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It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Patients and methods. Bien , Christian G. Correspondence to: C. Oxford Academic. Google Scholar. Guido Widman. Horst Urbach. Robert Sassen. Stefan Kuczaty. Otmar D.
Johannes Schramm. Christian E. Revision received:. Cite Cite Christian G. Select Format Select format. Permissions Icon Permissions. Open in new tab Download slide. Patient no. Age at first seizure years. Clinical course prior to first seizure. Affected hemisphere. The occurrence of this stage was mainly observed in the adolescent and adult patients. All patients went through an acute phase with a median duration of 8 months. During this stage, there were frequent simple partial motor seizures, development of hemiparesis and volume loss of the affected hemisphere.
After this, the patients passed into a residual stage with a marked decrease in seizure frequency. Mainly a childhood illness, the diagnosis may not be so obvious at first. The age of onset is between 1 and 14 years, with epilepsy beginning before 10 years of age There is no gender or genetic predilection.
Rasmussen syndrome is manifested by the onset of seizures, with the semiology varying but most commonly focal motor seizures. Long-term follow-up of patients has found varying manifestations of seizure activity with simple partial motor seizures occurring most commonly. Epilepsia partialis continua is characterized by continuous clonic activity of a group of muscles, usually the face, arm, or leg. It can persist for a period of hours to months as a focal motor status epilepticus.
Epilepsia partialis continua is very frequent in Rasmussen syndrome, and its development should raise concern; however, it is also found in structural lesions such as tumors, developmental abnormalities, and neurodegenerative conditions. Kozhevnikov and later Omorokov described this phenomenon in Russia. Omorokov, a Russian neurologist in the early s, kept account of 52 cases from his clinic in Siberia and noted onset of epilepsia partialis continua during the spring and summer, which is now thought to be Russian spring-summer encephalitis As the seizures become difficult to manage, the development of hemiparesis ensues.
One study has divided Rasmussen syndrome into 3 stages using clinical symptoms and MRI findings akin to the traditional 3 stages mentioned in the Montreal Neurological Institute MNI series.
A prodromal phase, acute disease, and residual stage have been described that correspond with MRI findings of hemispheric volume loss The prodromal phase consists of low seizure occurrence without much hemiparesis. This is similar to MNI Stage 1, which spans from onset of seizure activity to the development of hemiparesis.
The next phase, acute disease, is characterized by increased seizure frequency and hemiparesis. It was found that most hemispheric volume loss contralateral to side of weakness occurred at this time. Again, the definition of this acute phase is similar to MNI stage 2, which is characterized by increased seizure frequency with different semiology and clinical deterioration.
In the last stage, the residual stage, seizure frequency decreases while a fixed hemiplegia develops, which is consistent with MNI stage 3 definition of fixed neurologic findings of hemiplegia, cognitive impairment, and deficits such as visual field cuts. However, after a period of time, the seizure frequency may increase. This study implies that treating Rasmussen syndrome during the acute phase may have effects on future brain atrophy.
Variants of Rasmussen syndrome have been described. The disease course is prolonged and milder with less severe hemiparesis in adult-onset Rasmussen encephalitis Compared to the classical childhood-onset, patients with late-onset Rasmussen encephalitis, including adolescent and adult-onset, have more frequent focal seizures with impaired awareness, less frequent epilepsia partialis continua, a slower evolution with less cognitive deterioration, and a better outcome MRI discloses progressive atrophy and signal changes through the affected hemisphere, but rarely gadolinium enhancement, which when observed requires a brain biopsy to distinguish Rasmussen encephalitis from an alternative diagnosis as unihemispheric vasculitis 17 ; The authors hypothesize that the comparatively increased cortical volume in the contralateral hemisphere could be a result of compensatory structural remodeling in response to atrophy of the ipsilateral hemisphere Bilateral Rasmussen syndrome is extremely uncommon.
Different theories have been proposed like Wallerian degeneration or early treatment with immunotherapy to explain spread to the other hemisphere Movement disorders such as dystonias or chorea have been reported in cases where atrophy of the basal ganglia is seen on imaging. Two cases have been described where atrophy and hemiparesis preceded onset of seizure activity by several months.
Bihemispheric disease, basal ganglia, and brainstem variants exist as well, though rare Rasmussen syndrome is a progressive disease that results in fixed hemiparesis and intellectual decline.
Immunotherapies may play a role in the rate of progression, leading to preserved motor function for a period. However, inevitably surgical treatment is needed to manage refractory seizures as well as to improve motor deficits.
The timing of surgery has been a challenge with the advent of medical treatment. Hemispherectomy has been the only method of treatment to improve seizure frequency and stabilize motor deficits, though the risk of producing severe deficits exists. Long-term follow-up of patients treated with hemispherectomy for the most part have shown positive outcomes. In addition, before developing complete hemiparesis, some patients present frequent episodes of convulsive status epilepticus with high morbidity and mortality risk 08 ; 18 , which is a potential indication for functional hemispherectomy before the development of hemiparesis.
She had her first unprovoked generalized tonic-clonic seizure at 8 years of age. CT, MRI, and lumbar puncture done at that time were normal. An EEG revealed sharp transients in the left central region. She continued to have residual twitching of her right foot that she described as a sensation of her foot falling asleep.
This progressed to involve the entire right side of her body except her face. Despite multiple medication trials, her seizures became continuous and progressed to epilepsia partialis continua.
Her language and understanding was intact throughout the initial years of her disease. Sometime after the onset of epilepsia partialis continua, she began to have intellectual decline, requiring additional help in school.
Multiple EEGs revealed theta activity with continuous high voltage spike-wave discharges over the left hemisphere. Repeat MRI scans demonstrated progressive atrophy of the left hemisphere. Four years after the onset of epilepsia partialis continua, mild right hemiparesis developed and continued to worsen with time. She developed a typical hemiparetic gait and progressive weakness of her right arm but had relatively intact language function. Roughly 16 years after her initial presentation, epilepsia partialis continua progressed to involve facial twitching, resulting in deviation of her mouth to the right and a gaze deviation.
She lost the ability to verbalize at this time and remained mute for a few months. Her speech gradually returned, but she was not able to speak in complete sentences.
Throughout the course of her illness, she was admitted multiple times to a tertiary care center. She was treated with steroids, plasmapheresis, and IVIg. High doses of intravenous steroids over weeks seemed to provide temporary relief of symptoms.
Plasmapheresis was of questionable benefit, and IVIg was of no benefit. At the age of 26, she finally underwent a functional hemispherectomy. A preoperative left-sided intracarotid Amytal test showed that most of her language had shifted to the right. She underwent hemispherectomy without any deterioration of her motor or language function.
Pathology revealed evidence of chronic inflammation, gliosis, and perivascular lymphocytic cuffs. She has remained seizure-free for 7 years. She has been weaned from 5 antiseizure medications to just 1. In addition, her speech output and ability, as well as her mobility, have increased.
She now volunteers at a local library and for Meals on Wheels. The etiology of Rasmussen syndrome remains a mystery. Pathological findings of an inflammatory reaction have led to studies focusing on virology. Early studies to detect a viral etiology as the pathogenesis of Rasmussen syndrome have been unsuccessful Other studies have implicated cytomegalovirus and herpes simplex virus as some patients demonstrated positive cytomegalovirus polymerase chain reaction, but results remain unsatisfying In some patients with Rasmussen syndrome, polymerase chain reaction for cytomegalovirus has been positive but not distributed in a particular way in the brain, and the virus could not be cultured from affected tissue Studies have hypothesized a T-cell mediated response as a mechanism for the inflammatory response seen in Rasmussen syndrome They release granzyme B, a protease that plays a role in cell apoptosis.
However, an etiology that sets off this cascade has not been identified The role of autoantibodies to glutamate receptor 3 subunit GluR3 as the pathogenesis for Rasmussen syndrome was proposed when it was found that rabbits immunized with GluR3 protein developed symptoms similar to Rasmussen syndrome and high titers of antibodies of GluR3 These antibodies were also found in the sera of some patients with Rasmussen syndrome but not all.
One patient treated with plasmapheresis to remove GluR3 antibodies showed brief improvement in symptoms that correlated with decreasing titers during treatment.
Subsequent studies have failed to detect antibodies in a larger sample of Rasmussen syndrome patients on a consistent basis and have found the presence of antibodies in other neurologic disease and noninflammatory epilepsies 57 ; Therefore, the detection of GluR3 antibodies is not specific for Rasmussen syndrome.
It is likely that pathological mechanisms in Rasmussen encephalitis involve a combination of antibody-mediated degeneration, T-cell cytotoxicity, and microglia-induced degeneration 46 ; 39 ; Studies and signs in isolation will not lead to the diagnosis of Rasmussen syndrome; however, when analyzed together, a diagnosis is solidified. As seizure activity is the initial manifestation of the disease, certain findings are typical. EEG recording reveals abnormal background activity displayed by polymorphic delta activity.
Usually, findings are asymmetrical and unilateral with low voltage. Interictal discharges are either localized over 1 focus, lateralized over 1 hemisphere with multiple foci, or bilateral with multiple foci. Even with bilateral interictal discharges, a background asymmetry will still be present to indicate which lobe is diseased Imaging studies should be used in conjunction with other testing, as findings alone are nonspecific.
Serial imaging reveals cortical atrophy corresponding to disease progression. Atrophy of the frontal lobe and insula correlated significantly with epilepsy duration in a series of 19 patients with Rasmussen encephalitis A study analyzing 13 patients with histologically proven Rasmussen syndrome measured hemispheric ratio on MRI and found that the period of maximal brain atrophy corresponded to the acute phase of the disease Crossed cerebellar diaschisis can be seen on imaging studies of some patients with Rasmussen syndrome It is theorized that cerebellar hypometabolism occurs as a result of disruption of the cerebropontine-cerebellar pathway due to a dysfunctional contralateral cerebral hemisphere This phenomenon can also be seen in the setting of cerebral ischemia.
Specific histopathologic changes are seen on brain biopsy, confirming the diagnosis Rasmussen syndrome. Early in the disease process, microglial nodules, perivascular rounds cells, and glial scarring are seen.
There may be associated neuronophagia. As the disease progresses, nodules decrease, but there is increasing evidence of cuffs of perivascular lymphocytic round cells, neuronal loss, and gliosis Perivascular round cell cuffs are seen with subarachnoid inflammation as well. Spongiosis is not as extensive as in spongiform encephalopathies. Due to the implications that come with the diagnosis of Rasmussen syndrome, accurate identification is necessary.
Lesions causing focal seizures or even epilepsia partialis continua eg, cortical dysplasia, tuberous sclerosis, or tumors can be evaluated for by imaging. Though epilepsia partialis continua favors the diagnosis of Rasmussen syndrome, other syndromes can be diagnosed by certain distinguishing features.
Tuberous sclerosis presents as early-onset seizure activity often accompanied by intellectual disability. The cutaneous manifestations, such as shagreen patches and adenoma sebaceum, may appear later, confusing the picture. Sturge-Weber syndrome consists of a vascular nevus in the distribution of the ophthalmic division of the trigeminal nerve, with the onset of unilateral seizure activity with spastic hemiparesis.
Infectious diseases such as Russian spring summer encephalitis that cause epilepsia partialis continua or subacute sclerosing panencephalitis are included in the differential as well. Autoimmune encephalitis may present with clinical features resembling Rasmussen encephalitis Therefore, evaluations for autoimmune etiologies should be considered in patients with initial manifestations of Rasmussen encephalitis. The association of Rasmussen encephalitis with other comorbid autoimmune diseases raises the possibility of shared mechanisms of susceptibility, including common immunogenetic or environmental risk factors, or both Studies have suggested an association with Parry-Romberg syndrome, in which hemiatrophy could result from genetic mosaicism 47 ; 12 ; 33 ; One hypothesis is that genetic mosaicism in patients with Rasmussen encephalitis could lead to differential expression of an antigen in only one hemisphere, thus explaining the unilateral inflammation and progressive atrophy The challenge is recognizing early cases where motor deficits may not be present yet.
Clinically, increasing seizure activity with progressive cortical deficits is characteristic. The absence of a structural lesion on MRI will help rule out a secondary cause of focal seizures or weakness. EEG, especially early in the disease process, will show unilateral focal slowing in the delta range. MRI within at least 4 months of onset of symptoms will reveal focal cortical atrophy, white matter hyperintensity, and caudate head atrophy.
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