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Treatment Options in Patients with Prion Disease - the Role of Long Term Cerebroventricular Infusion of Pentosan Polysulphate

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Prions

Summary

Prion diseases (PrD), also known as transmissible spongiform encephalopathies, are believed to be caused by accumulation of an abnormal isoform of the prion protein (PrPSC) in the central nervous system. Creutzfeld-Jacob disease (CJD) in its sporadic and variant form is the most frequent and clinically important PrD. At present there is no proven specific or effective treatment available for any form of CJD, although some oral agents, such as quinacrine or flupirtine, are being investigated in clinical trials.

Pentosan polysulphate (PPS), a large polyglycoside molecule with weak heparin-like activity, has been shown to prolong the incubation period of PrPSC infection when administered to the cerebral ventricles in a rodent scrapie model. PPS also prevents the production of further PrPSC in cell culture models. However, PPS penetrates poorly the blood-brain barrier and only a minor fraction of orally administered drug may reach the CNS. These properties of PPS prompted its cerebroventricular administration in patients with vCJD and other PrD, such as iatrogenic CJD and Gerstmann-Sträussler-Scheinker syndrome (GSS). Long-term continuous infusion of PPS at doses of up to 110 µg/kg/d did not cause serious drug-related side effects. Follow-up CT and MRI imaging demonstrated that brain atrophy may progress further during PPS administration, while the neurological status may remain stable. Proof of clinical efficacy has not been the aim of the current clinical studies of PPS, however one patient with vCJD survived for 23 months after initial symptoms and 39 months after diagnosis, while the median duration of illness with vCJD is 13 months (range 6–39).

Some lessons have been learned from the early studies of application of PPS in PrD patients. Surgery in a brain affected by PrD may result in a higher rate of surgical complications than might be expected in analogous cases with other conditions. Secondly, efficacy of PPS or any other treatment option in advanced PrD cases will be very difficult to assess, due to the lack of specific and objective criteria for measurement of response. Overall survival may remain therefore one of the few objective ways of assessing outcome in treated patients. Finally, if clinically significant benefits to patients are to be expected, PPS administration should start as early as possible in the course of the respective disease and before irreversible loss of neurological function has occurred. Further clinical, neuroradiological and laboratory investigations of cerebroventricular PPS administration in the setting of a prospective clinical study will be essential for the assessment of possible clinical benefits of PPS in PrD.

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Authors and Affiliations

  1. Department of Neurological Science, The University of Liverpool, Lower Lane, Liverpool, L9 7LJ, UK

    Nikolai G. Rainov

  2. The Walton Centre for Neurology and Neurosurgery NHS Trust, Liverpool, UK

    Nikolai G. Rainov

  3. Department of Clinical Neuroscience, Western General Hospital, Edinburgh, UK

    Ian R. Whittle

  4. Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai, Japan

    Katsumi Doh-ura

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  1. Nikolai G. Rainov
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  2. Ian R. Whittle
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  3. Katsumi Doh-ura
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  1. Department of Prion Research, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Tetsuyuki Kitamoto M.D.

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Rainov, N.G., Whittle, I.R., Doh-ura, K. (2005). Treatment Options in Patients with Prion Disease - the Role of Long Term Cerebroventricular Infusion of Pentosan Polysulphate. In: Kitamoto, T. (eds) Prions. Springer, Tokyo. https://doi.org/10.1007/4-431-29402-3_4

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