TRIVASOSTIM
(2023)Objective
To determine whether external transcutaneous trigeminal nerve stimulation (TNS) decreases the incidence of cerebral infarction related to vasospasm in patients with aneurysmal subarachnoid hemorrhage compared to sham stimulation at 3-month follow-up
Study Summary
• Vasospasm-related infarctions: 23% (7/30) TNS vs 27% (8/30) sham
• No significant differences in functional disability (MRS, GOS), quality of life (EQ5D-3L), or mortality at 6 months
• TNS did not decrease the rate of cerebral infarction secondary to vasospasm
Intervention
Transcutaneous electrical trigeminal nerve stimulation (TENS) applied bilaterally to the supratrochlear and supraorbital nerves (ophthalmic division of trigeminal nerve) at 20 Hz frequency, intensity adjusted to sub-paresthesia threshold, continuously for 10 days (days 1-10) vs sham stimulation
Inclusion Criteria
Age 18-75 years, aneurysmal SAH within 48 hours, aneurysm secured by coiling or surgery, WFNS grade 1-4 after correction, modified Fisher grade 3 or 4, written informed consent
Study Design
Arms: TNS group (n=30): Active trigeminal nerve stimulation for 10 days; Sham group (n=30): Sham stimulation device (no electrical output) for 10 days
Patients per Arm: TNS: 30, Sham: 30 (total 60 enrolled, 59 analyzed, 1 withdrew consent)
Outcome
• Late infarction (not seen at D6): 10% TNS vs 20% sham (p=0.47)
• Modified Rankin Scale ≥3 at 6 months: 10% TNS vs 3% sham (p=0.65)
• GOS moderate disability: 18% TNS vs 27% sham (p=0.53)
• EQ5D-3L index: 0.79±0.23 TNS vs 0.79±0.22 sham (p=0.99)
• Perfusion abnormality on D6 PCT: 40% TNS vs 17% sham (p=0.084)
• Vasospasm on CTA: 47% TNS vs 33% sham (p=0.43)
• No significant differences in safety parameters between groups
Bottom Line
In this single-center, double-blind, randomized pilot trial of 60 patients with aneurysmal SAH, 10 days of transcutaneous trigeminal nerve stimulation did not significantly reduce the rate of vasospasm-related cerebral infarction at 3 months compared to sham stimulation (23% vs 27%, p=0.99). No significant differences were observed in functional outcomes or quality of life at 6 months. Two deaths occurred in the TNS group (2/30, 7%) versus none in the sham group; both were reported as severe adverse events considered unrelated to the intervention (no formal p-value reported for mortality). While the pathophysiological rationale based on animal studies and the trigeminovascular system's role in cerebral blood flow regulation was compelling, this proof-of-concept pilot trial was unable to demonstrate that TNS can decrease cerebral infarction secondary to vasospasm. The negative results may be attributed to maintaining stimulation intensity below the paresthesia threshold to preserve double-blinding, potentially underestimating a dose-effect relationship. It would be premature to promote trigeminal system neurostimulation in this context, and further research is needed before clinical application can be recommended.
Major Points
- Single-center, double-blind, randomized controlled pilot trial with 1:1 randomization
- 60 patients with aneurysmal SAH enrolled from single French institution (Poitiers University Hospital)
- 60 patients assessed for eligibility and randomized (30 TNS, 30 sham); all 60 analyzed on intention-to-treat basis; 8 patients left the study during follow-up including 2 unrelated deaths in TNS group
- Inclusion criteria: age 18-75 years, aSAH within 48 hours, WFNS grade I-IV, ruptured aneurysm confirmed by CTA/angiography, candidate for endovascular occlusion or microsurgical exclusion
- 30 patients randomized to active TNS, 30 to sham stimulation
- Intervention: bilateral transcutaneous electrical stimulation of supratrochlear and supraorbital nerves (ophthalmic division of trigeminal nerve)
- Stimulation parameters: 20 Hz frequency, intensity adjusted to sub-paresthesia threshold to maintain blinding
- Non-sedated patients: mean intensity 9.6±2.7 mA (TNS) vs 11.4±1.5 mA (sham), p=0.16
- Sedated patients: mean intensity 4.9±2.9 mA (TNS) vs 4.3±2.2 mA (sham), p=0.49
- Treatment duration: 10 days continuous stimulation (days 1-10 after SAH), mean 9.5 days TNS vs 9.9 days sham (p=0.2)
- Primary endpoint: cerebral infarction on MRI FLAIR at 3 months (or last CT/MRI before death)
- Primary outcome negative: 23% (7/30) TNS vs 27% (8/30) sham, p=0.99
- Late infarction (not observed at D6): 10% (3/30) TNS vs 20% (6/30) sham, p=0.47
- Modified Rankin Scale ≥3 at 6 months: 10% TNS vs 3% sham, p=0.65
- Glasgow Outcome Scale moderate disability at 6 months: 18% TNS vs 27% sham, p=0.53
- EQ5D-3L quality of life index at 6 months: 0.79±0.23 TNS vs 0.79±0.22 sham, p=0.99
- Mortality at 6 months: 2/30 (7%) TNS vs 0/30 sham; both TNS deaths reported as severe adverse events unrelated to the intervention; no p-value reported
- Perfusion CT abnormality at D6: 40% (12/30) TNS vs 17% (5/30) sham, p=0.084 (trend but not significant)
- Vasospasm on CT angiography at D6: 47% (14/30) TNS vs 33% (10/30) sham, p=0.43
- Moderate-severe vasospasm: TNS 43% (13/30) vs sham 27% (8/30)
- 50% (7/14) of TNS patients and 80% (8/10) of sham patients with vasospasm were asymptomatic
- No significant difference in secondary complications during hospitalization (37% TNS vs 33% sham, p=0.99); serious adverse events not separately quantified — only the two TNS deaths were reported as severe adverse events
- Hydrocephalus occurred in 33% TNS vs 30% sham patients during hospitalization (no separate p-value reported for this subrow)
- Strong correlation found between vasospasm severity and PCT abnormalities (p<0.0001)
- 100% of severe vasospasm patients had PCT abnormalities, 53.8% of moderate vasospasm, 5.1% of no/mild vasospasm
- Significant relationship between WFNS grade and vasospasm occurrence (p=0.016)
- Study hypothesis based on trigeminovascular system pathophysiology and vasodilator peptide (CGRP) release
- Stimulation maintained below paresthesia threshold to preserve double-blinding may have limited efficacy
Study Design
- Study Type
- Single-center, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept pilot trial
- Randomization
- Yes
- Blinding
- Double-blind. Randomization performed using a predefined list from the study methodologist provided to the clinical trial personnel of Poitiers University Hospital, with 1:1 allocation. Both patients and evaluators were blinded to allocation. Sham device identical in appearance to active device and displayed current intensity but delivered no electrical stimulation. Stimulation intensity was kept below the paresthesia threshold (determined with a separate reference TENS device before the blinded device was applied) so neither patient nor clinician could perceive whether stimulation was active
- Sample Size
- 60
- Follow-up
- 6 months
- Centers
- 1
- Countries
- France
Primary Outcome
Definition: Presence of cerebral infarction related to vasospasm on MRI FLAIR at 3 months (or on last CT/MRI scan before death), after exclusion of infarcts from other causes (procedure-related, hematoma-related) as primary or relevant cause, or considered not exclusively due to causes other than vasospasm. Both patients and evaluators were blinded to allocation.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 27% (8/30), 95% CI not reported | 23% (7/30), 95% CI not reported | - | 0.99 (Fisher's exact test) |
Limitations & Criticisms
- Single-center study limits generalizability
- Small sample size (60 patients) - pilot study not powered for definitive efficacy conclusions
- One patient (79 years old) exceeded age inclusion criterion of 75 years (protocol deviation)
- Primary endpoint based solely on radiological criteria (MRI FLAIR at 3 months), not clinical examination
- TNS intensity maintained below paresthesia threshold to preserve blinding may have limited therapeutic effect - potential dose-effect relationship underestimated
- Stimulation parameters (frequency 20 Hz, intensity) chosen empirically based on previous works without dose-optimization studies
- No assessment of whether effective dose reached target - no measurement of CGRP levels or other mechanistic biomarkers
- Sex imbalance despite randomization (males 27% TNS vs 43% sham, p=0.18) — not statistically significant but potential confounder
- CT perfusion performed only once at day 6 - single timepoint assessment
- Unexpectedly high perfusion abnormalities in TNS group (40% vs 17%, p=0.084) raises questions about potential adverse effects
- External TENS targets peripheral nervous system through autonomic ganglia, may not adequately reach central trigemino-cervical complex compared to direct neuraxis stimulation
- 57.1% of patients with moderate-severe vasospasm were asymptomatic - disconnect between radiological and clinical vasospasm
- Only radiological definition of DCI used, which may underestimate clinical impact
- No stratification for baseline characteristics in randomization
- Follow-up limited to 6 months - longer-term outcomes unknown
- Two deaths in TNS group (none in sham) though reported as unrelated to intervention raises safety questions and no formal p-value was provided for mortality
- Lower DCI incidence than predicted (23-27% vs expected 50-70%) may indicate early screening effect
- Pathophysiological mechanism assumes vasodilation via neuropeptide release, but DCI pathophysiology involves multiple factors beyond vessel caliber
- No measurement of cerebral autoregulation which may be impaired during vasospasm
- Distinction between clinical and radiological vasospasm difficult - complex neurological symptoms hard to attribute solely to vasospasm
- Almost half of severe vasospasm patients did not develop DCI - other factors involved beyond vessel narrowing
- Internal inconsistency in paper: Table 5 reports 7 (50%) symptomatic vasospasm in TNS and 2 (20%) in sham, whereas Section 3.5 text states 2 (7%) TNS and 3 (10%) sham
Citation
Int. J. Environ. Res. Public Health 2023, 20, 5836