Rehabilitation After Severe Traumatic Brain Injury with Acute Symptomatic Seizure: Neurofeedback and Motor Therapy in a 6-Month Follow-Up Case Study
, Stefania De Trane 3 and Gianvito Lagravinese 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Author,
This is an interesting case report however, as having a first seizure >7 days post-injury was definition, however, the case description states the injury occurred on April 21 and the seizure on April 27 (Day 6).
The manuscript may need to be reframed as treating "Severe TBI with acute symptomatic seizure" or the authors must provide evidence of subsequent unprovoked seizures to justify the PTE label.
The authors need to add details regarding attributing gains solely to NFB/Motor therapy versus natural history.
If the authors can clarify the diagnostic terminology and use more scientific language, the paper may be accepted for publication.
Needs editing for language and grammar
Author Response
Answer to Reviewer 1
Comment: “Dear Author,
This is an interesting case report however, as having a first seizure >7 days post-injury was definition, however, the case description states the injury occurred on April 21 and the seizure on April 27 (Day 6). The manuscript may need to be reframed as treating "Severe TBI with acute symptomatic seizure" or the authors must provide evidence of subsequent unprovoked seizures to justify the PTE label.
The authors need to add details regarding attributing gains solely to NFB/Motor therapy versus natural history. If the authors can clarify the diagnostic terminology and use more scientific language, the paper may be accepted for publication.”
Answer: “We thank the Reviewer for the constructive comments. We agree that, according to current ILAE criteria, the seizure occurring on day 6 after injury is classified as an acute symptomatic seizure and does not alone establish a diagnosis of post-traumatic epilepsy. The manuscript has therefore been reframed accordingly: the title, abstract, and case description now refer to severe traumatic brain injury with acute symptomatic seizure, and no diagnosis of established PTE is attributed to the patient. Clarifying statements have been added to the Introduction and Discussion to distinguish acute symptomatic seizures from PTE while highlighting their association with increased epileptogenic risk. Regarding treatment effects, we explicitly acknowledge that observed improvements cannot be attributed solely to neurofeedback and motor therapy. The Discussion has been revised to address the role of natural recovery, and causal language has been consistently softened, interpreting the findings as the result of an interaction between spontaneous recovery, conventional rehabilitation, and adjunctive neurofeedback. Finally, diagnostic terminology and scientific language have been refined throughout the manuscript to improve clarity, consistency, and adherence to current consensus definitions. All requested revisions, additions, and clarifications have been fully incorporated into the manuscript and are highlighted in blue for ease of review.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors have reported the possible beneficial effects of the combined use of neurofeedback and motor therapy in improving motor and cognitive functioning in a patient with post-traumatic epilepsy (PTE). They conclude that integrating NFB with motor therapy can foster sustained neuroplasticity and enhance recovery in PTE.
The manuscript is well written and provides detailed descriptions of the results and methods; the discussion is well supported by the authors' findings. Only a slight English revision is needed.
I recommend to better discuss on the impact of antiepileptic drugs on the combined use of neurofeedback and motor therapy.
Author Response
Answer to Reviewer 2
Comment: “The authors have reported the possible beneficial effects of the combined use of neurofeedback and motor therapy in improving motor and cognitive functioning in a patient with post-traumatic epilepsy (PTE). They conclude that integrating NFB with motor therapy can foster sustained neuroplasticity and enhance recovery in PTE. The manuscript is well written and provides detailed descriptions of the results and methods; the discussion is well supported by the authors' findings. Only a slight English revision is needed.I recommend to better discuss on the impact of antiepileptic drugs on the combined use of neurofeedback and motor therapy.”
Answer: “We thank the Reviewer for the positive evaluation of the manuscript and for the helpful suggestion. In response, we have expanded the Discussion to better address the potential impact of antiepileptic drug (AED) therapy on the combined use of neurofeedback and motor rehabilitation. Specifically, we now discuss how AEDs may influence cortical excitability, cognitive functioning, and neuroplastic processes, and how these effects could interact with neuromodulatory and rehabilitative interventions. We also clarify that the patient was treated with levetiracetam throughout the rehabilitation period and that the observed outcomes likely reflect an interaction between pharmacological stabilization, conventional motor therapy, and adjunctive neurofeedback, rather than the isolated effect of any single component. In addition, minor English revisions have been made throughout the manuscript to further improve clarity and readability.”
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsI read the manuscript as a rehabilitation-oriented case report that tries to connect neurofeedback, motor therapy, cognitive change, and electrophysiology over a meaningful follow-up interval. The clinical narrative is engaging, and the authors deserve credit for attempting a multimodal, longitudinal description rather than limiting the report to a single post-treatment snapshot. With a few epilepsy-focused clarifications and slightly more cautious causal language, the paper would be easier to endorse from an epileptologist’s perspective.
The largest issue is the diagnostic framing of “post-traumatic epilepsy.” In the current description, the clearly documented seizure occurs within the first week after the injury and is temporally linked to hyponatremia. That combination strongly favors an acute symptomatic early post-traumatic seizure rather than established epilepsy. If late unprovoked seizures occurred after day seven, the report should state this explicitly with dates, semiology, recurrence pattern, and any triggers. If no late unprovoked seizures occurred, it would be more accurate to reframe the case as traumatic brain injury with an early symptomatic seizure and elevated risk of subsequent epilepsy, while focusing the intervention narrative on neurorehabilitation and risk context rather than treatment of a confirmed epileptic disorder.
Closely related, the manuscript needs a seizure outcome statement as a primary endpoint. For an epilepsy readership, the central question is whether seizures recurred, whether there was seizure freedom, whether semiology or severity changed, and whether there were any nocturnal events, auras, emergency visits, or suspected subclinical episodes during the intervention and through the six-month follow-up. Even in a single case, a simple timeline-style narrative of seizure burden and monitoring is essential. Without this, it becomes difficult to interpret the clinical significance of the neurofeedback protocol in epilepsy-relevant terms, and the manuscript risks being read as implying seizure control without demonstrating it.
The EEG discussion would also benefit from a clearer distinction between post-injury slowing and epileptiform activity. Bilateral theta slowing after traumatic brain injury is common and not, by itself, evidence of epilepsy. When the report mentions rare graphoelements of uncertain epileptiform morphology, the reader needs a clearer explanation of what was seen and why it was or was not considered epileptiform. A concise, structured EEG impression using standard language (background, focal/generalized slowing, epileptiform discharges present or absent, activation responses) would add credibility. If there were meaningful changes on subsequent EEGs, describing the evolution plainly would strengthen the longitudinal argument.
Medication management is another area that will draw reviewer attention. The manuscript should state whether levetiracetam was continued unchanged, adjusted, or tapered, and clarify the rationale in the context of early symptomatic seizure versus late unprovoked seizure recurrence. If the intent is to present neurofeedback as adjunctive to antiseizure medication, that is reasonable, but the text should avoid implying medication replacement unless the case data truly support that claim and the clinical decision-making is transparent.
Regarding the neurofeedback protocol, the rationale for SMR-focused training is broadly consistent with historical approaches used in seizure-prone populations. Still, the shift in training montage and targets mid-course (for example, moving from a central to a more frontal emphasis) should be explained in a way that makes sense to epilepsy clinicians. If the latter phase was primarily aimed at executive functioning, attention, or affect regulation rather than seizure risk modulation, stating that explicitly would help align expectations. It would also be reassuring to include a brief safety description: whether any symptoms suggested seizure provocation, how sessions were monitored, and whether any adverse events occurred.
The statistical framing around qEEG in a single-case design should be softened. It is understandable to want to quantify change, but inferential p-values across multiple electrodes and frequency bands in a single individual may be overstated. The report will likely be better received if it emphasizes descriptive changes, movement toward normative ranges, and clinically interpretable patterns, while acknowledging that any statistical testing is exploratory and not a substitute for controlled inference.
Finally, a few editorial points would improve clarity and credibility. Using contemporary ILAE-style terminology for seizure descriptions and “antiseizure medication” language will make the epilepsy framing more professional. Some functional test values appear unusually fast and would benefit from a quick verification of the protocol and units to avoid a credibility hit. The ethics/consent section also needs to be complete and unambiguous about consent for publication and whether the work was handled as clinical care, quality improvement, or research. A simple visual timeline that aligns injury date, seizure(s), electrolyte disturbance, EEG/qEEG assessments, neurofeedback sessions, motor therapy, and follow-up would substantially improve readability and make the sequence of events immediately clear.
In summary, the paper has a compelling rehabilitation narrative and thoughtful follow-up, but it currently overreaches in the epilepsy diagnosis and underreports seizure outcomes. If the authors clarify whether late unprovoked seizures occurred, report seizure burden clearly, refine EEG interpretation, and temper causal claims, the manuscript will read as a much stronger and more credible contribution at the interface of neurorehabilitation and seizure risk management.
Author Response
Answer to Reviewer 3
Comment: I read the manuscript as a rehabilitation-oriented case report that tries to connect neurofeedback, motor therapy, cognitive change, and electrophysiology over a meaningful follow-up interval. The clinical narrative is engaging, and the authors deserve credit for attempting a multimodal, longitudinal description rather than limiting the report to a single post-treatment snapshot. With a few epilepsy-focused clarifications and slightly more cautious causal language, the paper would be easier to endorse from an epileptologist’s perspective.
Answer: We thank the Reviewer for this constructive evaluation. We appreciate the recognition of the longitudinal and multimodal rehabilitation framework and agree that epilepsy-focused clarification and cautious causal framing are essential for an epileptology-oriented readership. In response, we have carefully revised the manuscript to refine the diagnostic framing, clarify seizure outcomes, strengthen EEG interpretation, and temper causal language where appropriate, while preserving the rehabilitative focus of the case.
All requested revisions, additions, and clarifications have been fully incorporated into the manuscript and are highlighted in blue for ease of review.
Comment: The largest issue is the diagnostic framing of “post-traumatic epilepsy.” In the current description, the clearly documented seizure occurs within the first week after the injury and is temporally linked to hyponatremia. That combination strongly favors an acute symptomatic early post-traumatic seizure rather than established epilepsy. If late unprovoked seizures occurred after day seven, the report should state this explicitly with dates, semiology, recurrence pattern, and any triggers. If no late unprovoked seizures occurred, it would be more accurate to reframe the case as traumatic brain injury with an early symptomatic seizure and elevated risk of subsequent epilepsy, while focusing the intervention narrative on neurorehabilitation and risk context rather than treatment of a confirmed epileptic disorder.
Answer: We fully agree with the Reviewer. The seizure documented in this case occurred within the first 7 days after injury and in the context of hyponatremia, fulfilling ILAE criteria for an acute symptomatic seizure rather than post-traumatic epilepsy (PTE). The manuscript has been reframed accordingly. The title, abstract, Introduction, and Case Presentation now consistently describe the patient as having severe TBI with an early acute symptomatic seizure and an elevated risk of epileptogenesis, rather than a diagnosis of established epilepsy. Additional clarifications distinguishing acute symptomatic seizures from PTE have been added in both the Introduction and Discussion.
Comment: “Closely related, the manuscript needs a seizure outcome statement as a primary endpoint. For an epilepsy readership, the central question is whether seizures recurred, whether there was seizure freedom, whether semiology or severity changed, and whether there were any nocturnal events, auras, emergency visits, or suspected subclinical episodes during the intervention and through the six-month follow-up. Even in a single case, a simple timeline-style narrative of seizure burden and monitoring is essential. Without this, it becomes difficult to interpret the clinical significance of the neurofeedback protocol in epilepsy-relevant terms, and the manuscript risks being read as implying seizure control without demonstrating it.
Answer: We appreciate this important observation. A clear seizure outcome statement has now been explicitly included in the Results section at the end of the 6-month EEG follow-up. We clarify that no further clinical seizures, auras, nocturnal events, or emergency visits occurred during the inpatient rehabilitation period or throughout the 6-month follow-up. Antiseizure medication (levetiracetam 500 mg twice daily) was maintained unchanged, and follow-up EEG recordings showed no evidence of emerging epileptiform activity. This addition provides a transparent timeline-style account of seizure burden and monitoring.
Comment: The EEG discussion would also benefit from a clearer distinction between post-injury slowing and epileptiform activity. Bilateral theta slowing after traumatic brain injury is common and not, by itself, evidence of epilepsy. When the report mentions rare graphoelements of uncertain epileptiform morphology, the reader needs a clearer explanation of what was seen and why it was or was not considered epileptiform. A concise, structured EEG impression using standard language (background, focal/generalized slowing, epileptiform discharges present or absent, activation responses) would add credibility. If there were meaningful changes on subsequent EEGs, describing the evolution plainly would strengthen the longitudinal argument.
Answer: We thank the Reviewer for this key point. The EEG description has been revised using standard electroencephalographic terminology to clearly distinguish post-injury slowing from epileptiform activity. Bilateral theta slowing is now explicitly framed as a common and nonspecific post-traumatic finding. The previously mentioned rare graphoelements are described as isolated, non-reproducible sharp transients without consistent morphology or spatial distribution and therefore not meeting criteria for epileptiform discharges. Furthermore, longitudinal EEG evolution is now described plainly, highlighting stabilization of background alpha activity and the absence of progression toward a focal or generalized epileptic pattern on follow-up. These clarifications are incorporated in the EEG Methods, Results, and Discussion sections.
Comment: Medication management is another area that will draw reviewer attention. The manuscript should state whether levetiracetam was continued unchanged, adjusted, or tapered, and clarify the rationale in the context of early symptomatic seizure versus late unprovoked seizure recurrence. If the intent is to present neurofeedback as adjunctive to antiseizure medication, that is reasonable, but the text should avoid implying medication replacement unless the case data truly support that claim and the clinical decision-making is transparent.
Answer: This point has been clarified. The manuscript now explicitly states that levetiracetam (500 mg twice daily) was continued unchanged throughout the intervention and follow-up period, with no dose adjustments or attempts at withdrawal. Neurofeedback is consistently described as an adjunctive intervention within a multidisciplinary rehabilitation program and not as a replacement for antiseizure medication.
Comment: Regarding the neurofeedback protocol, the rationale for SMR-focused training is broadly consistent with historical approaches used in seizure-prone populations. Still, the shift in training montage and targets mid-course (for example, moving from a central to a more frontal emphasis) should be explained in a way that makes sense to epilepsy clinicians. If the latter phase was primarily aimed at executive functioning, attention, or affect regulation rather than seizure risk modulation, stating that explicitly would help align expectations.
Answer: We thank the Reviewer for this suggestion. The rationale for the shift from Cz to Fz electrode placement is now explicitly explained in the Methods and Discussion. This adjustment was guided by the patient’s clinical profile and baseline qEEG findings and was intended to target executive and affective domains rather than seizure control, thereby aligning expectations for epilepsy clinicians.
Comment: It would also be reassuring to include a brief safety description: whether any symptoms suggested seizure provocation, how sessions were monitored, and whether any adverse events occurred.
Answer: We have added a statement confirming that no adverse effects, seizure exacerbations, or clinical deteriorations were observed during or after neurofeedback sessions. Each session was monitored in real time by trained staff, and clinical status was assessed daily during inpatient rehabilitation.
Comment: The statistical framing around qEEG in a single-case design should be softened. It is understandable to want to quantify change, but inferential p-values across multiple electrodes and frequency bands in a single individual may be overstated. The report will likely be better received if it emphasizes descriptive changes, movement toward normative ranges, and clinically interpretable patterns, while acknowledging that any statistical testing is exploratory and not a substitute for controlled inference.
Answer: We agree with this methodological concern. The Discussion now explicitly states that all qEEG statistical analyses are exploratory and descriptive in nature. Greater emphasis is placed on directionality of change, movement toward normative ranges, and convergence with clinical outcomes, rather than inferential or causal conclusions.
Comment: Finally, a few editorial points would improve clarity and credibility. Using contemporary ILAE-style terminology for seizure descriptions and “antiseizure medication” language will make the epilepsy framing more professional. Some functional test values appear unusually fast and would benefit from a quick verification of the protocol and units to avoid a credibility hit. The ethics/consent section also needs to be complete and unambiguous about consent for publication and whether the work was handled as clinical care, quality improvement, or research. A simple visual timeline that aligns injury date, seizure(s), electrolyte disturbance, EEG/qEEG assessments, neurofeedback sessions, motor therapy, and follow-up would substantially improve readability and make the sequence of events immediately clear.
Answer: We have revised terminology throughout the manuscript to align with contemporary ILAE standards, consistently using “antiseizure medication” and standardized seizure classification language. Functional test values were rechecked to confirm correct units and administration. The Ethics section now clearly states that written informed consent for publication was obtained and that the intervention was conducted as part of standard clinical rehabilitation care. While a graphical timeline was not added due to space considerations, the temporal sequence of injury, seizure, EEG/qEEG assessments, rehabilitation, and follow-up has been made explicit in the text.
Comment: In summary, the paper has a compelling rehabilitation narrative and thoughtful follow-up, but it currently overreaches in the epilepsy diagnosis and underreports seizure outcomes. If the authors clarify whether late unprovoked seizures occurred, report seizure burden clearly, refine EEG interpretation, and temper causal claims, the manuscript will read as a much stronger and more credible contribution at the interface of neurorehabilitation and seizure risk management.”
Answer: We thank the Reviewer for this helpful concluding perspective. The manuscript has been revised to clarify diagnostic classification, explicitly report seizure outcomes over time, refine EEG interpretation, and adopt a more cautious causal framework. By doing so, we aimed to improve both clinical precision and interpretability for an epilepsy-focused readership, while maintaining the core rehabilitative narrative of the case.
Author Response File: Author Response.pdf
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have satisfied my comments.
