A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis

California Pacific Medical Center Research Institute

Status and phase

Completed

Phase 1

Conditions

Chronic Focal Encephalitis

Rasmussen's Encephalitis

Treatments

Drug: Rituximab

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00259805

Genentech CFE-001

CPMC-IRB25.102

Details and patient eligibility

About

The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis.

Full description

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.

Enrollment

10 patients

Sex

All

Ages

5 to 25 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Diagnosis of chronic focal encephalitis
IgG & IgM levels within normal limits
Adequate renal function
Stable anticonvulsant drug regimen

Exclusion criteria

Evidence of significant ongoing medical condition or progressive neurologic condition (other than CFE)
Previous treatment with rituximab
History of significant recurrent infections, or ongoing active infection
Receipt of a live vaccine within 4 weeks prior to treatment
History of severe allergic reactions to humanized or murine monoclonal antibodies
History of drug, alcohol or chemical abuse within 6 months
Concomitant malignancies or previous malignancy
Use of steroids or immunoglobulins during the 4 weeks prior to treatment
Hemoglobin <8.5 gm/dL, Platelets < 100,00/mm, AST or ALT >2.5 ULN
Positive Hepatitis B or C serology
History of positive HIV