A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis
Condition: Chronic Focal Encephalitis; Rasmussen's Encephalitis
MeSH terms: Encephalitis; Inflammation
Study type: Interventional
Phase: Phase 1

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

Detailed 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.
    

Intervention name(s): Rituximab
Intervention type(s): Drug
Intervention description(s): 375 mg/m2 given as an IV infusion once weekly for four doses
Intervention MeSH terms: Rituximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: encephalitis; epilepsy; Rasmussens; rituximab; autoimmune