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Systematic Review

Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease

[version 1; peer review: 1 approved with reservations, 1 not approved]
PUBLISHED 14 Sep 2022
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

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.

Keywords

Rasmussen encephalitis, tacrolimus, hemispherectomy, systematic review, neurological disorder, treatment

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 long-term 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 22nd 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 tool16 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.

Results

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.

b03447a7-e072-437c-841e-577669a1144f_figure1.gif

Figure 1. PRISMA 2020 flow diagram for study selection and screening.

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).

Table 1. Quality appraisal of the included studies.

SN No.Author and yearAdequate descriptionAccurate diagnosisComplication or whether the patient improved was mentioned
1C.G. Bien et al., 20044PartiallyYesPartially
2N. Bahi-Buisson et al., 200418PartiallyPartiallyYes
3Yuguang Guan et al., 201420PartiallyYesPartially
4Vera C. Terra-Bustamante et al., 200921YesYesYes
5Mary L. Zupanc et al., 199023YesYesYes
6Manuel Arias et al., 200624YesYesYes
7Catherine Grosmaitre et al., 201325YesPartiallyNo
8Rochelle Caplan et al., 199626YesPartiallyNo
9Sung-Min Cho et al., 201727YesPartiallyPartially
10Zuzana Liba et al., 201728YesYesPartially
11Jayaprakash et al., 200229YesYesYes
12C. Sanfilippo et al., 201530YesPartiallyPartially
13A. Stabile et al., 201831YesYesNo
14Taíssa P.F. Ferrari et al., 201132YesYesYes
15Danielle A. Nolan et al., 201833YesYesYes
16Katharina Hohenbichler et al., 201734YesYesPartially
17Flavio Villani et al., 201435YesYesYes
18L. Papetti et al., 201136YesYesNo
19Kevin Gurcharran et al., 201637YesPartiallyNo
20Yuguang Guan et al., 201138YesYesYes
21Barbara Thilo et al., 200939YesPartiallyYes
22Zuzana Liba et al., 201540YesPartiallyNo
23Bhooma R. Aravamuthan et al., 201541YesPartiallyNo
24Shalini Narayana et al., 201942YesYesNo
25Qun Wang et al., 201743YesYesNo
26Marie-Aude Spitz et al., 201444YesYesYes
27Vijay M. Ravindra et al., 201545YesYesPartially
28Stefan Bittner et al., 201346YesPartiallyNo
29Christian G. Bien et al., 201347PartiallyYesYes
30Tiziana Granata et al., 201348PartiallyYesNo
31M. Topçu et al., 199849YesYesNo
32Ali Hammed et al., 202150YesYesYes
33Anteneh M. Feyissa et al., 202151YesYesYes
34Arnold J. Sansevere et al., 202052YesYesYes
35Mohammad Bila Mazar et al., 202253YesYesYes
36Monika Mochol et al., 202154YesYesYes
37Ramesh Sharanappa Doddaman et al., 202155YesYesYes
38Ricardo Pires Alvin et al., 202056YesYesNo

Demographic characteristics

The total number of patients with Rasmussen encephalitis was 142 from 39 studies included in this review. The mean age of onset of seizure was 41.11 and 6.82 years in adult onset RE and children with RE (below 15 years of age) respectively. The male to female ratio was 55:74 among the children while 3:10 among the adult-onset RE.

Clinical features

Thirty-six out of 38 studies mentioned the clinical features of RE. In those studies, all the patients had at least one episode of seizure. Hemiparesis and focal neurological deficit were observed among 40–50% of patients. Two patients had double pathology of RE.

Treatment

Among thirteen patients who had adult onset RE, three (23.07%) patients were treated with intravenous immunoglobulin (IvIg), one (7.69%) with plasma exchange and two (15.38%) patients with rituximab, two (15.38%) patients were treated with IV mitoxantrone while five (38.46%) patients underwent surgery. Of the five patients who had surgery performed, two patients underwent hemispherectomy while in two others selective cortical resection was performed. The fifth patient underwent resection of focal epileptic tissue in the sensory cortex. Fluorodesoxyglucose was used along with IvIg and hemispherectomy for RE due to double pathology.

Tacrolimus and steroid therapy were used in 17 (13.17%) adults and 13 (10.07%) of the children. IvIg was used as a treatment option in 11 (8.52%) of the children. Two (1.55%) of the children were given methylprednisolone, cyclophosphamide, and mycophenolate mofetil. Only one (0.77%) child was treated with alemtuzumab with intrathecal methotrexate and natalizumab. Eighty-five (65.89%) of the children ultimately underwent surgery. Of these, hemispheretomy, craniotomy and hemispherectomy were done in 22, one and 56 children respectively. However, surgery was preferred only when other treatment options did not show clinical improvement.

Follow up and outcomes

The patients were followed up for a long duration of time (5.38 years). Patients with adult onset RE had better clinical outcomes. Of the thirteen patients with adult onset RE 12 (92.30%) showed clinical improvement: patients were seizure free, there was improvement in neurological function, verbal memory, and working intelligence. Plasma exchange, IvIg, rituximab, IV mitoxantrone, hemispherectomy all showed better treatment outcomes in terms of reduced seizure frequency and normal neurological function. Despite the follow up of one (7.69%) patient for 1.1 years, she had no clinical improvement due to focal cortical dysplasia (dual pathology involved).

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.

Table 2. Characteristics of the included studies.

No.Author and yearNo. of patientsAge/sexClinical symptomsTreatmentTreatment durationOutcomesSymptoms that did not improveComplications
1C.G. Bien et al., 200447Median age: 11.6 (4 F/3M) (2F patients were adult onset RE)Tacrolimus22.4 monthsSuperior outcome of neurologic function and progression rate of cerebral hemiatrophyNo better seizure outcome
2N. Bahi-Buisson et al., 200418116 years (5M, 6F)Simple partial seizure in 8 patients, complex partial seizure in 3 patientsSteroid therapy9±2 yearsFive had significant reduction of seizure frequency with disappearance of epilepsia partialis continua, and improved motor functionSix patients had no benefit from steroid therapy and underwent hemispherotomy, two died of unexpected sudden death 5 and 7 years after seizure control
3Yuguang Guan et al., 201420205.71 years (11F, 9M)Epilepsy was the first manifestation of the condition in all patients6 left hemispherectomy and 14 right hemispherectomy5.45 yearsAll of the patients had increases in cognitive abilities after surgery most patients could walk independently1 patient with bilateral RE, fine movement of the hands was lost
4Vera C. Terra-Bustamante et al., 200921254.4±2.0 years (13M, 12F)Epilepsia partialis continua in 24 patients and 1 patient had focal motor seizureHemispherectomy63.3 monthsEleven patients were completely seizure-free. Twelve patients with mild facial jerks (six patients), sporadic hemigeneralized tonic-clonic seizures (three patients), and frequent tonic-clonic seizures continued to experience seizures (three patients). After surgery, deterioration in the mental and linguistic functions was seen in 15 and 12 individuals, respectivelyComparing pre- and post-operative language deficiencies, it was shown that 66.7% of the 12 patients with language disorder did not improve after surgery. Only two patients showed improvement in their cognitive function.
5Mary L. Zupanc et al., 19902317/FSimple partial seizures which initially consisted of speech arrest, drooling, and burning and aching pain in her right legLeft partial hemispherectomy followed by functional hemispherectomy9 monthsDiedAcute cerebral hemorrhage
6Manuel Arias et al., 200624151/MGeneralized motor seizures, intermittent metallic tinnitus, like a bell ringingIV polyclonal immunoglobulins (0.4 mg/kg daily for 5 days) twice a month15 monthsNo motor deficit and only brief and very isolated partial visual seizures
Language partially improved.
Right homonymous hemianopsia did not change
7Catherine Grosmaitre et al., 201325111/FPartial seizures (collapse of her right leg leading to falls)Left hemispherectomy4.1 yearsVerbal intelligence, working memory, and language improved.
She also became seizure free
8Rochelle Caplan et al., 19962644/11.7/5/5 FComplex partial seizures deviation of the eyes and head to the left, tonic extension of the left arm and both legs, and flexion of the right arm/onset of clonic jerking of the left hand and arm following a viral tonsillitis/repeated eye fluttering, grimacing, drooling, sensation of a sore throat, and need to touch her throat/tonic clonic seizures, status epilepticus, coma, and left spastic hemiparesisRight hemispherectomy21/19.3/9.1/17.5 monthsLanguage and formal thought disorder
9Sung-Min Cho et al., 201727111/MRefractory status epilepticusIV immunoglobulin (IvIg) (0.5 g/kg) with tacrolimus1.5 yearsMotor deficit resolved completelySeizures occurred occasionally
10Zuzana Liba et al., 20172817/MRight-sided hemiparesis with refractory epilepticusIV alemtuzumab (total dose of 0.75 mg/kg for three consecutive days) with intrathecal methotrexate 12 mg for a single dose)At 18 months after the surgeryNo functional use of the right hand, hardly walks, and speaks in very simple sentencesrelapse occurredSystemic reaction and hyperpyrexia,
11Jayaprakash et al., 20022914/MTonic clonic seizure with feverSteroids and IVIG and left hemispherectomy3 yearsSteroids and IVIG failed but after surgery he ambulated, and speech was normalResidual hemiplegia
12Sanfilippo et al., 201530132/FAscending epigastric sensation, chest tightness and paresthesia and weakness of the left part of the body later motor seizure with clonic movement of left sideAED, steroids, and plasma exchange18 monthsPlasma exchange showed improvement of symptomsHigh dose steroids had poor outcome
13Stabile et al., 201831233/38/FFocal unaware seizures, right-hand EPC, ipsilateral hemiparesis, and aphasia/focal unaware seizures with tonic clonic evolution frequently leading to SE, right hemiparesisIV mitoxantrone mean dose 10.5 mg/m2 every 2–3 months25/24 monthsSeizure frequency decreased in both the cases
14Taíssa P.F. Ferrari et al., 20113215.5/FProgressive hemiparesis without epilepsy later developed seizureRight hemispherectomy16 monthsSeizure free and able to walk without assistanceWorsening of left hemiparesis
15Danielle A. Nolan et al., 20183319/FTypical absence seizures, 1 year after diagnosis new-onset frontal headache for one week before suddenly developing left neck twitching. This progressed to involve her left arm and leg, followed by sudden left hemibody loss of sensationHemispherectomy4 years 3 monthsDiedIV immunoglobulin, AED, high dose steroids failed
16Katharina Hohenbichler et al., 201734117/FTonic clonic seizures initially two months later, the patient developed motor status epilepticus with continuous jerks of the right hand, clinically corresponding to epilepsia partialis continua (EPC)Hemispherectomy, IvIg, fluorodesoxyglucose1.1 yearsNo clinical outcomesDue to focal cortical dysplasia (double pathology)
17Flavio Villani et al., 201435228/MEPC with myoclonic jerks involved the tongue and the right face muscles and spreading to right limbs in 6 yearsConservative management: AED regimens such as carbamazepine, valproate, phenytoin, levetiracetam, and clonazepam and different trials with immunomodulatory therapies (high dose and chronic steroids, IVIG, plasmapheresis, and immunoadsorption with A protein.
Surgical treatment: Selective cortical resection
54 months after surgeryPatient was seizure free, reduced AED drugsModerate to severe non-fluent language deficit in 1st patient
35/FSporadic secondary generalized convulsive seizures with focal motor onset (left face and upper limb) EPC months of the left facial muscles and later involving the oral territory and neck after 16 monthsConservative management: AEDs carbamazepine, levetiracetam, valproate, and benzodiazepine, and high dose and chronic steroids, IVIg, and plasmapheresis
Surgical treatment: Cortectomy of the right frontal operculum
31 monthsNo adjunctive neurologic deficits and no progression of atrophy at MRI were observed after surgery. Patient stable on prednisolone therapyOne secondary generalized seizure a few days after a benzodiazepine dose reduction after 31 months of surgery
18L. Papetti et al., 20113619/FEpisodic left complex partial seizuresIV immunoglobulin4 yearsReduction in seizure frequency and improvement of EEG pattern
19Kevin Gurcharran et al., 20163712/FSubacute onset of progressive right hemiparesis, speech regression and right-side focal seizuresIV immunoglobulin12 monthsRight sided weakness improved, speech normal
20Yuguang Guan et al., 20113815/MSeizure involving shaking in his right hand/had three secondarily generalized tonic–clonic seizures (GTCSs) and three complex partial seizures, consisting of blank staring with eye deviation and head turning to the rightBilateral hemispherectomyMore than a yearNo clinical improvementHe cannot talk, walk, or eat without assistance
21Barbara Thilo et al., 200939120/FFocal clonic and tonic seizures, involving the left arm and the left side of her face, sometimes accompanied by impaired awareness and responsivenessIV rituximab
375 mg/m2
1.5 yearsPatient remained seizure free for 6 monthsInitially treated with immunoadsorption but had no improvement
22Zuzana Liba et al., 20154016/MSudden onset of focal seizures that gradually increased in frequency seizures were characterized by behavioral arrest, eyelid fluttering, and staring, followed by eye deviation upward and left-hand twitchingmethylprednisolone 30 mg/kg for three days and seven monthly cycles of cyclophosphamide (750 mg/m2), oral mycophenolate mofetil (MMF, 600 mg/m2)6 monthscognitively intact and making progress in school and have a normal neurologic examination
23Bhooma R. Aravamuthan et al., 20154115/FSimple partial seizures without EPC were accompanied by right arm and face clonic movements. Later, she experienced dysarthria, a right lower face weakness, and cognitive and educational stagnationThree courses of methylprednisolone (30 mg/kg/mo), 7 courses of cyclophosphamide (750 mg/m2/mo), and mycophenolate mofetil (600 mg/m2/d)11 monthsRight facial paralysis has disappeared, seizure frequency has decreased from once daily to once weekly, and academic performance has improved
24Shalini Narayana et al., 20194214.11 year/FRight arm twitching and weakness and right leg weakness/ Face and right-sided weakness/Frequent low-amplitude jerks of the right hand, arm, and leg were noted/ Muscle strength and fine motor skills was reduced in the right upper and lower extremities and was unable to bear weight on right lower extremity/Mild tightness of heel cord was noted in the right foot/Deep tendon reflexes were brisk in the right side and sustained clonus in the right ankleFrameless stereotactic MRI-guided left frontotemporal craniotomy and microsurgical functional hemispherectomy2 weeksAfter surgical intervention, the patient was seizure free, had stable right-sided hemiparesis, and her speech remained intact and was maintained on oxcarbazepineStable right-sided hemiparesis
25Qun WANG et al., 201743129/FConvulsions originally manifested as at witching of the right thumb that extended to the right hand and later to the entire upper limb, reversible hemiplegia, and speech disordersfunctional hemispherectomy2 yearsShe was seizure-free, without aggravation of hemiplegia.
Verbal and IQ score were improved
26Marie-Aude Spitz et al., 20144414/FJerks on the right cheek followed by right leg hypertonia and myoclonus causing her to fall and the evolution was marked by bilateralization of seizures, rapidly followed by EPC and an enrichment of seizure types, refractory to antiepeleptic drugsConservative: AED, corticosteroids, intravenous
Immunoglobulins
Surgical treatment: Left hemispherectomy
4 months after surgeryNormal IQ, working memory, distractibility, and moderate reading abilities at schoolRight hemiparesis and hemianopsia
27Vijay M. Ravindra et al., 201545112/FOn a neurological examination, the patient had headaches, worsening handwriting, declining academic performance, and social withdrawal over a three-month period. Additionally, the patient had left hemiglossal atrophy, pronator drift of the right upper extremity, and mild weakness of the right hand's intrinsic muscles, grip, and wrist extensionSurgical treatment: Craniotomy, Conservative treatment after surgical intervention: Tacrolimus, methylprednisolone, and IvIg15 monthsHer right extremity strength had significantly increased, yet she still has some residual weakness. She no longer had seizures and her cognitive function had not worsened
28Stefan Bittner et al., 20134618/FRecurrent episodes of EPC as well as other focal seizures and developed a progressive right-sided hemiparesis with partial impairment of language abilitiesConservative management: Dexamethasone and azathioprine, IVIg and a combination therapy of AED (levetiracetam (4 g/day), pregabalin (500 mg/day), and zonisamide (400 mg/day) in, rituximab (1 cycle, 2 3 1,000 mg), IV natalizumab, 300 mg, monthly13 months after start of treatmentReduced seizure frequency
29Christian G. Bien et al., 201347165.7 years (10 F, 6M)Refractory epilepsy (9), Drug-responsive epilepsy (1), Undetermined responsiveness (2), EPC (4)Tacrolimus (n=9) and IVIG (n=7)6.3 yearsSlowed down tissue and function loss and prevent development of intractable epilepsySerious event in tacrolimus and No patient with refractory epilepsy became treatment-responsive under immunotherapy
30Tiziana Granata et al., 201348165.8 years (8M, 8F)N/AHemispherotomy9.5 yearsAt the time of the follow-up, all patients but three were seizure-free, ten had discontinued using AEDs, six had significantly reduced their use, and all had improved postural control. Gains in cognitive ability were significantly (p = 0.002) correlated with the severity of the illness
31M. Topçu et al., 19984967.1±2.2 years (3M,3F)Left-sided continuous partial epilepsy affecting her face and limbs and a left hemiparesis, seizures manifested as chewing movements, a rightward turn of the head, and difficulty speaking. Right-sided twitching of the face, drooling, deviation of the tongue to the right, and tonic posturing of his right arm were also present. clonic contractions, repeated seizures with tonic-clonic contractions that start in the right hand and move to the right side, epilepsia partialis continua that affects her left side, and persistent left focal motor seizures that impair his face and armSurgery32.3+17.2 yearsIn three cases IvIg therapy yielded temporary and partial improvement in seizure control, Seizures were fully controlled in one patient, in whom surgery was performed 3 months after the seizures first started
32Ali Hammed et al., 20215028 year/FRepeated episodes of clonic seizures including right upper and lower limbs with slurring of speech, cognitive delay, and abnormal gait/right hemiparesis/Muscle power Medical ResearchCouncil (MRC) grade 3/exaggerated tendon reflexes on the right side/severe global developmental delayImmunotherapy either IvIg followed by methyl prednisolone followed by oral prednisole for 28 days, (surgical intervention being considered)4 weeksIncrease in the frequency of seizure to three times a dayNo improvement
5 year/MMutiple episodes of clonic seizures of the upper and lower limbs since 8 months each episode lasting for 5-15 minutes with prolonged postictal state with sudden loss of consciousness and bladder incontinence/Left sided hemiparesis/Muscle power of grade 4. Seizure progressed to epilepsia partialis continuaConservative management: Levitiracetam, clonazepam, lamotrigin, carbamzepime and valproate sodium, IV steroids, Tacrolimus
IVIG immunoglobin and surgical treatment with functional hemispherectomy
6 monthsDiedEffacement of cortical sulci, asymmetry between two cerebral hemispheres with atrophy of right cerebral hemisphere
33Anteneh M. Feyissa et al., 202151132 year/FHeadache, fatigue, cognitive dysfunction, focal impaired awareness seizure focal to bilateral tonic-clonic seizures/right homonymous hamianopiaRituximab monotherapy
Neurostimulation therapy
Rituximab therapy: 4 years neurostimulation therapy:24 monthsGreater than 50% decline of seizure frequency after neurostimulation therapy and the seizure become shorter in durationImprovement in general intellectual, immediate attention, learning, retention of visual material constructional skills, verbal fluency, executive function and cognitive speed over time
34Arnold J. Sansevere et al., 20205216 year/MFocal to bilateral tonic-clonic seizures with visual phenomena, a leftward deviation, and retained consciousness. The nauseated feeling that follows the seizure is followed by limpness.Conservative therapy: AED like levetiracetam, oxcarbazepine, valproic acid, zonisamide, topiramate, and diazepam, fosphenytoin, IVIG immunoglobin, methylprednisolone, rituximab. Surgical treatment: Functional hemispherectomy5 yearsNo evidence of clinical seizures or hemichorea after surgical treatment. After 6 months of hemispherectomy all antiseizure medications were discontinued.
Improved impulse control and showed some improvements in many language-based areas with stable neuropsychological function
Struggle with executive function and working memoryPsoriasis in the ears, popliteal fossa, gluteal clefts and umbilicus/right sided non-reactive pupil with gray discoloration of the iris/ chronic anterior uveitis/cataract and decreased visual acuity
35Mohammad Bilal Mazar et al., 20225314.5 year/MWeakness of left side of the body for 7 moths/seizure of of either left upper limb or lower limb 8-10 episodes per day for 10-15 minutes/aphasic and disoriented in time and space/exaggerated deep tendon reflexes of the left sides/left-sided up-going plantar responseConservative treatment: Valproic acid, phenytoin, levetiracetam, methylprednisoloneSeizure persisted 2-3 times a day but duration is reduced to 15-20 secondsAphasia and hemiparesis involving the left side of the body still persistent.
36Monika Mochol et al., 202154145 year/FAt the age of 17, a focal seizure with diminished awareness was followed by a focused to bilateral tonic-clonic seizure.
Between the ages of 18 and 26: focal conscious seizures, usually beginning with jerking in the left shoulder, arm, and face, occasionally followed by head rotation/speech impediment, and sporadic focal to bilateral tonic-clonic seizures
Conservative treatment: valproate, fosphenytoin, levetiracetam, clonazepam, and lacosamide. Immunoglobulins and high dose i.v. steroids. Non-invasive trigeminal nerve stimulation, Anakinra
Surgical treatment: Resection of focal epileptic tissue in sensory cortex of the right parietooccipital region/subpial resections in the right motor cortex
28 yearsAfter injection with Anakinra seizure frequency decreased and after one week seizure stopped. discontinuation of anakinra after 2 months lead to relapse of seizures.
Cognitive function slightly improved
Pneumonia after ontroduction of anakinra, prone to rinary infections, spastic paralysis of the left arm
37Ramesh Sharanappa Doddaman et al., 202155112 year/FSeizure onset at the age of 10 years with aura of fear and nausea followed by the tonic deviation of the eyes to the right and blinking with speech arrest/Involuntary tonic-clonic of right upper limb suggestive of EPC/right sided hemiparesis loss of pincer grasp/MRC grade 2/5 and continuous movement of right handConservative treatment: Antiepileptic medications, methylprednisolone
Surgical treatment: Left sided endoscopic hemispherectomy
2 yearsPatient is seizure free and the weakness improved from Grade0/5 to 3-4/5 at one year of follow up after surgical treatment. The patient is able to walk independentlyDeveloped hemiplegia immediately after surgery
38Ricardo Pires Alvim et al., 202056256 year/MClonic movements in the left arm and oculocephalic deviation to the left, with 24 hours of impaired consciousness; a rapid decline in cognitive function over the previous three months, with temporal and spatial disorientation and impaired episodic memory; behavioral issues, including apathy and complex visual hallucinations; bradypsychism and dysarthria; and comprehension of brief commands. Katz Index of Independence in Activities of Daily Living score of 4 out of 6 due to modest left hemiparesis and spasticityCarbamazepine 600 mg/d and lamotrigine 150 mg/d; risperidone 1 mg/d
Immunoglobulin (2 g/kg), with cognitive stabilization
3 yearsScored 12 on the FAQ and 24 on the MMSE three years later, showing a marginal improvement in functional capacity
65 year/MAt the age of 48, visual hallucinations and partial motor seizures began. Neuropsychiatric symptoms included paranoid delusion, depression, and suicidal thoughts. Loss of complicated daily activities and cognitive decline related to spatial orientation and episodic memory. Simultaneous prosopagnosia and synarthria
Bilateral and asymmetric parkinsonism, worse on the left hemibody, and myoclonus on this side were all present on test score 13/30 in addition to mid-left hemiparesis (MRC grade IV/V) and pyramidal symptoms
AED and corticosteroid pulse therapy

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.

Reporting guidelines

Figshare: PRISMA checklist for ‘Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease’, https://doi.org/10.6084/m9.figshare.20477835.v1.15

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)

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Chamlagain R, Shah S, Thapa S et al. Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2022, 11:1049 (https://doi.org/10.12688/f1000research.124673.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 27 Sep 2023
Marie Studahl, Dep of Infectious Diseases, Sahlgrenska University Hospital/Östra, Göteborg, Västra Götaland, S-416 85, Sweden 
Not Approved
VIEWS 1
The authors have registered a pre-established protocol on the International Prospective Register of Systematic Reviews (PROSPERO) database in advance which is exemplary. (ID: CRD42021261999). As the authors mention in the Introduction the review of different treatments in published cases might lead ... Continue reading
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Studahl M. Reviewer Report For: Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2022, 11:1049 (https://doi.org/10.5256/f1000research.136895.r196739)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 22 Aug 2023
Sophie Binks, University of Oxford, Oxford, England, UK 
Approved with Reservations
VIEWS 2
Overall I felt this could be a useful project but it fell short on a few aspects.

I was missing details on statistical methods. When the authors state that "Plasma exchange, IvIg, rituximab, IV mitoxantrone, hemispherectomy all ... Continue reading
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HOW TO CITE THIS REPORT
Binks S. Reviewer Report For: Different modalities of the treatment of Rasmussen encephalitis: A systematic review of case reports of a rare disease [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2022, 11:1049 (https://doi.org/10.5256/f1000research.136895.r187227)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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