Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease [version 1; peer review: awaiting peer review]

Background: Rasmussen’s encephalitis (RE) is a rare chronic neurological disorder that presents with progressive neurological and cognitive deterioration, and intractable seizures that lacks definitive management. We aimed to identify case reports of RE in the literature to assess the treatment based on the symptoms and outcomes after the treatment. Methods: We searched the databases PubMed, Google Scholar, and the Cochrane Library from 1990 to 22nd February 2022 in order to review the case reports that included the treatment options and clinical outcomes of RE. A pre-established protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) database (ID: CRD42021261999). Results: The mean age of onset of seizure was 31.44 and 6.87 years in adult onset RE and children (below 15 years of age) with RE respectively. A total of four (44.44%) out of nine adult patients and 81 (66.39%) out of 122 children underwent surgery. Tacrolimus was used in 17 (13.93%) and steroid therapy was used in 11 (9.01%) of the children. Conclusions: Large scale-controlled trials are needed to study the beneficial effect of tacrolimus, IV Ig, and plasma therapy. Hemispherectomy should be opted as a treatment modality by assessing the impairment of patients’ motor or language functions following the treatment procedure.


Introduction
Rasmussen's encephalitis (RE) is a rare chronic neurological disorder characterized by unilateral inflammation of the cerebral cortex and presents with intractable seizures and progressive neurological and cognitive deterioration. 1 In Germany and the United Kingdom, the incidence of RE is 2.4 cases per 10 million persons and 1.7 cases per million per year, respectively. 2,3 However, there is no worldwide published statistics on sex, geography, or ethnic predilection. Acutely, patients with RE experience a progressive loss in neurological functions such as hemiparesis, hemianopia, cognitive impairment, and aphasia in the affected hemisphere. Patients also commonly experience intractable unilateral simple partial focal motor seizures, complex partial seizures, or secondary generalized seizures. The diagnosis is usually based on a European consensus panel for Rasmussen's encephalitis 2005. 4 The aetiology of RE is still not fully understood. A possible hypothesis was that the disease could be due a possible viral infection, however, this remains to be proven. Antibody-mediated immune response directed towards antigens of brain resident cells is another mechanism hypothesized. Antibodies to the AMPA receptor subunit 3 (GluR3 antibodies) have been suggested as the pathogenesis. They are, however, neither sensitive nor specific to RE. 5,6 Antibodies directed against non-GluR3 may play a role in the development of RE in some cases. RE has recently been linked to antibodies to the neuronal alpha7 acetylcholine receptor and the presynaptic protein Munc18-1. 7,8 RE is thought to be an immunological-mediated disease involving both adaptive and innate immune responses which are aided by microglia and astroglia. 9 However, in some case series, dual pathology has been found in patients with RE suffering from focal cortical dysplasia or tuberous sclerosis. 10,11 The most recent literature has described inflammation in conjunction with localized cortical dysplasia type 2b lesions. 12 The goal of disease management in RE patients is to reduce the frequency and severity of seizures, and to improve longterm functional outcomes. Seizures are managed by anti-epileptic drugs (AED). Long-term corticosteroids, intravenous immunoglobulins, plasmapheresis, or protein A immunoabsorption; T-cell inactivating medicines, tacrolimus and azathioprine; and surgery (hemispherectomy or hemispherotomy) have all been used to treat people with RE. 13 However, these treatment modalities are used only to alleviate symptoms. There is no definitive cure because of the disease rarity. Although a systematic evaluation of case reports cannot establish a link between definitive therapy and results, it can form a basis for hypothesis formulation in subsequent studies. Our aim in this review was to identify the cases of RE in the literature to assess the treatment based on the symptoms, and outcomes after the treatment.

Methods
This systematic review conforms to standard guidelines and is written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) statement. 14,15 A pre-established protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) database (ID: CRD42021261999).

Study selection
We searched electronic databases including PubMed, Google Scholar, and The Cochrane Library through 1990 to 22 nd February 2022 to review the case reports that included the treatment options and clinical outcomes following the treatment in patients diagnosed with RE. "Rasmussen", "encephalitis", "treatment", and "outcome" were used as keywords to search relevant literature. The keywords were combined with "OR" and "AND" Boolean operators. References of the articles included were also searched manually.
The inclusion criteria for the articles were: (1) Case reports and case series (2) Articles that were available in the English language (3) Articles containing information including gender, age, treatment methods, follow up, outcomes, and complications (4) Articles assessing patient management and outcome The exclusion criteria were: (1) Articles that were not available in English (2) Articles not mentioning the treatment Quality assessment A modified version of an appraisal tool 16 was used for quality assessment of the included case reports. 17 One author (SS) carried out the assessment and a random sample was cross checked by RC. Any disagreement was resolved with discussion by BSP, RD, and BK. We used three items to assess the quality of case reports: (1) chief complaint, history, treatments, follow up, outcomes were described adequately or not; (2) whether accurate diagnosis was provided; and (3) complication or whether the patient improved was mentioned. Items were graded with ratings noted as yes, partially, or no.

Data extraction
Two authors (SS and RC) extracted data on to a Microsoft Excel® 2019 sheet. The data from the included studies were extracted as follows: a) author and year of study; b) number of patients; c) age and gender; d) disease management; e) treatment duration; f) outcomes; and g) complications.
Extracted data was checked by another author (RD) and disagreement was resolved by discussion with other authors (BK and BSP) by consensus. We included all studies where the diagnosis was made by serology or any combination of serology with pathologic findings, and immunostaining.

Data synthesis and analysis
Data were summarized using descriptive statistics. We calculated the mean for continuous variables, and frequencies and percentages for dichotomous variables.

Publication characteristics
The literature search resulted in 732 studies from PubMed, Google Scholar, and the Cochrane Library. After the complete screening process of titles and abstracts 631 studies were excluded. A further five articles were not retrieved because full text was not available and a further 35 were excluded following full-text screening as they failed to fulfil the inclusion criteria. Finally, 39 articles that met the criteria were included in the review. A description of study selection is shown as a flow diagram in Figure 1.

Quality appraisal
The selected cases were good to moderate in quality. The included cases had an adequate description of the chief complaint, patient past medical history, laboratory investigations, treatment, follow-up and outcomes. The outcomes of treatment and follow-up were included in all (100%) of the studies. Accurate diagnosis with valid and reliable outcome measures were reported for 74.35% of studies. Complications and symptoms that did not improve were reported in 48.71% of the studies (Table 1).

Demographic characteristics
The total number of patients with Rasmussen encephalitis was 142 from 39 studies included in this review.  There was no clinical improvement in seven children who underwent surgery (three of them died while four had no clinical improvement). Tacrolimus, steroid therapy, methylprednisolone, cyclophosphamide, mycophenolate mofetil, alemtuzumab with intrathecal methotrexate and natalizumab all showed significant improvement in terms of seizure episodes, verbal intelligence and language. The details of the treatment outcomes are shown in Table 2.

Discussion
Rasmussen encephalitis has no reported incidence of male or female predominance, but our results showed that a higher number of females suffered from RE. Seizures were reported in all the patients. To lower the incidence of non-epilepsia partialis continua (EPC) seizures, patients with seizures should be treated with AEDs at any stage of the disease. 4 For periods of status epilepticus, steroid boluses or plasma exchange/Protein A IgG immunoadsorption are indicated. 4 When used early in the disease's active phase, less than two years following the onset of symptoms and signs, corticosteroids can be beneficial. Late treatment with steroid therapy, on the other hand, results in delayed recovery, recurrence, and hemisphere separation. As a result, new strategies for treating RE are needed, both to control seizures and to prevent the unavoidable neurological degeneration. 18 There is insufficient evidence for the definitive treatment regarding the particular choice of immunotreatment. No specific therapy should be preferred if there are no intractable seizures (e.g. in 'burned out' patients). 4 Steroids, IvIg, plasma exchange/Protein A IgG immunoadsorption, or tacrolimus appear to be the best options based on current literature. Immunotreated individuals survived more than the control group patients in a randomized controlled trial with tacrolimus and IvIg; however, neither was superior to the other. 2 Two patients who were on tacrolimus had substantial side effects (febrile infection and asymptomatic Epstein Barr virus (EBV) viremia). 2 Several untreated individuals had persistent epilepsy and later required hemispherectomy, whereas immunotreated patients had no seizures. 2 Similarly, under immunotherapy, no patient with refractory epilepsy became treatment responsive. 2 Another study assessing the therapeutic role of tacrolimus found that patients treated with tacrolimus had a superior outcome with improved neurologic motor functions and rate of progression of cerebral hemiatrophy. 19 However, the outcome with seizures was uneventful. 19 These studies currently show no evidence in favor of one treatment over another, and none of them has been demonstrated to be a viable alternative to surgery in terms of slowing the disease process.
Surgical treatment was done only when other therapies had no better outcomes in most of the studies. Surgical treatment is the preferred method; however, tailored resection, bipolar electrocoagulation on functional cortexes (BEFC), and multilobar resection are not effective for most individuals. Selective resection guided by intracranial monitoring is a good option for adolescent patients. The only successful therapy for obtaining no seizures in RE patients is hemispherectomy and hemispherotomy. In a study by Guan et al., the seizure-free rate was 80%. 20 The majority of the patients were able to walk without support, but their fine hand movements had been lost. 20 However, cognitive evaluation showed that the majority of the patients did not have significant improvement after the surgery in a study by Terra-Bustamante et al. 21 When the non-dominant hemisphere is afflicted epilepsy is severe, and where hemiparesis has already occurred in older patients hemipherotomy is required. 13 For older people with dominant-side RE, early-stage disease, and modest neurological abnormalities, surgery is a difficult therapeutic choice, thus the decision must be based on adequate follow up, a multidisciplinary approach, and the patient's and family's psychological preparation. 13,22 Our study had several limitations. The quality of the data in the reports limits our results. The information provided was not consistent or uniform. The higher number of cases with RE could be due to publication bias. Most crucially, case studies and reports are uncontrolled, and while they can suggest possibilities, they can't prove them. However, doctors should be mindful of the significant number of cases documented in the literature, which show that the pathophysiology of RE may be involved in treatment. While case reports are useful for identifying signals, they are insufficient for statistical inference. As a result, the evidence presented may not be sufficient to recommend regular screening in RE patients.

Conclusions
To investigate the efficacy of non-surgical treatment options such as tacrolimus, IvIg, and plasma therapy in terms of seizure control and neurologic function preservation, systematic randomized controlled trials are required. Once a patient has been identified with RE, it must be determined whether hemispherectomy would result in a significant impairment of motor or verbal functions. Hemispherectomy should be suggested if no significant worsening is expected.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.