Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances

Abstract

Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. 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.

Figure 1. Natural clinical course and expected effect of immunotherapy

The natural clinical course of Rasmussen’s encephalitis was characterised in the past century. The disease might have a preceding prodromal stage with infrequent seizures, and presents with an acute stage of drug-resistant epilepsy. The epilepsy is characterised by very frequent seizures of different semiologies in the same patient, often epilepsia partialis continua, with the emergence of a fluctuating then permanent hemiplegia (motor function) and concurrent progressive hemispheric volume loss on neuroimaging. With the advent of immunotherapy, the natural clinical course seems to be changing. The rate of motor function and hemispheric volume loss is slowed, and seizures decrease in frequency and plateau. Cognitive deterioration is not shown because it is more variable, although usually becomes manifest during the acute phase. EPC=epilepsia partialis continua.

Figure 2. Neuroimaging in Rasmussen’s encephalitis

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 centred 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 (centre), and 30 months (right) of disease course.

Figure 3. Histopathology of neurodegeneration and inflammation in Rasmussen’s encephalitis

(A–E) Cortical degeneration in Rasmussen’s encephalitis. (A) Staining for MAP2 shows intact cortical neurons on the left side while loss of MAP2 neurons is found on the right side. (B) Cortical degeneration in a later stage of the disease; most neurons are already lost. (C) The same areas stained for glial fibrillary acidic protein, showing strong activated astrocytes. (D) An almost complete loss of cortical neurons. (E) In this area, nearly complete fibrillary astrogliosis is present. (F and G) Microglia activation in the cortex is notable. (F) A microglial nodule positively stained by anti-HLA-DR. (G) Staining for CD68 shows activation of microglial cells in the cortex. (H) Staining for CD8 reveals infiltration of cytotoxic T lymphocytes in the cortex. Notably, this case is one from the collection of Dr Rasmussen (case no. 238–69D). Higher magnifications of this section in (I) and (J) show appositions of cytotoxic T cells to neurons (arrows). (K) Staining for granzyme B shows granzyme B-positive granules in close apposition to a neuron.

Figure 4. Suggested therapeutic management of the patient with Rasmussen’s encephalitis

*A judgment or decision to be made by the patient, carers or parents, and the treating physician. †This is a matter of consideration, not an objective measure. ‡This will mainly apply to patients with short disease duration and preserved function of the affected hemisphere. §There is no evidence to support any special agent. ¶No formal recommendation regarding the intervals can be given, and will be affected by the needs of the patient. If the course is unsatisfactory, the patient will most probably return to the treating institution needing reassessment. Modified from Bien and Schramm, by permission of Elsevier.