Epilepsy: A Comprehensive Textbook
2nd Edition

Chapter 243
Rasmussen’s Encephalitis (Chronic Focal Encephalitis)
François Dubeau
Frédérick Andermann
Heinz Wiendl
Amit Bar-Or
Chronic encephalitis is a relentlessly progressive disorder of childhood, associated with hemispheric atrophy, severe intractable focal epilepsy, intellectual decline, and hemiparesis. The etiology of this disorder remains unknown. Neuropathologic features described in the surgical specimens show characteristics of inflammatory changes including perivascular and leptomeningeal lymphocytic infiltration, microglial nodules, astrocytosis, neuronal degeneration, and spongy degeneration. There are variants of this syndrome with regard to age at onset, staging, localization, progression, and outcome. Treatment options are limited: Antiepileptic drugs (AEDs) usually show no significant benefit, and immunotherapy trials, undertaken mostly after the 1990 s, showed modest transient improvement in symptoms and disease progression in some patients. Only surgery, and specifically hemispherectomy, seems to produce persistent relief of seizures and functional improvement.
Historical Perspective
Dr. Theodore Rasmussen (Fig. 1) first described the disorder in 1958, and, together with Jerzy Olszewski and Donald Lloyd-Smith, published the clinical and histopathologic features of three patients with focal seizures due to chronic focal encephalitis.119 The original proband, F.S., was referred in 1945 to Dr. Wilder Penfield by Dr. Edgar Fincher, chief of neurosurgery at Emory University in Atlanta, GA, because of intractable right-sided focal motor seizures starting at 6 years of age.120 The child developed a right hemiparesis and underwent, between 1941 and 1956, three surgical interventions (two at the Montreal Neurological Hospital and Institute [MNHI]) at 7, 10, and 21 years in an attempt to control the evolution of the disease. In the first chapter of the monograph on chronic encephalitis published by Dr. Frederick Andermann in 1991, Dr. Rasmussen reported a letter of Dr. Fincher to Dr. Penfield (dated 1956) urging him to consider a more extensive cortical excision and concluded, “I note in your discussion that you list the cause as unknown, but if this youngster doesn’t have a chronic low-grade encephalitic process which has likely, by now, burned itself out, I will buy you a new hat.” The last intervention was a left hemispherectomy performed by Dr. Rasmussen, and histology showed sparse perivascular inflammation and glial nodules. W. G. remained seizure free until his last follow-up (Fig. 2B). He had a mild intellectual handicap and a fixed right hemiplegia. He developed hydrocephalus as a late complication of the surgical procedure and required a shunt. Dr. Penfield, who was consulted in this case, remained skeptical of the postulate that the syndrome was a primary inflammatory disorder, but raised most of the issues that continue to be debated: If it is an encephalitic process, would it not involve both hemispheres? Is the encephalitic process the result of recurrent seizures due to a small focal lesion in one hemisphere? Why it is that epileptic seizures are destructive in one case and not in another? Dr. Rasmussen himself recognized that Fincher’s 1941 diagnosis of chronic encephalitis in FS’s case was made 14 years before case two of the original 1958 report (Fig. 2).119 The story does not say, however, whether Dr. Penfield had to provide his colleague and friend Dr. Fincher with a new hat.5
This entity, later recognized as “Rasmussen’s encephalitis (RE),” became the subject of extensive discussion in the literature, initially debating the best timing for surgery and best surgical approaches, and, more recently, the etiology and pathogenesis of this unusual and enigmatic disease. A large number of publications can be found in the literature, and two international symposia were held in Montreal, in 1988 and in December 2002, and one in Vienna, in June 2004.21 The interest in this disease was initially driven by the severity and inescapability of its course, which rapidly led to its description as a prototype of “catastrophic childhood epilepsy.”
Physicians and scientists became interested by the unusual pathogenesis and evolution of the syndrome and are now trying to reconcile the apparent focal nature of the disease with the postulated viral and autoimmune etiologies that may or may not be mutually exclusive. This chapter updates a number of issues regarding RE, particularly the putative mechanisms of the disease, the variability of the clinical presentations, and the indications and rationale of new medical therapies, such as immunomodulation and receptor-directed pharmacotherapy.
There are no data available regarding the incidence of RE in different populations. As the disorder has been increasingly recognized, reports and verbal communications from all parts of the world have emerged. This indicates that RE exists in every area, with the reports depending on the presence of pediatric neurologists and epileptologists. There are, however, no clusters of the disease in any particular region or population.
FIGURE 1. Theodore B. Rasmussen, Director Emeritus of the Montreal Neurological Institute.
Etiology and Pathogenesis of Rasmussen’s Encephalitis
The etiology and pathogenesis of RE remain unknown. Typical histologic features reported in surgical or autopsy specimens involve perivascular lymphocytic cuffing, microglial proliferation and nodule formation, neuronal loss, and gliosis in the affected

hemisphere (Fig. 3). The microglial nodules are associated with frequent nonspecific neuronophagia, and occur particularly near perivascular cuffs of lymphocytes and monocytes. There is limited evidence of spongiosis, which is not as widespread as in the true spongiform encephalopathies. Lesions tend to extend in a confluent rather than a multifocal manner. Finally, the main inflammatory changes are found in the cortex, and their intensity is inversely correlated with disease duration with slow progress toward a “burnt-out” stage.23,122 Three putative immune-mediated (inflammatory) mechanisms, which are not mutually exclusive, have been proposed to explain the initiation and unusual evolution of this rare clinical syndrome: (a) viral infections directly inducing central nervous system (CNS) injury, (b) a viral infection of the CNS that triggers a secondary autoimmune CNS process, and (c) a primary autoimmune CNS process. It remains possible that RE has a noninflammatory origin, and that the observed inflammatory responses merely represent a reaction to another unknown primary injury (Fig. 4).
The observation of inflammatory responses found within the lesions of RE has led to multifaceted approaches to uncover possible infectious or immune-mediated (humoral or cellular) etiologies. In general, epidemiologic studies have not been able to identify clear genetic, geographic, seasonal, or clustering effect, and have failed to demonstrate any association between exposure to various factors, including viruses, and the subsequent development of RE. There appears to be no consistent increase in reports of pre-existent febrile convulsions, nor an association with an infectious illness preceding or associated with the development of RE. Serologic studies to detect antecedent viral infection have been contradictory or inconclusive.7,8,43,49,77,99,101,115,121,151,154 The search for a pathogenic virus has so far mostly focused on the herpes virus family, and direct brain tissue analysis has also yielded inconsistent results.7,8,77,99,116 Presently, the role of an infectious agent and the viral hypothesis in the causation of RE remains, at best, uncertain. It should be noted, however, that a few patients were reported to improve with antiviral therapy.35,37,96,100
Studies of both systemic62,87,93,118,127,132,133 and cerebrospinal fluid (CSF) compartment immune responses still fail to indicate clear evidence of either ongoing or deficient immune reactivity.60 A primary role for pathogenic antibodies in the etiology of RE was proposed after Rogers et al.123 described that rabbits immunized with fusion proteins containing a portion of the GluR3 (glutamate receptor 3 subunit) receptor developed intractable seizures. On histopathologic examination, the brains of these animals exhibited changes characteristic of RE with perivascular lymphocytic infiltrates and microglial nodules. The subsequent finding of autoantibodies to GluR3 in the sera of some affected patients with RE led to the GluR3 autoantibody hypothesis of RE and allowed new speculation into disease pathogenesis. GluR3 autoantibodies may cause damage to the brain, and eventually epilepsy, by excitotoxic mechanisms. In the animal model, GluR3 autoantibodies appear to activate the excitatory receptor that leads to massive influx of ions, neuronal cell death, local inflammation, and further disruption of the blood–brain barrier, allowing entry of additional immune mediators.90,145 Another proposed mechanism suggests that GluR3 autoantibodies can cause damage by activating complement cascades that lead to neuronal cell death and further inflammation.70,158 These hypotheses prompted a number of open-label therapeutic attempts in order to modulate the immune system of patients, especially by removing or blocking the circulating factors presumably responsible for the disease.3,6,70,109,123,145,158 Among cases with no detectable anti-GluR3 antibodies, several were also described to respond well to immunosuppressive treatments.5,66,155 Other reports in several patients showed no response to plasma exchange.3,82 More recent work, however, has shown that anti-GluR3 antibodies are not specific for RE but can be detected in other neurologic disorders and particularly in non-RE patients with severe epilepsy. Since the sensitivity of detection is low for the RE population and the presence of GluR3 antibodies does not distinguish RE from other forms of epilepsy, the anti-GluR3 antibody test is not useful for RE diagnosis.12,95,155,159 It remains unclear whether GluR3 or other autoantibodies in various forms of epilepsy are actually responsible for the onset of the seizure disorder, whether their presence contributes to ongoing pathophysiology of an established syndrome, or whether they merely result as an epiphenomenon of an underlying degenerative or inflammatory process.19,54 Passive transfer of the disease into naïve animals remains unsuccessful so far, and additional animal models of this illness are lacking to finally corroborate the potential pathogenic role of these antibodies.
Various other autoantibodies against neural molecules have been described in RE: Autoantibodies against munc-18,163 neuronal acetylcholine receptor α-7 subunit,156 and NMDAAR2 A to 2D—specifically GluR epsilon2136—have been reported in a number of patients. Again, however, these autoantibodies were not present in all the RE patients, and they could also be detected in neurologic diseases other than RE. This indicates that none of the described autoantibodies is specifically associated with RE, and that a variety of autoantibodies to neuronal and synaptic structures can be found that may contribute to the inflammatory process, or possibly represent an epiphenomenon of an activated immune system.


It is noteworthy that careful analysis of antibody gene rearrangement in lesions of chronic encephalitis patients demonstrated local clonal expansion of antibody producing cells12; the exact role of these humoral immune elements in the pathogenetic cascade of RE remains elusive. In the report by Takahashi et al.,136 anti-GluR epsilon2 antibodies were present only in patients with epilepsia partialis continua (EPC; 15 subjects, including ten with histologically proven or clinical RE, three with acute encephalitis/encephalopathy, and two with nonprogressive EPC), and were directed primarily against cytoplasmic epitopes, suggesting the involvement of T-cell–mediated autoimmunity.
FIGURE 2. A: W. G., a boy with intractable seizures, right-sided hemiparesis, and hemiatrophy. This is the original patient described by Rasmussen. B: The course of W. G.’s illness.
FIGURE 3. Pathologic findings in Rasmussen’s syndrome: Perivascular infiltrates, microglial nodules, and neuronophagia.
Recent reports have indeed implicated a T-cell–mediated inflammatory response as another potential initiating or perpetuating mechanism in RE. Active inflammatory brain lesions contain large numbers of T lymphocytes,17 which appear to be recruited early within the lesions, implicating a T-cell–mediated immune response in the early evolution of the disease. Li et al.91 analyzed T-cell receptor expression in the lesions of patients with RE and found that the local immune response is characterized by restricted T-cell populations that have likely expanded from a small number of precursor T-cell clones, responding themselves to discrete antigenic epitopes. However, the nature of the antigens that trigger such a response is unknown. Recent work provides further credence to the hypothesis that a T-cell–mediated reaction, mainly consisting of cytotoxic CD8+ T-cell responses, may induce damage and apoptotic death of cortical neurons in RE.13,17,18 The demonstration of such cytotoxic T cells in close apposition to neurons suggests that RE might be a paradigm for a CD8-driven (auto) immune attack against neuronal structures. It is interesting to note that granzyme B, a toxic molecule secreted by CD8+ T cells upon interaction with a target, is capable of generating an antigenic epitope from the glutamate receptor.53 This observation might indicate a link between cellular and humoral immune components contributing to RE pathogenesis. In an attempt to integrate existing knowledge, several investigators13,17,19 have proposed a new scheme of pathogenesis. First, a focal CNS event initiates the process (e.g., infection, trauma, immune-mediated brain damage, even focal seizure activity) resulting in an immune reaction, involving antigen presentation in the CNS and entry of cytotoxic T lymphocytes into the CNS across the disrupted blood–brain barrier. Second, activated cytotoxic T lymphocytes attack CNS neurons while the inflammatory process, together with the release of cytokines, causes a spread of the inflammatory reaction and recruitment of more activated cytotoxic T lymphocytes. Third, the generation of potentially antigenic fragments, including GluR3, gives rise to autoantibodies, and may lead to an antibody-mediated “second wave of attack.” From an immunologic point of view, the typical adherence of the disease to one hemisphere still remains difficult to explain.

FIGURE 4. The “vicious cycle” hypothesis may explain Rasmussen’s encephalitis. Focal blood–brain barrier disruption facilitates entry of antibodies into the brain, with local neural injury and focal seizures. The focal seizures, in turn, cause focal transient blood–brain barrier disruption.
Clinical Presentations
Typical Course of the Disease
In the early stages of the disease, the major issue is diagnosis. A combination of characteristic clinical, electrophysiologic, and imaging findings aids in the diagnosis. The 48 patients initially studied at the MNHI were collected over a period of 30 years and consisted mostly of cases referred from all over the world. Although now easier to recognize, this entity remains rare. During the last decade, an additional ten patients were studied in our institution, a small number compared to the 100 to 150 patients with intractable focal epilepsy due to other causes studied each year in our center. Typically, the disease starts in healthy children aged 1 to 13 years (mean age, 6.8 years) with 80% developing seizures before the age of 10 years.106 There is no difference in incidence between the sexes. In approximately half the patients, a history of infectious or inflammatory episode was described 6 months prior to the onset of seizures.
The first sign of the disease is the development of seizures. They are usually partial or secondarily generalized tonic–clonic seizures or status epilepticus (20% of the patients in the MNHI series presented with status epilepticus as the first manifestation). Early seizures could be polymorphic with variable semiology, but motor seizures are almost always reported. Other variable semiology of seizures with somatosensory, autonomic, visual, and limbic features has been described.58,106 The seizures rapidly become refractory, with little response to AEDs. EPC and other forms of focal motor seizures are particularly unresponsive to AEDs.39,63,114,142 We reviewed the AED therapy of 25 patients of the MNHI series and found no specific agent or combination therapy that appeared to be more effective or less toxic than other regimens.39 Our experience with newer AEDs in seven other patients with RE did not support improved effectiveness or tolerability for the new agents (personal data). The new antiepileptic agents levetira-cetam and topiramate may theoretically have a role in the treatment of RE, the first because of its efficacy in treating cortical myoclonus51,56 and the second because of its direct effect on glutamate receptors and release of N-methyl-D-glutamine.103 A variety of seizure types develop over time; the most common are focal motor and EPC (described in 56% of the patients in the MNHI series), with scalp electroencephalogram (EEG) patterns suggesting perirolandic onset. EPC is characterized by recurrent, asynchronous, and persistent (observed during wakefulness and sleep) myoclonias involving different muscle groups of the face, hand, or leg of one hemibody. Secondarily, generalized motor seizures are also described in many patients, but these appear to be easier to control with AEDs. Other less frequent types of motor seizures are a Jacksonian march (12%), posturing (25%), and versive movements of the head and eyes (13%), suggesting involvement of the primary, premotor, and supplementary motor areas. Drop attacks, however, are rare. Focal seizures with somatosensory (22% of patients), visual (16%), or auditory manifestations (2%) are also less frequent and appear later in the course of the disease, suggesting that the epileptogenic process has migrated from frontocentral and temporal regions to more posterior cortical areas, with a characteristic anteroposterior hemispheric march of the disease.106
Oguni et al.106 divided the progression of the disease into three stages: Stage 1, from the onset of the seizures and before the development of a fixed hemiparesis (3 months to 10 years, mean duration, 2.8 years); stage 2, from the development of a fixed hemiparesis (in 100% of the patients) to the completion of neurologic deterioration, including intellectual decline (in 85%), visual (49%) and sensory (29%) cortical deficits, and speech problems (dysarthria, 23%; dysphasia, 19%) dependent or independent of the burden of seizure activity (2 months to 10 years, mean duration, 3.7 years); and stage 3, stabilization of the condition in which further progression no longer occurs, and even the seizures may decrease in severity and frequency or, after some improvement, become again severe, continuous, and debilitating.
A more recent study by Bien et al.23 presented the clinical natural history of RE in parallel with the time course of brain destruction as measured by serial magnetic resonance imaging (MRI) in a series of 13 patients studied histologically. They separated the progression of the disease into prodromal, acute, and residual stages, comparable to the three stages of Oguni et al. Bien et al. distinguished two patterns of disease determined by the age at onset of RE: One with an earlier and more severe and rapidly progressive disorder starting during childhood (mean age at first seizure, 4.4 years; range, 1.6 to 6.4 years) and a second with a more protracted and milder course starting during adolescence or adult life (mean age at first seizure, 21.9 years; range, 6.4 to 40.9 years), the second pattern representing a variant of RE repeatedly described, particularly during the last decade.1,66,82,86,99
Clinical Variants of Rasmussen’s Syndrome
Rasmussen’s syndrome has been known for more than 50 years, and over 200 cases have now been reported.21 After the initial description, it became clear that the disease is clinically heterogeneous despite the pathologic hallmark of nonspecific chronic inflammation in the affected hemisphere. This heterogeneity may be explained by different etiologies (viral, viral- and non–viral-mediated autoimmune disease), by different reactions of the host’s immune system to exogenous or endogenous insults (age, genetic background, presence of another lesion, or “double pathology”), and by the modulating effect of a variety of antiviral, immunosuppressant, and immunomodulatory agents, or receptor-directed pharmacotherapy used in variable combinations and durations to treat these patients.
Atypical or unusual clinical features include early onset, usually before 2 years of age, with rapid propagation of the disease; bilateral cerebral involvement; relatively late onset during adolescence or adult life with slow progression; atypical anatomic location of the initial brain MRI findings; focal, protracted, or subcortical variants of RE; and double pathology. Also, two brothers developing bihemispheric disease early in

life and with a fatal outcome for one were reported by Silver et al.128 The brain biopsy of one of the brothers showed changes indistinguishable from the classical form of the disease.
Bilateral Hemispheric Involvement
Usually the disease affects only one hemisphere, and most autopsy studies available confirmed unilateral cerebral involvement.122 Over time, however, there may be some contralateral ventricular enlargement and cortical atrophy attributed either to the effect of recurrent seizures and secondary epileptogenesis or to wallerian changes.85 Patients with definite bilateral inflammatory involvement are exceptional, and so far this has been described in no more than a dozen of them.31,37,67,99,128,135,141 Bilateral disease tends to occur in children with early onset (before 2 years). In these children, the disorder is usually fatal. Bilateral disease was also described in the late-onset adolescent or adult forms and is less severe in these patients. A small number had received high-dose steroids or an intrathecal antiviral agent, which suggested that early aggressive immunologic therapy may have predisposed to contralateral spread of the disease.37,135
Late-onset Adolescent and Adult Variants
A number of papers have reported the development of RE in adolescence or adult life as representing approximately 10% of the total number of patients with RE described in the literature over the last 40 years.1,23,32,50,59,66,71,82,84,86,89,99,104,131,146,147,157,164 In the MNHI series, 9 of 55 patients (16%) collected between 1945 and 2000 started to have seizures after the age of 12 years. The largest series, described by Hart et al.66 included 13 adults and adolescents collected from five centers. In comparison with the childhood form, late-onset RE has a more variable evolution,23,66 a generally more insidious onset of focal neurologic defects and cognitive impairment, and an increased incidence of occipital involvement (23% in the series of Hart et al. vs. 7% in children <12 years old in the MNHI series). Hemiparesis and hemispheric atrophy are often late and may not be as severe when compared with the more typical childhood form.23 Occasionally, however, the outcome in late-onset RE is similar to or worse than in children,59,99,104,131 but because of the generally more benign and protracted course, hemispherectomy seems less appropriate in this group of patients in whom neurologic deficits are usually less pronounced. Due to lack of brain plasticity in adults, the decision for hemispherectomy is even more complicated due to potential risk of new irreversible postoperative deficits.
Focal and Chronic Protracted Variants
There are rare reports of patients with RE whose seizures were relatively well controlled with AEDs or focal resections, and in whom the neurologic status stabilized spontaneously.66,71,88,164 Rasmussen had already suggested the existence of a “nonprogressive focal form of encephalitis.” With Aguilar, he reviewed 512 surgical specimens from 449 patients and found 32 cases with histologic evidence suggesting the presence of active encephalitis.1 Twelve patients demonstrated progressive neurologic deterioration compatible with RE, and 20 (4.4%) showed no or mild neurologic deterioration. In his review of patients who underwent temporal resections for intractable focal seizures, Laxer88 found five patients (3.8% of a series of 160 patients) with what he thought was a benign, focal, nonprogressive form of RE. These patients, children or adults, with no evidence of progression are indistinguishable clinically from those with refractory seizures due to other causes, including mesial temporal sclerosis.71,88
Delayed Seizure Onset Variant
Korn-Lubetski et al. recently reported on two children with the typical progressive clinical course and contralateral hemispheric atrophy characteristic for RE, but no clinical and EEG epileptic activity observed for several months.80 Both children had a brain biopsy (performed before seizure onset) confirming the clinical diagnosis. The focal seizures started in the first child 7 months after initial symptomatology and in the second after 6 months.
Basal Ganglia Involvement
Epilepsia partialis continua and other types of focal motor seizures are a common finding in patients with RE. Chorea, athetosis, and dystonia were infrequently described and may have been overlooked because of the preponderance of the epileptic disorder and of the hemiparesis. In 27 of the 48 patients of the MNHI series who had EPC, nine additionally had writhing or choreiform movements, and a diagnosis of Sydenham chorea was made in three of them early in the disease course.106 Matthews et al.97 described a 10-year-old girl with a 1-year history of progressive right-sided hemiparesis, EPC, and secondary generalized seizures. MRI showed diffuse cortical and subcortical changes, maximum in the perisylvian frontotemporoparietal area. At examination, she had choreic movements of the right arm and hand in addition to EPC. Tien et al.140 were the first to describe in an 8.5-year-old girl with intractable focal motor seizures and atrophy of the caudate and putamen, with abnormal high signals and severe left hemispheric atrophy. They interpreted these findings as the result of gliosis and chronic brain damage. Topçu et al.142 described a patient who developed hemidystonia as a result of involvement of the contralateral basal ganglia. The movement disorder appeared 3 years after onset of seizures. A rather typical subsequent evolution suggested RE. The movement disorder started during intravenous immunoglobulin (IVIg) and interferon therapy, and did not respond to anticholinergic drugs nor to a frontal resection. Ben-Zeev et al.,15 Koehn and Zupanc,79 Frucht,50 and, finally, Lascelles et al.87 each reported a case of RE whose clinical presentation was dominated by a hemidys-kinesia, with EPC in three of those patients, and progressive hemiparesis. Two cases showed selective frontal cortical and caudate atrophy on MRI, one developed progressive left basal ganglia atrophy and later focal frontotemporoparietal atrophy, and one had only pronounced right caudate, globus pallidus, and putamen atrophy. In the case of Frucht, IVIg dramatically improved both the hyperkinetic movements and the EPC, but the effect was transient, suggesting a common neuroanatomic mechanism or humoral autoimmune process. In a series of 21 patients with RE, Bhatjiwale et al.16 looked specifically at the involvement of the basal ganglia. Fifteen (71%) showed mild to severe basal ganglia involvement on imaging in three different patterns: Predominantly cortical in six cases, predominantly basal ganglia in six, and with both cortical and basal ganglia involvement in six. In five cases, the changes found in the basal ganglia were static, whereas in the others there was steady progression. The caudate nucleus was generally more prominently involved, usually in association with frontal atrophy. Five cases also showed putaminal involvement, always with temporoinsular atrophy. Interestingly, two of the six patients with prominent basal ganglia involvement had dystonia as a presenting feature. The authors postulated that the disease may proceed from different foci, including cases where RE seems to start in deep gray matter. The Italian Study Group recently described similar findings on Rasmussen’s encephalitis,30 which found basal ganglia atrophy in 9 of 13 patients studied. They suggested that atrophy of the basal ganglia represents secondary changes due to disconnection from the affected overlying frontal and insular cortex.

Brainstem Variant
McDonald et al.98 reported a 3-year-old boy with RE manifested by chronic brainstem encephalitis. After a prolonged febrile seizure associated with an acute varicella infection, he developed within a few weeks recurrent partial motor seizures, EPC, and left hemiparesis. After a few more weeks, signs of brainstem involvement appeared; repeated MRI showed increased signal in the pons, but a complete infectious and inflammatory evaluation, including brain biopsy, was negative. He died 14 months after the onset of his illness. Neuropathologic findings in the brainstem were typical of those found in RE. Bilateral mesial temporal sclerosis was also present. The authors proposed that this case represents a rare focal form of RE with primary involvement of the brainstem, and hemiparesis and mesial temporal sclerosis resulting from seizure activity. One other patient with brainstem involvement and fatal outcome was included in the MNHI series of 48 patients.106
Multifocal Variant
Maeda et al.94 described a 6-year-old girl with typical RE. One year following the onset of seizures, MRI–fluid-attenuated inversion recovery (FLAIR) sequences showed multiple high-signal-intensity areas in the right hemisphere and a methionine–positron emission tomography (PET) performed at the same time exhibited multifocal methionine uptake areas concordant with the MRI lesions, suggesting multiple independent sites of chronic inflammation. The authors proposed that the inflammatory process in RE may spread from multifocal lesions and not necessarily originate from localized temporal, insular, or frontocentral lesions, as usually described, before spreading across adjacent regions to the entire hemisphere.
Double Pathology
A small number of reports have documented coexisting brain pathologies with RE: A tumor (anaplastic astrocytoma, ganglioglioma, and anaplastic ependymoma) in three patients,46,65,83 dysgenetic tissue in four,65,110,122,161 multifocal perivasculitis in seven,122 and cavernous angiomas with signs of vasculitis in two.21,51 Double pathology in RE supports the theory of a focal disruption (trauma, infection, or other pathology) of the blood–brain barrier allowing access of antibodies produced by the host to neurons expressing the target receptor and production of focal inflammation.5,145 So far, however, only one case of double pathology provided reasonable support to this hypothesis.110 Strongly positive anti-GluR3 antibodies were measured in one case of RE with concomitant cortical dysplasia in a 2.5-year-old girl with catastrophic epilepsy starting at age 2. She underwent a right, partial frontal lobectomy, plasmapheresis, and therapy with IVIg with a transient response, and finally a right functional hemispherectomy with good seizure control. GluR3 antibodies were measured serially throughout the course of her treatment and correlated with her clinical status. They were undetecTable 1 year after her last surgery.
There are also reports of coexisting autoimmune diseases such as Parry-Romberg syndrome,127,133 linear sclero-derma,118,132 and systemic lupus erythematosus87 with epilepsy and pathologic changes suggestive of RE. The clinical course in these patients, however, was not as severe as that of the classic childhood form. Changes of chronic progressive or smoldering encephalitis have also been described in disorders with impaired immunity such as agammaglobulinemia93 and multiple endocrinopathies, chronic mucocutaneous candidiasis, and impaired cellular immunity.62 The occurrence of two conditions presumably due to impaired immunity in the same individual may strengthen the view that immune-mediated mechanisms are responsible for the development of RE.
Lagrange et al.84 recently reported an interesting case of new-onset seizures and narcolepsy in a previously healthy 40-year-old man. The patient developed within 2 years daytime sleepiness and cataplexy, followed, after a course of few months, by protracted but refractory focal epilepsy and a progressively enlarging lesion in the temporoinsular region. Pathology from a left temporal resection was consistent with RE. An extensive infectious, autoimmune, and paraneoplastic workup was negative, but CSF hypocretin was undetectable and HLA haplotype of the patient was DQB1*0602. The authors proposed a common underlying disease process, possibly autoimmune, to explain in this patient the coincidence of two rare cerebral disorders.
Finally, the rare association of uveitis (three cases) or choroiditis (one case) with typical features of RE have led to the speculation that a viral infection may have been responsible for both.52,59,69 In all cases, the ocular pathology was ipsilateral to the involved hemisphere that showed chronic encephalitis. In three cases,59,69 the uveitis or choroiditis was detected 2 to 4 months after epilepsy onset. In one case,52 ocular diagnosis preceded the onset of chronic encephalitis. In light of these reports, it was hypothesized that a primary ocular infection, in particular a viral infection with herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), measles, or rubella, followed by vascular or neurotropic spread to the brain, was a possible mechanism for development of RE.
Diagnostic Evaluation
Electroencephalographic Findings
Few studies specifically reported the EEG changes associated with RE,10,11,40,58,75,129 and even fewer tried to correlate the clinical and EEG features of the disease over time. So and Gloor129 reported the scalp and peroperative (electrocorticogram [ECoG]) EEG findings in the MNHI series of patients with RE. They summarized the EEG features as (a) disturbance of background activity in all except one patient with more severe slowing and relative depression of background rhythms in the diseased hemisphere; polymorphic or rhythmic delta activity was found in all (more commonly bilateral with lateralized preponderance); (b) interictal epileptiform activity in 94% of patients, rarely focal (more commonly multifocal and lateralized to one hemisphere or bilateral independent, but strongly lateralized discharges with or without bilateral synchrony); (c) clinical or subclinical seizure onsets were variable and occasionally focal, but more often poorly localized, lateralized, bilateral, or even generalized; and (d) no clear electroclinical correlation apparent in many of the recorded seizures, in particular in EPC. The electrographic lateralization of these abnormalities (focal slowing, progressive deterioration of unilateral background activity, and ictal and multifocal interictal hemispheric activity) was sufficiently concordant with the clinical lateralization to provide essential information about the abnormal hemisphere in 90% of cases. These EEG features, indicative of a widespread destructive and epileptogenic process, in the specific clinical context of catastrophic epilepsy and worsening neurologic deficits involving one hemisphere, suggest the diagnosis of chronic encephalitis.
FIGURE 5. Computed tomography scan of a boy with Rasmussen’s syndrome. A: Three months after onset of seizures. B: Two years later. Severe parenchymatous atrophy and ventricular enlargement are apparent on the right.
The evolution of the EEG has been studied longitudinally in a small number of patients.4,14,26 The studies showed progression of the EEG abnormalities. At the onset of the disease, EEG abnormalities tend to be lateralized and nonspecific, with unilateral impoverishment and slowing of background activity during wakefulness and progressive disappearance of spindles

during sleep in the diseased hemisphere. As the disorder progressed, the epileptiform and slow-wave abnormalities tend to become bilateral and widespread, multifocal, or synchronous, suggesting a more diffuse hemispheric process, not always confined to one hemisphere. It is not clear if the late bilateralization of the EEG abnormalities represents functional interference, secondary epileptogenesis, or, much less likely, evidence for the inflammatory process directly involving the contralateral hemisphere.
Only one report has been published so far on the usefulness of MEG in the evaluation of patients with RE.76 MEG may provide insight on cortical function and useful information about cortical reorganization, for instance, before and after hemispherectomy.
Anatomic Imaging
Imaging studies, although not specific, are extremely important for the diagnosis of RE. Typically, they show progressive lateralized atrophy coupled with localized or lateralized functional abnormalities.16,22,23,30,42,45,47,58,76,114,137,140,149 Brain MRI studies early in the course of the illness may be normal, rapidly followed by a combination of characteristic features that parallel the clinical and electrophysiologic deterioration, reflecting the nature of the pathologic process. Recent studies using serial MRIs in a relatively large number of patients with RE provided better insight into the early, progressive, and late gray and white matter changes expected in this disease: Cortical swelling; atrophy of cortical and deep gray matter nuclei, particularly the caudate; a hyperintense signal in gray and white matter; and secondary changes.16,22,23,30,58 In the early phase of the disease, when the MRI still appears normal, a few studies demonstrated abnormalities of perfusion or metabolism by single photon emission computed tomography (SPECT) or PET, suggesting that these imaging procedures may aid in early identification of the disease and of the abnormal hemisphere.25,45,47,140 Rapidly on early MRI scans, however, the cortex shows focal hyperintense signals on T2 or FLAIR sequences30 and may appear swollen. This can be explained by brain edema at the onset of inflammation22 or, alternatively, it may be due to recurrent focal seizures.124 Very early signal change in the white matter (within 4 months) is also frequent, usually focal, with or without swelling.30 Later, progressive atrophy of the affected hemisphere occurs, reflecting the manner in which the disease spreads, and with most of the hemispheric volume loss occurring during the first 2 years22,30 (Figs. 5 and 6). The cortical atrophy is initially either temporal, frontoinsular, or frontocentral, and more rarely parieto-occipital, later spreading across the hemisphere. Basal ganglia involvement, mostly of the putamen and caudate, is also characteristic and may be due to direct damage by the pathologic process or secondary to changes due to disconnection of the basal ganglia from the affected overlying frontocentral and insular cortices.16,30 Other secondary changes usually associated with severe hemispheric tissue loss are atrophy of the brainstem, particularly of the cerebral peduncle and pons; thinning of the corpus callosum; and atrophy of the contralateral cerebellar hemisphere.98 Surprisingly, gadolinium enhancement on MRI is rarely observed.22,30,45,105,146,161,165

FIGURE 6. Magnetic resonance imaging in a 15-year-old boy with a 7-year history of Rasmussen’s syndrome. Axial (A) and coronal (B) images showing hemispheral and focal atrophy on the left.
Functional Imaging
Several studies, often case reports, emphasize the utility of functional imaging such as PET, SPECT, and proton magnetic resonance spectroscopy (MRS) in the diagnosis and follow-up. Functional abnormalities may be useful in cases in which MRI is normal, usually at the onset of the disease, or when structural imaging fails to provide satisfactory localizing information. Combined anatomic and functional neuroimaging may serve to focus the diagnostic workup, hasten brain biopsy for definitive diagnosis, or define the appropriate surgical approach. It may be useful to follow the evolution of the disease or the result of treatment. Finally, functional studies may provide insight into the cortical reorganization of speech areas and of motor and somatosensory cortices.
Fiorella et al.45 reviewed 18F-fluorodeoxyglucose (FDG)-PET and MRI studies of 11 patients with surgically proven RE. All had diffuse, unilateral cerebral hypometabolism on PET images, closely correlated with the distribution of cerebral atrophy on MRI. Even subtle diffuse atrophic changes were accompanied by marked decreases in cerebral glucose utilization that, according to the authors, increased diagnostic confidence and aided in the identification of the abnormal hemisphere. During ictal studies, patients had multiple foci of hypermetabolism, indicative of multifocal seizure activity within the affected hemisphere, and never showed such changes in the contralateral one. Fogarasi et al.47 also compared MRI and FDG-PET studies in children with RE (five from their own series and eight taken from the literature), emphasizing early metabolic changes and the complementary roles of structural and functional neuroimaging in the early diagnosis of RE. In five cases, the PET changes occurred before any lesions appeared on MRI (the time between seizure onset and functional changes was 1 to 8 months). Similar findings have been reported previously but in smaller series.30,41,64,74,78,105,140,165 Although MRI alone is generally sufficient to identify the affected hemisphere, FDG-PET unequivocally confirms the findings in each case. Blood flow or perfusion studies using O15 PET showed a similar correlation, with regions of perfusion change corresponding with structural MRI changes.74 Using a specific radioligand ([11C](R)-PK11195) for peripheral benzodiazepine binding sites on cells of mononuclear phagocyte lineage, Banati et al.9 demonstrated in vivo the widespread activation of microglia in three patients, confirming what is usually found by neuropathologic study.
SPECT was used to study regional blood flow in a number of patients.2,25,30,41,55,68,74,76,108,114,142,150,162 The findings may be of some help and more sensitive than anatomic neuroimaging early in the disease, but are nonspecific. As with FDG-PET, the regions of functional change usually correlate with anatomic abnormalities. Interictal SPECT scans reveal diminished perfusion in a large zone surrounding the epileptic area shown on EEG. This hypoperfusion may show some variability depending on fluctuation of the epileptic activity. Ictal studies often show zones of hyperperfusion representing likely areas of more intense seizure activity. Sequential scans may be helpful to follow the progression of the disease42 or the effect of treatment.150
Table 1 Criteria for (Early) Diagnosis of Rasmussen’s Encephalitis
  • Refractory focal motor seizures rapidly increasing in frequency and severity, and often polymorphic
  • Epilepsia partialis continua
  • Motor, progressive hemiparesis and cognitive deterioration
  • Focal or regional slow-wave activity contralateral to motor manifestations
  • Multifocal, usually lateralized, interictal and ictal epileptiform discharges
  • Progressive lateralized impoverishment of background activity
  • MRI: Focal cortical swelling with hyperintensity and white matter signal hyperintensity, insular cortical atrophy, atrophy of the head of caudate nucleus, and progressive gray and white matter atrophy, unilateral
  • PET: Unilateral, hemispheric, but during early stage may be restricted to frontal and temporal regions, glucose hypometabolism
  • SPECT: Unilateral interictal hemispheric hypoperfusion and ictal multifocal hyperperfusion
  • MRS: Unilateral reduced NAA and increased lactate, choline, myo-inositol, and glutamine/glutamate
  • None, except inconsistent finding of anti-GluR3 and other autoantibodies
  • None, except sometimes presence of oligoclonal bands and inconsistent elevated levels of anti-GluR3 and other autoantibodies
  • Microglial nodules, perivascular lymphocytic infiltration, neuron degeneration, and spongy degeneration; evidence for local clonal expansion of T cells and antibody-producing cells
  • Combination of active and remote, multifocal, intracortical, and white matter lesions
CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; PET, positron emission tomography; SPECT, single photon emission computed tomography.
MRS has been used in a number of patients with RE.29,30,97,112,113,125,126,134,144,150 Localized proton MRS was described for the first time in two patients by Matthews et al.97 They showed reduced N-acetylaspartate (NAA) concentrations—a compound exclusively found in neurons and their processes—in diseased areas in both patients, suggesting neuronal loss. In addition, MRS showed increased lactate in a patient with EPC, probably the result of excessive and repetitive seizure activity. Peeling and Sutherland113 and Cendes et al.29 confirmed those findings. Peeling and Sutherland also showed that the concentration of NAA in vitro (MRS on tissue obtained from surgical patients) was reduced in proportion to the severity and extent of the encephalitis. Cendes et al. did sequential studies at 1 year in three patients and demonstrated progression of the MRS changes. They noted that those changes were more widespread than the structural changes seen on anatomic MRI. Overall, the studies using NAA indicate

that MRS can identify and quantify neuronal damage and loss throughout the affected hemisphere, including areas that appear anatomically normal. In addition to NAA and lactate, other compounds measured included choline, creatine, myo-inositol, glutamine, and glutamate. Choline is usually elevated, which probably indicates demyelination and increased membrane turnover.29,55,126,134 Myo-inositol, a glial cell marker, was found to be elevated in a small number of patients,55,125,144 indicating glial proliferation or prominent gliotic activity. Hypothetically, myo-inositol signal should increase with the progression of the disease. Lactate was almost always elevated, and this increase probably results from ongoing or repetitive focal epileptic activity rather than from being a marker of the inflammatory process itself.95,96,97,99 The largest peaks in lactate were usually detected in patients with EPC. Glutamine and glutamate levels were also elevated, only in two patients, a finding of interest considering the potential role of excitatory neurotransmitters in the disease.55
There are only two reports on diffusion MRI changes observed in three cases of RE.125,126 These preliminary studies showed that diffusion MRI may provide data on brain tissue integrity and allows easy comparisons between the diseased and normal parenchyma.
Differential Diagnosis
The clinical changes of RE are nonspecific, particularly at the beginning of the disease, and clearly at this stage the major issue is diagnosis. We have better diagnostic criteria that can lead to early diagnosis (Table 1, and the Vienna consensus statement on RE held at the sixth European Congress on Epileptology, June 200421). The onset in a previously healthy child is of increasing frequency, and severe, simple focal, usually motor seizures often followed by postictal deficit. This, and lack of evidence of anatomic abnormalities on early brain MRI, should raise suspicion regarding the diagnosis of RE. Further course and evaluation with scalp EEG showing unilateral findings with focal or regional slowing, deterioration of background activity, multifocal interictal epileptiform discharges, and seizure onset or EPC, particularly corresponding to the cortical motor area, are major neurophysiologic features in favor of RE. Early MRI characteristics include the association of focal white matter hyperintensity and cortical swelling with hyperintense signal, particularly insular and peri-insular regions. This is later followed by hemispheric atrophy that is usually predominant in the peri-insular and frontal regions and the head of the caudate nucleus contralateral to the clinical manifestations. Functional imaging studies may reveal abnormalities before any visible structural changes. Typically, FDG-PET shows diffuse hemispheric glucose hypometabolism. SPECT shows unilateral interictal hypoperfusion and ictal multifocal areas of hyperperfusion, confirming the lateralized hemispheric nature of the lesion and its extent. MRS may also help in the early detection of brain damage and shows a lateralized decrease in NAA intensity relative to creatine, suggesting neuronal loss or damage in one hemisphere. There is no consistent systemic and CSF response that may contribute to the diagnosis, and, in fact, the most common feature is the lack of cellular or protein response in the CSF of patients with RE. Brain biopsy is often used as a diagnostic tool in many centers for confirming the diagnosis. However, histologic findings in RE are nonspecific chronic inflammatory changes that may be subtle enough to be missed by an inexperienced pathologist. Furthermore, the brain involvement may be patchy, and a normal biopsy does not rule out the diagnosis of RE.44,111,122 In more experienced centers, brain biopsy is not considered diagnostic of RE, and the key features remain the clinical evolution and the presence of progressive atrophy on repeated MRI scans. The European consensus group proposed a series of diagnostic criteria, and a two-step approach, to help the (early) diagnosis of RE.21
The differential diagnosis is from focal cortical dysplasia, hemimegalencephaly and some neurocutaneous disorders (such as tuberous sclerosis, Sturge-Weber syndrome, and

linear sebaceous nevus syndrome), mitochondrial encephalopathy (such as mitochondrial encephalopathy with lactic acidosis and strokelike episodes [MELAS]), brain tumors, cerebral vasculitis, degenerative cortical gray matter diseases (such as Kufs disease and Alpers syndrome), some forms of meningoencephalitis (such as Russian summer meningoencephalitis and subacute sclerosing panencephalitis), some paraneoplastic syndromes, and maybe rare chromosomal epileptogenic disorders (such as the ring-20 chromosome).21,28 EPC can be found in many of those conditions, but each has its own clinical and laboratory characteristics that usually distinguish it from RE. Although several diagnostic criteria have recently been proposed, especially for an early diagnosis of RE, the correct identification of patients with this disease remains a matter of experience, particularly if specific investigative or therapeutic interventions are considered. When a constellation of clinical and laboratory findings highlights the possibility of RE, close follow-up is necessary to assess progression of the disease and eventually confirm its diagnosis.
Treatment and Outcome
The typical evolution of RE is characterized by the development of intractable seizures, progressive neurologic deficits, and intellectual impairment. This has led clinicians to try a variety of empiric treatments, including antiviral agents and immunomodulatory or immunosuppressive therapies. Surgery, and specifically hemispherectomy, appears to be successful in controlling the disease process and arresting the seizures. However, the ensuing neurologic deficits due to surgery usually lead to reluctance to carry out this procedure until significant hemiparesis or other functional deficit has already occurred. Apart from the surgical treatment, there is no established treatment of RE. The natural history suggests that the disease burns itself out with maximal residual deficit and reduction, but not cessation of the seizures. On the other hand, anecdotal evidence suggests that in some patients, long-term recurrent seizures may lead to contralateral epileptogenicity by a mechanism of secondary epileptogenesis as opposed to bilateral disease development.
Antiepileptic Drug Therapy
Guidelines for AED treatment in RE are difficult to define and have always empirical. No AED, or any polytherapy regimen, has been proven to be superior,114 and the choice of the ideal AED rests on its clinical efficacy and side effect profile. Because of the nature of this disease, the danger of overtreatment is high. AED pharmacokinetics, toxicity, and interactions may be better determinants of AED selection and combination therapy. EPC is particularly difficult to treat, but AEDs can reduce the frequency and severity of other focal and secondarily generalized seizures. Since the original report on AED efficacy in RE,114 several new agents have been introduced. Drugs such as topiramate that act on excitatory neurotransmitters or those that may affect cortically generated myoclonus, such as levetiracetam in EPC, may have a more specific role in treatment.
Antiviral Therapy
Most treatments directed at aborting the progression of the disease were based on the assumption that RE is an infectious, a viral, or an autoimmune disorder. Examples of antiviral treatments are scarce, and only two reports37,100 are published: One on the treatment of four patients with ganciclovir, a potent anticytomegalovirus drug, and another on the treatment of a single patient with zidovudine. Although definite improvement was documented in four of the five patients, no further reports using antiviral agents in RE have been published.
Immune Therapy
Evidence implicating humoral and cellular immune responses in the pathophysiology of RE has led to various therapeutic initiatives.19 A number of case reports and small series suggesting potential therapeutic roles of immune-directed interventions have now been published. These included interferon, steroids, IVIg, plasmapheresis, selective IgG immunoadsorption by protein A, and immunosuppression with drugs such as cyclophosphamide or tacrolimus. Rarely, such approaches have been associated with sustained cessation of seizure activity and arrest in the progression of the inflammatory process. In the majority of the cases, only transient or partial improvements due to immunomodulators or immunosuppressors have been noted. Of importance is the observation that, to date, the more aggressive immune therapies have been deferred to later stages of the disease, where the burden of the disease is considered to outweigh the toxicity of these interventions. The challenge is to develop safe therapeutic protocols that can be tested in patients soon after the diagnosis, and at a time when less damage has occurred and the process may have a better chance to respond to therapy. Also, different approaches or protocols may be envisaged depending on the time of onset, progression, severity, and hemispheric localization of the disease.21,57,67
Intraventricular interferon-α has been tried in only two children35,96 with the rational that interferons have both immunomodulating (enhancement of phagocytic activity of macrophages and augmentation of the cytotoxicity of target-specific lymphocytes) and antiviral activity (inhibition of viral replication in virus-infected cells). In both cases, improvement of the epileptic and neurologic syndrome was observed.
Relatively low- and high-dose steroid regimens (dexamethasone, prednisone, methylprednisolone, and adrenocorticotropic hormone [ACTH]) were used either alone or in association with other agents such as IVIg. Initial reports were somewhat disappointing,93,114 but eventually the use of high-dose IV boluses led to encouraging results. When applied during the first year of the disease, pulse IV steroids appeared effective in suppressing, at least temporarily, the inflammatory process in some patients.31,67,82,150 The proposed modes of action of steroids include an antiepileptic effect, an improvement of blood–brain barrier function—and hence reduction of entry into the brain of potentially deleterious toxic or immune mediators—and a direct anti-inflammatory effect. Steroids may be helpful when used in pulses to stop status epilepticus.57 The long-term risk/benefit profile of steroids in RE remains unknown; in the Dulac series of 17 patients treated with steroids, all eventually required treatment by hemispherectomy (O. Dulac, personal communication). Because of a less favorable response and the adverse effects of prolonged high-dose steroids, Hart et al.67 suggested the use of IVIg as initial treatment followed by high-dose steroids, or both, to control seizures.
Walsh used for the first time IVIg in RE153 in a 9-year-old child who received repeated infusions of IVIg over a period of several months with initial improvement, but later

followed by protracted deterioration and eventual cessation of the treatment. Eight subsequent studies reported on the effect of IVIg, alone or in combination with other treatment modalities.27,67,82,89,147,150,153,160 These reports have shown similar results with initial benefit, but a much less clear-cut, long-term effect. They indicated variable results, ranging from no benefit to significant improvement, maintained in a single case for a period of close to 4 years.160 IVIg is usually much better tolerated than steroids. The basis for a potential therapeutic effect of immune globulin in RE is not known, but may reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. Leach et al.89 showed a delayed but more persistent response in two adults and suggested that IVIg is more effective in adults than in children. They also proposed that IVIg might have a disease-modifying effect. This phenomenon is probably real, but to date, no one has shown that the early use of immune therapy can modify the long-term outcome of RE. IVIg treatments are usually well tolerated and complications are rare.
Plasmapheresis and Selective IgG Immunoadsorption
Plasma exchange is used with the assumption that circulating factors, likely autoantibodies, are pathogenic in at least some patients.3,6,82,109,123 The majority of patients treated with apheresis showed repeated, at times dramatic, but transient responses. Because of the lack of long-term efficacy, the complications, and the expense, plasmapheresis should probably be used as adjunctive therapy and may be especially useful in patients with acute deterioration, such as status epilepticus.3,57
Immunosuppressive Therapy
One study reported a single patient treated with intermittent cyclophosphamide,82 suggesting the possibility of steroid-sparing treatment with intermittent pulse IV cyclophosphamide for patients with steroid-responsive RE. The authors proposed that such intermittent cyclophosphamide might well replace steroid therapy because it is associated with less risk of systemic complications. Granata et al.,57 however, observed no consistent effect in four patients with RE treated with cyclophosphamide for a period of approximately 6 months (range, 2 to 10 months).
Based on the notion that T-cell–mediated processes play a role in the pathogenesis of RE,13,17,18,53,91 a recent study tested the effects of tacrolimus (FK-506) in RE.20 Tacrolimus is an immunosuppressant that is successfully used in the prevention of transplantation reactions and preferentially acts on T cells. Seven patients with RE were treated with tacrolimus and followed for a median of 22.4 months. They were compared with 12 historical untreated RE patients (median follow-up, 13.9 months). The tacrolimus-treated patients had a superior outcome regarding neurologic function and progression rate of cerebral hemiatrophy, but no better seizure outcome. None of the treated patients (but 7 of 12 control patients) became eligible for hemispherectomy, suggesting that here again, the immunosuppressive therapy at least modified the natural course of the disease. Tacrolimus appeared to have no major side effects.20
Azathioprine (150 mg/day) was used in one of our patients for approximately a year (personal data), 4 years after the beginning of her epilepsy (seizure onset was at 12 years old) and after two limited frontal lobe resections. During the same period, she received IV pulses of steroids and IVIg for periodic acute exacerbations of her epileptic condition. The immunosuppressant drug was finally stopped and replaced by periodic IVIg without significant changes in the course of the disease.
The only effective surgical procedure seems to be the resection or disconnection of the abnormal hemisphere.38,48,81,117,143,148,149 Alternative procedures such as partial corticectomy, subpial transaction, and callosal section have limited results and did not render patients seizure free.73,102,107,114,130 The recent publications by Kossoff et al.81 and by Pulsifer et al.117 clearly demonstrated the benefits of hemispherectomy in children with RE. They showed that 91% of 46 children (mean age at surgery, 9.2 years) with severe RE who underwent hemispherectomy (in the majority hemidecortication) between 1975 and 2002 became seizure free (65%) or had nondisabling seizures (26%) that often did not require medications. Patients were walking independently, and all were talking at the time of their most recent follow-up with relatively minor or moderate residual speech problems. Twenty-one had left-sided pathology (presumably involving the dominant hemisphere) with a mean age at surgery of 8.8 years. A subset of 37 children was further followed to assess cognitive outcome (a mean of 5.5 years after surgery). The majority remained seizure free (73%) at the time of follow-up, and 70% attended school, half only with supportive services.
Hemispherectomy, hemidecortication, functional hemispherectomy, or hemispherotomy have proven efficacy for control of seizures in patients with RE. The decision on how early in the course of the disease surgery should be undertaken depends on the certainty of the diagnosis, the severity and frequency of the seizures, and the impact on the psychosocial development of the patient. The natural evolution of the disease and the severity of the epilepsy often justify early intervention, even prior to maximal neurologic deficit. The decisions about such a radical procedure requires considerable time and thought. The recent use of immunomodulating agents may have been responsible for the considerable reduction in hemiparesis, which increases the difficulty in deciding on hemispherectomy. There is, however, no evidence that these treatments lead to a favorable end-point in the evolution of the disease. Also, the psychological preparation of the patients and their families is essential.61,149 Finally, involvement of the dominant hemisphere by the disease process provides important observations on brain plasticity, especially on the shift of language.24,33,34,36,72,92,138,139,152 Recent reports looking at language outcomes after long-term RE, serial Amytal tests, functional MRI studies, and hemispherectomy illustrate the great plasticity of the child’s brain and the ability of the nondominant hemisphere to take over some language function even at a relatively late age.
Long-term Prognosis
Progression is characteristic of the disease, although there is some variability in the rate of advance. The advent of immunomodulating therapy has most likely been the reason for lesser tissue loss and atrophy, which leads to maintained motor function. This makes surgical decision difficult. Following hemispherectomy, residual minor seizures, usually involving the face, may persist. Bilateral involvement by the original disease process has been described, mainly in children with early onset. There is, however, no good evidence for eventual contralateral spread over time in most patients. Secondary epileptogenesis without evidence for bilateral disease may occur, and personal observations suggest that this is more

likely to happen in children in whom surgical treatment was delayed.
Summary and Conclusions
Rasmussen’s encephalitis, although a rare disorder, is now much better delineated and understood by both the wider clinical and scientific community. However, recognition of the disease in a naïve patient to make an early diagnosis continues to be a challenge. Although confirmation of the clinical diagnosis of RE rests on pathologic findings, in vivo combinations of diagnostic approaches such as clinical course, scalp EEG findings, and high-resolution repeated MRI suggest the diagnosis with a high degree of accuracy. The syndrome also appears more clinically heterogeneous than initially thought: More localized, protracted, or slowly progressive forms of the disease have now been described, suggesting that distinct pathophysiologic mechanisms may be at play. The different patterns of evolution of the disease observed in children compared to older individuals are probably explained by a higher vulnerability of the developing brain to insults (persistent inflammatory mechanisms and recurrent seizures). Evidence implicating immune responses in the pathophysiology of RE has accumulated involving both B- and T-cell–mediated processes, but the mechanisms by which the immune system is activated remain to be elucidated. The identification of autoantigens provides evidence that RE may be associated with an immune attack on synaptic antigens and impaired synaptic function leading to seizures and cell death. In addition, T-cell–mediated cytotoxicity may lead to neuronal damage and apoptotic death. Identification of the initiating event (possibly the antigen that triggered the autoimmune response) and of the sequence of immune reactivities occurring in the course of the disease will hopefully allow timely and more specific immunotherapy. While pursuit of novel and less toxic immune strategies (such as B-cell depletion with rituximab) remains appealing, at present patients with RE usually present with rapid progression, and questions on the type and timing of surgical intervention are still being raised. It seems clear that most will fare better with earlier surgery, and only hemispherectomy techniques can provide definitive and satisfactory results with good seizure, cognitive, and psychosocial outcome.
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