What is Rasmussen encephalitis

Rasmussen’s encephalitis also known as chronic focal encephalitis, is a rare chronic neurological disorder, characterized by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration of unknown origin ¹. Rasmussen’s encephalitis usually occurs in children under the age of 10 (more rarely in adolescents and adults), and is characterized by frequent and severe seizures, loss of motor skills and speech, paralysis on one side of the body (hemiparesis), inflammation of the brain (encephalitis), and mental deterioration.

Rasmussen encephalitis was first described by American neurologist Theodore Brown Rasmussen (1910-2002) in 1958 ².

Most Rasmussen encephalitis (85% cases) occur in children under the age of 10 years ³. However, detection in adults is increasing with routine MRI investigations for intractable seizures ⁴.

Investigators in a German study ⁵ estimated the countrywide incidence at 2·4 cases per 10 million people aged 18 years and younger per year. Similarly, researchers in a recent UK surveillance study ⁶ estimated an incidence of 1·7 per 10 million people aged 16 years and younger per year (a prevalence of 0·18 per 100 000 people). Sex, geographical, and ethnic predominance have not been reported.

Most individuals with Rasmussen’s encephalitis will experience frequent seizures and progressive brain damage in the affected hemisphere of the brain over the course of the first 8 to 12 months, and then enter a phase of permanent, but stable, neurological deficits. The seizures are intractable despite aggressive medical management ³. Apart from seizures, patient may have hemiparesis [weakness affecting one side of the body] and speech disturbances, as well as hemianopia [blindness over half the field of vision] (pertaining to unilateral cerebral involvement). Mental deterioration over time may also be seen, especially in patient presenting later in adolescence.

Three disease stages of Rasmussen’s encephalitis

1. Prodromal stage: Non-specific, low seizure frequency, and mild hemiplegia
2. Acute stage: Frequent seizures, often epilepsia partialis continua; progressive hemiparesis, hemianopia, cognitive deterioration, and aphasia (if dominant hemisphere affected)
3. Residual stage: Permanent and stable neurological deficits and continuing seizures

Rasmussen encephalitis has features of an autoimmune disease in which immune system cells enter the brain and cause inflammation and damage.

Neuropathological and immunological studies support the notion that Rasmussen’s encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen’s encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen’s encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen’s encephalitis, without changing the eventual outcome. Research is ongoing into the causes of this rare disease.

Typically, affected individuals develop focal seizures that may progress to near continuous seizures termed epilepsia partialis continua (generalized status epilepticus). Generalized status epilepticus is characterized by a rapid, rhythmic succession of contractions and relaxations of a muscle or muscle group (myoclonus), particularly of the arms, legs, and face, that may occur singularly or in a repetitive, continuous series. In Rasmussen encephalitis this occurs consistently on one side of the body opposite the side of the inflammation.

Most affected children will exhibit progressive paralysis of one side of the body (hemiparesis) and if the seizures continue developmental disabilities. In many cases, the development of physical and mental abilities of affected children may cease (developmental arrest). In addition, affected children may lose previously acquired physical and mental abilities (developmental regression). Some affected children may exhibit degeneration (atrophy) of one side of the brain and/or progressive confusion, disorientation, and deterioration of intellectual abilities (dementia).

Rasmussen encephalitis occurs mostly, but not always, in children between the ages of two and ten years, and in many patients the course of the disease is most severe during the first 8 to 12 months. After the peak inflammatory response is reached, the progression of this disorder appears to slow or stop and the patient is left with permanent neurological deficits.

Rasmussen encephalitis causes

The cause of Rasmussen encephalitis is unknown. On the basis of the earliest immunological response, the inflammation in the brain seems to be driven by an antigen, which could be foreign (an infectious agent) or autoimmune. Another possibility could be that Rasmussen’s encephalitis is the consequence of dysfunction of the immune response to the presentation of an otherwise minor antigen. That dysfunction could be genetic in origin. The hunt for the Rasmussen virus or antigen needs further research.

So far, data from histopathology studies suggest that the earliest components of change include microglia and early death of glia and neurons. Findings of studies using tissue samples from cases of Rasmussen’s encephalitis support the notion that only one or a few antigens probably produce the disease in the brain. Previous attempts to find viral antigens used techniques that were not sensitive enough, and state-of-the-art analyses should be used to confirm or refute the viral hypothesis. This study ⁷ adds to previous findings and highlights that CD4+ TCCs and γδ T cells that secrete IFN-γ and TNF are also involved. These findings underline the complexity of T-cell immunity in Rasmussen encephalitis and suggest a specific role for CD4+ T cells in orchestrating the CD8+ T-cell effector immune response. It will be important now to identify the target antigens of both CD4+ and CD8+ TCCs and clarify if these are self- or foreign antigens and if molecular mimicry is involved. Future studies about the possible antigens causing or driving the disease should investigate all 3 T-cell populations, CD8+ and CD4+ T-cell clones, and γδ T cells.

Aspects that deserve further consideration are genetic and environmental interactions. To date, no clear pattern of familial inheritance in Rasmussen’s encephalitis has emerged, but in one early study93 decreased IgA concentrations and increased frequency of HLA type DR6 were more likely in patients with Rasmussen’s encephalitis and in first degree relatives than in controls, suggesting a possible genetic predisposition. More research will be needed to confirm these preliminary observations. In 2008, a mutation in SCN1A was described in association with a case of Rasmussen’s encephalitis ⁸.

Why does Rasmussen’s encephalitis only affect one cerebral hemisphere?

The answer to this question would depend on the source of the presumed antigen that initiates Rasmussen’s encephalitis. If the antigen is a foreign infectious agent, this could explain why Rasmussen’s encephalitis is unihemispheric but without a side preference. If Rasmussen’s encephalitis is an autoimmune disease, attention might need to be focused on recently discovered genes and proteins related to individual cerebral hemisphere brain development expressed only on one side.

Rasmussen encephalitis radiology

MRI of the brain has become a mainstay for diagnostic assessment and follow-up in Rasmussen’s encephalitis ⁹. Usually, within months of onset of the acute stage, most patients show unilateral enlargement of the ventricular system. A T2/FLAIR hyperintense signal is often present in cortical or subcortical regions, or both, the distribution is heterogeneous, and temporal fluctuation might be related to seizure frequency in patients without epilepsia partialis continua (generalized status epilepticus) ¹⁰. The perisylvian region is a predilection site for signal change and volume loss (Figure 2). Ipsilateral atrophy of the head of the caudate nucleus is a typical but not an invariable accompanying feature of hemispheric atrophy, and can be an early sign ⁹. Serial MRIs typically show progression of signal change and atrophy. Recent radiological volumetric approaches describe the highest rate of volume loss in the first 8 months of disease, the acute clinical phase,6 and putamen predominance, rather than caudate predominance, in the basal ganglia ¹¹. Some atrophy is always evident, even of the unaffected hemisphere, probably as a result of degeneration of commissural fibers ¹². Functional studies using 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) show diffuse unilateral cerebral hypometabolism that might manifest when MRI atrophy is still at a minimum ¹³.

Figure 1. Rasmussen encephalitis MRI (unilateral left sided cerebral atrophy is seen with multiple T2/FLAIR hyperintense areas in left basal ganglia and parieto-occipital region, and ex-vacuo dilatation of left lateral ventricle)

Figure 2. Rasmussen encephalitis MRI

Note: MRI brain scans of children with Rasmussen’s encephalitis, showing contrasting cases of radiological progression. (A) Progressive right hemisphere atrophy, high signal and basal ganglia loss over 1 year (from left to right) in a child with Rasmussen’s encephalitis. The disease was mostly centered near the right Sylvian fissure (arrow). (B) Slowly progressive disease with more subtle right hemisphere atrophy in a child on immunosuppressant treatment at 6 months (left), 18 months (center), and 30 months (right) of disease course.

Rasmussen encephalitis diagnosis

A European consensus panel proposed formal diagnostic criteria for Rasmussen’s encephalitis in 2005 ¹⁴. The most characteristic features are the progressive unilateral loss of function and contralateral hemispheric atrophy that happen over several months or a few years. Findings of previous serial and cross-sectional investigations lend confidence to the diagnosis. However, with the use of immunosuppressive treatment, the expected progressive changes, especially in the MRI hemispheric atrophy, might be slower (Figure 2), making the clinician less confident in making the diagnosis of Rasmussen’s encephalitis and hence its treatment. Additional descriptive and larger cohort studies are needed to better characterise and refine the more recent clinical characteristics and course of Rasmussen’s encephalitis, particularly with increasing use of immunosuppressive treatments.

Rasmussen’s encephalitis diagnostic criteria

Part A (all three)

1. Clinical: Focal seizures (with or without epilepsia partialis continua) and unilateral cortical deficits
2. Electroencephalogram: Unihemispheric slowing with or without epileptiform activity and unilateral seizure onset
3. MRI: Unihemispheric focal cortical atrophy and at least one of the following:
   • Grey or white matter T2/FLAIR hyperintense signal
   • Hyperintense signal or atrophy of the ipsilateral caudate head

Or

Part B (two of three)

1. Clinical: Epilepsia partialis continua or progressive* unilateral cortical deficits
2. MRI: Progressive* unihemispheric focal cortical atrophy
3. Histopathology: T-cell-dominated encephalitis with activated microglial cells typically, but not necessarily, forming nodules and reactive astrogliosis; numerous parenchymal macrophages, B cells, or plasma cells or viral inclusion bodies exclude the diagnosis of Rasmussen’s encephalitis

Rasmussen encephalitis prognosis

The prognosis for individuals with Rasmussen’s encephalitis varies. Despite the advances in medical treatment, none has yet been shown to halt the progress of the disease in the long term. The disorder may lead to severe neurological deficits or it may cause only milder impairments. For some children, surgery decreases seizures. However, most individuals with Rasmussen’s encephalitis are left with some paralysis, cognitive deficits, and problems with speech. In some cases, the disease can progress to involve the opposite brain hemisphere.

Rasmussen encephalitis treatment

Treatment in Rasmussen’s encephalitis aims to reduce seizure severity and frequency and improve the functional long-term outcome, as measured by both motor and cognitive performance. However, to date, treatments have only alleviated the symptoms ¹⁵ and have not tackled the underlying causes.

Seizures

Antiepileptic drugs have a limited effect on seizures and disease progression in Rasmussen encephalitis. Epilepsia partialis continua (generalized status epilepticus) in particular tends to be refractory to antiepileptic drugs. A realistic aim of antiepileptic drug therapy in Rasmussen encephalitis should be to protect the patient from the most severe seizures, namely bilateral convulsive seizures, rather than to achieve seizure freedom. Treatment should therefore be adjusted to achieve optimum seizure control with the fewest side-effects ¹⁶. Cases are reported of botulinum toxin successfully injected into the zygomaticus for facial myoclonus and into upper limb muscles for localised epilepsia partialis continua, reducing painful spasms and improving functional use of the limb ¹⁷. Case series of short-term intense immuno-interventions, such as steroid pulses, apheresis treatment ¹⁸ and a case report and an open-label trial of rituximab infusions ¹⁹ have shown a temporary beneficial effect on seizure frequency. In 2011, case reports were published of seizure improvement with vagus nerve stimulation therapy and transcranial magnetic stimulation ²⁰. However, most cases of Rasmussen’s encephalitis are resistant to antiepileptic drugs.

Treatment directed against the primary process

In view of the belief that Rasmussen encephalitis is an immune-regulated process, immunosuppressive or immunomodulatory treatments are being assessed. The effects of long-term immunotherapy for Rasmussen encephalitis have been described in case reports or small, uncontrolled patient series. Findings from these publications show the most positive experience with long-term corticosteroids ¹⁸, intravenous immunoglobulins ¹⁸, plasmapheresis or protein A immuno-absorption ²¹, and the T-cell inactivating drugs tacrolimus ²² and azathioprine ²³. Strategies have also been proposed that start with steroid pulse treatment and change to tacrolimus ²⁴. A recent prospective randomised trial ⁵ assessed the effect of long-term immunotherapy with tacrolimus or intravenous immunoglobulins. Compared with a historical control group, immunotherapy with either of these agents protected against functional or structural damage. However, the study was underpowered to assess the superiority of one of the drugs. The discrepancy between the (likely) antidegenerative effect and the apparently absent anti-seizure effect might lead to a novel artificial situation in some patients. With preserved functions, these patients are difficult to refer for hemispherectomy surgery despite having intractable and severe epilepsy.

Whether such treatments improve the long-term outcome of patients, particularly cognitive endpoints, remains unclear. Certainly in the open-label case series of azathioprine treatment, cognitive decline continues; therefore, imperfectly effective immunological interventions might unacceptably postpone hemispherectomy ²⁵. This concern seems particularly relevant in patients with very active, drug-resistant epilepsy who might otherwise be considered for a diagnosis of Rasmussen’s encephalitis. Therefore, the search continues for immunological treatments that can halt both the seizures and the functional decline (ie, loss in motor and cognitive performance). Promising candidates might come from multiple sclerosis treatments ²⁶, including compounds reducing the likelihood of T-cell entry into the CNS, although the potential toxic effects and adverse effects are concerning, particularly for a disorder that affects mainly a pediatric population. Promising results have been seen in one case study of natalizumab, which blocks entry of T cells into the CNS ²⁷.

Surgery

Surgery still remains the only cure for the seizures caused by Rasmussen’s encephalitis. This has functional consequences because the only effective surgery remains complete disconnection of the affected hemisphere (hemidisconnection), either as (functional) hemispherectomy or hemispherotomy. Homonymous hemianopia and hemiplegia are inevitable, although both might be present before surgery. Rehabilitation to independent walking is expected although fine motor movement in the hand on the affected side is not. Small resections can sometimes be preferable to preserve function, but no investigators have reported sustained seizure freedom after limited resection in patients with Rasmussen’s encephalitis. Hemispherectomy offers one of the best chances of making patients with Rasmussen’s encephalitis seizure free (>70–80% long-term seizure-free outcome) ¹⁵. The decision in older children and adults can be more difficult if the disease affects the dominant hemisphere.

Timing of surgery can be guided by the severity of epilepsy. Some advocate for early surgery to protect the contralateral normal hemisphere from repeated seizures and progressive neuropsychological loss. Few longitudinal studies of children with Rasmussen encephalitis have been done. Available data suggest that not all children with Rasmussen encephalitis show a decline in intellectual ability over time, but in those who do, the decline is associated with the appearance of contralateral, independent interictal epileptiform discharges ²⁸. Therefore, although cognitive decline is not inevitable, the appearance of contralateral EEG abnormalities might highlight those at risk, and consequently those for whom surgery should be discussed. Group data suggest little change in psychological outcome before and after the operation ²⁹. Moreover, findings of studies of children undergoing hemispherectomy for pathologies including Rasmussen’s encephalitis show short seizure duration is associated with better cognitive outcome ³⁰, suggesting that earlier surgery should be considered to improve these outcomes. Most results show cognitive stabilisation after hemispherectomy ³¹, with better cognitive outcome in non-dominant-hemisphere surgery and poorer outcome in dominant-hemisphere surgery and in individuals with refractory seizures after surgery.80 Extrapolation of these findings to the individual patient should be done with caution because global measures, such as full-scale intelligence quotient measurement, do not adequately describe or assess functional outcome, particularly in the setting of language or memory deficit.

How much language transfer is possible from the dominant hemisphere is probably dependent on age at the start of the disease process. Disease in the hemisphere that is designated to become the hemisphere responsible for language in individuals younger than 5–6 years usually results in recruitment of the contralateral hemisphere for language functions ³². Anecdotal reports have shown transfer of language clinically or through functional MRI (fMRI) ³³. The question remains of whether such a process is driven more effectively through early surgery, or whether waiting will enhance the process. However, it is rare for an individual to be rendered completely aphasic by such a procedure ³⁴, and useful aspects of language might be retained even after surgery in patients with a late onset of disease (most receptive functions are retained, whereas expressive language is restricted to telegraphic speech [two or three word] output).

Advances in fMRI for language enable an indication of the degree of transfer at any time, and this helps to predict whether useful aspects of language can be retained and help with the surgical decision-making process. The gold standard for prediction of postoperative language performance in epilepsy surgery remains the Wada test, which is done by injection of a barbiturate into the affected hemisphere. The balance has to be made between what is to be lost by waiting, and likely gained by surgery; the danger of the seizures themselves and the presumed neuropsychological compromise need to be considered. A decision aid based on the relative severity of motor deficit and seizure disorder has been suggested ¹⁵. Although this aid might be useful as a guide, the disease process will differ between individuals and therefore such decisions need to be made on an individual basis.

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