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An entry from K.K. Jain’s Textbook Of Hyperbaric Medicine

Cerebral palsy is a chronic neurological disorder that can be due to several causes of brain damage in  utero, in the perinatal period, or postnatally. Hyperbaric oxygen has been shown to be useful in treating  children with cerebral palsy. This topic is discussed under following headings:

Causes of Cerebral Palsy 

Oxygen Therapy in the Neonatal Period Treatment of Cerebral Palsy with HBOT Conclusions 

Causes of Cerebral Palsy The term cerebral palsy (CP) covers a group of non-progressive, but often changing, motor impairment  syndromes secondary to lesions or anomalies of the brain arising in the early stages of development.  Between 20 to 25 of every 10,000 live-born children in the Western world have the condition (Stanley et  al 2000). Problems may occur in utero, perinatal, and postnatal. Infections, traumatic brain injury, near drowning and strokes in children suffering from neurological problems come under the heading of  cerebral palsy. Diagnosis of cerebral palsy resulting from in utero or early perinatal causes may be made  immediately after birth, but more commonly occurs between 15 and 24 months. It is possible that CP may  be misdiagnosed for years because specific symptoms may show up very late in childhood. Some of the  possible causes of Cerebral Palsy and are listed in Table 21.1.

Although several antepartum causes have been described for CP, the role of intrapartum asphyxia in  neonatal encephalopathy and seizures in term infants is not clear. There is no evidence that brain  damage occurs before birth. A study using brain MRI or post-mortem examination was conducted in 351  full-term infants with neonatal encephalopathy, early seizures, or both to distinguish between lesions  acquired antenatally and those that developed in the intrapartum and early postpartum period (Cowanet  al 2003). Infants with major congenital malformations or obvious chromosomal disorders were excluded.  Brain images showed evidence of an acute insult without established injury or atrophy in (80%) of infants  with neonatal encephalopathy and evidence of perinatal asphyxia. Although the results cannot exclude  the possibility that antenatal or genetic factors might predispose some infants to perinatal brain injury, the  data strongly suggest that events in the immediate perinatal period are most important in neonatal brain  injury. These findings are important from management point of view as HBOT therapy in the perinatal  period may be of value in preventing the evolution of cerebral palsy.

Oxygen Therapy in the Neonatal Period Following World War II, oxygen tents and incubators were introduced, and premature infants were given  supplementary oxygen to improve their chances of survival, with levels up to 70% being given for  extended periods. Epidemics of blindness due to retrolental fibroplasia followed in the 1950s, which led to  a restriction of the level of supplemental oxygen to 40%. A reduction in the incidence of blindness  followed, which appeared to confirm the involvement of oxygen in the development of the retinopathy.  The link between the use of recurrent supplemental oxygen and the rise of retinopathy was rapidly  accepted, even though it was suggested that retrolental fibroplasia was produced by initially  preconditioning a child to an enriched oxygen environment and then suddenly withdrawing the same: The  disease occurred only after the child’s removal from the high oxygen environment (Szewczyk 19 51). It  was also noted that retinopathy developed upon the withdrawal from the high level of oxygen, and that  probably the best thing to do was to return the child to the oxygen environment (Forrester 1964). Under  these circumstances, in many of the patients, the results were encouraging, and vision returned to

normal. A slow reduction of oxygen and final return to the atmospheric concentration for several weeks  was all that was needed to restore the vision. Thus, there is no rational basis for withholding oxygen  therapy in the neonatal period. As mentioned in other chapters of this textbook, retrolental fibroplasia is  not associated with HBOT. It is unfortunate that nearly all affected newborns today are deprived of  appropriate oxygen therapy because of the fear that it will cause retrolental fibroplasia (see Chapter 31).  Some observations indicate that since the practice of administration of high levels of oxygen has been  abandoned, there is a rise in the incidence of cerebral palsy as compared to previous levels.

Treatment of Cerebral Palsy with HBOT 

The use of hyperbaric oxygenation in the pediatric patient was relatively common in Russia (see Chapter  28) . HBOT has been used in Russia for resuscitation in respiratory failure, for cranial birth injuries, and  for hemolytic disease of the newborn. HBOT was reported to reduce high serum bilirubin levels and  prevent development of neurological disorders. In cases of respiratory distress, delayed use of HBOT  (12-48 h after birth) was considered useless. However, early use (1-3 h after birth) led to recovery in 75%  of cases. The Italian physicians began treating the small fetus in utero in 1988 demonstrating a reduction  of cerebral damage. Patients were hospitalized before the 35th week and hyperbaric treatments were  given every 2 weeks for 40 min at 1.5. The fetal biophysical profile showed a remarkable improvement as  soon as the second treatment.

At the conference “New Horizons for Hyperbaric Oxygenation” in Orlando, Florida, in 1989, results were  presented of HBOT therapy of 230 Cerebral Palsy patients who had been treated in the early stages  since 1985 in Sao Palo, Brazil (Machado 1989). Treatment consisted of 20 sessions of 1 h each at 1.5  ATA (100% oxygen), once or twice daily in a Vickers monoplace chamber. A few of the children had  exacerbation of seizures or developed seizures. The results showed significant reduction of spasticity:  50% reduction in spasticity was reported in 94.78% of the patients. Twelve patients (5.21%) remained  unchanged. However, follow-up included only 82 patients, and 62 of these (75.6%) had lasting  improvement in spasticity and improved motor control. The parents reported positive changes in balance  and “intelligence with reduced frequency of seizure activity.” Results of a continuation of this work in  Brazil were presented by in 2001 at the 2nd International Symposium on Hyperbaric Oxygenation and the  Brain Injured Child held in Boca Raton, Florida, to include 2,030 patients suffering from childhood chronic  encephalopathy that had been treated since 1976, 232 of whom were evaluated with long-term follow-up;  age ranged from 1 to 34 years. The improvements were noted as follows: 41.81% decreased spasticity,  18% noted global motor coordination improvement. Improvements were also noted in attention: 40.08%,  memory, 10.77%, comprehension, 13 .33%, reasoning, 5.60%, visual perception, 12.93%, sphincter  control, 6.46%. It was concluded from this study that HBOT therapy should be instituted as early as  possible in such cases.

Another presentation at the 2nd International Symposium was a study by Chavdarov, Director of the  Specialized Hospital for Residential Treatment for Rehabilitation of Children with Cerebral Palsy in Sofia,  Bulgaria, where HBOT had been considered an important part of the management of children with CP  since 1997. This study included 50 children with distribution of various types as follows: spastic Cerebral  Palsy (n = 30), ataxic/hypotonic cerebral palsy (n = 8), and mixed cerebral palsy (n = 12). Measurements  included motor ability, mental ability, functional development, and speech. Overall psycho-motor function  (single or combined) improved in 86% of the patients following 20 HBOT sessions at 1.5-1.7 ATA lasting  40-50 min once daily.

The first North American case of Cerebral Palsy treated with HBOT was in 1992. The case was presented  by Paul Harch at the Undersea and Hyperbaric Medical Society meeting in 1994 (Harch 1994). In 1995,  Richard Neubauer began treating Cerebral Palsy using HBOT. Because of the growing worldwide  anecdotal reports, a small pilot study of HBOT therapy in cerebral palsy children was conducted in the UK  in 1995, which showed similar improvements in a group of seriously brain-injured children and led to the  foundation of the Hyperbaric Oxygen Trust, a charity to treat Cerebral Palsy and the brain injured  children. The Trust, which has since changed its name to Advance, has treated over 350 patients, though  no scientific appraisals have been published. Positive anecdotal reports of its use in cerebral palsy  started to accumulate. As more HBOT treatment clinics for Cerebral Palsy opened in the United States

and Canada, further studies were conducted. It is estimated that over 5000 children with Cerebral Palsy  have been treated worldwide with HBOT.

Published Clinical Trials 

In 1999 the first pilot study in the use of HBOT in Cerebral Palsy was published (Montgomery et al 1999).  This study involved 23 children (10 female, 15 male; age range 3.1 to 8.2 years) with spastic diplegia.  Absence of previous surgical or medical therapy for spasticity was one of the prerequisites for inclusion  as well as a 12-month clinical physiotherapy plateau. The study was performed at McGill University  Hospital’s Cleghorn Hyperbaric Laboratory in a monoplace chamber at 1.75 ATA (95% oxygen) for 60 min  daily and at the Rimouski Regional Hospital in a multiplace chamber ( 60 min at 1.75 ATA twice daily) for  20 treatments in total. Assessments, pre- and post-treatment, included gross motor function  measurement (GMFM), fine motor function assessment (Jebsen’s Hand Test), spasticity assessment  (Modified Ashworth Spasticity Scale) as well as parent questionnaire and video analysis. Results  following treatment were an average of 5.3% improvement in GMFM and a notable absence of  complications or clinical deterioration in any of the children. “Cognitive changes” were observed, but  these were nonspecific. Video analysis was also positive. The obvious flaws of this study were the lack of  placebo control and the application of two different HBOT protocols. The assessment tools utilized also  had inherent variations. Montgomery achieved improvement in Cerebral Palsy children using 20  treatments at 1.66 ATA oxygen (1.75 ATA 95% O2)/60 min), but the children experienced rapid  regression of neurological gains after cessation of treatment. The number of treatments was inadequate  as the authors of this chapter had recommended 40 treatments at 1.5 ATA/60 min, because consolidation  of the gains does not occur until 30 to 35 treatments. This first study, however, provided useful data  regarding the potential efficacy of HBOT therapy and provided the justification for a larger controlled,  randomized study.

The results of just such a prospective, hyperbaric-air controlled, randomized multicenter study have been  published “with intriguing results” (Collet et al 2001). This study included 111 Cerebral Palsy children  (ages 3-12 years) that were randomized into two groups: receiving either 1.75 ATA 100% oxygen or 1.3  ATA room air (the equivalent of 28% oxygen at 1 ATA) for 1 h for a total of 40 treatments. Gross and fine motor function, memory, speech, language, and memory were assessed. Improvement in global motor  function was 3% in the hyperbaric air group and 2.9% in the hyperbaric-oxygen-treated group. Although  the results were statistically similar in both groups, the HBOT-treated group had a more rapid response  rate in the more severely disabled children. Cognitive testing was performed on a subset of the preceding  study to investigate the effect of HBOT on cognitive status of children with CP (Hardy et al 2002). Of the  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 HBOT or sham treatment over a 2-month period. Children in the active treatment group were exposed for 1 h to 100% oxygen at 1.75 atmospheres absolute (ATA), whereas 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. Unfortunately, the Collet study increased the pressure to 1.75 ATA of 100% oxygen for 60 min (40  treatments) and to 1.3 ATA in the control group breathing air for 60 min, i.e., a 30% increase in oxygen for  the controls. This dose of HBOT had not been used previously in Cerebral Palsy patients and was  possibly an overdose (Harch 2001) and likely inhibited the HBOT group’s gains. Evidence for this was  seen in the GMFM data where five of the six scores increased in the HBOT group from immediate post  HBOT testing to the 3-month retest versus three of six scores in the controls. Some of the negative  effects of 1.75 ATA likely had worn off by this time. Results of the Collet study showed significant  improvements in both groups, but no difference between groups. The serendipitous flaw in the study was  the 1.3 ATA air control group, which also improved significantly. This underscored the fact that the ideal  dose of HBOT is unknown in chronic pediatric brain injury, but it suggested that oxygen signaling may  occur at very low pressures. Mild HBOT therapy can be effective in improving SPECT as well as attention

and reaction times (Heuser & Uszler 2001). Therefore, the beneficial effect in patients described by Collet  and colleagues is probably related to the beneficial effects of slightly pressurized air rather than to the act  of participating in the study. In addition a biphasic sham pressurization, which is highly recommended for

a control group, was not used in this study. The duration of this study was only 2 months. Perhaps this  length of time is not sufficient for evaluating neuropsychological effects of HBOT in a chronic neurological  condition.

The controversy regarding this study will undoubtedly take a long time to resolve, but it has already  begun to raise some very important issues and some very important questions about the validity of “mild”  HBOT (1.3-1.35 ATA air or the same pressure supplemented with oxygen concentrator). The first issue is  that 1.3 ATA ambient air was not an inert or true placebo, but had a real effect on the partial pressure of  blood gases and perhaps other physiological effects as well. Compressed air at 1.3 ATA increases the  plasma oxygen tension from 12.7 kPa (95 mmHg) to 19.7 kPa (148 mmHg), and the increase of a  concentration of a reactive substrate by 50% is substantially notable. Rather than answer the question of  effectiveness of HBOT in CP the Collet study and its offspring Hardy (2002) substudy confused the  scientific community not familiar with hyperbaric oxygen. The unequivocal finding of these studies is that  both pressure protocols achieved statistically significant objective neurocognitive gains, a phenomenon  that cannot be attributed to placebo. This reinforced the findings of the other non-controlled studies in the  chronic category above, and was strengthened by the studies using functional brain imaging as surrogate  markers (Harch 1994a, Neubauer 2001, and Golden et al 2002).

Unpublished Studies 

The Cornell Study 

Upon the urging of interested parents, Dr. Maureen Packard of Cornell University in New York City  agreed to perform such a study. This study was randomized to immediate and delayed (6 months later)  treatment with HBOT (the delayed treatment group to serve as an untreated control group). Age range  was 15 months to 5 years with moderate to severe Cerebral Palsy and patients were given 40 1-h  sessions at 1.5 ATA, once a day, 5 days a week for 4 weeks. The study population included 26 children  with cerebral palsy secondary to prenatal insults, premature birth, birth asphyxia, and post-natal  hemorrhage. The average age of enrollment was 30 months. Nine patients presented with cortical visual  impairment. Assessment was neurodevelopmental, Bayley II (cognitive), Preschool Language Scale,  Peabody Motor Scale, Pediatric Evaluation of Disabilities Inventory(PEDI), parental report of specific skills  including mobility, self-care and social interaction. Final assessments were available on 20 subjects. The  only side effects of the study were barotrauma in nine children requiring placement of a ventilation tube or  myringotomy.

Assessments were performed at four time points: enrollment (Tl), after the immediate group had received  treatment (T2), prior to the delayed groups’ HBOT therapy 5 months after enrollment (T3), and after the  delayed groups’ treatment (T4). There was a significant difference (p < 0.05) in the improvement of scores  on the mobility sub-domains for the time period T2 minus Tl in favor of the immediately treated group. For  the period T4 minus T3 there was a trend favoring the recently treated delayed group and a trend in the  social function subdomain in the more recent treated group. Parental diaries over the month of treatments  demonstrated 83% marked improvement in mobility, 43% marked increase in attention, and 39% marked  increase in language skills. Overall, there was some improvement in mobility in 91%, in attention in 78%,  in language in 87%, and in play in 52%. One family saw no improvement and six families minimal  improvement for a total of 30%. Five families (22%) reported major gains in skills, and 11 families  reported modest gains (48%). Four of the nine children with cortical visual impairment had improvement  in vision noted by families, vision therapists, and ophthalmologists. There was no statistical difference in  Peabody or Bayley II scores on blinded assessment.

Their conclusions at 6-month post-interview were that although changes in spasticity may diminish over  time, improvements in attention, language and play were sustained. ‘”This increase in attention is  particularly important for children must be aware’ in order to learn. This represents a direct impact on  cognitive functioning. The main differences between HBOT and traditional therapies are the rapid gains

over time and the impact on cognitive skills, which, in general are not improved by physical, occupational  and speech therapies.” This study was presented At the University of Graz, on 18 November 2000.

The United States Army Study on Adjunctive HBOT 

Treatment of Children with Cerebral Anoxic Injury 

Shortly after the previous studies were begun, the US Army conducted a small study on functional  outcomes in children with anoxic brain injury. Baseline and serial evaluations showed improvement in  gross motor function and total time necessary for custodial care in nine children with Cerebral Palsy.  Eight volunteer (parental) subjects with varying degrees of Cerebral Palsy and one near-drowning victim  were included in this investigation. Of the Cerebral Palsy cases studied, the mean age was 6.4 years  (range 1.0- 16.5 years), and the near drowning patient was 5.6 years of age seen 1 year post incident.  Pretreatment evaluation included gross motor function ( GMPM, lying, rolling, crawling and kneeling,  sitting, standing and walking, running, and jumping), the Modified Ashworth Scale (MAS) for spasticity,  rigidity, flexion/extension, the Functional Independence Measure for Children (WeeFIM) regarding self care, sphincter control, transfers, locomotion, communication and social cognition, video, 24-h time  measure, parental questionnaire, and single photon emission computerized tomography (SPECT)  scanning. Testing was conducted every 20 treatments with the exception of SPECT and parental  questionnaire which were completed at 40 and 80 sessions.

All subjects received 80 HBOT treatments in a multiplace chamber (100% oxygen) at 1.75 ATA (60 min  for each session) daily (Monday to Friday) for 4 months. Each patient served as his or her own control as  compared to the baseline scores. Improvements in GMFM in the categories of lying and rolling, crawling  and walking, sitting and walking, running and jumping were statistically significant (p < 0.05) . The total  time necessary for parental care also showed a statistically significant improvement (p < 0.03%) in  reduction of custodial time required. In the parental questionnaire, overall improvement was indicated  through the end of the study, including other assessments not included in the survey. Three children  demonstrated improved swallowing function and were able to ingest a variety of liquids and foods; there  was reduction in strabismus in two subjects, nystagmus was resolved in one participant, and one patient  experienced complete resolution of a grade 3 vesicoureteral reflux, obviating the need for surgery.  Unfortunately, the SPECT scan results were omitted due to multiple technical and procedural problems.

Overall improvement was 26.7% at 30 treatments, up to 58.1% at 80 treatments. Their conclusions were  that HBOT therapy seemed to effect overall improvement in Cerebral Palsy (with little response in the  near-drowning case), although the optimum number of treatments remained undetermined, since the  improvements were noted at the end of the study. They advised further research and follow-up studies to  determine the true potential of HBOT for children with anoxic injury and Cerebral Palsy.

Ongoing Studies in Hyperbaric Oxygen Therapy  Treating Cerebral Palsy 

Studies of the use of mild HBOT, hyperbaric air, supplemental oxygen, and higher pressures of HBOT  must be continued to eventually determine the ultimate benefits for cerebral palsy and to identify the  subgroups of patients who may benefit from each. Investigations of mild HBOT therapy are currently  ongoing in Russia, the United States, and South America. Up to April 2003, the Ocean Hyperbaric  Neurologic Center (Fort Lauderdale, Florida) has treated over 600 children suffering from Cerebral Palsy  and brain injury. Analysis of these cases has not yet been completed. Another 200 children with Cerebral  Palsy and a large variety of neurological disorders have been treated at the Harch Hyperbaric Center in  New Orleans (Louisiana, USA). One case is shown here as an example.

HBOT in the Management of Cerebral Palsy  Case Reports 

Patient 1: Cerebral Palsy

The patient is a 2-year-old boy whose twin died in utero at 14 weeks. He was delivered at term by  vacuum extraction and developmental delay was detected at the age of 4- 5 months. He was diagnosed  as a case of cerebral palsy. At 2 years of age SPECT brain imaging was performed and showed a  heterogeneous pattern of cerebral blood flow. The patient underwent a course of twice daily, 5 days/week  HBOT treatments in blocks of 50 and 30 treatments. At the conclusion of treatments he showed  improvement in spasticity, speech, chewing/swallowing, cognition, and ability to sit in his car seat and  stroller for prolonged periods. Repeat SPECT brain imaging showed a global improvement in flow and  smoothing to a more normal pattern consistent with the patient’s overall clinical improvement. The two  SPECT scans are shown side by side in Figure 21.1. Three dimensional reconstructions of the two scans  are shown in Figures 21.2 and 3.

Patient 2: Cerebral Palsy 

The patient is an 8-year-old boy with a history of cerebral palsy. He had spastic diplegia secondary to  premature birth from a mother with eclampsia. Patient was delivered by emergency Cesarean section at  27 weeks when his mother developed seizures. APGARS scores were 7 and 8. The patient spent 5  months in the hospital primarily because of feeding problems. The patient did not achieve normal  milestones and developed infantile spasms at 2 years of age. Baseline SPECT brain imaging (Figure  21.4) showed a mildly/moderately heterogeneous pattern and reduction of blood flow. Three hours after a  single HBOT session at 1.5 ATA for 60 min, repeat SPECT showed global improvement and smoothing to  a more normal pattern in Figure 21.5. The patient underwent a course of 80 HBOT sessions (1.5 ATA/60  min) over the next 6 months in two blocks of treatment (twice daily, 5 days/week x 40, then once-daily 5  days/week x 40), and showed improvement in his impulsive inappropriate behavior, motor function,  vision, and constipation. Repeat SPECT brain imaging reflected these neurological gains (Figure 21.6),  showing generalized improvement in cerebral blood flow and pattern. Three-dimensional surface  reconstruction of Figures 21.4, 21.5, and 21.6 are presented in Figures 21.7, 21.8, and 21.9, respectively.  While there is a global increase in blood flow, the most significant relative increase in flow is to the  temporal lobes as shown in the three-dimensional figures.

All SPECT brain imaging was performed on a Picker Prism 3000 at West Jefferson Medical Center. All  scans were identically processed and three dimensional thresholds obtained by Phillip Tranchina.  Pictures of the scans in the above figures were produced by 35 mm single frame photography under  identical lighting and exposure conditions.

Figure21.1

SPECT brain imaging transverse images of baseline pre-HBOT study on the left and after 80 HBOT  treatments on the right. Note the global increase in flow and change from heterogeneous to the more  normal homogeneous pattern. Slices begin at the top of the head in the upper left corner and proceed to  the base of the brain in the lower right corner of each study. Orientation is standard CT: the patient’s left  is on the viewer’s right and vice versa with the patient’s face at the top and the back of the head at the  bottom of each image. Color scheme is white, yellow, orange, purple, blue, black from highest to lowest  brain blood flow.

Figure 21.2

Three-dimensional reconstruction of baseline SPECT study in Figure 21.1 (study on left side). Note  reduction in flow to both temporal lobes, inferior frontal lobes, and the brainstem (central round structure  between the temporal lobes below the large colored area-frontal lobes).

Figure 21.3

Three-dimensional reconstruction of SPECT after 80 HBOT treatments (right hand study in Figure 21.1)  Note the increased flow to the temporal lobes, inferior frontal lobes, and brainstem.

Figure21.4

Sagittal slices of baseline SPECT brain imaging through the center of the brain. Note the heterogeneous  pattern of blood flow. Slices proceed from the right side of the head in the upper left corner to the left side  of the head in the lower right corner. The front of the brain (face) is on the left side and the back of the  brain (back of the head) is on the right side of each slice.

Figure21.5

Sagittal slices of SPECT three hours after a single 1.5 ATA/60 min HBOT treatment. Note the generalized  increase in flow and smoothing to a more normal pattern.

Figure 21.6

Sagittal slices of SPECT after 80 HBOT treatments. Note the marked increase in flow and smoothing of the pattern compared to the baseline in Figure 21.4.

Figure21.7

Three-dimensional surface reconstruction of SPECT in Figure 21.4. Note reduction in flow to the temporal  lobes and coarse appearance of flow to the surface of the brain.

Figure 21.8

Three-dimensional surface reconstruction of SPECT in Figure 21.5. Note improvement in flow to the  temporal lobes and slight smoothing of flow to the surface of the brain.

Figure21.9

Three-dimensional surface reconstruction of SPECT in Figure 21.6. Note improvement in flow to the  temporal lobes and slight smoothing of flow to the surface of the brain.

Conclusions 

Cerebral palsy is the result of a large variety of causes, and it is difficult to design trials with subgroups of  patients with similar pathomechanisms. The results of several studies have been presented including one  controlled study that did not show improvement in neuropsychological status. A large number of patients  have been treated, and some have been followed up for long periods to document improvement that can

be correlated with imaging studies. Cognitive improvement is usually seen by the 40th treatment in  patients with chronic neurological disorders such as Cerebral Palsy (Golden et al 2002). Controlled  studies of HBOT in CP should continue, but they may not resolve all the issues. The extensive  experience of open clinical studies with some good results cannot be ignored. In a condition where there  is nothing else to offer, HBOT therapy is considered to be worth a trial. The concept of personalized  medicine as described in Chapter 38 can be applied to HBOT treatments in Cerebral Palsy. One cannot  recommend a standard protocol, but the ideal treatment schedule should be determined for each patient  including the pressure, dose, and duration of treatment. It may be possible to identify responders early on  in the treatment. Although molecular diagnostic procedures may be used in the investigation of patients  with Cerebral Palsy, genotyping and gene expression studies have not yet been done as a guide to  treatment but this is a promising field for future investigation (Jain 2003i).