Jack Zyroff

Cladribine in treatment of chronic progressive multiple sclerosis

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

Recurrent carotid artery stenosis following endarterectomy

Spectral analysis was used to examine 257 carotid arteries in 227 patients who had undergone carotid endarterectomy at 1, 3, 6, and 12 months after surgery and annually thereafter. Routine intraoperative completion angiography ensured that the operations were technically satisfactory. Postoperative restenoses were identified in 38 patients (15%). In 23 arteries (9%), the restenosis exceeded a 50% diameter reduction while in 15 arteries (6%) the stenosis was less than 50% of the diameter. Restenosis developed in 24/96 women (25%) and 14/161 men (9%). Twenty-nine (70%) stenotic lesions occurred within 12 months. In three patients early lesions regressed. Reoperation with patch angioplasty was required in six patients. When the 219 carotid arteries that remained widely patent were compared to the 38 that restenosed, no differences were noted for age, diabetes mellitus, hypertension, smoking, or degree of preoperative stenosis. Early stenotic lesions appear to be due to myointimal hyperplasia, which is probably platelet mediated. The predominant female sex distribution may be explained by differences in platelet responsiveness in men and women.

Primary intracranial hypotension and bilateral isodense subdural hematomas

A 39-year-old woman with headache and an organic mental syndrome was found to have primary intracranial hypotension (PIH). Bilateral isodense subdural hematomas were discovered in association with an absence of detectable CSF pressure on two lumbar punctures. This case study emphasizes that PIH is not an entirely benign condition and that intracranial hemorrhage may accompany persistent intracranial hypotension.

2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

We used a flow cytometry assay to measure proliferation and cytokine production of self-antigen-specific T cells in individual patients during the clinical course of multiple sclerosis (MS). Myelin-associated oligodendrocytic basic protein (MOBP) was selected for proof of principles in the assay, along with myelin basic protein (MBP) to assess specific activated T cells in 10 MS patients over an 18-month period, in parallel with brain magnetic resonance imaging (MRI) scans and clinical rating scale. A positive correlation occurred between antigen-specific T cell proliferation and interferon-gamma production with clinical relapses and MRI lesion activity that was absent when the same patients were in remission.

Development of cladribine treatment in multiple sclerosis

Cladribine is a new type of drug with properties of selective lymphocyte suppression that appear to favorably alter the clinical course of progressive multiple sclerosis (MS). The history of the development of cladribine treatment in chronic progressive MS is discussed, and the application of cladribine treatment to progressive multiple sclerosis in a double-blind, placebo crossover study is reviewed. Cladribine selectively targets both resting and dividing lymphocytes and may be able to destroy the activated lymphocytes that induce CNS demyelination, thus producing stabilization or improvement in chronic MS. Although the role of cladribine has not yet been fully defined, additional studies are underway to evaluate the efficacy and safety of cladribine in both progressive MS and relapsing-remitting MS.

The contribution of spectral analysis to the diagnosis of carotid artery disease

Pulsed and continuous-wave Doppler examinations with spectral analysis were performed on 258 carotid arteries in 220 patients and compared with multiplane contrast angiography. Each artery was examined for stenosis and assigned to one of four groups: normal to 19%, 20% to 49%, 50% to 99%, and occlusion. The incidence of disease was 70%. Diagnostic sensitivity with all noninvasive techniques varied from 76% to 90% depending on the degree of stenosis, with an overall accuracy rate of 86%. In an attempt to evaluate the diagnostic contribution of spectral analysis, stenosis classification by peak frequency alone was compared with that of the full laboratory profile, including spectral analysis. In the 147 carotid arteries in which such data were available, diagnostic sensitivity was improved with spectral analysis by 8% to 29% depending on the degree of stenosis. Detection of occlusions was unchanged. The major contribution of spectral analysis was in detecting non-flow-limiting stenoses of 20% to 49%. Spectral analysis added little to the diagnostic ability of peak frequency to detect lesions with greater than 50% stenosis. Spectral analysis of either pulsed Doppler or continuous-wave Doppler signals is an accurate noninvasive method for evaluating carotid bifurcation disease, which particularly improves the detection of non-flow-limiting stenoses.

Adverse reactions to iopamidol and iohexol myelography with special attention to headache: role of myelographic technique.

SYNOPSIS

Radiation-Induced Cavernous Malformations of the Cauda Equina Mimicking Carcinomatous or Infectious Meningitis. A Case Report†

The authors present a case of multiple radiation‐induced cavernous malformations of the cauda equina in a patient with a remote history of testicular cancer and extended field radiation therapy. Magnetic resonance imaging (MRI) demonstrated multiple nodular areas of enhancement coating the nerve roots of the cauda equina, mimicking an aggressive leptomeningeal process such as carcinomatous or infectious meningitis. Biopsy of one of these lesions revealed ectatic vascular channels devoid of intervening neuroglial tissue consistent with cavernous malformation.

Treatment of Multiple Sclerosis with Cladribine

Cladribine, also known as 2-chlorodeoxyadenosine (2-CdA) or Leustatin®, is an adenosine deaminase-resistant purine nucleoside that selectively targets lymphoid cells, with relatively low toxicity toward other tissues (Beutler 1992). The history of the development of cladribine begins with the discovery of a relationship between severe combined immunodeficiency disease (SCID) with severe lymphopenia and inherited deficiency of the enzyme adenosine deaminase (ADA). ADA deficiency was discovered serendipitously by Giblett et al. in 1972 while investigating the linkage of immunodeficiency to a variety of genetic markers. For many years the severe lymphopenia in SCID that results from complete ADA deficiency was not understood.