Rasmussen’s Encephalitis

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Chapter 12 Rasmussen’s Encephalitis

Clinical Features in Typical RE

The disease is sporadic, affecting both males and females. RE typically starts in childhood or early adolescence, with a mean age of presentation at 6 years. The previous personal history is uneventful, but in about half of the patients, a trivial febrile illness in the months preceding the onset of seizures or a remote head trauma have been reported.

In its typical form, the onset of RE is marked by epileptic seizures, either focal or secondary-generalized. In most patients, seizures are isolated, but in a proportion of cases, the presenting symptom is status epilepticus (SE) or, more rarely, EPC.34 In a few patients, slowly progressive hemiparesis may precede seizure onset.45 A rarely reported presenting symptom is hemidystonia or hemiathetosis;6 this modality of presentation is not surprising, given the early damage of the basal ganglia in RE (see later discussion), and mild movement disorders are likely to be frequently overlooked or underreported, as suggested by Andermann.7

EPILEPSY AND EEG FEATURES

The main characteristic of seizures in RE is their polymorphism in a given patient. Besides simple motor seizures that are almost always present, the patient may experience postural, versive, somatosensory, autonomic, visual, auditory, and limbic seizures (Figure 12-1). This polymorphism, which may be evident from the onset and is invariably present during the disease course, can be due to the multifocal—albeit hemispheric—origin of the seizures, or to the progressive enlargement of the original epileptic zone. Seizures are refractory to antiepileptic (AE) treatment, their frequency usually increases rapidly, and partial SE may recur.34

EPC, defined as spontaneous regular or irregular clonic twitching confined to one part of the body (Figure 12-2), aggravated by action or sensory stimuli, and persisting during sleep,8 occurs in most of the patients (56 to 92% according to different series) at some time during the disease course, unresponsive to AE drugs.34,9

The striking EEG feature at onset is the presence of slow focal activity mainly involving the temporal and central leads on the affected hemisphere, associated with few epileptic abnormalities on the same regions. Additional distinctive features, in the first few months, are the early evidence of ictal and interictal hemispheric multifocality, the presence of subclinical ictal discharges, and the unilateral impoverishment of the background activity and of sleep spindles (Figure 12-2).4,10

During the disease course, the background activity further flattens, and sleep organization deteriorates further; epileptic and slow activity tend to increase and spread within the affected hemisphere and the unaffected one. With time, the contralateral abnormal activity, either resulting from diffusion or seemingly asynchronous, may become more frequent than that recorded in the affected hemisphere (i.e., “false lateralization”).11 In any case, the seizure onset, albeit multifocal, is closely unilateral; the recording of seizure from the supposed unaffected hemisphere strongly questions the diagnosis of RE.

EPC, like in other conditions, is often not clearly related to electroencephalogram (EEG) changes recorded by scalp electrodes; however, auxiliary neurophysiologic techniques may contribute to define the cortical origin of the jerks. Back-averaging may identify the spikes preceding the motor phenomena, and somatosensory-evoked potentials of the rolandic cortex are often abnormally enlarged.12

NEUROLOGIC SYMPTOMS OTHER THAN EPILEPSY

Hemiparesis invariably develops during the disease course. As already mentioned, the motor deficit may be the symptom of onset, and exceptionally remains the one and only manifestation of RE.5 In the first stages of the disease, hemiparesis may be limited to the postictal phase, but rapidly becomes constant, albeit fluctuating in severity as it worsens with increasing seizure activity. With time, hemiparesis, sometimes associated with a dystonic component, stabilizes. In an Italian series of 12 patients, focal motor deficits appeared from 15 days to 24 months after the first seizure and invariably worsened to severe hemiparesis, leading three patients to be wheelchair bound within 3 years of onset.4

Movement disorders, which seldom mark the onset of RE, are rarely reported during the disease course, probably because they are misinterpreted or overlooked in patients whose clinical picture is dominated by epilepsy and hemiparesis. Additional neurologic symptoms include hemianopia, cortical sensory loss, and aphasia when the dominant hemisphere is affected.13

Cognitive impairment is another constant feature of RE, and as for motor deficits, its appearance may be subtle. Behavioral changes, with irritability, emotional lability, or hyperactivity, often herald the first signs of mental decline, which consist mainly of memory and attention disorders and learning difficulties. In the Italian series, these symptoms were detected within 4 to 36 months after the first seizure and progressively worsened until surgery. At the time of surgery, performed between 7 months and 14 years after disease onset, the mean IQ was 61.3 ± 15.1 (range 44–87).4 In most patients, the progression of mental impairment seems to correlate with the severity of epilepsy and particularly with the bilateral spreading of EEG epileptic abnormalities (personal experience), or with the appearance of asynchronous contralateral foci.14

The natural history of RE is summarized in the seminal paper by Oguni from the Montreal Neurological Institute3 and in the more recent report from the Bonn group, correlating the clinical course with the development of brain damage as documented by serial MRIs.9 Both groups recognize three stages that are virtually comparable. In the “prodromal stage,” lasting from 0 months to 8 years, seizures manifest at low frequency, and rarely, mild hemiparesis may be present. The “acute stage,” which in a significant number of cases appears to be the initial clinical manifestation, lasts 4 to 8 months and is characterized by frequent seizures, EPC (not always present), and rapid neurological deterioration. Finally, the patient enters the “residual stage,” with stable neurological deficits and persisting, albeit less frequent, seizures.

Atypical RE

Under this heading, the less-common manifestations of RE, with regard to age at onset, association with other diseases, and bilateral involvement, are included.

ADOLESCENT- AND ADULT-ONSET RE

A limited, but increasing number of patients with adult-onset RE have been reported, accounting for about 10% of all RE reported cases.12,15 The overall features in childhood and adult onset are similar with regard to clinical, electrophysiological, and neuroimaging findings. The main differences consist of a more frequent posterior onset and a milder, more protracted, clinical course. Motor and mental deterioration are less severe than in typical childhood RE, hemispheric damage less pronounced, and quality of life somewhat preserved. However, in a number of cases, late-onset RE runs a malignant course, comparable to that of childhood-onset disease. In a recent paper Villani and coworkers identified two distinct patterns of disease presentation, one characterized by focal motor epilepsy (the “epileptic” phenotype), and the other by focal cortical myoclonus (the “myoclonic” phenotype). Unilateral neurologic deficits and brain atrophy were progressive in both phenotypes, but they were more prominent and detected earlier in the “epileptic” phenotype.12

RE PROTRACTED VARIANTS

A few RE patients are reported to have an acceptable seizure frequency and not invalidating motor deficits.15 This was already described in the pioneering study by Aguilar and Rasmussen,16 who reported that some patients may have mild neurologic deficits, despite the neuropathological evidence of active encephalitis.

RE ASSOCIATED WITH OTHER DISEASES (DOUBLE PATHOLOGY)

Patients affected by preexisting brain lesions account for about 10% of RE cases.1 This dual pathology has been documented in low-grade tumors, cortical dysplasia, tuberous sclerosis, vascular malformations, or old ischemic lesions. The association of structural abnormalities and inflammation is still a matter of investigation. The hypothesis that structural or acquired brain lesions, and the resulting epilepsy, may alter the blood–brain barrier permeability, allowing the entry of compounds with immunogenic or inflammatory potential, is conceivable but, at least to date, not demonstrated.17

The association of RE with definite autoimmune diseases, such as SLE,18 linear scleroderma,19 Parry–Romberg syndrome,20 although rarely reported, is noteworthy, as it provides a further hint for the role of immune-mediated mechanisms in the pathogenesis of RE.

BILATERAL RE

The hallmark of RE is the unilateral brain damage, and this distinctive and unique characteristic should be, in the opinion of the authors, mandatory for diagnosis, as it entails the surgical indication, as discussed in the treatment section.

The term “bilateral RE” has been used in the literature to include two different conditions: (1) the secondary involvement of the unaffected hemisphere, as indicated by spreading of focal seizures from the original focus, by the appearance of interictal epileptic abnormalities, and by the mild brain atrophy, that most probably results from Wallerian degeneration of commissure fibers;21 (2) a familiar22 and few sporadic cases of early-onset malignant epilepsy with neuropathology consistent with chronic encephalitis resembling RE;2324 and (3) rare adult-onset cases.25

The frequently observed secondary involvement of the unaffected hemisphere, of course, does not rule out the diagnosis of RE because in no cases is there evidence of truly contralateral disease. It should also be underlined that in RE patients surgically treated, even after a very protracted disease, by hemispherectomy (or hemispheric disconnection), no relapse of seizures from the contralateral hemisphere was ever recorded. Conversely, in “bilateral RE,” symptoms and, when available, MRI findings pointed to bilateral brain damage within the first months of the disease. In our opinion, from a pragmatic point of view, these cases should be kept separate from true RE (and probably named differently), given the different clinical picture, MRI findings, and, overall, the ensuing therapeutic approaches.

Pathogenesis of RE

The etiology of RE remains unknown, but our understanding of its pathogenesis improved considerably in recent years. The initiating event triggering RE remains unknown. A viral etiology was first proposed, based on the features of lymphocyte infiltration and microglial reaction within the brain and on similarities with known forms of viral encephalitis.2 However, no attempt of isolation of a pathogenic virus has been successful.26 The interest in RE has been renewed by histopathological and experimental studies showing the involvement of the immune system in the pathogenesis of the disease, providing evidence for both humoral and cellular factors.

In 1994, Rogers and coworkers observed that rabbits immunized with a recombinant fragment of the glutamate receptor (GluR3) developed seizures and that the histopathological examination of their brain showed inflammatory changes reminiscent of those found in patients with RE. In parallel, the same authors detected antiGluR3 antibodies in three patients with RE and observed clinical improvement after plasma exchange in one of them.27 Further reports of transient clinical improvement after removal of antibodies have been subsequently published.13,2829 These preliminary findings fostered the search for such autoantibodies in larger series of patients with RE. AntiGluR3 antibodies, at first assayed by ELISA techniques, were found in serum and cerebrospinal fluid (CSF) not only in a proportion of patients with RE, but also in other forms of epilepsy, particularly in the catastrophic epilepsy of children. Therefore, their presence is not specific for RE but seems to correlate with epilepsy and its severity.3031 However, the importance of antiGluR3 antibodies has been recently questioned by means of different laboratory techniques (ELISA, Western blot, immunoprecipitation, immunohistochemistry, and electrophysiology).32

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