Early Treatment with Growth Hormone (GH) and Rehabilitation Recovers Hearing in a Child with Cerebral Palsy

Round 1

Reviewer 1 Report

Please, include the text editing provided, and submitted as an E-mail of the paper with the suggested changes in red.

This is a Clinical Case. The authors should include in the conclusion that further studies in a group of patients would be necessary to confirm the results of this report.

I suggest that the authors present the MRI pictures before and after treatment. This would objectively support the therapeutic effect of the GH.

Suggest the authors review and add the following reference: Varela-Nieto et al. IGF-I and hearing loss: molecular clues and clinical implications. Pediatric Endocrinology Reviews, 10(4) July 2013.

Author Response

Please, include the text editing provided, and submitted as an E-mail of the paper with the suggested changes in red.

Changes have been made and appear in red color. 

This is a Clinical Case. The authors should include in the conclusion that further studies in a group of patients would be necessary to confirm the results of this report.

Done. 

I suggest that the authors present the MRI pictures before and after treatment. This would objectively support the therapeutic effect of the GH.

I do agree with you, but it has been impossible to obtain the MRIs. We have only the reports of them. Most likely it is due to the fact that the child was born in a private hospital and they deny to give us a copy of these MRIs. 

Suggest the authors review and add the following reference: Varela-Nieto et al. IGF-I and hearing loss: molecular clues and clinical implications. Pediatric Endocrinology Reviews, 10(4) July 2013.

It has been included now. Thank you for your suggestions.

Reviewer 2 Report

The authors present an interesting hypothesis supported by animal data that a hearing disorder could be improved by growth hormone. But I’m not totally convinced that this is the only possible causal relation in this case. Therefore I would be a little bit more cautious in the discussion and include other points. Some information and discussion about potential risk factors are missing, i.e. could an infection be the cause for the symptoms at the age of three month for the initially after birth obviously healthy child with an Apgar of 9/10 and normal brain ultrasound, EEG, and metabolic and otoacoustic emission tests? Was there a treatment with antibiotics? On the other hand a mild hyperbilirubinemia without necessary treatment is not a risk factor for a hearing disorder (JCIH Year 2007 Position Statement).

The treatment with melatonin is not discussed at all.

Otherwise I have only some smaller points to recommend:

Sometimes the English language could be improved (i.e. line 53-56)

Line 33: To my knowledge the risk factor to have a hearing loss is ten times higher for children from ICU than for healthy newborns and not only doubled. This is also in contrast to line 39

Line 136 and table 1 and 2: The start of treatment at "admission" and "discharge" should be replaced by the infant’s age. Was the age corrected for the slightly premature infant?

Line 189: All abbreviations in the manuscript should be explained (i.e. EINA?)

Line 190/212: With a hearing level of 50dbHL it is a moderate and not profound hearing loss.

Table 1: I’m not sure if this table is necessary at all but I think it is enough to report only the abnormal values and all the abbreviations should be explained. Is there an explanation for the high levels of triglycerides?

Table 2 and figure 2 (GMFM-88): It would be helpful to have information about the normal values. The Abbreviation GMFM should be explained next to the table

To my opinion chapter 2.3.1- 2.3.4 could be shortened as the kind of therapy is not further discussed and is not the most important point for this case report.

Line 339: From the data I would not say it is clear that the GH was the reason for the improvement- maybe it’s better to say it is possible

Line 342: is the beginning of the treatment with 3.5 months of age early?

Line 346-348: this hypothesis is not supported by the data and should be omitted

Overall a very interesting hypothesis that needs more studies to be confirmed

Author Response

Reviewer 2

Comments and Suggestions for Authors

The authors present an interesting hypothesis supported by animal data that a hearing disorder could be improved by growth hormone. But I’m not totally convinced that this is the only possible causal relation in this case. Therefore I would be a little bit more cautious in the discussion and include other points. Some information and discussion about potential risk factors are missing, i.e. could an infection be the cause for the symptoms at the age of three month for the initially after birth obviously healthy child with an Apgar of 9/10 and normal brain ultrasound, EEG, and metabolic and otoacoustic emission tests? Was there a treatment with antibiotics? On the other hand a mild hyperbilirubinemia without necessary treatment is not a risk factor for a hearing disorder (JCIH Year 2007 Position Statement).

The child was not treated with antibiotics, there were no infections. I do agree with you about hyperbilirubinemia, in fact, the child was not treated for it, it has been deleted now.  With regard to the Apgar, health, etc, we cannot be sure of these health reports (Apgar, tests, etc), because the patient was born in a private secondary hospital and it is an usual practice in some bad hospitals to change birth data (if they are abnormal) for avoiding judicial problems. Unfortunately, we know many cases of children with CP that we treated and we treat, due to delivery problems, with medical reports indicating full normality at birth. However, when he was discharged from the hospital where he was born he was diagnosed with cerebral palsy. Why if everything was normal? we don’t know but we suspect that the initial reports were not correct. In fact, this child before coming to us had been examined in one of the better Spanish hospitals for children and the prognosis was very bad. We believe that the main reason for his problems was thesustained hypoglycemia after birth and the fetal distress (for developing CP), but we don’t have any explanation for it, neither how it was controlled (rather it was uncontrolled). 

The treatment with melatonin is not discussed at all.

It has been discussed now, although we usually administer melatonin to any patient with brain damages, mainly for controlling the inflamed microglia. This had been written in the first manuscript we sent, but now more information has been given. 

Otherwise I have only some smaller points to recommend:

Sometimes the English language could be improved (i.e. line 53-56)

It has been corrected now, it was a mistake. 

Line 33: To my knowledge the risk factor to have a hearing loss is ten times higher for children from ICU than for healthy newborns and not only doubled. This is also in contrast to line 39

Corrected  now

Line 136 and table 1 and 2: The start of treatment at "admission" and "discharge" should be replaced by the infant’s age. Was the age corrected for the slightly premature infant?

Line 189: All abbreviations in the manuscript should be explained (i.e. EINA?)

They have been explained now. 

Line 190/212: With a hearing level of 50dbHL it is a moderate and not profound hearing loss.

You are right. It was our mistake because when the child was admitted to our Center, his family said to us that he suffered a profound hearing loss, and the child reacted as if there was an important deafness.  

Table 1: I’m not sure if this table is necessary at all but I think it is enough to report only the abnormal values and all the abbreviations should be explained. Is there an explanation for the high levels of triglycerides?

We wrote all the plasma values during the time of treatment for indicating the lack of negative effects induced by GH or melatonin. Now we corrected this Table. 

We don’t have a reason other tan the kind of nutrition that the mother gave to the child for explaining the high levels of triglycerides. Lastly we convinced her that the nutrition of the baby was very inappropriate. The mother was convinced that giving him high caloric intake (fattty food) would help him to improve. The mother was markedly obese at that time and she continues to be. 

Table 2 and figure 2 (GMFM-88): It would be helpful to have information about the normal values. The Abbreviation GMFM should be explained next to the table. 

The abbreviation GMFM has been explained. 

Normal values in GMFM-88 are difficult to be explained, because they depend on the age of the child analyzed. In this case, the child reached a value similar to the mean observed in normal children aged 0-2 years old. This is now indicated in the Figure 2. 

To my opinion chapter 2.3.1- 2.3.4 could be shortened as the kind of therapy is not further discussed and is not the most important point for this case report.

It has been shortened now, However, take in mind that the child had CP, apart of hearing loss, and I think that it is important that his problems due to the brain affectation have been corrected. This is important, because it indicates that an early treatment after birth may be useful to correct or improve the problems that CP implies.

Line 339: From the data I would not say it is clear that the GH was the reason for the improvement- maybe it’s better to say it is posible

It has been corrected now. 

Line 342: is the beginning of the treatment with 3.5 months of age early?

Yes, it is. In general, GH is used to treat GH deficiency. In this case the hormone is administered around 4 years of age. However, we use the hormone to treat CP. In these cases of CP we try to start with GH as early as possible, given the important neurotrophic effects of the hormone, mainly when the brain is still developing. For instance, we treated a child that suffered a cardiac arrest during 25 minutes in utero and was without electrical activity in the brain at birth. After some minutes of cardiac stimulation some signs of activity appeared in the EEG. He was maintained under vital support and an MRI carried out 15 days later showed an important encephalomalacy and cystic cavities in the brain. His prognosis was mutism, deafness, blindness and spastic tetraplegia. His parents were asked for signing the authorization for disconnecting him from the vital support in the ICU. They denied it and we began to treat the child at 3 weeks of age. Two years later he was a totally normal child. Now he is 8 years old and he is like any child of his age. We published it in a special chapter of InTech Open: Growth Hormone and kynesitherapy in the recovery of brain injuries. 2011. Brain Injury-Pathogenesis, Monitoring, Recovery and Mangament. Currently we are treating a girl born with extreme prematurity; we began to treat her at age 2 months old. Now, almost 2 years later, she walks normally, she speaks, she has a high cognitive level, full normality. These supports our idea that as early the treatment begins better are the results achieved. 

Line 346-348: this hypothesis is not supported by the data and should be omitted

I think that our data, including our previous publications, above indicated, support this affirmation. 

Overall a very interesting hypothesis that needs more studies to be confirmed

I do agree with you. Thank you for your suggestions.

Reviewer 3 Report

Congratulations on a very interesting case presentation.  If this treatment method can be shown to be replicable in other patients that would be very exciting indeed.  

This paper would benefit from an English language review - several minor issues that need attention.  Of note is lines 51 - 55, sentence starting "In addition..."  This sentence is too long, confusing, and should be re-worked.  Also the paragraph starting at line 290 has multiple English errors.  

Some technical questions or observations about the ABR testing.  First, the initial waveforms suggest a conductive hearing loss rather than sensorineural:  grossly delayed wave I, normal interpeak latencies, decent wave morphology - all hallmarks of conductive hearing loss.  Second, there is no evidence that bone conduction ABR testing was performed during the first hearing evaluation (age 2 months) to conclusively exclude middle ear pathology (e.g. effusion).  Later in the paper it is suggested parenthetically that tympanograms were normal at the time of this initial hearing evaluation.  This is vital to the whole premise of this paper:  if conductive hearing loss was conclusively excluded at the first hearing evaluation that needs to be explicitly stated and in detail.  Was bone conduction ABR performed?  Tympanometry?  If tympanometry, was a 1.0 kHz probe tone used as should have been done for a 2-month-old?  Third, was only click ABR performed at each evaluation?  This provides very limited information about hearing thresholds.  Arguably enough to determine approximate degree of hearing loss but this would be much more compelling if we had before and after tone thresholds for at least a couple of frequencies.  Fourth, it is stated (line 96; figures 1 and 3 caption) that "contralateral masking of -30 dB" was used during testing.  Is this really meaning masking of -30 dB or does it mean 30 dB lower than stimulus (i.e. +30 dB SNR)?

Line 86, authors state the infant was 3240 kg birth weight...I think you mean grams rather than kilograms?  

Line 113, what is meant by "auditory follow-up"?

Line 190, authors state the patient initially had "profound hearing loss."  Stated ABR thresholds are 50 dBnHL, considered a moderate hearing loss rather than profound (at least in the U.S.). 

Line 260, authors state that passed newborn hearing screen in light of later hearing loss may reflect a "false positive."  I would suggest that is a false negative hearing screen result.

Overall a well-written paper and a nice summary of the case.  Again potentially very exciting and worthy of much more study.    

Author Response

Congratulations on a very interesting case presentation.  If this treatment method can be shown to be replicable in other patients that would be very exciting indeed.  

This paper would benefit from an English language review - several minor issues that need attention.  Of note is lines 51 - 55, sentence starting "In addition..."  This sentence is too long, confusing, and should be re-worked.  Also the paragraph starting at line 290 has multiple English errors.  

Lines 51-55 have been reduced and corrected.

The paragraph starting at line 290 has been corrected. 

Some technical questions or observations about the ABR testing.  First, the initial waveforms suggest a conductive hearing loss rather than sensorineural:  grossly delayed wave I, normal interpeak latencies, decent wave morphology - all hallmarks of conductive hearing loss.  Second, there is no evidence that bone conduction ABR testing was performed during the first hearing evaluation (age 2 months) to conclusively exclude middle ear pathology (e.g. effusion).  Later in the paper it is suggested parenthetically that tympanograms were normal at the time of this initial hearing evaluation.  This is vital to the whole premise of this paper:  if conductive hearing loss was conclusively excluded at the first hearing evaluation that needs to be explicitly stated and in detail.  Was bone conduction ABR performed?  Tympanometry?  If tympanometry, was a 1.0 kHz probe tone used as should have been done for a 2-month-old?  Third, was only click ABR performed at each evaluation?  This provides very limited information about hearing thresholds.  Arguably enough to determine approximate degree of hearing loss but this would be much more compelling if we had before and after tone thresholds for at least a couple of frequencies.  Fourth, it is stated (line 96; figures 1 and 3 caption) that "contralateral masking of -30 dB" was used during testing.  Is this really meaning masking of -30 dB or does it mean 30 dB lower than stimulus (i.e. +30 dB SNR)?

Yes, there is a delay in wave I and normal wave V latency. According to the literature “sensory hearing loss is characterized by wave I falling outside the normal latency-intensity function. Wave V latency is normal at high intensities, but as the intensity is decreased, it will be prolonged, showing an L-shaped latency-intensity function. The interwaves latencies are either normal or shortened. When we are looking at the degree of hearing loss, we are looking at at where wave V treshold falls”. We think that it was a cochlear hypoacusia not a conductive hypoacusia. 

Yes, tympanograms were performed and were normal. Only click ABR was performed at each evaluation. I do agree with you that more tone frequencies would provide much more information, but they were not done. 

-30 dB was a mistake, now corrected.  

Line 86, authors state the infant was 3240 kg birth weight...I think you mean grams rather than kilograms?  

It was a mistake, now corrected. 

Line 113, what is meant by "auditory follow-up"?

It has been corrected.

Line 190, authors state the patient initially had "profound hearing loss."  Stated ABR thresholds are 50 dBnHL, considered a moderate hearing loss rather than profound (at least in the U.S.). 

It was a mistake based on the initial report of the mother of the child. It was not profound but moderate hearing loss, now corrected. 

Line 260, authors state that passed newborn hearing screen in light of later hearing loss may reflect a "false positive."  I would suggest that is a false negative hearing screen result.

Yes, it was a false negative. 

Overall a well-written paper and a nice summary of the case.  Again potentially very exciting and worthy of much more study.