How and why hyperbaric oxygen therapy can bring new hope for children suffering from cerebral palsy - An editorial perspective

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Copyright © 2014 Undersea & Hyperbaric Medical Society, Inc.
How and why hyperbaric oxygen therapy can bring new hope
for children suffering from cerebral palsy – An editorial perspective
Shai Efrati 1,2,3,4, Eshel Ben-Jacob 1,2,4,5,6
1
The Institute of Hyperbaric Medicine, Assaf Harofeh Medical Center, Zerin, Israel
2
Research and Development Unit, Assaf Harofeh Medical Center, Zerin, Israel
3
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
4
Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
5
The Raymond and Beverly Sackler Faculty of Exact Sciences, School of Physics and Astronomy,
Tel-Aviv University, Tel-Aviv, Israel
6
Center for Theoretical Biological Physics, Rice University, Houston, Texas USA
CORRESPONDING AUTHORS: Dr. Shai Efrati – efratishai@013.net and Prof. Eshel Ben-Jacob – eshel@rice.edu
UHM 2014, VOL. 41, NO. 2 – HBO2 FOR TREATMENT OF CEREBRAL PALSY: EDITORIAL PERSPECTIVE
Cerebral palsy (CP) is generally considered a non-
progressive condition resulting from neurological injury
in the antenatal or perinatal period. The increased
survival rates of premature infants due to advances in
neonatal intensive care has led to increased incidence
of CP, which is now higher than three in 1,000 births.
Perinatal hypoxic-ischemic (HI) events resulting in
cellular necrosis, neuronal inactivation and cerebral
white matter injury are the most common causes of
severe neurological handicaps in children with CP.
The challenge
Physiologically, hypoxic-ischemic brain injury could be
dened as acute oxygen and nutrient deprivation to
the brain caused by faulty cerebral circulation, resulting
in cellular bioenergetics failure and neurological
dysfunction. As in stroke, traumatic brain injury (TBI)
and age-related metabolic brain disorders, there is
no effective treatment/metabolic intervention in
routine clinical practice for children with CP.
Intensive therapy and rehabilitation programs are
valuable tools for improving the quality of life
for these unfortunate children, but they offer, at best,
only partial relief.
New results
In this current issue of UHM, Mukherjee et al.
present convincing evidence that hyperbaric oxygen
(HBO2) therapy in combination with standard
intensive rehabilitation (SIR) could be the coveted
neurotherapeutic method for children suffering from
neurological dysfunctions due to CP [1]. The idea that
HBO2 therapy can provide a valuable brain repair tool
for CP is not new and has been investigated in several
earlier clinical trials, but the results were conicting
[2-6]. What makes the current ndings persuasive is the
methodical, multifaceted comparison: The short-term
and long-term outcomes of SIR in conjunction with
normal air (21% oxygen) HBO2 sessions at 1.3 atmo-
spheres absolute (atm abs) were compared with those
of SIR in conjunction with:
(a) 100% oxygen HBO2 sessions at 1.5 atm abs and
(b) 100% oxygen HBO2 sessions at 1.75 atm abs.
For long-term follow-up, patients were evaluated two
and eight months after the beginning of treatment.
Interestingly, signicant long-term benecial effects
were observed for all combined treatments, including
the case of normal oxygen at 1.3 atm abs, compared to
SIR alone.
A call for consensus
While the ndings support the idea that “low-dose”
HBO2 can provide new hope for children with cerebral
palsy, additional, larger-scale clinical studies are needed
to further conrm the ndings and determine the most
effective and personalized treatment protocols. Further-
more, before initiating future clinical trials, some issues
associated with the optimal practice of HBO2 therapy
for children with CP should be explored:
• proper sham control;
• the optimal dose-response curve (oxygen and
pressure levels);
• the optimal treatment duration/number of HBO2
sessions; and
• the proper selection criteria of the study cohort.
Further below we reect on the optimal HBO2 therapy
practice in light of the recent ndings by Mukherjee
et al. – of new understanding of the brain damage

UHM 2014, VOL. 41, NO. 2 – HBO2 FOR TREATMENT OF CEREBRAL PALSY: EDITORIAL PERSPECTIVE
72 S. Efrati, E. Ben-Jacob
associated with CP and of new understanding regarding
the neurotherapeutic effects of hyperbaric oxygen.
We hope that our reections will ignite in-depth
discussions within the hyperbaric medicine community,
to help reach consensus on whether, why and how
HBO2 therapy can give hope to children with cerebral
palsy.
Underlying repair mechanisms
It is now understood that the recently observed re-
storation of neuronal activity in the metabolically
dysfunctional stunned areas following HBO2 treatments
is accomplished via an assortment of intricate mecha-
nisms. The combined action of hyperoxia and hyperbaric
pressure leads to signicant improvement in tissue
oxygenation and affects both oxygen-sensitive and
pressure-sensitive genes. HBO2 therapy can initiate
vascular repair and improve cerebral vascular ow,
induce regeneration of axonal white matter, stimulate
axonal growth, promote blood-brain barrier integrity,
and reduce inammatory reactions as well as brain
edema [7-12].
At the cellular level, HBO2 can improve cellular
metabolism, reduce apoptosis, alleviate oxidative stress
and increase levels of neurotrophins and nitric
oxide through enhancement of mitochondrial function
in both neurons and glial cells, and may even pro-
mote neurogenesis of endogenous neural stem cells
[7-13]. It is important to note that, as in stroke and
TBI, the hypoxic-ischemic conditions following
cerebral palsy engender depolarization of the mito-
chondria membrane and induction of mPTP (mito-
chondrial permeability transition pore), which reduces
the efciency of energy production and elevates
the level of reactive oxygen species (ROS).
Tissue oxygenation via HBO2 can inhibit mPTP
and thus has the potential to reverse this abnormality
[8]. However, it must be applied carefully to ensure
that the increased tissue oxygen does not cause
cellular toxicity due to overly high ROS levels.
The control group dilemma
There are inherent ethical and logistic difculties in
handling the sham-control in HBO2 therapy trials.
The standard requirement for proper sham-control is:
“Medically ineffectual treatment for medical conditions
intended to deceive the recipient from knowing which
treatment is given.”
Hyperbaric oxygen therapy includes two active in-
gredients: pressure and oxygen. The pressure is being
utilized for increasing plasma oxygen, but the pressure
change by itself may have signicant effects on the
cellular level. The pressure effect may be of greater
signicance in human tissues that are under tight au-
toregulation pressure control, such as the brain and
kidneys [14-18]. The intracranial pressure, the
pressure within the skull and thus in the brain tissue
and cerebrospinal uid (CSF), is normally 0.0092-
0.0197 atm (7–15 mm Hg). Any increase in cranial
pressure may have a signicant effect on neurons,
glial cells and the function of endothelial cells [14,15,
18].
A classical example that highlights the signicance
of small changes in pressure is acute mountain
sickness (AMS) and high-altitude cerebral edema
(HACE). In AMS and HACE, even a small increase in
ambient air pressure – less than a sixth of an atmosphere
– may reverse the pathology [19]. Put together, the
observations imply that any increase in pressure, even
with reduced oxygen percentage, cannot serve as a
placebo since it exerts at least one of the two
active ingredients of HBO2 therapy.
Elevated pressure with low oxygen
can be an effectual treatment
To generate the sensation of pressure, the chamber
pressure must be 1.3 atm abs or higher. However,
breathing normal air, even at 1.3 atm abs, cannot serve
as a proper sham-control since it is not an “ineffectual
treatment,” as required by the placebo denition;
it leads to signicant physiological effects resulting
from the elevated pressure and the tissue oxygenation.
Therefore, as we discuss below, such doses should be
regarded as a dose-comparison study, as was correctly
done by Mukherjee et al., who demonstrated that it
is effective in the treatment of children with CP [1].
Other clinical trials also found that patients treated with
low oxygen showed improvements similar to patients
treated with higher dosages [2,4,20,21]. However, in
those trials, the low-dose treatments were mistakenly
regarded as sham-control, leading to incorrect con-
clusions. In studies 4, 20 and 22, room (21% oxygen)
air at 1.3 atm abs was used as a sham-control to
test the HBO2 effect on CP and patients with mild TBI
(mTBI) treated with 100% oxygen at 2.4 atm abs.
Another study used lower-than-normal (14% oxygen)
air at 1.5 atm abs to test the effect of hyperbaric

UHM 2014, VOL. 41, NO. 2 – HBO2 FOR TREATMENT OF CEREBRAL PALSY: EDITORIAL PERSPECTIVE UHM 2014, VOL. 41, NO. 2 – HBO2 FOR TREATMENT OF CEREBRAL PALSY: EDITORIAL PERSPECTIVE
73
S. Efrati, E. Ben-Jacob
oxygen on children with cerebral palsy who were treated
with 100% air at 1.5 atm abs [2]. In all of those
studies, the treated group and the low-oxygen
group, which the authors mistakenly considered
to be sham-control, show similar improvements [2,4,
20,21]. Consequently, the authors in both studies con-
cluded that the observed improvements were merely
placebo effects and therefore that HBO2 therapy had
no neurotherapeutic effects on mTBI and CP.
Their conclusions are clearly challenged by the nd-
ings of Mukherjee et al. published in this volume and
by recent clinical trials testing the effect of HBO2 on
post-stroke and mTBI patients [1,23,24]. Changes in
brain activity that were assessed by SPECT imaging,
as described next, further support this under-
standing [23,24].
HBO2 therapy can activate neuroplasticity and re-
vitalize brain functions: New trials provide convincing
evidence that hyperbaric oxygen can induce neuro-
plasticity, leading to repair of chronically impaired
brain functions and improved quality of life in post-stroke
and mTBI patients with prolonged post-concusssion
syndrome, even years after the brain insult [23,24].
These trials adopted the crossover approach in
order to overcome the inherent sham-control constraints
of HBO2 therapy. In this approach, the participants
are randomly divided into two groups. One, the trial
group, receives two months of HBO2 treatment
while the other, the control group, goes without treat-
ment during that time. The latter are then given the
same treatment two months later. The advantage of the
crossover approach is the option for a triple comparison:
• between treatments of two groups,
• between treatment and non-treatment periods
of the same group, and
• between treatment and non-treatment periods
in different groups.
The study endpoint included blinded detailed comput-
erized clinical evaluations that were blindly compared
for all patients, with single-photon emission computed
tomography (SPECT) scans. HBO2 sessions led to
similar signicant improvements in tests of cognitive
function and quality of life in both groups. No signi-
cant improvements occurred by the end of the non-
treatment period in the control group. What made the
results particularly persuasive was that the results of
SPECT imaging were well correlated with clinical
improvements and revealed restored activity mostly
in metabolically dysfunctional stunned areas. Those
observations indicate hyperbaric oxygen as a potent
means of delivering to the brain sufcient oxygen to
activate neuroplasticty and restore impaired functions
that are accomplished via an assortment of intricate
mechanisms, some of which were mentioned earlier.
Rethinking the HBO2 dose-response curve
The aforementioned recent trials provide convincing
evidence that HBO2 can repair brain damage in post-
stroke and mTBI patients. These results, and in parti-
cular the remarkable agreement between clinical
improvements and SPECT imaging, imply that the
observed improvements following HBO2 therapy in
the earlier studies on mTBI patients and children
with CP were due to the neurotherapeutic effect of
hyperbaric oxygen rather than being a placebo effect.
By the same token, the observed improvements
following either normal air at 1.3 atm abs (on patients
with mTBI) or 14% air at 1.5 atm abs (on children with
CP) imply that HBO2 sessions can have signicant
neurotherapeutic effects even at low dosage, provided
there is pressure elevation. Therefore, as we mentioned
earlier, such doses should be considered as dose-
comparison studies rather than sham-control, as was
correctly done by Mukherjee et al., who demonstrated
normal air at 1.3 atm abs to be an effective treatment
for children with CP rather than a placebo effect [1].
These results are also in agreement with the earlier
ndings by Collet et al. [4] that were perceived as
puzzling for more than a decade. Yet, as stated by
Collet et al. (Collet et al. 2001): “The improvement
seen in both groups for all dimensions tested deserves
further consideration.” The results by Mukherjee et
al. clearly responded to this suggestion by considering
room air at 1.3 atm abs as dose-comparison. Their
ndings could have been even more persuasive had
they included metabolic imaging as part of their
evaluations. Since they did not, this issue should be
further addressed in future studies.
Clearly, large-scale, well-controlled, pressure dose-
response studies are required to determine the optimal
HBO2 therapy protocol for different conditions. Until
such information is available, any treatment involving
change in the environmental pressure should be con-
sidered as a dose-comparison rather than a sham-control
study. Moreover, since at a young age, brain protection
is stronger (reected by high ROS levels associated with
CP) and neuroplasticity is more potent, it is reasonable
to expect that optimal efcacy will be achieved by lower

UHM 2014, VOL. 41, NO. 2 – HBO2 FOR TREATMENT OF CEREBRAL PALSY: EDITORIAL PERSPECTIVE
74 S. Efrati, E. Ben-Jacob
tissue oxygenation. Along such line of reasoning, the
previously described trials used 2.0 atm abs for post-
stroke patients and 1.5 atm abs for patient with
mTBI with an intact macrovascular bed [23,24].
Due to the high diversity in the manifestation of
cerebral palsy and in its severity, future efforts
should also be directed towards a personalized
dose-response curve. For example, it is likely that
higher tissue oxygenation will be the practice of
choice for children with a high expression of ApoE4,
which is an inhibitor of mitochondrial respiration.
Treatment duration and monitoring protocols:
Treatment duration is another elusive issue that needs
to be resolved by future studies. It is quite clear that
weeks to months would be necessary for brain tissue r
egeneration and angiogenesis, but the upper time limit
from which no further improvements are expected
remains unknown. The rst clinical evaluation (not
metabolic/physiological evaluation) should be done
after a sufcient number of HBO2 sessions and
should expect sizable changes. One must bear in
mind that children with CP suffer neurological
deciency since birth, so it will take time for the brain
repair to become clinically apparent. For example, it
is not reasonable to administer 20 daily HBO2
sessions to children with pervasive developmental
disorders (PDD) and expect to see signicant clinical
progress within a time frame of less than a month [25].
On the other hand, it is important to perform fre-
quent metabolic/physiological evaluations, which may
provide valuable information for adjusting the dose-
response curve. More studies are needed to determine
the minimal effective dosage and the treatment duration
for specic brain injuries. Non-invasive, in-chamber
measurements that are currently being developed, speci-
cally EEG and DTI, may shed some light on this
important question.
It is also crucial to perform long-term post-treatment
evaluation, as done by Mukherjee et al., who performed
evaluations after two and eight months [1]. Especially,
when children are concerned, one expects that HBO2
therapy will ignite the brain’s innate repair system so
that improvements will continue long after the treatment.
As Mukherjee et al. have found, different doses may
generate similar short-term improvements but can lead to
different long-term post-treatment effects. In other words,
dose-response curves should be assessed based on long-
term effects. Clearly, there is an urgent need for larger-
scale, prospective studies with long-term follow-up.
Optimal candidates for HBO2 therapy
Brain insults may result in a variety of brain injuries.
The most severe is necrosis, which cannot be reversed.
However, as was mentioned earlier, necrotic foci are
often surrounded by metabolically dysfunctional,
stunned areas, which manifest as regions of high
anatomy-physiology mismatch. Current imaging tech-
nologies reveal that the stunned brain areas may persist
for months and years after an acute brain event [24,
26-28] and this is where metabolic intervention can be
most effective [23,24]. For this reason, the optimal
candidate for hyperbaric oxygen is a patient with
unrecovered brain injury where tissue hypoxia is
the limiting factor for the regeneration processes.
In this patient, HBO2 may induce neuroplasticity
in the stunned regions where there is a brain
anatomy/physiology (e.g., SPECT/CT) mismatch [23,
24]. Unfortunately, in many – if not most – clinical
studies done with hyperbaric oxygen on brain-in-
jured patients, including those with cerebral palsy, the
stunned areas have not been assessed by imaging. The
anatomical/physiological imaging should be incorpor-
ated as an essential part of the basic evaluation of
every candidate for hyperbaric oxygen therapy. In a
similar manner, transcutaneous oximetry at the ulcer bed
serves as a basic evaluation for patients suffering from
peripheral non-healing wounds [29,30}.
An urgent call
In conclusion, we call on the hyperbaric community to
rethink the neurotherapeutic effects of HBO2 therapy
and to agree on common and scientically sound guide-
lines to best conduct prospective, controlled HBO2
clinical trials. Reaching a consensus on the way to
handle the control group, dose vs. efcacy, selection
criteria of the study cohort and duration of treatment
will pave the way for future studies that will explore
the full potential of neurotherapeutic HBO2.
We envision future studies that will demonstrate the
effectiveness of HBO2 therspy for a wide spectrum of
syndromes that currently have partial or no solutions,
such as central sensitization (bromyalgia), radiation
damage, vascular dementia and other metabolic aging
effects.
The authors report that no conict of interest exists
with this submission.
n

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