Rasmussen’s encephalitis (RE) is a very rare, chronic inflammatory neurological disease that unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, progressive neurological drug-resistant focal epilepsy, hemiplegia, cognitive decline, with unihemispheric brain atrophy, and cognitive deterioration that usually affects only one hemisphere (half) of the brain. It most often occurs in children under the age of 10 but can also affect adolescents and adults. It has features of autoimmune disease in which immune system cells enter the brain and cause damage. RE is characterized by frequent and severe seizures, progressive loss of neurological functions including motor skills, speech, and eventual paralysis on one side of the body (hemiparesis), inflammation of the brain (encephalitis), and mental deterioration. Children with RE frequently enter a phase of permanent, but stable, neurological deficits after 8 to 12 months; the disease in adults and adolescents may continue to progress slowly.
Rasmussen’s encephalitis is a rare inflammatory neurological disease, characterized by frequent and severe seizures, loss of motor skills and speech, hemiparesis (weakness on one side of the body), encephalitis (inflammation of the brain), and dementia. The illness affects a single cerebral hemisphere and generally occurs in children under the age of 15.
- Causes of Rasmussen’s Encephalitis
- Symptoms of Rasmussen’s Encephalitis
- Diagnosis of Rasmussen’s encephalitis
- Treatment Of Rasmussen’s Encephalitis
Causes of Rasmussen’s Encephalitis
- Exposure to certain bacteria and viruses, including streptococcus and herpes simplex virus.
- A type of tumor called a teratoma, generally in the ovaries, causes the immune system to produce specific antibodies.
- Rarely, some cancers that can trigger an autoimmune response (when the immune system attacks the body’s own tissues).
- Aseptic Meningitis
- Bell palsy
- Brain metastasis
- Cardioembolic stroke
- Cauda Equina and Conus Medullaris syndrome
- Cavernous sinus syndromes
- Central nervous system complications in HIV
- Cerebral venous thrombosis
- Churg-Strauss disease
- Another autoimmune encephalitis
- Primary psychiatric disorder
- Viral encephalitis
- Neuroleptic malignant syndrome
- Acute disseminated encephalomyelitis
- Mitochondrial encephalitis
- Cerebral space-occupying lesions
- Exposure to drugs, toxins, or withdrawal symptoms
- Intracranial hemorrhage
- Subdural hemorrhage
- Subarachnoid hemorrhage
- Cerebral sinus venous thrombosis
- Posterior circulation ischemic or hemorrhagic stroke
- Thrombosis of the basilar artery
- Vasculitis of the central nervous system
- Herpes simplex encephalitis
- Autoimmune encephalitis
- Uremic encephalopathy
Symptoms of Rasmussen’s Encephalitis
These include weakness of one side of the body (hemiparesis), loss of vision for one side of the visual field (hemianopia), and cognitive difficulties (affecting learning, memory, or language, for example). Epileptic seizures are also a major part of the illness, although these are often partial. Focal motor seizures or Epilepsia partialis continua are particularly common and may be very difficult to control with drugs
- Cognitive, and particularly memory, impairment predominantly due to the involvement of the limbic system
- Frequent but not invariable seizure activity arising from one or both temporal lobes
- Frequent but not invariable MRI signal change within limbic structures, particularly the hippocampus.
- Personality changes
- Delusional behavior
- Concentration and memory problems
- Jerks in the muscles (myoclonus – 65% of cases)
- Lack of coordination (ataxia – 65% of cases)
- Partial paralysis on the right side
- Seizures (60% of cases)
- Sleep abnormalities (55% of cases)
- Speech problems (transient aphasia – 80% of cases)
- Status epilepticus (20% of cases)
- Tremors (80% of cases)
Common symptoms include
- Impaired memory and understanding
- Unusual and involuntary movements
- Involuntary movements of the face (facial dyskinesia)
- Difficulty with balance, speech, or vision
- Weakness or numbness
- Severe anxiety or panic attacks
- Compulsive behaviors
- Altered sexual behaviors
- Behavior changes such as agitation, fear or euphoria
- Loss of inhibition
- Paranoid thoughts
- Loss of consciousness or coma
- Problems with memory and the process of thinking (also known as cognition)
- Abnormal movements
- Problems with balance or coordination (or ataxia)
- Having trouble speaking
- Changes in vision
- Loss of consciousness or coma
- Hallucinations, delusions, or paranoia (or psychosis)
- Aggressive behavior
- Inappropriate sexual behaviors
- Anxiety or panic attacks
- Compulsive behaviors
- Agitation, fear
- Difficulty sleeping
Brain-related symptoms include
- Short-term memory loss
- Slow thinking
- Slurred speech
- Personality changes
- Severe headaches, often with vomiting.
Vision-related symptoms include
- A dark area in one part of your visual field
- Visual disturbances such as loss of side vision or a dark shade drawn over part of your vision
Inner-ear symptoms include
- Hearing loss
- Ringing in your ears
Diagnosis of Rasmussen’s encephalitis
History and Physical
It is a rare paraneoplastic syndrome that affects the medial temporal lobe and may be presented with cognitive dysfunction with a subacute beginning, change in the personality, seizure in partial and generalized type, irritability, hallucinations, disorientation, limbic paresis, and disruption of consciousness and short-term memory loss[rx],[rx],[rx]. A study of patients with this syndrome showed that most of the patients presented with an altered level of consciousness. Usually, early manifestations are psychiatric symptoms, so many patients may be treated in the psychiatric ward before making the diagnosis of paraneoplastic limbic encephalitis.[rx]
Cognitive function may be accessed through a mini mental-state examination, clock test, or instrumental activity of daily living.[rx] Also, this syndrome may be a part of the larger syndrome in which the brain stem and spinal cord are also involved in the inflammatory process.[rx]
Any patient who is suspected to have paraneoplastic limbic encephalitis should undergo the following tests:
Exclusion of other neuro-oncological complications
CSF with inflammatory changes but negative cytology
MRI showing abnormalities in the temporal lobe
EEG showing epileptic activities in the temporal lobe
Not all of the patients will fulfill these criteria, but the diagnosis of paraneoplastic limbic encephalitis also may be done in the presence of a neuropathological examination.[rx]
Other diagnostic criteria which may be used include Graus and Saiz criteria. These include the following
Subacute onset of seizure or confusion (less than 12 weeks)
Neuropathological or radiological involvement of limbic system
Exclusion of other causes
Diagnosing the tumor within 5 years of diagnosing the syndrome [rx]
Laboratory and radiological findings
- Increased liver enzyme levels (55% cases)
- Increased thyroid-stimulating hormone (55% cases)
- Increased erythrocyte sedimentation rate (25% cases)
Cerebrospinal fluid findings
- Raised protein (25% cases)
- Negative for 14–3–3 protein
- May contain antithyroid antibodies
- Magnetic resonance imaging abnormalities consistent with encephalopathy (26% f cases)
- Single-photon emission computed tomography shows focal and global hypoperfusion (75% of cases)
- Cerebral angiography is normal
Thyroid hormone abnormalities are common (>80% of cases)
- Subclinical hypothyroidism (35% of cases)
- Overt hypothyroidism (20% of cases)
- Hyperthyroidism (5% of cases)
- Euthyroid on levothyroxine (10% of cases)
- Euthyroid not on levothyroxine (20% of cases)
In adults, a diagnosis of “possible AE” is made when all three of the criteria listed below have been met
- Subacute onset (rapid progression of symptoms over less than 3 months) of working memory problems (short-term memory loss), altered mental state (such as confusion or decreased ability to interact with other people or surroundings), or psychiatric symptoms (such as hallucinations)
- At least one of these findings:
Abnormal findings on the physical examination that suggest a problem in the brain or spinal cord (such as arm or leg weakness, abnormal reflexes, or problems with coordination)
• Seizures that are not explained by a previously known seizure disorder
• High levels of white blood cells in the spinal fluid
• MRI abnormalities that fit with AE
- A reasonable number of test results show that symptoms are not caused by more common conditions, such as infections or cancers
In children and teenagers, a diagnosis of possible AE is made when all three of the criteria listed below have been met. New neurological and/or psychiatric symptoms developing over less than three months in a previously healthy child.
- Reduced ability to interact with other people or surroundings (or slowing on EEG)
- Abnormal findings on the physical examination that suggest a problem in the brain or spinal cord (such as arm or leg weakness, abnormal reflexes, or problems with coordination)
- Problems with memory and the process of thinking
- Loss of developmental milestones
- Abnormal movements (except tics)
- Psychiatric symptoms (such as low mood or hallucinations)
- Seizures that are not explained by a previously known seizure disorder or other condition
A reasonable number of test results show that symptoms are not caused by more common conditions, such as infections or cancers
|Antibody||Syndromes||MRI: T2/Flair Sequences||Tumor||F/M||Age (Median)|
|NMDA-R||Prodromal stage, global encephalopathy||Normal or transient non-region specific changes (~33%)||10–50%, (age-dependent) ovarian teratoma||4:1||1–85 (21)|
|LGI1||Faciobrachial dystonic seizures, limbic encephalitis, hyponatremia, sleep disorders, myoclonia||Hyperintense signal in medial temporal lobes and basal ganglia (>80%)||<10–20% Bronchial carcinoma, thymoma||1:2||30–80 (60)|
|AMPA-R||Limbic encephalitis (predominant psychosis), seizures||Hyperintense signal in medial temporal lobes (90%)||70% Bronchial- or Mamma carcinoma, Thymoma||9:1||38–87 (60)|
|GABA-R||Limbic encephalitis, seizures||Hyperintense signal in medial temporal lobes (>60%)||60% Bronchial carcinoma, neuroendocrine tumors||1:1||24–75 (62)|
|CASPR2||Morvan syndrome, neuromyotonia, polyneuropathy, bulbar weakness, limbic encephalitis||Normal or Hyperintense signal in medial temporal lobes (~40%)||<20–40% bronchial carcinoma, thymoma||1:4||46–77 (60)|
|Glycine-R||PERM, Myelopathy, Stiff person syndrome||Normal or nonspecific changes (~10%)||~10% Lymphoma, thymoma||6:5||5–69 (43)|
|mGLUR5||Ophelia syndrome||Normal or hyperintense signal in various brain regions (~50%)||Hodgkin lymphoma||1:2||35|
|GAD||Stiff person syndrome, limbic encephalitis, seizures, cerebellar ataxia||n/k||25% Thymoma, small cell lung carcinoma||n/k||n/k|
|GABAa-R||Encephalitis with refractory seizures||Hyperintense signal in multiple cortical and subcortical regions||25% Thymoma||n/k||n/k|
|DPPX||Encephalitis, diarrhea, hyperlexia||Normal or nonspecific changes||<10% Lymphoma||n/k||n/k|
|Dopamine-2-R||Basal ganglia encephalitis with abnormal movements, gait disturbance||Hyperintense signal in basal ganglia||n/k||1:1||2–15 (6)|
|IgLON5||NREM and REM sleep disorder, brain stem dysfunction||Normal||n/k||n/k||n/k|
|mGLUR1||Cerebellar ataxia||Normal or cerebellar atrophy||A few cases described, Hodgkin disease||n/k||n/k|
|Nach-R||Encephalitis, postural tachycardia syndrome, Chronic intestinal pseudo-obstruction||Not applicable||30% thymoma, mamma/bladder/rectum/bronchial carcinoma, lymphoma||2:1||20–76 (58)|
|MOG||Acute disseminated encephalomyelitis||Diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly in the white matter||0%||n/k||n/k|
|Adenylate-kinase 5||Isolated severe short-term memory loss, no seizures||Not applicable||No association||n/k||n/k|
Another way of dividing autoimmune encephalitis is on the grounds of whether the antibodies are against intracellular antigens or cell surface antigens. The antibodies, in turn, correlate both to an underlying cause and pattern of involvement. As a general rule, antibodies targeted to intracellular antigens are more frequently associated with an underlying tumor.
- group I – antibodies to intracellular antigens
- anti-Hu antibodies
- most common
- small cell carcinoma of the lung in 75% of cases
- the anti-Hu syndrome consists of paraneoplastic encephalomyelitis, paraneoplastic sub-acute sensory neuropathy, and paraneoplastic cerebellar degeneration
- anti-Ma/Ta antibodies
- better prognosis than anti-Hu
- testicular tumors
- diencephalic and brainstem involvement more common
- ophthalmoplegia is common
- anti-CV2 antibodies
- small cell carcinoma of the lung and malignant thymoma
- involvement of the striatum prominent
- choreiform movement disorders common
- anti-GAD (glutamic acid decarboxylase) antibodies
- usually not associated with tumors
- usually classical limbic involvement with prominent seizures and stiff person syndrome
- anti-amphiphysin antibodies
- small cell carcinoma of the lung and breast cancer
- myelopathy, myoclonus, and stiff person syndrome
- anti-Ri antibodies
- small cell carcinoma of the lung and breast cancer
- brain stem involvement
- opsoclonus-myoclonus syndrome
- anti-Yo antibodies
- ovarian cancer and breast cancer
- typically presents with paraneoplastic cerebellar degeneration
- anti-Hu antibodies
- group II – antibodies to surface antigens
- anti-NMDA antibodies
- usually in children and young women with no underlying tumor
- older patients may have underlying tumors (e.g. ovarian teratoma)
- typically present with psychiatric symptoms
- mild or often absent imaging changes
- anti-VGKC (voltage-gated potassium channel) antibodies
- classic features of “limbic encephalitis” with prominent seizures
- extra-limbic involvement very uncommon
- anti-GABA (gamma-aminobutyric acid) antibodies
- similar to VGKC but less common
- two subtypes:
- frequent extralimbic involvement
- not infrequent underlying cancer (pulmonary neuroendocrine tumors)
- anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) antibodies
- predominantly psychiatric symptoms
- imaging changes limited to the hippocampi
- anti-D2 dopamine antibodies
- basal ganglia encephalitis
- anti-GlyR1 (glyoxylate reductase) antibodies
- stiff leg syndrome or stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus
- anti-mGluR1(metabotropic glutamate receptor) antibodies
- lymphoma with cerebellar ataxia
- anti-mGluR5 antibodies
- associated with Ophelia syndrome
- anti-GluR3 (glutamate receptor) antibodies
- associated with Rasmussen encephalitis
- anti-NMDA antibodies
A brain scan, can determine inflammation and differentiate it from other possible causes.
- 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
Blood test – for monoclonal antibodies (anti-Hu, anti-Ta, anti-Ma, anti-GABA B receptor, and anti NMDA receptor) but the absence of these antibodies does not exclude the disease. A complete blood count with differential is a general index of health. It checks the number of red and white blood cells in your blood. White blood cells fight infection. The count is usually elevated in meningitis.
Lumbar puncture – should be negative for malignant cells or infection and may show pleocytosis, the elevation of protein levels, and intensification of immunoglobulin synthesis and oligoclonal bands.[rx] Lumbar puncture (spinal tap) helps determine via a test using the cerebral-spinal fluid, obtained from the lumbar region.
PET-CT – which will show abnormal metabolic activities in the limbic system. Diagnosis is difficult and should be by exclusion because clinical markers are often absent. A study on 1047 patients used the following criteria to diagnose paraneoplastic limbic encephalitis.
- An electroencephalogram (EEG) – small electrodes are placed on your scalp, which picks up the electrical signals from your brain and shows abnormal brain activity
- Spinal fluid analysis – By doing a lumbar puncture (also called a spinal tap), your doctor can check the spinal fluid for an increase in white blood cells and protein. The bacteria, virus, parasite, or fungus causing the encephalitis also may be found in the spinal fluid. Examination of cerebrospinal fluid (CSF) shows elevated numbers of lymphocytes (but usually < 100 cells/μl); elevated CSF protein (but usually <1.5 g/l), normal glucose, elevated IgG index, and oligoclonal bands. Patients with antibodies to voltage-gated potassium channels may have a completely normal CSF examination.[rx][rx][rx]
- Urine analysis – A urinalysis is a simple test that looks at a small sample of your urine. It can help find problems that need treatment, including infections or kidney problems. It can also help find serious diseases in the early stages, like kidney disease, diabetes, or liver disease. A urinalysis is also called a “urine test.
- Polymerase chain reaction (PCR) testing – of the cerebrospinal fluid, to detect the presence of viral DNA which is a sign of viral encephalitis.
- Blood cultures identify bacteria in the blood – Bacteria can travel from the blood to the brain. N. meningitides and S. pneumonia can cause both sepsis and meningitis.
- Cerebrospinal fluid (CSF) – CSF is the fluid that surrounds your brain and spinal cord. It helps to support and protect the brain and spinal cord from trauma.
- Chest X-rays – can reveal the presence of pneumonia, tuberculosis, or fungal infections. Meningitis can occur after pneumonia. A chest radiograph called a chest X-ray, or chest film is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in medicine
- Thyroid antibodies – both antithyroid peroxidase antibodies (anti-TPO, antithyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) – in the disease are elevated, but their levels do not correlate with the severity.
- Electroencephalogram studies – while almost always abnormal (98% of cases), are usually not diagnostic. The most common findings are diffuse or generalized slowing or frontal intermittent rhythmic delta activity. Prominent triphasic waves, focal slowing, epileptiform abnormalities, and photo paroxysmal and photogenic responses may be seen.[rx]
- A CT scan – of the head may show problems like a brain abscess or sinusitis. Bacteria can spread from the sinuses to the meninges. A computerized tomography (CT) scan combines a series of X-ray images taken from different angles around your body and uses computer processing to create cross-sectional images (slices) of the bones, blood vessels, and soft tissues inside your body. CT scan images provide more detailed information than plain X-rays do.
- MRI – to be oversure about meningitis. Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body.
- Anti NMDAR IgG antibodies – detected by indirect immunofluorescence assay in the serum and the CSF, are diagnostic for the disease. Antibody titers are higher in the CSF, and in some cases, diagnosis is possible after CSF testing with concurrent negative serum reports. CSF also can have low-grade hypercellularity and oligoclonal bands.[rx] Brain MRI can be normal, but nonspecific white and gray matter T2/FLAIR signal hyperintensity can be present, most commonly in the hippocampus. Diffusion restriction positivity has been reported, as well as cerebellar atrophy, as the only irreversible radiologic finding with this encephalitis.[rx]
- Transvaginal ultrasonography – is the most crucial test for young women presenting with the illness due to the high incidence of underlying ovarian teratoma. If these tests are unrevealing, PET scans and exploratory laparotomy are options.[rx] In cases of negative initial screening, follow-up MRI of abdomen and pelvis should be repeated every six months for at least four years.[rx]
- Electroencephalography – Patients with ALE may occasionally have a normal EEG, which does not rule out the diagnosis.[rx] Usually, however, EEG shows slow-wave activity or epileptiform discharges from the temporal lobes of patients with ALE — a clue to brain inflammation. In a retrospective analysis of 19 patients with autoimmune encephalitis and seizures, 10 of 16 patients with ictal EEGs (63%) had seizure onset over the temporal lobe region, which closely mirrored the medial temporal lobe abnormalities seen on MRI in three-quarters of those studied.[rx] Importantly, EEG abnormalities of the temporal lobes without any observed changes on imaging are not sufficient to make a diagnosis of ALE in the absence of a positive antibody. In clinical practice, an EEG that shows slow-wave activity or epileptiform discharges from the temporal lobes in a patient with possible ALE should raise suspicion of the condition even if the initial MRI is normal; in such cases, repeat MRI may be considered, to look for the interval development of medial temporal lobe abnormalities.[rx]
Treatment Of Rasmussen’s Encephalitis
Treatment (which is based on supportive care) is as follows
- Antiviral medications (if virus causes)
- Antibiotics, (if bacteria cause)
- Steroids are used to reduce brain swelling
- Sedatives for restlessness
- Acetaminophen for fever
- Occupational and physical therapy (if the brain is affected post-infection)
|Comment||Level of clinical experience (if any)|
|Natalizumab||Monoclonal antibody; A4-integrin cellular adhesion molecule, reduces T-cell ability to pass across the blood-brain barrier||Case report, 22-year-old female, the 1-year outcome of improved Epilepsia partialis continua and focal seizures[rx]|
|Rituximab||Monoclonal antibody; CD20 B-cell lysis; loss of antigen presentation, resulting in less T-cell activation||Case series of nine patients (ages 6–22 years), well-tolerated; eight patients had improvement in seizures, motor, and cognitive function at 3–22 months;[rx] case report of use to stabilize 20-year-old female in focal motor status epilepticus[rx]|
|Disruption of T and B cells|
|Azathioprine||Used initially as a steroid-sparing agent, azathioprine might allow continuation of the anti-seizure effect of oral steroids||Case series of 16 children, response in 13 of 16; reduction in seizure frequency; follow-up 1·6–15 years;[rx] might slow MRI tissue and motor function loss, but does not slow cognitive decline (personal observation, SV and JHC)|
|Fingolimod||Prevents migration of lymphocytes from nodes||No experience in Rasmussen’s encephalitis|
|Cladribine||Disrupts lymphocyte cellular processes; can penetrate CNS||No experience in Rasmussen’s encephalitis|
|Mycophenolate||Inhibits purine synthesis in lymphocytes; induces apoptosis in activated T lymphocytes; depletes tetrahydrobiopterin, a cofactor for inducible nitric oxide synthase, which is activated in inflammation||Anecdotal; patients in case reports for other treatments stated as treated13|
|Alemtuzumab||T-cell and B-cell depletion might also turn on neurotrophic factors||No experience in Rasmussen’s encephalitis|
|Inhibition of microglia|
|Minocycline and related tetracycline derivatives||Highly potent poly (ADP-ribose) polymerase (PARP) inhibitors; PARP-1 is activated by DNA damage and by cytokines such as tumor necrosis factor α (TNFα); PARP-1 interaction with NF-κB regulates expression of several pro-inflammatory mediators, including proteases, inducible nitric oxide synthase, ICAM-1, and TNFα||No experience in Rasmussen’s encephalitis|
|Perindopril||A brain-penetrating angiotensin-converting enzyme inhibitor reported to reduce cognitive decline in Alzheimer’s disease; suppresses microglia and astrocyte activation, and decreases inducible nitric oxide synthase expression[rx]||No experience in Rasmussen’s encephalitis|
|COX-2 inhibitors||Experimentally, non-selective COX inhibitor naproxen and specific COX-2 inhibitor rofecoxib ameliorate excitotoxic neuronal damage[rx]||No experience in Rasmussen’s encephalitis|
- Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like asthma. Because most patients respond to corticosteroids or immunosuppressant treatment, this condition is now also referred to as steroid-responsive encephalopathy. Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days.
- Pyrimethamine-based maintenance therapy – is often used to treat Toxoplasmic Encephalitis (TE), which is caused by Toxoplasma gondii and can be life-threatening for people with weak immune systems. The use of highly active antiretroviral therapy,
- Immunoglobulin infusion(IVIG) – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune encephalitis.[rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
- Plasmapheresis – can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual.
- Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.
- Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of encephalitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects. Gradual reduction of AEDs is possible during follow-up, and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx]
- Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this encephalitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine.ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx]
- Antiviral Medication – Herpes simplex encephalitis is the commonest sporadic encephalitis. Any patient who presented with clinical features of acute encephalitis should be treated empirically with IV acyclovir, pending the result of HSV PCR results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of the encephalitis is often due to anti-NMDAR encephalitis triggered by the viral encephalitis. It is reasonable and understandable that HSV is a neurotropic virus with predominant involvement of the limbic gray matter, which has a high concentration of NMDA receptors. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary immune encephalitis.
- Hemispherectomy – Surgery under the form of a HE remains the only cure for the seizures caused by RE. HE (disconnection of the affected side of the brain from the healthy brain) in one of its modern variants offers a very high chance of seizure resolution. However, HE can have significant consequences:
- irreversible loss of functions located in the affected hemisphere.
- hemiplegia (if there isn’t one already from the disease); the patients are expected to walk again but they are not expected to have fine finger function.
- hemianopia (loss of vision for objects coming from one side).
- speech loss if the surgery is on the side of the brain generating language (language dominant side).
- swallowing difficulties.
Despite these concerns, HE has fewer side-effects in children than in adults. Rehabilitation is very important and should begin early in the postoperative period. The decision to go ahead with the surgery and choosing the best time is difficult and individual to each child. Careful decisions should be made by the parents and young person in conjunction with a specialist epilepsy surgery service. Medical therapy prior to HE may be considered in two scenarios:
- in patients with minimal or no motor deficits.
- in patients with RE involving the dominant hemisphere or bilateral hemisphere.
Three disease stages of Rasmussen’s encephalitis
- Prodromal stage: Non-specific, low seizure frequency, and mild hemiplegia
- Acute stage: Frequent seizures, often Epilepsia partialis continua; progressive hemiparesis, hemianopia, cognitive deterioration, and aphasia (if dominant hemisphere affected)
- Residual stage: Permanent and stable neurological deficits and continuing seizures
Part A (all three)
- Clinical: Focal seizures (with or without Epilepsia partialis continua) and unilateral cortical deficits
- Electroencephalogram: Unihemispheric slowing with or without epileptiform activity and unilateral seizure onset
- 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
Unihemispheric epileptic syndromes
- Cortical dysplasia
- Tuberous sclerosis
- Sturge-Weber syndrome
- Hemiconvulsion–hemiplegia–epilepsy syndrome
Epilepsia partialis continua due to metabolic disorders
- Diabetes mellitus
Ketotic or non-ketotic hyperglycemia
Type 1 diabetes and anti-GAD-65 antibodies
- Renal or hepatic encephalopathy
Metabolic or degenerative progressive neurological diseases
- MELAS and other mitochondriopathies
- Alpers’ syndrome
- Kufs’ disease
Inflammatory and infectious diseases
- Cerebral vasculitis in systemic connective tissue disease (eg, lupus erythematosus)
- Unihemispheric cerebral vasculitis mimicking Rasmussen’s encephalitis
- Subacute sclerosing panencephalitis and other delayed subacute measles encephalitis with or without immunodeficiency
- Paraneoplastic syndrome
- Onconeural antibodies (anti-Hu)
- Russian Spring-Summer meningoencephalitis
- Multiple sclerosis
- Creutzfeldt-Jakob disease
- Cat scratch disease
- Proconvulsive drugs (eg, metrizimide, penicillin, and azlocillin-cefotaxim)
- Bone marrow transplant
- Gliomatosis cerebri
At least two sequential clinical examinations or MRI studies are needed to meet the respective criteria.
What causes Rasmussen’s encephalitis?
The cause of Rasmussen’s 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. These possibilities can be explored in hypothesis-driven studies.
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.
What approaches might be used to advance research and treatment?
Efforts directed by the professionals and families of the RE Children’s Project are addressing the key questions regarding the identification of the cause of Rasmussen’s encephalitis. With up-to-date molecular techniques, studies are underway to elucidate whether antigens are associated with Rasmussen’s encephalitis and if these antigens are foreign or autoimmune. Studies will examine, with exome sequencing, whether signs exist of germline or somatic mutations in the brains of patients with Rasmussen’s encephalitis. If infectious antigens can be effectively ruled out, empirical treatments with many already FDA-approved anti-inflammatory drugs could be tried in patients with Rasmussen’s encephalitis. The response to particular drugs might provide clues to the cause of Rasmussen’s encephalitis. For any of these approaches to be successful, large numbers of patients with Rasmussen’s encephalitis need to be identified for studies, a challenge for a very rare brain disease. Here again, the RE Children’s Project could be key—a non-profit international organization bringing together patients, their families, and key centers interested in Rasmussen’s encephalitis research and treatment development with social media.