Acta Neurochir (Wien) (2006) 148: 677–679 DOI 10.1007/s00701-006-0772-y
Case Report Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease I. R. Whittle, R. S. G. Knight, and R. G. Will Department of Clinical Neurosciences and National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK Received September 27, 2005; accepted February 21, 2006; published online April 7, 2006 # Springer-Verlag 2006
Summary Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced. Keywords: Pentosan polysulphate; Creutzfeldt-Jakob disease.
prion
disease;
variant;
Introduction Attention has recently focussed on the use of pentosan polysulphate (PPS) as a potential treatment for human prion diseases, including variant Creutzfeldt-Jakob disease (vCJD) [1, 2]. In an experimental setting PPS may prolong the incubation period or even result in the survival of laboratory rodents if given parenterally prior to, or immediately after, inoculation with an infectious challenge [3, 4]. PPS is, however, unlikely to be an effective treatment by the oral or intraperitoneal route at the stage of clinical disease because it does not cross the blood brain barrier. A Japanese group have recently described prolongation of the incubation period in transgenic mice treated with an intraventricular infusion of PPS at a late stage of infection and suggested that this may be a useful treatment for human prion disease [5]. There is, however, a paucity of experimental data and considerable doubt about the appropriate PPS dosage in humans, the safety of intraventricular PPS and how to
measure efficacy. We report a case of vCJD in which treatment with intraventricular PPS was started at a relatively early stage of the clinical course. Case report A 39-year-old female presented with a 9-month history of psychiatric disturbance with depressive symptoms and aggressive behaviour, requiring admission to a psychiatric hospital. Evidence of cognitive impairment and mild gait ataxia had developed 6 months from the onset and as these signs evolved after hospital admission a neurology opinion was obtained. An organic cause for the presentation was suspected and investigation instituted, including a request for an MRI brain scan. No clear diagnosis was suggested at this stage but the possibility of a human prion disease was raised. Routine investigations were normal but MRI brain scan showed the ‘pulvinar’ sign, suggesting a diagnosis of vCJD. However, there were insufficient clinical features to diagnose vCJD with confidence (for example there were no involuntary movements) and tonsillar biopsy was carried out. This showed accumulation of protease resistant prion protein in the germinal centres, consistent with a ‘probable’ diagnosis of vCJD, according to published diagnostic criteria. After detailed discussion with the patient and her family, and following legal advice, a decision was made to start treatment with intraventricular PPS. At the time of insertion of bilateral frontal ventricular catheters and an epigastric implantable programmable drug infusion pump (Medtronic, Minneapolis, USA) the patient was alert but confused (GCS ¼ 14), ataxic but able to walk, and had neither incontinence nor involuntary movements. Treatment with PPS (Pentosan Polysulphate SP 54, beneArzneimittel GmbH, Munich, Germany) was commenced one week after surgery, a year after onset of the initial clinical symptoms. The dosage was increased over 18 days from 1.1 ug=kg=day to 110 ug=kg=day, the dosage recommended by Rawlins et al. in December 2002. There were no immediate adverse effects from treatment. Serial CSF measurements via the reservoir revealed no intraventricular bleeding and an MRI scan two months post surgery was unchanged, with no evidence of haemorrhage. However there was an inexorable clinical decline with progressively worsening gait and truncal ataxia, deterioration in speech
678 and progressive cognitive decline documented by serial neuropsychological assessments. The MMSE score declined from 20 two weeks prior to starting PPS treatment to 18 at the time of surgery, 9 two weeks later and 1 after a further five weeks. She developed myoclonus and increasing drowsiness. Six weeks after treatment was started the patient was discharged to a hospice and during this admission the medical staff felt the clinical status had plateaued, although the family reported some improvement, with occasional appropriate verbal comments, some return of coordinated movements of the arms and less restlessness. Nineteen days later she was readmitted after a series of tonic-clonic seizures, which were treated with intravenous benzodiazepines and sodium valproate 400 mg twice daily, with prompt control of seizures. She was pyrexial and had a urinary tract infection, which was treated with antibiotics. The PPS infusion was stopped. A range of investigations, including CT scan and CSF analysis, were normal. Over several days her condition stabilised, but at best she was mute, unable to obey commands, bedridden due to ataxia, and had chorea of the face and limbs. After one week the PPS infusion was resumed at 10 ug=kg=day and six days later increased to 25 ug=kg=day. A higher dosage was not given because of the possibility that the PPS had caused the seizures, although these may have been related to the disease itself or to the urinary infection. Subsequently her condition deteriorated progressively to a state of akinetic mutism and the decision was made to stop the PPS after 4 months treatment. The patient died 3 weeks later with a total duration of illness of 16 months. Post-mortem was not carried out in accordance with the wishes of the patient’s family.
I. R. Whittle et al.
The poor outcome in this case is in contrast to the prolonged survival, albeit in a severely disabled state, of the first case of vCJD treated with intraventricular PPS that has been reported in some detail [1]. Additionally our patient received ten times the dose delivered to the first case. Since that time an increasing number of patients with various types of prion disease have been treated with PPS with variable outcomes [2]. There is a clear need for a harmonised protocol for therapy and outcome assessment in experimental treatments of human prion disease (and the MRC has funded an independent neurologist to make such an assessment of PPS), but our experience does not suggest that PPS had any sustained therapeutic benefit in this single case of vCJD. Clearly further experimental studies are required in large animal models to characterise dose related PPS toxicity, penetration of PPS into the brain and potential efficacy.
References Discussion Experimental models of PPS treatment show not only the potential for some benefit but also the possibility of severe adverse effects, including haemorrhage, seizures and death [5]. The limited preliminary experience with intraventricular PPS in vCJD suggests that in the dose escalation adopted, the immediate risks of intraventricular or intracerebral haemorrhage are probably small [1, 2], despite the mild anticoagulant effect of PPS. However after several weeks generalised seizures occurred with no radiological evidence of intracerebral haemorrhage or CSF infection. This suggests that either the proposed maximum levels of infusion are very close to the threshold for causing epilepsy, an important side effect in one animal model of this therapy [3], or that the seizures may just have been attributable to the clinical course of vCJD in this patient. Treatment with PPS was started in this case at a relatively early stage in the clinical course and at a stage when the patient was able to converse and to walk, albeit with some ataxia. Despite this there was relentless progression in the neurological deficits and, although the family reported a transient improvement mainly in speech, overall there was no definite clinical benefit. The survival of 16 months was a little greater than the median of 14 months in vCJD (range 6–40 months), but in view of the marked range of survival in vCJD this cannot be regarded as significant [6].
1. Todd NV, Morrow J, Doh-ura K et al (2005) Cerebroventricular infusion of pentosan polysulphate in human variant CreutzfeldtJakob disease. J Infect 50: 394–396 2. Rainov NG, Whittle IR, Doh’ura K (2005) Treatment options in patients with prion disease-the role of long term cerebrovascular infusion of pentosan polysulphate. In: Kitamoto T (ed) Prions: food and drug safety. Springer Berlin Heidelberg New York Tokyo, pp 41–66 3. Diringer H, Ehlers B (1991) Chemoprophylaxis of scrapie in mice. J Gen Virol 72: 457–460 4. Farquhar C, Dickinson A, Bruce M (1999) Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet 353: 117 5. Doh-Ura K, Ishikawa K, Murakami-Kubo I et al (2004) Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol 78: 4999–5006 6. Pocchiari M, Puopolo M, Croes EA et al (2004) Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 127: 2348–2359
Comments This case report from a leading group in Edinburgh concerns a subject of great medical and public interest, namely variant CJD. It is the second report of the result of intraventricular Pentosan Polysulphate into a patient with the disease. A previous patient elsewhere treated with this drug is still alive. The current patient did not show apparent clinical benefit and survived for 16 months. Peter G. E. Kennedy Glasgow The authors offer a brief anecdotal overview of their experience with a single patient with variant Creutzfeldt-Jakob disease (vCJD treated with intraventricular pentosan polysulphate (IVPPS)). The case report is important and should be published because it offers a contrasting and somewhat steadying or counterbalancing perspective compared to
Unsuccessful intraventricular PPS treatment of variant Creutzfeldt-Jakob disease the optimism generated from previous, very limited use of IVPPS as a treatment for human prion disease. Steven Collins Melbourne There have been a handful of patients with vCJD and GSS treated with intraventricular pentosan polysulphate. The scientific basis for treatment of vCJD with pentosan is extremely limited. If this was not a universally fatal condition with no known treatment, treatment with pentosan could not be justified. It is a pity that the patients that have been treated in the UK have not been entered on a central database, and therefore we rely on individual case reports, such as this report. This is a well written article which discusses the relevant points in a clear and cogent manner. The first two patients with vCJD that were treated with a dose of 11 mg=kg=day. The authors have increased that dose ten fold to 110 mg=kg=day. Pentosan is a heparan and it has a weak anticoagulant effect. Obviously the infusion of a heparan into the ventricular system raises concerns about intracranial haemorrhage.
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In Doh-Ura’s studies high doses of pentosan caused intracranial haemorrhage. I think the general consensus now is that intraventricular infusion with pentosan is not associated with great morbidity and this paper clearly makes that important point, even at the higher dosage that was used in this patient. I think this is an important article. Patients with vCJD, classical CJD, and also GSS are aware of potential treatment with pentosan. The first two patients that were treated are still alive, one patient four years after diagnosis, and one patient over two years after diagnosis which might suggest a treatment effect in these two patients. This paper clearly demonstrates that in their patient there was no observable clinical effect. Both the positive and negative sides of this treatment need to be available to patients and potential treating doctors. N. V. Todd Newcastle-upon-Tyne Correspondence: I. R. Whittle, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. e-mail:
[email protected]
