Dear Sir,

We thank Dr Nadeem, for highlighting that the clinical features of drowsiness and infant focal seizures in our case report indicates that early treatment for viral/herpes encephalitis was an imperative.

We would like to reassure Dr Nadeem that our infant did indeed receive a combination of early intravenous antiviral treatment (acyclovir) and antibiotics (cefotaxime and amoxicillin) and this was continued until final viral/bacterial PCR and CSF culture results were obtained. The use of acyclovir and amoxicillin was omitted from the original report due to word count limitations.

Viral PCR tested was negative for a range of viruses including herpes simplex (HSV). Although PCR assay is an important diagnostic modality for viral encephalitis HSV, we would add that due to focal seizures, our infant case received investigations and treatment as per national (1) and local guidelines: immediate brain CT imaging was performed to exclude neurosurgical conditions, and a later cranial MRI scan did not show selective damage to the mesial temporal lobe structures or the hippocampus. In addition, an early electroencephalogram (EEG) was normal. The EEG severity and the presence of epileptic seizures at the initial presentation would be significant indicators for predicting the 6-month clinical outcome in patients with HSE.

The seriousness of HSV CNS infections suggests that clinicians maintain a high index of suspicion to initiate evaluation under suitable circumstances. We are grateful to the Editors for now publishing Dr Nadeem’s response to our letter to highlight this to our readers.

References
(1) Meningitis Research Foundation (MRF). Management of Bacterial Meningitis in infants <3 months (Neonatal Algorithm) [PDF]. London, United Kingdom: Meningitis Research Foundation (MRF); 2017 [updated Nov 2017]. Available from: https://www.meningitis.org/getmedia/75ce0638-a815-4154-b504-b18c462320c8....

I refer to the paper published by Palmer et al in Archives Diseases Childhood March 20181 that states the recommendation to avoid tramadol when breastfeeding and the contraindication to its use in children (including neonates) is inappropriate in their view. 1
I disagree with the authors that tramadol is a safe for babies of breastfeeding mothers. Their conclusion, in my opinion, is premature and not adequately evidence-based. While they acknowledge, the US Food and Drug Administration (FDA) reported cases, they ignore the serious warnings by both Manufacturer and FDA about administering tramadol to children and breast-feeding mothers. There is increasing concern that narcotics used for treating pain in breastfeeding mothers may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the FDA and the American College of Obstetricians and Gynecologists (ACOG) advocate against the use of codeine and tramadol in women who are breastfeeding because their babies may suffer adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5 Patient safety should be foremost in our minds in making any recommendations that are contrary to Manufacturer, FDA, and AAP recommendations. It would be difficult to justify use of tramadol in a breastfeeding mother in the event of litigation arising from adverse effects of tramadol in the baby, when safer alternatives are available.
MANUFACTURER WARNING
In March 2008, Janssen Ortho, the manufacturer of tramadol (ULTRAM®) stated that the effects of tramadol on growth and functional maturation of child, and safety in infants and newborn has not been studied and it is not recommended for use in the pediatric population. It issued the following information concerning tramadol:
• LABOR AND DELIVERY
1. ULTRAM® should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn.
2. Tramadol crosses the placenta. The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.
• NURSING MOTHERS
ULTRAM® is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours, post-dose was 100μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
• PEDIATRIC USE
The safety and efficacy of ULTRAM® in patients under 16 years of age have not been established. The use of ULTRAM® in the pediatric population is not recommended. 6

FDA WARNINGS
1. In 2013, FDA placed restrictions on its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.7
2. FDA reviewed adverse event reports submitted to it from January 1969 to May 2015, and identified 64 cases of serious breathing problems, including 24 deaths, with codeine-containing medicines in children younger than 18 years. As this included only reports submitted to FDA, there may be additional cases about which FDA is unaware. FDA also identified nine cases of serious breathing problems, including three deaths, with the use of tramadol in children younger than 18 years from January 1969 to March 2016. Most of the serious side-effects with both codeine and tramadol occurred in children younger than 12 years, and some cases occurred after a single dose of the medicine.8
3. On July1, 2015, FDA issued warning about the potential risks of using codeine cough-and-cold medicines in children on July 1, 2015,4 and in September 21, 2015, FDA issued warning on the risks of using the pain medicine tramadol in children aged 17 and younger issued on September 21, 2015. 9
4. On 1-11-2018, the FDA restricted the use of codeine and tramadol medicines in children as these medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. FDA warned against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants. 10
5. Use of tramadol during pregnancy could make the baby dependent on the drug and cause Life-threatening withdrawal effects that may necessitate medical treatment for several weeks. 11
Additional concerns relating to the use of tramadol are suicidal thoughts and suicide attempts have emerged. In the article: Tramadol and Suicide attempt - from FDA reports, dated November 8, 2018, suicide attempt is found among people who take Tramadol, especially female, 40-49 old, who have been taking the drug for < 1 month. In the study based on reports of 102,114 people who have side effects when taking Tramadol from FDA, and is updated regularly. 102,114 people reported side effects when taking Tramadol. Among them, 765 people (0.75%) have attempted suicide. Suicide attempts are reported in children from the age of 10 years.12
In the light of the above data, there does not appear to be adequate evidence to support Palmer et al.’s contention that both Manufacturer and FDA recommendation to avoid use of tramadol when breastfeeding and contraindication to its use in children (including neonates) should be ignored.1 The AAP, the FDA, and the ACOG recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5
Practice of medicine should be evidence-based. Patient safety comes foremost. Safer alternatives to tramadol are available. Acetaminophen and/or ibuprofen is recommended for pain management in women who are breastfeeding. If narcotic treatment is considered necessary, the lowest effective dose of morphine for the shortest time possible could be prescribed. 2
REFERENCE
1. Greta M Palmer, Brian J Anderson, David K Linscott, Michael J Paech, Karel Allegaert. Tramadol, breast feeding and safety in the newborn. (http://dx.doi.org/10.1136/archdischild-2017-313786).
2. Robert L. Barbieri. Editorial. Stop using codeine, oxycodone, hydrocodone, tramadol, and aspirin in women who are breast-feeding. OBG Manag. 2017 October;29(10):8-10,12. https://www.mdedge.com/obgyn/article/148018/obstetrics/stop-using-codein....
3. Sachs HC; Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796–e809.
4. US Food and Drug Administration. FDA Drug Safety Communication. FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD: US Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/ucm118113.htm. Published April 2017.
5. Practice advisory on codeine and tramadol for breast feeding women. American College of Obstetricians and Gynecologists website. https://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-A.... Published April 27, 2017.
6. ULTRAM® (tramadol hydrochloride) Tablets. Full Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033...
7. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. (2-20-2013). https://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf - accessed February 16, 2019.
8. FDA Drug Safety Communication: FDA evaluating the potential risks of using codeine cough-and-cold medicines in children. https://www.fda.gov/Drugs/DrugSafety/ucm453125.htm
9. FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger. https://www.fda.gov/Drugs/DrugSafety/ucm462991.htm (9-21-2015).
10. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm (1-11-2018)
11. Kaci Durbin. (Updated 29-12-2018) Tramadol. https://www.drugs.com/tramadol.html
12. Tramadol and Suicide attempt - from FDA reports. http://www.ehealthme.com/ds/tramadol/suicide-attempt/

Conflict of Interest
None declared
Professor Dr. Davendralingam Sinniah

In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.

In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.

References.
1. Paes B, Mitra S. Palivizumab for Children with Down syndrome: is the time right for a universal recommendation? Arch Dis Child doi:10.1136/archdischild-2018-316408
2. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009; 360: 588-98.
3. Hall CB, Weinberg GA, Blumkin AK, et al. Respiratoy syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 2013; 132: e341-8.
4. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531-7.
5. Olchanski N, Hansen RN, et al. Palivizumab prophylaxis for respiratory syncytial virus: examining the evidence around value. Open Forum Infectious Diseases OFID 2018. Doi: 10.1093/ofid/ofy031.
6. Blanken MO, Frederix GW, et al. Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants. Eur J Pediatr 2018; 177: 133-44 Doi.org/10.1007/s00431-017-3046-1.

Many thanks for your response to the editorial ‘What are you looking at?’, which highlights some important principles for this extensively studied research area (despite being a relatively new field in healthcare) [1]
Despite the emergence of new methods to analyse gaze behaviour terminology has not been revised to reflect scientific advances. A recent article by Hessels et al. outlined significant inconsistencies in the definitions of fixations and saccades held by eye movement researchers and highlighted the conceptual confusion surrounding these terms.[2]

The term saccade is derived from the French for ‘jerk’. The phrase appears to have been coined by Emile Javal, a French ophthalmologist, in the 1800’s.[3] By 1916 it had been accepted into the English literature.[4]

Saccades are frequently defined in the literature as rapid, ballistic movements of the eyes that abruptly change the point of fixation.5 Definitions have included;

‘Rapid eye movements used to voluntarily move gaze from one target of interest to another.’[6]

‘Ballistic movements, 20-150ms long, reaching a velocity up to 800°/s. They direct the eye so that external visual objects are projected onto the fovea.’[7]

‘Rapid eye movements used in repositioning the fovea to a new location in the visual environment.’[8]

The term ballistic refers to the fact that the saccade-generating system cannot respond to subsequent changes in the position of a target during the course of an eye movement. If the target was to move a second saccade would be required to correct the error. Acceptance of such definitions suggests that the primary function of saccades is to bring objects of interest onto or near the fovea. The fovea operates at high resolution and, although it only provides 1-2 degrees of vision, it plays a central role in resolving objects. Whilst saccades assist vision by moving the eyes rapidly to various objects of interest so that parts of a scene can be seen in greater resolution, there is probably little or no meaningful information absorbed during the saccadic movements.

However, other papers have been more liberal in their definitions defining a saccade as the inter-fixation interval.[9,10] These definitions imply that a saccade is any movement outside of periods of fixation. This definition will therefore also capture smooth pursuit movements (slower tracking movements), vestibulo-ocular movements (stabilise eyes relative to external world) and visual scanning movements. Consequentially during saccades defined in this manner visual information may be absorbed both consciously and/or subconsciously including, for example, the presence or absence of pathology, as outlined in your letter.

As the field of eye tracking research in healthcare expands it is imperative that authors explicitly define their key measurements, including fixations, dwell time and saccades, to allow accurate interpretation and comparison of results and to minimise ambiguity. Without this it will be difficult to examine the links between visual scanning patterns and decision making. For example it may be hypothesised that subconscious visual scanning behaviours may be a clue to understanding the concept of gut feeling, whereby a particular clinician sees things perhaps others do not.

We certainly agree greater understanding of saccade pathways should undoubtedly be an area for future research in eye tracking studies in healthcare.

References:
1. Roland D. What are you looking at? Arch Dis Child 2018; 103: 1098-1099.

2. Hessels RS, Niehorster DC, Nyström M, Andersson R, Hooge IT. Is the eye-movement field confused about fixations and saccades? A survey among 124 researchers. Royal Society open science. 2018 Aug 29;5(8):180502.

3. Javal E. Essai sur la physiologie de la lecture. Annales d'Ocilistique. 1878;80:61-73.

4. Wade NJ. Scanning the seen: Vision and the origins of eye-movement research. In Eye Movements 2007 (pp. 31-63).

5. Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, Williams SM. Neuroscience 2nd Edition. Sunderland (MA) Sinauer Associates.

6. Ramat S, Leigh RJ, Zee DS, Optican LM. What clinical disorders tell us about the neural control of saccadic eye movements. Brain. 2006 Nov 21;130(1):10-35.

7. Falkmer T, Dahlman J, Dukic T, Bjällmark A, Larsson M. Fixation identification in centroid versus start-point modes using eye-tracking data. Perceptual and motor skills. 2008 Jun;106(3):710-24.

8. Duchowski AT. Eye tracking methodology. Theory and practice. 2007;328.

9. Holmqvist K, Nyström M, Andersson R, Dewhurst R, Jarodzka H, Van de Weijer J. Eye tracking: A comprehensive guide to methods and measures. OUP Oxford; 2011 Sep 22.

10. Larsson L, Nyström M, Andersson R, Stridh M. Detection of fixations and smooth pursuit movements in high-speed eye-tracking data. Biomedical Signal Processing and Control. 2015 Apr 1;18:145-52.