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Summary
Rasmussen encephalitis (RE) is a rare but severe immune- of the disease, its clinical and paraclinical presentation,
mediated brain disorder leading to unilateral hemispheric and therapeutic approaches are summarized. Based on
atrophy, associated progressive neurological dysfunction these data, we propose formal diagnostic criteria and a
and intractable seizures. Recent data on the pathogenesis therapeutic pathway for the management of RE patients.
Abbreviations: AED = anti-epilepsy drug; BBB = blood–brain barrier; CTL = cytotoxic T lymphocyte;
EPC = epilepsia partialis continua; FDG = fluorodeoxyglucose; GluR3 = glutamate receptor subunit 3; GrB = Granzyme B;
HE = hemispherectomy or any of its variants; IVIG = intravenous immunoglobulins; PEX/PAI = plasma exchange/protein
A IgG immuno-adsorption; RE = Rasmussen encephalitis; SPECT = single photon emission computed tomography;
TCR = T cell receptors
Received September 21, 2004. Revised January 6, 2005. Accepted January 7, 2005. Advance Access publication
February 2, 2005
Introduction
In 1958, Theodore Rasmussen and co-workers from the in Rasmussen’s encephalitis’ held at the 6th European
Montreal Neurological Institute reported three patients Congress on Epileptology in Vienna on 1 June 2004.
suffering from ‘focal seizures due to chronic localized
encephalitis’ (Rasmussen et al., 1958). Since the late Aetiology and pathogenesis of RE
1980s, most researchers and clinicians have adopted the RE is a rare disease that should be envisaged as sporadic,
term Rasmussen encephalitis (RE) or Rasmussen syndrome since there is no evidence for a genetic component
for this condition (Piatt et al., 1988; Andermann, 1991). In (Andermann et al., 1991; Grenier et al., 1991). There is, at
recent years, important new insights have added to our under- present, no conclusive evidence why and how RE starts.
standing of the pathophysiology, the diagnosis and the A viral aetiology was already suggested by Rasmussen based
management of the condition. Here, we present a summary on the constituents of the immune reaction in the brains such
of the existing knowledge and experience with an emphasis as lymphocyte infiltration and microglial nodules (Rasmussen
on the clinical management of RE patients. The consensus et al., 1958). The similarities of RE and Russian spring sum-
proposed here for the diagnosis and therapy of RE results mer meningoencephalitis, which is caused by a flavivirus, fur-
from a symposium entitled ‘Current concepts and controversies ther supported this hypothesis (Asher and Gajdusek, 1991).
# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Consensus on Rasmussen encephalitis 455
However, so far all attempts to identify a pathogenic viral expanded B lymphocytes in RE, but the IgGVH-CDR3
agent have been contradictory and inconclusive (Friedman sequences were diverse among the four cases. Possible reas-
et al., 1977; Rasmussen, 1978; Walter and Renella, 1989; ons put forward for this included determinant spreading and
Power et al., 1990; Farrell et al., 1991; Gilden and Lipton, genetic or antigenic heterogeneity (Baranzini et al., 2002).
1991; Vinters et al., 1993; McLachlan et al., 1993, 1996; Xiong and colleagues showed that the sequential application
Atkins et al., 1995; Jay et al., 1995). Available data continue of the complement cascade proteins C5b6, C7, C8 and C9,
to suggest an immune basis to the pathogenesis of RE. Evid- which are known to lead to the formation of the membrane
ence has emerged both of a role for humoral factors, namely attack complex (MAC), into the hippocampi of rats lead to
autoantibodies, as well as more recently T lymphocytes, epileptic seizures and massive necrotic hippocampal cell
namely cytotoxic T cells. death (Xiong et al., 2003).
Taken together, there is highly conflicting evidence regard-
ing the pathogenic effect and even the mere presence of
Humoral autoimmunity elevated GluR3 autoantibodies in RE. This does not exclude
In the course of raising antibodies against subunit 3 of the that other humoral mechanisms may contribute to the patho-
ionotropic glutamate receptor (GluR3) in rabbits, two out of genesis of RE. Future antibody research in RE will probably
four rabbits immunized with the GluR3 fusion protein concentrate on detecting possibly pathogenic antibodies other
humoral autoimmunity in systemic autoimmune diseases place. However, this cannot be clarified at this stage and there
(Casciola-Rosen et al., 1999). However, in view of the are at present no data to distinguish potential pathogenetic
doubtful relevance of the GluR3 antibodies the study by subgroups, especially not with regard to specific therapeutic
Gahring and colleagues can, at present, not serve as a valid strategies.
explanation for RE pathogenesis.
Clinical features
RE as an epileptic encephalopathy Clinical disease course
In analogy to other conditions of childhood epilepsies with Reported cohorts of individuals with RE are not large, but
progressive neurological deterioration, it has been suggested conclusions about the natural history of the disease can be
that in RE, too, the epileptic activity itself may contribute to drawn (Oguni et al., 1991; Bien et al., 2002c,d; Chiapparini
the functional decline (Nabbout and Dulac, 2003). After a few et al., 2003; Granata et al., 2003b). Although seen in adult-
months, partial motor seizures affect, in an apparently inde- hood, the majority present in childhood with an average age
pendent fashion, various areas of the same side of the body, at disease manifestation of 6 years of age (Oguni et al., 1991).
the affected part of the body increasing over time. EEG Three disease stages have recently been proposed. Initially,
recordings show unilateral deterioration of the background there may be a rather non-specific ‘prodromal stage’ with a
the epileptic focus) across the hemisphere’ (Oguni et al., course with less residual functional deficits and lower degrees
1991). Congruent observations have been made by serial of hemiatrophy and more frequent occipital lobe seizure onset
neuroimaging studies. However, apart from the rare cases (Hart et al., 1997; Bien et al., 2002d ), but identical histo-
of bilateral RE, all seizures originate in one hemisphere. pathological as well as clinical, electrophysiological and
Oguni and co-workers quantified the clinical seizure types neuroimaging findings.
during the disease course of their series of 48 patients. Simple
partial motor seizures involving one side of the body were the Dual pathology
most common (occurring in 77% of cases), followed by sec-
Cases with dual pathology (RE plus low grade tumour,
ondarily generalized tonic clonic seizures (42%), complex
cortical dysplasia, tuberous sclerosis, vascular abnormalities
partial seizures (19% with automatisms and 31% with sub-
or old ischaemic lesions) have been described (Hart et al.,
sequent unilateral motor involvement), postural seizures
1998; Firlik et al., 1999; Palmer et al., 1999; Thom et al.,
probably originating in the supplementary motor region
1999; Bien et al., 2002d ). In the Montreal series, 10% of
(24%) and somatosensory seizures (21%) (Oguni et al.,
cases had dual pathology (Hart et al., 1998). The diagnosis of
1991).
dual pathology has, in part, been suspected based on MRI
EPC has been reported to occur in 56–92% of patients at
findings, but always been confirmed by histopathology
some time during their disease course (Oguni et al., 1991;
(biopsy or resective epilepsy surgery).
when the affected hemisphere was not removed but purely relevant observation was that <5% of the CD68+ HLA-
disconnected (Delalande and Bulteau, 2002). DR + cells had macrophage morphology (the remainder
had microglial morphology). Inclusion bodies suggestive
of a viral infection have not been observed in RE. CD20 +
RE with delayed seizures onset
cells (B cells) and CD138 + cells (plasma cells) are extremely
An Israeli-German group studied two patients with progress- rare. Signs of immunoglobulin deposits or activated comple-
ive hemiparesis and biopsy evidence of RE. These patients ment were not found (Bien et al., 2002a).
developed unilaterally generated seizures only after several
months (Korn-Lubetzki et al., 2004).
Paraclinical features of RE
Movement disorders in RE EEG features
Frucht (2002) presented a RE case with features of hemidy- As early as 4 months after disease onset in a series of
stonia and hemiathetosis in addition to EPC. On MRI, this 12 patients, Granata and colleagues found pronounced
case had atrophy of the ipsilateral caudate and lentiform EEG changes in their patients (Granata et al., 2003b).
nuclei in addition to one-sided cortical affection. In an They described polymorphic delta waves over the affected
accompanying editorial, Andermann (2002) argued that hemisphere, mainly in a temporal and central location. Nine
The German group combined similar observations with quant- the affected hemisphere. In most cases, large areas of
itative evaluation of cell densities of inflammatory cells and hypometabolism were observed; in the remainder (mostly
reactive astrocytes in brain specimens obtained from regions ‘ictal’ studies in patients with ongoing EPC), additional areas
with MRI abnormalities. In areas with increased signal, the of focal hypermetabolism were found (Hajek et al., 1991;
number of T cells, microglial nodules and GFAP + astrocytes Hwang et al., 1991; Tampieri et al., 1991; Caplan et al.,
was increased compared with more chronically affected areas 1996; Duprez et al., 1997; Banati et al., 1999; Kaiboriboon
with advanced atrophy and no more signal increase (Bien et al., 2000; Fiorella et al., 2001; Lee et al., 2001; Chiapparini
et al., 2002c). Using a quantitative approach (calculation of et al., 2003; Maeda et al., 2003; Shah et al., 2003). In the
the ‘hemispheric ratio’, i.e. the ratio affected/unaffected hemi- largest available study (15 patients), FDG-PET changes in
sphere on planimetry of axial and coronal slices including the early stages (disease duration up to 1 year) were confined to
Sylvian fissure) to assess the temporal evolution of hemi- frontotemporal areas. In later stages, abnormalities also affec-
atrophy, the same group found that most of the tissue loss ted posterior cortical regions (Lee et al., 2001). One case
occurs during the first 12 months after onset of the acute study suggested that FDG-PET-hypermetabolism correlates
disease stage (Bien et al., 2002d ). However, it may, in with ongoing electrical seizure activity whereas methionin-
some cases, go on for several years (Bhatjiwale et al., 1998; PET-hypermetabolism indicates areas of inflammation, but
Chiapparini et al., 2003). In 11 immunotreated RE patients, this needs to be confirmed in larger patients group (Maeda
Table 2 Continued
HIV (Ferrari et al., 1998; Bartolomei et al., 1999) Blood antibody tests
Cat scratch disease (Nowakowski and Katz, 2002; Puligheddu History
et al., 2004) Cutaneous papules, lymphoadenopathy
Serology (Bartonella henselae)
5. Other
Proconvulsive drugs: History
Metrizimide (Shiozawa et al., 1981)
Penicillin, Azlocillin-Cefotaxim (Wroe et al., 1987)
Bone marrow transplant (Antunes et al., 2000) History
Gliomatosis cerebri (Shahar et al., 2002) MRI
disease) and without brain biopsy. The Part A criteria of (Piatt et al., 1988; Dubeau and Sherwin, 1991; Topcu et al.,
Table 1 are highly characteristic of early cases. To cover 1999). No anticonvulsive mono- or combination-therapy has
also the RE cases with a different presentation, we added been described to be superior to other regimens (Dubeau and
Part B. If a patient fails to fulfil the criteria of Part A, he Sherwin, 1991).
immediately pre-operatively (Loddenkemper et al., 2003). recommendations: (i) corticosteroids (Chinchilla et al.,
The second with disease onset at the age of 11 years became 1994; Hart et al., 1994b; Granata et al., 2003a); (ii) intravenous
profoundly aphasic and underwent HE at the age of sixteen. immunoglobulins (IVIG) (Walsh, 1991; Hart et al., 1994b;
Post-operatively, language dramatically improved (Telfeian Wise et al., 1996; Leach et al., 1999; Villani et al., 2001;
et al., 2002). A functional correlate for transfer of language Granata et al., 2003a); (iii) corticosteroids plus IVIG
functions in RE was suggested by Hertz-Pannier and col- (Hart et al., 1994b; Krauss et al., 1996; Vinjamuri et al.,
leagues in their report of a patient with onset of left sided 2000); (iv) plasmapheresis (PEX) or protein A IgG immuno-
RE at age 5.5 years. This boy underwent left sided HE at the adsorption (PAI) (Andrews et al., 1996; Palcoux et al., 1997;
age of 9 years. The post-operative course was like that of Antozzi et al., 1998; Granata et al., 2003a); and (v) tacrolimus
Boatman’s patients (see above). Interestingly, the post- (Bien et al., 2004).
operative improvement mainly of receptive language func-
tions was reflected in a right-hemisphere inferior frontal,
temporal and parietal activation on fMRI in areas not activ- Corticosteroids
ated during a fMRI obtained early in the disease course Prednisolone/prednisone started at high doses and slowly
(Hertz-Pannier et al., 2002). tapered down have been reported to have beneficial effects
Studies on the HE outcome in children with an onset of on seizures and neurological functions in several series, par-
well as those without specific treatment because of apparent immunotherapy may prolong the period of high seizure fre-
inactivity of the destructive disease process (field 8 in Fig. 1) quency and deterioration without finally preventing the loss
should be monitored for further progression. We suggest of function. Thus, the patient will at last be offered radical
examining those patients every 6–12 months clinically and surgery, that is, the very treatment that had been withheld
by brain MRI. If significant deterioration becomes evident, at the earlier stage in view of the preserved language and
the patient should again be evaluated for eligibility for HE as motor functions. However if this is found for one immuno-
described above (field 2 in Fig. 1). If there is still a risk of therapeutic regimen, another one may still be beneficial. At
impairment by HE, the patient should proceed to immuno- present, it is far from clear how to rank the immunotherapies
therapy (field 9 in Fig. 1) [because the criteria of ongoing described above in RE.
progression (field 7 in Fig. 1) is fulfilled in these cases as
evident from their passing through field 10 in Fig. 1], i.e.
immunotherapy should either be initiated (if patients have Recommended future therapeutic research
been on no specific treatment before i.e. field 8 in Fig. 1) From these and other considerations, the following general
or changed (if patients have received immunotherapy before, principles of future therapeutic research are outlined:
field 9 in Fig. 1). Regular follow-up studies to detect a
relevant disease progression (field 10 in Fig. 1) should be (i) Any kind of valid therapeutic report should inform
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