Neuroprotective Effects of Pulsed Electromagnetic Fields in Acute Stroke

Article information

J Stroke. 2024;26(3):458-462
Publication date (electronic) : 2024 September 27
doi : https://doi.org/10.5853/jos.2024.01529
1Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry, Università Campus Bio-Medico di Roma, Roma, Italy
2Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
3IRCCS Istituto delle Scienze Neurologiche di Bologna, Department of Neurology and Stroke Center, Maggiore Hospital, Bologna, Italy
4Neurology Unit, Neuromotor & Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
5Stroke Unit, Tor Vergata Polyclinic Hospital, Tor Vergata University, Roma, Italy
6Department of Neuroscience and Rehabilitation, Division of Neurology, University Hospital of Ferrara, Ferrara, Italy
7University Vita-Salute San Raffaele, Milan, Italy
8Experimental Neurophysiology Unit, Institute of Experimental Neurology, Scientific Institute San Raffaele, Milan, Italy
9Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy
10Department of Information Engineering, Electronics and Telecommunications (DIET), Sapienza University of Rome, Roma, Italy
11Medical Division, IGEA, Carpi, Italy
Correspondence: Vincenzo Di Lazzaro Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21 - 00128 Roma, Italy Tel: +39-06-22541-1 E-mail: v.dilazzaro@policlinicocampus.it
Received 2024 April 25; Accepted 2024 July 3.

Dear Sir:

Currently, treatments for acute ischemic stroke (AIS) are based on reperfusion therapies; however, the time window for these interventions is limited to the first few hours after stroke onset. Therefore, alternative neuroprotective therapies are urgently required.

Acute blood flow disruption leads to early neuronal death in the core of the ischemic area, later, secondary processes, such as inflammation, excitotoxicity, and oxidative stress enlarge the infarct core into the surrounding tissue, the “penumbra,” [1] which represents the perfect target for neuroprotective strategies. Adenosine receptors (ARs) have recently emerged as potential therapeutic targets in brain ischemia [2], granting AR agonists a role to prevent “penumbra” evolution [3-5]. Grant et al. [6] showed that pulsed electromagnetic fields (PEMFs) promote significant neuroprotection in a rabbit model of transient focal ischemia. This effect is explained by the selective agonist activity for A2A AR of PEMFs, first described by Varani et al. [7].

Based on preclinical and early clinical experiences (phase 1 and 2 studies) [8-10], we designed a double-blind, placebo-controlled, randomized study to assess whether PEMF exposure was effective in reducing cerebral ischemic volume (primary endpoint) and promoting functional recovery (secondary endpoint) (I-NIC study, NCT02767778). I-NIC clinical trial protocol is provided as Supplementary Materials.

One hundred and sixty-eight patients were screened, and 37 patients with ischemic stroke in the middle cerebral artery (MCA) territory were enrolled: 16 patients were assigned to the active group and 21 to the placebo group (sham device) (Figure 1). The detailed methodology is described in the Supplementary Methods. There were no significant differences in the demographic and clinical characteristics at baseline between the groups (Supplementary Table 1). Magnetic resonance imaging (MRI) was conducted at baseline and 7 and 45 days after stroke onset (Supplementary Table 2). The average lesion volume decreased from 23.3±25.3 cm3 to 11.9±12.8 cm3 in the active group (P=0.023), and from 12.1±17.7 cm3 to 7.3±7.5 cm3 in the placebo group (P=0.065) (Figure 2A and B, Supplementary Figure 1).

Figure 1.

CONSORT study flow diagram. CONSORT, Consolidated Standards of Reporting Trials; FU, follow-up; MRI, magnetic resonance imaging. *Of the 16 patients in the active group, 14 were available for analysis at the 7-day FU: two patients were excluded from the analysis because they did not meet the inclusion criteria “2” and “3” (Supplementary Methods); 11 patients were available for analysis at the 45-day and 90-day FUs: three patients did not return for follow-up visit during the COVID-19 pandemic, but when interviewed by telephone, they were in good health and did not mention any negative effect related to the treatment; Of the 21 patients in the placebo group, 20 were available for analysis at the 7-day FU: one patient was excluded from the analysis because he did not meet the inclusion criteria “3” (Supplementary Methods), 19 patients were available for analysis at the 45-day and 90-day FUs: one patient died from causes unrelated to the treatment.

Figure 2.

Primary and secondary outcomes. (A) Line graph showing mean lesion volumes (±SE) at baseline, 7 days, and 45 days in the placebo and active groups. (B) Normalized MRI volume reduction (mean±SE). (C) Distribution of scores on the mRS at 90 days. (D) BI over time in the active and placebo groups (mean±SE). (E) NIHSS over time in the active and placebo groups (mean±SE). SE, standard error; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; BI, Barthel Index; NIHSS, National Institutes of Health Stroke Scale. *P<0.05; **P<0.01; P=nonsignificant (vs. baseline).

Clinical scores, Barthel Index (BI), modified Rankin Scale (mRS) scores, and National Institutes of Health Stroke Scale (NIHSS) scores showed significant improvements at 7, 45, and 90 days compared with baseline in both groups (Figure 2C-E and Supplementary Table 3). Excellent outcome at 90 days (defined as a score on the mRS of 0 or 1) was achieved in 10 out of 11 patients (90.9%) in the active group and in 12 out of 18 patients (66.7%) in the placebo group (Figure 2C).

Twenty patients underwent reperfusion therapies: 12 in the placebo group and eight in the active group. PEMF treatment resulted in significant MRI volume reduction compared with baseline in the active group only (P=0.04) (Figure 3); and the average normalized MRI volume reduction at 45 days over baseline was 50.0% in the active group and 22.7% in the placebo group, with a significant difference between the groups (P=0.04).

Figure 3.

Subgroup analysis. (A) Line graph showing mean lesion volumes (±SE) at baseline, 7 days, and 45 days in the placebo and active groups. (B) NIHSS score (means±SE) over time in the active and placebo. NIHSS score significantly improved over baseline in both groups. (C) Distribution of scores on the mRS at 90 days. Excellent outcome at 90 days was achieved in 85.7% of patients in the active group and in 63.6% of patients in the placebo group (P=0.634). (D) BI score (means±SE) over time in the active and placebo groups. The BI score improved from 42.5±30.9 at baseline to 92.9±16.8 (PP<0.01) at 90 days in the active group; whilst in the placebo group, BI increased from 54.2±37.2 at baseline to 82.7±37.2 (P=0.100) at 90 days. SE, standard error; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index. *P<0.05; **P<0.01; P=nonsignificant (vs. baseline).

The clinical scores at 7, 45, and 90 days improved from baseline in both groups. Notably, the improvements in clinical scores were larger and earlier in the active group than in the placebo group, in line with the volumetric changes in the lesions. MRI volume reduction and BI clinical score improvement were the largest in the active group in the first 7 days after AIS, that is, when PEMF treatment was delivered. Moreover, the BI score reached the widest recovery as early as 45 days in the active group compared to 90 days in the placebo group.

Among patients who underwent reperfusion treatment, the BI score improved from 42.5±30.9 at baseline to 92.9±16.8 (P<0.01) at 90 days in the active group; whilst in the placebo group, BI increased from 54.2±37.2 at baseline to 82.7±37.2 (P=0.10) at 90 days.

The safety of PEMFs was carefully monitored during treatment; no severe adverse events that would require treatment interruption occurred (Supplementary Table 4). At follow-up visits, the patients did not report any side effects that could be attributed to the PEMF treatment.

Our results show that PEMF treatment is safe, well tolerated, and efficiently deployed in stroke units. It is performed at the patient’s bed (Supplementary Figures 2 and 3), does not require dedicated infrastructure or specialized personnel, does not extend the length of hospital stay, and costs are expected to be contained.

In summary, the instrumental and clinical results of the I-NIC study showed that PEMF treatment protects the central nervous system following ischemic stroke. At 45 days, the area of neuronal sufferance identified by MRI was significantly reduced over baseline in the actively treated patients only (P=0.02), whereas no statistically significant reduction was observed in the placebo group (Figure 2B and Supplementary Figure 1).

Among patients receiving reperfusion therapy, PEMF treatment favored MRI volume reduction and clinical amelioration, showing that the treatments can be successfully combined to prevent the enlargement of structural damage.

The present study has limitations: (1) PEMF treatment was restricted to patients with lesions located in the MCA territory; (2) the difference in average lesion volume at baseline between the groups was wide; and (3) the low number of patients included, resulting from the stringent inclusion criteria and the clinical protocol request for three MRI exams over 45 days. Then, the COVID-19 pandemic further slowed enrolment and access to follow-up visits.

In the interim analysis, the primary endpoint of the study was reached and the safety and tolerability of PEMF treatment were proven; therefore, the study was interrupted.

This is the first human clinical trial to use PEMF treatment to limit neuronal damage in patients with ischemic stroke. Our results show that PEMF treatment should be considered to reduce the neuronal damage occurring in the “penumbra,” offering to clinicians the opportunity to extend the time for intervention to the first week after ischemic stroke.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.01529.

Supplementay Materials

Low-frequency Pulsed Electromagnetic Fields (ELF-MF) as Treatment for Acute Ischemic Stroke (I-NIC)

jos-2024-01529-Supplementary-Materials.pdf
Supplementay Table 1.

Patient characteristics at baseline

jos-2024-01529-Supplementary-Table-1-4.pdf
Supplementay Table 2.

MR sequence parameters

jos-2024-01529-Supplementary-Table-1-4.pdf
Supplementay Table 3.

BI score values

jos-2024-01529-Supplementary-Table-1-4.pdf
Supplementay Table 4.

Adverse events during the 5 days of treatment

jos-2024-01529-Supplementary-Table-1-4.pdf
Supplementay Figure 1.

Normalized volume reduction at 45 days in (A) individual active patients and (B) individual placebo patients.

jos-2024-01529-Supplementary-Figure-1,2.pdf
Supplementay Figure 2.

I-NIC device. The figure shows the components of the I-NIC device: (A) generator, (B) power supply, (C) coil, and (D) helmet to keep the solenoid in place. pulsed electromagnetic field (PEMF) treatment was delivered for 5 consecutive days after stroke, for 2 hours every day.

jos-2024-01529-Supplementary-Figure-1,2.pdf
Supplementay Figure 3.

Magnetic field distribution in the brain. (A) Distribution of the magnetic field in the infarct area: a representative patient is shown. In this clinical trial, the magnetic field amplitude was set to expose the brain areas suffering the ischemic event to at least 1 mT. MRI images of a representa- tive active patient at (B) baseline, (C) 7 days, and (D) 45 days. MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery.

jos-2024-01529-Supplementary-Figure-3.pdf

Notes

Funding statement

The I-NIC study was sponsored by IGEA.

Conflicts of interest

FC has received travel grants and/or speaking honoraria from Biogen, Merck, Sanofi-Genzyme, and Roche and research grants from Merck, which are not relevant to this work. AZ reported consultancies with Bayer, Astra Zeneca, Boehringer Ingelheim, and CSL Behring, which were not relevant to this work. RC owns shares in IGEA. SSa and SSe are employees of IGEA.

The other authors have no conflicting interests to declare.

Author contribution

Conceptualization: FC, RC, VDL. Study design: FC, AZ, FV, RC, VDL. Methodology: NA, MC, ML, FC, VDL. Data collection: FC, AZ, FV, MD, VT, GC, LL, SC, SSe. Investigation: FC, AZ, FV, MD, VT, GC, LL, SC. Statistical analysis: FC, SSa, MC, ML, RC. Writing—original draft: FC, SSa, RC, VDL. Writing—review & editing: FC, AZ, SSa, RC, VDL. Funding acquisition: RC, VDL. Approval of final manuscript: all authors.

Acknowledgements

The authors are grateful to all patients and healthcare professionals for their participation. The authors wish to thank Francesca de Terlizzi, MSc, Roberta Fusco, PhD, and Elisa Merelli, MD for their contribution to the study execution and manuscript preparation.

References

1. Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016;15:869–881.
2. Borea PA, Gessi S, Merighi S, Varani K. Adenosine as a multisignalling guardian angel in human diseases: when, where and how does it exert its protective effects? Trends Pharmacol Sci 2016;37:419–434.
3. Capone F, Salati S, Vincenzi F, Liberti M, Aicardi G, Apollonio F, et al. Pulsed electromagnetic fields: a novel attractive therapeutic opportunity for neuroprotection after acute cerebral ischemia. Neuromodulation 2022;25:1240–1247.
4. Melani A, Corti F, Cellai L, Vannucchi MG, Pedata F. Low doses of the selective adenosine A2A receptor agonist CGS21680 are protective in a rat model of transient cerebral ischemia. Brain Res 2014;1551:59–72.
5. Choi IY, Lee JC, Ju C, Hwang S, Cho GS, Lee HW, et al. A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol 2011;179:2042–2052.
6. Grant G, Cadossi R, Steinberg G. Protection against focal cerebral ischemia following exposure to a pulsed electromagnetic field. Bioelectromagnetics 1994;15:205–216.
7. Varani K, Gessi S, Merighi S, Iannotta V, Cattabriga E, Spisani S, et al. Effect of low frequency electromagnetic fields on A2A adenosine receptors in human neutrophils. Br J Pharmacol 2002;136:57–66.
8. Capone F, Liberti M, Apollonio F, Camera F, Setti S, Cadossi R, et al. An open-label, one-arm, dose-escalation study to evaluate safety and tolerability of extremely low frequency magnetic fields in acute ischemic stroke. Sci Rep 2017;7:12145.
9. Colella M, Camera F, Capone F, Setti S, Cadossi R, Di Lazzaro V, et al. Patient semi-specific computational modeling of electromagnetic stimulation applied to neuroprotective treatments in acute ischemic stroke. Sci Rep 2020;10:2945.
10. Capone F, Dileone M, Profice P, Pilato F, Musumeci G, Minicuci G, et al. Does exposure to extremely low frequency magnetic fields produce functional changes in human brain? J Neural Transm (Vienna) 2009;116:257–265.

Article information Continued

Figure 1.

CONSORT study flow diagram. CONSORT, Consolidated Standards of Reporting Trials; FU, follow-up; MRI, magnetic resonance imaging. *Of the 16 patients in the active group, 14 were available for analysis at the 7-day FU: two patients were excluded from the analysis because they did not meet the inclusion criteria “2” and “3” (Supplementary Methods); 11 patients were available for analysis at the 45-day and 90-day FUs: three patients did not return for follow-up visit during the COVID-19 pandemic, but when interviewed by telephone, they were in good health and did not mention any negative effect related to the treatment; Of the 21 patients in the placebo group, 20 were available for analysis at the 7-day FU: one patient was excluded from the analysis because he did not meet the inclusion criteria “3” (Supplementary Methods), 19 patients were available for analysis at the 45-day and 90-day FUs: one patient died from causes unrelated to the treatment.

Figure 2.

Primary and secondary outcomes. (A) Line graph showing mean lesion volumes (±SE) at baseline, 7 days, and 45 days in the placebo and active groups. (B) Normalized MRI volume reduction (mean±SE). (C) Distribution of scores on the mRS at 90 days. (D) BI over time in the active and placebo groups (mean±SE). (E) NIHSS over time in the active and placebo groups (mean±SE). SE, standard error; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; BI, Barthel Index; NIHSS, National Institutes of Health Stroke Scale. *P<0.05; **P<0.01; P=nonsignificant (vs. baseline).

Figure 3.

Subgroup analysis. (A) Line graph showing mean lesion volumes (±SE) at baseline, 7 days, and 45 days in the placebo and active groups. (B) NIHSS score (means±SE) over time in the active and placebo. NIHSS score significantly improved over baseline in both groups. (C) Distribution of scores on the mRS at 90 days. Excellent outcome at 90 days was achieved in 85.7% of patients in the active group and in 63.6% of patients in the placebo group (P=0.634). (D) BI score (means±SE) over time in the active and placebo groups. The BI score improved from 42.5±30.9 at baseline to 92.9±16.8 (PP<0.01) at 90 days in the active group; whilst in the placebo group, BI increased from 54.2±37.2 at baseline to 82.7±37.2 (P=0.100) at 90 days. SE, standard error; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index. *P<0.05; **P<0.01; P=nonsignificant (vs. baseline).