Rasmussen's Syndrome - A Prime for Parents
BY MARY B. CONNOLLY, MB, FRCP(C), MRCP(I), MRCP(UK) CLINICAL ASSOCIATE PROFESSOR, DIRECTOR, EPILEPSY SURGERY PROGRAM, DIVISION OF NEUROLOGY, DEPARTMENT OF PEDIATRICS, UNIVERSITY OF BRITISH COLUMBIA CHILDREN'S AND WOMEN'S HEALTH CENTER OF BRITISH COLUMBIA VANCOUVER, BRITISH COLUMBIA
Rasmussen's syndrome is a rare, progressive neurological disorder, which begins in childhood and is characterized by difficult-to-control seizures, slowly progressive hemiparesis (weakness on one side of the body) and a progressive decline in learning and mental function. Typically, the disease affects one side of the brain, causing atrophy (shrinkage). Involvement of both sides of the brain is very rare. Epilepsia partialis continua (EPC), which means continuous seizure activity in one area of the body, occurs in half of patients. Rasmussen's syndrome is the most common cause of EPC in childhood.
CLINICAL FEATURES
The illness usually begins between 14 months and 14 years of age, although rarely, symptoms may onset in adulthood. In 40% of patients, a viral or inflammatory illness may occur in the month before seizures begin, and iritis (inflammation of the eye's iris) has been reported.
Seizures are the most common symptom. Partial motor seizures (focal jerking of one bodily area) are the most common type. EPC, which occurs in half of patients, is often difficult to control. Complex partial seizures (partial seizures with alteration of awareness), secondarily generalized tonic-clonic seizures and status epilepticus may also occur.
Seizures are usually difficult to control with antiepileptic medications. Two-thirds of patients have daily seizures. All patients have progressive hemiparesis. It usually evolves over months or years. Fine finger movement is eventually lost, but patients are able to walk as the disease progresses. Cognitive decline is characteristic, and 85% of patients develop a significant learning disability. Hemianopsia (loss of vision in one visual field) occurs in 50% of patients. Sensory deficits, dysarthria (difficulty with articulation), dysphasia (difficulty with understanding and use of language) and psychiatric abnormalities are common.
DIFFERENTIAL DIAGNOSIS
Cortical dysplasia (a developmental brain abnormality), mitochondrial disease (a metabolic disorder), subacute measles in the immunocompromised patient and other forms of encephalitis may cause intractable seizures and the progressive deterioration of function in one brain hemisphere.
INVESTIGATIONS
Electroencephalography
A persistent slowing of electroencephalographic (EEG) readings in one region region of the brain, followed by a slowing of the posterior dominant rhythm in the same hemisphere occurs early in the course of disease. Gradually, this slow-wave activity spreads to several brain lobes. When the disease is established, disturbance of background activity and focal slow activity occur in nearly all patients. These abnormalities may be bilateral, but there is a clear asymmetry in 90% of patients. Many independent interictal epileptiform discharges are usually seen. It occurs over the affected hemisphere in half of patients and independently over both hemispheres in one-third. Bilateral synchronous spike- or sharp- and slow-wave complexes are observed in half of patients, often with bifrontal predominance.
EPC may be associated with a spike-wave focus in the opposite side of the brain, involving the Rolandic area, but there is often no EEG correlate. Seizures arising independently from both hemispheres are reported rarely, usually late in the course of disease.
NEUROIMAGING
Computed tomography (CT) and magnetic resonance imaging (MRI), which look at brain structure, show progressive shrinkage of the brain (cerebral atrophy), which may eventually involve an entire hemisphere. Positron emission otomography (PET) and single photon emission computed otomography (SPECT), which assess brain function, may show a decrease in blood flow and glucose metabolism in the affected hemisphere.
OTHER INVESTIGATIONS
Spinal fluid examination is usually normal but occasionally shows signs of inflammation. Brain biopsy may be considered when brain surgery or immunosuppressive therapy is under consideration to confirm the diagnosis. However, if clinical symptoms and investigations are classical, it may not be necessary. As Rasmussen's syndrome involves the brain in a patchy manner, a brain biopsy may occasionally be normal, and a negative biopsy does not exclude the diagnosis. In rare situations, more than one diagnosis may be found at biopsy, e.g., an area of abnormal brain development (cortical dysplasia) or brain tumor.
PATHOLOGY
The characteristic pathological features consist of perivascular lymphocytic cuffing with proliferation of microglial nodules. The pathological process primarily involves the cerebral cortex. Inflammation of deep white matter is rarely observed. Neuronal loss may be seen multifocally within the inflamed cortex, and patchy distribution of abnormalities may result in a falsely negative brain biopsy. Involvement of the basal ganglia, cerebellum and inflammation of the meninges have been described in autopsy studies. Although neuropsychologic and EEG studies show bilateral abnormalities in many patients, 7 of 10 autopsied brains show no involvement of the contralateral hemisphere; scattered perivascular cuffs are found only in three.
CAUSE
The cause of Rasmussen's syndrome is unknown, but theoretical evidence suggests that it may be due to immune factors.
Several lines of evidence suggest an autoimmune etiology. Iritis has been described in some patients. Immunoglobulins (IgM, IgG, IgA) and complement (C3) have been found in vessel walls. Antibodies against glutamate receptors (GluR3) have produced an illness similar to Rasmussen's encephalitis in animals. Antibodies to GluR3 have been detected in the sera of humans with Rasmussen's syndrome, although this test has not been established as a reliable investigation. Finally, treatment with immunomodulating drugs has improved seizure control in some patients.
DNA evidence of infection with various viruses, such as cytomegalovirus, herpes simplex virus types 1 and 6 and Epstein-Barr virus have been identified in brain tissue from some but not all patients with Rasmussen's syndrome. There is no evidence of a prion disease (prions are the agents linked to mad cow disease), and attempts to transmit this disease to animals have been unsuccessful.
TREATMENT
Antiepileptic drugs are not effective in the long-term prevention of seizures but may control seizures for short periods. Resection of small areas of the brain has only limited benefit. The most effective treatment is hemispheric surgery. Most often, this procedure involves hemispheric disconnection (cutting the links between one half of the brain and the other). It is the surgical treatment of choice.
Surgery is usually performed when fine finger movement is lost, but early hemispheric surgery is advocated to limit the loss of motor function and prevent progressive cognitive decline. Surgery in the side of the brain that controls language requires careful evaluation of language function. Corticosteroids, intravenous immunoglobulin and plasmapheresis may slow the progression of disease, particularly if used early, but these treatments are not associated with long-term seizure control. Antiviral agents, such as ganciclovir and zidovudine, have been used with limited success in a small number of patients.
Printed with permission of Epilepsy Canda.
