The Effects of Intensive Rehabilitation Combined with Thiamine Treatment on Cognitive Recovery in a Case of Non-Alcoholic Wernicke–Korsakoff Syndrome

Round 1

Reviewer 1 Report

Wernicke-Korsakoff syndrome (WKS) is the best known consequence of thiamine deficiency, frequently associated with patients with chronic and excessive alcohol consumption, but it can be produced by other causes that produce thiamine deficiency and since it is an underdiagnosed disease it is essential that there is a high clinical suspicion, mainly in patients who do not have alcohol consumption as a risk factor. Consequently, the diagnosis is mainly clinical with the added difficulty of high clinical variability. The authors are aware of this situation and should therefore describe the complementary tests they have used to support the diagnosis and rule out other causes that may produce similar symptoms, with magnetic resonance imaging being the most cost-effective imaging test according to the experts.

This is an interesting healthcare and clinical issue given that WKS K causes the symptoms described by the authors and that it is rarely associated with hemorrhagic pancreatitis, as the authors state; but they should justify that they have ruled out the patient's alcoholic habit and comment on the specific complementary diagnostic tests they have used to establish the diagnosis of Wernicke-Korsakoff Syndrome.

The work done is well described by the authors and the discussion of the case is adequate; but from the professional point of view the authors should describe more precisely the complementary diagnostic tests performed on the patient.

On the other hand, I would highlight the result for the patient, which is the most important thing; but also that the treatment with thiamine and others carried out by working as a team with Psychiatrists, Psychologists and Physiotherapists has been very positive and effective because the assistance has been carried out by a Multidisciplinary Team, which is a competence that should be encouraged in the health care field and in Hospitals to improve the Quality of Care and the Safety of Patient Care. Also because it is convenient to fight to leave behind the fragmentation that exists in the hospital environment with the different clinical services that should work more with the central services such as the Rehabilitation Services.

Author Response

REVIEWER 1

Wernicke-Korsakoff syndrome (WKS) is the best known consequence of thiamine deficiency, frequently associated with patients with chronic and excessive alcohol consumption, but it can be produced by other causes that produce thiamine deficiency and since it is an underdiagnosed disease it is essential that there is a high clinical suspicion, mainly in patients who do not have alcohol consumption as a risk factor. Consequently, the diagnosis is mainly clinical with the added difficulty of high clinical variability. The authors are aware of this situation and should therefore describe the complementary tests they have used to support the diagnosis and rule out other causes that may produce similar symptoms, with magnetic resonance imaging being the most cost-effective imaging test according to the experts.

This is an interesting healthcare and clinical issue given that WKS K causes the symptoms described by the authors and that it is rarely associated with hemorrhagic pancreatitis, as the authors state; but they should justify that they have ruled out the patient's alcoholic habit and comment on the specific complementary diagnostic tests they have used to establish the diagnosis of Wernicke-Korsakoff Syndrome.

The work done is well described by the authors and the discussion of the case is adequate; but from the professional point of view the authors should describe more precisely the complementary diagnostic tests performed on the patient.

Answer: We gratefully thank the reviewer for the comments and we agreed with the suggested changes.
The clinical assessment has been updated with the missing information.  The complementary tests used to support the diagnosis have been added as suggested (Please find the updated text from line 92 to line 110). Neuropsychological assessment has been described in extent (line 149-186). Since the diagnostic process of WKS included a combination of clinical assessment, medical history review, physical examination, and various diagnostic tests, in order to ameliorate the flow, clinical and neuropsychological assessments have been divided into two separate paragraphs.
Furthermore, to make the diagnostic process more conceivable to the reader, we included a Table (see Table 1, line 95) with the DSM-5 diagnostic criteria of Wernicke and Korsakoff syndrome as well as the symptoms of the described patients.

On the other hand, I would highlight the result for the patient, which is the most important thing; but also that the treatment with thiamine and others carried out by working as a team with Psychiatrists, Psychologists and Physiotherapists has been very positive and effective because the assistance has been carried out by a Multidisciplinary Team, which is a competence that should be encouraged in the health care field and in Hospitals to improve the Quality of Care and the Safety of Patient Care. Also because it is convenient to fight to leave behind the fragmentation that exists in the hospital environment with the different clinical services that should work more with the central services such as the Rehabilitation Services.

Answer: We agree with the reviewer on the importance of a multidisciplinary team in order to diagnose rare syndromes. We implemented the matter in the discussion and modified the text accordingly. Please, find text included from Line 264-281.

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Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript is a case report of a 28 year old women presenting with WKS after surgery for acute pancreatitis. The authors describe the clinical presentation of the patient before and after treatment, high doses thiamine paired with physiokinesitherapy and occupational therapy. There are minor edits that should be corrected before publication but overall the content of the work is novel, as the case outlines a unique incidence of the syndrome that is more often linked to alcoholism, and the writing is clear.

Major Considerations:

The authors should consider providing more images at different anatomical planes of the hyperintensity within the MB, currently only one axial image is presented. This image is not compelling and the reviewer believes that the authors should consult with the radiologist to provide better leveled images showing the hyperintensity (sources for good quality images: Jung, Y. C., Chanraud, S., & Sullivan, E. V. (2012). Neuroimaging of Wernicke’s encephalopathy and Korsakoff’s syndrome. Neuropsychology review, 22, 170-180. or Sullivan, E. V., & Pfefferbaum, A. (2009). Neuroimaging of the Wernicke–Korsakoff syndrome. Alcohol & Alcoholism, 44(2), 155-165.). The authors should also include what scan protocol and the system was used to acquire the images. 

Additionally, within the methodology the exact tests used to assess the patient should be included. These are listed within the table of the results but the authors should provide context for what the tests are and why they were conducted for the readers.

Finally, the reviewer noticed the bloodwork conducted and results of the lumbar puncture were not reported. Was this patient tested for thiamine deficiency and what were levels like at the conclusion of the observations. Was a cause ever established to the development of the deficiency, did the patients care giver report dietary problems? 

Minor Edits:     

There are some small sentence issues in the final paragraph of the case report section that should be clarified:

"Difficulties of anterograde memory emerged, while the retrograde one was preserved,..." this should say while retrograde memory was preserved.

"The tone of mood during the interview was fluctuating." The reviewer thinks that this sentence could be clearer, perhaps During the interview, the patient's mood flucuated... then provide an example: they were cheerful then morose.

"The tone of voice was low. Good understanding of simple and complex sentences." These seem like sentence fragments. The patient had a low tone of voice but their understanding of simple and complex sentences was good.     

The writing in general was very good, however, as outlined within the author comment section the final paragraph in the Case Report section will need some correction for quality.

Author Response

REVIEWER 2

The manuscript is a case report of a 28 year old women presenting with WKS after surgery for acute pancreatitis. The authors describe the clinical presentation of the patient before and after treatment, high doses thiamine paired with physiokinesitherapy and occupational therapy. There are minor edits that should be corrected before publication but overall the content of the work is novel, as the case outlines a unique incidence of the syndrome that is more often linked to alcoholism, and the writing is clear.

Answer: We are sincerely grateful to Reviewer 2 for their comments and feedback that have greatly enriched our work and contributed to its overall quality. We agreed with the suggested changes. 

Major Considerations:

The authors should consider providing more images at different anatomical planes of the hyperintensity within the MB, currently only one axial image is presented. This image is not compelling and the reviewer believes that the authors should consult with the radiologist to provide better leveled images showing the hyperintensity (sources for good quality images: Jung, Y. C., Chanraud, S., & Sullivan, E. V. (2012). Neuroimaging of Wernicke’s encephalopathy and Korsakoff’s syndrome. Neuropsychology review, 22, 170-180. or Sullivan, E. V., & Pfefferbaum, A. (2009). Neuroimaging of the Wernicke–Korsakoff syndrome. Alcohol & Alcoholism, 44(2), 155-165.). 

The authors should also include what scan protocol and the system was used to acquire the images. 

Answer: We thank the reviewer for the suggestion. We added more images with evidence of hyperintensity. We added the text as follows:

- Figure 1: “FLAIR Axial View of the Mammillary Bodies. Figure 1 demonstrates a FLAIR axial MRI image with increased signal intensity in the mammillary bodies, reflecting the classic neuropathological changes of Wernicke Encephalopathy, including neuronal loss, gliosis, and edema. The mammillary bodies are crucially implicated in the pathology of this disease, correlating with the clinical triad of confusion, ophthalmoplegia, and ataxia”.

- Figure 2: “Axial View of the Colliculi. Figure 2 presents a FLAIR axial MRI image showing hyperintense signal alterations in the region of the colliculi, indicative of edema and potential gliosis, commonly associated with Wernicke Encephalopathy. These findings highlight the characteristic involvement of central midbrain structures in this condition”.

- Figure 3: “FLAIR Views of the Periventricular Region of the Third Ventricle in Axial and Coronal Perspectives. Figures 3a and 3b showcase FLAIR MRI images in axial and coronal views, respectively, highlighting symmetric hyperintense signals around and in the periventricular region of the third ventricle. These images underscore the characteristic involvement of thalamic and hypothalamic regions in Wernicke Encephalopathy, reflecting the disease's predilection for periaqueductal gray matter.” (Line 123 to 148).

Additionally, within the methodology the exact tests used to assess the patient should be included. These are listed within the table of the results but the authors should provide context for what the tests are and why they were conducted for the readers.

Answer: Thank you for your insightful comment. We revised the neuropsychological assessment to include a comprehensive explanation of each test, along with its relevance to assessing the patient's condition. Please find the added text from Line 149-186.

Finally, the reviewer noticed the bloodwork conducted and results of the lumbar puncture were not reported. 

Was this patient tested for thiamine deficiency and what were levels like at the conclusion of the observations. Was a cause ever established to the development of the deficiency, did the patients care giver report dietary problems? 

Answer: We appreciate the reviewer bringing attention to the bloodwork conducted and the results of the lumbar puncture that were not reported in the initial submission. Please find the missing data in the text (see line 98-103 and table 2 at line 116). 

Regarding thiamine deficiency testing, the patient was indeed tested, and the results indicated a deficiency at the onset of observation. Please find the missing data in table 2 (line 116). 

Unfortunately the thiamine test at the conclusion of the observation period is missing data and we could not retrieve it. 

Patient's caregiver did not report dietary problems. As we write line 241 to 243 “We can assume that fasting weight loss and the hypercatabolic state secondary to acute pancreatitis led to a critical malnutrition state with a severe thiamine deficiency”.

We acknowledge the importance of including these details in our report and will ensure that they are properly addressed in the revised version. Thank you for bringing these concerns to our attention.

Minor Edits:     

There are some small sentence issues in the final paragraph of the case report section that should be clarified:

Answer: All sentences have been accordingly modified as suggested. All spelling and grammatical errors pointed out by the reviewers have been corrected.

"Difficulties of anterograde memory emerged, while the retrograde one was preserved,..." this should say while retrograde memory was preserved.

Answer: We agree with this comment. Therefore, we have accordingly modified the text to “ Difficulties of anterograde memory emerged, while retrograde memory was preserved” (Line 154-155)

"The tone of mood during the interview was fluctuating." The reviewer thinks that this sentence could be clearer, perhaps During the interview, the patient's mood flucuated... then provide an example: they were cheerful then morose.

Answer: Thank you for pointing this out. We changed accordingly to “During the interview, the patient’s mood appeared unstable and fluctuated from elated and cheerful to overwhelmed, sad or frustrated”. (Line 156-158) 

"The tone of voice was low. Good understanding of simple and complex sentences." These seem like sentence fragments. The patient had a low tone of voice but their understanding of simple and complex sentences was good.

Answer: Thank you for the comment. We apologize for this huge oversight. Text changes have been done accordingly. Please find the modified text: “The patient had a low tone of voice but their understanding of simple and complex sentences was good”. (Line 160-161).

Author Response File: Author Response.pdf