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Case Report · Falldarstellung

Forsch Komplementmed 2011;18:283–287 Published online: October 13, 2011

DOI: 10.1159/000333795

Brain Ischemia and Hypometabolism Treated by

Ozone Therapy
Bernardino Clavoa,b,f,h Gerardo Suareza,b,f Yolanda Aguilare Dominga Gutierreza,b,f
Pedro Poncec Alberto Cuberod Francisco Robainaa Jose L. Carrerasg
Department of Radiation Oncology, Research Unit,
Department of Radiation Oncology, Chronic Pain Unit,
Department of Neuro-Radiology,
Department of Neurology, Dr. Negrin University Hospital,
Department of Nuclear Medicine, DIMEC Center,
Canary Islands Institute for Cancer Research (ICIC), Las Palmas,
Grupo de Investigación Clínica en Oncología Radioterápica (GICOR), Madrid, Spain

Keywords Schlüsselwörter
Leukoencephalopathy · Ozone therapy · Leukenzephalopathie · Ozontherapie ·
Positron emission tomography · PET · Radiation-induced brain Positronen-Emissionstomographie · PET · Strahleninduziertes
injury · Side effects · Single photon emission computed Hirntrauma · Single-Photon-Emissionscomputertomographie ·
tomography · SPECT · Radiosurgery · Stroke SPECT · Nebenwirkungen · Radiochirurgie · Schlaganfall

Summary Zusammenfassung
Background: Radiation-induced brain injury (RBI) and low-per- Einleitung: Strahleninduziertes Hirntrauma (RBI) und Durchblu-
fusion brain syndromes are mediated by ischemia and hypome- tungsstörungen im Gehirn werden durch Ischämie und Hypome-
tabolism and have limited treatment options. Ozone therapy as tabolismus herbeigeführt; für beide gibt es nur begrenzte Behand-
treatment in vascular diseases has been described, but the effects lungsmöglichkeiten. Die Ozontherapie wurde als Behandlung bei
on brain tissue have not been well documented. Case Report: We Gefäßerkrankungen beschrieben, aber die Auswirkungen auf
describe a 75-year-old patient with vascular risk factors and menin- Hirngewebe wurden nicht gut dokumentiert. Falldarstellung: Wir
gioma who was treated with stereotactic radiosurgery. 14 months berichten über eine 75-jährige Patientin mit vaskulären Risikofak-
later the patient presented with progressive clinical impairment de- toren, welche mit stereotaktischer Radiochirurgie an einem Me-
spite the use of acetylsalicylic acid and corticosteroids. Clinical and ningeom behandelt wurde. 14 Monate später zeigte die Patientin
imaging evaluations before/after ozone therapy were done by mag- fortschreitende klinische Verschlechterungen trotz der Verwen-
netic resonance imaging (MRI), computed tomography (CT), single dung von Acetylsalicylsäure und Kortikosteroiden. Für die klini-
photon emission computed tomography (SPECT), and positron sche und bildgebungsgestützte Beurteilung vor/nach der Ozon-
emission tomography (PET); performance status assessment was therapie wurden Magnetresonanztomographie (MRT), Computer-
done using Barthel Index and World Health Organization/Eastern tomographie (CT), Single-Photon-Emissionscomputertomo-
Cooperative Oncology Group Scale (WHO/ECOG Scale). Ozone graphie (SPECT) und Positronen-Emissionstomographie (PET)
therapy was performed by autohemotransfusion. Results: Basal im- eingesetzt und für die Performance-Status-Bewertung der Barthel-
ages showed brain areas with ischemia and hypometabolism com- Index und die World Health Organization/Eastern Cooperative
patible with ischemic processes and/or RBI. There were no changes Oncology Group-Skala (WHO/ECOG-Skala) genutzt. Ozontherapie
in MRI or CT scan images following ozone therapy. However, im- wurde als Autohemotransfusion durchgeführt. Ergebnisse: Basale
provements in brain perfusion and metabolism were demonstrable Bilder zeigten Hirnareale mit Ischämie und Hypometabolismus,
with SPECT and PET; they correlated with clinical development and kompatibel mit ischämischen Prozessen und/oder RBI. Weder im
performance status scales. Conclusion: This report supports our MRT noch im CT gab es Veränderungen nach der Ozontherapie.
previous works about the effect of ozone therapy in cerebral blood Allerdings wurden Verbesserungen bei der Hirndurchblutung und
flow, and it suggests the use of ozone therapy in ischemic and beim Stoffwechsel mit SPECT und PET nachgewiesen; sie korre-
hypometabolic brain syndromes such as stroke or RBI. lierten mit der klinischen Entwicklung und den Performance-
Status-Skalen. Schlussfolgerung: Dieser Bericht stützt unsere bis-
herigen Arbeiten über die Wirkung von Ozontherapie auf den
zerebralen Blutfluss und schlägt die Anwendung von Ozon-
therapie bei ischämischen und hypometabolischen Syndromen - 11/20/2014 5:56:00 AM

des Gehirns wie Schlaganfall oder RBI vor.

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© 2011 S. Karger GmbH, Freiburg Bernardino Clavo, MD, PhD

1661–4119/11/0185-0283$38.00/0 Department of Radiation Oncology, Chronic Pain Unit and Research Unit
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Fax +49 761 4 52 07 14 Dr. Negrin University Hospital Accessible online at: C/Barranco la Ballena s/n, 35020 Las Palmas, Spain Tel. +34 928-450284, Fax -449127

Cerebrovascular diseases and radiation-induced brain injury

(RBI) are mediated by ischemia and hypometabolism.
Ischemic brain syndromes have significant clinical and social
repercussions. In the USA, approximately 610,000 people each
year had de novo stroke and about 185,000 recurrence of the
disease. Mortality data from 2006 indicate that stroke ac-
counted for approximately 1 in every 18 deaths (around 130,000
people). The estimated direct and indirect costs for the year
2010 are USD 73.7 billion [1]. Stroke and RBI not only share
similar features, but also have limited therapeutic options.
Ozone therapy has been used for the last 100 years in the
treatment of ischemic disorders, particularly those of the
lower limbs, although there are no data from clinical trials yet.
It has been described that ozone can enhance antioxidant
systems and regulate immune/inflammatory response [2–4],
improve vascular rheology [5–7], and increase blood flow in
carotid and middle cerebral arteries [8] and tissue oxygena-
tion in hypoxic tissues [9]. We have previously treated several
Fig. 1. Basal studies. Upper panel: MRI images. Meningioma in the ante-
ischemic syndromes [10] and radiation-induced side effects
rior right temporal lobe (yellow arrow). Vasogenic edema, signal increase
[11, 12] with this procedure. However, the effects of ozone in juxta-cortical ‘temporal and parietal’ right lobes and periventricular.
therapy on brain tissues have not been well documented. Middle panel: ECD-SPECT images showing decreased blood perfusion in
‘temporal and parietal’ right lobes. Lower panel: FDG-PET images show-
ing slight increase in metabolism in anterior right temporal lobe (menin-
gioma) and decreased metabolism in ‘temporal and parietal’ right lobes.
Case Report Areas of leukoencephalopathy in MRI correlated with areas of hypoper-
fusion in SPECT and hypometabolism in PET. All these alterations were
A 75-year-old woman receiving treatment for high blood pressure and compatible with a chronic ischemic process and/or RBI.
diabetes was diagnosed and treated for epilepsy. She received valproic
acid after an intolerance to phenytoin had been observed. Magnetic reso-
nance imaging (MRI) showed meningioma in the anterior right temporal
lobe and vasogenic edema in the ‘temporal and parietal’ right lobes. She
underwent stereotactic radiosurgery. A gamma-knife device was used to
administer a single fraction of radiotherapy. Eight months later she pre-
sented with Parkinson’s syndrome, and treatment with levodopa was initi-
ated. However, general impairment and bradypsychia were progressive,
and 14 months after the radiosurgery she presented hyponatremia (Na+
of 120 meq/l) and low osmolality (248 mosm/l). The diagnosis of inappro-
priate antidiuretic hormone secretion (SIADH) syndrome was made.
MRI showed no changes in the anterior right temporal lobe, but there
was a signal increase in 2 previously altered sites: juxta-cortical ‘temporal
and parietal’ right and periventricular lobes; both compatible with white
matter alterations secondary to radiotherapy (fig. 1, upper panel). In
these basal pictures, areas of leukoencephalopathy in MRI correlated
with areas of hypoperfusion (fig. 1, middle panel) and hypometabolism
(fig. 1, lower panel). Single photon emission computed tomography
(SPECT) with technetium-99m ethylcysteinate dimer (ECD-SPECT)
showed a decreased blood perfusion in the ‘temporal and parietal’ right
lobes which suggested vascular etiology such as an ischemic process and/
or RBI (fig. 1, middle panel). Fluorine-18 fluorodeoxyglucose positron
emission tomography (FDG-PET) showed 1) a slight increase in metabo-
lism, as measured by the maximum standardized uptake value (SUVmax)
of 1.8 in the anterior right temporal lobe (meningioma) compared to the Fig. 2. Functional studies during ozone therapy. Upper panel: ECD-
SUVmax of 1.5 in the contralateral area of the anterior left temporal lobe SPECT at 3 months of treatment showing an overall increase in blood
and 2) a decreased metabolism in ‘temporal and parietal’ right lobes with perfusion, including the lesions in ‘temporal and parietal’ right lobes as
SUVmax value of 1.3; features compatible with edema, ischemic process well as right basal ganglia. Lower panel: FDG-PET at 5 months of ozone
and/or RBI (fig. 1, lower panel). therapy showing, relative to the basal study, an overall increase in me-
The patient showed progressive clinical impairment necessitating sev- tabolism, including hypometabolic lesions in ‘temporal and parietal’ right
eral hospital admissions despite the use of acetylsalicylic acid and corti- lobes as well as right basal ganglia. - 11/20/2014 5:56:00 AM
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Table 1. Clinical development of some nervous system disorders before and after ozone therapy

CTCAE/CTC a Before ozone therapy After ozone therapy

Hyponatremia grade 3 grade 0
<130–120 mmol/l
Cognitive disturbance grade 2 grade 0
moderate cognitive disability; interfering with work/
school/life performance but capable of independent living;
specialized resources on part-time basis indicated
Memory impairment grade 2 grade 0
moderate memory impairment; limiting instrumental
Lethargy grade 2 grade 0
moderate symptoms; limiting instrumental ADL
Leukoencephalopathy grade 2 grade 1
moderate symptoms; focal T2/FLAIR hyperintensities, asymptomatic; small focal T2/FLAIR hyperintensities;
involving periventricular white matter extending into involving periventricular white matter or <1/3 of
centrum semiovale or involving 1/3 to 2/3 of susceptible susceptible areas of cerebrum ± mild increase in
areas of cerebrum ± moderate increase in SAS and/or subarachnoid space and/or mild ventriculomegaly
moderate ventriculomegaly
Cerebrovascular ischemia grade 2 grade 1
moderate symptoms asymptomatic; clinical or diagnostic observations only;
intervention not indicated
According to the ‘Common Terminology Criteria for Adverse Events (CTCAE)’ and ‘Common Toxicity Criteria (CTC)’ of the Cancer Therapy
Evaluation Program of the National Cancer Institute (–06–14_QuickReference_8.5×11.pdf
accessed October 6, 2011).
There were 4 different episodes of hyponatremia: 2 grade 2 and 2 grade 3.
ADL = Activities of daily living, T2/FLAIR = T2-weighted fluid attenuated inversion recovery.

costeroids and appropriate control of high blood pressure and hypergly- ing hypometabolic lesions in ‘temporal and parietal’ right lobes as well as
cemia. The potential diagnoses were 1) ischemic process and/or 2) RBI. right basal ganglia (fig. 2, lower panel). The clinical improvement paral-
No additional standard management was planned, but the patient’s family leled the increased perfusion observed by ECD-SPECT at the 3rd month
requested further treatment. We offered her some therapeutic options of treatment, which was maintained at the last follow-up at 30 months
which we used in our university hospital for selected patients with after terminating ozone therapy, that is 40 months after the initiation of
ischemic syndromes. Ozone therapy was her preference. Informed con- ozone therapy.
sent was obtained before the commencement of treatment. Over a period
of 11 months 58 sessions of ozone therapy were administered, using a
one-way central venous catheter (Hickman®) as follows: 150 cc/m2 (blood/
body surface); O3/O2 concentration 30 μg/ml initially and slowly increas-
ing to 60 μg/ml. The sessions had a low frequency and progressively
dropped off from 3 sessions per week in the first month to once per This case suggests that ozone therapy could improve blood
month for the last months. flow and metabolism in ischemia-related syndromes such as
During and after ozone therapy a clear clinical improvement was as-
RBI or stroke. Clinical improvement (general physical status)
sessed by 2 functional scales. Performance status before/after treatment
was 65/100 (from 0 to 100, where 100 is better) as measured by Barthel
was long-lasting sustained. For this patient the potential diag-
Index [13] and 3/1 (from 0 to 4, where 0 is better) as measured by World noses were: 1) ischemic process with risk factors, albeit not of
Health Organisation/Eastern Cooperative Oncology Group Scale (WHO/ a typical clinical presentation, and 2) RBI, albeit ‘temporal
ECOG Scale). Table 1 describes additional clinical information before and parietal’ vasogenic lesions visible in MRI were present
and after ozone therapy in relation to some nervous system disorders
prior to radiosurgery; periventricular vasogenic lesions were
using the Common Toxicity Criteria of the National Cancer Institute.
Clinical improvement was maintained up to the last follow-up which
distant from the highly limited irradiated volume of radiosur-
was 30 months after terminating the ozone therapy. There were no new gery. Probably both factors were implicated in the ischemic
episodes of hyponatremia. MRI and computed tomography (CT) did not and metabolic alterations in this patient. The existing high
show any changes at 4, 19, or 30 months. However, increases in brain per- blood pressure and diabetes were risk factors for vascular
fusion and metabolism relative to basal values were noted. ECD-SPECT
diseases and also for RBI, while brain irradiation increases
at 3 months of treatment showed an overall increase in blood perfusion in
lesions of the ‘temporal and parietal’ right lobes, as well as right basal
the risk of cerebrovascular diseases and stroke [14].
ganglia (fig. 2, upper panel). FDG-PET at 5 months of ozone therapy Stroke, the main presentation of cerebrovascular diseases,
has limited therapeutic options. For aspirin consistent benefi- - 11/20/2014 5:56:00 AM

showed an overall increase in metabolism (approximately 25%), includ-

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cial effects have been shown but it is of only limited value in information on vascular and metabolic effects in brain tissues
preventing new attacks [15], while antithrombolytic treatment can be found in a recent review [24].
with recombinant tissue plasminogen activator has been Our findings are further supported by isolated preclinical
somewhat effective if applied within the first 3 h of the epi- [25] and a clinical study [26] in ischemic brain syndromes as
sode, but only in selected patients [16]. well as in radiation-induced tissue toxicity reports [11, 12].
RBI is also mediated by vascular, inflammatory and degen- Finally, of note is that clinical development correlated bet-
erative changes, including demyelization and leukoencepha- ter with functional imaging techniques than with MRI or CT
lopathy [14]. Limited approaches are available for RBI when scan. Functional imaging techniques could be more useful in
symptoms are progressive and lesions are not suitable for assessing the effects of ozone therapy in these syndromes, and
surgery. Proposed therapies with the objective of improving they should be more extensively evaluated in clinical studies.
blood perfusion/oxygenation include anticoagulants [17], hy- This report supports our previous works about the effect of
perbaric chambers [18, 19], spinal cord stimulation [20], and ozone therapy in cerebral blood flow, and it suggests the
modification of the radiation-induced pro-oxidative status potential usefulness of ozone therapy in the treatment of
using vitamin E [21]. ischemic/metabolic brain syndromes such as those secondary
In ischemic processes and in RBI decreased blood flow to cerebrovascular diseases and/or RBI. Further research is
leads to decreased oxygen delivery and ischemia/reperfusion. planned.
These induce a cascade of metabolic disorders such as de-
crease in aerobic glucose metabolism (and reduction of ATP
levels) and inflammation changes followed by tissue acidosis Acknowledgements
and increase in free radicals. Additionally, ischemia leads to
excitotoxicity mediated by glutamate receptor activation and Research activity related with this work was supported, in part, by the
I3SNS-Program (INT07/030) from the Instituto de Salud Carlos III, Ma-
the subsequent increase of nitric oxide and calcium accumu-
drid, Spain. The ozone therapy device Ozonosan Alpha-plus® was pro-
lation, resulting in a damage of the pump systems and serious vided by Dr. Hänsler GmbH (Iffezheim, Germany).
disturbances in ionic conductance which are associated with Preliminary data have been presented as invited lectures at the Meet-
apoptosis and necrosis of neurons [22] and white matter ing of the European Cooperation of Medical Ozone Societies (Baden
injury [23]. Ozone therapy could regulate these mediators and Baden, Germany, November 2008), the II. Meeting of the World Federa-
tion Oxygen-Ozone Therapy (Madrid, Spain, December 2008), I. Na-
reduce the pathological oxidative stress, as demonstrated in
tional and International Ozone Therapy Congress (Istanbul, Turkey, De-
liver [3] and renal [4] rat models. cember 2009) and the International Meeting of Ozone Therapy Schools
Within this context, other interesting actions of ozone ther- at the Royal Academy of Medicine (Madrid, Spain, June 2010).
apy have been described: improvement in vascular rheology
[5, 6], increase in blood flow in the carotid and middle cere-
bral arteries [7], improvement in tissue oxygenation in hy- Disclosure Statement
poxic tissues [8, 9], enhancement of antioxidant systems, and
modulation of immune/inflammatory response [2–4]. More The authors have no conflict of interest.

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