Severe Encephalopathy and Polyneuropathy Induced by Dichloroacetate

J Neurol (2010) 257:2099–2100
DOI 10.1007/s00415-010-5654-9
LETTER TO THE EDITORS
Severe encephalopathy and polyneuropathy induced

by dichloroacetate
Dieta Brandsma • Thomas P. C. Dorlo •
John H. Haanen • Jos H. Beijnen • Willem Boogerd
Received: 3 June 2010 / Revised: 27 June 2010 / Accepted: 29 June 2010 / Published online: 15 July 2010
Ó Springer-Verlag 2010
Dear Sirs, glioblastoma patients treated with various DCA doses.

Grade II and grade III polyneuropathy occurred in patients
In 2007, an article in the New Scientist presented dichlo-
treated with DCA 25 mg/kg/day and 50 mg/kg/day,
roacetate (DCA) as ‘a cheap and safe drug that kills most
respectively. The maximum DCA dose at which none of
cancers’ [1]. This statement was based on the findings of
the patients had a clinically significant peripheral neurop-
Bonnet et al. (2007) [2], who showed that DCA induces
athy was 6.25 mg/kg orally, twice a day (12.5 mg/kg/day)
apoptosis and decreases in vitro tumor growth in several
for at least 3 months [4]. For the first time, we present a
cancer cell lines by shifting the metabolism of cancer cells
patient who developed encephalopathy and grade III sen-
from glycolysis to glucose oxidation. In the same study,
sorimotor polyneuropathy after 4 weeks of DCA treatment
DCA was administered to nude rats in the drinking water
(15 mg/kg/day).
(75 mg/L, during 3 months) and could prevent and reverse
A 46-year old patient with melanoma which had
tumor growth without apparent toxicity. Dichloroacetate
metastasized to the lung and lymph nodes 2 years previ-
was proposed as an attractive candidate for proapoptotic
ously, was admitted to the Antoni van Leeuwenhoek
cancer therapy [3]. Without any clinical data, DCA was
Hospital in The Netherlands because of confusion and gait
hailed as a ‘miracle drug’ on internet-based patient forums
disturbance. Four weeks before admission he had started
and has since been prescribed off-label by alternative
taking capsules with identified DCA (400 mg, thrice daily,
physicians or bought directly by patients via webshops
corresponding with 15 mg/kg/day) and vitamin A capsules
(http://www.puredca.com and http://www.pharma-dca.com).
(150,000 IU/day), prescribed by an alternative physician.
Recently, a small clinical study was performed in five
On neurological examination he showed impaired mental
processing, dysarthria and an unsteady gait. MRI of the
brain and serum blood tests were normal. In the following
D. Brandsma (&) W. Boogerd
Department of Neuro-oncology, Antoni van Leeuwenhoek days he became more confused, showed aggressive
Hospital/The Netherlands Cancer Institute, Plesmanlaan 121, behaviour, had visual hallucinations and dysphasia. Cere-
1066 CX Amsterdam, The Netherlands brospinal fluid (CSF) examination demonstrated normal
e-mail: d.brandsma@nki.nl
biochemical parameters, no malignant cells and negative
D. Brandsma W. Boogerd PCRs for neurotrophic viruses. Antineuronal antibody
Department of Neurology, Slotervaart Hospital, Amsterdam, screening was negative. Both the DCA and vitamin A
The Netherlands capsules were stopped on the day of admission. The DCA
concentration in the CSF on day 2 after hospital admission
T. P. C. Dorlo J. H. Beijnen
Department of Pharmacy & Pharmacology, Slotervaart Hospital/ was 78 lg/mL, as measured by liquid chromatography
The Netherlands Cancer Institute, Amsterdam, The Netherlands tandem mass-spectrometry. On day 16, the DCA CSF
concentration decreased to 11 lg/mL, indicating an elim-
J. H. Haanen
ination half-life for DCA in the CSF of approximately
Department of Medical Oncology, Antoni van Leeuwenhoek
Hospital/The Netherlands Cancer Institute, 5 days. No serum samples for DCA measurement were
Amsterdam, The Netherlands available.
123
2100 J Neurol (2010) 257:2099–2100
Meanwhile, the patient was treated with haloperidol and The presented patient illustrates that DCA administered
lorazepam. His confusional state improved within 2 weeks, in a recommended dose range can be highly neurotoxic,
but severe dysarthria remained. A bilateral facial nerve leading to encephalopathy and a disabling sensorimotor
paresis (grade II), a profound sensory ataxia of arms and axonal polyneuropathy. As clinical data on the efficacy of
legs and a severe distal paresis of the legs were present on DCA in cancer patients are lacking and serious neurolog-
further neurological examination. He was unable to walk. ical side effects can occur, we strongly advise the use of
Electromyography demonstrated a severe sensorimotor DCA in clinical trials only.
axonal polyneuropathy. In the following 8 months, all
neurologic deficits gradually improved. Only a slight
paresis of the foot extensors (MRC 5-) but no cognitive
deficits remained. References
Most of our knowledge on DCA comes from random-
1. Coglan A (2007) Cheap, ‘safe’ drug kills most cancers. New
ized clinical trials in children and adults with lactic aci- Scientist magazine 11
dosis complicating mitochondrial diseases, who were 2. Bonnet S, Archer SL, Allalunis-Turner J et al (2007) A
treated with DCA (12.5 mg/kg twice a day). No significant mitochondria-K? channel axis is suppressed in cancer and its
clinical efficacy was seen in these patients, but reversible normalization promotes apoptosis and inhibits cancer growth.
Cancer Cell 11:37–51
axonal polyneuropathy occurred in 10% of the children and 3. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate
86% of the adults [5, 6]. This age-dependent DCA (DCA) as a potential metabolic-targeting therapy for cancer. Br J
peripheral neurotoxicity was found to be due to an age- Cancer 99:989–994
related decrease in plasma clearance of DCA, probably 4. Michelakis ED, Sutendra G, Dromparis P et al (2010) Metabolic
modulation of glioblastoma with dichloroacetate. Sci Transl Med
because of inhibition of the DCA metabolism on repeat 2(31):31–34
dosing in adults [7]. 5. Stacpoole PW, Kerr DS, Barnes C et al (2006) Controlled clinical
In our patient, the DCA CSF concentration of 78 lg/ trial of dichloroacetate for treatment of congenital lactic acidosis in
mL, 2 days after cessation of DCA intake (15 mg/kg/day children. Pediatrics 117:1519–1531
6. Kaufmann P, Engelstad K, Wei Y et al (2006) Dichloroacetate
during 1 month), is even higher than the average maximal causes toxic neuropathy in MELAS: a randomized, controlled
blood plasma concentrations (Cmax) of 53 lg/mL (±18 lg/ clinical trial. Neurology 66:324–330
mL) measured in adults taking 12.5 mg/kg twice a day for 7. Shroads AL, Guo X, Dixit V, Liu HP, James MO, Stacpoole PW
6 months [7]. It is therefore likely that DCA accumulation (2008) Age-dependent kinetics and metabolism of dichloroacetate:
possible relevance to toxicity. J Pharmacol Exp Ther
has occurred in our patient, resulting in severe neurologic 324:1163–1171
side-effects. We can not exclude that the metabolism of
DCA has been influenced by concurrent use of high dose
vitamin A in our patient.
123

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J Neurol (2010) 257:2099–2100

LETTER TO THE EDITORS

Severe encephalopathy and polyneuropathy induced

Dear Sirs, glioblastoma patients treated with various DCA doses.

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