brain hemiatrophy, unilateral focal deficits, and drug-refractory focal epilepsy. Epilepsia partialis continua (EPC) is a hallmark of the disease. Several immunomodulatory treatments may slow but not halt the disease progression. The treatment of choice still relies on surgical hemispheric disconnection, which is burdened by heavy neurologic morbidity. More limited cortical resections, although more tolerable, are usually considered to be, at best, only transiently effective in RE. Hemispheric disconnections may be not feasible when neurologic functions are preserved and the dominant hemisphere is affected. Adult patients with a milder RE course that preserves neurologic function for a long period are particularly at risk of developing severe deficits after surgery. In this study we present the histories of two patients with adult-onset RE who have undergone selective cortical resections to control EPC, avoiding, at the same time, the severe postsurgical deficits that may be induced by hemispheric disconnective surgery. The good result obtained on EPC has been stable over a prolonged period; however, this result was not paralleled by the stop of neurologic progression in one of the two cases. A PowerPoint slide summarizing this article is available for download in the Supporting Information section KEY WORDS: Epilepsy surgery, Drug-refractory epilepsy, Resective surgery, Cortectomy, Inflammatory encephalopathy, Rasmussen encephalitis. Rasmussen encephalitis (RE) is an inflammatory neurologic disorder characterized by progressive brain hemiatrophy associated with unilateral focal deficits and drugrefractory focal epilepsy. Epilepsia partialis continua (EPC) is considered a hallmark of RE. 1 Although several medical treatments are available, and some may slow disease progression and prevent severely refractory epilepsy, 2 the treatment of choice for RE still relies on functional hemispherectomy or hemispherotomy (FH). 3 This surgical treatment option, however, may be not Accepted February 14, 2014; Early View publication March 4, Divisions of *Clinical Epileptology & Experimental Neurophysiology, Neurosurgery III, Child Neurology, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy; and Neurosurgery Unit Bambino Gesu Children Hospital, Rome, Italy Address correspondence to Flavio Villani, Epilepsy & Sleep Disorders Monitoring Unit, Epilepsy Surgery Center, Foundation IRCCS Neurological Institute, Carlo Besta, Via Celoria 11, Milano, Italy. fvillani@istituto-besta.it Wiley Periodicals, Inc International League Against Epilepsy feasible in patients with preserved neurologic function because of the severe deficits that it may induce, particularly when surgery is performed in the dominant hemisphere and in adolescent or adult patients, in which RE is usually characterized by a slower and milder course that preserves motor and speech function for a long period of time. 4 In this study we present the paradigmatic histories of two patients with adult-onset RE, who underwent selective cortical resection to avoid severe postsurgical deficits, that were not present when indication to surgical treatment was given. The good result obtained on EPC over a fairly prolonged period was not paralleled by a halt in progression of neurologic deficits in one of the two cases. Cases Case 1 A 28-year-old right-handed woman, with no significant familial or personal medical history, started to present EPC e38

2 e39 Cortectomy in Rasmussen Encephalitis at the age of 19 years. The myoclonic jerks involved the tongue and the right face muscles. In the following 6 years the jerks spread from the face to the right limbs. No other seizure types were described. Several episodes of focal motor status epilepticus (SE) required admission to an intensive care unit (ICU), and were treated acutely with intravenous benzodiazepines and steroids in high doses, with subsequent SE remission. EPC, on the contrary, was never completely controlled. In addition, the patient progressively developed a mild right hemiparesis and very mild expressive aphasia. A functional magnetic resonance imaging (fmri) study confirmed the left hemisphere dominance for language. The electroencephalography (EEG) picture changed over time from irregular focal theta abnormalities with rare sharp waves over the left frontocentral regions (Fig. 1A), to a more prominent picture (Fig. 1B, C) with irregular theta and delta abnormalities associated with spike and wave complexes with the same spatial distribution. Repeat brain MRI studies demonstrated a progressive atrophy of the frontal and perisylvian regions (Fig. 1E, F). Several different antiepileptic drug (AED) regimens (carbamazepine [CBZ], valproate [VPA], phenytoin [PHT], levetiracetam [LEV], and clonazepam [CNZ]) and different trials with immunomodulatory therapies (highdose and chronic steroids, intravenous immunoglobulin A B C D E F Figure 1. Case 1. (A) EEG few months after EPC onset showing mild slow activity in the left frontocentral regions. On polygraphic recording there are myoclonic jerks on the right orbicularis oris muscle (EMG1, orbicularis oculi; EMG2, orbicularis oris; EMG3 right platysma; EMG4, right deltoid; EMG5, left deltoid; EMG6, right quadriceps). (B) EEG 6 years after onset showing diffuse slowing and spike and wave complexes on the left frontocentral regions with myoclonic jerks in the right deltoid muscle. (C) EEG during general anesthesia for superrefractory status epilepticus showing subcontinuous epileptiform activity on the left frontocentral regions. (D) Sleep EEG 38 months after surgery showing electrographic seizure on the left centroparietal regions. EEG calibration lv. (E) Brain MRI: axial T 1 - weighted image (w.i.) few months after onset showing mild atrophy of the left frontal lobe. (F) Axial T 1 -weighted image 6 years after onset showing worsening of the atrophy involving the whole left hemisphere, particularly in the frontoinsular regions. Note (arrow) atrophy of the head of the nucleus caudatus. Epilepsia ILAE

3 e40 F. Villani et al. [IVIg], plasmapheresis, and immunoadsorption with A protein) produced only mild and temporary reductions of seizures, and no clear effect on atrophy progression (Fig. 1E, F). A super-refractory focal motor SE, 5 years after onset, was interrupted with deep brain stimulation (DBS) in the caudal zona incerta, 5 but the benefit was only temporary. After recovery from the SE, the patient presented a mild right hemiparesis and expressive aphasia, slightly worsened compared to the pre-se period. RE diagnosis was at that point confirmed by open brain biopsy (Fig. 2A E). At the age of 25 (6 years after the onset), the patient presented a new super-refractory SE that required anesthesia. A cortectomy confined to the central lobe (precentral and postcentral gyri), preserving the frontal operculum, was at that point performed after intraoperative electrocorticography (ECoG) and functional mapping. The SE and EPC were interrupted by the surgical procedure. A B C D E F G H Figure 2. Histopathologic hallmarks of Rasmussen encephalitis in case 1 (A E) and case 2 (F H). Case 1. (A C) Decrease in cortical thickness and foci of cortical spongiosis are well visualized by Kluver-Barrera staining (asterisks in A indicate the regions shown at higher magnification in B and C, respectively). Immunohistochemical staining confirms the presence of respectively perivascular infiltration with T lymphocytes (D) and microglial nodules (E). Case 2. Cortical spongiosis (F, hematoxylin and eosin) and severe inflammation with nodular infiltration of T lymphocytes (G) and microglia (H) are also present in case 2. Bar: 4.5 mm (A); 280 lm (B); 800 lm (C); 60 lm (D, E); 120 lm (F, H)40 lm(g).

4 e41 Cortectomy in Rasmussen Encephalitis After surgery the patient presented right hemiplegia, but language did not worsen as compared to the presurgical state. One year after surgery, only during sleep, frequent electrographic seizures were observed over the left frontocentral regions (Fig. 1D), and language abilities continued to slowly decline. At last follow-up (54 months after surgery) the patient remained seizure free, with reduced AED doses (CBZ, phenobarbital [PB], LEV, and CNZ), and low-dose chronic steroid. A moderate to severe nonfluent language deficit was also present. EEG was unchanged (frequent electrographic seizures during sleep). MRI showed a clear-cut progression of cortical atrophy with an increased signal in T 2 -weighted images over the left frontoinsular regions compared to the presurgical examination. Case 2 A 35-year-old right-handed woman, without significant familial or personal medical history, started to present, at the age of 26, sporadic secondary generalized convulsive seizures with focal motor onset (left face and upper limb). A brain MRI performed soon after epilepsy onset revealed atrophy of the right frontoinsular regions (Fig. 3B), extended to the head of the caudate nucleus. Sixteen months after seizure onset she developed EPC, initially with a limited involvement of the left facial muscles (mouth and eyelid) (Fig. 3A), and later involving the oral territory (tongue and soft palatal muscles) and neck (platysma). The brain MRI showed a progression of the atrophy (Fig. 3C). A B C D E Figure 3. Case 2. (A) EEG few months after EPC onset showed mild slow activity in the left frontal-parietotemporal regions and myoclonic jerks in the left orbicularis oris and oculi muscles (EMG1, right orbicularis oculi; EMG2, right orbicularis oris; EMG3, left orbicularis oculi; EMG4, left orbicularis oris). (B) Coronal Inversion Recovery image few months after onset showing atrophy of the right insular region, enlargement of the lateral ventricle, and atrophy of the head of the nucleus caudatus. (C) Coronal T 1 -weighted image 7 years after onset showing worsening of the atrophy in the right frontoinsular regions and increased enlargement of the lateral ventricle. Note: head of the nucleus caudatus no more recognizable. (D and E) Intraoperative ECoG showing epileptiform activity in the frontal operculum (P, parietal lobe; F, frontal lobe; T, temporal lobe; the resection borders are delimited by the light blue line). Epilepsia ILAE

5 e42 F. Villani et al. The EPC did not recede despite several tentative treatments with AEDs (CBZ, LEV, VPA, and benzodiazepine [BDZ], and different immunomodulatory therapies (highdose and chronic steroids, IVIg, and plasmapheresis) produced only mild and temporary benefits. The neurologic examination revealed a progressive mild left hemiparesis. At the age of 33 years (7 years after epilepsy onset), the patient underwent cortectomy of the right frontal operculum corresponding to the face motor area, identified intraoperatively by means of cortical electrical stimulation and ECoG (Fig. 3D). Histopathologic examination confirmed the diagnosis of chronic encephalitis consistent with RE (Fig. 2F H). One year after surgery, scalp EEG showed mild slow and epileptic abnormalities located on the right centrotemporal regions. The EEG picture remained stable at a control performed 2 years after surgery. After 31 months of follow-up the patient is EPC free. She presented one secondary generalized seizure a few days after a BDZ dose reduction, 27 months after surgery. No adjunctive neurologic deficits and no progression of atrophy at MRI were observed after surgery. The patient is still treated with low doses of prednisone. Discussion The aim of RE treatment is twofold: (1) for seizure control and (2) to arrest or slow down the progression of brain hemiatrophy, thereby minimizing the long-term neurologic deficits that follow the acute or atrophic phase of the disease. Although according to Bien and Schramm 3 some promising, therapeutic options are now available for RE, the sources of therapeutic dissatisfaction are still multiple. First, seizure control is never completely achieved, and EPC is usually super-refractory to old and new AEDs or to shortterm intense immunomodulatory treatment that may be temporarily effective for SE and focal seizures other than EPC. 6,7 Second, although recent data suggest that treatments with some immunomodulatory agents such as tacrolimus, IVIg, or natalizumab (a T-cell central nervous system [CNS] entry blocker agent) may slow down disease progression, prevent development of intractable epilepsy, 2 and significantly reduce seizure frequency, 8 controlled studies are needed to test the effects of such treatments on disease progression. For all of these reasons surgery still remains the treatment of choice for RE: hemispherectomy and its functional disconnective variants 9 are considered the only effective epilepsy surgical approach to RE, 3 whereas more limited cortical resections have long been considered, at best, only transiently effective. 10 Hemispheric disconnection, however, may induce severe neurologic deficits, and may not be feasible in adolescents and adults with good neurologic function and the price to pay in terms of postsurgical neurologic deficits too high. This may trap the patient in a state of continuous refractory epilepsy, thereby severely impairing quality of life and exposing the patient to the risks of SE and its intensive treatments. Starting from this question related to the timing of surgery (when neurologic function is preserved, at least partially), we have presented the positive epilepsy outcome of two patients with adult-onset RE with super-refractory EPC and SE. In these patients, a limited cortical resection, defined on the basis of a highly congruent electroclinical picture (i.e., focal motor seizures arising from the primary motor area), was, in our opinion, the only meaningful choice available at that point in the presence of still well-preserved language (case 1) and motor (case 2) functions. The followup, being an average of 42.5 months, is sufficiently meaningful to consider the surgical outcome fairly stable. In case 1 the disease course was not modified by the surgical treatment: repeat EEG studies, clinical/neuropsychological examinations, and high-resolution MRI demonstrated a slow progression of aphasia; the appearance, 1 year after surgery, of infraclinical epileptic discharges on the diseased hemisphere; and progression of the cortical atrophy over the frontoinsular regions. Stopping the disease evolution must remain the main goal of any therapeutic intervention in RE. However, in this particular case, with the disease confined to the dominant hemisphere and in the course of a super-refractory SE, we felt that the result achieved was the best compromise possible at the time; the patient s life was preserved and its quality definitely improved after surgery. In case 2, on the contrary, the neurologic picture has remained stable at repeat EEG studies and clinical/neuropsychological tests. Furthermore, no progression in brain atrophy was observed by repeat MRI. Although our data suggest the feasibility of this conservative surgical option in highly selected clinical settings (adolescent/adult patients with preserved neurologic functions, slow disease progression, and limited extension of the epileptogenic zone), the available data and the expert opinion strongly suggest hemispheric disconnective surgery as the elective treatment for the more aggressive typical childhood-onset forms. Controlled comparison of the two surgical approaches to RE treatment is lacking in the literature. The past 10 to 20 years of RE surgical literature is almost completely devoted to hemispherectomy, and in the few cases treated with limited resections the seizure outcome is usually reported as poor. In our opinion, however, the available data suggest as worthwhile a conservative surgical approach, considering that most of the patients reported in different case series have been classified in Engel s class III after long-term follow-up. 11,12 In addition, rare positive results are reported when the epileptogenic zone is spatially limited, as in the cases reported by Ramesha et al. 13 and by Abd-El-Barr et al. 14 In the former case, EPC was located only in the tongue district, causing dysarthria. In this case the epilepsy outcome was optimal, with EPC abated still

6 e43 Cortectomy in Rasmussen Encephalitis after 24 months of follow-up, and no functional deficits were reported (dysarthria not present at follow-up). In the latter, an atypical case with signs of inflammation limited to the temporomesial structures, seizures were controlled for at least 2 years. No information is available, however, on the neurologic progression of the disease for these cases. From these reports it is not clear what prompted the decision to apply a more selective surgical procedure versus FH. Prognostic parameters, necessary to help in the decision of applying one or the other surgical technique, are definitely lacking. The available data on surgical treatment of RE, with seizure-free results on long-term follow-up from 62.5 to 85%, 1 advocates the early application of FH in the typical childhood-onset RE, usually characterized by a rapid and severe evolution. The absence of prognostic factors does not allow identification of the patients who most likely will be good responders to a more conservative surgical approach compared to FH. Our data and the few cases reported in the literature suggest that motor seizure with an easily recognizable and possibly spatially limited epileptogenic zone (i.e., facial motor area), a late onset, and slower disease progression may be predictive of a good seizure outcome for limited cortical resections, at least on a temporal span of three to five years. The disease course will not likely be changed by this approach, as our first case clearly showed. Larger case series with long follow-up are needed to be more conclusive at this regard. Acknowledgment Italian Ministry of Health and the Paolo Zorzi Association for Neurosciences. Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References 1. Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128: Bien CG, Tiemeier H, Sassen R, et al. Rasmussen encephalitis: Incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia 2013;54: Bien CG, Schramm J. Treatment of Rasmussen encephalitis half a century after its initial description: promising prospects and a dilemma. Epilepsy Res 2009;86: Villani F, Pincherle A, Antozzi C, et al. Adult-onset Rasmussen s encephalitis: anatomical-electrographic-clinical features of 7 Italian cases. Epilepsia 2006;47(Suppl. 5): Franzini A, Messina G, Marras C, et al. Deep brain stimulation of two unconventional targets in refractory non-resectable epilepsy. Stereotact Funct Neurosurg 2008;86: Granata T, Fusco L, Gobbi G, et al. Experience with immunomodulatory treatments in Rasmussen s encephalitis. Neurology 2003;61: Villani F, Spreafico R, Farina L, et al. Positive response to immunomodulatory therapy in an adult patient with Rasmussen s encephalitis. Neurology 2001;56: Bittner S, Simon OJ, G obel K, et al. Rasmussen encephalitis treated with natalizumab. Neurology 2013;81: Marras CE, Granata T, Franzini A, et al. Hemispherotomy and functional hemispherectomy: indications and outcome. Epilepsy Res 2010;89: Olivier A. Cortical resection for diagnosis and treatment of seizures due to chronic encephalitis. In Andermann F (Ed) Chronic encephalitis and epilepsy: Rasmussen s syndrome. Boston: Butterworth- Heinemann, 1991: Kim SJ, Park YD, Pillai JJ, et al. A longitudinal MRI study in children with Rasmussen syndrome. Pediatr Neurol 2002;27: Terra-Bustamante VC, Machado HR, dos Santos Oliveira R, et al. Rasmussen encephalitis: long-term outcome after surgery. Childs Nerv Syst 2009;25: Ramesha KN, Rajesh B, Ashalatha R, et al. Rasmussen s encephalitis: experience from a developing country based on a group of medically and surgically treated patients. Seizure 2009;18: Abd-El-Barr MM, Wu B, Rahman M, et al. Atypical Rasmussen s encephalitis treated with temporal lobectomy. J ClinNeurosci 2011;18: