Ischemic-Hemorrhagic Stroke in New Onset Type 1 Diabetes Mellitus with Diabetic Ketoacidosis in a Two-Year-Old Toddler: The First Reported Case in Indonesia

Round 1

Reviewer 1 Report

Lines 9-10: please change in “Stroke in DKA causes the remaining 10% of intracerebral complications, and is under-recognized because its presentation may be subtle.”

Lines 14-5: I think you can simply say “Computed tomography and angiography revealed subacute ischemic transformative to subacute hemorrhagic stroke”.

Line 17: “…remains…” should be changed in “…remaining…”.

Line 40: the acronym GCS (even if well known), should be explained anyway.

Table 1: if you explain all those acronyms in the footnotes (which is fine), then you should also explain HbA1C, at least.

Revise all the references: you must be consistent with the journal Instructions for Authors

Author Response

Author's Response:

Thank you very much to the editors, and reviewers for their time and valuable insight. I appreciate every single advice that has been given. Please see the specific point-to-point response to the reviewers enclosed below.

Reviewer 1:

Comments 1: Lines 9-10: please change in “Stroke in DKA causes the remaining 10% of intracerebral complications, and is under-recognized because its presentation may be subtle.”

Response 1: Thank you for your valuable suggestion, it was really helpful. I already changed the sentence according to the sentence above in lines 9-10.

Comments 2: Lines 14-5: I think you can simply say “Computed tomography and angiography revealed subacute ischemic transformative to subacute hemorrhagic stroke”.

Response 2: Thank you for the valuable corrections, I have changed the sentence according to your suggestions in lines 14-15.

Comments 3: Line 17: “…remains…” should be changed in “…remaining…”.

Response 3: Thank you for the corrections, I have changed the word in lines 16-17.

Comments 4: Line 40: the acronym GCS (even if well known), should be explained anyway.

Response 4: Thank you for the revision, I have changed the acronym in line 44.

Comments 5: Table 1: if you explain all those acronyms in the footnotes (which is fine), then you should also explain HbA1C, at least.

Response 5: Thank you for the valuable advice, I have attached the explanation of HbA1c in Table 1.

Comments 6: Revise all the references: you must be consistent with the journal Instructions for Authors.

Response 6: Thank you for the suggestion. All of the reference has been edited according to the journal Instructions for Authors.

Reviewer 2 Report

Lines 13,14 “After 14 days of hospitalization, the patient had recurrent seizures and developed left hemiparesis, which was reported to occur earlier.” 

It is not clear what the authors mean.

Line 19 “Cerebral edema as an intracerebral complication of DKA is common,...” It is not common; clinically apparent cerebral edema occurs in 0.5 to 1.0% of DKA events. It is more common than ischemic stroke.

Lines 25,26 Only references 2 and 3 are relevant

Lines 29,30 The incidence of DKA at time of presentation varies widely across the globe. One-third  only applies to certain countries. Add the statement from line 137 “… 71% of T1DM cases in Indonesia were diagnosed at onset with DKA

Lines 30,31 Manifestations of stroke are not “vague”; the neurologic manifestations of brain injury are evident irrespective of age. Brain imaging will reveal the cause.

Line 37 do you mean 1 day before admission to your hospital?

Line 38 can a 2-year-old complain of polyphagia, polydipsia or did the child’s parents observe that the child was more hungry and thirsty?

Line 42 Was a precise blood glucose concentration measured?

Line 43 Lack of vital signs and biochemical parameters at time of presentation is an important omission

Line 47 Where was the central venous catheter placed?  

Line 49 How long did it take for DKA resolve? I presume DKA had resolved but child’s GCS remained abnormal (10). 

Line 51 When was the hemiparesis first observed?

Line 63 Describe neurologic status in more detail.

Table 1 shows markedly increased blood urea nitrogen and creatinine concentrations consistent with kidney injury. The reference range for creatinine is not correct for a 2-year old child.

Likewise AST and ALT concentrations are consistent with liver injury from hypoperfusion (ischemia).

Line 73 PT and aPTT were mildly decreased. Were any other coagulation studies obtained? In addition to severe hypoperfusion of vital organs resulting in ischemia, was there any evidence of a procoagulation diathesis?

Line 122 What does luxury perfusion mean?

Figure 4 is a graphical recapitulation already described and does not add important information.

Line 139 intracerebral complication rate of 0.3%-1% in DKA has been reported from USA and UK but may not be the same in other countries where diabetes is not common and patients typically present late and in severe DKA?

Reference #15 is redundant (see reference #11)

Lines 151-153 None of the references (4,6,12) are actually appropriate to support the statement. Please refer to the primary sources for these observations

Line 158 CVC insertion increases the risk of venous thrombosis. What is the relationship between CVC insertion and cerebral ischemia?

Line 162 Was there laboratory evidence of disseminated intravascular coagulation or is this speculation?

Lines 193,194 There is no doubt this child has type 1 (insulin-dependent) diabetes mellitus. The precise etiology (i.e., is it caused by autoimmunity?) may be uncertain owing to inability to measure pancreatic islet autoantibodies.   

This can be improved

Author Response

Emergency Care and Medicine

Author's Response:

Thank you very much to the editors, and reviewers for their time and valuable insight. I appreciate every single advice that has been given. Please see the specific point-to-point response to the reviewers enclosed below.

Reviewer 2: Comments:

Comments 1: Lines 13,14 “After 14 days of hospitalization, the patient had recurrent seizures and developed left hemiparesis, which was reported to occur earlier.” It is not clear what the authors mean.

Response 1: Thank you for pointing this out. I agree with you that that sentence wasn’t clear enough. I changed the sentence to “The recognition of left hemiparesis was on the 9^th day of hospitalization. After 14 days of hospitalization, the patient had recurrent seizures.” In lines 13-14

Comments 2: Line 19 “Cerebral edema as an intracerebral complication of DKA is common,...” It is not common; clinically apparent cerebral edema occurs in 0.5 to 1.0% of DKA events. It is more common than ischemic stroke.

Response 2: Thank you for the correction. I have changed the sentence to “Cerebral edema is more common than ischemic stroke as an intracerebral complication of DKA.” In lines 18-19.

Comments 3: Lines 25,26 Only references 2 and 3 are relevant

Response 3: Thank you for the correction. The references in lines 25-26 changed into references 1 and 2 in line 25.

Comments 4: Lines 29,30 The incidence of DKA at time of presentation varies widely across the globe. One-third only applies to certain countries. Add the statement from line 137 “… 71% of T1DM cases in Indonesia were diagnosed at onset with DKA.

Lines 30,31 Manifestations of stroke are not “vague”; the neurologic manifestations of brain injury are evident irrespective of age. Brain imaging will reveal the cause.

Response 4: Thank you for your insight. The sentence in lines 28-29 has changed to “In the United States, one-third of T1DM patients are initially diagnosed with diabetic ketoacidosis (DKA) [4]. Meanwhile, in Indonesia, the awareness of T1DM is low, around 71% of T1DM cases were diagnosed at the onset with DKA[5].” In lines 28-30.

The sentence from lines 30-31 has changed into lines 34-35.

Comments 5: Line 37 do you mean 1 day before admission to your hospital?

Line 38 can a 2-year-old complain of polyphagia, polydipsia or did the child’s parents observe that the child was more hungry and thirsty?

Response 5: Thank you for the valuable input. Those complaints were reported a week before the presentation to the emergency department. The complaints of polyphagia and polydipsia were reported by the parents. The word polyphagia and polydipsia was changed according to the lines 40-42.

Comments 6:

Line 42 Was a precise blood glucose concentration measured?

Line 43 Lack of vital signs and biochemical parameters at time of presentation is an important omission

Line 47 Where was the central venous catheter placed? 

Response 6:

Thank you for your valuable insight.

Line 42 became line 47, the blood glucose measurement was done by the bedside, thus the exact measurement couldn’t be determined.

Line 43 became lines 47-48, we’ve realized those were our limitations. The explanation is written in lines 207-210.

Line 47 became line 51, the CVC was inserted into the femoral vein.

Comments 7: Line 49 How long did it take for DKA resolve? I presume DKA had resolved but child’s GCS remained abnormal (10).

Response 7: Thank you for your input. In lines 52-53, the DKA resolved within 12 hours. It’s true that the child’s GCS indeed remained abnormal even though the DKA had been resolved.

Comments 8: Line 51 When was the hemiparesis first observed?

Response 8: Thank you for the insight. The hemiparesis was first observed on the ninth day of hospitalization, but it was thought to occur earlier and the recognition of left hemiparesis on the ninth day was late (Line 56, and line 158).

Comments 9: Line 63 Describe neurologic status in more detail.

Response 9: Thank you for the insight. The neurologic status described by GCS 12 (line 68).

Comments 10: Table 1 shows markedly increased blood urea nitrogen and creatinine concentrations consistent with kidney injury. The reference range for creatinine is not correct for a 2-year old child.

Likewise AST and ALT concentrations are consistent with liver injury from hypoperfusion (ischemia).

Response 10: Thank you for the valuable insight. The patient had a severe hypoperfusion state for several days of hospitalization, marked by kidney and liver injury. I changed the reference range for creatinine and urea in Table 1.

The SGOT and SGPT changed to AST and ALT in Table 1.

Comments 11: Line 73 PT and aPTT were mildly decreased. Were any other coagulation studies obtained? In addition to severe hypoperfusion of vital organs resulting in ischemia, was there any evidence of a procoagulation diathesis?

Response 11: There were no other coagulation studies obtained on day 33 of hospitalization (lines 56-60) because the patient’s condition was stable and had no involving signs and symptoms of neurologic deficit at that time. There was an increase in D-dimer on day 9 of hospitalization when the signs of neurological deficit were apparent.

Comments 12:  Line 122 What does luxury perfusion mean?

Response 12: Thank you for your insight. Luxury perfusion is a hyper-vascularization zone that occurs after an ischemic episode (lines 127).

Comments 13: Figure 4 is a graphical recapitulation already described and does not add important information

Response 13: Thank you for your valuable insight. The description of symptoms and laboratory/imaging of the patient in Figure 3 has been removed. I suggest that the treatment timeline is needed to describe time-to-time management that hasn’t been described in detail in the paragraph.

Comments 14: Line 139 intracerebral complication rate of 0.3%-1% in DKA has been reported from USA and UK but may not be the same in other countries where diabetes is not common and patients typically present late and in severe DKA?

Response 14: Thank you for your valuable insight. I agree with you that the complication rate was not applicable in other countries where diabetes is not common, the data on intracerebral complication rate was limited in Asian countries thus I changed the sentence to lines 149-151.

Comments 15:
Reference #15 is redundant (see reference #11)

Response 15:

Thank you for the insight. Reference #15 has been removed.

Comments 16: Lines 151-153 None of the references (4,6,12) are actually appropriate to support the statement. Please refer to the primary sources for these observations

Response 16: Thank you for the valuable insight. I found that the actual references referred to reference 18,19 (line 166).

Comments 17: Line 158 CVC insertion increases the risk of venous thrombosis. What is the relationship between CVC insertion and cerebral ischemia?

Response 17: Thank you for the valuable insight. CVC insertion was related to CVC-related DVT, it increases the probability of DMT 1 patients having clinically apparent DVT. In this case, DVT did not happen, but CVC insertion still played a role in mechanical and iatrogenic vascular injury that exaggerates the existing pathomechanism of vascular endothelial injury.

Comments 18: Line 162 Was there laboratory evidence of disseminated intravascular coagulation or is this speculation?

Response 18: Thank you for the valuable insight. The laboratory evidence of DIC was not found, thus the other possible mechanisms of the hemorrhagic transformation were added in lines 176-179.

Comments 19: Lines 193,194 There is no doubt this child has type 1 (insulin-dependent) diabetes mellitus. The precise etiology (i.e., is it caused by autoimmunity?) may be uncertain owing to inability to measure pancreatic islet autoantibodies

Response 19: Thank you for your wonderful insight. The limitation in lines 209-210 has been changed to the underlying autoimmunity cannot be identified.

Comments 20: Comments on the Quality of English Language - This can be improved

Response 20: Thank you for the valuable advice. The English Language in this report has been revised by English editing services.

Reviewer 3 Report

The authors present an interesting case of stroke, late recognized, in a 2-year-old child with ketoacidosis from Indonesia. The author mentioned their country's low awareness of this kind of complication. This made the presentation of the case so important, and maybe the distribution of the paper in some countries may help improve the care of such patients.

The paper is, in general, well-written and uses the English language correctly. Some improvements regarding the use of abbreviated words must be made. 

In the Introduction, there may be more data on the stroke or cerebral edema as complications of the DKA must be included.

In line 51, the authors may specify when the left hemiparesis was present. This could be important to see the delay in recognizing the complication and may tell readers when to expect such subtle signs of the complications.

Table 2 may be left out, and data may be inserted in the text (lines 72-73) as there are very few. Could no other results be significant from day 33? (admittance to the authors' hospital).

I would enlarge Figures 1 and 2 to make them easily viewed.

In Figure 4, the days may be as numerals to be easily understandable.

The conclusions must be rewritten; there should be no cited reference in this section, and the authors must underline the findings linked to this case. The emphasis on early recognition of these complications must be increased. 

The quality of the English language in this paper is good. Some minor improvements must be made, mainly for editing (abbreviated words).

Author Response

Author's Response:

Thank you very much to the editors, and reviewers for their time and valuable insight. I appreciate every single advice that has been given. Please see the specific point-to-point response to the reviewers enclosed below.

Reviewer 3: Comments:

Comments 1: The authors present an interesting case of stroke, late recognized, in a 2-year-old child with ketoacidosis from Indonesia. The author mentioned their country's low awareness of this kind of complication. This made the presentation of the case so important, and maybe the distribution of the paper in some countries may help improve the care of such patients.

Response 1: Thank you for the recognition, and your kindness. It was such an honor to get expertise from you. We hope that this case report could have an impact on increasing the early recognition of stroke-associated DKA in low-awareness countries.

Comments 2: The paper is, in general, well-written and uses the English language correctly. Some improvements regarding the use of abbreviated words must be made. 

Response 2: Thank you for the advice, the abbreviated words have been corrected.

Comments 3: In the Introduction, there may be more data on the stroke or cerebral edema as complications of the DKA must be included.

Response 3: Thank you for the advice, further explanation for intracerebral complication has been added to the introduction in lines 31-33.

Comments 4: In line 51, the authors may specify when the left hemiparesis was present. This could be important to see the delay in recognizing the complication and may tell readers when to expect such subtle signs of the complications.

Response 4: Thank you for the suggestion. The presentation of left hemiparesis has been added to line 56 and in the discussion line 158.

Comments 5: Table 2 may be left out, and data may be inserted in the text (lines 72-73) as there are very few. Could no other results be significant from day 33? (admittance to the authors' hospital).

Response 5: Thank you for the suggestions. Table 2 has been deleted, and the laboratory result has been inserted in the text lines 88-90. The other lab result that has been significant other than written in the manuscript was the patient was still hyperglycemia and it was difficult to achieve glycemic control at that time. (Explanation inserted in lines 85-87)

Comments 6: I would enlarge Figures 1 and 2 to make them easily viewed.

Response 6: Thank you for the suggestion, figure 1 and 2 have been enlarged according to your suggestion.

Comments 7: In Figure 4, the days may be as numerals to be easily understandable.

Response 7: Thank you for your suggestion. The days in Figure 3, have been revised to numerals.

Comments 8: The conclusions must be rewritten; there should be no cited reference in this section, and the authors must underline the findings linked to this case. The emphasis on early recognition of these complications must be increased. 

Response 8: Thank you for the suggestion. The conclusions have been rewritten according to the patient’s clinical findings, the citation has been deleted. I hope the emphasis on early recognition is strong enough in lines 211-218.

Comments 9: Comments on the Quality of English Language

The quality of the English language in this paper is good. Some minor improvements must be made, mainly for editing (abbreviated words).

Response 9: Thank you for the advice, the misuse of abbreviated words in this article has been changed.

Round 2

Reviewer 2 Report

The authors have addressed my previous comments, criticisms and suggestions.

Additional suggestions:

lines 9-10 Change the wording "Stroke has been reported to account for 10% of intracerebral complications of DKA in children. It may be under-recognized because its presentation may be subtle."  

Lines 19-20 this is redundant. Delete these sentences. The frequency of cerebral edema has already been stated on lines 8-10

lines 25-26 The prevalence 13.5 to 17.4 million people worldwide includes children and adults

Lines 34-35 ... [6-10]; recognition may be challenging when symptoms and signs mimic those of cerebral edema 

Lines 40-41 '... ate and drank more eagerly than usual ... and had weight loss of ... (omit significant - you have provided the actual amount of weight loss)

Line 155 Level of consciousness (GCS) typically improves and becomes normal within approximately 24 hours of starting treatment for DKA. Lack of improvement by 24 hours should raise suspicion for an intracerebral complication.

Line 171-172 I can understand how insertion of a femoral vein catheter would predispose to a femoral vein thrombosis, but it is difficult for me to understand how this would increase the of a cerebral arterial or venous thrombosis. Surely, it is the severe dehydration and hypoperfusion that accounts for the cerebral complications and not insertion of a femoral venous catheter?

Line 197-199 Although the initial biochemical data were not available, the authors described Kussmaul respiration and a diagnosis of DKA at the first hospital. It is highly likely, therefore, that the presentation was a mixed picture of hyperosmolar DKA and not HHS.

Line 212 The case report is not subtle. Failure to recover complete consciousness within 24 hours and a L. hemiparesis wre important features that should have immediately raised suspicion for an intracerebral complication.

There are poorly constructed sentences. I have pointed some out in comments to authors.

Author Response

Dear Reviewer 2,

Please see the attachment below.

Author Response File: Author Response.docx