Approaching Headaches—A Guide to Differential-Diagnostic Considerations and Causal Claims

Round 1

Reviewer 1 Report

The manuscript entitled "Approaching headaches – guide to differential-diagnostic considerations and causal claims" brings a real contribution to differential diagnosis of headache, useful for neurologists.

The following observation has to be made:

Introduction

Please include migraine, tension headache, cluster headache etc in your classification, together with a summary of their causes and mechanisms. Do you consider these type of headache a neuropathic pain or other type of pain and why.

The last classification of headache  (ICHD-3) was made in 2017/2018

- line 55-56 - please insert an example of phantom limb phenomenon (to be better understood).

- line 57 - please describe neuropathyic pain, as headache mechanism, more detailed. You only gave one example of neuropathic pain (poststroke pain that is rare). There are many other neuropathic pain types, and, since this is a review, please offer more examples, eventually in a table. Even more, a definition of neuropathic pain is needed because neuropathic pain can occur in various type of CNS lesions, not only in stroke. See please: Front. Neurol. Volume 13 - 2022 | https://doi.org/10.3389/fneur.2022.1024033.

- line 58 -60 - please reformulate the sentence about nociplastic pain because is confusing.

- line 99 - please give more details about the mechanisms implied in various types of headache, including molecular mechanisms. For example the role of oxidative and nitrosative stress, the role of nitric oxide, the role of proinflammatory cytokines, prostaglandins, substance P, VIP, CGRP - that already have treatments applied on their contribution of pain mechanisms. 

The aim of the study is missing/not clear

The method of the research is missing. You need to mention if it is a narrative review. 

- line 116 - please insert references here.

-line 130-131 - same observation (please insert references). 

-line 140 - please insert the importance of anamnesis (history) and neurological clinical examination for headache diagnosis/differential diagnosis. 

Please describe the "information" as anamnesis (history) (line 152-161).

- line 165-169 - please reformulate that sentence, is confusing.

- line 195 - the risk factors are only correlation factors and not the causality.

You need to mention precisely if the Table 1 contains risk factors or etiological factors. 

- pag 7 - table - please replace in the last row with "transient visual acuity changes" - the patients can have positive or negative visual sensations associated with headache, not only "obscuration".

Please offer a scheme about how to explore and have a diagnosis in headache patients, in order to guide the patients toward a personalized treatment.

Line - 248-249 - the headache can occur before the causality is established. 

Author Response

Dear Editor-in-Chief

I am pleased to submit the revised manuscript titled “Approaching headaches – guide to differential-diagnostic considerations and causal claims” for re-consideration for publication in Clinical and Translational Neuroscience.

The referees’ thoughtful comments on my original submission allowed considerable refinement of the manuscript’s quality and structure. Thank you!

I have studied, answered, and corrected all points carefully. All changes in the manuscript are highlighted (track changes).

Yours sincerely,

Heiko Pohl

 

Introduction

Please include migraine, tension headache, cluster headache etc in your classification, together with a summary of their causes and mechanisms. Do you consider these type of headache a neuropathic pain or other type of pain and why.

REPLY: Thank you for this suggestion. I agree that it may be helpful to add that information. I now point out in line 61 that primary headaches such as migraine and cluster headache are primary headaches and must thus be viewed as nociplastic pain.

 

The last classification of headache (ICHD-3) was made in 2017/2018

REPLY: The first edition was published in 1988, and the third edition in 2018. I added the information, as suggested.

 

- line 55-56 - please insert an example of phantom limb phenomenon (to be better understood).

REPLY: Thank you for that suggestion. However, I did not add the phantom limb phenomenon as an example of neuropathic pain because I believe that headache is hardly ever due to a phantom limb phenomenon.

 

- line 57 - please describe neuropathic pain, as headache mechanism, more detailed. You only gave one example of neuropathic pain (poststroke pain that is rare). There are many other neuropathic pain types, and, since this is a review, please offer more examples, eventually in a table. Even more, a definition of neuropathic pain is needed because neuropathic pain can occur in various type of CNS lesions, not only in stroke. See please: Front. Neurol. Volume 13 - 2022 | https://doi.org/10.3389/fneur.2022.1024033.

REPLY: Thank you for drawing my attention to this interesting article. I updated the definition of neuropathic pain; it now corresponds to the IASP definition. Also, I agree that stroke is not the only CNS disorder that can cause neuropathic pain. I added neuropathies and central pain due to multiple sclerosis.

 

- line 58 -60 - please reformulate the sentence about nociplastic pain because is confusing.

REPLY: I am unsure in what way the sentence confused you. However, I assume that omitting the word “headache” might have prevented easy understanding. Hence, I reformulated the sentence. It now reads, “nociplastic headaches are referred to as primary headaches (e.g., migraine, cluster head-ache, and tension-type headache)”.

 

- line 99 - please give more details about the mechanisms implied in various types of headache, including molecular mechanisms. For example the role of oxidative and nitrosative stress, the role of nitric oxide, the role of proinflammatory cytokines, prostaglandins, substance P, VIP, CGRP - that already have treatments applied on their contribution of pain mechanisms. 

REPLY: The purpose of these paragraphs was to show that there are hypotheses about the pathophysiology of several secondary headaches. However, I did not intend to provide in-depth information about the quickly growing body of research, as the focus is elsewhere. Doing so might confuse the readers.

 

The aim of the study is missing/not clear. The method of the research is missing. You need to mention if it is a narrative review. 

REPLY: Thank you for indicating that mistake. I adapted the last paragraph of the introduction to clarify the article’s aim. Also, I added that it is a narrative review. (Thank you for pointing out that the article type wasn’t clear.) The sentence now reads as follows. “This narrative review aims to discuss the thought process behind diagnosing headaches.”

 

- line 116 - please insert references here.

REPLY: The references were identical for both sentences of the paragraphs. Hence, I wrote them just once. Yet, I understand your objection. Thus, I put the reference after each sentence in the revised version.

 

- line 130-131 - same observation (please insert references). 

REPLY: I put the reference after each sentence in the revised version.

 

-line 140 - please insert the importance of anamnesis (history) and neurological clinical examination for headache diagnosis/differential diagnosis. 

REPLY: Thank you for the comment, with which I agree entirely. I added to line 153 that history and clinical examination provide that information.

 

Please describe the "information" as anamnesis (history) (line 152-161).

REPLY: I absolutely agree that this information is relevant and should be in the manuscript. Hence, I adapted the sentence accordingly. It now reads as follows. “There are two types of information (provided by history and clinical examination) that support the detection of a potential cause of a headache”

 

- line 165-169 - please reformulate that sentence, is confusing.

REPLY: The paragraph is a central part of the manuscript and I would like the reader to understand it. Hence, I tried to simplify it reformulating two sentences. They now read as follows. “A risk factor implies that the patient may develop a specific headache eventually; however, it allows no conclusions about the pathophysiology of the current headache.”

 

- line 195 - the risk factors are only correlation factors and not the causality.

REPLY: I agree with you. However, I’d prefer not to add that thought in this part of the manuscript, as causality is discussed further below.

 

You need to mention precisely if the Table 1 contains risk factors or etiological factors. 

REPLY: May I assume that you are referring to Table 2? In this article, I prefer the term “Red Flags with temporal information”, because most of them are neither risk factors nor etiological factors. Instead, they are other symptoms of the underlying disease that help to identify the aetiology.

 

- pag 7 - table - please replace in the last row with "transient visual acuity changes" - the patients can have positive or negative visual sensations associated with headache, not only "obscuration".

REPLY: I agree that patients report many different types of changes in transient visual acuity. However, obscurations are relatively specific for intracranial hypertension. Since the table lists Red Flags pointing to particular diseases (second row), I’d prefer not to change the wording to include unspecific symptoms.

 

Please offer a scheme about how to explore and have a diagnosis in headache patients, in order to guide the patients toward a personalized treatment.

REPLY: I agree that it may be challenging to keep an overview of the vast amount of information provided in the article. Hence, I added Figure 1.

 

Line - 248-249 - the headache can occur before the causality is established.

REPLY: I agree with you. In fact, in many clinical situations, the headache appears before the causality is established. However, the cause is always present before its effect. There cannot be any exceptions.

Reviewer 2 Report

The author can enhance and simplify work so that it can be more straightforward; The following points could be addressed to make it more lucid

1. The introduction ending is a little confusing, ie from line number 46 to 50. The section 1 , section 2 is not clear . It better to avoid this terms

 

2. There needs a restructuring of the sections. I feel we first search for the various causes of headache and then identify not other way round. So there writing of Searching for potential causes for headache should be explained first followed by identification of potential cause of headache.

 

3. The Section with the heading identification of potential causes of headache does overlap with the idea of searching the stimulus and in a more clear way describing the pathophysiology of different types of headache mentioned in bullet points from line 99 onwards. So its better to make it more pathophysiology-based discussion if the author wants to keep it as separate section at all. Example read line number 70... Also Section titled identification and search of potential causes of headaches can be clubbed together, making it easy for the author to revise and streamline the discussion.

 

4. I will suggest the addition of some etiopathological diagrams to be included in the draft which makes it easier for the readers to follow the textual description.

5.Flow diagrams ie decision tree diagram of what to look and think after finding a particular cue could be added as this review title itself reads a guide to differential diagnostic consideration. So flow diagram guiding decision-making will be a great aid for the readers to use this text in their daily care and decision-making. Else it will be another addition to the scientific literature on headache without many new things to look into.

5. The temporality and diagnostic information explanation given from line number 152 onwards may be graphically represented for better clarity like factors with and out temporal relation may be shown in pictoral way for easy understanding. A guide should be very catchy rather than monotonous with texts only

6. There are some repetitive statements and sections like line 278 onwards. Such description is mentioned in earlier sections also. Please avoid such twist of wordings. Be very simple and clear delivering the message through the text.

 

7. A section on current updates of headache diagnosis consensus may be put forward and explained to show what newer information has been added in this draft. This can be a highlight section also of the draft that could be added at the beginning.

The language needs to be little simple and direct to make it a easy to follow guide for differential diagnosis consideration

Author Response

Dear Editor-in-Chief

I am pleased to submit the revised manuscript titled “Approaching headaches – guide to differential-diagnostic considerations and causal claims” for re-consideration for publication in Clinical and Translational Neuroscience.

The referees’ thoughtful comments on my original submission allowed considerable refinement of the manuscript’s quality and structure. Thank you!

I have studied, answered, and corrected all points carefully. All changes in the manuscript are highlighted (track changes).

Yours sincerely,

Heiko Pohl

 

 

The author can enhance and simplify work so that it can be more straightforward; The following points could be addressed to make it more lucid

1. The introduction ending is a little confusing, ie from line number 46 to 50. The section 1 , section 2 is not clear . It better to avoid this terms

REPLY: Thank you for pointing out the issue with the sections. When I wrote the manuscript, there were only three numbered sections. When adapting the text to the template, more sections were numbered, hence the confusion. I deleted these sentences, as suggested by you.

 

2. There needs a restructuring of the sections. I feel we first search for the various causes of headache and then identify not other way round. So there writing of Searching for potential causes for headache should be explained first followed by identification of potential cause of headache.

REPLY: I firmly believe that when searching for a cause, it is sensible to bear a list of potential causes in mind. It would not be easy to decide which examination to order if one does not know which possible causes there are. Of course, establishing a list of potential causes is not part of daily clinical practice but the result of systematic research; clinical work starts at the second point.

 

3. The Section with the heading identification of potential causes of headache does overlap with the idea of searching the stimulus and in a more clear way describing the pathophysiology of different types of headache mentioned in bullet points from line 99 onwards. So its better to make it more pathophysiology-based discussion if the author wants to keep it as separate section at all. Example read line number 70... Also Section titled identification and search of potential causes of headaches can be clubbed together, making it easy for the author to revise and streamline the discussion.

REPLY: There is a difference between knowing the stimuli that can cause headaches and identifying the trigger of one specific patient's headache. For example, knowing that 26% of all patients with non-traumatic intracranial haemorrhage have headaches does not prove that a specific patient’s headaches are due to his non-traumatic intracranial haemorrhage. Some authors refer to this issue as “Confusion of the inverse”. So, I am convinced that the two sections must be kept separate.

 

4. I will suggest the addition of some etiopathological diagrams to be included in the draft which makes it easier for the readers to follow the textual description.

REPLY: I agree that the article requires a figure (see below). However, I cannot draw diagrams depicting the physiopathology of each secondary headache. This article does not strive to review the pathophysiology of every secondary headache thoroughly. Instead, the section about the pathophysiology aims to show that there are indeed hypotheses regarding their aetiology.

 

5. Flow diagrams i.e. decision tree diagram of what to look and think after finding a particular cue could be added as this review title itself reads a guide to differential diagnostic consideration. So, flow diagram guiding decision-making will be a great aid for the readers to use this text in their daily care and decision-making. Else, it will be another addition to the scientific literature on headache without many new things to look into.

REPLY: I am grateful for this suggestion and agree that this part was missing in the manuscript. I added a description which examinations to order in which case. The paragraph now reads as follows.

“Should the information collected, as outlined above, indicate the presence of a secondary headache, further diagnostic tests should be ordered to confirm the suspicion. The pertinent examination depends on the suspected disorder.

• Cerebral imaging is helpful when a haematoma, haemorrhage, ischemia, blood vessel malformation, tumour, hydrocephalus, and other causes of increased intracranial pressure or inflammation are suspected.[155]
• A spinal tap allows measuring the intracranial pressure and searching for inflammation, haemorrhage, and tumour cells.
• An ophthalmic examination may help detect signs of raised intracranial or intraocular pressure, inflammation, including keratitis, and refractive errors.[156]
• An ear, nose, and throat specialist should be consulted when local inflammation (e.g., otitis, mastoiditis) and craniomandibular dysfunction are suspected.[157]
• Monitoring the blood oxygen levels during sleep can detect sleep apnoea.
• Occasionally, myelography can help to detect a cerebrospinal fluid leak.[158]”

 

5. The temporality and diagnostic information explanation given from line number 152 onwards may be graphically represented for better clarity like factors with and out temporal relation may be shown in pictorial way for easy understanding. A guide should be very catchy rather than monotonous with texts only

REPLY: Thank you for that comment. It is challenging to keep an overview of the different types of information. I added Figure 1 to summarise them and highlight differences.

 

6. There are some repetitive statements and sections like line 278 onwards. Such description is mentioned in earlier sections also. Please avoid such twist of wordings. Be very simple and clear delivering the message through the text.

REPLY: The distinction between direct and indirect mechanistic evidence may be utterly irrelevant in daily clinical practice. However, I'm afraid I must disagree: the sentences do not merely twist words. As this article discusses the theory behind everyday clinical thought processes, it is crucial to mention that direct and indirect evidence are not identical.

 

7. A section on current updates of headache diagnosis consensus may be put forward and explained to show what newer information has been added in this draft. This can be a highlight section also of the draft that could be added at the beginning.

REPLY: I am sorry to confess that I am unsure what a “headache diagnosis consensus” is. However, I would like to point out that the article discusses the thought process behind making headache diagnoses. Doctors have been diagnosing headaches for centuries, so I think it is essential to understand what one is doing intuitively.

Round 2

Reviewer 1 Report

Accept in present form.

Author Response

Thank you for your kind evaluation. I very much appreciate you taking the time to review the article.

Reviewer 2 Report

Thank you for revising the draft. I have some comments to make.

 

1. As the author says that the article needs a figure for pathophysiology and interestingly again says this draft is not about the pathophysiology of headaches then the author should either choose to add the figure or delete or reduce the pathophysiology discussion of headaches. If not describe all different types of headaches through figures, a single figure can also convey a lot of important information at a time. The author either chooses to seek help from people to help this aspect as we know we alone can't do everything.

 

2. If the author thinks that the article just describes the thought process behind diagnosis and Doctors have been doing that for centuries, itself undermines the importance of the article author is writing. in that case, I will suggest being more focussed on that instead of iterating known sections of types of headache,redflags etc. These are all known facts as author says. The author can then instead write the thought process article as letter to editor being more straight & focused distilling exactly new ideas author wants to convey

3.I couldn't understand what the author wanted to say about direct and indirect mechanistic evidence. Does the author mean it's not distinguishable ? Or author doesn't want to? As the reply is contradicting itself.

 

Needs minor English editing 

Author Response

Thank you for reviewing the draft. I very much appreciate you taking the time to help improve the article.

1. As the author says that the article needs a figure for pathophysiology and interestingly again says this draft is not about the pathophysiology of headaches then the author should either choose to add the figure or delete or reduce the pathophysiology discussion of headaches. If not describe all different types of headaches through figures, a single figure can also convey a lot of important information at a time. The author either chooses to seek help from people to help this aspect as we know we alone can't do everything.

REPLY to point 1: I agree that figures generally foster understanding. However, the article lists ten different types of physiopathology, and not all are equally well studied (e.g., only scarce evidence indicates that hypothyreosis causes headaches). 

As it is impossible to squeeze all pathophysiological considerations into one figure, the interested reader must read the entire paragraph; methinks, an image is not helpful in this case. However, if you feel that a specific aspect merits further attention, please let me know, and I will be happy to try to create a figure.

2. If the author thinks that the article just describes the thought process behind diagnosis and Doctors have been doing that for centuries, itself undermines the importance of the article author is writing. in that case, I will suggest being more focused on that instead of iterating known sections of types of headache, redflags etc. These are all known facts as author says. The author can then instead write the thought process article as letter to editor being more straight & focused distilling exactly new ideas author wants to convey

REPLY to point 2: It is correct that I want to describe the thought process of something that doctors have been doing for centuries. However, most make diagnoses intuitively and unawares that there is an underlying thought process. So, this article provides suggestions new to many doctors, especially the younger ones.

Of course, many experts in the field (including you) will know everything I have to say. Moreover, the thought of reducing the paper to stating the pure thought process, as you suggested, has occurred to me. Still, I prefer the more detailed versions presented here, primarily because I have yet to find a single article summarising this knowledge.

3. I couldn't understand what the author wanted to say about direct and indirect mechanistic evidence. Does the author mean it's not distinguishable? Or author doesn't want to? As the reply is contradicting itself.

REPLY to point 3: I am very sorry that I failed to explain better what I meant. I have now revised and expanded the paragraph.

The revised paragraph reads as follows. “A high degree of certainty can be reached if the mechanism through which the stimulus causes pain is substantiated directly or indirectly.

Direct evidence is evidence of the underlying pathophysiologic mechanism. For example, in a patient in whom a brain tumour caused pain by increasing the intracranial pressure, the confirmation of increased intracranial pressure is direct mechanistic evidence.

On the other hand, indirect evidence comprises further (and potentially less specific) consequences of the suspected pathophysiology. For example, indirect mechanistic evidence in said patient would be another effect of intracranial pressure, such as papilledema and vomiting – Table 3 lists additional suggestions for evidencing the mechanism of pain.”