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No Pengarang/Penel Judul/Tahu Sampel/Resp Jenis Lit Variabel Dosis Hasil

iti n onden Intervensi Lit/temuan


1 1. Jessada Hyperbaric 7 responden Eksperime Pengaruh Pemberian P <0,001 = (p
Chungpai Oxygen (5 laki-laki ntal design pemberian terapi <0,05)
bulpatana Therapy in dan 2 pre-post terapi HBOT 1.3 didapati hasil
MD Thai perempuan) test HBOT 1.3 atm 100% adanya
2. Tappana Autistic dengan usia atm 100 % oksigen pengaruh
Sumpatan Children 5-9 tahun oksigen murni. pemberian
arax MD (2008) murni Durasi 1 terapi HBOT
3. Noppol dengan kali dalam 1.3 atm 100%
Thadakul peningkat seminggu oksigen
MD an 10 sesi murni
4. Chasin kemampu dengan terhadap anak
Chanthara an diberi autis.
treerat kognitif evaluasi.
MD anak,
5. Maytinee keterampil
Konkaew an sosial,
MA dan
6. Methira mampu
Aroonlims menyelesa
awas BA ikan
(Psycholo permasala
gy) han
dengan
tepat.

?
Hyperbaric Oxygen Therapy in Thai Autistic Children
Jessada Chungpaibulpatana MD*, Tappana Sumpatanarax MD**,
Noppol Thadakul MD***, Chansin Chantharatreerat MD*,
Maytinee Konkaew MA**, Methira Aroonlimsawas BA (Psychology)**

* Department of Medicine, Phuket Hospital, Phuket


** Department of Psychiatry, Phuket Hospital, Phuket
*** Department of Pediatrics, Phuket Hospital, Phuket

Background: Autism is a developmental and behavioral pattern, the triad of impairments, 1. social interaction,
2. social communication, 3. imagination. Their memories are seemingly in picture or photo records. Difficulties
in the treatment, management, and handling of autistic children are the main problems. Hyperbaric oxygen
therapy (HBOT) is a modern treatment in Thailand for nitrogen imbalance (Decompression sickness syndrome
or Caisson disease). HBOT can increase plasma oxygen to the tissues including the brain.
Objective: To determine whether Hyperbaric Oxygen Therapy is safe to use in children with autism, and has a
statistically significant effect on autistic symptoms. This is the first study in Thailand.
Material and Method: Thai Autistic children (n = 7) received HBOT (1.3 atm., 10 sessions) treatment. Assess-
ment was done before and after treatment in five domains: Social development, Fine motor and Eye - hand
coordination, Language development, Gross motor development, Self - help skills.
Results: Improvement was shown in five domains with a significant level. Seventy-five percent of children
shown improvement while 25% did not seem to respond to the treatment.
Conclusion: HBOT is a new treatment for Thai autistic children. Many scientific studies recently have shown
that HBOT could be an effective treatment for autistic children. It could improve the major autistic symptoms.

Keywords: HBOT (hyperbaric oxygen therapy), Autistic (autism), Oxidative stress (free radicals), Oxygen (O2)

J Med Assoc Thai 2008; 91 (8): 1232-8


Full text. e-Journal: http://www.medassocthai.org/journal

Hypotheses: 1. Hyperbaric Oxygen Therapy therapies, the authors can help numerous autistic chil-
(HBOT) will be safe to use in children with autism, dren. Generally many studies were done, but only one
2. Hyperbaric Oxygen Therapy will have a statistically author’s report can be found in PubMed (Rossignol,
significant effect on autistic symptoms. DA and LW Rossignol, 2006). Practically many HBOT
Directed goals: 1. Is Autism able to be a new were well-known used in autistic, treatment, but little
indication for HBOT? 2. Is HBOT able to be a new knowledge was publicized in this field. There is no
treatment for Autism? 3. Educational purposed aspects: definite conclusion.
family, social, and professional. Early identification of autistic spectrum
HBOT is a new way in the treatment for disorders in children and intervention is extremely
decompression sickness syndrome (Caisson disease) important. Can autism be treatable and preventable in
and it can be applied to intervene or concomitant treat- the early stage of the symptoms? According to many
ments with some symptoms such as diabetic wounds, studies, they had shown brain injury could be caused
and burn wounds. This HBOT center is the only one by heavy metal effects, chemical poisoning, infection,
stand-alone center of provincial hospitals in Thailand. autoimmune response, poor blood flow, and lack of
If HBOT can be an effective method in alternative oxygen.
Correspondence to: Chungpaibulpatana J, Vachira Phuket
There are many alternative therapies that
Hospital, Phuket 83000, Thailand. Phone: 076-361-234, were claimed to have some effects to make better
E-mail: director@vachiraphuket.go.th results in autistic symptoms, but no definite one which

1232 J Med Assoc Thai Vol. 91 No. 8 2008


could absolutely cure autism. In the authors’ pro- amygdala (Courchesne, 1991, 1995; Kemper and
ceeding study, it was found that HBOT was the least Bauman, 1993; Ritvo et al, 1986; Bailey et al, 1998: Welsh
interesting method of alternative therapies for autism et al, 2002; Kern, 2003). A significant neuronal loss
in parental opinions (Fig. 1). The researchers think that was observed in the cerebral cortex of the youngest
the parents’ knowledge about each therapy affected autistic patients. The neuronal and glial density was
to their choosing. Vachira Phuket Hospital has a very different in control and autism in the adolescence.
Hyperbaric Chamber, which is the new therapy for Neurons showing lipofuscin intracytoplasmic deposits
Autistic children. But the parents don’t have the increased with age both in controls and autistic patients,
knowledge about it. but the latter had significantly more such cells at all
Whatever, it is our opportunities to prove aged studies. According to their lipofuscin content,
how effective of HBOT in the treatment for autism a residual sign of an excessive oxidative stress, the
and represent autistic pathological mechanisms in surviving neurons show signs of an accelerated
preceding hypotheses. process of aging (E. López-Hurtado, J. De Felipe and
J. J. Prieto, 2002).
What is HBOT?
Hyperbaric Oxygen Therapy, “hyper” means Heavy metals and oxidative stress
more and “baric” means pressure. It uses pressure to There is a particularly negative correlation
allow more oxygen into blood cells, blood plasma, and between glutathione (GSH) levels and oxidative stress
cerebrospinal fluid. Under pressure, the lungs breathe associated with toxic metal exposure. GSH is found in
in more oxygen per breath. Also, more gas is dissolved almost every cell of the body and is responsible for
in fluid under pressure. This is how more oxygen is the removal of toxic metals. A study by Lenzi et al
delivered to body tissues, including the brain. (1994) found that glutathione not only reduced lipid
peroxidation and oxidative stress (Roy et al, 2000), but
How does HBOT work? also reversed some of the damage of the cell mem-
Oxygen exists in the blood in two forms, branes (Lenzi et al, 1994). Another more recent study
combined with hemoglobin (Hb) and dissolved in had shown that glutathione exerted neuroprotective
plasma (0.3 ml/100 ml). More oxygen is transported by properties and reduced neuropathy (Cascinu et al,
Hb. Best oxygen is delivered to the tissue in dissolved 1995).
form by the liquid portion of blood.
Neurochemistry
Neuropathology of the autism spectrum disorders The environment chemicals exert toxic effects
Reduced number of Purkinje cells in the not only to dopaminergic neurons but also to multiple
cerebellum, and small tightly placed nuclei of the kinds of neurons, such as noradrenergic and sero-
tonergic (New technology to Identify Environmental
Chemicals Causing Mental Disorders Assessment of
Psychotropic Chemical with Experimental Animals,
Translation of The AIST press released on August 25,
2004).
Similarities between symptoms produced by
N-methyl-D-aspartate (NMDA) antagonists in healthy
subjects and those seen in autism, it is proposed that
infantile autism is a hypoglutamatergic disorder. The
possible benefit of treatment may be glutamate ago-
nists, as well as the potential usefulness of a selective
5-HT2A receptor antagonist (Lam et al, 2006).
Cholinergic neurons in the basal forebrain, an
area of the brain known to be involved in attention,
have been found to be abnormally plentiful, and
Fig. 1 Autistic parental attitude surveys in effective, abnormally large, in children with autism.
knowledge and interesting in various therapies at Chemicals known to influence the develop-
Vachira Phuket Hospital, July 2007 ment and function of cholinergic neurons in the basal

J Med Assoc Thai Vol. 91 No. 8 2008 1233


Table 1. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

1. Both sexes 1. Uncontrolled severe explosive behavior


2. All aged-group 2. Uncontrolled organic or physical symptoms such as
seizure, ear infection
3. All educated group 3. Severe phobic or fearful symptoms
4. Diagnosis - autistic disorder, autistic spectrums 4. No parent or caretaker
5. Major symptoms - delayed development, speech

Table 2. Pre- and post-treatment assessment in five domains: Population: Sample size: seven (5 male and
social development, fine motor and eye-hand co- 2 female), age: 5-9 years old, education: preschool to
ordination, language development, gross motor primary school, diagnosis: (DSM III-R, DSM IV) Autistic
development, self-help skills disorder, Autistic spectrums, material: development
and skill training assessment, Rajanukul Hospital,
Pre treatment Post treatment
5th Edition, five domains assessment: Pre and Post
Social score t = 5.17 15.00-9.13 Treatment evaluated in 1. Social development 2. Fine
Fine motor score t = 6.83 14.67-9.40 motor and Eye-hand coordination 3. Language develop-
Language score t = 2.83 5.83-11.62 ment 4. Gross motor development 5. Self - help skills,
Gross score t = 1.67 9.17-17.52 Equipment: HBOT 1.3 atm., 100% oxygen concentration,
Self help score t = 13.67 19.67-16.43 Duration: 1 time per week, 10 sessions with evaluation,
Statistic: percents, t-test, p-value and descriptive
study in subjective findings.
forebrain area - brain-derived neurotrophic factor -
abnormally high levels of it had been found in the Results
bloodstreams of newborns with autism: Joan Arehart- Data analysis: There were improvements in
Treichel (Psychiatric News, July 20, 2001). five domains with significant level p < 0.001. Positive
An important relationship between brain finding was seventy-five percent of the children shown
opioid systems and social attachment were found improvement and negative finding was 25% of children
in infant animals (Chamberlain and Herman, 1991). did not seem to respond. Most beneficial results were
Administrations of low doses of morphine decreased 33.34% of children show well sleeping, better improve-
the separation anxiety of infant dogs, guinea pigs, ment in cognitive abilities, social skills, more flexibility
and chickens. When Naloxone, a specific opiate anta- and more proper problem and solving and this data was
gonist, was administered, the frequency of distress confirmed by subjective findings from their parents.
vocalizations increased. The present study suggests There was no serious adverse effect in any case and
that the lack of socialization behaviors in autism is tinnitus was a mild side effect in one case and it dis-
possibly related to an increased circulation of brain appeared in one week.
opioids (Herman and Panksepp, 1984).
GABAergic receptor system is significantly Discussion
reduced in high binding regions in brain of the autism Important finding was objective and subjec-
(Blatt et al, 2001). tive improvements. Problems and difficulties were
duration and experiences. It was quite safe to use
Material and Method HBOT.
Experimental design: Reviewed literatures, Comparative study of Rossignol, DA and LW
Proposal drafting, Vachira Pkuket Hospital Ethics Rossignol, 2006, represented that it had shown the
committee approval, Volunteers’ preparation, Education improvement at 31.6% of cases by HBOT 1.3 atm. and
and informed consent, Study Type: Interventional, Study 28-30% of oxygen concentration with 40 sessions.
Design: Treatment, Non-Randomized, Open Label, Comparison to the present study, it was shown that
Single Group Assignment, Safety/Efficacy Study. the improvement at 75% of cases by HBOT 1.3 atm.

1234 J Med Assoc Thai Vol. 91 No. 8 2008


and 100% of oxygen concentration with 10 sessions. Se is also a component of enzymes involved
Differences were found in oxygen concentration and in conversion of T4 to T3 (Foster, H.D, 1993), which is
duration of HBOT that may influence the results. critical for normal brain development. It is of interest
Benefits in educational and practical that hypothyroidism has been reported in autistic
knowledge may need to have a guideline to this field. children (Gillberg et al, 1992). Another less known func-
Hopefully a lesson learnt for the future. tion of Se is its ability to counteract the neurotoxicity
Role of oxidative stress in the pathology of of heavy metals, such as Hg (Whagner, PD, 2001).
neuropsychiatric disorders. There is evidence support- Mitochondria do not only produce less ATP,
ing the role of oxidative stress involvement in autism but they also increase the production of reactive
(Zoroglu et al, 2004; Chauhan et al, 2004, 2006; Ming et oxygen species (ROS) as by-products of aerobic
al, 2005; Yao et al, 2006; Sogut et al, 2003; Sweeten et al, metabolism in the aging tissues of humans and animals
2004; Golse et al, 1978; Yorbik et al, 2002; James et al, (Yau-Huei Wei and Hsin-Chen Lee, 2002).
2004, 2006; McGinnis, WR, 2004; Kern et al, 2006; Pasca It is now generally accepted that aging-
et al, 2006; Vargas, et al, 2005; Rossignol, DA and LW associated respiratory function decline can result
Rossignol, 2006). in enhanced production of ROS in mitochondria (Yau-
1. Increased lipooxidation markers in blood Huei Wei and Hsin-Chen Lee, 2002).
2. Increased lipooxidation markers in urine
3. Increased nitric oxide (NO) Debate
4. Increased thiobarbituric acid-reacting sub- “There is no evidence in any brain problem
stances that a hyperbaric chamber helps” (Dr. Gary W. Goldstein,
5. Lower levels of plasma glutathione levels president and CEO of the Kennedy Krieger Institute in
6. Lower levels of two major serum antioxidant Baltimore, which specializes in children’s development
metalloproteins ceruloplasmin (copper-binding protein) problems, Oxygen therapy for kids with autism
and transferring (iron-binding protein) debated, baltimoresun.com, April 27, 2007 by Kirsten
7. Lower levels of naturally occurring free Scharnberg). It is not a good idea to rely on “may be”.
radical scavengers “We don’t know what the cause of autism is.” “There
8. Impaired methionine metabolism in autism is little or no evidence that hyperbaric oxygen is help-
and associated with glutathione levels ful for established brain injury.” “It can cause seizures
9. There is a correlation between antioxidant and oxygen toxicity in a limited number of patients.”
proteins and loss of previously acquired skills in a “Doctor question benefit of hyperbaric oxygen therapy
subset of children with autism for autistic children.” (NorthJersey.com Jan 17,2006 by
10. High levels of circulating prooxidant Jessica Adler, Herald news).
organic toxins, heavy metals, xanthine oxidase and
cytokines have also been observed in autism The reality
11. A strong oxidant, homocysteine, is The authors’ preliminary study has shown
increased in plasma from children with autism subjective responses from children with autism and
12. An increase in inflammatory cytokines subjective findings from their parents in beneficial
has been reported in autistic brain tissue results, such as attention, communication, hearing,
13. Hypoperfusion, promoting oxidative emotions, postures, and manners. They had improved
stress, has been documented in several regions of in their study from child chiropractic therapy and child
autistic brains by both SPECT and PET scans developmental therapy. Whatever, the authors could
not conclude which one was more effective than the
Antioxidant status in autism other. Furthermore, the authors did not have the other
Decreased Selenium (Se) levels in the red alternative therapies in our experiences, such as music
blood cells have been reported in autism (Audhya et therapy, art therapy, animal therapy, acupuncture; so
al, 2004). It has been suggested that supra-nutritional the authors could not know in other viewpoints.
levels of Se may be needed to prevent degenerative
disease (Rayman MP, 2002). Se is an essential compo- Multidisciplinary approaches are as a holistic
nent of various enzymes, such as glutathione peroxi- Many alternative therapies were known that
dase (GSHPx). Lower levels of Se and GSPHx in autistic they could have some beneficial effects for the children
children may favor lipid peroxidation. with autism. There is no one-answer for many questions

J Med Assoc Thai Vol. 91 No. 8 2008 1235


but there are many answers for one question. Multiple 4. Cascinu S, Cordella L, Del Ferro E, Fronzoni M,
factors are the possible causes of the autism. The Catalano G. Neuroprotective effect of reduced
curative factors may be from multidisciplinary glutathione on cisplatin-based chemotherapy in
approaches. A holistic approach includes different advanced gastric cancer: a randomized double-
techniques, combines them altogether. blind placebo-controlled trial. J Clin Oncol 1995;
13: 26-32.
Conclusion 5. Chamberlain RS, Herman BH. A novel biochemical
Abnormalities had been found in the limbic model linking dysfunctions in brain melatonin,
system, association of cortex and cerebellum. Defects proopiomelanocortin peptides, and serotonin in
in all of these structures correlated with some symp- autism. Biol Psychiatry 1990; 28: 773-93.
toms in autism. Therefore, it was very difficult to tell 6. Chauhan A, Chauhan V, Brown WT, Cohen I.
what abnormalities influenced which symptoms. Oxidative stress in autism: increased lipid peroxi-
Future ther goals: Is early identification able dation and reduced serum levels of ceruloplasmin
to have a benefit? Interaction with other factors, the and transferrin - the antioxidant proteins. Life Sci
pathophysiology, the side effects, the other beneficial 2004; 75: 2539-49.
effects, and the long-lasting healing effects. Further 7. Chauhan A, Chauhan V. Oxidative stress in autism.
planning is: Long-term study, Follow-up phase. Pathophysiology 2006; 13: 171-81.
Eligible outcome, HBOT is a new treatment 8. Courchesne E. Neuroanatomic imaging in autism.
for Thai autistic children. Many scientific studies Pediatrics 1991; 87: 781-90.
recently have shown that HBOT could be an effective 9. Courchesne E. New evidence of cerebellar and
treatment for autistic children. It could ameliorate brainstem hypoplasia in autistic infants, children
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Hashimoto and colleagues. J Autism Dev Disord
Suggestion 1995; 25: 19-22.
Multidisciplinary approaches are the most 10. López-Hurtado E, De Felipe J, Prieto JJ. A micro-
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11. Foster HD. The iodine-selenium connection: its
Acknowledgements possible roles in intelligence, cretinism, sudden
The authors wish to thank the former infant death syndrome, breast cancer and multiple
committee of Vachira Phuket Hospital, Ministry of sclerosis. Med Hypotheses 1993; 40: 61-5.
Health of Thailand. The authors also wish to thank the 12. Gillberg IC, Gillberg C, Kopp S. Hypothyroidism
autistic children and their parents, caregivers who are and autism spectrum disorders. J Child Psychol
the utmost important teachers that light up the candles Psychiatry 1992; 33: 531-42.
of our knowledge. 13. Golse B, Debray-Ritzen P, Durosay P, Puget K,
Michelson AM. Alterations in two enzymes:
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การรักษาด้วยออกซิเจนความดันสูง สำหรับเด็กออทิสติกในประเทศไทย

เจษฎา จงไพบูลย์พฒ ั นะ, ทัปปณ สัมปทณรักษ์, นพพล ธาดากุล, ชาญสิน จันทรตรีรตั น์, เมธินี ก้อนแก้ว,
เมธิรา อรุณลิม่ สวัสดิ์

ภูมิหลัง: ออทิสติกเป็นภาวะผิดปกติทางพัฒนาการและพฤติกรรมที่สำคัญ 3 ประการ คือ 1. ทักษะทางสังคม


2. การสื่อสาร 3. จินตนาการ ความจำมักเป็นรูปหรือภาพ การรักษา, การจัดการและการแก้ปัญหายังเป็นเรื่องยาก
การรักษาด้วยออกซิเจนความดันสูงนับเป็นเรื่องใหม่สำหรับประเทศไทยโดยเฉพาะการนำมาใช้ดูแลช่วยเหลือเด็ก
ออทิสติกนอกเหนือจากการใช้หลักคือภาวะโรคน้ำหนีบจากการดำน้ำลึกที่มีภาวะไนโตรเจนในร่างกายสูง การรักษา
โดยใช้ออกซิเจนความดันสูงทำให้ออกซิเจนไปสู่เนื้อเยื่อโดยเฉพาะสมองมีเพิ่มมากขึ้น
วัตถุประสงค์: เพื่อทดสอบความปลอดภัยในการนำมาใช้ และพิสูจน์ผลที่ได้ต่ออาการสำคัญของเด็กออทิสติกว่า
มีนัยสำคัญทางสถิติหรือไม่อีกทั้งยังไม่มีการศึกษามาก่อนในประเทศไทย
วิธีการศึกษา: ทำในเด็กออทิสติกไทย (จำนวน 7 ราย) รักษาด้วย เครื่องปรับออกซิเจน ความดันสูง (1.3 เท่าของ
ความดันบรรยากาศ, 10 ครัง้ ) ประเมินก่อนและหลังการรักษา 5 ด้านได้แก่ พัฒนาการด้านสังคม, กล้ามเนือ้ มัดเล็ก
และการทำงานประสานกัน, ด้านภาษา, กล้ามเนื้อมัดใหญ่, ทักษะการช่วยเหลือตนเอง ผลที่ได้พบว่ามีอาการดีขึ้น
ทัง้ 5 ด้านอย่างมีนยั สำคัญทางสถิติ โดยมีรอ้ ยละ 75 ดีขน้ึ ชัดเจน อีกร้อยละ 25 ได้ผลไม่ชดั เจน
สรุป: การรักษาด้วยเครื่องปรับออกซิเจนความดันสูงนับว่าเป็นการรักษาชนิดใหม่ในการรักษาเด็กออทิสติกของไทย
การศึกษาทางวิทยาศาสตร์หลายผลงาน สนับสนุนแนวคิดในการนำมาใช้ และมีประโยชน์ในการช่วยเหลือบรรเทา
อาการที่สำคัญในเด็กออทิสติกได้

1238 J Med Assoc Thai Vol. 91 No. 8 2008


Br J Ophthalmol: first published as 10.1136/bjo.68.2.113 on 1 February 1984. Downloaded from http://bjo.bmj.com/ on 1 June 2018 by guest. Protected by copyright.
British Journal of Ophthalmology, 1984, 68, 113-117

Nuclear cataract and myopia during hyperbaric


oxygen therapy*
BRITT-MARIE PALMQUIST,' BO PHILIPSON,' AND PER-OLOF BARR2
From the 'Department of Ophthalmology, Karolinska Hospital, and the 2Hyperbaric Unit,
Rosenlunds Hospital, Stockholm

SUMMARY The effect on the human lens of prolonged hyperbaric oxygen therapy is reported. Eye
examinations were given to 25 patients before, during, and after a series of 150 or more exposures
to hyperbaric oxygen. All patients changed refraction in the direction of myopia during treat-
ment. Fifteen of the patients had clear lens nuclei before treatment. Seven of these developed
a nuclear cataract with reduced visual acuity during treatment. Reversible lens myopia has pre-
viously been noticed as a side effect of exposure to hyperbaric oxygen, but the cataractogenic effect
in man has not been reported by other workers. This report strongly supports the theory of an
oxidative damage to the lens proteins as a cause of nuclear cataract.

Hyperbaric oxygen therapy is of growing interest for cataract has been reported by Lyne7 and by Anderson
the treatment of persistent ulcers due to impaired and Farmer.8
peripheral circulation. An increase in the partial In this study the effect of a prolonged series of
pressure of the oxygen in the lungs results in an hyperbaric oxygen treatments on the human lens is
increased uptake of oxygen in the arterial blood in reported.
physically dissolved form. This increase in oxygen
content of the blood can compensate for the decrease Material and methods
in the blood flow in the ischaemic areas.
Hyperbaric oxygen therapy has been used for many In a series of patients accepted for hyperbaric oxygen
years, but there are only a few reports on its long-term treatment of persistent leg ulcers (Rosenlunds
side effects in the human eye. Several toxic effects on Hospital, P.O. Barr) those patients expected to need
the eye have been reported experimentally. Guinea- prolonged treatment were referred for ophthalmo-
pigs exposed to 100% oxygen at 3 ata (atmospheres logical examination. Of these, 25 cases were treated
absolute pressure) showed thinning of the corneal for 150 hours or more and were examined before,
endothelium and damage to the lens epithelium.' during, and after treatment. Most patients suffered
Mice repeatedly exposed to hyperbaric oxygen from peripheral ischaemic ulcers of arteriosclerotic
developed cataract.2 In man a constriction of the origin. Five of the patients were diabetic. The total
retinal vessels and narrowing of the visual fields has number of treatments varied from 150 to 850
been shown.3 Retrolental fibroplasia is a well-known exposures during 2 to 19 months (one exposure=one
manifestation of oxygen toxicity in premature hour). Daily treatments were given 7 days a week
infants.4 Cicatricial retrolental fibroplasia is regularly with pure oxygen for 2 x I hours at 2-2 5 times normal
accompanied by myopia, and its degree roughly atmospheric pressure. Vickers monoplace acrylic
parallels the severity of the cicatricial changes.5 In plastic chambers (Vickers Ltd, Hampshire, England)
1977 we presented a report on lens myopia and were used. The full hyperbaric pressure was main-
nuclear cataract following long-term hyperbaric tained for 50 minutes during every treatment. The
oxygenation.6 Reversible lens myopia without pressure was raised during 10 minutes and reduced
during half that time. Additional therapy during the
*This study was presented in part at the Fourth International hyperbaric oxygen treatment consisted of vitamin E
Congress of Eye Research (ISER), New York, 2 October 1980.
(Ephynal) 0-3 gx3, as a prophylactic against oxygen
Correspondence to Dr B-M. Palmquist, Department of Ophthal- toxicity effects, zinc sulphate, 0 2 gx2, in case of zinc
mology, Karolinska Hospital, S-104 01 Stockholm, Sweden. deficiency, and antibiotics if the ulcers were severely
113
Br J Ophthalmol: first published as 10.1136/bjo.68.2.113 on 1 February 1984. Downloaded from http://bjo.bmj.com/ on 1 June 2018 by guest. Protected by copyright.
114 Britt-Marie Palmquist, Bo Philipson, and Per-Olof Barr
Table I The age and sex distribution of treated and priority for treatment. The reference group did not
untreated groups get any oxygen treatment during the examination
Treated Untreated
period of 12 months.
Nuclear cataract is defined as an increased turbidity
Number of patients 25 19 in the lens nucleus to such an extent that it appears
Age distribution (mean-SD) 65-5±15-9 691 ±11 75 equal to or more opaque than the cortex when seen in
Sex distribution the slit-lamp. Generally it then causes some reduction
(M=male, F=female) 14M IIF 9M 8F of visual acuity. Nuclear turbidity (cataract) was
graded from 1 + to 4+, where 1+ corresponded to an
infected. Two patients were treated with cortico- increased light scattering in the nucleus equal to the
steroids. inner cortical region and 4+ to a totally opaque
During the study the eyes were examined after each nucleus.
100 treatments (approximately 2 months) by one of A yellow-brown colouration was not considered to
the 2 ophthalmologists (B-M.P. and B.P.). The represent cataract. Grading of the nuclear colour was
corrected visual acuity tested by Monoyer's chart and made from 1 + to 4+, where 1 + corresponded to pale
the refraction by Donders's subjective method were yellow and 4+ to brown or darker.
recorded. Distance and illumination were the same Data on the development of cataract in the treated
during the whole study. The pupils were dilated with and untreated groups of patients were statistically
Mydriacyl alone or in combination with Neo- analysed by Fisher's exact test (one-sided).
synephrine 10% if needed.
The biomicroscopic appearance of the lens was Results
examined with a Haag-Streit 900 slit-lamp micro-
scope. Photographic records with a Nikon photo slit- MYOPIA
lamp were made initially and whenever lens changes In all but one of the 25 patients studied the refraction
were found. The central fundus was also inspected. In changed in the direction of myopia by 1 dioptre or
a few cases when the 2 eyes of a patient were more during the oxygen treatment. Both eyes were
unequally affected the eye with the largest refractive equally affected, with only a few exceptions. In 23 of
change after 100 hours of treatment was selected for 25 patients myopia was noted after 100 treatment
further comparisons and analysis. hours. The mean value of all patients' maximal
Nineteen patients on the waiting list for hyperbaric change in refraction was 3 0 dioptres (Fig. 1). This
oxygen treatment were selected as a reference group. maximal change occurred between 100 and 300 treat-
These where comparable to the oxygen-treated group ment hours in 24 patients. In one patient the
in most aspects except for the age distribution (Table maximum occurred after 500 treatment hours. The
1). The mean age for the treated group was 65 5 years large variation in maximal refractive change was not
and for the reference group 69- 1. This was explained age related. Of the 18 patients over 60 years of age 9
by the fact that younger patients had a relative had clear lens nuclei and 9 had nuclear cataract before
treatment. The patients with clear lens nuclei before
* Nuclear cataract before treatment treatment developed a significantly (p<005) higher
grade of myopic change (4-2+2.3 dioptres) than the
0 Nuclear cataract during treatment patients with a nuclear cataract before treatment
Minor nuclear changes during treatment (2.1 ± 1-3 dioptres). In most of the cases with
7-i extended treatment programmes the myopia started
to reverse during therapy. In 11 patients myopia was
16 persistent for at least 6 months after termination of
a Manula oxygen therapy. The remaining myopic change was 1
dioptre or more.
a- The mean value of the maximal change in refrac-
tion was the same for the diabetic patients as for the
whole group (3.1 dioptres).
No one in the reference group showed a myopic
change in refraction of 1 dioptre or more during the
1 2 3 4 5 6 7 8 9 10 11 follow-up time of 1 year.
Dioptres
Fig. 1 The maximal refractive change in the myopic CATARACT
direction of the 25 patients. Patients developing a nuclear Fifteen of the 25 oxygen treated patients had clear
cataract also show the greatest myopic change. lens nuclei before treatment. In 7 of these a nuclear
Br J Ophthalmol: first published as 10.1136/bjo.68.2.113 on 1 February 1984. Downloaded from http://bjo.bmj.com/ on 1 June 2018 by guest. Protected by copyright.
Nuclear cataract and myopia during hyperbaric oxygen therapy 115

1Fig. 2b
Fig. 2 Appearance of the lens in a 79-year-old male (a) before treatment and (b) after 8 months of treatment. Note the
increased turbidity of the lens nucleus. Visual acuity was I 0 (6/6) and 0 7 (6/9) respectively.

cataract with a definite increase of the grey turbidity (nos. 12 and 14 in Table 2) the lens changes were
in the nucleus and with a reduced visual acuity of 0 3 partly reversible. After termination of oxygen
or more developed during treatment (Fig. 2). In therapy their visual acuity improved and the simul-
addition in all but one of these lenses an increasing taneous myopia was reduced (Fig. 3). However, the
yellow-brown colour was seen. The increase in lens nucleus never became normal.
yellowing and turbidity of the nucleus were not In 7 of the remaining 8 subjects an increased
always parallel and were therefore recorded nuclear light-scattering was seen, though without a
separately (Table 2). In 4 of the 7 patients the cataract significant effect on the visual acuity. The youngest
and the reduction of visual acuity developed within 6 patient, only 23 years of age, did not develop any lens
months of treatment and in the other 3 within a year. changes.
Mean reduction of visual acuity was 0 5. In 2 patients Twelve of the 19 patients in the reference group
Table 2 Relationship between treatment duration in patients with clear lens nuclei before start of treatment and changes
in visual acuity, refraction, and lens parameters
Patient Age Refractive change
Treatment Visual acuity (dioptres) Turbiditv Colour
Hours Months Before After Max After Before After Before After
1 45 150 4 1.0 10 -2 0 -20 - + - -
2 23 160 4 1.0 10 -1.0 -1 0 - - - -
3 44 190 4 1.0 1.0 -1 75 -1 25 - + - -
4 53 200 5 1.o 06 -70 -70 - ++ - -
5 46 230 8 1.o 1.0 -1-25 -125 - + - -
6 68 300 12 100o 9 -1 5 -10 - + - ++
7 74 335 9 1.0 06 -40 -20 - + + ++
8 79 400 11 1.0 06 -3.0 -10 - ++ + +++
9 70 510 18 1.o 08 -3 25 -2 75 - ++ + ++
10 62 540 19 10 03 -100 -6-0 - ++ - ++
I11 62 600 18 1.0 05 -4.5 -4.5 - ++ + ++
12 72 600 13 1.o 0-7 -3-5 -1-25 - + - ++
13 56 630 16 1.0 09 -40 -0o5 - ++ + ++++
14 60 700 17 1.0 03 -35 -35 - ++ - +
15 60 850 17 0-9 0-7 -4-5 -2-5 - ++ + ++
Br J Ophthalmol: first published as 10.1136/bjo.68.2.113 on 1 February 1984. Downloaded from http://bjo.bmj.com/ on 1 June 2018 by guest. Protected by copyright.
116 Briu-Marie Palmquist, Bo Philipson, and Per-Olof Barr

r
.,
Fig. 3 The change in visual acuity a

and refraction during oxygen


treatment in a 72-year-old male (no.
12, Table 2). The patient developed
a partly reversible nuclear cataract.
In the treatment schedule each line
indicates 10 hours of treatment.
Visual acuity 1 0 and 0 5
corresponds to 6/6 and 6/12
respectively.

14
mnt hs

had clear lens nuclei at the initial examination. None change in refraction seen by us after about 200
of them developed a nuclear cataract with reduction treatment hours might be explained by some sort of
of visual acuity of 0 3 or more during the follow-up reparative process taking place in the lens itself. The
time of 12 months (Table 3). However, 2 of them refractive change is considered to be due entirely to
showed a slightly increased nuclear light scattering. changes in the lens, as no changes in the cornea or
The difference between the exposed group and the axial length of the eye have been found.78
reference group was statistically significant (p<001). We consider the myopic change to be a sign of
All the remaining patients ofboth groups had more increasing nuclear cataract. The relationship between
or less pronounced nuclear cataract initially. Eight of increasing myopia and senile nuclear cataract is well
10 nuclear cataracts progressed during oxygen known. Among the oxygen treated patients over 60
treatment, while 1 of 7 nuclear cataracts in the years of age there was an inverse correlation between
reference group showed progression during a year. the degree of myopic change and the degree of pre-
A slight subcapsular cataract was found in about treatment nuclear cataract. This can be explained by
one-third of all patients. In a few cases it progressed the much greater possibility for the clear lens nucleus
during treatment. Cortical cataract was found in to develop an increasing myopia, together with an
about half of the patients. A slight increase was seen increasing nuclear cataract.
in a few cases during the follow-up time. The The cataractogenic effect of hyperbaric oxygen in
prevalence and progress of these changes was equal man has not been reported by others. This is
in exposed and controls. explained by the uniquely prolonged and intensive
treatment program used on our patients, in which 14
Discussion were treated between 300 and 850 hours. In general,
Hyperbaric oxygen therapy is known to cause Table 3 Comparison between the treated and untreated
reversible lens myopia.'8 In this study a change in groups ofpatients
refraction towards myopia was found in all exposed
patients. There was a large individual variation in the Treated Untreated
degree of refractive change, but it was not related to Patients with clear lens nuclei
age or length of treatment. The induced myopia was at first examination 15 (60%) 12 (63%)
found to be reversible in most patients, though it was Age distribution (mean+SD) 58-3±14-4 65-4±11-9
not complete in all cases. This reversal in refraction Sex distribution
usually began after approximately 200 treatment (M=male, F=female) 1IM 4F 8M 4F
Nuclear cataract fonnation with
hours. visual impairment of 0 3 or more
In the investigations of Lyne' and Anderson and within a year* 7 0
Farmer8 the myopia reversed after finishing the Myopic refractive change of I
therapy. Almost all patients in their series were dioptre or more 15 0
treated for less than 200 hours, which explains why * Corresponding approximately to a decrease in visual acuity from 6/6
the reversibility was not seen during treatment. The to 6/9.
Br J Ophthalmol: first published as 10.1136/bjo.68.2.113 on 1 February 1984. Downloaded from http://bjo.bmj.com/ on 1 June 2018 by guest. Protected by copyright.
Nuclear cataract and myopia during hyperbaric oxygen therapy 117

patients developing nuclear cataract with visual the oxidising free radicals. Several defence systems
impairment were subjected to more extensive treat- against these radicals are found in the lens. The most
ment than those who did not. It could be objected important is the glutathione system. Lack of protec-
that the definition and grading of the nuclear cataract tive agents against the oxidising free radicals or
was subjective. However, the results were supported excessive amounts of oxidising radicals could theo-
by the registered visual acuity and refraction. The retically be cataractogenic.
increasing myopia and the decreasing (best corrected) The rapid development of nuclear cataract in
visual acuity both paralleled the increasing nuclear patients under hyperbaric oxygen treatment strongly
cataract. supports the oxidative theory of nuclear cataract
Seven out of 15 patients with clear lens nuclei formation.
developed a nuclear cataract with visual impairment, The obvious cataractogenic effect of hyperbaric
4 within 6 months and 3 within a year. This incidence oxygen treatment should be considered before
(47%) of nuclear cataract with visual impairment is starting therapy. The patient must be informed and
extremely high. Our reference group consisted of the treatment period must be kept as short as possible.
patients on the waiting-list for hyperbaric oxygen
treatment and could be considered equal to the This investigation was supported by grants from the Swedish Medical
treated group according to state of primary illness. Research Council (12X4204), Carmen and Bertil Regner's Founda-
tion for Eye Research, and from the Karolinska Institute, Stockholm.
The difference between the 2 groups (Table 3) in
development of nuclear cataract and myopia is References
marked and significant. Consequently, the rapid I Nichols CW, Yanoff M, Hall DA, Lambertsen CJ. Histologic
development of nuclear cataract in the treated group alterations produced in the eye by oxygen at high pressure. Arch
can by no means be explained by the normal incidence Ophthalmol 1972; 87: 417-21.
of senile nuclear cataract. 2 Schocket SS, Esterson J, Bradford B, Michaelis M, Richards RD.
The partly reversible nuclear cataract observed in 2 Induction of cataracts in mice by exposure to oxygen. Isr J Med
Sci 1972; 8: 1596-601.
patients has not been reported previously. So far 3 Nichols CW, Lambertsen CJ. Effects of high oxygen pressures on
nuclear cataract in humans has been considered to be the eye. N Engl J Med 1969; 281: 25-30.
irreversible, but apparently the lens can sometimes 4 Kinsey VE. Retrolental fibroplasia: cooperative study of retro-
recover from an acute toxic event of this kind. The lental fibroplasia and the use of oxygen. Arch Ophthalmol 1956;
56:481-529.
myopia seems to be a very early sign of the toxic 5 Fletcher MC, Brandon S. Myopia of prematurity. Am J
damage to the lens, while the nuclear cataract is Ophthalmol 1955; 40: 474-81.
probably a sign of a more definite damage, much 6 Palmquist BM, Barr PO, Fagerholm PP, Philipson BT. Lens
harder to repair. In young patients with short treat- myopia and nuclear cataract induced by hyperbaric oxygen
therapy. Transactions of the Swedish Ophthalmological Society
ments an increase in turbidity, but not in colour, was 1977. Acta Ophthalmol (Kbh) 1978; 56: 476.
found. In patients with long treatments both turbidity 7 Lyne AJ. Ocular effects of hyperbaric oxygen. Trans Ophthalmol
and colour increased. Soc UK 1978; 98: 66-8.
Apparently the turbidity is affected primarily and 8 Anderson B, Farmer JC. Hyperoxic myopia. Trans Am
the colour secondarily. The increase in colour may be Ophthalmol Soc 1978; 76: 116-24.
9 Spector A. Aggregation of a-crystallin and its possible relation-
a function of age only. A widely accepted theory on ship to cataract formation. Isr J Med Sci 1972; 8: 1577-82.
the development of nuclear cataract suggests an 10 Spector A, Gamer MH, Roy D, Gamer WH, Farnsworth PN,
oxidative damage to the lens proteins causing the Shyne S. Oxidation of lens proteins. In: Srivastava SK, ed. Red
blood cell and lens metabolism. New York: Elsevier. North
formation of large and dense molecular aggre- Holland, 1980: 81-93.
gates."' Each aggregate will scatter light and if 11 Spector A, Gamer MH. Interaction of human cataract fiber cell
present in sufficiently high concentration results in membrane polypeptides with cytoplasmic components. In:
lens opacity. 12 Possible oxidative agents include Srivastava SK, ed. Red blood cell and lens metabolism. New
York: Elsevier North Holland, 1980: 233-236.
oxygen, which is known to be toxic to most tissues in 12 Benedek GB. Theory of transparency of the eye. Appl Optics
excessive amounts. The toxicity is mediated through 1971; 10: 459-73.
University of Richmond
UR Scholarship Repository
Math and Computer Science Faculty Publications Math and Computer Science

2014

Effects of hyperbaric oxygen on eye tracking


abnormalities in males after mild traumatic brain
injury
Joanna R. Wares
University of Richmond, jwares@richmond.edu

David X. Cifu

Kathy W. Hoke
University of Richmond, khoke@richmond.edu

Paul A. Wetzel

George Gitchel
See next page for additional authors

Follow this and additional works at: http://scholarship.richmond.edu/mathcs-faculty-publications


Part of the Neurosciences Commons, and the Ophthalmology Commons

Recommended Citation
Wares, Joanna R., David X. Cifu, Kathy W. Hoke, Paul A. Wetzel, George Gitchel, and William Carne. "Effects of Hyperbaric Oxygen
on Eye Tracking Abnormalities in Males after Mild Traumatic Brain Injury." Journal of Rehabilitation Research and Development 51, no. 7
(2014): 1047-1056. doi:10.1682/JRRD.2014.01.0013.

This Article is brought to you for free and open access by the Math and Computer Science at UR Scholarship Repository. It has been accepted for
inclusion in Math and Computer Science Faculty Publications by an authorized administrator of UR Scholarship Repository. For more information,
please contact scholarshiprepository@richmond.edu.
Authors
Joanna R. Wares, David X. Cifu, Kathy W. Hoke, Paul A. Wetzel, George Gitchel, and William Carne

This article is available at UR Scholarship Repository: http://scholarship.richmond.edu/mathcs-faculty-publications/58


JRRD Volume 51, Number 7, 2014
Pages 1047–1056

Effects of hyperbaric oxygen on eye tracking abnormalities in males


after mild traumatic brain injury

David X. Cifu, MD;1–2 Kathy W. Hoke, PhD;3 Paul A. Wetzel, PhD;4 Joanna R. Wares, PhD;3 George Gitchel,
MS;4 William Carne, PhD1*
1
Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University, Richmond, VA; 2Physical
Medicine and Rehabilitation Program Office, Department of Veterans Affairs, Richmond, VA; 3Department of Mathe-
matics and Computer Science, University of Richmond, Richmond, VA; 4Department of Biomedical Engineering, Vir-
ginia Commonwealth University, Richmond, VA

Abstract—The effects of hyperbaric oxygen (HBO2) on eye INTRODUCTION


movement abnormalities in 60 military servicemembers with at
least one mild traumatic brain injury (mTBI) from combat As a result of the significant numbers of Veterans and
were examined in a single-center, randomized, double-blind, servicemembers (SMs) who sustained mild traumatic
sham-controlled, prospective study at the Naval Medicine brain injuries (mTBI) from the Gulf wars, the U.S.
Operational Training Center. During the 10 wk of the study, Department of Veterans Affairs (VA) and Department of
each subject was delivered a series of 40, once a day, hyper- Defense (DoD) established integrated systems of care [1–
baric chamber compressions at a pressure of 2.0 atmospheres 2]. Through 2011, nearly 1 in 10 Veterans who served in
absolute (ATA). At each session, subjects breathed one of three Operation Enduring Freedom and Operation Iraqi Free-
preassigned oxygen fractions (10.5%, 75%, or 100%) for 1 h, dom and enrolled in the VA were diagnosed with at least
resulting in an oxygen exposure equivalent to breathing either one deployment-related mTBI [3]. Of these individuals,
surface air, 100% oxygen at 1.5 ATA, or 100% oxygen at 2.0
ATA, respectively. Using a standardized, validated, computer-
ized eye tracking protocol, fixation, saccades, and smooth pur-
suit eye movements were measured just prior to intervention
and immediately postintervention. Between- and within-groups Abbreviations: ANOVA = analysis of variance, ATA = atmo-
spheres absolute, DoD = Department of Defense, HBO2 =
testing of pre- and postintervention means revealed no signifi-
hyperbaric oxygen, mTBI = mild traumatic brain injury,
cant differences on eye movement abnormalities and no signif-
NMOTC = Naval Medicine Operational Training Center,
icant main effect for HBO2 at either 1.5 ATA or 2.0 ATA
PPCS = persistent postconcussive syndrome, RPQ = River-
equivalent compared with the sham-control. This study demon- mead Post-Concussion Questionnaire, SD = standard devia-
strated that neither 1.5 nor 2.0 ATA equivalent HBO2 had an tion, SM = servicemember, SPEM = smooth pursuit eye
effect on postconcussive eye movement abnormalities after movement, TBI = traumatic brain injury, VA = Department of
mTBI when compared with a sham-control. Veterans Affairs.
*
Address all correspondence to William Carne, PhD;
Department of PM&R, Virginia Commonwealth Univer-
Key words: blast injury, blinded, concussion, eye tracking, sity, 1223 East Marshall Street, Richmond, VA 23298; 804-
hyperbaric oxygen, postconcussive syndrome, randomized, 828-4231; fax: 804-828-6755. Email: lasile@aol.com
saccades, sham controlled, traumatic brain injury. http://dx.doi.org/10.1682/JRRD.2014.01.0013

1047
1048

JRRD, Volume 51, Number 7, 2014

more than 90 percent were also diagnosed with at least Common assessments of eye tracking include the
one additional condition (e.g., posttraumatic stress disor- measurement of saccades, smooth pursuit eye movement
der or pain) that likely complicated both the clinical pre- (SPEM), and fixation [23–24]. Saccades, the simultane-
sentation and subsequent treatment [3–4], a finding that ous movements of both eyes in the same direction allow-
has been labeled Postdeployment Syndrome [5] and may ing for fixation of the image on the fovea, are likely to be
help explain the higher rate of persistent postconcussive affected by even mild brain injuries because they involve
syndrome (PPCS) in military personnel than civilian the concerted interactions of multiple and diverse areas
individuals [3]. Moreover, the high incidence of repeated of the brain [23]. Additionally, the various components of
exposures to blast, with potential for cumulative brain saccades are largely free of cognitive influence and not
injury, may also contribute to prolongation of recovery interdependent. SPEM has been examined in the trau-
and difficulty in symptom attribution [6–7]. The persis- matic brain injury (TBI) population and, although
tence of often disabling symptoms in a high proportion of believed to be a potential component of the difficult to
returning SMs and Veterans has prompted the use of a identify and diagnose visual complaints seen with mTBI,
significant number of alternative treatment strategies, research has produced equivocal results [24]. Data
including meditation, acupuncture, tai chi, continuum involving fixation, defined as maintaining a foveal
image, in individuals with TBI have not been well stud-
movement therapy, and hyperbaric oxygen (HBO2) [3–8].
ied, in part due to technical difficulties in measurement;
HBO2 has been advocated for the acute treatment of however, advances in both technology and data process-
carbon monoxide poisoning, burns, crush injuries, and air ing have overcome this.
embolism; the chronic management of pressure ulcers, Investigation of these movement parameters demon-
gangrene, radiation necrosis, brain abscess, anemia, strated differences between SPEM and saccades in indi-
osteomyelitis, and retinal artery blockage; and to improve viduals with PPCS and injury-free controls [20]. These
the long-term effects of ischemic stroke, autism, and differences were noted in horizontal and vertical stepwise
cerebral palsy [9]. However, investigations evaluating the target displacement task responses between individuals
effect of HBO2 on subjective measures of PPCS have not with symptomatic mTBI and controls. Subjects with
demonstrated clinically meaningful improvement [8,10– symptomatic mTBI had smaller predicted peak veloci-
12]. In contrast to this lack of efficacy in subjective mea- ties, longer durations, larger position errors, and smaller
sures of brain dysfunction, there are many basic science saccadic amplitudes. These symptomatic subjects also
studies supporting the effects of HBO2 on objective find- had amplitudes that were significantly larger for the hori-
ings of brain recovery in animals [13]. For example, in zontal smooth pursuit task, were more likely to respond
brain-injured rodents, HBO2 promotes mitochondrial with smaller primary saccades to step changes in target
recovery and decreases apoptosis in hypoxic nerve cells, position, less accurately tracked the stepwise moving
which is associated with cognitive recovery and a reduc- targets, and had lower pursuit gain than controls [20].
tion in hippocampal neuronal cell loss [13–15]. The pur- No between-group differences were noted for fixation
ported mechanisms of HBO2 on brain injury include measures.
enhanced neural stem cell activation and growth, reduced For this investigation of the effects of HBO2 on
hypoxic-induced myelin damage, elevated cellular ATP mTBI-related symptoms, we hypothesized that there
(adenosine triphosphate) levels, and upregulated HIF-1 would be significant differences in postcompression
(hypoxis-inducible factor-1) alpha-enhancing neuronal SPEM and saccadic eye movements between the sham
tolerance to hypoxia [16–19]. Based on these positive and intervention groups.
findings of HBO2 in animal models, we hypothesized
that objective measures of clinical brain function and
recovery would demonstrate improvements. To test this METHODS
hypothesis, we identified the central visual pathways as
an objective and readily accessible indicator of brain This study was a sham-controlled, blinded, randomized,
health. Eye tracking, which measures the integrity of three-arm trial of HBO2 exposure on combat-related,
these pathways, has been demonstrated as a user-friendly, symptomatic mTBI that was begun in 2009 at the Naval
low-cost, noninvasive marker of individuals with mTBI Medicine Operational Training Center (NMOTC) at
[20–24]. Naval Air Station Pensacola. Other outcome measures
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CIFU et al. Hyperbaric oxygen effects on eye tracking

from this trial have been reported [11–12]. This study


received appropriate governmental and institutional
review board approvals. Sixty-one Active Duty military
SMs with PPCS were recruited from U.S. military bases.
Inclusion criteria included confirmed diagnosis of mTBI
by a TBI specialist, postconcussive symptoms for at least
3 mo, injury occurrence within 3 yr, at least 2 mo stable
psychiatric status, and no change in psychotropic medica-
tions for at least 1 mo. The study physiatrist confirmed a
diagnosis of TBI based on history, physical examination,
and a review of all the medical records of the subjects,
including any available battlefield information, from the
time of the traumatic event to the present. Exclusion cri-
teria included any contraindication to hyperbaric expo-
sure, previous exposure to HBO2, or inability to undergo
testing (e.g., superimposed ophthalmic conditions such as
ocular injury and strabismus). All subjects were ques-
tioned as to whether they had any double vision, blurred
vision, or floaters. Demographics; clinical information;
and physical, cognitive, and measures of behavioral func-
tioning were obtained.
After baseline testing, all subjects were relocated to
NMOTC for 2 mo to undergo the hyperbaric chamber
exposures. The hyperbaric chamber exposures, which
approximate the community standard of care and meet all
safety guidelines [8–9], have been described in prior pub-
lications from this research team [10–12].
Figure.
Statistical Analyses Measures for comparing saccadic and smooth pursuit data.
This article presents an analysis of the effects of the
hyperbaric chamber exposures on eye tracking character-
istics of the control and treatment group members by mality, we used nonparametric methods (Kruskal-Wallis
comparing baseline (time 1) measures to immediate post- for between-group analysis and Friedman two-way
compression (time 2), and 3 mo postcompression (time 3) ANOVA by ranks for within-group). Levene’s test was
results. Immediate postcompression outcome measure- used to check homogeneity of variances and Box test was
ments were obtained within the first week following last used to check the assumptions of covariances. Sphericity
exposure. Statistical measures of eye tracking were used assumptions were also verified and, when violated, were
to test for changes within and between subject groups at corrected using the Greenhouse-Geisser correction.
times 1, 2, and 3. Previous research has demonstrated the
When the interaction term was significant, the
utility of these measures in distinguishing between mTBI
and normal controls [20]. assumption of homogeneity of covariances was not met.
We analyzed multiple measures (see Figure) using a In these cases, we used nonparametric tests and per-
mixed-model analysis of variance (ANOVA), with time formed separate repeated-measures ANOVAs for each
(times 1, 2, and 3) as the within-subjects factor and oxy- oxygen-level group, as well as separate one-way ANO-
gen-level (groups A, B, and C) as the between-subjects VAs between oxygen-level groups at each time point.
factor. The studentized residuals were analyzed for outli-
ers and normality. If there was only one outlier, the analy- Eye Tracking Procedures
sis was done with and without it. In the cases of multiple The techniques used to obtain the pre- and posthyper-
outliers or a large deviation from the assumption of nor- baric chamber exposure saccadic movement and SPEM
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JRRD, Volume 51, Number 7, 2014

have been described in prior publications from this [11]. Specific to this analysis, no subjects reported any
research team [20]. active difficulty with vision on the three vision-related
RPQ items—blurred vision, light sensitivity, and double
vision.
RESULTS To determine if a treatment effect existed, analyses
were conducted for the eye tracking variables that had
One-hundred twenty-eight subjects met the initial been identified as abnormal in prior research [20]. These
study eligibility and consented for evaluation. Of the 128 variables were compared for between- and within-group
candidates, 61 met the full study criteria and were randomly differences over the three time periods. At pretreatment,
assigned into one of the three groups. Primary reasons for there were no significant differences between groups for
exclusion were active medication changes, schedule con- eye movement variables, verifying the efficacy of random-
flicts, and the inability to confirm the diagnosis of mTBI. ization. At immediate and 3 mo postcompression, both
One of the 61 study participants was unavailable for the between- and within-group differences were examined.
immediate postintervention assessment. Less than 1 per-
cent of all scheduled chamber sessions were postponed Saccades
because of medical complaints and all were rescheduled Saccadic data from each group were compared from
per the protocol. All study subjects were male and had the horizontal and vertical target displacement tasks.
sustained at least one mTBI, with the most recent TBI Data from horizontal and vertical direction eye move-
occurring a mean of 8.5 mo (standard deviation [SD] = ments were analyzed for the horizontal and vertical target
6.58 mo, range = 3–39 mo) prior to the baseline assess- displacement tasks, respectively. For each subject, dura-
ments. The etiologies of mTBI included improvised tion, peak velocity, saccadic amplitude, and peak acceler-
explosive device blast (85.3%), uncategorized blasts ation for all saccades were fit to models for both
(10.0%), rocket propelled grenades (3.0%), and mortar horizontal and vertical displacement tasks using the non-
attacks (1.7%). Self-reported additional concussions linear curve fitting toolbox in MATLAB (MathWorks;
(mean = 2.1, SD = 0.95, range = 1–4) prior to the most Natick, Massachusetts). For peak velocity and accelera-
recent blast injury were reported by just over 25 percent tion of saccades, exponential models were used, while for
of the subjects. Of the 60 subjects who completed all of saccadic duration a power function model was used [26].
the pre- and postcompression procedures, 21 were in the After curves were fit for each subject, the predicted dura-
sham-control group, 18 were in the 1.5 atmospheres abso- tion, peak velocity, and peak acceleration from the mod-
lute (ATA) equivalent group, and 21 were in the 2.0 ATA els for both the 1° and 5° saccades were compared
equivalent group. There was no precompression between between and within groups. Other measures of saccadic
group differences on these variables, as previously accuracy known to differ between mTBI and normal con-
reported [11–12]. trols were also compared (Figure) [20]. Measures ana-
The 60-subject final sample had a mean age of 23.2 yr lyzed were mean (normalized and non-normalized) of the
(SD = 2.95). Forty-seven (78.3%) were Caucasian, 10 absolute value and SD of the primary and final position
(16.7 %) were Hispanic, 2 (3.3%) were African Ameri- errors.
can, and 1 (1.7%) was Native American. Of the 60 sub-
jects, 19 were married, 38 were single, and 3 were Horizontal Tracking
divorced. One-way ANOVA and chi-square analysis All of the fit data (peak velocity at amplitudes 1 and
revealed no between-group differences on demographics. 5, peak acceleration at amplitudes 1 and 5, and duration
There were no clinician-recommended or self-reported at amplitudes 1 and 5), the mean of the normalized pri-
alterations of psychotropic medications by any subjects mary position error, and the number of primary saccades
during the study period. for the horizontal tracking tasks met the assumptions
The symptoms of the research cohort were character- needed for repeated measures ANOVA. For all measures,
ized using the Rivermead Post-Concussion Questionnaire there was no statistically significant interaction (α = 0.05
(RPQ) [25], and these results, which demonstrated no level) between the oxygen-condition and time. The main
between-group differences before or after hyperbaric effect of oxygen-level showed no statistically significant
chamber compressions, have been previously reported differences between groups, and there were no significant
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CIFU et al. Hyperbaric oxygen effects on eye tracking

within-group differences over time. When a potential sta- Of those variables for whom separate repeated mea-
tistical trend was identified (the p-value was between 0.05 sures ANOVAs for each group were calculated, no signif-
and 0.10 for the interaction term), we performed separate icant between-group differences on the factor of oxygen
repeated measures ANOVAs for each oxygen-condition level were found. Analyses of these measures within
and found no significant differences. p-Values and partial groups found a statistically significant effect (or trend)
eta-squared values are reported for each of the variables of time for two conditions: predicted velocity (51.25,
that met the assumptions for the mixed model ANOVA in 53.23, 49.30 °/s) and acceleration (2,982.98, 3,109.20,
the Table. 2,835.02 °/s2) at both 1° and predicted velocity (209.21,
The mean of the normalized final position error, the 216.37, 203.19 °/s) and acceleration (11,294.69,
mean of the non-normalized primary position error, and 11,792.24, 10,934.80 °/s2) at 5° amplitudes for group B.
the SD of the normalized position error did not meet The difference was only statistically significant between
assumptions and so univariate nonparametric tests were times 2 and 3 and reflected a slowing (or worsening) in
performed. No significant differences between or within predicted values between times 2 and 3. The clinical rele-
groups were found. vance of slowing in these two parameters is unclear. No
other significant differences were found.
Vertical Tracking
When nonparametric analyses were utilized, no sig-
All of the data for the vertical tracking tasks met the
nificant between- or within-group results were found. p-
assumptions for parametric tests except for the mean and
Values and partial eta-squared values are reported for
SD of the normalized primary position errors. The data
each of the variables that met the assumptions for the
for the mean of the normalized final error, predicted
mixed-model ANOVA in the Table.
velocity at 1° and 5°, predicted acceleration at 5°, and
predicted duration at 1° did not meet the assumption of
equal covariance, and therefore separate repeated mea- Smooth Pursuit
sures ANOVAs were performed for each oxygen level. Data for the horizontal and vertical smooth pursuit
Each variable that met the assumptions was analyzed eye movement tasks were analyzed. The minimum gain
using a mixed-model ANOVA, with time (1, 2, and 3) as and mean absolute normalized saccadic amplitude for
the within-subjects factor and oxygen level (groups A, B, both pursuit tasks were analyzed. Only data for the mini-
and C) as the between-subjects factor. No significant mum gain from the horizontal smooth pursuit task met
interactions between time and oxygen level were found. the assumptions for parametric tests. No significant inter-
The main effect of oxygen condition showed no statisti- action was found between the oxygen-condition factor
cally significant differences between groups, and there and time (p = 0.36, partial η2 = 0.047). The main effect of
were no significant within-group differences over time. oxygen condition also showed no statistically significant

Table.
Mixed-model analysis of variance results: tracking variables.
Interaction, Oxygen Level (Between-Subjects) Main (Within-Subjects) Main
Tracking and Time Effect, Oxygen Level Effect, Time
p-Value Partial Eta 2 p-Value Partial Eta2 p-Value Partial Eta2
Vertical
Mean of Non-Normalized Primary Position 0.44 0.051 0.53 0.037 0.24 0.042
Error
Number of Primary Saccades 0.59 0.036 0.84 0.011 0.19 0.048
Horizontal
Mean of Normalized Primary Position Error 0.68 0.028 0.92 0.004 0.66 0.010
Number of Primary Saccades 0.58 0.035 0.66 0.020 0.35 0.026
Predicted Velocity, 1° Amplitude 0.09 0.103 0.74 0.015 0.89 0.002
Predicted Velocity, 5° Amplitude 0.07 0.109 0.81 0.011 0.96 0.000
Predicted Acceleration, 1° Amplitude 0.14 0.088 0.52 0.032 0.90 0.000
Predicted Acceleration 5° Amplitude 0.14 0.087 0.68 0.019 0.99 0.000
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JRRD, Volume 51, Number 7, 2014

Table.
Mixed-model analysis of variance results: tracking variables.
Predicted Duration, 1° Amplitude 0.69 0.026 0.82 0.010 0.40 0.022
Predicted Duration, 5° Amplitude 0.24 0.066 0.85 0.008 0.29 0.031

differences between groups (p = 0.10; η2 = 0.097), and continued recovery for the next 3 mo [21,30–31]. Heitger
there were no significant within-group differences over et al., in 2009, reported on 36 civilians who were within
time (p = 0.85, η2 = 0.004). Nonparametric univariate 6 mo of mTBI, and the mean RPQ score for light sensi-
tests (within- and between-group) were performed on the tivity was 1.42, 0.2 for double vision, and 0.78 for
other three variables with no significant within- or blurred vision, all of which indicated that none of these
between-group differences found. symptoms were more of a problem than prior to the
injury [31]. These findings are consistent with our find-
ings of no meaningful visual complaints on the RPQ.
DISCUSSION

This investigation presents injury-related eye track- CONCLUSIONS


ing characteristics from a subanalysis of a DoD-VA col-
laborative trial studying the effects of HBO2 on PPCS. This study has a number of inherent limitations, as
This represents the first examination utilizing objective previously described [11–12]. The small sample size lim-
eye tracking measurements to assess the potential effect its the study’s power. Generalizability may be limited by
of HBO2. In this study, there were no clinically signifi- sex. Additionally, the high follow-up rate seen secondary
cant between-group differences on any of the eye track- to the paid travel and Active Duty status (i.e., they
ing variables following hyperbaric chamber received additional duty orders to be on the base) may be
compressions. While there were within-group differences atypical of nonmilitary populations. A number of factors
on two of the saccade parameters for one of the oxygen- common to most of the study participants may have an as
condition groups, there were no clinical improvements yet undetermined effect on eye movements, including
seen in any of the HBO2 conditions. Interestingly, the general combat exposure with associated posttraumatic
changes seen between times 2 and 3 in this group B stress, depression, anxiety, substance abuse, and pain,
reflected saccadic slowing rather than improvements in which all have been associated with deployment [3–4].
eye functioning. The implications of this change are unclear Future studies examining the effect of these comorbidi-
but certainly cannot be interpreted as beneficial. There ties on eye tracking may be of interest. Better understand-
were no other statistically significant differences identi- ing of the influence of deployment and other possible
fied over the array of multiple eye movements studied. variables seen with the subjects, such as time postinjury,
The overall findings of this study were similar to severity of injury, repeated injury, and medication usage
findings utilizing other outcome measures in this study and adjustments, may allow for a greater refinement of
sample [11–12] and the initial DoD-VA study [10]. The treatment protocols. Diagnosing mTBI relies on partici-
lack of differences among the three experimental condi- pant self-report, which is sensitive to subjective patient
tions on these objective eye tracking measures suggests interpretation, memory, social desirability, and other
the HBO2 exerted no treatment effects on the parameters issues such as personality factors and willingness to
studied. These findings are noteworthy because this study reveal problems; thus, subjects who report mTBI from
specifically utilized the typical treatment pressures advo- combat exposure may have characteristics that are not
cated by hyperbaric clinicians [13,27–29]. typical of all individuals.
Examinations of oculomotor abnormalities and This well-controlled study of HBO2 use in symptom-
reports of visual dysfunction after mTBI, most com- atic subjects with chronic mTBI demonstrated no signifi-
monly using the saccadic eye movements and the RPQ as cant eye movement improvements at either 1.5 or 2.0 ATA
outcome measures, have demonstrated that they are most equivalent over sham-control. Importantly, this investiga-
likely seen in the first week after injury, maximally tion incorporated many features lacking in prior studies
recover in the initial 3 mo postinjury period and have of HBO2 use, including randomization, blinding, objec-
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CIFU et al. Hyperbaric oxygen effects on eye tracking

tive outcome measure, and control groups. This investi- REFERENCES


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