A 3-year-old boy was in good health until 5 months prior to presentation, when he began having seizures. Seizures consisted of a sudden turning of the head and eyes to the left, tonic posturing of the left arm with or without the left leg, and loss of awareness for 2 to 3 minutes. He had another less frequent type of seizure, with staring, rapid eye blinking, and impaired consciousness for a few seconds. Seizures occurred 8 to 12 times daily. The child was born at term with an uneventful antenatal, perinatal, and postnatal history. There were no risk factors for epilepsy, including head trauma, infection, or hypoxia. Initial neurologic examination revealed age-appropriate cognitive development with a subtle upper motor neuron type of left facial weakness and impaired dexterity in the left hand. Results of complete blood count and routine blood biochemistry were normal. Video electroencephalography suggested a right hemispheric origin of the epilepsy. Magnetic resonance imaging of the brain (Figure 1) showed mild volume loss in the right cerebral hemisphere with linear areas of abnormal signal in the subcortical and periventricular areas on T2 images. Despite intensive pharmacotherapy with anti-epileptic medications, the boy's seizures continued to worsen, with accompanying decline in cognitive and motor performance.
Because of the focal origin and intractability of the epilepsy, surgical resection of the epileptogenic area was performed. Microscopically, scattered foci of chronic, predominantly perivascular, inflammation were present in the leptomeninges, cortex, and white matter (Figure 2). Occasional microglial nodules (Figure 3) and areas of diffuse microglial proliferation were identified. Focal cortical atrophy marked by neuronal loss, gliosis, and spongiform degeneration was present (Figure 4). No viral inclusions were seen. There was no evidence of cortical dysplasia.
What is your diagnosis?
Pathologic Diagnosis: Rasmussen's Syndrome
Rasmussen's syndrome (RS) is a progressive neurologic disease characterized by intractable partial epilepsy, ipsilateral focal neurologic deficits, and atrophy of the congruent cerebral hemisphere with histopathologic evidence of chronic encephalitis in the form of perivascular chronic inflammation, microglial nodules, and neuronal loss. The most common age of onset is 18 months to 14 years, with a mean of 7 years. Rasmussen's syndrome is rare in adults.1 In one series of 48 patients,2 the onset of RS was preceded in the previous 6 months by a minor viral infection in 50% of patients. The first symptom of the disease in the majority of the patients was development of seizures, and 20% presented with status epilepticus. Most patients develop a variety of focal and generalized seizures over time. Focal seizures invariably involve one side of the body and are most commonly motor seizures. Seizures are resistant to standard anti-epileptic medications and become severe and frequent over a few months. Focal neurologic deficits such as hemiparesis, speech difficulties (dominant hemisphere involvement), and visual field defects gradually ensue ipsilateral to the side of seizures. Progressive intellectual deterioration is also a feature of RS. The neurologic deficits can appear at any time between 3 months to few years after the onset of seizures. The initial course of RS is one of relentless progression, but at a stage when moderate to severe neurologic deficits and cognitive decline have occurred, the disease tends to dissipate. Seizures remit or significantly decrease in frequency. The patient is left with significant neurologic morbidity. Death is rare.3
Useful clinical investigations for the diagnosis of RS are electroencephalography monitoring and brain magnetic resonance imaging studies. The electroencephalography helps in confirming the localization of the epileptogenic zones) to the involved hemisphere. Magnetic resonance imaging of the brain shows atrophy in the involved cerebral hemisphere with abnormal hyperintense signals in the T2 weighted images. In the early stages of RS, cerebral atrophy may be apparent only in the temporo-insular area.4 Unilateral neurologic findings on history, examination, electroencephalography, and imaging are the clinical hallmarks of RS and should alert a pathologist to consider the diagnosis in an appropriate clinical setting.
Pathologic findings are suggestive of chronic multifocal encephalitis. The affected hemisphere shows microglial nodules with or without neuronophagia, perivascular cuffs of small lymphocytes and monocytes, and gliosis. In the more active cases, chronic inflammatory cells fill the Virchow-Robin spaces and extend into the neuropil, forming microscopic clusters or larger aggregates. There is associated neuronal loss and spongiosis in the inflamed cortex. The smaller foci of inflammation tend to coalesce into larger areas of structural collapse, with surrounding inflammatory changes and sprouting of capillaries resembling granulation tissue. Subarachnoid adhesions are not infrequently seen.5 Pathologic findings in RS are nonspecific, and therefore other causes of chronic encephalitis must be considered in the differential diagnosis, and specific studies for infectious agents should be done as indicated. However, the characteristic evolution of the clinical picture and unilateral hemispheric involvement would argue against a chronic infection or vasculitis. Rasmussen's syndrome typically shows patchy brain involvement, and therefore absence of pathologic findings in a small brain biopsy specimen does not rule out the diagnosis. About 10% of children with RS have histologic evidence of cortical dysplasia in addition to typical findings.5 A report described the presence of previously unsuspected second pathology in 5 patients with typical clinical and pathologic findings of RS. They were cavernous angioma-like vascular anomalies in 2, a pilocytic astrocytoma-like pathology in 1, and tuberous sclerosis lesions in 2.6
No definite etiology of RS has yet been discovered. Based on the histopathologic findings, a viral infectious process has long been suspected. Various studies have implicated herpes simplex virus, Epstein-Barr virus, and cytomegalovirus based on the presence of viral DNA in the brain tissue. But the viral studies have not been consistently reproducible, and a direct role of viruses in causing RS remains a matter of speculation.7 An auto-immune process of injury was suggested by a report that found a link between RS and the circulating antibodies to glutamate receptor 3 (GluR3), a ligand-gated ion channel receptor in the central nervous system.8 The presence of double pathology in brains of some children with RS has also led some authors to suggest a third mechanism: a localized alteration in the blood-brain barrier in and around a structural lesion causing increased likelihood of focal viral infection.6
The mainstay of treatment of RS is functional hemispherectomy. Surgery produces a remarkable decline in seizure burden and improves cognitive outcome, at the cost of postoperative hemiparesis with or without aphasia and visual field deficits. The timing of surgery is still debated, but most authorities favor an early surgery in view of the progressive neurologic devastation and dementia that may directly result from the catastrophic epilepsy. Early surgery in young children may also improve chances of the transfer of neurologic function to the good hemisphere, especially when speech is at stake because of involvement of the dominant hemisphere. Other medical treatments directed against the proposed mechanisms of RS have included antiviral drugs, immunosuppressive doses of steroids, immunoglobulins, and plasmapheresis alone or in various combinations. Despite promise shown by these medical interventions in a few patients with transient improvement, none has been successful in altering the ultimate clinical course of the disease.1,9
1. Gorden N. Rasmussen's encephalitis. Dev Med Child Neurol. 1996;38:133136.
2. Andermann F, Oguni H, Rasmussen TB. The syndrome of chronic encephalitis and epilepsy: a study on the MNI series of 48 cases. J Epilepsy. 1990;3: 325-326.
3. Oguni H, Andermann F, Rasmussen TB. The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MNI series of forty-eight cases. In: Andermann F, ed. Chronic Encephalitis and Epilepsy: Rasmussen Syndrome. Boston, Mass: Butterworth-Heinemann; 1991:7-35.
4. Yacubian EM, Marie SK, Valerio RM, et al. Neuroimaging findings in Rasmussen's syndrome. Neuroimaging. 1997;7:16-22.
5. Robitaille Y. Neuropathologic aspects of chronic encephalitis. In: Andermann F, ed. Chronic Encephalitis and Epilepsy: Rasmussen's Syndrome. Boston, Mass: Butterworth-Heinemann; 1991:79-110.
6. Hart YM, Andermann F, Robitaille Y, et al. Double pathology in Rasmussen's syndrome: a window on the pathology. Neurology. 1998:50;731-735.
7. Atkins MR, Terrell W, Hulette CM. Rasmussen's syndrome: a study of potential viral etiology. Clin Neuropathol. 1995;14:7-12.
8. Rogers SW, Andrews PI, Gahring LC, et al. Autoantibodies to glutamate receptor GIuR3 in Rasmussen's encephalitis. Science. 1994;265:648-651.
9. Andermann F, Hart Y. Rasmussen's syndrome, with particular reference to cerebral plasticity: a tribute to Frank Morrell. Int Rev Neurobiol. 2001;45:173208.
Ajay Gupta, MD; Richard A. Prayson, MD
Accepted for publication August 3, 2001.
From the Departments of Child Neurology (Dr Gupta) and Anatomic Pathology (Dr Prayson), Cleveland Clinic Foundation, Cleveland, Ohio.
Reprints not available from the author.
Copyright College of American Pathologists Mar 2002
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