Chronic Focal Encephalitis Clinical Trial
Official title:
A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis
The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis.
Chronic Focal Encephalitis (Rasmussen's Encephalitis) is a condition characterized by a
progressive hemiparesis, cognitive decline (including loss of language skills if the
language dominant hemisphere is involved) and epileptic seizures that are typically
refractory to medical treatment (Rasmussen). Attempts to control the seizures with
anticonvulsants are ineffective and the only effective treatment to date is a
hemispherectomy (surgical removal of half of the brain). Children with CFE who undergo
cortical resections or hemispherectomies demonstrate an inflammatory histopathology
consisting of perivascular lymphocytic cuffing, gliosis, neuronal loss, microglial nodules
and later laminar necrosis and spongy degeneration
Rituximab is a genetically engineered, chimeric; murine/human monoclonal antibody directed
against the CD20 antigen found on the surface of normal and malignant pre-B and mature B
cells. It was approved by the FDA in 1997 for the treatment of relapsed or refractory low
grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma (NHL). Rituximab binds
specifically to the CD20 antigen expressed on the surface of both normal and malignant pre-B
and mature B cells. In vitro mechanism of action studies have demonstrated that the Fc
portion of Rituximab binds human complement and can lead to cell lysis of the targeted cell
through complement-dependent cytotoxicity. Additionally, it has been demonstrated that
Rituximab has significant activity in assays of antibody dependent cellular cytotoxicity
(Reff et al. 1994). More recently, Rituximab has been shown to induce apoptosis in vitro in
DHL-4, a human B cell lymphoma line (Maloney et al. 1997). The relative extent to which
these individual mechanisms account for the observed depletion of normal and malignant B
cells in vivo is unknown.
While CFE represents only a very small percentage of patients with epilepsy, the devastating
progressive nature of the disease with out any adequate treatments, relegates these children
to the relentless loss of cognitive and motor skills, and continuing seizures. Recent
evidence suggests this condition is immune mediated and includes the development of
antibodies directed against various brain components including glutamate receptors (GluR3)
(Rogers). Brain samples from patients with CFE have demonstrated immunoreactivity for IgG,
C4 C8, and MAC (Andrews and Whitney) and involvement of both B and T-lymphocytes. Evidence
supporting a role for clonally expanded B lymphocytes was found by Baranzini . By analyzing
the T-cell receptor expression in brain lesions using PCR these investigators also
demonstrated the local immune response in CFE included restricted T-cell populations
probably expanding from a few precursor T-cells responding to discrete antigenic epitopes
(Li). Following demonstration of antibodies directed against brain elements in CFE, a
patient was treated with plasma exchange which produced a significant improvement in seizure
frequency, cognition and hemiparesis, lending support to the hypothesis that circulating
antibodies contribute to the disease pathogenesis. Subsequently attempts to modify this
disease by immune modification (plasmaphoresis, steroids, gamma globulin) have demonstrated
modest improvements but the improvements have been short-lived and have not affected the
natural progression of this disease. This pilot study proposes to directly attack the cells
(B-cells) thought to be instrumental in the development of this condition. Should this
approach to treating CFE be successful it will have a major impact on these children's
lives.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment