Clinical Anatomy of the Lower Extremity Veins—Topography, Embryology, Anatomical Variability, and Undergraduate Educational Challenges

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. This paper is written obviously by a phlebologist (s) of the endovenous era of varicose vein treatment. and brings attention to features of lower limb venous anatomy recognised in the application of modern era clinical diagnostic tools  This paper is an attempt to address some of these  and relate this to the learning/teaching of a more correct anatomy.

2. It is a large topic as described in the title. What is the focus message of the paper ? The authors attempt too much with too many subjects so that important facets in each get lost.  For example If it wants to address education then  it should include the many other imaging tools and educational approaches to do this  but not to get lost in the embryology  with written text and modest quality images.

3. Who is the paper written for ?   This must qualify the level of knowledge  presented. Do undergraduates require to have the level of detail given for some of this topographical  information ? Post grads in the field who treat venous disease obviously do.

4. The emphasis on the importance of fascial layers  in understanding venous anatomy is well made. This alone deserves more focused attention. What is fascia ?

5. While there is  useful distinction and description of the 3 levels of veins  Perforators receive very little attention. They are clinically and therapeutically relevant – they are all physiologically relevant  and  not just a few with names! They are critical to understanding the relationship of deep to superficial and critical to physiology and the muscle pump. This is a real oversight and should be addressed.

6. The venous anatomy of the foot

7..The message is clear that even modern texts are not upto date in their venous anatomy  it would be helpful in making this claim  that references are given  demonstrating the short comings of what is written in ‘text books”. You have said  that  over the last two decades nothing has changed in the anatomical manuals and textbooks. Is this really true ? Is this paper therefore the first to do so ? Who is going to write the  correct text book ?   Would not references to better venous anatomy in current vascular, venous , phlebology, ultrasound  manuals  be helpful ?

7. Lots of interesting information and clinical snippets to apply from the anatomical features are described  but will the undergraduates be aware of  the conditions referred to?

8. While figures show fascia and vessels they do not point to other features within the fascial sheath – but do get commented  on in the text.. Why not point them out in the figures e.g fig 3 ?   By the way  what is the point of the “Egyptian Eye”-maybe explain it.

9. A lot of the anatomical detail seems far than needed by an  undergraduate student but could be more at a level    required by phlebologists . Who is this for?

Diagrams for the embryology are unfortunately of poor quality and reproduced from another publication. Can better ones be created?

10. Where is the foot venous anatomy?   Part of the lower limb!

11. The authors make a case for using other approaches to imaging for teaching. . This is rather a contrast between this long section in this paper using   written text to describe the anatomy in words. It seems contrary to the sentiment of  the paper on teaching anatomy.

12. Plastination as an anatomical method is great for showing fascia and the relationship to veins  and can be readily examined closely with simple magnification b y students – worth mentioning.

What is the place for MR imaging etc. For this paper to comment on teaching methods these should be referred to

Video and drive through imaging , virtual reality are tools for the future  also worth acknowledging

13. Ultrasound is great tool  and is  well described , but how this  is particularly helpful to demostrate functional anatomy  is not mentioned and it can be done on living specimans by students . It is a pity that this is not mentioned  in this  paper.  How about direction of flow and seeing valves and seeing them work?

 14.    The figures  Fig 13 and 14   living anatomy is not very instructive please provide pictures that illustrate the important features.. Presumably these students are identifiable -have they given their permission?

15. The point about fascia is important. The comment that formalin fixed  destroys fascia is not entirely true but rather fascia layers are removed  (dissected) to display the vessel anatomy – easier to see!  It would be valuable to have an image other than U/S  which shows

Plastination as an anatomical method is great for showing fascia and the relationship to veins  and can be readily examined closely with simple magnification b y students

16. While these two dimensional tools  are helpful they are often difficult to conceptualize in 3 D.  Therefore presenting  topography  as in  cadaver dissection and ‘atlases’ of the anatomy are still invaluable. This article does not provide any

Comments on the Quality of English Language

minor grammer

Author Response

Response to the remarks of the Reviewer 1:

We express gratitude for pointing out the limitations of our paper.

Amended parts of the text are underlined in red.

1. Thank you for acknowledging the necessity of teaching a more correct anatomy, especially in the context of current, primarily endovenous, treatment modalities. We added more information pointing out the fact that the revised anatomy of lower extremity veins is more than 20 years old:

“Basing on this research, the revised description of the lower extremity venous anatomy has been agreed at the pre-congress meeting of the 14^th Congress of the International Union of Phlebology, which was held in Rome on September 8-9, 2001. This document has been created under the auspices of the International Union of Phlebology, the International Federation of Associations of Anatomists, and the Federative International Committee on Anatomical Terminology, and has been published in 2002 [4]. During following years there were some, rather minor revisions to this terminology [5,7-11], which followed new discoveries and better understanding of anatomy of these veins, especially in the context of their topographic relation to the fascia and adjacent nerves.”

We also added information on how anatomy of these blood vessels is described in the current anatomical textbooks:

“Unfortunatelly, of as yet, these relevant amendments have not been included in the anatomical textbooks and atlases. For example, in current editions of the “Gray's Anatomy for Students”anatomy textbook (5^th Edition; Drake RL, Vogl AW, Mitchell AWM, editors; Elsevier 2024),which is used by medical students worldwide, there is still an unprecise and misleading information that the great and small saphenous veins are located in the subcutaneous connective tissue. Similarly, in the “Moore’s Clinically Oriented Anatomy” textbook (9^th Edition; Agur AMR, Dalley II AF, editors; Wolters Kluwer 2023), which is also recommended for medical students, there is no information regarding topographic relationship between saphenos veins and fascias, and there is incorrect information regarding accessory saphenous vein. Both student textbooks describe saphenous veins in relation to the bones, instead of fascial compartments. The information about clinically relevant valves of the saphenofemoral junction is lacking as well. Specialist anatomical textbook, the “Gray’s Anatomy. The Anatomical Basis of Clinical Practice (42^nd Edition; Standring S, editor; Elsevier 2021), gives similarly scarce and rather obsolete information, although the document presenting the revised anatomical nomenclature [4] is mentioned, still without revising these anatomical terms.”

2. We do not agree that venous embryology of the lower extremity veins is not important, even in the undergraduate education. Quite the contrary - since the development of the adult pattern of venous system in this part of the body is quite complex, with 3 steps of complete remodeling of the venous outflow routes, embryology provides reasonable explanation of a high, yet quite predictable, anatomical variability. It also helps understanding the close connection of the nerves with the veins in this part of human body (of note, iatrogenic injuries of the saphenous and sural nerves belong to the most frequent causes of legal litigations; thus this knowledge seems important, even for medical students). In the beginning of the 21th century there was a big progress in embryology of the veins of lower extremity, which enabled proper understanding adult anatomy of these veins. We feel that such a chapter is indispensable.
3. We do not agree that undergraduate students would not benefit from current, fascia-oriented topography of the lower extremity veins. Anatomical textbooks provide quite a lot topographic information on these veins, yet in relation to the bones and tendons. This knowledge was useful in the past, when, for example, venotomy of the great saphenous vein in the ankle region was a standard procedure, which is no longer performed since there are far better monographic-guided access sites available. Also, surgical stripping of the saphenous veins from the ankle region, for the varicose veins treatment, when indeed such a bone and tendon-oriented topography is useful, is no longer recommended, considering high rate of nerve injury and high rate of varicose vein recurrence. We added a summary of the aim of this review paper:

“We hope that this paper can provide a useful framework for planning anatomical classes, especially considering limitations of current textbooks and traditional cadaver dissections.”

4. We do not think that the term ‘fascia’ (a membranous structure built by connective tissue) needs further explanation. Composition of the fascial layers surrounding muscular compartments of the lower extremity has already been described in the Chapter 2:

“However, actually this fascial sheath consists of two fibrous layers. These layers usually are not seen during traditional cadaver dissection, but can be easily recognized during ultrasonographic examination. These two sheaths, the superficial (proper anatomical term of this fascia is: the membranous layer of subcutaneous tissue) and muscular ones, fuse with each other, except for small areas surrounding the interfascial veins (Figure 2). “

5. We added more information about perforating veins, especially regarding their physiologic and pathologic meaning.

“Perforating veins are equipped with valves that promote the flow from the epifascial and interfascial veins towards the deep veins. In the past, it was believed that physiological flow in perforators is unidirectional. Actually, it is bidirectional, depending on the current hemodynamic situation in their area; still a net flow should be as above described. There is an ongoing debate among doctors on clinical meaning of perforating veins that exhibit reversed, i.e. from the deep towards the epifascial and interfascial veins, flow. Such a discussion is beyond the scope of this paper. Yet, it should be mentioned that there is a common agreement that perforating veins located above the knee level, which exhibit such a reversed flow direction, are always pathological. It is associated with topography of the femoral vein, which is covered only by the sartorius muscle; consequently the muscle pump in the thigh is not very efficient, resulting in obviously pathological flows if such an above-the-knee perforator becomes incompetent. On the contrary, perforators located below the knee, where deep veins are situated inside muscular compartments, should be assessed in the context of the entire venous hemodynamic anatomy of the lower extremity. A reversed flow in these veins should not be considered an isolated abnormality.”

6. We added chapter on foot veins anatomy.

“Veins of the foot, in spite of their rather small size, play an important role in the lower extremity venous return, particularly through the so-called foot venous pump. This pump, together with calf and femoral pumps, is indispensable for physiological venous outflow from the lower limb. Although anatomic organization of the foot veins may seem similar to that of the lower leg and thigh, actually these veins differ significantly, especially regarding their functional anatomy. Foot perforators typically promote blood flow from the deep towards the superficial veins, which is unique in the lower extremity. Functionally, veins of the foot should not be seen in the context of the superficial and deep systems, but rather as the medial and the lateral units. The medial unit, comprising both superficial and deep (particularly, the medial plantar vein) veins, either empties to the posterior tibial vein system, or towards the great saphenous vein. The flow from the lateral unit (the lateral plantar vein is here the main blood vessel), is directed either towards the anterior tibial vein system, or to the small saphenous vein. The medial and lateral units are connected by the deep venous plantar arch. During contraction of the lower leg muscles, outflow route to the deep veins of the lower leg is blocked; consequently the venous outflow from the foot is directed to the saphenous veins. On the contrary, during lower leg muscle relaxation, blood flows out of the foot through deep veins of the lower leg. During walking, there is a dynamic interplay between foot and lower leg veins, and between foot and calf muscle pumps, which is facilitated by the above-mentioned unique valve orientation in the foot perforators. This interplay can be compromised if the foot is deformed, or improper footwear is used “

7. We provided a summary of knowledge given in current anatomical textbooks – see point 1. The message - who should rewrite anatomical textbooks is beyond the scope of our paper; still it becomes quite obvious that they need revision. Perhaps a similar joint meeting to that held in 2001 should be done again.

8. Typically, lymphatic vessels are not seen in standard ultrasonography (even if they obviously are inside the saphenous compartment; it is the main reason why anatomical studies on lymphatics are so difficult: in living subjects they can be visualized only using lymphoscitnigraphy, which is very imprecise; in cadavers a special technique enabling their good visualization, with zinc oxide contrast, was developed quite recently (Yamazaki S, Suami H, Imanishi N, et al. Three-dimensional demonstration of the lymphatic system in the lower extremities with multi-detector-row computed tomography: a study in a cadaver model. Clin Anat. 2013;26:258-66.)

Nerves accompanying saphenous veins can sometimes be visualized, still Figure 3 shown ultrasonographic picture of the upper thigh, were no big nerves are present; besides, in order to visualize small nerves a high frequency probe should rather be used (like 15-20 MHz).

“Egyptian eye” is a common term used in clinical medicine – the superficial and deep fascias, together with the vein inside, look like an eye pained by ancient Egyptians.

9. This issue has already been discussed:

“Therefore, ultrasonographic anatomy is currently a backbone of postgraduate medical education in such medical specialties as vascular surgery, phlebology and angiology. Since postgraduate medical education primarily relies on practical courses, assisted by specialist manuals, scientific papers and lectures given by experts, the problem of an obsolete anatomy is so important. On the contrary, the undergraduate medical education still struggles with this obstacle.”

See also point 3.

9a.  Unfortunately, since majority of embryological studies on lower extremity veins come from animals (usually rabbits), all pictures in this area are rather schematic (e.g. see: Uhl JF. Focus on venous embryogenesis of the human lower limbs. Phlebolymphology. 2015;22:55-63.)

Besides, the limb in embryo does not look like an adult limb. Figure 4 should be regarded a schematic representation of 3 main venous outflow routes, which develop thanks to stimulation by angio-guiding nerves.

10. See point 6
11. The aim of this paper was not to create a manual of anatomical classes. As has been stated at the end of Introduction:

“This review paper serves purpose of summarizing current anatomical knowledge of these veins. Besides, some proposals of the revised anatomical curriculum for the undergraduate medical education will be presented. We hope that this paper would provide a useful framework for planning anatomical classes, especially considering limitations of current textbooks and traditional cadaver dissections.”

12. Unfortunately, during standard plastination process veins are not preserved (I have recently discussed this issue with people from the von Hagens Plastination company; they said that typically they dissolve chemically adipose tissue before proper plastination process, and it seems that veins disintegrate together with fat; theoretically it would be possible to inject veins with a filler, still only those injected will be intact afterwards; it is easier to do it with arteries).

Regarding MR, it is quite good in visualizing soft tissues, yet in term of veins and fascial compartments it is inferior to ultrasonography, even of mediocre quality. And for obvious reasons cannot be used during ‘living anatomy’ classes.

Still, we added commentary on this issue – see point 15.

13. Following your suggestion, we added the text - what medical students can learn during such anatomical classes.

“During such classes students can comprehend topographic anatomy of lower extremity veins, relation of these blood vessels to adjacent anatomical structures, functioning valves (Supplementary file 1), normal and abnormal blood flow direction, as well as many anatomical variants.”

We also added multimedia file showing the area of saphenofemoral junction with functioning valve

14. We provided photos from ‘living anatomy’ classes just to show that such a possibility exists, not to provide details. It is clearly seen that students are using ultrasonographic set and are studying anatomical details.

Since indeed the students may be identifiable, they provided their written consents that were submitted to the Editorial Office

15. We added discussion on other potential educational tools:

“The other potentially valuable option could be the use of specially prepared plastinated specimens. Of note, during typical plastination process, the veins and fascia sheath are removed; for the purpose of teaching anatomy of the lower extremity veins such specimens should be adequately prepared. Also, traditional cadaver dissections, which are still a backbone of the undergraduate anatomical education, may remain its role. Still, anatomical educators should be aware of the topographic features of the lower extremity veins, especially of their relationship to the fascias. Such information should also be included in the anatomical dissection manuals. Considering the shortage of cadaver bodies at many medical universities, new possibility of 3-dimensional scanning (nowadays it can be done with a standard smartphone) of cadaver specimens, and preserving each step of the dissection digitally, provides an additional possible educational tool.”

16. We added commentary how traditional cadaver dissections, which are still the backbone of anatomical education, could be undertaken – see point 15.
17. Typographic and grammar errors were corrected

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors

very interesting paper.

Did you consider Ultrasonography as first tools for the examination of the lower limb's veins. Is it possible to consider others tools?

It is very exciting to study anatomy on alive patients and to overcome the use of cadaver lab. All the vessels have to be studied during their functions.

How you consider the impact of variations on that learning? we are more confindent studying normal anatomies first and then possible variations. Please comment

Author Response

Response to the remarks and proposals of the Reviewer 2:

Thank you for reviewing the manuscript. The following changes have been performed regarding your remarks and proposals.

1. We added discussion on potential alternative educational tools for teaching anatomy of the lower extremity veins:

“The other potentially valuable option could be the use of specially prepared plastinated specimens. Of note, during typical plastination process the veins and fascia sheath are removed; for the purpose of teaching anatomy of the lower extremity veins such specimens should be adequately prepared. Also, traditional cadaver dissections may have its role in the educational process. Still, anatomical educators should be aware of the topographic features of the lower extremity veins, especially their relationship to the fascias. Such information should also be included in the anatomical dissection manuals. Considering the shortage of cadaver bodies in many medical universities, new possibilities of 3-dimensional scanning (nowadays it can be done with standard smartphone) of cadaver specimens, and preserving each step of the dissection digitally, provide additional possible educational tools.”

2. Following your suggestion, we added the video presenting functioning terminal valve of the great saphenous vein.
3. Regarding “normal anatomy” and ”variations” – actually, no such thing as normal anatomy of the lower extremity veins exists, at least regarding interfascial veins. An idea that almost every lower limb presents with “textbook” anatomy in is one of the most important causes of failed treatments for varicose veins.

Students should rather be taught that there is a general pattern of venous outflow, which results from embryological development, still with many options. Since there are only 4 interfascial veins, the material to memorize is not so big; the message that they are differently interconnected in each limb is pivotal. We added commentary on that issue:

“Since students cannot find an adequate information on the lower extremity veins in their textbooks, while they will need such a knowledge a few years later, during undergraduate clinical classes, as well as after graduation, “living anatomy” classes, with the use of ultrasonography (Figures 13 and 14), seem to be a reliable option, especially regarding anatomy of the lower extremities. During such classes students can comprehend topographic anatomy of the lower extremity veins, relation of these blood vessels to the adjacent anatomical structures, functioning valves (Supplementary File 1), normal and abnormal blood flow direction, as well as many anatomical variants. Importantly, “living anatomy” class enables the presentation of a high variability of interfascial veins.”

4. Typographic and grammar errors were corrected

Reviewer 3 Report

Comments and Suggestions for Authors

The paper titled “Clinical Anatomy of the Lower Extremity Veins – To-2 pography, Embryology, Anatomical Variability, Under-3 graduate Educational Challenges. ” presents the topography with the latest classification of the venous system of the lower extremities. This is an overview article that is a good educational resource for young medics.The article consists of 20 pages and contains 6 sections and references (36 citations), and 14 figures. This article outlines the important role that ultrasound currently plays in the venous system of the lower extremities. The article is an interesting educational resource and can be published with minor revisions.

Author Response

Response to the remarks and proposals of the Reviewer 3:

Thank you for reviewing the manuscript. All corrections to the text and amendments are discussed in the responses to other reviewers

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

It is encouraging to see the authors have given thorough attention to the reviewer’s comments and enhanced the substance of their paper. Well done

There will be of course some differences of opinion. Some relate to differences in educational approach  and expectation.

However this reviewer does wish to point out some aspects which the authors should consider in what they have written

Response 1 provides useful additional information

Response 2 It is not disagreed that embryology is important , quite the contrary as pointed out, it is very informative of the principles. However the challenge is in the presentation keeping it simple without bamboozling the student with its detail.

Response 3 Similarly this reviewer does not disagree with the fascia oriented topography – and agree that it is a prime focus in this paper. It is about how this is presented to the undergraduate student

Response 4 Apologies missed this detail    -   what you quote is a good description

Response 5  The discussion of bidirectional perforating veins needs to take in to account the paper  “Bidirectional perforators in the lower limb are not physiologically normal: A brief commentary. Phlebology 2023  DOI: 10.1177/02683555231213146”  The suggestion of "common agreement " on what you have written would need reference to an evidence base for what  is stated

Response 6. This is very  helpful. You comment on the unique valve orientation of valves in foot perforators – it would be helpful to say what that orientation is

Response 7 this was a comment on the side – but perhaps you as the  authors with this special interest are well placed to do this !

Response 8 Your comments regarding lymphatics is correct. It was the nerves  and small arteries  - which are regularly identified in clinical venous practice with ultrasound. The images you used suggest tother components within the inter fascial space  .eg fig 3,7

Response 9  understood

Response 12  A plastination specimen  is shown here  - veins and fascia  are well shown  without   caste of injected filler. With this method fat is dissolved out and ‘replaced by the plastinator.  

Line 577     the statement “Of note, during typical plastination process, the veins and fascia sheath are

removed; for the purpose of teaching anatomy of the lower extremity veins  .”   This is not correct they show up very cleaqrly . Indeed specimens such as this  are a very good tool when cadaver material is not readily available.                                                                                                     

Response 14   The comment was about clarity of the photo used to make the point. You could do better to clearly show and describe what is going on.   Please consider what the reader is to learn , you may be very familiar with what is going on but what about anatomists unfamiliar with the methodology whom you want to convince. At least only one photo should be  used and please delete fig 13  where it is very obscure about what is meant to be seen . A better photograph would help greatly with your cause.

Comments on the Quality of English Language

minor syntax

Author Response

Response to the remarks of the Reviewer :

We express gratitude for pointing out the remaining limitations of our paper.

1. Following your suggestion, the fragment on perforating veins has been rewritten, and corresponding references have been added:

“Perforating veins are equipped with valves that promote the flow from the epifascial and interfascial veins towards the deep veins. The net flow through the perforators flow should be as above described. Still, some studies have revealed bidirectional flow in otherwise competent perforating veins [10,11]. There is an ongoing debate among doctors on clinical meaning of perforating veins that exhibit reversed, i.e. from the deep towards epifascial and interfascial veins, flow. Such a discussion is beyond the scope of this paper. Yet, it should be mentioned that there is a common agreement that perforating veins located above the knee level, which exhibit such a reversed flow direction, are always pathological. It is associated with topography of the femoral vein, which is covered only by the sartorius muscle; consequently the muscle pump in the thigh is not very efficient, resulting in obviously pathological flows if such an above-the-knee perforator becomes incompetent. On the contrary, perforators located below the knee, where deep veins are situated inside muscular compartments, should be assessed in the context of the entire venous hemodynamic anatomy of the lower extremity. A reversed flow in these veins should not be considered an isolated abnormality. Of note, it is generally accepted that such a reversed flow that exceeds 0.5 seconds is pathological. Shorter-duration outward flows still remain controversial. With the better ultrasonographic equipment, it appears that some of these refluxes actually represent vortical flow in tortuous perforators or develop after non-physiological provoking maneuvers, such as the leg compression/sudden release test [12-14].”

2. Valve orientation in the foot perforators has already been described. Yet, we added another sentence to avoid confusion:

“Foot perforators typically promote blood flow from the deep towards the superficial veins, which is unique in the lower extremity. Such a flow is possible, because their valves are oriented inversely to other lower extremity perforators.”

3. Response 7. This paper does not seem to be a god place for such a suggestion. It would rather need inter-societ activities.
4. Response 8. There may be some nerves and small arteries visible in Figures 3,7, yet in these particular pictures it is not obvious (in order to show the nerves they should be visualized in longitudinal section, to reveal parallel fibers; small arteries would require another imaging preset)
5. We added information on sheet plastinates and glass prints as possible educational methods:

“The so-called sheet plastinates, which are thin (1-5 mm thick) slices of the human bodies, where the liquids have been replaced by polymers, provide such an educational tool. In the sheet plastinates of thigh or lower leg, the veins are clearly visible, and their topography fully revealed [47,48]. Alternatively, high resolution glass prints, which are less expensive copies of the sheet plastinates, can be used.”

References on this method have been added

6. We replaced the photograph and provided more detailed legend.

Figure 13. Undergraduate medical students during anatomical classes; “living anatomy” with the use of ultrasonography. On the left: student is examining his colleague’s lower leg, trying to reveal sapheno-popliteal junction in the popliteal fossa, other students either look at the screen of the ultrasonographic set, or look at big screen (blue arrow) connected to the ultrasonographic set; on the right: details of the examination.

With kind regards,

Marian Simka, PhD MD