Neuropsychological effects of hyperbaric ... - Wiley Online Library

Neuropsychological effects of hyperbaric oxygen therapy in cerebral palsy Paule Hardy, Groupe de Recherche en Neuropsychologie Expérimentale, Université de Montréal; Jean-Paul Collet; Joanne Goldberg; Thierry Ducruet, Randomized Clinical Trial Unit, SMBD, Jewish General Hospital; Michel Vanasse, Pediatric Neurology Department, SainteJustine Hospital; Jean Lambert, Department of Social and Preventive Medicine, Faculty of Medicine, University of Montréal; Pierre Marois, Centre de réadaptation Marie-Enfant, SainteJustine Hospital, Montréal; Maxime Amar, Centre Hospitalier Régional de Rimouski and Institut Maritime du Québec; David L Montgomery; Jacqueline M Lecomte, Seagram Sports Science Centre, Cleghorn Hyperbaric Oxygen Lab, McGill University; Karen M Johnston, McGill University Health Centre (MUHC), Division of Neurosurgery, McGill University; Maryse Lassonde*, Department of Psychology, University of Montréal, PO Box 6128, Downtown Station, Montréal, Québec, H3C 3J7 Canada. *Correspondence to final author at above address E-mail: [email protected]

We conducted a double-blind placebo study to investigate the claim that hyperbaric oxygen treatment (HBO2) improves the cognitive status of children with cerebral palsy (CP). Of 111 children diagnosed with CP (aged 4 to 12 years), only 75 were suitable for neuropsychological testing, assessing attention, working memory, processing speed, and psychosocial functioning. The children received 40 sessions of HBO2 or sham treatment over a 2-month period. Children in the active treatment group were exposed for 1 hour to 100% oxygen at 1.75 atmospheres absolute (ATA), whereas those in the sham group received only air at 1.3 ATA. Children in both groups showed better self-control and significant improvements in auditory attention and visual working memory compared with the baseline. However, no statistical difference was found between the two treatments. Furthermore, the sham group improved significantly on eight dimensions of the Conners’ Parent Rating Scale, whereas the active treatment group improved only on one dimension. Most of these positive changes persisted for 3 months. No improvements were observed in either group for verbal span, visual attention, or processing speed.

Motor dysfunction is often the most obvious, but not necessarily the predominant, disability in cerebral palsy (CP). In fact, 88% of children with CP have three or more disabilities (Shapiro et al. 1983), one of the most frequently associated dysfunctions being cognitive impairments (50–75%; Williams et al. 1991). The incidence of learning disability* is estimated to be as high as 65% (Eicher and Batshaw 1993), while more subtle and specific learning disorders are frequently reported. In high-functioning children, the most common behavioural symptoms are attentional deficits and impulsivity (Eicher and Batshaw 1993). Indeed, regardless of the lesion location or laterality, most children with CP have been reported to exhibit lower visual and auditory selective attention skills (Laraway 1985, Craft et al. 1994), poor concentration (Laraway 1985), and working memory deficits regardless of their social background (Dammann et al. 1996). These impairments are most likely to result from abnormalities in, or interruption of, the frontal brain maturation process due to gestational complications, prematurity and/or low birthweight. Although by definition CP is non-progressive, the clinical syndrome can change during maturation and its manifestations or symptoms can diminish with time as a result of of neurological organization (Nelson et al. 1982, 1993). Supportive occupational, speech, and physical therapies, as well as palliative treatments (medication and surgery), are the most standard approaches for improving their condition and developing compensatory strategies. In recent years, hyperbaric oxygen (HBO2) therapy has been used by several centres in Canada, China, England, Germany, Russia, and the USA to treat children with CP. Websites and numerous anecdotal cases report ‘miraculous’ changes, suggesting that HBO2 might help to improve the children’s physical and psychological conditions. Nevertheless, the therapeutic potential of this therapy has not been scientifically demonstrated. The Undersea and Hyperbaric Medical Society, overseeing hyperbaric medicine, currently approves its application for 13 medical conditions in adult and paediatric patients, for which in vitro and in vivo research and extensive positive clinical experience became convincing (Hampson 1999). For specific neurological disorders such as CP, there is controversy still over the appropriateness of HBO2 therapy. Despite the lack of scientific evidence and the risk of side effects (such as oxygen toxicity, pneumothorax, barotrauma, and reversible myopia), families of children with CP are eagerly seeking HBO2 treatments. The hypothesis being put forward with clinical trials, in an attempt to explain the mechanism underlying the potential efficacy of HBO2 therapy in brain injuries, consists of the following: the hypoxic–ischaemic penumbra zone surrounding the necrosis may be reactivated metabolically or electrically by increasing the oxygen level mainly in plasma (Jain 1996). Indeed, oxygen-induced metabolic changes in potentially recoverable brain tissues has been documented in traumatic brain-injured and stroke patients (Neubauer et al. 1992, Nighoghossian and Trouillas 1997, Barrett et al. 1998, Neubauer and James 1998), some with SPECT. On the basis of comparison of serial scans showing an increase in blood flow in formerly hypoactive areas, Neubauer and colleagues (1994) suggested a metabolic reactivation to support the cognitive *North American usage: mental retardation.

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Developmental Medicine & Child Neurology 2002, 44: 436–446

and motor improvements experienced by the patients. This rationale was applied to CP, although the presence of such necrosis (as opposed to atrophy) and penumbra zones is not supported by any data in this static encephalopathy and remains to be demonstrated. In fact, researchers are still no closer to understanding the operant mechanism of the causal injury or how the injury results in the expressed disorder. Research on the effects of HBO2 therapy in children with CP is poor and anecdotal. The most common improvement reported is an increased muscular flexibility. A case series presented by Machado (1989) reported that children with spastic CP had their muscular flexibility increased. The frequency of epileptic seizures also seemed to be diminished (Qibiao et al. 1995). Although encouraging, these results must be interpreted with caution because they are based essentially on clinical observations of highly selected children, without adequate scientific rigor and objective measurements. A more scientific approach was used in a later pilot project, in which 25 children with a functional diagnosis of spastic diplegic CP showed reduced spasticity and significant improvements in gross and fine motor function after 20 sessions (Montgomery et al. 1999). However, there was no control group and the assessment was not blind. Cognitive changes were rarely studied and/or documented with standardized measurements to render the clinical observations objective. Only anecdotal studies report greater concentration, increased vigilance, and better speech articulation, but these studies provide little convincing and conclusive evidence. Nevertheless, it is reasonable to believe that these cognitive and motor improvements, potentially induced by HBO2 therapy, could be quantified in rigorous research. If the trend were confirmed, it would be a major advance for neurological rehabilitation. As an outcome of knowing that cerebral plasticity in the child’s brain increases the potential for recovery, reactivation of cerebral areas early in life could have a major impact on intellectual and physical functioning. We therefore conducted a double-blind placebo-controlled randomized clinical trial to assess the therapeutic effects of HBO2 therapy on children with CP in which gross motor function, cognition, and language were evaluated. Although the motor effects are described and discussed by Collet and colleagues (2001), the present article gives a fuller account of the neuropsychological constituent of the study. The objective was to determine whether 40 treatments would improve attention, working memory, and impulse control, and to evaluate whether the positive changes (if any) would persist 3 months after the end of the intervention. Method PARTICIPANTS

As stated in a previous study (Collet et al. 2001), children were recruited from 17 rehabilitation centres across the

province of Québec. They were considered eligible for the study if they had a documented diagnosis of CP due to a history of hypoxic–ischaemic event in the perinatal period, age range from 3 to 12 years, motor developmental age between 6 months and 4 years, and psychological developmental age greater than 24 months. Children with CP of perinatal onset, with peripheral neuropathy, and with other causes of encephalopathy were excluded. Children who presented with a condition that put them at risk of HBO2 complications, such as active asthma (at least one episode within the previous year), previous thoracic surgery or pneumothorax, convulsions or any other serious disease, including those who had one episode of otitis within the previous month before inclusion, or those with chronic otitis (at least three episodes within the previous year), also had to be refused.

Table II: Medical information HBO2

Sham group n %

n

%

Problems at birth Low birthweight Prematurity Convulsions Respiratory distress Brain bleeding Infection Other

24 32 3 24 4 3 7

60 80 7.5 60 10 7.5 17.5

20 27 2 21 7 2 7

57.1 77.1 5.7 60 20 5.7 20

Mother Gestational diabetes Placenta praevia Placenta abruptio Bleeding (Pre)eclampsia Multiple birth Others

6 0 4 2 2 2 12

15 0 10 5 5 5 30

1 0 3 1 2 5 8

2.9 0 8.6 2.9 5.7 14.3 22.9

Medical history Cardiovascular Abdominal Eyes, respiratory, nose Diabetes Convulsions Asthma Surgery

2 2 14 0 2 6 22

5 5 35 0 5 15 55

0 1 15 0 5 8 27

0 2.9 42.9 0 14.3 22.9 77.1

Type of CP Spastic diplegia Spastic triplegia Spastic quadriplegia Spastic double hemiplegia Spastic hemiplegia

19 1 13 5 1

47.5 2.5 32.5 12.5 2.5

19 0 8 6 0

54.3 0 22.9 17.1 0

Table I: Demographic characteristics at inclusion Group

n 4–5

Age, y 6–8

Sex 9–12

Male

Female

Developmental age, m Mean (SD)

Birthweight, g Mean (SD)

HBO2, n (%)

40

13 (32.5)

18 (45)

9 (22.5)

19 (47.5)

21 (52.5)

22.4 (16.2)

1810 (855)

Sham, n (%)

35

11 (31.4)

10 (28.6)

14 (40)

15 (42.9)

20 (57.1)

22.1 (16)

1754 (801)

Hyperbaric Oxygenation and Cerebral Palsy Paule Hardy et al.

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Furthermore, children recently treated with botulinum toxin injections or who had received orthopaedic surgery (within the previous 6 months) or dorsal rhizotomy (within the previous 2 years) were excluded. Behavioural problems that were at risk of interfering with the treatment procedure and could be detrimental to the assessment quality were considered as exclusion criteria, thus allowing a relatively homogeneous sample in terms of psychological variables. Any medications (such as methylphenidate or anti-spasticity medications) acting on the CNS were stopped 6 weeks before initiation of the trial, to preclude any putative side effects on the trial outcomes. Previous exposure to HBO2 therapy was also an exclusion criterion. Finally, all rehabilitative services (i.e. speech, occupational, and physical therapies) were interrupted during the course of the study, because such interventions could affect either cognitive or motor measurements. After parents had signed the consent form, the inclusion/exclusion criteria were systematically verified by the HBO2 physician. The children were then randomized to one of two treatment groups, namely HBO2 or sham. Randomization was centralized, stratified by centre with blocks of size four to six randomly distributed. Centres received a set of sealed and numbered envelopes

corresponding to the computer-generated allocation list. Treatment consisted of 40 one-hour sessions of either HBO2 or sham treatments over a 2-month period for each child. Depending on the treatment centres, HBO2 treatment was administered either in a monoplace chamber, where the internal environment of the chamber was maintained at 100% of O2, or in a multioccupancy chamber, where the air in the chamber was kept pressurized and children inhaled pure O2 using a hood covering their head. The number of treatments was based on HBO2 experts’ opinion that a minimum of 10 to 15 treatments is necessary to achieve some results (Holbach et al. 1978) and that benefits become more obvious after 40 sessions (PG Harch, personal communication). Participants receiving HBO2 were exposed to 100% pure oxygen at a pressure of 1.75 atmospheres absolute (ATA), whereas sham therapy refers to a slightly pressurized room air, namely air (21% oxygen), administered at 1.3 ATA. This pressure level was required to create a pressure effect in the ears so as to keep the children and parents blinded as to their experimental condition. It further remained in the range of what is used as a sham intervention of HBO2 in other studies because it is considered insufficient to produce any clinical

Table III: Within-group and between-group comparisons for changes over time in working memory Test

Group

Visual span Corsi Block Pictures Span Word span Familiar Words Unfamiliar Words

n

Baseline Mean (SD)

Mid-intervention,20 treatments Mean differencea p valueb p valuec (95% CI)

HBO2 Sham HBO2 Sham

31 32 33 34

3.03 (2.33) 3.22 (2.52) 2.06 (1.99) 2.74 (2.18)

+0.06 (–0.46; 0.62) +0.56 (0.11; 1.02) +0.36 (–0.03; 0.76) +0.21 (–0.2; 0.62)

0.813 0.018 0.07 0.314

0.104

HBO2 Sham HBO2 Sham

32 30 28 30

5.19 (2.01) 5.87 (2.22) 4.61 (1.57) 5.5 (2.37)

–0.47 (–0.9; –0.04) –0.43 (–1.03; 0.16) –0.57 (–1; –0.14) –0.6 (–1.3; –0.1)

0.033 0.146 0.011 0.092

0.321

0.915

0.262

Post-intervention,40 treatments Mean differencea p valueb p valuec (95% CI)

+0.61 (+0.09; +1.14) +0.94 (+0.35; +1.52) +0.7 (+0.35; +1.05) +0.79 (+0.27; +1.32)

0.024 0.003 0.0003 0.004

0.251

–0.19 (–0.76; +0.38) +0.1 (–0.39; +0.59) –0.04 (–0.64; +0.57) –0.13 (–0.81; +0.54)

0.506 0.682 0.904 0.69

0.108

0.549

0.749

a Positive score means improvement over time; b Paired t-test for within-group changes in comparison with baseline assessment; c Comparison

between groups: ANCOVA model controlling for baseline values, age, and developmental age.

Table IV: Within-group and between-group comparisons for changes over time in auditory attention and self-control (TOVA) Test

Group n

Baseline Mean (SD)

HBO2 Sham HBO2 Sham HBO2 Sham

32 32 23 25 23 25

36.6 (29) 45.9 (28.1) 1903 (516) 1734 (290) 556 (198) 513 (205)

Self-control Correct non-responses HBO2 Sham

32 32

Attention Correct responses Reaction time (ms) Variability in reaction time (ms)

Mid-intervention, 20 treatments Mean differencea p valueb p valuec (95% CI)

+3.8 (+1 ; +3.2) –1 (–5.2 ; +3.2) –23 (–173; +127) +68 (–27; +163) +40 (–104; +25) –23 (–77; +30)

0.011 0.628 0.751 0.154 0.213 0.373

160.5 (102.1) +25.2 (+6.3 ; +44.1) 183.1 (101.8) +10.3 (–6.1; +26.7)

0.009 0.208

0.117

Post-intervention, 40 treatments Mean differencea p valueb p valuec (95% CI)

+7.5 (+1.6; +13.5) +3.9 (–2.4; +10.3) +57 (–111; +225) +1 (–109; +111) +11 (–58; +80) +1 (–67; +70)

0.015 0.217 0.488 0.989 0.746 0.968

0.374 +44.8 (+18.4; +71.3) +24.3 (+0.7; +48)

0.001 0.044

0.32 0.574

0.914 0.157 0.756

0.451

a Positive score means improvement over time, except for reaction time and variability in reaction time; b Paired t-test for within-group changes in comparison with baseline assessment; c Comparison between groups: ANCOVA model controlling for baseline values, age, and developmental age.

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effect. The inclusion of a ‘neutral’ control group in which children would not be subjected to experimental manipulation was rejected, because it would have been impossible to have the families blinded and because of the current sample size, it would not have been possible to keep a reasonably appreciable statistical power. The content of oxygen dissolved in the human plasma is directly proportional to the alveolar partial pressure of oxygen (PAO2) and is a function of the following equation: PAO2 = (PBTPS×FiO2) – (PACO2÷R), where FiO2 is the inspired oxygen concentration, PBTPS is the barometric pressure at body temperature and saturated with water vapour, PACO2 is the partial pressure of alveolar carbon dioxide, and R is the respiratory quotient. Therefore, the PAO2 in the lung of a child in the sham group who breathed 21% oxygen at 1.3 ATA was approximately 148mmHg in comparison with 1233mmHg for the one breathing 100% oxygen at 1.75 ATA (HBO2 group), whereas the normal environmental condition at sea level is 98mmHg. Each session (HBO2 or sham) was standardized and consisted of the following elements: a

Table III: continued Follow-up at 3 months Mean differencea p valueb p valuec (95% CI)

+1.1 (+0.4; +1.8) +1.03 (+0.31; +1.78) +0.56 (+0.02; +1.1) +0.75 (+0.15; +1.35)

0.003 0.007 0.042 0.016

+0.73 (+0.19; +1.28) +0.82 (+0.24; +1.4) +0.15 (–0.53; +0.84) +0.46 (–0.09; +1.02)

0.01 0.007 0.647 0.097

0.91 0.306

0.373 0.078

Table IV: continued Follow-up at 3 months Mean differencea p valueb p valuec (95% CI)

+10.1 (+3.9; +16.4) +5.8 (–1.8; 13.5) +55 (–108; +218) –7 (–109; +94) –19 (–87; +50) –58 (–131; +15)

0.002 0.13 0.486 0.883 0.577 0.112

+42.9 (–0.7; +86.6) +31.3 (+0; +62.7)

0.054 0.05

0.941 0.529 0.572

0.667

compression phase lasting approximately 10 minutes, a 60minute treatment phase, and a decompression phase lasting approximately 10 minutes. Five hyperbaric centres across the province of Québec that had been accepted by the internal review boards and the provincial ethics committee were involved in the study. The project was approved by the ethics committees of each centre and the provincial ethics committee. Before participating in the trial, each centre developed specific written procedures for treatment administration and safety monitoring. All sites were audited before the onset of the study and during the intervention. Specific procedures were also put in place to keep parents blind as to the actual nature of the intervention their child was receiving (for example, by covering the control panels and by masking switches). MATERIALS AND PROCEDURE

Assessment of developmental age To attribute a developmental age to each participant, the Denver Developmental Screening Test (DDST; Frankenburg et al. 1973) was administered after completion of the baseline evaluation. The DDST is a standardized observational test, designed to detect early indications of developmental deviations in young children. It is divided into four areas: personal–social (awareness of and response to people and things in the environment), fine motor adaptive (eye–hand coordination activities, visuoperceptual and audioperceptual activities), language (receptive and expressive), and gross motor (large muscle coordination activities). The scale proceeds at 1-month increments from 1 month to 24 months of age, and then at 3-month increments from 2 years to 6 years of age. Each area was scored on the basis of observations made by the therapist responsible for each relevant field of rehabilitation, that is, neuropsychologists (personal/social), occupational therapists (fine motor adaptive), speech therapists (language), and physiotherapists (gross motor) respectively. The items of the DDST that they were unable to score on the basis of observations during their evaluation were credited through parental report or information. Neuropsychological assessment The neuropsychological evaluation was performed in French and included five tests assessing working memory, selective and sustained attention, and self-control in both the visual and auditory modalities (see below). Computerized standardized tests requiring minimal motor manipulation and verbal functions were used, because most children with CP presented physical limitations and/or language deficits. Participants were evaluated before the beginning of the study, at mid-session (between the 18th and 22nd treatment) and upon completion of the 40th treatment. A fourth evaluation was carried out 3 months after the end of the intervention to assess the persistence of the putative effects over time. Finally, a questionnaire, Conners’ Parent Rating Scale – Revised (CPRS–R), was completed by the parents in order to assess the children’s cognitive and psychosocial functioning. Working memory. Visuospatial working memory was assessed by using computerized versions of the Corsi Blocks and the Picture Span tests adapted from the Institut National de Santé et de la Recherche Médicale battery for children (Delatolas and Hardy 1993). In the Corsi Block test, nine 3.5cm squares were randomly displayed on the computer


439

screen. Series of squares were darkened according to a predetermined order and, after the presentation of each series, the participant had to point out the squares in the same order. The initial series included two presentations of two blocks. If the participant succeeded at any one of the two trials, the number of blocks was increased until the maximum span was reached (two consecutive failures in the same sequence of blocks). The Picture Span test consisted of showing successive pictures of objects and animals to the child, beginning with a series of two, then three, etc. After each series, the participant was asked to identify the exact sequence of pictures among a nine-picture mosaic. Two trials were given for each sequence of pictures until a failure in two same-length trials. Verbal working memory was evaluated by using the Word Span test from the Institut National de Santé et de la Recherche Médicale battery for children (Delatolas and Hardy 1993). The examiner read a series of familiar words (e.g. chat, oeuf) that the child had to recall in the same order. The trials began with two words and the number of words was successively increased until a maximum span was reached. The second part of the test was performed identically to the first part just described, except with unfamiliar words (e.g. daim, flot). All working memory tests involved the same scoring procedure: a score of 1 was allocated for each correct sequence and a 0 was scored for a failure. The tasks were discontinued after two consecutive failures within the same span level. To minimize learning effects (Lezak 1995), parallel forms of these working memory tests were used at each testing interval. Alternative versions being unavailable, we attempted to make them similar to the original test in level of difficulty. For the verbal span, comparable forms were prepared by selecting words of matched length and familiarity, in accordance with the vocabulary repertory of children aged from 5 to 9 years (Préfontaine and Préfontaine 1968). Attention and self-control. Visual and auditory attention, as well as self-control, were evaluated with the 10.8-minute vigilant condition of the Test of Variables of Attention (TOVA; Greenberg et al. 1996). This computerized continuous performance test is objective, highly accurate, and has been

standardized with over 2200 respondents. Four aspects of the attentional and impulse control processes were measured: (1) attention (number of correct responses); (2) selfcontrol (number of correct non-responses); (3) information processing speed (reaction time in milliseconds); and (4) attention fluctuation (response time variability). The child’s task was to press the response button as quickly as possible every time he/she saw or heard the target stimulus (either a square with a hole near the top or a high-pitched sound), but to disregard the non-target one (either a square with a hole near the bottom or a low-pitched sound). A practice session was carried out with the auditory version only, so that the child could discriminate between the two different sounds. Parents’ questionnaire: CPRS–R. This questionnaire was completed by parents at the baseline, after 40 treatments, and 3 months later, to evaluate the child’s global function in areas of both cognitive and psychosocial functioning. This instrument allows the assessment of behavioural and attentional problems in children aged between 3 and 17 years, based on the criteria for attention-deficit–hyperactivity disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; American Psychiatric Association 1994). The questionnaire comprises 80 statements related to learning, behaviour, anxiety, emotional lability, and interpersonal relations. Parents were asked to quote the intensity of each situation and problem exposed, using an ordinal scale from 0 to 3 (0=not at all true, 3=always true). Training of therapists, testing protocol, and material Four psychologists involved in the evaluations completed a 10-hour training course, which included a practice session with a child. Whenever possible, therapists were also encouraged to use the tests in their clinical practice up to the time of the study. Testing procedure and schedules (the testing hours were the same before treatment, at mid-session, at the end of treatment, and at 3 months after treatment) were meticulously respected during the entire study. The evaluation was performed in the following order: Image Span, Auditory TOVA, Word Span, Visual TOVA, and finally the Corsi Blocks test. Furthermore, assessments and analysis

Table V: Within-group and between-group comparisons for changes over time in visual attention and self-control (TOVA) Test

Group n

Baseline Mean (SD)

HBO2 Sham HBO2 Sham HBO2 Sham

33 32 27 31 27 31

37.2 (27.4) 37 (23.9) 1494 (362) 1535 (427) 507 (171) 448 (145)

+0.8 (–2 ; +3.7) +6.9 (–0.7 ; +14.5) +39 (–113; +192) +82 (–94; +257) –61 (–124; +3) +67 (–22; +157)

0.565 0.073 0.347 0.601 0.061 0.135

Self-control Correct non-responses HBO2 Sham

33 32

178.3 (88.5) 213 (64.5)

+17 (+3.1 ; +30.9) +10.7 (–12.4 ; +33.9)

0.017 0.351

Attention Correct responses Reaction time (ms) Variability in reaction time (ms)


0.109 0.344 0.064

0.833

Post-intervention, 40 treatments Mean differencea p valueb p valuec (95% CI)

+3 (–2.1; +8) +5.1 (–0.7; +10.9) +22 (–106; +149) –19 (–169; +131) –32 (–103; +38) +50 (–38; +138)

0.24 0.082 0.728 0.8 0.358 0.259

+41 (+17.4; +64.5) +16.4 (–2.1; +35)

0.0083), whereas the sham group showed an increase close to the level of significance at midtreatment (p=0.018). All children improved at the end of the intervention, but only the improvements seen in the sham group were statistically different (p=0.003). Results obtained at 3 months after treatment showed that such improvements persisted in both groups and that the children’s performance increased in similar proportions with regard to their baseline (HBO2, mean +1.1; p=0.003; sham, mean +1.03; p=0.007). However, between-group comparisons showed no differences (p>0.05). On the Picture Span test, the children’s performance was similar to baseline at mid-intervention (p>0.0083) but increased significantly in both groups at the post-treatment evaluation (HBO2, p=0.0003; sham, p=0.004). These gains slightly decreased after 3 months, the performance being not statistically different from baseline (p>0.0083). Furthermore, there were no differences between the two groups at any of the testing intervals (p>0.05). Except for the Picture Span test (r=–0.194, p>0.05), positive changes in working memory were correlated to the baseline performances (p≤ 0.001), with children presenting lower scores being more likely to improve. As for age, only the improvements in the Corsi Block test were found to be correlated with this variable (r=–0.257, p=0.04).


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Verbal working memory For both groups and on both tests (familiar and unfamiliar Word Span), there was a reduction in scores at mid-testing (see Table III). Performances returned close to baseline upon completion of the intervention, and both HBO2 and sham groups showed further improvement on the tests at 3 months. Nevertheless, with respect to baseline levels, none of these differences from baseline was significant, except for the sham group on the familiar Word Span test at 3 months after intervention (p=0.007). A slightly smaller, and consequently less significant, increase occurred in the HBO2-treated children at 3 months. As a result, the between-group comparison was not significant at this stage or at the two previous assessment stages. ATTENTION AND SELF- CONTROL

Auditory attention and self-control Evaluation of auditory attention (see Table IV) showed that children in the sham group did not produce more correct responses at mid-intervention in comparison with baseline and showed only slight gradual increases on subsequent testing (p>0.0083). The performance of the children treated with HBO2 also improved progressively over time, but only the changes after 3 months reached the level of significance (p=0.002). The improvements were not significant upon

statistical comparisons of both groups (p>0.05). Regarding self-control in the auditory modality (Table III), which was measured by the number of correct non-responses to the non-target stimulus, all children performed better over time. However, only the increases in the HBO2 group were statistically significant upon completion of 20 and 40 treatments (p≤ 0.0083). Once again, there were no group differences between the oxygen-treated and air-treated children (p>0.05). Finally, we found that changes in attention and self-control were strongly related to children’s baseline performance and age. Children with lower initial scores, that is fewer correct responses and fewer non-responses, showed greater improvements (attention, r=–0.53, p0.05).

Table VI: Within-group and between-group comparisons for changes over time in CPRS–R Test

Group n

Oppositional Cognitive Problems/ Inattention Hyperactivity Anxious–Shy Perfectionism Social Problems Psychosomatic Conners’ ADHD Index Conners’ Global Index: Restless–Impulsive Conners’ Global Index: Emotional Lability Conners’ Global Index: Total DSM-IV: Inattentive DSM-IV: Hyperactive– Impulsive DSM-IV

HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham HBO2 Sham

Baseline Mean (SD)


36 4.81 (4.13) –0.28 (–1.42; +0.87) 34 5.41 (4.88) –0.79 (–2.04; +0.45) 36 7.25 (6.15) –0.53 (–2.03; +0.97) 34 9.03 (7.4) –1.88 (–3.63; –0.13) 36 3.56 (3.75) +0.19 (–0.61; +1) 34 4.06 (4.42) –0.77 (–1.55; +0.02) 36 6.17 (4.64) –1.33 (–2.27; –0.4) 34 6 (4.61) –1.35 (–2.5; –0.2) 36 4.78 (4.32) +0.08 (–0.9; +1.07) 34 5.38 (4.13) –0.56 (–1.72; +0.6) 36 1.31 (2.23) –0.14 (–0.66; +0.38) 34 1.62 (2.34) –0.21 (–0.87; +0.46) 36 1.33 (1.97) –0.42 (–0.97; +0.13) 34 1.74 (2.15) –0.79 (–1.36; –0.23) 36 7.72 (6.54) –1.11 (–2.33; +0.1) 34 9.06 (7.54) –2 (–3.66; –0.34) 36 4.33 (3.8) +0.03 (–0.98; +1.04) 34 5.32 (4.35) –1.27 (–2.1; –0.43) 36 1.56 (1.93) –0.25 (–0.72; +0.22) 34 2.03 (2.02) –0.59 (–1.18; 0) 36 5.89 (5.21) –0.22 (–1.49; +1.05) 34 7.35 (5.83) –1.85 (–3.08; –0.63) 36 5.19 (4.72) –0.06 (–1.10; +0.99) 34 6.65 (5.86) –1.29 (–2.63; +0.05) 36 4.53 (3.71) +0.39 (–0.43; +1.21) 34 4.77 (4.72) –0.41 (–1.42; +0.60) 36 9.72 (7.3) +0.33 (–1.11; +1.78) 34 11.41 (10.03) –1.71 (–3.79; +0.38)

0.626 0.203 0.48 0.036 0.626 0.055 0.006 0.023 0.867 0.333 0.59 0.533 0.134 0.007 0.072 0.019 0.956 0.004 0.292 0.051 0.724 0.004 0.915 0.058 0.341 0.413 0.642 0.105

0.677 0.379 0.136 0.988 0.519 0.904 0.523 0.546 0.114 0.633 0.150 0.240 0.242 0.162

Follow-up at 3 months Mean differencea p valueb p valuec (95% CI) –0.91 (–2.22; +0.4) –2.51 (–2.51; +0.38) –1.03 (–2.77; +0.71) –1.83 (–3.71; +0.04) –0.38 (–1.58; +0.82) –0.5 (–1.58; +0.58) –2.26 (–3.43; –1.1) –1.93 (–3.63; –0.02) –0.91 (–1.81; –0.01) –0.27 (–1.76; +1.22) –0.18 (–0.78; +0.42) –0.23 (–0.69; +0.92) –0.24 (–0.99; +0.53) –0.57 (–1.55; +0.42) –1.67 (–3.1; –0.26) –1.37 (–3.17; +0.43) –0.76 (–1.72; +0.39) –1.03 (–2.14; +0.07) –0.48 (–1.14; +0.16) –0.83 (–1.56; –0.1) –1.32 (–2.93; +0.28) –1.87 (–3.5; –0.23) –0.85 (–2.05; +0.34) –0.93 (–2.33; +0.46) –0.65 (–1.97; +0.68) –0.5 (–1.46; +0.46) –1.5 (–3.53; +0.53) –1.43 (–3.61; +0.74)

0.166 0.144 0.236 0.056 0.521 0.351 0.0004 0.027 0.047 0.718 0.552 0.495 0.535 0.248 0.022 0.132 0.188 0.066 0.139 0.026 0.103 0.027 0.155 0.182 0.329 0.295 0.142 0.188

aScore increase means improvement over time; bPaired t-test for within-group changes in comparison with baseline assessment; cComparison between groups: ANCOVA model controlling for baseline, age, and developmental age.

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0.904 0.708 0.930 0.708 0.309 0.792 0.689 0.681 0.954 0.679 0.859 0.813 0.853 0.899

Visual attention Children’s visual attention remained unchanged over time (Table V). In both groups the number of correct responses was not significantly different from baseline after the treatments and 3 months later (p>0.0083). With regard to selfcontrol, all children exhibited an increased amount of correct non-responses, but only the change in the HBO2 group was found statistically significant at the post-intervention evaluation (p0.05). As in the auditory modality, changes in visual attention and self-control were statistically related to children’s baseline performance (attention, r=–0.59, p0.05). OBSERVATIONS

All four psychologists performing the evaluations observed that most children became less motivated and cooperative along the testing intervals. Being more comfortable and friendly with the examiner, they visibly showed a lack of enthusiasm and spontaneously verbalized their boredom in performing the computer tests. CPRS – R

All children’s baseline cognitive and psychosocial functioning, as rated by their parents, were within normal limits on all dimensions listed in Table VI (between the 45th and 60th centiles). Upon completion of the 40 treatments, scores of the HBO2-treated group were significantly reduced only in the Anxious–Shy subscale (p=0.006), whereas improvements in sham group were significant or ‘borderline’ significant on eight dimensions: Cognitive Problems/Inattention (p=0.036), Hyperactivity (p=0.055), Anxious–Shy (p=0.023), Psychosomatic (p=0.007), Conners’ Attention Deficit Hyperactivity Disorder (ADHD) Index (p=0.019), Conners’ Global Index: Restlessness–Impulsive (p=0.004), Conners’ ADHD Index: Emotional Lability (p=0.051), Conners’ Global Index: Total (p=0.004), and finally DSM-IV: Inattentive (p=0.058). Most of these improvements persisted after 3 months. Nevertheless, no differences were found between the two groups in any of these dimensions or at testing intervals (p>0.05). Correlation analyses further demonstrated that changes were related to the baseline levels for each dimension (p0.05). Discussion The present study demonstrated that HBO2 therapy did not produce greater cognitive improvements than the sham treatment in children with CP. With regard to working memory, children from both the HBO2 and sham groups were progressively more capable of manipulating visual information after a short time lapse, with both meaningful (Picture Span) and non-meaningful (Corsi Block) stimuli. In contrast, their ability to recall verbal material decreased slightly at the midtreatment evaluation and later returned close to baseline levels after conclusion of the intervention. Closer inspection of the results revealed that this deterioration in the Word Span might be related to an unequal ‘parallel version’ of the test, the familiar and unfamiliar words being intrinsically more difficult to articulate than the ones in the first and third forms. The 3-month follow-up evaluation showed a further improved performance in recalling familiar words, but such a trend could have resulted from a learning effect, the baseline version having been used de novo for the 3-month evaluation even though the follow up took place 5 months later. With regard to the attentional processes, the children’s capacity to focus and sustain their auditory attention was improved at the end of the study, but both visual attention and speed of auditory and visual information processing were unchanged in both groups. All children further showed more self-control after completion of the treatments. Comparisons of the children’s performance at mid-intervention and post-intervention, and also at the 3-month followup, did not show any trend in differential efficacy between the two interventions, the performances increasing in relatively comparable proportions. Finally, parental perceptions of their child’s cognitive functioning, with regard to attention and impulsivity/hyperactivity, were higher than their actual ability. It is also interesting to observe that parents of the sham group subjectively perceived more improvements in their child than those from the HBO2 therapy, specifically in 8 of the 13 subscales of the CPRS-R. Such findings certainly raise some questions related to the influence of the parents’ expectations of the trial outcomes, especially considering that several parents were visibly surprised when, after conclusion of the study, they were told the group that their child was in (HBO2 or sham), some firmly believing their child had received the opposite treatment. In this sense, conducting a parental survey on their initial impression before being told which group their child belonged to might have helped in understanding the influence of false belief on the parents’ perception of changes. It becomes possible that such expectations account, at least in part, for some personality changes reported to consultant doctors and on websites by parents claiming their child became more alert and attentive, more aware of their surroundings, and more outgoing or better behaved. Admittedly, these improvements are clinically important, given the stability of cognition deficits generally reported in


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CP (Laraway 1985, Eicher and Batshaw 1993, Craft et al. 1994, Dammann et al. 1996). It is clear that the neurodevelopmental outcome of low-birthweight and prematurity, which accounted for up to 79% of the sample in this study, is compromised at preschool and school age. This population is thought to be at double the risk of cognitive and neurological impairments because of a shortened gestational period compounded by intrauterine retardation of brain growth (Wallace and McCarton 1997). Therefore, such significant improvements manifested in similar proportions in both HBO2 and sham groups and within a short time lapse, namely a 2-month or 5-month period, give rise to some questions for which few explanations can be provided. Children’s response to both treatments surely provide some evidence of a combination of factors that could be explored and exploited in rehabilitation. Participation in the present study was a very stimulating experience for both the children and the parents, thus promoting the parent–child interaction in different ways than in everyday life. These children are usually very stimulated by their parents and therapists, but within this specifically motivating and hopeful research context, they most probably developed a closer relationship in spending more intimate time together. Parents might have promoted or differently supported their child’s initiatives, strongly encouraging him/her to be more involved and persevere in new activities. Children further learned to face uncertainties and to be comfortable with complex situations induced by the experimental setting, as well as to form new friendship alliances with the other children and families sharing therapy, who had different interests or ideas. In fact, such a stimulating environment might have facilitated cognitive progress, considering that children facing such opportunities usually show accelerated intellectual, emotional and social development, control, and self-esteem (Pervin 1993). Once again, this might account for some clinical improvements reported in anecdotal and retrospective studies, claiming that the children treated with HBO2 become more active and willing to interact with peers. Furthermore, cognitive improvements have been observed in children with spastic diplegic CP after selective dorsal rhizotomy (partial deafferentation of lumbar dorsal roots). To account for enhancement in visual attention and working memory, Craft and coworkers (1995) suggested that these improvements might result from improved mood in response to alleviation of spasticity-related physical discomfort. Considering that gross motor function and spasticity improved significantly in children of both HBO2 and sham groups during the course of our trial (Montgomery et al. 1999), it is indeed possible that increased muscular flexibility might have improved their overall ability to concentrate if they were not distracted by spasms and/or as a result of a better physical comfort. It might have also enhanced their selfesteem and self-confidence. Monitoring changes in functions also involves repeated assessments, a procedure that is inevitably open to improvement owing to learning and familiarity with the specific tests rather than recovery itself (Wilson et al. 2000). Indeed, there is evidence of practice effects in neuropsychological testing, and the amplitude of the gains varies according to the type of measure (particularly likely on memory tests; Lezak 1995), test–retest interval, and competence level of the person

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(Dikmen et al. 1999). Using alternative forms of the tests as in the present study, Wilson et al. (2000) recently showed that the working memory (backward digit span) of stable braininjured people was significantly improved across testing sessions, whereas speed of information processing measured with simple reaction time showed no practice effect (McCaffrey et al. 1993, Wilson et al. 2000). These results are consistent with the trend observed in both HBO2 and sham groups: significant improvements were found in spatial spans, whereas response times remained stable across evaluations. Performance, especially in spatial working memory tests, increased progressively along the study; most positive changes were mild to moderate at mid-treatment assessments and became significant on the third assessment. This might have reflected cumulative practice effects induced by a growing familiarity with the tasks and testing procedures. Having a control group undergoing no form of treatment might have helped to resolve this hypothesis, although the stimulating experimental context itself might have constituted an interesting, stimulating and ‘hope-inducing’ experience for these children and parents. It is also possible that the children’s potential was underestimated in the baseline assessment. Their initial performance might have been artificially depressed because of anxiety and fear of these impending treatments, which were unfamiliar to them. Furthermore, a new testing context is especially intimidating and stressful for this vulnerable population, for whom previous experience with health professionals and hospitals might have made them timorous. Such a situation is likely to create the illusion of greater improvements on subsequent evaluations. Enhanced motivation might also have accounted for the pattern of results obtained. We might indeed assume that all children were particularly motivated to perform well upon completion of the intervention, to demonstrate its beneficial effects, and to meet their parents’ expectations. However, given that most children visibly showed themselves to be less enthusiastic and cooperative during the course of testing intervals, the possibility of a motivational effect is unlikely. The improvements might also be related to cerebral function, suggesting direct and/or indirect neurological changes. A possible explanation is indeed that the two treatments are equally effective rather than equally ineffective, the administration of air at a pressure of 1.3 ATA being sufficient to produce an effect equivalent to 1.75 ATA with 100% oxygen. In relation to the direct effects of oxygen increase, this hypothesis is difficult to uphold because the increase in alveolar partial pressure of oxygen (PAO2) under the HBO2 treatment is substantially higher than under sham intervention: 1233mmHg versus 148mmHg respectively, in comparison with 98mmHg in the normal environmental condition (sea level). Such a small increase in PAO2 at 1.3 ATA was a priori considered insufficient to produce any clinical effect and it is in the range of what is used as sham in other HBO2 studies. Although the particular effects of such a slightly pressurized room air remain unknown, the same PAO2 might be obtained by administering 28% FiO2 with a mask at sea level and under normobaric conditions: it is well documented that oxygen transport is virtually unchanged, haemoglobin saturation increasing from 97% to 100%. In this sense, Moss and Scholey (1996) and Moss et al. (1998) demonstrated that oxygen administration with a facemask might have beneficial effects on cognitive

processes in specific circumstances. In a placebo-controlled double-blind study they found that in comparison with controls transient inhalation of oxygen before learning significantly improved attention and vigilance and also verbal long-term memory, including encoding and consolidation processes. However, no effect on spatial working memory was observed. The authors further showed that cognitive enhancement seemed to differ with the duration of oxygen inspired and the temporal position of the individual task relative to gas administration: longer oxygen administration and shorter time interval before testing (within 24 hours) had stronger effects on performance. These observations suggest that the oxygen effect is not a long-term one but has a more immediate impact on neuronal metabolism in that the efficiency of cognitive processes depends on oxygen availability, and that greater levels of circulating oxygen would facilitate this processing. Therefore, on the basis of these studies, if the improvements in cognitive functioning of children with CP depended on such a slight increase in oxygen supply to the brain, we would have found consistent significant improvements at the mid-treatment assessments in both groups, given that the oxygen level in tissues remains elevated for several hours after the end of a hyperbaric treatment (Hampson 1999). Furthermore, no significant changes would have been found at the 3-month followup while the blood oxygen level returned to normal, and the mean reaction times reflecting the information processing speed remained stable over the course of the study. Therefore we must envisage the possibility of another factor: could these improvements result from hyperbaria only, a ‘pure’ pressure effect? Unfortunately the hypothesis of a physiological effect at 1.3 ATA that would not be mediated by increased PAO2 is not supported by any data and does not correspond to the rationale behind the HBO2 therapy, which is based on the penumbra phenomenon, although the exact mechanisms of action remain unclear in brain injuries. In any case, such physiological explanations are worth exploring. Conclusion This double-blind randomized trial demonstrated that HBO2 therapy did not produce greater therapeutic effects than a small increased pressure (sham) on the cognition of children with CP. Visual working memory, auditory attention and selfcontrol showed comparable improvements in both groups upon completion of the intervention, whereas speed of information processing, verbal working memory, and visual attention remained undifferentiated over time. The positive changes might be related to a practice effect induced by a growing familiarity with the tasks and testing procedures. Furthermore, it is highly probable that exposure to this particularly stimulating intervention context has produced beneficial effects on the children’s cognitive functions and on their selfesteem and self-confidence, considering the high expectations of most families regarding this technique. Finally, enhanced capacity to concentrate might also result from relief of spasticity-related physical discomfort, knowing that the children’s gross motor function and spasticity improved significantly during the course of our trial. However, the physiological action of a small hyperbaria, although unlikely, cannot be ruled out on the grounds that no data are available regarding the short-tern and long-term effects of a slight increase in PAO2 on encephalopathy. However, the same amount of

blood oxygen can be achieved without hyperbaric treatment, using mask-administered oxygen. Such findings open doors to rehabilitation, and further investigation is required to identify the specific mechanisms involved. They are important considering that many parents spend substantial amounts of money to have their child treated with HBO2 in Canadian, American, and European clinics, despite the potential risks of complications. Disclosure Dr M Vanasse and Dr P Marois are the owners of one of the hyperbaric centres involved in this trial, namely the Centre de Médecine Hyperbare in Longueuil. Dr M Amar offered consultations to this centre for its development. None of the other investigators have any personal interest (honoraria, consultancies or ownership) in this domain. Accepted for publication 8th February 2002. Acknowledgements This research project was funded by the Fonds de Recherche en Santé au Québec (FRSQ) and a postgraduate scholarship was awarded to Paule Hardy by the REPAR (FRSQ network). We also wish to recognize the research support from the TOVA. Research Foundation, in providing a grant to cover the use of the attentional tests. This trial was carried out with the cooperation of a coordinating centre from the Randomized Clinical Trial Unit, at the Jewish General Hospital in Montreal. The treatment centres involved were: Institut Maritime du Québec; Seagram Sport Sciences Centre, Cleghorn Hyperbaric Oxygen Lab of McGill University; Centre Intégré de Médecine Hyperbare; Centre Hospitalier Hôtel-Dieu de Lévis; and Hôpital du Sacré-Coeur de Montréal. Finally, the research group wishes to thank the consultants and the Foundation of the Centre de rédaptation Marie-Enfant for their important involvement, as well as all rehabilitation centres that participated in the study: Hôpital Sainte-Justine, Centre de réadaptation Marie-Enfant, Centre de réadaptation Interaction, and Institut de réadaptation en déficience physique du Québec, Site Cardinal Villeneuve. References American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association. Barrett KF, Masel BE, Harch PG, Ingram F, Corson KP, Mader JT. (1998) Cerebral blood flow changes and cognitive improvement in chronic stable traumatic brain injuries treated with hyperbaric oxygen therapy. Neurology 50: A178–9. Collet JP, Vanasse M, Marois P, Amar M, Goldberg J, Lambert J, Lassonde M, Hardy P, Fortin J, Tremblay SD, Montgomery DL, Lacroix J, Robinson Ann, Majnemer A and the HBO-CP Research Group. (2001) Hyperbaric oxygen therapy for children with cerebral palsy: a multicenter placebo controlled randomized clinical trial. Lancet 357: 582–6. Conners CK. (1997) Conners’ Parent Rating Scale – Revised. Ontario: Multi-Health Systems Inc. Craft S, White DA, Park TS, Figiel G. (1994) Visual attention in children with perinatal brain injury: asymmetric effects of bilateral lesions. Journal of Cognitive Neuroscience 6: 165–73. Craft S, Park TS, White DA, Schatz J, Noetzel M, Arnold S. (1995) Changes in cognitive performance in children with spastic diplegic cerebral palsy following selective dorsal rhizotomy. Pediatric Neurosurgery 23: 68–75. Dammann O, Walther H, Allers B, Schröder M, Drescher J, Lutz D, Veelken N, Schulte FJ. (1996) Development of a regional cohort of very-low-birthweight children at six years: cognitive abilities are associated with neurological disability and social background. Developmental Medicine & Child Neurology 38: 97–108. Delatolas J, Hardy P. (1993) Étude épidémiologique sur la latéralité, le langage et la préférence manuelle chez des enfants de 3 à 8 ans en milieu scolaire. Programme de Recherche épidémiologique de l’Institut National de la Santé et de la Recherche Médicale, France.


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