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Exploring conservative avenues in subacute subdural hematoma: the potential role of atorvastatin and dexamethasone as lifesaving allies

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Title: Exploring conservative avenues in subacute subdural hematoma: the potential role of atorvastatin and dexamethasone as lifesaving allies Authors: Tao Liu et al. DOI: 10.1186/s41016-025-00393-8 PMID: 40176171

Type of Study

This is a retrospective case series involving five patients with subacute subdural hematoma (sASDH), who were managed conservatively using atorvastatin and low-dose dexamethasone without surgical intervention. It also includes a non-systematic narrative review of existing literature, lacking formal meta-analytic methodology.

Critical Appraisal

Strengths

  • The article raises an important question: can we optimize conservative treatment for sASDH in inoperable patients?
  • A novel hypothesis is proposed, leveraging two commonly available pharmacologic agents.

Fatal Flaws

1. Sample Size and Selection Bias

The study is limited to five hand-picked cases, all of whom refused surgery. There is no control group, no randomization, and no standardization in patient selection. This introduces massive selection bias and confounding, rendering the findings anecdotal at best.

2. Lack of Statistical Power

With only five patients, the study is grossly underpowered to draw any conclusions on safety or efficacy. Even if all patients improved, the positive predictive value is negligible.

3. Absence of Mechanistic Evidence

The article alludes vaguely to the “possible mechanisms” of action of atorvastatin and dexamethasone but fails to elaborate with any molecular, imaging, or biomarker-based support. The hypothesized synergy is speculative and not experimentally validated.

4. Cherry-Picking Literature

The review portion pulls from only six studies without PRISMA methodology, inclusion/exclusion criteria, or risk-of-bias assessments. This is not a systematic review but rather a collection of cherry-picked studies to support a preconceived narrative.

5. Logical Fallacy: Post Hoc Ergo Propter Hoc

The authors infer that improvement after administration of atorvastatin and dexamethasone implies causality. This is a classic post hoc fallacy. No causation can be inferred from such a weak observational structure.

6. Ethical and Practical Concerns

Presenting this treatment strategy without rigorous evidence could mislead clinicians, delay necessary surgery, or foster false confidence in a pharmacological approach for a condition where deterioration can be catastrophic.

Bottom Line

The article is a speculative and weakly documented case series attempting to repurpose two drugs in the treatment of sASDH. While the intention is noble, the scientific execution is fundamentally flawed. No clinical decisions should be influenced by this paper. What is needed is a properly designed randomized controlled trial, not a narrative built on five anecdotal successes.

See also: subdural_hematoma, conservative_management, evidence_based_medicine

Mayo Clinic Vestibular Schwannoma Quality of Life Index 

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“Improving access to vestibular schwannoma quality of life research through multilanguage translations of the Mayo Clinic Vestibular Schwannoma Quality of Life Index” (*Carlson et al., J Neurosurg. 2025;142(Suppl):S2. doi:10.3171/2024.11.JNS242317*)

This article reports on the translation of the Mayo Clinic Vestibular Schwannoma Quality of Life Index into six widely spoken languages: Simplified Chinese, Spanish, Japanese, Arabic, French, and Norwegian. It is presented as a digital supplement to the *Journal of Neurosurgery* and is positioned as a response to a key limitation in vestibular schwannoma research: the lack of validated, multilingual tools to assess the quality of life (QOL) in a culturally diverse patient population.

The VSQOL Index, developed originally in English, is a domain-specific tool covering eight core categories that reflect the multidimensional burden of VS, ranging from hearing loss to psychosocial and cognitive impacts. The article emphasizes accessibility, global equity in research, and the potential for cross-cultural validation.

2. Strengths

– Timely and Inclusive Effort: In a field increasingly aware of the importance of patient-reported outcomes (PROs), the expansion of the VSQOL Index to multiple languages addresses a real and urgent need. The effort reflects a commitment to diversity, equity, and inclusion (DEI) in neurosurgical research.

– Breadth of Domains: The eight domains covered are comprehensive and clinically relevant, reflecting an understanding of VS as a condition that affects patients beyond physical symptoms.

– Noncommercial Open Access: Making the tool freely available for noncommercial use significantly boosts its adoption potential in both research and clinical settings.

– Forward-Looking Implementation Strategy: By inviting further translations and offering a methodology for doing so, the authors promote scalability and community collaboration.

3. Limitations and Areas for Improvement

– Lack of Validation Data for Translations: A critical omission is the absence of psychometric validation data for the translated versions. Translation alone does not ensure cultural equivalence or measurement validity. Were back-translations performed? Were cognitive interviews or pilot tests conducted in native-speaking populations?

– No Discussion on Linguistic/Cultural Adaptation Challenges: Certain concepts (e.g., “regret” or “impact on employment”) may not translate directly or may have different cultural connotations, particularly in non-Western contexts. This nuance is missing.

– Digital Supplement Format: The article feels more like a resource announcement than a full scientific paper. There’s no detailed methodology on how the translations were produced, reviewed, or tested. A table comparing the original and translated items or discussing challenges in specific languages would have enriched the value.

– Unclear How This Affects Clinical Decision-Making: Although QOL is important, the article could have outlined practical examples of how this tool has been or could be used to guide treatment planning, shared decision-making, or monitoring outcomes in real-world clinics.

4. Future Directions

– Cross-Cultural Validation Studies: Essential next steps include conducting validation study in diverse populations to confirm that the VSQOL Index is both reliable and sensitive across languages and cultures.

– Integration into Registries and Trials: The authors could propose integrating the VSQOL Index into prospective multicenter studies or national registries, which would increase the visibility and utility of the tool.

– Digital Implementation: The use of a mobile app or integration with electronic health records (EHRs) for real-time patient input could enhance its impact and usability in clinical workflows.

Conclusion

Carlson et al. make a significant and commendable contribution to the field of vestibular schwannoma research by expanding the reach of a multidimensional QOL assessment tool through multilingual translation. However, to truly fulfill its potential, the translated versions must undergo rigorous psychometric validation, and future work should aim to embed the Index in clinical and research settings more explicitly. As it stands, this is a valuable first step—but just the beginning—in making QOL data accessible and actionable in a globalized neurosurgical landscape.

Disparities and Variability in Hospital Management of Mild Traumatic Brain Injury

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Disparities and Variability in Hospital Management of Mild Traumatic Brain Injury

Latest Pubmed Titles

1. Socioeconomic Disparities

Insurance status significantly influences management decisions:

Uninsured patients are less likely to be admitted, even when clinical factors may justify observation.

Privately insured or Medicare/Medicaid-covered individuals often receive more resource-intensive care, including imaging, neurosurgical consults, and longer admissions.

2. Racial and Ethnic Disparities

Non-White, non-Black, non-Hispanic patients may experience:

Lower odds of discharge to home

Longer hospital stays but not necessarily associated with better outcomes

Potential underuse or delayed access to follow-up care (rehabilitation, neuropsychology)

3. Hospital-Level Variability

Wide differences exist between hospitals in:

Admission rates for mTBI

Length of stay (LOS) for admitted patients

Discharge disposition (home vs. skilled nursing facility vs. rehab)

Level 1 trauma centers tend to have longer LOS, but paradoxically, their patients are less likely to be discharged home, possibly reflecting:

More cautious or protocol-driven care

Complex patient populations

System inefficiencies or defensive medicine practices

4. Geographic Variation

Rural vs. urban hospitals may differ in resource availability:

Rural centers might discharge more patients directly from the ED due to lack of neuroimaging or neurosurgical backup.

Urban or academic centers may admit more patients for observation and follow-up care coordination.

5. Clinical Protocols and Decision Tools

Variability is also driven by a lack of standardization:

Some centers use evidence-based decision rules (e.g., Canadian CT Head Rule), while others rely on individual clinician judgment.

Institutional differences in admission criteria for elderly patients, those on anticoagulants, or those with minor CT findings.

🧩 Implications for Practice and Policy

Disparities in mTBI care may lead to:

Under-treatment of vulnerable populations

Over-utilization in low-risk cases due to defensive medicine

Inefficient use of hospital resources

There’s a growing need for:

Nationally standardized care pathways

Cultural competence training

Policy reform targeting access and equity

Quality benchmarking across institutions

Scoping reviews

A scoping review, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, was used to explore three electronic databases- PubMed, Medline, and CINAHL. Searches identified peer-reviewed empirical literature addressing aspects of the Social determinants of health and HDs related to TBI. A total of 123 records were identified and reduced to 27 studies based on the inclusion criteria. Results revealed that race/ethnicity was the most commonly reported Social determinant of health impacting TBI, followed by an individual’s insurance status. Health disparities were noted to occur across the continuum of TBI, including TBI risk, acute hospitalization, rehabilitation, and recovery. The most frequently reported HD was that Whites are more likely to be discharged to inpatient rehabilitation compared to racial/ethnic minorities. Health disparities associated with TBI are most commonly associated with the race/ethnicity SDoH, though insurance status and socioeconomic status commonly influence health inequities as well. The additional need for evidence related to the impact of other, lesser-researched SDoH is discussed, as well as clinical implications that can be used to target intervention for at-risk groups using an individual’s known Social determinants of health 1)

Retrospective observational cohort studies

A total of 122,406 patients with mTBI were included.

Vattipally et al. performed hierarchical logistic regression to investigate associations of patient-level variables with inpatient admission. Among hospitalized patients, a hierarchical linear regression was constructed for associations with LOS, including hospitals as a random effects term. Based on random effects coefficients, hospitals were classified as high-LOS outliers or non-outliers.

Main measures: Univariable comparisons on facility characteristics were performed. Patients were propensity score matched across hospital outlier status, and a multivariable logistic regression for associations with discharge to home was performed.

Results: The median age was 63 years (interquartile range [IQR], 42-77 years), and 111 306 (91%) patients experienced inpatient admission. Uninsured status was associated with lower odds of inpatient admission (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.65-0.76; P < .001). After excluding very low-volume hospitals, 80,258 admitted patients were treated across 469 hospitals, and 98 were designated as high-LOS outliers. These were more likely to be Level 1 trauma centers (76% vs. 26%; P < .001). After matching, patients treated at high-LOS outlier hospitals were less likely to experience home discharge (OR, 0.89; 95% CI, 0.85-0.93; P < .001). This effect was amplified for patients identifying as non-White, non-Black, non-Hispanic other races (P = .003).

Inpatient admission after mTBI varies by insurance status, with uninsured patients less likely to be admitted. There is significant interhospital variation in LOS, with Level 1 trauma centers more likely to be high-LOS outliers. Despite their longer LOS, patients treated at outlier hospitals experienced lower odds of home discharge 2).

This study provides valuable evidence on disparities and variability in the hospital management of patients with mild traumatic brain injury (mTBI) in the United States. Using a large national dataset and robust statistical methods, the authors demonstrate that factors such as insurance status, hospital type, and patient race/ethnicity significantly influence decisions around hospital admission, length of stay (LOS), and likelihood of discharge to home.

However, the retrospective design and reliance on administrative data limit causal interpretation and prevent adjustment for key clinical variables. The classification of hospitals as LOS outliers should also be interpreted with caution, as longer stays may reflect more comprehensive care or greater patient complexity, rather than inefficiency.

Overall, the study highlights the urgent need for healthcare policies aimed at reducing inequities and standardizing care criteria for mTBI, while still respecting patient-level nuances and hospital contexts. Future research should integrate more detailed clinical data and explore targeted interventions to improve both equity and efficiency in mTBI care.

A secondary analysis of ED visits in the National Hospital Ambulatory Medical Care Survey for the years 1998 through 2000 was performed. Cases of mTBI were identified using ICD-9 codes 800.0, 800.5, 850.9, 801.5, 803.0, 803.5, 804.0, 804.5, 850.0, 850.1, 850.5, 850.9, 854.0, and 959.01. ED care variables related to imaging, procedures, treatments, and disposition were analyzed along racial, ethnic, and gender categories. The relationship between race, ethnicity, and selected ED care variables was analyzed using multivariate logistic regression with control for associated injuries, geographic region, and insurance type.

The incidence of mTBI was highest among men (590/100,000), Native Americans/Alaska Natives (1026.2/100,000), and non-Hispanics (391.1/100,000). After controlling for important confounders, Hispanics were more likely than non-Hispanics to receive a nasogastric tube (OR, 6.36; 95% CI = 1.2 to 33.6); nonwhites were more likely to receive ED care by a resident (OR, 3.09; 95% CI = 1.9 to 5.0) and less likely to be sent back to the referring physician after ED discharge (OR, 0.47; 95% CI = 0.3 to 0.9). Men and women received equivalent ED care.

There are significant racial and ethnic but not gender disparities, in ED care for mTBI. The causes of these disparities and the relationship between these disparities and post-mTBI outcome need to be examined 3).

1)

Johnson LW, Diaz I. Exploring the Social Determinants of Health and Health Disparities in Traumatic Brain Injury: A Scoping Review. Brain Sci. 2023 Apr 23;13(5):707. doi: 10.3390/brainsci13050707. PMID: 37239178; PMCID: PMC10216442.
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Vattipally VN, Jiang K, Weber-Levine C, Kramer P, Davidar AD, Hersh AM, Winkle M, Byrne JP, Azad TD, Theodore N. Patient and Hospital Factors Associated With Hospital Course for Patients With Mild Traumatic Brain Injury. J Head Trauma Rehabil. 2025 Apr 1. doi: 10.1097/HTR.0000000000001056. Epub ahead of print. PMID: 40167490.
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Bazarian JJ, Pope C, McClung J, Cheng YT, Flesher W. Ethnic and racial disparities in emergency department care for mild traumatic brain injury. Acad Emerg Med. 2003 Nov;10(11):1209-17. doi: 10.1111/j.1553-2712.2003.tb00605.x. PMID: 14597497.

Monocarboxylate transporter

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Monocarboxylate transporter

Monocarboxylate transporters (MCTs) are a family of membrane proteins that mediate the transport of monocarboxylates such as lactate, pyruvate, and ketone bodies across the plasma membrane, often coupled with H⁺ ions. These transporters are essential for maintaining intracellular and extracellular pH homeostasis and supporting metabolic adaptation, particularly under hypoxic and glycolytic conditions common in malignant tumors.

🔍 MCTs in Glioma Pathobiology

🧬 Key Isoforms: MCT1 (SLC16A1): High affinity for lactate, expressed in both oxidative and glycolytic cells.

MCT4 (SLC16A3): Low affinity but high capacity, induced by hypoxia-inducible factor 1 (HIF-1α) and upregulated in highly glycolytic, hypoxic tumors.

MCT2 (SLC16A7): Highest affinity for lactate, recently recognized for its nuanced regulation in astrocytes and glioma cells in response to pH, hypoxia, glucose, and lactate, as shown by Caruso et al. 1).

🧪 Molecular Functions in GBM: Glioblastoma (GBM), the most aggressive primary brain tumor, exhibits a hallmark aerobic glycolytic phenotype (Warburg effect), leading to excessive lactate production. MCT1 and MCT4 mediate lactate efflux to prevent “self-poisoning,” facilitating:

Tumor cell survival under metabolic stress

Invasion of surrounding tissue

Immune evasion via acidic microenvironment

🏥 Relevance in Neurosurgical Practice 1. Tumor Aggressiveness & Surgical Planning High MCT1/4 expression correlates with aggressive tumor biology in GBM 2)

Their presence may mark invasive margins or hypoxic cores, which are difficult to resect and more likely to recur. Future intraoperative imaging (e.g., hyperpolarized MRI or pH-sensitive probes) may enable visualization of metabolically active MCT-rich zones to optimize resection margins.

2. Pathological Diagnosis and Immunohistochemistry MCT1/4 immunoreactivity can aid in distinguishing IDH-wildtype GBM from lower-grade gliomas when molecular data is incomplete. Pathologists and neurosurgeons may use MCT staining to infer tumor grade, prognosis, and potential therapeutic vulnerability.

3. Adjunctive Therapies Post-Resection Targeting MCTs offers a metabolism-based adjuvant approach.

Syrosingopine, a dual MCT1/4 inhibitor with CNS penetration, demonstrates apoptotic and anti-invasive effects in glioma cell lines and is a candidate for clinical repurposing.

Combined therapies (e.g., with metformin) may synergize to exhaust tumor metabolic plasticity.

4. Neurosurgical Research and Innovation MCTs are a valuable focus in translational neuro-oncology:

Biopsy targeting, tumor banking, and delivery of MCT inhibitors (e.g., via convection-enhanced delivery) are emerging research avenues.

Understanding the pH-lactate-hypoxia interplay via MCT regulation (as described by Caruso et al.) may lead to new molecular imaging markers or pH-responsive delivery systems.

⚠️ Current Limitations

No MCT-targeting therapy is yet approved for clinical neurosurgical use.

Expression heterogeneity within tumors and across patients complicates therapeutic targeting.

Isoform-specific inhibitors with safe CNS profiles are needed.

Non-invasive radiological detection of MCT activity is still under development.

🧩 Clinical Takeaway for Neurosurgeons

Monocarboxylate transporters—particularly MCT1 and MCT4—are more than molecular curiosities; they are critical markers and mediators of glioma aggressiveness. Their expression informs diagnosis, surgical planning, and offers a metabolic Achilles’ heel that could be exploited through adjuvant therapy. As glioma therapy moves toward precision medicine, MCTs represent a bridge between metabolic biology and neurosurgical practice.

References

1)

Caruso JP et al. pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma. Neoplasia. 2017;19(2):121-134. doi: 10.1016/j.neo.2016.12.011.
2)

Behera MM et al. The Monocarboxylate Transporters MCT1 and MCT4 Are Highly Expressed in Glioblastoma and Crucially Implicated in the Pathobiology. Neuropathology. 2025 Mar 27. doi: 10.1111/neup.70006. PMID: 40145253.

Arginine Vasopressin Deficiency Diagnosis

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🧪 Arginine Vasopressin Deficiency Diagnosis

(*formerly known as Central Diabetes Insipidus*)

🧠 Background

Deficiency results in:

Common causes:

🔍 Initial Assessment

Test Finding in AVP Deficiency
Serum sodium Often elevated
Plasma osmolality >295 mOsm/kg
Urine osmolality <300 mOsm/kg
Urine specific gravity <1.005 g/mL

💧 Water Deprivation Test (optional if diagnosis unclear)

see Water Deprivation Test

– Progressive fluid restriction – Measure: body weight, plasma osmolality, urine osmolality – Administer desmopressin (DDAVP) when appropriate

Finding AVP-D (Central) Nephrogenic DI Primary Polydipsia
Baseline urine osm Low Low Low-normal
Response to DDAVP ↑ >50% No change Slight ↑

🧠 Imaging

* Pituitary MRI to rule out structural causes * Look for loss of posterior pituitary bright spot

🏥 Postoperative Bedside Screening

Red flags (first 72h post-surgery):

  • Urine output >250 mL/h for 2–3 h
  • Urine SG <1.005 g/mL
  • Rising serum sodium >145 mmol/L

Patient self-monitoring strategy:

  • Use urine dipsticks (e.g., Combur-10)
  • Cut-off ≥1.015 g/mL reliably excludes hypotonic urine

→ Reduces need for nurse-led testing by ~50% 1).

It advances the concept of patient-participatory diagnostics and offers a replicable approach to screen for AVP-D. With thoughtful implementation, it has the potential to optimize workflows and empower patients, though accuracy limitations and clinical oversight remain essential.

👤 Patient Self-Monitoring Strategy for AVP Deficiency

Self-monitoring of urine specific gravity (SG) offers a non-invasive, accessible method for early identification of Arginine vasopressin deficiency (AVP-D) — particularly useful in the early postoperative period after pituitary surgery.

🎯 Objective

To enable patients to detect hypotonic urine (SG < 1.005 g/mL), a hallmark of AVP-D, using simple tools and clear thresholds, reducing reliance on continuous nurse monitoring.

🧪 Tools Required

Tool Description
Urine dipsticks e.g., Combur-10 test strips
SG reference chart Provided to patient (color guide or numeric)
Fluid intake/output diary Optional but useful
Basic education Brief verbal or written instructions

📌 Step-by-Step Monitoring Protocol

1. Frequency: Every 2–4 hours during the first 72h post-op (or as indicated) 2. Record:

  1. Urine SG using dipstick
  2. Time of measurement
  3. Urine volume (if known)

3. Interpretation:

  1. If SG < 1.005 → Alert nurse or clinician
  2. If SG ≥ 1.015 → No action needed

4. Look for associated symptoms:

  1. Excessive thirst (polydipsia)
  2. Frequent urination (polyuria)
  3. Light-colored or clear urine
  4. Dizziness or fatigue

A threshold of 1.015 g/mL is considered safe to rule out hypotonic urine and avoid missing AVP-D, based on current evidence.

✅ Advantages

  • Reduces nurse-led SG testing by ~50% 2)
  • Promotes early detection of AVP-D
  • Encourages patient engagement and education
  • Minimizes unnecessary interventions

⚠️ Considerations

  • Patients must be briefly trained on dipstick use and interpretation
  • Not suitable for:
    1. Patients with cognitive impairment
    2. Pediatric patients (without caregiver)
    3. Severe visual deficits
  • Always confirm low SG findings with clinical review and serum sodium

Combine self-monitoring of SG with daily weight and serum sodium trends for robust early detection of AVP-D in neurosurgical patients.

✅ Summary Table

Step Goal
Clinical evaluation Identify symptoms: polyuria, polydipsia
Serum/urine osmolality Confirm dilute urine & hyperosmolar plasma
Water deprivation test Differentiate AVP-D from other causes
Pituitary MRI Identify structural abnormalities
Urine SG monitoring post-op Early detection & workload reduction

When feasible, train patients to monitor urine SG using dipsticks. Use a safety threshold (SG ≥ 1.015) to minimize false negatives.

🔬 Imaging & Laboratory Markers of Diabetes Insipidus (DI)

🧠 T1-weighted MRI: Hyperintensity and ADH

Antidiuretic hormone (ADH) appears as a hyperintensity (HI) on T1-weighted magnetic resonance imaging in:

Key findings:

  • Disappearance of HI in the posterior lobe is a marker of ADH deficiency, often observed in DI.
  • Appearance of HI in the stalk suggests disturbances in ADH transport.

3)

💉 Serum Sodium: Perioperative Laboratory Markers

* An increase in serum sodium ≥2.5 mmol/L is a positive marker of postoperative diabetes insipidus with:

  • 80% specificity

* A serum sodium ≥145 mmol/L postoperatively indicates DI with:

  • 98% specificity

These thresholds help identify patients at risk and guide early treatment decisions after endoscopic transsphenoidal surgery (ETSS).

4)

Early changes in T1 hyperintensity and postoperative serum sodium can serve as non-invasive predictors of DI and support clinical decision-making.

References

1)

Nollen JM, Brunsveld-Reinders AH, Biermasz NR, Verstegen MJT, Leijtens E, Peul WC, Steyerberg EW, van Furth WR. Patient Participation in Urine Specific Gravity Screening for Arginine Vasopressin Deficiency in an Inpatient Neurosurgical Clinic. Clin Endocrinol (Oxf). 2025 Mar 27. doi: 10.1111/cen.15241. Epub ahead of print. PMID: 40145244.
2)

Nollen JM et al., *Clin Endocrinol (Oxf)*, 2025
3)

Hayashi Y, Kita D, Watanabe T, Fukui I, Sasagawa Y, Oishi M, Tachibana O, Ueda F, Nakada M. Prediction of postoperative diabetes insipidus using morphological hyperintensity patterns in the pituitary stalk on magnetic resonance imaging after transsphenoidal surgery for sellar tumors. *Pituitary*. 2016 Dec;19(6):552-559. PMID: 27586498
4)

Schreckinger M, Walker B, Knepper J, Hornyak M, Hong D, Kim JM, Folbe A, Guthikonda M, Mittal S, Szerlip NJ. Post-operative diabetes insipidus after endoscopic transsphenoidal surgery. *Pituitary*. 2013 Dec;16(4):445-51. PMID: 23242859

Anterior cervical discectomy and fusion complications

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Anterior cervical discectomy and fusion complications

ACD is known to be associated with a higher risk either of residual increased neck and shoulder pain 1) 2) or of developing a postoperative kyphotic deformity of the cervical spine 3) ; and this, in turn, can lead to the development of degenerative changes at adjacent levels

A 2-page survey was distributed to attendees at the 2015 Cervical Spine Research Society (CSRS) meeting. Respondents were asked to categorize 18 anterior cervical discectomy and fusion-related adverse events as either: “common and acceptable,” “uncommon and acceptable,” “uncommon and sometimes acceptable,” or “uncommon and unacceptable.” Results were compiled to generate the relative frequency of these responses for each complication. Responses for each complication event were also compared between respondents based on practice location (US vs. non-US), primary specialty (orthopedics vs. neurosurgery) and years in practice.

Of 150 surveys distributed, 115 responses were received (76.7% response rate), with the majority of respondents found to be US-based (71.3%) orthopedic surgeons (82.6%). Wrong level surgery, esophageal injury, retained drain, and spinal cord injury were considered by most to be unacceptable and uncommon complications. Dysphagia and adjacent segment disease occurred most often, but were deemed acceptable complications. Although surgeon experience and primary specialty had little impact on responses, practice location was found to significantly influence responses for 12 of 18 complications, with non-US surgeons found to categorize events more toward the uncommon and unacceptable end of the spectrum as compared with US surgeons.

These results serve to aid communication and transparency within the field of spine surgery, and will help to inform future quality improvement and best practice initiatives 4).

Systematic reviews and meta-analysis

A systematic review of the literature was performed in PubMed/MEDLINE, Embase, and the Cochrane Library for observational studies published between January 1996 and March 2023 and reporting postoperative complications associated with ACDF. Randomized controlled trials and interventional investigations were not included in this study. Meta-regression was also performed using generalized linear mixed models with a binomial probability distribution on various potential predicting factors.

A total of 222 studies reporting the rate of complications associated with ACDF in 50,584 patients were included in the present study. The overall postoperative complication rate was 16%. The most common complications were excessive neck swelling (11.3%), pseudarthrosis (10.0%), dysphagia (9.5%), cage/graft subsidence (9.4%), worsening myelopathy (7.7%), and hoarseness (2.3%). Nonhome discharge, readmission, and mortality rates were 13.8%, 3.7%, and 0.1%, respectively. Based on meta-regression, more levels of fusion and increased age were significantly associated with an increase in the pooled overall postoperative complication rate. Moreover, the rate of some postoperative complications was significantly associated with several perioperative characteristics.

This study is the most extensive meta-analysis conducted on the existing literature regarding ACDF-related complications and potential risk factors. However, future high-quality prospective studies or clinical trials are highly required to provide further evidence and validate the present findings 5).

This study provides a valuable and timely synthesis of ACDF-related complications in clinical practice. It successfully quantifies complication rates and identifies key risk factors, which can guide patient counseling and surgical planning. However, its findings should be interpreted in light of the limitations of observational data and study heterogeneity. Future prospective studies and RCTs are needed to validate these associations and explore modifiable risk factors more thoroughly.

Narrative Reviews

In multiple studies, overall morbidity rates for ACDF varied from 13.2% to 19.3%. These included in descending order; dysphagia (1.7%-9.5%), postoperative hematoma (0.4%-5.6% (surgery required in 2.4% of 5.6%), with epidural hematoma 0.9%), exacerbation of myelopathy (0.2%-3.3%), symptomatic recurrent laryngeal nerve palsy (0.9%-3.1%), cerebrospinal fluid (CSF) leak (0.5%-1.7%), wound infection (0.1-0.9%-1.6%), increased radiculopathy (1.3%), Horner’s syndrome (0.06%-1.1%), respiratory insufficiency (1.1%), esophageal perforation (0.3%-0.9%, with a mortality rate of 0.1%), and instrument failure (0.1%-0.9%). There were just single case reports of an internal jugular veing occlusion and a phrenic nerve injury. Pseudarthrosis occurred in ACDF and was dependant on the number of levels fused; 0-4.3% (1-level), 24% (2-level), 42% (3 level) to 56% (4 levels). The reoperation rate for symptomatic pseudarthrosis was 11.1%. Readmission rates for ACDF ranged from 5.1% (30 days) to 7.7% (90 days postoperatively).

Conclusions: Complications attributed to ACDF included; dysphagia, hematoma, worsening myelopathy, recurrent laryngeal nerve palsy, CSF leaks, wound infection, radiculopathy, Horner’s Syndrome, respiratory insufficiency, esophageal perforation, and instrument failure. There were just single case reports of an internal jugular vein thrombosis, and a phrenic nerve injury. As anticipated, pseudarthrosis rates increased with the number of ACDF levels, ranging from 0-4.3% for 1 level up to 56% for 4 level fusions 6)

Retrospective observational cohort studies

Twenty-seven patients with 54 levels and a mean age of 50.8 years were enrolled between January 2005 and August 2006. They underwent ACDF using polyetheretherketone cages packed with demineralized bone matrix without plate fixation at two contiguous levels. Mean follow-up period was 25.5 months (range, 13-60). Clinical outcome was evaluated using two Visual Analog Scales and the Neck Disability Index (NDI). We assessed fusion, regional alignment (RA) of the operated levels and cervical global alignment (GA) preoperatively in the immediate 1-week postoperative period and at the final follow-up. An interspinous distance ≥2 mm was used as an indicator of pseudoarthrosis at each level.

Findings: All patients showed improvements in clinical outcome, with 96% of patients showing mild NDI scores (<14). Radiological solid fusion was obtained at 48 of 54 levels (88.9%) and in 21 of 27 patients (77.8%). Lower cervical levels were significantly more vulnerable to pseudoarthrosis (100%). Fusion rate had no significant correlation with outcome (p > 0.05). RA of the operated levels was improved at the final follow-up compared with preoperatively in 76% of patients, although it had decreased compared with the immediate postoperative period due to subsidence in 84% of patients. In total, 80.8% of patients showed improvements in GA. Furthermore, improvements in RA showed a significant positive correlation with those in GA (p = 0.001), although improvement in RA and GA did not correlate significantly with clinical outcome (p > 0.05).

Conclusions: Though some degree of subsidence occurred in most cases, RA had improved at the last follow-up compared with preoperatively, which contributed to the significant improvement in GA. However, improvement of RA and GA was not correlated with outcomes 7)

Vocal cord palsy

see Vocal cord palsy after anterior cervical discectomy.

Cervical adjacent segment disease

Cervical adjacent segment disease

Hoarseness

Hoarseness, approximately in 5% 8).

Dysphagia

Dysphagia after anterior cervical discectomy

Postoperative hemorrhage

see Postoperative hemorrhage after anterior cervical discectomy and fusion

Cerebrospinal fluid fistula after anterior cervical discectomy and fusion

Cerebrospinal fluid fistula after anterior cervical discectomy and fusion.

Pharyngoesophageal perforation

see Esophageal perforation.

Spinal subdural hematoma

A spinal subdural hematoma is a rare clinical entity with considerable consequences without prompt diagnosis and treatment. Throughout the literature, there are limited accounts of spinal subdural hematoma formation following spinal surgery. This report is the first to describe the formation of a spinal subdural hematoma in the thoracic spine following surgery at the cervical level. A 53-year-old woman developed significant paraparesis several hours after anterior cervical discectomy and fusion of C5-6. Expeditious return to operating room for anterior cervical revision decompression was performed, and the epidural hematoma was evacuated without difficulty. Postoperative imaging demonstrated a subdural hematoma confined to the thoracic level, and the patient was returned to the operating room for a third surgical procedure. Decompression of T1-3, with evacuation of the subdural hematoma was performed. Postprocedure, the patient’s sensory and motor deficits were restored, and, with rehabilitation, the patient gained functional mobility. Spinal subdural hematomas should be considered as a rare but potential complication of cervical discectomy and fusion. With early diagnosis and treatment, favorable outcomes may be achieved 9).

Carotid artery compression

Legatt et al., report herein a case of anterior cervical discectomy and fusion (ACDF) surgery in which findings on somatosensory evoked potential (SSEP) monitoring led to the correction of carotid artery compression in a patient with a vascularly isolated hemisphere (no significant collateral blood vessels to the carotid artery territory). The amplitude of the cortical SSEP component to left ulnar nerve stimulation progressively decreased in multiple runs, but there were no changes in the cervicomedullary SSEP component to the same stimulus. When the lateral (right-sided) retractor was removed, the cortical SSEP component returned to baseline. The retraction was then intermittently relaxed during the rest of the operation, and the patient suffered no neurological morbidity. Magnetic resonance angiography demonstrated a vascularly isolated right hemisphere. During anterior cervical spine surgery, carotid artery compression by the retractor can cause hemispheric ischemia and infarction in patients with inadequate collateral circulation. The primary purpose of SSEP monitoring during ACDF surgery is to detect compromise of the dorsal column somatosensory pathways within the cervical spinal cord, but intraoperative SSEP monitoring can also detect hemispheric ischemia. Concurrent recording of cervicomedullary SSEPs can help differentiate cortical SSEP changes due to hemispheric ischemia from those due to compromise of the dorsal column pathways. If there are adverse changes in the cortical SSEPs but no changes in the cervicomedullary SSEPs, the possibility of hemispheric ischemia due to carotid artery compression by the retractor should be considered 10).

Heterotopic Ossification

Heterotopic ossification (HO) has been reported following total hip, knee, cervical arthroplasty, and lumbar arthroplasty, as well as following posterolateral lumbar fusion using recombinant human morphogenetic protein 2 (rhBMP-2). Data regarding HO following anterior cervical discectomy and fusion (ACDF) with rhBMP-2 are sparse. A subanalysis was done of the prospective, multicenter, investigational device exemption trial that compared rhBMP-2 on an absorbable collagen sponge (ACS) versus allograft in ACDF for patients with symptomatic single-level cervical degenerative disc disease.

To assess differences in types of HO observed in the treatment groups and effects of HO on functional and efficacy outcomes, clinical outcomes from previous disc replacement studies were compared between patients who received rhBMP-2/ACS versus allograft. Rate, location, grade, and size of ossifications were assessed preoperatively and at 24 months, and correlated with clinical outcomes. RESULTS Heterotopic ossification was primarily anterior in both groups. Preoperatively in both groups, and including osteophytes in the target regions, HO rates were high at 40.9% and 36.9% for the rhBMP-2/ACS and allograft groups, respectively (p = 0.350). At 24 months, the rate of HO in the rhBMP-2/ACS group was higher than in the allograft group (78.6% vs 59.2%, respectively; p < 0.001). At 24 months, the rate of superior-anterior adjacent-level Park Grade 3 HO was 4.2% in both groups, whereas the rate of Park Grade 2 HO was 19.0% in the rhBMP-2/ACS group compared with 9.8% in the allograft group. At 24 months, the rate of inferior-anterior adjacent-level Park Grade 2/3 HO was 11.9% in the rhBMP-2/ACS group compared with 5.9% in the allograft group. At 24 months, HO rates at the target implant level were similar (p = 0.963). At 24 months, the mean length and anteroposterior diameter of HO were significantly greater in the rhBMP-2/ACS group compared with the allograft group (p = 0.033 and 0.012, respectively). Regarding clinical correlation, at 24 months in both groups, Park Grade 3 HO at superior adjacent-level disc spaces significantly reduced range of motion, more so in the rhBMP-2/ACS group. At 24 months, HO negatively affected Neck Disability Index scores (excluding neck/arm pain scores), neurological status, and overall success in patients in the rhBMP-2/ACS group, but not in patients in the allograft group.

Implantation of rhBMP-2/ACS at 1.5 mg/ml with polyetheretherketone spacer and titanium plate is effective in inducing fusion and improving pain and function in patients undergoing ACDF for symptomatic single-level cervical degenerative disc disease. At 24 months, the rate and dimensions (length and anteroposterior diameter) of HO were higher in the rhBMP-2/ACS group. At 24 months, range of motion was reduced, with Park Grade 3 HO in both treatment groups. The impact of Park Grades 2 and 3 HO on Neck Disability Index success, neurological status, and overall success was not consistent among the treatment groups. The study data may offer a deeper understanding of HO after ACDF and may pave the way for improved device designs 11).

Cage subsidence

see Cage subsidence

Anterior cervical pseudarthrosis

Anterior cervical pseudarthrosis.

Case series

Analysis of 1000 consecutive patients undergoing Anterior cervical discectomy and fusion (ACDF) in an outpatient setting demonstrated surgical complications occur at a low rate (<1%) and can be appropriately diagnosed and managed in 4-hour ASC PACU window. Comparison with inpatient ACDF surgery cohort demonstrated similar results, highlighting that ACDF can be safely performed in an outpatient ambulatory surgery setting without compromising surgical safety. To decrease cost of care, surgeons can safely consider performing 1- and 2-level ACDF in an ASC environment 12).

A retrospective case series of 37 patients, paying special attention to immediate complications related to the use of mechanical retraction of soft tissue (dysphagia, dysphonia, esophageal lesions and local hematoma); and a comparative analysis of the outcomes after changes in the retraction method.

All selected cases had a positive neurological symptom response in relation to neuropathic pain. Dysphagia and dysphonia were found during the first 72 h in 94.1% of the cases in which automatic mechanical retraction was used for more than one hour during the surgical procedure. A radical change was noted in the reduction of the symptoms after the use of only manual protective blades without automatic mechanical retraction: 5.1% dysphagia and 0% dysphonia in the immediate post-operative period, P = 0.001.

Soft tissue damage due to the use of automatic retractors in MACDF is not minor and leads to general discomfort in the patient in spite of good neurological results. These problems most often occur when automatic retractors are used continuously for more than 1 hour, as well as when they are used in multiple levels. Dysphagia, dysphonia and local pain decreased with the use of transient manual blades for retraction, and with intermittent release following minimally invasive principles 13).

1)

LUNSFORD LD, BISSONETTE DJ, JANNETTA PJ, SHEPTAK PE, ZORUB DS. Anterior surgery for cervical disc dis- ease: Part-1 treatment of lateral cervical disc herni- ation in 253 cases. J Neurosurg 1980; 53: 1-11.
2)

LUNSFORD LD, BISSONETTE DJ, ZORUB DS. Anterior surgery for cervical disc disease: Part-2 treatment of cervical spondylotic myelopathy in 32 cases. J Neurosurg 1980; 53: 12-19.
3)

ABD-ALRAHMAN N, DOKMAK AS, ABOU-MADAWI A. An- terior cervical discectomy (ACD) versus anterior cervical fusion (ACF), clinical and radiological outcome study. Acta Neurochir (Wien) 1999; 141: 1089-1092.
4)

Wilson JR, Radcliff K, Schroeder G, Booth M, Lucasti C, Fehlings M, Ahmad N, Vaccaro A, Arnold P, Sciubba D, Ching A, Smith J, Shaffrey C, Singh K, Darden B, Daffner S, Cheng I, Ghogawala Z, Ludwig S, Buchowski J, Brodke D, Wang J, Lehman RA, Hilibrand A, Yoon T, Grauer J, Dailey A, Steinmetz M, Harrop JS. Frequency and Acceptability of Adverse Events After Anterior Cervical Discectomy and Fusion: A Survey Study From the Cervical Spine Research Society. Clin Spine Surg. 2018 Apr 27. doi: 10.1097/BSD.0000000000000645. [Epub ahead of print] PubMed PMID: 29708891.
5)

Tavanaei R, Ansari A, Hatami A, Heidari MJ, Dehghani M, Hajiloo A, Khorasanizadeh M, Margetis K. Postoperative complications of anterior cervical discectomy and fusion: A comprehensive systematic review and meta-analysis. N Am Spine Soc J. 2025 Feb 8;21:100596. doi: 10.1016/j.xnsj.2025.100596. PMID: 40145067; PMCID: PMC11938155.
6)

Epstein NE. A Review of Complication Rates for Anterior Cervical Diskectomy and Fusion (ACDF). Surg Neurol Int. 2019 Jun 7;10:100. doi: 10.25259/SNI-191-2019. PMID: 31528438; PMCID: PMC6744804.
7)

Moon HJ, Kim JH, Kim JH, Kwon TH, Chung HS, Park YK. The effects of anterior cervical discectomy and fusion with stand-alone cages at two contiguous levels on cervical alignment and outcomes. Acta Neurochir (Wien). 2011 Mar;153(3):559-65. doi: 10.1007/s00701-010-0879-z. Epub 2010 Dec 4. PMID: 21132445.
8)

Morpeth JF, Williams MF. Vocal fold paralysis after anterior cervical diskectomy and fusion. Laryngoscope. 2000 Jan;110(1):43-6. PubMed PMID: 10646714.
9)

Protzman NM, Kapun J, Wagener C. Thoracic spinal subdural hematoma complicating anterior cervical discectomy and fusion: case report. J Neurosurg Spine. 2015 Oct 13:1-5. [Epub ahead of print] PubMed PMID: 26460756.
10)

Legatt AD, Laarakker AS, Nakhla JP, Nasser R, Altschul DJ. Somatosensory evoked potential monitoring detection of carotid compression during ACDF surgery in a patient with a vascularly isolated hemisphere. J Neurosurg Spine. 2016 Nov;25(5):566-571. PubMed PMID: 27285667.
11)

Arnold PM, Anderson KK, Selim A, Dryer RF, Kenneth Burkus J. Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2. J Neurosurg Spine. 2016 Sep;25(3):292-302. doi: 10.3171/2016.1.SPINE15798. Epub 2016 Apr 29. PubMed PMID: 27129045.
12)

McGirt MJ, Mehrlich M, Parker SL, Asher AL, Adamson TE. 165 ACDF in the Outpatient Ambulatory Surgery Setting: Analysis of 1000 Consecutive Cases and Comparison to Hospital Inpatient ACDF. Neurosurgery. 2015 Aug;62 Suppl 1:220. doi: 10.1227/01.neu.0000467129.12773.a3. PubMed PMID: 26182011.
13)

Ramos-Zúñiga R, Díaz-Guzmán LR, Velasquez S, Macías-Ornelas AM, Rodríguez-Vázquez M. A microsurgical anterior cervical approach and the immediate impact of mechanical retractors: A case control study. J Neurosci Rural Pract. 2015 Jul-Sep;6(3):315-9. doi: 10.4103/0976-3147.158748. PubMed PMID: 26167011; PubMed Central PMCID: PMC4481782.

Peginterferon alfa-2a for cystic craniopharyngioma treatment

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Peginterferon alfa-2a for cystic craniopharyngioma treatment

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Craniopharyngiomas, especially their cystic forms, pose unique management challenges due to their proximity to critical neurovascular structures. Intracystic therapies offer a minimally invasive alternative to repeated surgical interventions. Over the past decade, interferon-alfa-2a/2b emerged as a viable intracystic treatment due to its anti-proliferative and immune-modulating properties, coupled with low toxicity. However, discontinuation of commercial availability prompted the search for alternatives.

Hedrich et al. describes a retrospective case series, including five patients with intracystic peginterferon alfa-2a for cystic craniopharyngioma treatment according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI.

Patients’ age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage.

Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic craniopharyngioma. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes 1).

The authors propose peginterferon alfa-2a, a pegylated form with extended half-life and established safety profile in other indications, as a substitute, presenting a retrospective case series evaluating its feasibility and safety.

Study Design and Methodology

– Design: Retrospective case series

– Sample: 5 patients (age 4–54; 4 children, 1 adult)

– Protocol: After initial cyst aspiration, peginterferon alfa-2a was administered weekly for 6 weeks via an Ommaya reservoir.

– Follow-up: MRI for response assessment

– Pre-treatment: Permeability study was highlighted as essential following one adverse case of leakage.

🔎 Strengths:

– Innovative use of peginterferon alfa-2a to fill a therapeutic gap.

– Uniform protocol across cases.

– Clear documentation of safety and early efficacy.

– Broad age range increases generalizability.

⚠️ Limitations:

– Very small sample size (n=5) limits statistical validity.

– Retrospective nature introduces potential bias and lacks standardized outcome metrics.

– Short-term follow-up; no data on recurrence, endocrine impact, or long-term survival.

– No comparator group (e.g., standard interferon alfa-2a or surgery-only) limits interpretation of relative efficacy.

Results

– Safety: No major toxicities reported in any patient.

– Efficacy: Cyst shrinkage achieved in all five patients.

– Complication: One patient experienced leakage, underscoring the need for a permeability test.

The data supports the hypothesis that peginterferon alfa-2a is a safe and potentially effective intracystic agent in this context.

Discussion and Clinical Relevance

This study provides preliminary real-world evidence that peginterferon alfa-2a can serve as an effective intracystic treatment option for cystic craniopharyngiomas, particularly important in the wake of discontinued access to interferon alfa-2a. The lack of significant toxicity is encouraging, especially in pediatric patients.

However, due to the small number of cases and lack of long-term outcome data, the findings should be interpreted as hypothesis-generating rather than practice-changing. Further research in prospective, multi-institutional trials with larger cohorts is warranted.

Conclusion Hedrich et al. offer a promising alternative approach for managing cystic craniopharyngiomas using peginterferon alfa-2a. The treatment appears feasible, safe, and effective in the short term. Yet, the study’s limitations — particularly its size and retrospective design — mean that broader validation is essential before widespread clinical adoption.

Comparative Analysis of Intracystic Treatments

Peginterferon alfa-2a vs Bleomycin vs Radioisotopes

Feature/Agent Peginterferon alfa-2a Bleomycin Radioisotopes (e.g., P-32, Y-90)
Mechanism of Action Immunomodulatory and antiproliferative Cytotoxic antibiotic causing DNA strand breaks Beta radiation causing localized cyst wall necrosis
Dosing Protocol Weekly x6 via Ommaya Multiple instillations (e.g., 4–6 doses over weeks) Single or repeated instillation; dosimetry-based
Age Use Pediatric and adult Caution in young children due to neurotoxicity Generally avoided in children <5–6 years old
Safety Profile Excellent short-term tolerability in small series Risk of chemical meningitis, neurotoxicity Risk of CSF leak, radiation necrosis, hypothalamic damage
Key Risks Cyst leakage (1 case in 5); minimal toxicity Seizures, necrosis if drug leaks to parenchyma Radiation exposure to critical adjacent structures
Regulatory Access Off-label, emerging use Widely available Often restricted, requires radiopharmacy services
Onset of Response Gradual shrinkage over weeks Moderate to rapid Rapid but with potential delayed adverse effects
Imaging Follow-up MRI after 6 weeks MRI at regular intervals Imaging + dosimetry (CT/SPECT) required
Long-Term Data Limited (new approach, case series only) Moderate, decades of use Available, esp. from Europe, but often in outdated protocols
Procedure Requirements Ommaya reservoir; permeability test recommended Ommaya reservoir or catheter Ommaya + radiation safety protocols

Summary Recommendations

Agent Advantages Disadvantages
Peginterferon alfa-2a Favorable safety, non-cytotoxic, off-label alternative to IFN-α2a Limited experience, unclear long-term outcomes
Bleomycin Effective and accessible; longer track record Neurotoxicity risk if leakage occurs; more systemic side effects
Radioisotopes Potent and often effective with fewer instillations Technically demanding; radiation risks; contraindicated in very young children

When to Consider Each Treatment?

* Peginterferon alfa-2a → Ideal for younger children or when minimal toxicity is essential. Requires close monitoring and permeability testing. * Bleomycin → Suitable where experience exists with its use. Effective but requires caution regarding leakage and systemic toxicity. * Radioisotopes → Best reserved for specialized centers with radiation safety protocols and older pediatric or adult patients with refractory cysts.

.

🧠 Flowchart Logic

Is the patient under 5 years old?

→ Yes → ❌ Avoid radioisotopes

→ No → ✅ Radioisotopes may be considered

Is radiation facility & radiopharmacy available?

→ Yes → Consider radioisotopes

→ No → Proceed to next

Is cyst accessible with Ommaya and permeability confirmed?

→ No → ❌ Intracystic therapy not recommended

→ Yes → Proceed to next

Is neurotoxicity a major concern (e.g., very young child, hypothalamic proximity)?

→ Yes → ✅ Prefer Peginterferon alfa-2a

→ No → Proceed to next

Institutional experience with bleomycin?

→ Yes → Consider bleomycin

→ No → Consider peginterferon alfa-2a

1)

Hedrich C, Patel P, Haider L, Taylor T, Lau E, Hook R, Dorfer C, Roessler K, Stepien N, Lippolis MA, Schned H, Koeller C, Mayr L, Azizi AA, Peyrl A, Lopez BR, Lassaletta A, Bennett J, Gojo J, Bartels U. Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma. Front Oncol. 2024 Jul 10;14:1401761. doi: 10.3389/fonc.2024.1401761. PMID: 39050573; PMCID: PMC11266088.

Racial disparities in hydrocephalus treatment

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Racial disparities in hydrocephalus treatment

Several studies of administrative data have noted higher mortality rates for Black/African American children with shunted hydrocephalus. A longitudinal study of children with hydrocephalus secondary to myelomeningocele showed lower lifetime rates of shunt revision in minority children compared to White children, indicating a possible disparity in hydrocephalus treatment. The goal of this study is to identify racial and ethnic disparities in mortality or shunt revision rates by using the Hydrocephalus Clinical Research Network (HCRN) hydrocephalus registry sample.

The HCRN registry was queried for patients with shunted hydrocephalus for whom data on all lifetime hydrocephalus procedures were available. Patients with a primary shunt placement before 2023 were included, with follow-up extending through March 19, 2024. A Cox proportional hazards model was created to determine the effect of race and ethnicity on mortality while controlling for age at initial shunt placement, sex, hydrocephalus etiology, gestational age at birth, and the presence of complex chronic conditions. Similarly, a proportional means model was used to evaluate the association with the lifetime number of shunt revision surgeries. The author hypothesized that when controlling for other variables, minority children would have higher mortality and fewer shunt revision surgeries than White children.

A total of 5656 children were included in the analysis of mortality. There were 579 deaths. Race and ethnicity were independently associated with mortality, with Black (HR 1.32, 95% CI 1.05-1.65), other non-White (HR 1.39, 95% CI 1.03-1.86), and Hispanic (HR 1.50, 95% CI 1.22-1.84) children having a higher mortality rate than White children. In the analysis of 4081 children with shunts, Hispanic ethnicity was also independently associated with fewer total shunt revisions (HR 0.84, 95% CI 0.72-0.98).

In children with hydrocephalus, when controlling for other factors, there is a higher mortality rate among Hispanic, Black, and other non-White children, and fewer shunt revisions among Hispanic children. These findings highlight important potential disparities in hydrocephalus treatment 1).

Patient race (i.e., White; Native Hawaiian, or other Pacific Islander) was found to be associated with iNPH development. Meanwhile, after excluding those with cerebrovascular disease, cardiovascular risk factors were not found associated with iNPH. Lastly, iNPH cases were more inclined to have a history of alcohol use disorder and prior psychiatric disorder. Overall, this data reveals that a racial disparity exists amongst iNPH, as well as highlights the role of various cardiovascular and psychiatric risk factors, which can potentially provide direction in etiology elucidation 2).

Among preterm infants with intraventricular hemorrhage and resultant PHH, black infants and those insured by Medicaid have significantly increased mortality but these 2 effects are independent. Further studies are needed to fully understand the factors affecting these racial and socioeconomic disparities 3).

Findings in a study, that utilized US population-level data, suggest the presence of racial and socioeconomic status outcome disparities following pediatric CSF shunting procedures 4).

A retrospective chart review was performed on all pediatric patients who underwent ventriculoperitoneal shunting from 1990-2010 at the Department of Neurological Surgery, University of Rochester Medical Center, 601 Elmwood Ave., Box 670, Rochester, NY, 14642, USA. Race and insurance type were recorded and assessed against specific outcome measures to statistically compare complication rates.

A complete record was found for 373 patients who received 849 shunting procedures at the institution. No differences were found between racial groups and insurance type for overall shunt survival, total revision number, or average time to failure. However, nonwhite patients spent an average of 3 days longer in the hospital at initial shunting (p = 0.04), and those with public insurance stayed for 5 days longer (p = 0.002). Patients with public insurance were more likely to present with shunt failure from outside hospitals (p = 0.005) and be born prematurely (p < 0.001). Private patients were more likely to have a neoplasm present at the time of initial shunt placement (p = 0.003).

While the overall revision rate was not affected by race or insurance status, there were significant delays in discharge for patients with public insurance. Moreover, potential disparities in outpatient access to primary physicians and specialists may be affecting care 5)

The literature examining racial and ethnic disparities in pediatric hydrocephalus reveals consistent evidence that minority populations, particularly Black, Hispanic, and other non-White children, experience worse outcomes compared to their White counterparts. The primary study by Rocque et al. (2025) using the Hydrocephalus Clinical Research Network (HCRN) registry strengthens the case for systemic inequities in healthcare delivery and outcomes.

1. Strengths of the Primary Study (Rocque et al., 2025)

Large, prospective dataset: With 5,656 children included in the mortality analysis and 4,081 in the shunt revision cohort, the study offers robust statistical power. Rigorous methodology: The use of Cox proportional hazards models and control for confounding variables (e.g., age at initial shunt, gestational age, chronic conditions) increases the reliability of the observed associations. Novel findings: The association of higher mortality in minority children and fewer revisions in Hispanic children, despite controlling for clinical variables, points to care process disparities rather than purely biological explanations.

2. Limitations and Interpretative Cautions

Causality remains unclear: The study is observational. While associations are strong, they do not establish causality. The lower revision rate among Hispanic children could either reflect undertreatment, barriers to access, or better surgical outcomes — though the higher mortality suggests the former. Socioeconomic data not directly integrated: While race and ethnicity are analyzed, insurance status, income level, and neighborhood-level SES indicators are not included. This limits insight into the complex interplay between race and class. Data source limitations: The HCRN centers may not be fully representative of all geographic or institutional contexts, potentially introducing bias. Synthesis with Supporting Literature The findings of Rocque et al. are echoed across several studies:

Jin et al. (2016) and Attenello et al. (2015) highlight that racial and economic disparities are independent predictors of increased mortality in hydrocephalus and related pathologies (e.g., PHH). Medicaid coverage — a proxy for low SES — independently correlates with worse outcomes, reinforcing the notion that both race and poverty are crucial risk factors.

Walker et al. (2014) found no differences in shunt survival or revision numbers, but nonwhite and publicly insured children had longer hospital stays and were more likely to present with complications from outside facilities, suggesting disparities in pre- and post-hospital care access, rather than in acute management.

Ghaffari-Rafi et al. (2020), while focused on iNPH, support that race (and potentially psychiatric comorbidities) may play a role in disease development and care patterns. Though not directly comparable to pediatric hydrocephalus, these data emphasize broader racialization of neurological care.

Key Themes and Implications

A. Structural and Institutional Bias These disparities may arise from implicit bias, differential access to care, differences in follow-up protocols, or parental engagement shaped by historical mistrust in healthcare institutions. Fewer shunt revisions in Hispanic children, despite higher mortality, may suggest under-recognition or under-treatment of shunt failures.

B. Socioeconomic Determinants

Insurance status, hospital of origin, and perinatal history (e.g., prematurity) are proxies for healthcare fragmentation and unequal resources. The intersection of race and poverty likely amplifies risks.

C. Need for Systems-Level Interventions

Enhance equity in post-operative follow-up and early complication detection. Implement community-based interventions and education programs to support families from underserved populations. Broaden inclusion of socioeconomic variables in large-scale registries like HCRN to better understand root causes.

Conclusions

The consistent signal across studies — that racial and socioeconomic disparities affect outcomes in pediatric hydrocephalus — underscores an urgent need for targeted policy, educational, and clinical interventions. The findings from the HCRN dataset should galvanize the neurosurgical community to address not only technical outcomes but also systemic inequities in pediatric neurosurgical care.

1)

Rocque BG, Jensen H, Reeder RW, Rozzelle CJ, Kulkarni AV, Pollack IF, McDowell MM, Naftel RP, Jackson EM, Whitehead WE, Pindrik JA, Isaacs AM, Strahle JM, McDonald PJ, Tamber MS, Hankinson TC, Browd SR, Hauptman JS, Krieger MD, Chu J, Riva-Cambrin J, Limbrick DD, Holubkov R, Kestle JRW, Wellons JC. Racial disparities in hydrocephalus mortality and shunt revision: a study from the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2025 Mar 21:1-9. doi: 10.3171/2024.12.PEDS24371. Epub ahead of print. PMID: 40117669.
2)

Ghaffari-Rafi A, Gorenflo R, Hu H, Viereck J, Liow K. Role of psychiatric, cardiovascular, socioeconomic, and demographic risk factors on idiopathic normal pressure hydrocephalus: A retrospective case-control study. Clin Neurol Neurosurg. 2020 Jun;193:105836. doi: 10.1016/j.clineuro.2020.105836. Epub 2020 Apr 28. PMID: 32371292.
3)

Jin DL, Christian EA, Attenello F, Melamed E, Cen S, Krieger MD, McComb JG, Mack WJ. Cross-Sectional Analysis on Racial and Economic Disparities Affecting Mortality in Preterm Infants with Posthemorrhagic Hydrocephalus. World Neurosurg. 2016 Apr;88:399-410. doi: 10.1016/j.wneu.2015.12.046. Epub 2015 Dec 28. PMID: 26732967.
4)

Attenello FJ, Ng A, Wen T, Cen SY, Sanossian N, Amar AP, Zada G, Krieger MD, McComb JG, Mack WJ. Racial and socioeconomic disparities in outcomes following pediatric cerebrospinal fluid shunt procedures. J Neurosurg Pediatr. 2015 Jun;15(6):560-6. doi: 10.3171/2014.11.PEDS14451. Epub 2015 Mar 20. PMID: 25791773.
5)

Walker CT, Stone JJ, Jain M, Jacobson M, Phillips V, Silberstein HJ. The effects of socioeconomic status and race on pediatric neurosurgical shunting. Childs Nerv Syst. 2014 Jan;30(1):117-22. doi: 10.1007/s00381-013-2206-5. Epub 2013 Jun 30. PMID: 23811830.

Salovum for severe traumatic brain injury

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Salovum for severe traumatic brain injury

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Antisecretory Factor and Salovum® in Severe Traumatic Brain Injury: A New Frontier in Neurocritical Care

Severe traumatic brain injury (TBI) remains a leading cause of disability and mortality worldwide despite continuous advancements in neuroimaging, neurocritical care, and surgical techniques. Elevated intracranial pressure (ICP) is a major contributor to secondary brain injury, often determining patient prognosis. Current treatments, including hyperosmolar therapy, decompressive craniectomy, and sedation, provide variable efficacy with significant risks.

A promising new approach involves the use of antisecretory factor (AF), a naturally occurring protein with anti-inflammatory and fluid-regulating properties, commercially available as Salovum®. Recent studies suggest that AF may play a crucial role in reducing ICP and improving clinical outcomes in severe TBI.

Clinical Evidence Supporting Antisecretory Factor in Severe TBI

The AFISTBI and SASAT Trials

Two exploratory randomized, placebo-controlled clinical trials are currently evaluating the role of AF in severe TBI. The AFISTBI trial (ClinicalTrials.gov NCT04117672) is a single-center phase 2 study conducted at Skane University Hospital, Sweden. This trial examines the impact of Salovum® supplementation for five days in adults with severe TBI (GCS < 9) requiring ICP monitoring and microdialysis catheter insertion. The primary endpoint is ICP reduction, while secondary endpoints include inflammatory mediator levels in plasma and cerebrospinal fluid.

Similarly, the SASAT trial (ClinicalTrials.gov NCT03339505) is a phase 2, double-blind, randomized trial conducted at Tygerberg University Hospital, South Africa. It evaluates 30-day mortality, treatment intensity level (TIL), and ICP control in 100 patients randomized to receive either Salovum® or placebo.

Pilot Studies and Case Series

Several preliminary studies have demonstrated the potential of AF in reducing ICP. A pilot study by Gatzinsky et al. investigated four patients with severe TBI and refractory intracranial hypertension treated with Salovum®. The study found that when administered rectally, AF significantly reduced ICP without adverse events, offering a novel delivery route for neurocritical care patients with impaired gastric emptying.

Additionally, a case series by Cederberg et al. evaluated five patients with severe TBI who received Salovum® via nasogastric tube for five days. Three patients exhibited successful ICP control without the need for barbiturates, while four had favorable long-term outcomes. Importantly, no toxicity or adverse effects were observed, underscoring the safety of AF therapy in this population.

Mechanism of Action and Potential Therapeutic Implications

AF exerts its effects by modulating fluid balance and inflammatory responses in the brain. Preclinical models suggest that AF can suppress excessive cerebrospinal fluid production, reduce blood-brain barrier permeability, and attenuate neuroinflammation, all critical mechanisms in controlling ICP and secondary brain injury.

The ability of AF to reduce ICP through non-invasive means could have profound implications for the management of TBI. In resource-limited settings where advanced neurosurgical interventions may not be readily available, Salovum® presents a cost-effective adjunct to standard neurocritical care.

Challenges and Future Directions

While preliminary data are promising, larger, multicenter randomized controlled trials (RCTs) are needed to validate these findings. Understanding the optimal dosing, administration route, and long-term effects of AF therapy remains crucial. Additionally, integrating AF into current TBI treatment protocols will require further evaluation of its interactions with existing therapies.

Conclusion

Antisecretory factor, as delivered via Salovum®, represents an exciting new frontier in TBI management. With ongoing trials exploring its efficacy, AF has the potential to become a groundbreaking adjunctive therapy for reducing ICP and improving outcomes in severe TBI patients. If confirmed in larger studies, the use of Salovum® could redefine the standard of care in neurocritical care settings, providing a safer and more accessible treatment alternative for ICP control.

Despite recent advances in neuroimaging and neurocritical care, severe traumatic brain injury (TBI) is still a major cause of severe disability and mortality, with increasing incidence worldwide. Antisecretory factor (AF), commercially available as Salovum®, has been shown to lower intracranial pressure (ICP) in experimental models of, e.g., TBI and herpes encephalitis. A study by Réen et al. aims to assess the effect of antisecretory factors in adult patients with severe TBI on ICP and inflammatory mediators in extracellular fluid and plasma.

In a single-center, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement for 5 days to adults with severe TBI (Glasgow Coma Scale (GCS) < 9), admitted to the neurocritical intensive care unit (NICU) at Skane university hospital. All patients with GCS < 9 and clinical indication for insertion of ICP-monitor and microdialysis catheter will be screened for inclusion and assigned to either the treatment group (n = 10) or placebo group (n = 10). In both groups, the primary outcome will be ICP (mean values and change from baseline during intervention), registered from high-frequency data monitoring for 5 days. During trial treatment, secondary outcomes will be inflammatory mediators in plasma and intracerebral microdialysis perfusate days 1, 3, and 5.

Trial registration: ClinicalTrials.gov NCT04117672. Registered on September 17, 2017. Protocol version 6 from October 24, 2023 1).

A study aims to assess the effect as measured by 30-day mortality, treatment intensity level (TIL), and intracranial pressure (ICP).

This single-center, double-blind, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement to adults with severe TBI (GCS < 9), presenting to the trauma unit at Tygerberg University Hospital, Cape Town, South Africa, that are planned for invasive ICP monitoring and neurointensive care, will be screened for eligibility, and assigned to either treatment group (n = 50) or placebo group (n = 50). In both groups, the primary outcome will be 30-day mortality, recorded via hospital charts, follow-up phone calls, and the population registry. Secondary outcomes will be treatment intensity level (TIL), scored from hospital charts, and ICP registered from hospital data monitoring.

Trial registration: ClinicalTrials.gov NCT03339505 . Registered on September 17, 2017. Protocol version 3.0 from November 13, 2020 2)

Four patients with severe TBI (Glasgow Coma Scale < 9) that required neurointensive care with ICP monitoring due to signs of refractory intracranial hypertension were investigated. One hundred milliliters of Salovum®, a commercially available egg yolk powder with high contents of AF peptides, was administrated either via nasogastric (patients 1 and 2) or rectal tube (patients 2, 3, and 4) every 8 h for 2 to 3 days as a supplement to the conventional neurointensive care. ICP was registered continuously. Plasma levels of AF were measured by enzyme-linked immunosorbent assay (ELISA) to confirm that Salovum® was absorbed appropriately into the bloodstream.

Results: In the first two patients, we observed that when delivered by the nasogastric route, there was an accumulation of the Salovum® solution in the stomach with difficulties to control ICP due to impaired gastric emptying. Therefore, we tested to administer Salovum® rectally. In the third and fourth patients, who both showed radiological signs of extensive brain edema, ICP could be controlled during the course of rectal administration of Salovum®. The ICP reduction was statistically significant and was accompanied by an increase in blood levels of AF. No adverse events that could be attributed to AF treatment or the rectal approach for Salovum® administration were observed.

Conclusions: The outcomes suggest that AF can act as a suppressor of high ICP induced by traumatic brain edema. Use of AF may offer a new therapeutic option for targeting cerebral edema in clinical practice 3).

A case series of five adult patients with severe TBI, treated with Salovum. The objective of the intervention was to evaluate safety and, if possible, its effect on intracranial pressure and outcome. Patients received 1 g Salovum per kilo of body weight divided into six doses per 24 h. Each dose was administered through the nasogastric tube. Patients were scheduled for 5 days of treatment with Salovum. Intracranial pressure was controlled in all patients. In three of five patients, intracranial pressure could be controlled with Salovum and deep sedation (no barbiturates), except during periods of gastroparesis. Five of five patients had a favorable short-term outcome, and four of five patients had a favorable long-term outcome. No toxicity was observed. We conclude that at least three of the five treated patients experienced an effect of Salovum with signs of reduction of intracranial pressure and signs of clinical benefit. To validate the potential of antisecretory factors in TBI, a prospective, randomized, double-blind, placebo-controlled trial with Salovum has been initiated. The primary outcome for the trial is 30-day mortality; secondary outcomes are treatment intensity level, intracranial pressure, and number of days at the neurointensive care unit 4).

References

1)

Réen L, Cederberg D, Marklund N, Visse E, Siesjö P. Antisecretory factor in severe traumatic brain injury (AFISTBI): protocol for an exploratory randomized placebo-controlled trial. Trials. 2025 Feb 7;26(1):43. doi: 10.1186/s13063-025-08760-7. PMID: 39920739.
2)

Cederberg D, Harrington BM, Vlok AJ, Siesjö P. Effect of antisecretory factor, given as a food supplement to adult patients with severe traumatic brain injury (SASAT): protocol for an exploratory randomized double blind placebo-controlled trial. Trials. 2022 Apr 23;23(1):340. doi: 10.1186/s13063-022-06275-z. PMID: 35461285; PMCID: PMC9034076.
3)

Gatzinsky K, Johansson E, Jennische E, Oshalim M, Lange S. Elevated intracranial pressure after head trauma can be suppressed by antisecretory factor-a pilot study. Acta Neurochir (Wien). 2020 Jul;162(7):1629-1637. doi: 10.1007/s00701-020-04407-5. Epub 2020 May 22. PMID: 32445122; PMCID: PMC7295841.
4)

Cederberg D, Hansson HA, Visse E, Siesjö P. Antisecretory Factor May Reduce ICP in Severe TBI-A Case Series. Front Neurol. 2020 Mar 6;11:95. doi: 10.3389/fneur.2020.00095. PMID: 32210902; PMCID: PMC7067821.

Subarachnoid hemorrhage treatment research

by

He et al. aim to investigate whether Dental Pulp Stem Cells can improve early brain injury after subarachnoid hemorrhage, and explore the mechanisms. In the study, they utilized the endovascular perforation method to establish a subarachnoid hemorrhage mouse model and investigated whether DPSCs administered via tail vein injection could improve early brain injury after subarachnoid hemorrhage. Furthermore, they used hemin-stimulated HT22 cells to simulate neuronal cell injury induced by SAH and employed a co-culture approach to examine the effects of DPSCs on these cells. To gain insights into the potential mechanisms underlying the improvement of SAH-induced EBI by DPSCs, they conducted bioinformatics analysis. Finally, they further validated the findings through experiments. In vivo experiments, they found that DPSCs administration improved neurological dysfunction, reduced brain edema, and prevented neuronal apoptosis in SAH mice. Additionally, they observed a decrease in the expression level of miR-26a-5p in the cortical tissues of SAH mice, which was significantly increased following intravenous injection of DPSCs. Through bioinformatics and luciferase reporter assay, they confirmed the target relationship between miR-26a-5p and PTEN. Moreover, we demonstrated that DPSCs exerted neuroprotective effects by modulating the miR-26a-5p/PTEN/AKT pathway. The study demonstrates that DPSCs can improve EBI after SAH through the miR-26a-5p/PTEN/AKT pathway, laying a foundation for the application of DPSCs in subarachnoid hemorrhage treatment. These findings provide a theoretical basis for further investigating the therapeutic mechanisms of DPSCs and developing novel subarachnoid hemorrhage treatment research strategies 1).

Critical Review of He et al.: Investigating the Therapeutic Potential of Dental Pulp Stem Cells in Early Brain Injury After Subarachnoid Hemorrhage

Introduction

The study by He et al. explores whether Dental Pulp Stem Cells (DPSCs) can mitigate early brain injury (EBI) following subarachnoid hemorrhage (SAH) and investigates the underlying mechanisms. The authors utilize a well-established endovascular perforation method to induce SAH in mice and assess the therapeutic efficacy of DPSCs administered via tail vein injection. Additionally, in vitro experiments using hemin-stimulated HT22 cells provide mechanistic insights, particularly in relation to the miR-26a-5p/PTEN/AKT signaling pathway.

Strengths of the Study

Robust Animal Model: The use of the endovascular perforation model is a significant strength, as it closely mimics human SAH pathophysiology, including intracranial pressure dynamics and delayed cerebral ischemia.

Comprehensive Methodological Approach: The combination of in vivo and in vitro models strengthens the validity of the findings. The authors systematically explore neuronal apoptosis, brain edema, and neurological function in SAH mice, correlating these findings with cellular responses in cultured HT22 cells.

Bioinformatics and Molecular Mechanism Analysis: The study provides a mechanistic framework by identifying the miR-26a-5p/PTEN/AKT pathway as a key player in DPSC-mediated neuroprotection. The use of luciferase reporter assays to confirm miR-26a-5p’s interaction with PTEN adds rigor to the molecular analysis.

Potential Clinical Relevance: The findings provide a promising avenue for cell-based therapy in SAH, an area with limited treatment options beyond supportive care and neurosurgical intervention.

Limitations and Areas for Improvement

Lack of Long-Term Outcome Assessment: While the study effectively demonstrates short-term improvements in neurological function, brain edema, and apoptosis, long-term assessments (e.g., beyond the early post-SAH phase) are lacking. Chronic neurological outcomes, cognitive function, and potential long-term integration of DPSCs into neural circuits remain unexplored.

Limited Characterization of DPSCs: The authors do not provide sufficient details on the characterization and differentiation potential of the DPSCs used. Information on their immunophenotype, differentiation capabilities, and potential risk of ectopic differentiation would strengthen the study.

Potential Immune Response Not Addressed: Although DPSCs are considered immune-privileged, their systemic administration raises concerns about potential immunogenicity, inflammatory responses, or unwanted differentiation, which the authors do not investigate.

Reliance on a Single Cell Line for In Vitro Experiments: The study uses HT22 cells to model neuronal injury, but HT22 cells are immortalized murine hippocampal neurons, which may not fully represent primary cortical or hippocampal neurons. The use of primary neuronal cultures would enhance translational relevance.

Lack of Functional Validation of miR-26a-5p/PTEN/AKT Pathway: While the study establishes a correlation between miR-26a-5p expression and neuroprotection, direct functional validation via miR-26a-5p knockdown or overexpression in vivo would further solidify the mechanistic claims.

Absence of Dose-Response and Optimization Studies: The authors do not explore different DPSC doses, delivery routes, or timing of administration. Optimizing these parameters is crucial for translational applications.

Conclusion and Future Directions

He et al. present a well-designed study demonstrating the therapeutic potential of DPSCs in SAH-induced EBI. Their findings highlight the importance of the miR-26a-5p/PTEN/AKT pathway in mediating neuroprotection, providing a strong foundation for future research. However, several limitations, including the lack of long-term assessments, immune response considerations, and dose-optimization studies, must be addressed before DPSCs can be considered for clinical translation. Future studies should explore the safety and efficacy of DPSCs in larger animal models and examine their impact on long-term neurocognitive recovery.

1)

He P, Zhang H, Wang J, Guo Y, Tian Q, Liu C, Gong P, Ye Q, Peng Y, Li M. Dental Pulp Stem Cells Attenuate Early Brain Injury After Subarachnoid Hemorrhage via miR-26a-5p/PTEN/AKT Pathway. Neurochem Res. 2025 Jan 30;50(2):91. doi: 10.1007/s11064-025-04340-y. PMID: 39883266.