E-Table 7:Prion Disease Treated Patients: Case reports/ patient series

Study code
Reference
Study type / Intervention
Drug, dose, mean duration (range) / Study
period / Country / Diseases
included
Method
diagnosis / Number of patients
sex , age at treatment / Disease
stage[a] / Reported effect / Survival beyond start of treatment
Duration disease / Toxicity / Author’s
conclusions
Antiviral drugs
Acyclovir[b]
David 19841
Letter
Case report / Acyclovir
10mg/kg x3 daily / 1982 / UK / CJD
Definite (biopsy) / 1 F 59 / Late / Condition did not change EEG did not change / 4w post treat
DD 10m / Stated as none / No effect
Newman 19842
Letter
Case report / Acyclovir
500mg x3 daily
10d / - / UK / CJD
- / 1 F
- / - / No response
Treatment failure / - / - / No effect
Amantadine[c]
Braham 19713
Short report
Case report
Same case reported in:
Braham 19844 / Amantadine
600mg/day
>34d / 1971 / Israel / CJD
Clinical / 1 M 65 / Late / Improvement
From mute and immobile to sitting in wheelchair, limitedcommunication / Alive at time report. Another paper (Sanders 19735) states death from sepsis at 9m / - / Benefit, recommends further trials
Sanders 19735
Full paper
Case reports / Amantadine
200-800 mg/day
till death, 18m / 1970 - 1971 / UK / CJD
Supported
(EEG,CSF) / 2
1 M 69
1 F 55 / Late / Transient improvement in 1 patient (M), mental & physical improvement rigidity disappeared who subsequently died
Progressive improvement in other (F) who was alive at time of report / 1 died 3.5m after first symptoms (Broncho pneumonia).
DD 4.5m
1 alive DD > 30m / Possible hallucination / Benefit
Has some action & use justified
Scully 19806
MGH case record
Case report / Amantadine
Dose not stated
27d
Also adrenocorticotropic hormone, dexamethosone, BCG vaccine / - / USA / CJD
Definite (biopsy) / 1 M 43 / Mid / No effect / 14m post treat (septicemia)
DD 26m / - / No effect
Herishanu 19737
Full Paper
Case report / Amantadine
200-600mg/day
Also dexamethosone
idoxuridine / 1972 / Israel / CJD
Supported
(EEG) / 1 M 61 / Mid / Without positive effect / 28d post treat
DD 2m / Liver toxicity, leukopenia, septicemia / No effect
Ratcliffe 19758
Full Paper
Case report / Amantadine
1000 mg/day
till death
seizures controlled diphenylhydantoin, phenobarbitol / 1973 / USA / CJD
Definite
(autopsy) / 1 F 65 / Late / No benefit / 2w post treat
DD 4m / - / No benefit
Sanders 19799
Short report
Case report / Amantadine
100 – 400 mg/day / 1972 - 1977 / UK / CJD
Definite
(autopsy) / 1 M 56 / Late / Improvement
Clinical improvement followed by long period of stability
Rigidity disappeared, incontinence cleared, sometimes more communicative & rational / 4.5y post treatment accidental death (inhalation vomit).
DD 5y / - / Benefit
Vidarabine
Furlow 198210
Letter
Case report / Vidarabine
15mg/kg/day
14d
previously treated with clonazepam / 1981 / USA / CJD
Definite (biopsy) / 3
1 F 62 in detail
mentions outcome for 2 others / Mid / Transient improvement
Repeated treat & response shown
No adventitious movement all neurological symptoms improved / 9/10 months from treat (febrile, resp failure) DD 12m / - / Benefit
Favorable palliative response 2/3 patients
Antimalarial drugs
Quinacrine / Mepacrine
Wroe 200611
Full paper
Case report / Quinacrine
300mg/day / 2005 / UK / vCJD
Definite (autopsy) / 1 M 31[d] / Early/Mid / No effect.
Patient continued to decline / DD 33 months / No toxicity recorded / No conclusions drawn re treatment effect
Martinez-Lage 200512
Full paper
Case report / Quinacrine
300mg/day
3w
followed by
Chlorpromazine 300mg/day
Time period unclear / 2002 / Spain / iCJD
Definite (autopsy) / 1 F 46 / Mid/Late / No effect / 7 months from treat
DD 19m / Hepatic impairment and yellowish skin pigmentation / No clinical or EEG signs of improvement, treatment complicated by liver dysfunction.
Bertrand 200513
Full paper
(in French)
Case report / Quinacrine
300mg/day
6w / 2003-2004 / France / fCJD
(PrP E200K but with no family history) / 1 F 39 / Late / No effect
Patient continued to decline.
Treatment stopped due to liver toxicity / 4 months from treat
DD 8m / Cytolytic hepatitis / No benefit
Nakajima 200414
Full paper
Prospective case series
also
Nakajima 200215
(Conference abstract) / Quinacrine
300mg/day
3m / Oct 2001 – Feb 2002 / Japan / 3 sCJD
1 iCJD
- / 4
6 others mentioned but not reported in abstract. Unclear if might be those reported by Satoh / Late / Transient clinical improvement
(2-8w)
Increased responsiveness, arousal
reduced myoclonus, restoration of some cognitive function / DD mean 5m for sCJD (2-11)
DD 6y iCJD / Liver dysfunction
yellow pigmentation / Benefit
Benito-Leon 200416
Full paper
Case reports / Quinacrine
600mg daily 5 days then
300mg/day (patient 1)
300mg/day (patient 2)
Chlorpromazine
-225mg/day increasing to 600mg/day (pt 1)
- 225mg/day (pt 2) / Sept 2001 - Feb 2002 / Spain / 2 iPD
Definite autopsy / 1 F 43
1 M 52 / 1 Mid
1 Early / Patients both continued to deteriorate. Treatment was withdrawn in both patients owing to lack of efficacy and toxicity / Mid stage patient 52d
Early stage patient several months / Quinacrine:
Psychosis, psoriasis
Chlorpromazine:
Orthostatic hypotension / Treatment harmful and that “sufficient data have accumulated to eliminate this form of treatment of human prion diseases”
Satoh 200417
Case reports / Patient 1
Quinacrine 300mg/day for 2 weeks then 600mg/day
Patients 2 and 3
Quinacrine 200mg/day
Verapamil 120mg/day / - / Japan / 3 sCJD
Possible CSF/MRI / 1 F 64
1 M 71
1 M 65 / Patient 1 unclear, patients 2 and 3 probably late stage / Patient 1 treated with quinacrine alone showed marked improvement in myoclonus, gaze and smile. Quinacrine discontinued because of liver toxicity.
Patients 2 and 3 showed marked improvements in eye control and myoclonus. Benefit was transitory – 8w in patient 2, duration not stated for patient 3 / - / Liver dysfunction in patient 1 treated with high dose quinacrine alone / Clinical improvements from lower dose quinacrine plus verapamil were similar to high dose quinacrine, and had no associated toxicity.
Kennedy 200318
Conference abstract
Pilot study/case series / Quinacrine
300mg/day / - / UK / 1 sCJD
3 vCJD
6 iPD
- / 10 / - / - / 4 died
at 16, 20, 69, 44w after treatment / Dose modifying liver toxicity (5), dose modifying rash (3) / -
Scoazec 200319
Letter
Case series / Quinacrine
1000mg loading, then 300mg/day
37d (7-80) / - / France / sCJD
Definite
(autopsy) / 3
- / - / No significant clinical improvement / 28, 29, 125d post treat (mean 67d) respiratory failure / Liver toxicity
Bone marrow aplasia / No effect & notes toxicity
Kobayashi 200320
Full paper
(in Japanese)
Case report / Quinacrine
300mg/day
2m / 2001 / Japan / iCJD / 1 F 37 / Late / Transient (3w) improvement in symptoms
Regained limb movement & pursuit eye movement. / - / Liver dysfunction
Treatment stopped / Benefit
Biacabe 200221
Conference abstract
Also:
Barret 200322
(As pers comm)
Information from website ( / Mepacrine
300mg/day / - / France / Prob CJD
1 sCJD,
1 iCJD
2 not specified
2 definite
(autopsy)
website
13 sCJD
4 iCJD
1 vCJD
2 iPD / 4
2 M, 2 F
32-70 (53)
(mentions another 40 treated )
20
67 (sCJD)
29 (iCJD)
45 (fCJD)
36 (vCJD)
19 (FFI)
unclear if overlap between the 4 and 20 patients / Late / No apparent effect, no clinical improvement
Pers com in another paper (Barret et al., 2003) states that the French human quinacrine cohort of 20 patients found no significant benefit in clinical status
No improvement (even transient) in any of the patients. / 2 patients died, timing not clear
2 alive at time of report
14 died between 1w to 3m post treat / -
Liver anomalies (5)
Digestive intolerance (1)
Urticaria (1)
Convulsions(1)
Not all necessarily attributable to treatment / No effect
No benefit
Anticoagulant drugs
Pentosan polysulphate
Parry 200723
Full paper
Case report / Pentosan polysulphate
Initial dose 1μg/kg/day increased to 11μg/kg/day over 15 days. Increased to a maximum dose of 32μg/kg/day from Oct 04 to Apr 05 / 2003-present / UK / vCJD
(positive tonsil biopsy) / 1 M 18 / Mid/Late / Slow progression over 18 months followed by apparent stabilization of clinical symptoms,
Authors state this may reflect reduced sensitivity for detection of change / Alive at time of report
31m after treatment
51m after first symptoms / PPS dose of 32μg/kg/day appears to have been safe and well tolerated with no adverse effects / Treatment was safe and well tolerated and associated with prolonged survival when compared to natural history studies.
However, PPS did not appear to arrest progression of the disease.
Rainov 200724
Full paper
Supersedes
Rainov 200525 / Pentosan polysulphate
Maximum dose administered varied from 11μg/kg/day to 220μg/kg/day / 2003-present / Various / 1 vCJD[e]
7 iPD
7 iCJD
8 sCJD / 23 / - / Mixed results, reports initial improvement then deterioration (2), initial stabilization followed by slow progression (1), stable disease (5), slow progression (4), continuousdeterioration (6), not stated (5) / 11m
(2-27)
n=12
n= 11 still alive:
19m
(1.5 – 35) / No side effects clearly attributable to PPS / Long term IV administration of PPS appears to be safe.
PPS administration seems unable to reverse the course of advanced disease.
Whittle 200626
Full paper
Case report / Pentosan polysulphate
1.1ug/kg/day increased to 110ug/kg/day over 18 days
Treatment interrupted due to onset of seizures;resumed at a dose of 10ug/kg/day, increased 6 days later to a dose of 25ug/kg/day.
(Higher dose not given in case the PPS had caused the seizures. / - / UK / vCJD
Probable (biopsy) / 1 F 39 / Early/Mid / No effect. Medical staff reported relentless clinical decline although family reported some improvement - occasional appropriate verbal comments, some return of coordinated movements of the arms and less restlessness.
Treatment was interrupted due to onset of seizures before being resumed after 1 week / 5 months post treatment
DD 16m / Seizures possibly attributable to treatment / No definite clinical benefit
Todd 200527
Full paper
Case report
Supersedes
Dealler 200328 / Pentosan polysulphate
Initial dose 1g/kg/day escalating to 111g/kg/day via intraventricular catheter / 2001 - present / UK / vCJD
Probable
(tonsil biopsy) / 1 M 18 / Late / Clinical improvement
Able to fix eyes on people, obey simple commands, make verbalization attempts in response to stimuli. Sleep/wake cycle, reflex swallow restored, myoclonus reduced. Weight gain.
Brain atrophy progression. / Alive at time of report.
18m after treatment[f], 30m after diagnosis, 37m after first symptoms / Stated as none / Treatment safe. Requires further study.
Antifungal drugs
Amphotericin
Masullo 199229
Letter
Case reports / Amphotericin B
0.25 – 1.0 mg/kg
6 days/week
20d / - / Italy / 2 uCJD[g]
- / 2
1 F 71
1 F 50 / 1 Mid
1 Late / Did not improve neurological deficits or prolong DD / 20d post treat (cardiac failure)
DD 4m
?3m post treat
DD 8m / Stated as none in 1 pt, not reported for other / No effect
Biological Response Modifiers
Interferon
Kovanen 198030
Short report
Case reports / Interferon
(Human leukocytic) / 1978 - 1979 / Finland / 1 sCJD
1 iPD
Definite / 2
1 F 50
1 F 50 / 1 Early
1 Late / No change / 7m post treat
DD 15m
DD >21m
date death not given / - / No effect
Antidepressant drugs
Clomipramine
Dervaux 200131
Paper (in French)
Case report / Clomipramine 125mg/day 3w
Venlafaxine 200mg/day
7w / - / France / v CJD
Definite
(brain biopsy) / 1 F 36 / Early? / No effect / 8m post treat
DD 14m / - / No effect
Anticonvulsant drugs
Levetiracetam
Imperiale 200332
Short report
Case report / Levetiracetam
1000 – 2000mg/day
ongoing
for myoclonus control
In addition to valproateclonazepam, phenobarbitol / 2001 / Italy / uCJD
Supported / 1 M 35 / Late / Improvement
Marked reduction in myoclonus / Alive at time of report / Stated as none / Benefit
Topiramate/ phenytoin
Floel 200333
Case report / Topiramate/ phenytoin
Phenytoin - 750mg then 300mg/day
topiramate 50mg – 100mg x 2 / 2002 / Germany / CJD
Supported
(EEG)
but subsequently classified as misdiagnosed / 1 M 69 / Mid? / Improvement
Clinical improvement
Myoclonus & rigidity improved movement & communication / Alive at time of report > 1m post treat
Died ~ 7m post treat (pers comm) / - / Benefit
but subsequently classified as misdiagnosed
Antioxidants
Drisko 200234
Paper
Case report / Various antioxidants & vitamins
until death
Dilantin for myoclonus control was discontinued / ? / USA / CJD
? iCJD
Definite
(autopsy) / 1 F 69 / Late? / Improvement
Clinical improvement in responsiveness, myoclonus, apnea , rigidity / 19m post treat
DD 22m / - / Benefit

-= not reported, M = male, F = female, d = days, w= weeks, m = months, y = years, DD = duration of disease, treat = treatment.

References

1. David AS, Grant R, Ballantyne JP. Unsuccessful treatment of Creutzfeldt-Jakob disease with acyclovir. Lancet 1984;1:512-513.

2. Newman PK. Acyclovir in Creutzfeldt-Jakob disease. Lancet 1984;1:793.

3. Braham J. Jakob-Creutzfeldt disease: treatment by amantadine. BMJ 1971;4:212-213 .

4. Braham J. Amantadine in the treatment of Creutzfeldt-Jakob disease. Archives of Neurology 1984;41:585-586.

5. Sanders WL, Dunn TL. Creutzfeldt-Jakob disease treated with amantadine. A report of two cases. Journal of Neurology, Neurosurgery & Psychiatry 1973;36:581-584.

6. Scully RE, Galdabini JJ, McNeely BU. Case records of the Massachusetts GeneralHospital. New England Journal of Medicine 1980;303:1162-1171.

7. Herishanu Y. Antiviral drugs in Jakob-Creutzfeldt disease. Journal of the American Geriatrics Society 1973;21:229-231.

8. Ratcliffe J, Rittman A, Wolf S, Verity MA. Creutzfeldt-Jakob disease with focal onset unsuccessfully treated with amantadine. Bulletin of the Los Angeles Neurological Societies 1975;40:18-20.

9. Sanders WL. Creutzfeldt-Jakob disease treated with amantadine. Journal of Neurology, Neurosurgery & Psychiatry 1979;42:960-961.

10. Furlow TWJ, Whitley RJ, Wilmes FJ. Repeated suppression of Creutzfeldt-Jakob disease with vidarabine. Lancet 1982;2:564-565.

11. Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006;368:2061-2067.

12. Martinez-Lage JF, Rabano A, Bermejo J, Martinez Perez M, Guerrero MC, Contreras MA, et al. Creutzfeldt-Jakob disease acquired via a dural graft: failure of therapy with quinacrine and chlorpromazine. Surgical Neurology 2005;64:542-545.

13. Bertrand A, Martinez-Almoyna L, De Broucker T. Hereditary Creutzfeldt-Jakob disease caused by a mutation at codon 200. Revue Neurologique 2005;161:351-354.

14. Nakajima M, Yamada T, Kusuhara T, Furukawa H, Takahashi M, Yamauchi A, et al. Results of quinacrine administration to patients with Creutzfeldt-Jakob disease. Dementia and Geriatric Cognitive Disorders 2004;17:158-163.

15. Nakajima M, Yamada T, Kusuhara T, Furukawa H, Takahashi M, Kataoka Y, et al. Restored cognition in patients with Creutzfeldt-Jakob disease. Presented at New Perspectives for Prion Therapies. Dec 1-3, 2002; Paris. Abstract O-26.

16. Benito-Leon J. Combined quinacrine and chlorpromazine therapy in fatal familial insomnia. Clinical Neuropharmacology 2004;27:201-203.

17. Satoh K, Shirabe S, Eguchi K, Yamauchi A, Kataoka Y, Niwa M, et al. Toxicity of quinacrine can be reduced by co-administration of p-glycoprotein inhibitor in sporadic Creutzfeldt-Jakob disease. Cellular & Molecular Neurobiology 2004;24:873-875.

18. Kennedy AM, Walker S, Darbyshire J, Collinge J. The MRC Prion-1 trial: development of a protocol to evaluate quinacrine and other potential therapeutics for human prion disease. Presented at Prion Diseases: From Basic Research to Intervention Concepts. Oct 8-10, 2003; Munich. Abstract BR-115.

19. Scoazec JY, Krolak-Salmon P, Casez O, Besson G, Thobois S, Kopp N, et al. Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease. Annals of Neurology 2003;53:546-547.

20. Kobayashi Y, Hirata K, Tanaka H, Yamada T. Quinacrine administration to a patient with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft - an EEG evaluation. Rinsho Shinkeigaku. Clinical Neurology 2003;43:403-408.

21. Biacabe AG, Peoc'h K, Delasnerie-Laupretre N, Brandel J, Martin C, Beaudry P, et al. Mepacrine therapy in CJD patients does not affect CSF 14-3-3 accumulation. Presented at: New Perspectives for Prion Therapies. Dec 1-3, 2002; Paris. Abstract P-24.

22. Barret A, Tagliavini F, Forloni G, Bate C, Salmona M, Colombo L, et al. Evaluation of quinacrine treatment for prion diseases. Journal of Virology 2003;77:8462-8469.

23. Parry A, Baker I, Stacey R, Wimalaratna S. Long term survival in a patient with variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulphate. Journal of Neurology, Neurosurgery & Psychiatry 2007;78:733-734.

24. Rainov NG, Tsuboi Y, Krolak-Salmon P, Vighetto A, Doh-Ura K. Experimental treatments for human transmissible spongiform encephalopathies: is there a role for pentosan polysulfate? Expert Opinion on Biological Therapy 2007;7:713-726.

25. Rainov N, Whittle IR, Doh-ura K. Treatment options in patients with Prion Disease – the role of long term Cerebroventricular infusion of Pentosan Polysulphate. Prions. Food and Drug Safety.
. Springer, 2005: 41-66.

26. Whittle IR, Knight RS, Will RG. Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease. Acta Neurochirugica (Wien) 2006;148:677-679.

27. Todd NV, Morrow J, Doh-ura K, Dealler S, O'Hare S, Farling P, et al. Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease. Journal of Infection 2005;50:394-396.

28. Dealler S, Rainov N, Pomfrett C. Variant CJD case treated by intraventricular PPS: improvements over the following 6 months. Presented at Prion Diseases: From Basic Research to Intervention Concepts. Oct 8-10, 2003; Munich. Abstract IV-01.

29. Masullo C, Macchi G, Xi YG, Pocchiari M. Failure to ameliorate Creutzfeldt-Jakob disease with amphotericin B therapy. Journal of Infectious Diseases 1992;165:784-785.

30. Kovanen J, Haltia M, Cantell K. Failure of interferon to modify Creutzfeldt-Jakob disease. BMJ 1980;280:902.

31. Dervaux A, Vicart S, Lopes F, Le Borgne MH. Psychiatric manifestations of a new variant of Creutzfeldt-Jakob disease. Apropos of a case. Encephale 2001;27:194-197.

32. Imperiale D, Bortolotto S, Cucatto A, Schiffer P, Cassano D, Buffa C. Levetiracetam control of myoclonus in a patient with Creutzfeldt-Jakob disease. European Neurology 2003;49:189-190.

33. Floel A, Reilmann R, Frese A, Ludemann P. Anticonvulsants for Creutzfeldt-Jakob disease? Lancet 2003;361:224.

34. Drisko JA. The use of antioxidants in transmissible spongiform encephalopathies: a case report. Journal of the AmericanCollege of Nutrition 2002;21:22-25.

[a] Disease stage at the time of treatment was categorised broadly based on mobility and ability to function independently. Further details are given in the Supplemental Data.

[b] Untreated cohort papers also mention briefly that a) one patient was treated with acyclovir to no effect (Taratuto 1989), b) one treated with acyclovir without success (Kovanen 1993).

[c] Untreated cohort papers also mention briefly that a) one patient was treated with amantadine in combination with halopidol, anticholinergic drugs & diphenylhydatin with no effect (Taratuto 1989), b) three patients were treated with amantadine with no success (Kovanen 1993), c) 3 patients were treated with amantadine with no success (Esmonde 1992), d) 29 patients were treated with amantadine of which 28 derived no benefit, whereas one did benefit (Will 1984). The patient that did benefit from treatment was published and included in table (Terzano 1983). Cohort potentially also included the other two UK patients (Sanders 1973) but this is not clear. In total 35 patients treated without benefit and not published (other than brief mention in cohort).

[d] This patient was enrolled in the MRC Prion-1 trial, which closed to recruitment in June 2006. Results from this trial are not yet available.

[e] Rainov reports on 26 pts including 3 with vCJD described in greater detail in Parry, Todd and Whittle. To avoid duplication these pts were removed from the Rainov entry.

[f] In Rainov 2007, this patient is described as having survived 48 months after initiation of treatment

[g]uCJD = unspecified CJD