Disequilibrium, Rather than Postural Orthostatic Tachycardia Syndrome, Is the Primary Determinant of Orthostatic Intolerance in Patients with Long COVID
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsPlease see attached pdf
Comments for author File: 
Comments.pdf
Author Response
Response to the Editor and the Reviewers:
Thank you very much for your kind opinions and thoughtful comments which no doubt served to improve our manuscript. Now I have completed necessary corrections. I hope this version will be acceptable for publication in the Journal of Clinical Medicine.
The amended portions of the manuscript were indicated by highlighting in yellow.
Specifically,
Reviewer 1:
Title
Response:
Thank you very much for your comment.
I think this title would be fine because the main scope is completely covered.
Null hypothesis
Response:
Introduction
The potential role of disequilibrium in the development of OI has been neglected or ignored.
The aim of the study
Response:
In this study, in order to determine which factor, disequilibrium or POTS, plays a more crucial role in the development of OI in patients with long COVID, disequilibrium was assessed through neurological examinations, and POTS was evaluated during the active 10-min standing test.
The number of patients is very small.
Response:
Last in Discussion
The present study had a couple of limitations. First, the direct evidence showing the causal role of disequilibrium for OI is still lacking. Second, this study had the small sample size of 32 participants with long COVID from a single institute, which may destabilize regression coefficients, inflate correlation estimates, reduce generalizability, and limit subgroup analyses. Obviously, further investigation in a larger number of patients will be required to clarify the precise relation or causal relation between disequilibrium and OI, and its neural origin in patients with long COVID.
Power analysis for determining the minimal number
Response:
No, I did not, but just referred the previous my reports (Refs 11-13).
Statistical analysis
Response:
Materials and Methods
- Statistical analysis
Continuous variables are presented as mean ± standard deviation. Student's t-test was used to compare continuous variables. Proportional data were analyzed using Fisher's exact test. Independent factors including age, sex, disease duration, fibromyalgia, POTS, and disequilibrium, associated with OI were evaluated using a multiple regression analysis (BellCurve for Excel, version 4.07, Social Survey Research Information Co., Ltd). Statistical significance was set at two-sided p < 0.05.
(p <0.001, 95 % confidence interval, 0.32–0.96)
(p =0.049, 95 % confidence interval, -0.31 – -0.62)
Any other factors were not significantly associated.
The discussion section is very poor
Response:
Discussion
Almost all researchers have reported that OI is related to POTS associated with reduced cerebral blood flow [7-9, 18-20].
The exact cause of the disequilibrium observed in patients with long COVID remains to be clarified. Although a positive Romberg test suggests a significant visual sensory compensation for the apparent truncal ataxia, proprioceptive sense was not impaired in the patients, suggesting that spinal or sensory ataxia seems unlikely [13]. Also limb ataxia was not observed in the patients, suggesting that the main cause of the ataxia appears to be not of cerebellar origin. It appears to be of central vestibular origin, which is consistent with the previously revealed results of vestibular function tests in patients with chronic fatigue syndrome [21,22], although other mechanisms except central vestibular origin cannot be completely excluded. The vestibular system provides information on head translation, rotation, and orientation in a gravitational environment [23], critically contributing to postural stability. The corticovestibular network among the vestibular nucleus, several vestibular cortex, midbrain, and cerebellum is distributed throughout the brain and has a high degree of functional connectivity [23–25]. The pathogenesis of the observed neurologic defect of disequilibrium is probably caused by global neural inflammation in the brain [26].
[21] Furman JM. Testing of vestibular function: an adjunct in the assessment of chronic fatigue syndrome. Reviews of Infectious Diseases. 1991; 13: S109–S111. https://doi.org/10.1093/clinids/ 13.supplement_1.s109.
[22] Ash-Bernal R, Wall C, Komaroff AL, et al. Vestibular function test anomalies in patients with chronic fatigue syndrome. Acta Oto-Laryngologica. 1995; 115: 9–17. https://doi.org/10.3109/00016489509133339.
[23] Raiser TM, Flanagin VL, Duering M, et al. The human corticocortical vestibular network. NeuroImage. 2020; 223: 117362. https://doi.org/10.1016/ j.neuroimage.2020.117362.
[24] Brandt T, Strupp M, Arbusow V, Dieringer N. Plasticity of the vestibular system: central compensation and sensory substitution for vestibular deficits. Advances in Neurology. 1997; 73: 297–309.
[25] Brandt T, Dieterich M. The dizzy patient: don’t forget disorders of the central vestibular system. Nature Reviews. Neurology. 2017; 13: 352–362. https://doi.org/10.1038/nrneurol.2017.58.
[26] Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. Journal of Nuclear Medicine. 2014; 55: 945–950. https://doi.org/10.2967/jnumed.113.131045.
Importance of oral health
Response:
Oral health is not related to OI.
Table 3 should be in the Results section.
Response:
This table should be in the Discussion because this table does not show the individual results from the present study.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript presents a clinical evaluation of 32 patients with long COVID to assess whether disequilibrium—rather than postural orthostatic tachycardia syndrome (POTS)—constitutes the principal determinant of orthostatic intolerance (OI). Neurological assessments (Romberg and tandem gait tests) and an active 10‑minute standing test were used to evaluate the association between postural instability and OI. The authors report that disequilibrium strongly correlates with OI, whereas POTS appears inversely correlated. The findings are interesting and clinically relevant, particularly given the growing recognition of neurological and vestibular manifestations in long COVID. The paper is straightforward and generally well structured. However, several improvements are needed to strengthen the scientific rigor and interpretability of the findings.
1. Statistical Power and Limitations of Small Sample Size
With only 32 subjects and multiple covariates examined via regression analysis, the study is underpowered to draw definitive conclusions. Please explicitly acknowledge the risk of overfitting, type I errors, and type II errors, which are more likely with small n and multiple predictors. The limitations section should discuss how the restricted sample size may destabilize regression coefficients, inflate correlation estimates, reduce generalizability, limit subgroup analyses (e.g., POTS with vs. without disequilibrium).
2. Clarify That the Study Shows Correlation, Not Causation
Several sections imply a directional relationship (“disequilibrium… plays an etiologic role”), but only correlational data were collected. Please adjust phrasing throughout the manuscript to avoid causal inference unless supported by mechanistic or longitudinal evidence. More details in the comment below.
3. Expand the Physiological / Pathophysiological Rationale
To strengthen the biological plausibility and interpretation of the findings, the discussion should elaborate on: 1) How central or peripheral vestibular dysfunction could contribute to OI. 2) The interplay between postural reflexes, cerebellar pathways, and autonomic responses during upright posture. 3) Potential shared neurological pathways between disequilibrium in ME/CFS and long COVID, as suggested by the cited literature. 4) Why disequilibrium might serve as a sensitive clinical marker for OI, particularly in patients with long COVID. Adding this physiological context would help justify why disequilibrium may correlate more strongly with OI than POTS in this clinical cohort.
4. Methods for Statistical Analysis and Software
The manuscript does not specify the statistical methods used (e.g., type of regression model, assumptions tested, how missing data were handled),the statistical software/environment used. Please include a dedicated subsection in the Methods that describes, including all statistical tests applied (e.g., regression, correlation, group comparisons), significance thresholds (e.g., two‑sided p<0.05), software used (R, SPSS, GraphPad, etc.), any correction for multiple comparisons (if none, state so explicitly).
5. Visualization of Statistical Results
The manuscript would benefit significantly from visual representations of the data. Author is suggested to show the scatter plots with regression lines showing disequilibrium vs. OI outcome; Bar charts or violin plots comparing standing time between groups (with vs. without disequilibrium); A correlation matrix visualizing relationships among variables (age, sex, disease duration, POTS, disequilibrium, OI). Such figures would make the findings more accessible and visually support the authors’ conclusions.
Minor Comments
1. Consider reporting effect sizes and confidence intervals, which improve interpretation beyond p-values alone.
2. Consider briefly discussing potential selection bias (e.g., patients able to ambulate and attend clinic visits).
Author Response
Response to the Editor and the Reviewers:
Thank you very much for your kind opinions and thoughtful comments which no doubt served to improve our manuscript. Now I have completed necessary corrections. I hope this version will be acceptable for publication in the Journal of Clinical Medicine.
The amended portions of the manuscript were indicated by highlighting in yellow.
Specifically,
Reviewer: 2
Reviewer’s comments:
- Statistical power and limitations of small sample size
Response:
Last in Discussion
The present study had a couple of limitations. First, the direct evidence showing the causal role of disequilibrium for OI is still lacking. Second, this study had the small sample size of 32 participants with long COVID from a single institute, which may destabilize regression coefficients, inflate correlation estimates, reduce generalizability, and limit subgroup analyses. Obviously, further investigation in a larger number of patients will be required to clarify the precise relation or causal relation between disequilibrium and OI, and its neural origin in patients with long COVID. Also whether disequilibrium is related to possible cerebral hypoperfusion while standing upright in the study patients with long COVID remains to be elucidated.
- Clarity that the study shows correlation, not causation
Response:
Introduction
suggesting that disequilibrium or truncal ataxia may play an etiologic role in OI.
Last in Discussion
In conclusion, disequilibrium, rather than POTS, wasappeared to be the primary determinant of OI in patients with long COVID.
- Expand the physiological/pathophysiological rationale
Response:
Almost all researchers have reported that OI is related to POTS associated with reduced cerebral blood flow [7-9, 18-20].
The exact cause of the disequilibrium observed in patients with long COVID remains to be clarified. Although a positive Romberg test suggests a significant visual sensory compensation for the apparent truncal ataxia, proprioceptive sense was not impaired in the patients, suggesting that spinal or sensory ataxia seems unlikely [13]. Also limb ataxia was not observed in the patients, suggesting that the main cause of the ataxia appears to be not of cerebellar origin. It appears to be of central vestibular origin, which is consistent with the previously revealed results of vestibular function tests in patients with chronic fatigue syndrome [21,22], although other mechanisms except central vestibular origin cannot be completely excluded. The vestibular system provides information on head translation, rotation, and orientation in a gravitational environment [23], critically contributing to postural stability. The corticovestibular network among the vestibular nucleus, several vestibular cortex, midbrain, and cerebellum is distributed throughout the brain and has a high degree of functional connectivity [23–25]. The pathogenesis of the observed neurologic defect of disequilibrium is probably caused by global neural inflammation in the brain [26].
- Furman JM. Testing of vestibular function: an adjunct in the assessment of chronic fatigue syndrome. Reviews of Infectious Diseases. 1991; 13: S109–S111. https://doi.org/10.1093/clinids/ 13.supplement_1.s109.
- Ash-Bernal R, Wall C, Komaroff AL, et al. Vestibular function test anomalies in patients with chronic fatigue syndrome. Acta Oto-Laryngologica. 1995; 115: 9–17. https://doi.org/10.3109/00016489509133339.
- Raiser TM, Flanagin VL, Duering M, et al. The human corticocortical vestibular net work. NeuroImage. 2020; 223: 117362. https://doi.org/10.1016/ j.neuroimage.2020.117362.
- Brandt T, Strupp M, Arbusow V, Dieringer N. Plasticity of the vestibular system: central compensation and sensory substitution for vestibular deficits. Advances in Neurology. 1997; 73: 297–309.
- Brandt T, Dieterich M. The dizzy patient: don’t forget disorders of the central vestibular system. Nature Reviews. Neurology. 2017; 13: 352–362. https://doi.org/10.1038/nrneurol.2017.58.
- Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. Journal of Nuclear Medicine. 2014; 55: 945–950. https://doi.org/10.2967/jnumed.113.131045.
Methods for statistical results
Response:
Materials and Methods
- Statistical analysis
Continuous variables are presented as mean ± standard deviation. Student's t-test was used to compare continuous variables. Proportional data were analyzed using Fisher's exact test. Independent factors including age, sex, disease duration, fibromyalgia, POTS, and disequilibrium, associated with OI were evaluated using a multiple regression analysis (BellCurve for Excel, version 4.07, Social Survey Research Information Co., Ltd). Statistical significance was set at two-sided p < 0.05.
(p <0.001, 95 % confidence interval, 0.32–0.96)
(p =0.049, 95 % confidence interval, -0.31 – -0.62)
Any other factors were not significantly associated.
- Visualization of statistical results
Response:
Only 7 patients failed to complete the 10-min standing test while the other 25 patients completed the test. Therefore, only 7 points of standing time scatters while the other 25 points stands on the same line of 10 min. The figure is not so impressive and maybe redundant, so I would like to give up adding such a figure.
Minor comments
Response:
Included above
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript has beem improved
