Rasmussen's Encephalitis

Abstract Rasmussen's encephalitis (RE) is a childhood epilepsy syndrome characterized by drug-refractory focal seizures especially epilepsia partialis continua, progressive hemiparesis, and neurocognitive decline. Diagnosis is mainly clinical and can be ambiguous during the early stages of the disease. Its underlying etiology is still elusive, but is suspected to be immune mediated. Treatment of seizures and disease progression is challenging, and although immunotherapy may delay its course, to date, surgical disconnection of the diseased hemisphere remains to be the only effective treatment providing seizure freedom in 60 to 85% of cases. The following review summarizes the current knowledge of the pathophysiology, clinical presentation, management, and treatment of RE.


Introduction Pathogenesis
The macroscopic hallmark of RE is hemispheric atrophy, centered on the frontotemporal and insular regions, 4 while its characteristic histopathologic findings include hemispheric cortical inflammation, perivascular cuffing, gliosis, microglial nodules, and neuronal cell loss and injury. 5 Staged pathological findings have been described. 6 In stage 1, the affected cerebral cortex shows T-lymphocytic infiltration, astrogliosis, and microglial cell activation. Multifocal and marked panlaminar inflammatory reaction with neuronophagia, lymphocyte clusters, and perivascular astroglial reaction are seen in the intermediate stage (stage 2). Neuronal loss, focal spongiosis, panlaminar astroglial reaction with less T cell infiltration, and cortical atrophy marked stage 3. Stage 4 is characterized by extensive cortical vacuolation and panlaminar degeneration. The early T cell infiltration suggests initial involvement of adaptive immune system. Thus, cytotoxic CD8 þ T cell-induced neurodegeneration and astrocytic destruction has been proposed as one of the underlying pathogenic mechanisms in RE. 7,8 However, the triggering factors remain unclear. The pathologic findings of chronic encephalitis led investigators to speculate a localized viral infection of the diseased hemisphere. Epstein-Barr virus, 9 cytomegalovirus, 10 and herpes simplex virus 11,12 have been implicated in some studies, but there is lack of convincing evidence for the causal relationship between these viruses and RE. Autoimmune process driven by certain autoantibodies has also been suggested. Initially, circulating antineuronal antibodies against ionotropic glutamate receptor type 3 (GluR3) was speculated to be triggering the neuronal activation and seizures in RE, 13 but further studies suggested that GluR3 antibodies are nonspecific to RE, 14 can be been found in other neurologic disorders, and may not be present in biopsy-proven RE cases. 15 Other investigators have reported antibodies against α-7 nicotinic acetylcholine receptor (nAChRs) 16 and mammalian uncoordinated (Munc) 18-1. 17,18 Although RE cases harbor these neuronal antibodies, Pardo et al suggested that their presence may be due to epiphenomenon rather than the underlying cause. 19 Innate immune system activation may also be involved as suggested by the presence of microglial activation, microglial nodules, and microgliosis in RE pathology. 19 Microglia activation is observed in the early stages, and its magnitude follows the pattern of disease progression and the extent of T lymphocyte infiltration. 6 Furthermore, microglial reactivity was found to be increased in severely affected RE areas compared with minimally affected RE regions, cortical dysplasia, and tuberous sclerosis complex. 20 In vivo, microglial activation in RE has been demonstrated using 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK 11195) positron emission tomography (PET) scans. 21 Induction of inflammasomes, which are complex protein aggregates located within the microglia that regulate interleukin-1β release, has also been shown in the cortex and white matter of RE brain tissues, suggesting its role in the pathogenesis of RE. 22 With the expanding experimental and clinical evidence supporting the link between proinflammatory pathways and epilepsy, the role of high-mobility group box-1 (HMGB1) toll-like receptor (TLR) signaling pathway in RE has been studied. The TLR signaling pathway plays a key role in pathogen recognition triggering inflammation by inducing the transcription of genes encoding cytokines, including interleukin-1β, and in the absence of pathogen, it may be activated by molecules released by injured tissue which include the endogenous HMGB1, a ubiquitous chromatin component passively released by necrotic cells, retained by cells undergoing apoptosis, and actively secreted by cells in profound distress. 23 Using immunohistochemistry technique, Luan et al demonstrated the cytoplasmic expression of HMGB1 in the neuronal cells and reactive microglial cells and TLR2 up-regulation and TLR4 expression in RE specimens. 24 Recently, adenosine, an endogenous neuromodulator of neuronal excitability, has been implicated in RE. In the brain, adenosine exerts potent depressant effects on neuronal firing and synaptic transmission. 25 Upregulation of adenosine A1 receptor (A1R) and overexpression of adenosine kinase (ADK), a major adenosine-removing enzyme, in RE lesions have been observed. 26,27 These recent findings unveil a potential new avenue for research for future therapeutic targets in RE.

Clinical Features
RE typically affects children with average age of onset of 6 years, 28 but may also present in adolescence and adulthood. 29,30 Its course is progressive over months or years, with development of hemiparesis, visual field deficits, and cognitive decline as well as aphasia, if the dominant hemisphere is involved. The course in adolescent or adult-onset cases may be more variable and slower, and the deficits may not be as severe compared with childhood-onset RE. 31,32 Staged clinical presentation has been described: 33 prodromal stage, nonspecific phase with low seizure frequency, mild hemiparesis (median duration: 7 months; range: 0 months to 8.1 years); acute stage (median duration: 8 months; range 4 to 8 months), marked by frequent seizures, mostly partial motor seizures and EPC which occurs in 50% of cases, 28 but other seizure types may emerge, and residual stage, defined by the presence of fixed and stable neurological deficits, with persistent drug-refractory seizures though maybe less frequent than during the acute stage.
Early in the disease, seizures may be variable, and the spectrum includes visual, autonomic, and sensory symptoms and loss of contact, but motor involvement is almost always present. 34 Atypical presentations have been reported including two adult cases: first case presented with chronic temporal lobe epilepsy without significant neurologic deficits or progressive MRI changes and had favorable outcome following temporal lobectomy; 35 second case presented with slowly progressive hemiparesis with absence and delayed onset of seizure 36 and RE associated with dual pathology. 37 RE can also present with movement disorders including chorea, athetosis and dystonia. 38

Neuroimaging and Electroencephalography Findings
Serial neuroimaging in RE typically shows progressive unihemispheric atrophy. Brain MRI has become a key diagnostic tool providing clues for its early diagnosis. 39 Bien et al described the MRI staging of RE as follows-stage 0: no abnormality noted; stage 1: swelling and hyperintense signal; stage 2: hyperintense signal and normal volume; stage 3: atrophy and hyperintense signal; and stage 4: atrophy (usually progressive) and normal signal. 40 Some investigators noted frontoinsular atrophy (►Fig. 1A) with ipsilateral lateral ventricle enlargement and caudate atrophy associated with cortical and/or subcortical T2W and FLAIR white matter signal abnormalities during the first few months of the disease. 34,39 Functional neuroimaging using 18 F-fluorodoexyglucose (FDG)-PET shows diffuse, unilateral cerebral glucose hypometabolism corresponding to the regions of cerebral atrophy on MRI, and during ictal studies, discrete areas of hypermetabolism corresponding to site of seizure activity may be seen (►Fig. 1B). 41 FDG-PET maybe particularly useful during the early stages of the disease when MRI abnormality is subtle or absent. 42 As previously alluded, PK11195 scan may show areas of increased uptake representing activated microglia in RE (►Fig. 1C).
The EEG findings supportive of the diagnosis of RE include unihemispheric impairment of the background activity and sleep spindles, focal slow activities, and multifocal and subclinical ictal discharges involving one hemisphere. 3 EEG during EPC may however fail to show epileptiform activity because the cortical activity may be too small to show up over prominent background activity or because the dipole of the discharge is oriented at an unfavorable angle not picked up by the recording electrodes on the scalp. 43 Contralateral EEG abnormalities may emerge overtime within 6 months in 25% and within 3 to 5 years in 62% from seizure onset and may be a marker of cognitive decline. 44 Magnetoencephalogram (MEG) in RE demonstrated the presence of clusters of spikes of variable localization suggesting its progression in a multifocal and fluctuating manner though these cortical areas did not correlate with the most atrophic areas on MRI. 45

Differential Diagnosis
There are other neurologic conditions that may present with EPC in childhood and mimic RE including focal cortical dysplasia, 46 Sturge-Weber syndrome, 47 and hemimegalencephaly. 48 Brain MRI features may help differentiate these disorders from RE. 49 Early in the course, no specific EEG pattern can distinguish focal cortical dysplasia from RE, but as the condition evolves, persistent delta activities over the affected hemisphere with contralateral normal background activity, followed by development of independent epileptiform discharges over the unaffected hemisphere may support the diagnosis of RE. 44 Alpers syndrome is an important cause of EPC in childhood 50 and can be diagnosed clinically and by biochemical assessment and genetic testing. 51 Idiopathic hemiconvulsion-hemiplegia syndrome or IHHS 52 is worth mentioning as an important differential diagnosis of RE. It typically occurs in previously normal young children (<4 years of age), with younger age of onset than RE and is characterized by the combination of unilateral convul-sive status epilepticus (mainly clonic), followed by transient or permanent hemiplegia. During the acute stage, seizures start with either unilateral rhythmic 2-3 Hz jerk or head and eye version and may last for several hours (up to 24 hours), while during the chronic phase, majority of patients develop temporal lobe seizures. 53 Brain MRI during the acute stage typically shows diffusion restriction on one side (mainly in the perisylvian and parietooccipital regions) suggestive of cytotoxic edema followed by unilateral atrophy during the chronic stage. 54 Similar to RE, affected children develop hemispheric brain atrophy with contralateral hemiplegia and variable cognitive deficits. Parry-Romberg syndrome (PRS), also known as progressive hemifacial atrophy, present in childhood and in young adults with progressive unilateral facial atrophy, focal seizures, and unilateral brain lesion ipsilateral to the site of facial atrophy, and co-existence of PRS with RE has been reported. 55,56 However, PRS is also associated with other systemic findings including skin and ophthalmologic involvement. 57 According to some reports, RE and PRS may share a common autoimmune cause. 58

Diagnosis
The diagnosis of RE is mainly clinical and is based on the presence of history of focal motor seizures, motor involvement, neuroimaging, and EEG findings supported by histopathological changes in brain biopsy, but a negative biopsy will not exclude its diagnosis due to the multifocal nature of its pathology, as suggested by Pardo et al. 6 Furthermore, biopsies performed at the later stages of the disease may only show nonspecific findings consisting of atrophy, residual gliosis with minimal inflammatory cellular infiltratesreferred to as "burned-out encephalitis." 3, 41 Granata et al reported that refractory focal seizures with prominent motor component, focal slowing on EEG, and focal white matter hyperintensity with insular atrophy on neuroimaging contralateral to the motor symptoms may allow the diagnosis of RE 4 to 6 months from disease onset. 34 Currently, there is no laboratory test available to support the diagnosis of RE, and CSF studies may be normal in 50%, but some may show pleocytosis (15-60 cells/μL) with lymphocytic predominance and increased CSF protein (50-100 mg/dL). 3 However, CSF studies are typically still done to exclude other causes especially CNS infection.
In 2005, the European Consensus on pathogenesis, diagnosis and treatment of RE proposed a diagnostic criterion (►Table 1), 3 which currently remains to be an accepted guideline with high sensitivity of 81% and specificity of 92% and good clinical-pathologic correlation in the majority of cases. 59

Treatment Anti-Seizure Medications
There have been no reports of antiseizure medications proven to be superior in the treatment of seizures in RE. Control of seizures especially EPC is usually unattainable. Rather, the realistic goal of seizure treatment is control of the severe seizures including generalized tonic-clonic seizures while minimizing the adverse effects of medications. Furthermore, the pharmacokinetic profile of antiseizure medications should be carefully considered especially if the patient is also on immunotherapy. Non-enzyme-inducing or inhibiting anti-seizure medications are preferable. Vagus nerve stimulation (VNS) 60 and transcranial magnetic stimulation 61 have been reported to provide improvement in seizure control in some individuals. For those with painful myoclonic activity from EPC, botulinum toxin treat-ment has been reported to provide benefit 62 and may improve functional use of the limb affected by involuntary movements. 63

Surgical Treatment
Complete surgical disconnection of the affected hemisphere (hemidisconnection), by either hemispherectomy or hemispherectomy, remains to be the only effective treatment in RE to arrest the disease progression and to provide complete seizure control which has been reported in 60 to 85% of cases. 64,65 Less extensive surgeries like temporal lobectomy has been performed with resultant short-term improved seizure control, 35 but sustained seizure freedom with small resections has not been reported. The efficacy of hemispherectomy should however be weighed against its permanent functional consequences and should be thoroughly discussed with the patient and family.
The timing of surgery may be dictated by the severity of epilepsy and neurocognitive decline and by the dominance of the affected hemisphere.
Early hemispherectomy has been proposed by some investigators for it may favor the compensatory reorganization of the contralateral healthy brain and avoid the interference of seizures with early brain development. 66,67 Even with dominant hemisphere involvement, in children less than 6 years of age, hemispherectomy is considered given the higher chance of brain plasticity and language transfer. 65,68 Conversely, some investigators advocated performing hemispherectomy only when the neurological deficits (hemiparesis with impaired finger movement, hemianopsia, and aphasia if dominant hemisphere is involved) which would be induced by the In addition, if no biopsy is performed, MRI with administration of gadolinium and cranial computed tomography needs to be performed to document the absence of gadolinium enhancement and calcifications to exclude the differential diagnosis of unihemispheric vasculitis. 81 a Progressive means that at least two sequential clinical examinations on MRI studies are required to meet the respective criteria. To indicate clinical progression, each of these examinations must document a neurological deficit, and this must increase overtime. To indicate progressive hemiatrophy, each of these MRIs must show hemiatrophy, and this must increase over time.
surgery, have been brought by the disease' natural course, 69,70 while others suggested immunotherapy for those with nonrapidly progressing and fluctuating course and with mild deficits and early hemispherectomy to those with very rapid progression of seizures. 71 A therapeutic algorithm for patients with RE based on the severity of seizures and neurological deficits has been suggested. 64,65 Immunotherapy Since the pathogenesis of RE is suspected to be immunemediated, immunotherapy including intravenous immunoglobulin (IVIg), plasma exchange (PLEX), and corticosteroid treatment have been utilized. These treatment modalities are used either as "short-term" treatment for seizure alleviation for those who are too functional to be offered hemispherectomy for surgery results in inevitable hemianopsia, hemiparesis with loss of fine motor skills and aphasia, if dominant hemisphere or as chronic treatment to halt immune-mediated brain damage and tissue loss during the early stage of the disease. However, it is probably useless during the residual stage of the disease once the neurological deficit has stabilized. 68 Immunotherapy is also considered in those with slow disease progression and bilateral involvement, and when RE is suspected, yet the typical disease progression and unilateral hemispheric atrophy have not developed. 43,72 Corticosteroids Corticosteroid treatment typically starting at high doses (pulses of methylprednisolone) and slowly tapering with oral prednisone has been reported to have beneficial effect especially when initiated during the early stage of the disease. 3,73,74 In two studies, IV daily bolus of methylprednisolone (400 mg/m 2 /day in adults and 20 mg/kg/day in children) terminated RE-associated status epilepticus. 72,74 Following highdose IV methylprednisolone, chronic prednisone treatment at 1 mg/kg/day was utilized in these studies, but the efficacy of which was uncertain due to its fluctuating course though attempts to withdraw prednisone resulted in decline. 72 One study showed that although corticosteroids can be useful in the treatment of RE when started early in the active phase of the disease, it does not give a sustained effect, and in many cases, long-term relapse can occur leading to delayed decision for hemispheric disconnection. 75 Furthermore, long-term use of corticosteroids is associated with significant side effects.

Intravenous Immunoglobulin
Intravenous Immunoglobulin (IVIg) at a dose of 0.4 g/kg/day for 5 days followed by monthly maintenance therapy (0.4 g/ kg 1 day each month) for several months appeared to be effective in adult-onset RE with improvement in seizure control, hemiparesis, and cognition, 76 whereas regular IVIg therapy in some pediatric patients was discontinued due to seizure aggravation. 77 The combination of steroids and IVIg may also be considered when the two treatments alone are ineffective. 68,72,74 Plasma Exchange and Immunoadsorption Plasma exchange and immunoadsorption (IA) are used based on the premise that it can potentially remove circulating pathogenic autoantibodies 68 and have been shown to provide transient improvement in neurologic functions and seizure frequency in some patients supporting the suspected role of humoral or antibody mediated immune system in this disorder. 78 PLEX has been performed at three to six single volume exchanges every 2 to 8 weeks. 72,78 IA has been shown to improve seizure control and neurologic treatment in few cases. 72,79 Long-term experience with PLEX and IA is lacking. Some authors suggest that in children, these treatments should be reserved to patients with acute deterioration or to assess residual and motor function prior to surgery. 68

Tacrolimus
Tacrolimus, a T cell-depleting agent, has been shown to arrest the functional and cognitive decline, but without impact on the seizure progression. 80 Compared with historical control who did not have immunotherapy, Bien et al showed that immunotherapy-treated patients with either tacrolimus or IVIg had delayed deterioration of functional and motor outcome without improvement in seizure control. 2 Takahashi et al examined the seizure, cognitive, and motor outcomes in RE following hemispherectomy and various forms of immunotherapy. 77 Seizure-freedom rate was the highest with hemispherectomy (71% seizure-freedom rate), whereas response rate (defined as > 50% seizure reduction) was 81% with regular steroid pulse therapy, 42% with tacrolimus, and 23% with IVIg. However, cognitive outcome as measured by the rate of patients with full-scale intelligence quotient/developmental quotient (FSIQ/DQ) >80 was the lowest among patients who had functional hemispherectomy of the non-dominant hemisphere. As expected, motor function aggravation was the highest in the hemispherectomy group, and improvement in motor function was observed only in the immunotherapy group.
The authors suggested early immunotherapy in cases of early stages of RE (preferably before any motor or cognitive dysfunction) and among those with no MRI lesions with initiation of regular pulse IV methylprednisolone therapy with dose ranging from 30 mg/kg/day in children to 1 g per day in adults for 3 days at an interval of once a month for several months, then switching to tacrolimus at starting dose of 0.1 mg/kg/day (for children) or 3 mg/day (for adults) with dose escalation after 2 months. 77 Conclusion RE is a rare form of chronic focal encephalitis characterized by intractable focal seizures especially EPC, hemiplegia, and progressive encephalopathy, associated with inflammation and progressive atrophy of a single hemisphere. A diagnostic criteria proposed by the European Consensus in 2005 using clinical, EEG, and MRI findings remain to be a useful guideline in its diagnosis. Complete disconnection of the affected hemisphere is currently the only effective treatment, but has functional consequences. In patients who are too functional to be offered hemispherectomy, immunotherapy has seen used to slow down the neurologic decline and to control acute deterioration especially status epilepticus, but it may also inadvertently lead to the risk of delaying the initiation of definitive surgical treatment. The benefits and risk of each treatment modalities should be discussed with the patients and families. Future studies preferably in randomized control fashion are needed to clarify the short-and long-term benefits of immunotherapy.