In the early stages of the disease, the major issue is diagnosis. A combination of characteristic clinical, electrophysiologic, and imaging findings aid in the diagnosis. The 48 patients studied at the MNHI were collected over a period of 30 years and consisted mostly of referrals from outside Canada. Although now easier to recognize, this disease remains rare. During the last decade, an additional 10 patients at the MNHI were studied, a small number compared to the 100 to 150 patients with intractable focal epilepsy due to other causes studied each year at the center. Typically, the disease starts in healthy children between 1 and 13 years (mean age, 6.8 years) with 80% developing seizures before the age of 10 years (4). 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. Seizures are usually partial or secondarily generalized tonic-clonic seizures; 20% of 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 psychic features has been described (4,5). The seizures rapidly become refractory, with little response to AEDs. Epilepsia partialis continua (EPC) and other forms of focal seizures are particularly unresponsive to AEDs (6, 7, 8, 9). 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 (8). Our experience with newer AEDs in seven other patients with RE did not support improved effectiveness or tolerability for the new agents. The new AEDs levetiracetam and topiramate may theoretically have a role in the treatment of RE, because levetiracetam has efficacy in treating cortical myoclonus (10,11) and topiramate has a direct effect on glutamate receptors and release of N-methyl-D-glutamine (NMDA) (12).

A variety of seizure types develop over time. The most common are focal motor and EPC (in 56% of the patients), with scalp electroencephalogram (EEG) patterns suggesting perirolandic onset. Secondarily generalized motor seizures are also common in many patients, but these appear to be easier to control with AEDs. Other, less frequent types of motor seizures include jacksonian march (12%), posturing (25%), or versive movements of the head and eyes (13%), suggesting involvement of the primary motor, premotor, and supplementary motor areas. Drop attacks, however, are rare. Focal seizures with somatosensory (22% of the patients), visual (16%), or auditory (2%) manifestations are less frequent and appear later in the course of the disease, suggesting that the epileptogenic process has migrated from frontocentral regions to more posterior cortical areas.

Oguni and colleagues (4) empirically 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 (occurring in all 48 patients) to the completion of neurologic deterioration, including intellectual decline (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 tend to decrease in severity and frequency.

A study by Bien and colleagues (13) 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 and colleagues. However, Bien and colleagues distinguished two patterns of disease: one with an earlier and more severe 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 well-described variant of RE in the last decade (14, 15, 16, 17, 18).

RE has been known for more than 50 years. 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 nonviral-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 younger than 2 years of age) with rapid progression 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 or protracted or subcortical variants of RE; and double pathology.

Usually the disease affects only one hemisphere, and most autopsy studies available confirmed unilateral cerebral involvement (19). 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. Patients with definite bilateral inflammatory involvement are exceptional and such involvement has been described so far in no more than a dozen patients (15,20, 21, 22, 23, 24, 25). Bilateral disease tends to occur in children with early onset (before age 2 years), but was also described in the late-onset adolescent or adult forms. A small number had received high-dose steroids or an intrathecal antiviral agent, which suggested that early aggressive immunologic therapy may have predisposed them to contralateral spread of the disease.

A number of papers report 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 (13, 14, 15, 16, 17, 18,26, 27, 28, 29, 30, 31, 32, 33, 34). In the MNHI series, 9 (16%) of 55 patients collected between 1945 and 2000 started to have seizures after the age of 12 years. The largest series, described by Hart and colleagues (18), included 13 adults and adolescents collected from 5 centers. In comparison with the childhood form, late-onset RE has a more variable evolution (13,18), a generally more insidious onset of focal neurologic defects and cognitive impairment, and an increased incidence of occipital involvement (23% in the series described by Hart and coworkers versus 7% in children younger than 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 (13). Occasionally the outcome in late-onset RE is similar to or worse than in children (15,26,27), but because of the generally more benign and protracted course, early hemispherectomy seems less appropriate in this group of patients in whom neurologic deficits are usually less pronounced. Moreover, because of a lack of plasticity in adults, the decision for hemispherectomy is complicated because of potential risk of new irreversible postoperative deficits in the form of severe motor, visual, and speech and language (dominant hemisphere) impairment.

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 (18,30,33,35). 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 (14). Twelve 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, Laxer (35) found 5 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 (33,35).

EPC and other types of focal motor seizures are a common finding in patients with RE. Chorea, athetosis, or 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, 9 additionally had writhing or choreiform movements, and a diagnosis of Sydenham chorea was made in 3 of the patients early in the disease course (4). Matthews and colleagues (36) 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 and colleagues (37) were the first to describe in an 8.5-year-old girl with intractable focal motor seizures, 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 and colleagues (9) described a patient who developed hemidystonia as a result of involvement of the contralateral basal ganglia. The movement disorder appeared 3 years after the 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 and colleagues (38), Koehn and Zupanc (39), Frucht (34) and, finally, Lascelles and colleagues (40) each reported a case of RE whose clinical presentation was dominated by a hemidyskinesia, 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 and colleagues (41) looked specifically at the involvement of the basal ganglia. Fifteen (71%) patients showed mild to severe basal ganglia involvement on imaging in three different patterns: predominantly cortical in six cases, predominantly basal ganglia in six cases, and both cortical and basal ganglia involvement in three cases. 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. Similar findings were recently described by the Italian Study Group on Rasmussen encephalitis (42), which found basal ganglia atrophy in 9 of 13 patients studied. They suggested that atrophy of the basal ganglia represents only secondary change because of disconnection from the affected overlying frontal and insular cortex.

McDonald and colleagues (43) recently 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 recurrent partial motor seizures, EPC, and left hemiparesis within a few weeks. 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 primarily involvement of the brainstem, and hemiparesis and mesial temporal sclerosis resulting from seizure activity. However, this is an isolated case report in a complicated patient, and existence of this variant is questionable.

Maeda and colleagues (44) described a 6-year-old girl with typical RE. One year following the onset of seizures, MRI-FLAIR (fluid attenuated inversion recovery) sequences showed multiple high-signal-intensity areas in the right hemisphere, and a methionine-PET (positron emission tomography) 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.

A small number of reports have documented coexisting brain pathologies with RE: a tumor (anaplastic astrocytoma, ganglioglioma) in two patients (45,46), dysgenetic tissue in four patients (19,45,47,48), multifocal perivasculitis in seven patients (19), and cavernous angiomas with signs of vasculitis in two patients (19,45). Double pathology in RE supports the theory of focal disruption (trauma, infection, or other pathology) of the blood-brain barrier (BBB), allowing access of antibodies produced by the host to neurons expressing the target receptor and production of focal inflammation (3,49). So far, however, only one case of double pathology provided reasonable support for this hypothesis (48). Strongly positive anti-GluR3 (glutamate receptor 3 subunit) 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 years. 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 (50,51), linear scleroderma (52,53), and systemic lupus erythematosus (40) with changes suggestive of RE. Such changes have also been described in disorders with impaired immunity such as agammaglobulinemia (54) and multiple endocrinopathies, chronic mucocutaneous candidiasis, and impaired cellular immunity (55). The occurrence of two conditions presumably caused by impaired immunity in the same individual may strengthen the view that immune-mediated mechanisms are responsible for the development of RE.

Finally, the rare association of uveitis (three cases) or choroiditis (one case) with typical features of RE has led to the speculation that a viral infection may have been responsible for both (26,56,57). In all cases, the ocular pathology was ipsilateral to the involved hemisphere that
showed chronic encephalitis. In three cases (26,56), the uveitis or choroiditis was detected 2 to 4 months after epilepsy onset. In one case (57), ocular diagnosis preceded the onset of chronic encephalitis. In light of these cases, 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.

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 (5,7,13,37,41,42, 47,66, 67, 68, 69, 70). Brain magnetic resonance 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 (5,13,41,42,70). 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 (37,69,71). Rapidly on early magnetic resonance scans, however, the cortex shows focal hyperintense signals on T2 or FLAIR sequences (42) and may appear swollen. This can be explained by brain edema at the onset of inflammation (70) or, alternatively, by recurrent focal seizures (72). Very early signal change in the white matter (within 4 months) is also frequent, usually focal, with or without swelling (42). 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 years (42,70). The cortical atrophy is initially either temporal, frontoinsular, or frontocentral, and, more rarely, parietooccipital, later spreading across the hemisphere. Basal ganglia involvement, mostly of the putamen and caudate, is also characteristic and may be a result of direct damage by the pathologic process or secondary to changes caused by disconnection of the basal ganglia from the affected overlying frontocentral and insular cortices (41,42). 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 (42). Surprisingly, gadolinium enhancement on MRI is rarely observed (31,42,47,69,70,73,74).