Rasmussen's Encephalitis - A Semi-Detailed Summary

03/12/2008

For those of you that have made it this far in the blog, here is a fairly detailed summary of Rasmussen's Encephalitis by Dr. Vining at John's Hopkins. Jessie's Neurologist in Baltimore. Anyway, if you are not into the details, skip this blog entry. This is a couple of levels higher than the super detailed medical papers, and a couple of levels deeper than most of what you read in the news journals. It is a very well written paper for the non-medical, but curious mind. Thanks Dr. Vining.

Epilepsy Currents, Vol. 6, No. 1 (January/February) 2006 pp. 20–21
Blackwell Publishing, Inc.
C_ American Epilepsy Society
Struggling with Rasmussen’s
Syndrome
Eileen P.G. Vining, MD
Professor of Neurology and Pediatrics, Johns Hopkins University
School of Medicine, Baltimore, Maryland
Address correspondence to Eileen P.G. Vining, MD, Professor ofNeurology
and Pediatrics, Johns Hopkins University School of Medicine,
Meyer 2-147, 600 N. Wolfe St., Baltimore, MD 21287; E-mail:
evining@jhmi.edu.

Rasmussen’s syndrome has remained an enigma since it
was first described as a clinical and pathological entity in 1958.
Determining the etiology and how best to treat the condition
has been an enduring struggle for clinicians, pathologists, surgeons,
neuroscientists, and above all, for the families who need
to make treatment decisions for their children. Bien and colleagues
capture the tension of this struggle in an excellent, recently
published review that provides the basis for the European
consensus statement (1).
Frustration with understanding Rasmussen’s syndrome begins
with efforts to determine the cause of this devastating disorder,
which can destroy a cerebral hemisphere in previously normal
children. When the pathologic findings were first noted
(lymphocytic infiltration and microglial nodules), it was assumed
that a viral etiology would shortly be discovered. This line
of investigation was avidly pursued, with increasingly sophisticated
methodology, until about a decade ago. No consistently
reliable viral cause has been found. The next wave of enthusiasm
in determining the etiology focused on the report of elevated
GluR3 antibodies (2) in some patients with Rasmussen’s syndrome
and improvements that were seen when patients underwent
plasmapheresis (3). Theories were postulated to explain
how these circulating antibodies were responsible for unihemispheric
abnormalities. For example, one hypothesis suggested
that a localized dysfunction (e.g., trauma, infection, etc.) led
to a breakdown of the blood–brain barrier, which then allowed
the GluR3 antibodies to attack neurons—either through cytotoxic
activation of the glutamate receptor or through complement
activation. However, elevated GluR3 antibodies have
been found in other types of seizure disorders, and certainly they
are not found in all patients with Rasmussen’s syndrome. Interest
continues in pursuing other humoral-related mechanisms,
but in the last decade, the focus of much research has shifted
to examining the role of T-cell–mediated toxicity. This line of
investigation is fueled by the recognition that the vast majority
of inflammatory cells involved in Rasmussen’s syndrome are T
cells; in fact, they are cytotoxic CD8+ lymphocytes, which have
been shown to attack neurons.
The pathologic findings underscore the problems associated
with understanding the cause of Rasmussen’s syndrome.
Abnormal and normal tissue can be found in juxtaposition to
each other. What is the pathogenesis that can cause regions of
multifocal destruction to be surrounded by normal appearing
tissue? This feature of Rasmussen’s syndrome leads to a sense
of futility for performing brain biopsies, and it also forces consideration
of mechanisms postulated for multiple sclerosis and
postinfectious encephalomyelitis (4).
The clinical manifestations of Rasmussen’s syndrome are
often confusing. Although the hallmark of the disease is epilepsia
partialis continua, it does not occur in all patients and the
nature of the focal seizures is very unusual. While the progression
of partial seizures is usually envisioned as a Jacksonian
march, this image is routinely not the case in Rasmussen’s syndrome.
Clonic activity may begin in the face; then in the hand,
then the leg, and then the shoulder—the progression obviously
reflects the patchy nature of the hemispheric pathology. Children
also can manifest features of a movement disorder before
seizures are clearly apparent. The EEG often is confusing. It
may show a paucity of epileptiform activity, even with epilepsia
partialis continua. Bilateral abnormalities are not uncommon.
MRI has become one of the most important tools to confirm the
presence of Rasmussen’s syndrome. Atrophy, particularly progressive
atrophy, will appear. This feature, too, does not always
reflect the clinical situation. Extensive atrophy has been noted
at clinical onset in some children while other children show
minimal change for varying periods of time. Clinical and MRI
progression of the disease is quite variable. Disease progression
can happen quickly with devastating results, and it can happen
insidiously, with periods of respite that circumvent more definitive
treatments. The European consensus group devotes a long
table to elaborating the differential diagnosis of Rasmussen’s
syndrome; however, close inspection of the list reveals that the
critical aspects of diagnosis are the history, EEG, and MRI (1).
There is no test that is specific for Rasmussen’s syndrome, even
biopsy.
Medical treatment of Rasmussen’s syndrome has largely
been a failure. Standard anticonvulsant therapy does not stop
Current Review in Clinical Science 21
the seizures. There has been more than a decade of experience
in using various forms of immunotherapy, but these are unsatisfactory
as well. Corticosteroids are probably effective in the
short-term and when status epilepticus is present. Long-term
use is problematic. Intravenous immunoglobulin replacement
therapy may stabilize patients for varying periods of time and
has been used in combination with steroids for some individuals.
Side effects, including aseptic meningitis and phlebitis, exist,
and the cost of treatment is not inconsequential. Plasmapheresis
was popular when GluR3 antibodies were believed to be the
etiologic factor but does not appear to be effective for long-term
use.Newer forms of immunomodulation are hopeful, including
one described in an earlier report by Bien et al. (5) on the use of
tacrolimus to stabilize neurological function and prevent further
atrophy (without improved seizure control). In addition, preliminary
work using immunoablation with cyclophosphamide
to eliminate the T-cell population that apparently is activated
and then destroying brain seems promising (6). Following cyclophosphamide
treatment, the lymphocytes that subsequently
are generated presumably are na¨ıve and would not continue the
destruction of brain.
Surgery also has been part of the artillery used to battle
Rasmussen’s syndrome. In the earliest days it became clear that
the entire hemisphere had to be removed to produce a cure.
However, in the 1960s and early 1970s, there was virtually a
moratorium on using surgery because of concerns about longterm
problems, such as hemosiderosis. The moratorium ended
when better techniques, as well as neuroimaging, became available
in the late 1970s and early 1980s. Surgeons continue to
search to define the best technique, with variations that include
hemidecorticectomy and hemispherotomy with disconnection.
Proposed diagnostic criteria are at the heart of the consensus
statement paper by Bien et al., and they convey a sensitivity
to properly diagnosing patients before extensive tissue
destruction has occurred (1). Early diagnosis is important to
avoid the only cure currently available—removal of the hemisphere.
If caught early, before the process destroys much of the
hemisphere, the child might have seizures that could be controlled
with medication, without the significant handicap of a
hemiplegia. Although previous attempts to establish diagnostic
criteria have failed, the consensus reached by the European
group is significant. According to their statement, diagnosis is
achieved in one of two ways (1). First, a diagnosis is reliably
made when all three criteria found in Part A of the consensus
statement are fulfilled: (i) focal seizures with unilateral cortical
deficit; (ii) EEG showing unihemispheric slowing (± epileptiform
activity), with unilateral seizure onset; and (iii) MRI,
with unihemispheric focal cortical atrophy and either grey or
white matter T2/FLAIR hyperintense signal or by changes in
the ipsilateral caudate head. Second, diagnosis is attained if two
out of three of the features in Part B are fulfilled: (i) epilepsia
partialis continua or progressive unilateral cortical deficit, (ii)
progressive unihemispheric focal cortical atrophy on MRI, or
(iii) appropriate histopathology on biopsy. Using these criteria,
the majority of individuals can be diagnosed without biopsy.
The ultimate frustration in coping with Rasmussen’s syndrome
lies in the failure to be able to effectively treat this
obviously immune-mediated disease. The European consensus
group has provided a thoughtful algorithm for the therapeutic
approach to patients with Rasmussen’s syndrome (1). The
algorithm appropriately considers the seizures as well as the progressive
neurologic decline that accompanies the disease—both
of which clearly should influence decisions regarding therapy.
Although the authors describe patients with ongoing progression
of neurologic dysfunction, who do not have intractable
seizures and can be referred for continuing immunotherapy,
this scenario is virtually unknown. The consensus group also
provided a list of recommended areas for future therapeutic
research, which is admirable. The group recognizes the difficulties
in studying this population, particularly in regard to efficacy
parameters.
A few final thoughts about the struggle: parents and patients
engage in a particularly difficult process, as the affected
children were normal before this insidious process began. Parents
are looking for a cure that will halt the progression and
return their child to previous functional levels. Anticonvulsants
and hemispherectomy cannot achieve this result. And so far, immunotherapy
has not been effective. Early diagnosis is critical—
before significant neurological deterioration and destruction of
the brain occurs. And finally, greater understanding of the etiology
of Rasmussen’s syndrome is essential to the ability to
determine specific therapies.

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