Vagus nerve stimulation for enhanced stroke recovery after intracerebral hemorrhage: illustrative case

Abstract

BACKGROUND

Randomized controlled trial (RCT) evidence has revealed the efficacy of vagus nerve stimulation (VNS) paired with rehabilitation therapy, over therapy alone, for upper-limb functional recovery after ischemic stroke. However, this technique has not yet been described for the recovery of chronic motor deficits after hemorrhagic stroke.

OBSERVATIONS

Three years after left putaminal intracerebral hemorrhagic stroke with chronic upper-limb functional deficits, a patient was treated with VNS for enhanced stroke recovery. VNS was paired with 6 weeks of in-clinic physical therapy, resulting in upper-limb functional improvement of 14 points on the Fugl-Meyer Assessment Upper Extremity (FMA-UE) index for stroke recovery (maximum score of 66 equating to normal function). This improvement was more than 1 standard deviation above the improvement documented in the first successful RCT of VNS paired with therapy for ischemic stroke (5.0 ± 4.4 improvement on FMA-UE).

LESSONS

VNS is a promising therapy for enhanced recovery after hemorrhagic stroke and may offer greater improvement in function compared to that after ischemic stroke. Improvement in function can occur years after the time of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is an often devastating condition, with a mortality rate of up to 50%.¹ In many survivors of ICH, functional motor deficits contribute to disability and impede a good quality of life.¹ Because these deficits often persist despite maximizing physical and occupational therapies after stroke, various neuromodulation technologies have garnered attention for enhancing stroke recovery.² Vagus nerve stimulation (VNS) is one potential avenue for enhancing recovery after ICH.

One randomized controlled trial has evaluated invasive VNS paired with 6 weeks of in-clinic physical therapy for enhanced ischemic stroke recovery. In that study, Dawson et al.³ demonstrated significant improvements in function, as measured by Fugl-Meyer Assessment Upper Extremity (FMA-UE) index, using VNS plus physical therapy (mean 5.0 ± 4.4 points of improvement from baseline) compared to physical therapy alone (mean improvement of 2.4 ± 3.8; p = 0.0014). If VNS could be as safely and effectively applied to patients with ICH as it has for ischemic stroke, it could serve as an important tool in the neurorehabilitation of patients with deficits after ICH. Therefore, we present the first case of VNS for enhanced stroke recovery in a patient with chronic upper-limb functional deficits after ICH.

Illustrative Case

ICH Presentation and Evacuation

A 67-year-old male with a past medical history of hypertension initially presented with 1 hour of right-sided hemiparesis and aphasia. Baseline noncontrast head computed tomography (CT) revealed a 4.0 × 3.1 × 1.8 cm, left putaminal ICH (Fig. 1A and B). With repeat CT showing a slight increase in size and midline shift (Fig. 1C), the patient underwent stereotactic ICH evacuation (Fig. 1D), as previously described.⁴ Postoperative management was otherwise uncomplicated, and the patient was discharged with routine rehabilitation, with motor function of 1/5 in the right upper extremity and 1/5 to 3/5 in the right lower extremity. By 3 years after the stroke, the patient had reached a plateau of functional recovery despite continued therapy three times per week, including strength in the upper extremity of 3/5 in shoulder abduction, 1/5 wrist extension and hand grip, and 0/5 in hand opening. Right lower-extremity strength was 5/5 proximally and 1/5 distally. The patient’s baseline FMA-UE score was 16.

FIG. 1.

Axial (A) and coronal (B) noncontrast head CT of the patient’s ICH at presentation. Repeat CT 8 hours later (C) demonstrating new midline shift, which prompted surgical ICH evacuation. Postoperative CT (D) demonstrating successful ICH evacuation.

VNS

Given the persistent functional deficits in upper-limb function limiting his quality of life, the patient was treated with left-sided VNS for enhanced stroke recovery of upper-limb function. In both the Food and Drug Administration approval and the first randomized controlled trial (RCT) for VNS for stroke recovery by Dawson et al.,³ hemorrhagic stroke was considered an exclusion criterion. In our institutional review board approval for the study of VNS treatment for stroke recovery, we included “other related neurological pathology” (such as hemorrhagic stroke) as inclusion criteria for VNS treatment. Informed consent was also obtained from the patient with the understanding that VNS plus rehabilitation remained an experimental treatment for hemorrhagic stroke. A schematic of the final VNS implant is shown in Fig. 2. During repeated sessions of in-clinic therapy over 6 weeks, VNS was applied at a frequency of 30 Hz, amplitude up to 0.8 mA as tolerated, pulse width of 100 µsec, and lasting 0.5 seconds. Therapy and VNS settings matched those of the largest RCT of VNS for functional recovery after ischemic stroke.³

FIG. 2.

Left: The implantable pulse generator is placed in a left infraclavicular subcutaneous pocket and connected to the VNS wire. Right: The VNS wire is wrapped in a helical shape around the left vagus nerve, with securing stitches placed to maintain permanent positioning around the vagus nerve.

Functional Recovery After VNS

After the conclusion of in-clinic therapy and VNS over 6 weeks, the patient was noted to have an FMA-UE score of 30 (improvement of 14 points from 16 at baseline). Improvements were also seen in sensation (from 2/12 at baseline to 10/12 after VNS + therapy) and passive joint motion (from 5/24 at baseline to 11/24 after VNS + therapy). Lower-extremity function was not assessed at the long-term follow-up.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

We describe the first case of VNS paired with physical therapy for enhanced stroke recovery after ICH, with improvement in upper-extremity function per an FMA-UE score of 14, which exceeded the mean improvement in patients with ischemic stroke in a published RCT (5.0 ± 4.4 points).³ Although noninvasive VNS has been reported after ICH in the acute setting, no difference in functional outcomes was seen from sham stimulation.⁵ Conversely, delayed VNS at 3 years after initial stroke, in a patient with stable deficits, was shown to improve objective upper-extremity function when paired with in-clinic therapy. Most motor recovery after ICH is classically thought to occur in the first 6 months after stroke.^6,7 We note that the plateau in function for our patient occurred despite active therapy three times per week prior to VNS therapy (the same as that given after VNS). Although the therapy given with VNS was not necessarily the same as prior to VNS implant placement, randomized evidence from Dawson et al.³ for ischemic stroke indicates that VNS plus therapy provides a significant synergistic benefit above the same rehabilitation therapy alone. Based on our results in one patient, VNS paired with therapy may be able to provide a similar functional benefit for patients with chronic functional deficits after hemorrhagic stroke.

Lessons

Despite advances in the acute management of ICH, including the advent of minimally invasive evacuation, there are few treatment options for improving function for patients living with chronic functional deficits after ICH. This report of one initial patient indicates VNS as one neuromodulation strategy for improving function in patients with ICH. Given the success of VNS in ischemic stroke, it may not be surprising that VNS holds potential for patients with hemorrhagic stroke. Patients with ischemic stroke may have large regions of infarcted cortex involved in motor function. In contrast, patients with ICH have a pathology that causes local mass effect and secondary injury to surrounding brain tissue,⁸ which may be further addressed by acute treatments such as surgical evacuation, as in our case. Prior work has shown that patients with ICH have a greater propensity for functional improvement from the acute to chronic period compared to patients with ischemic stroke.⁹ This propensity for recovery may be driven by the neuroplastic potential of surrounding brain tissue after ICH,¹⁰ which may in fact be greater than that after ischemic stroke.¹¹ In conjunction with this, our documented improvement in function of 14 on the FMA-UE for stroke recovery was more than 1 standard deviation above the improvement documented by Dawson et al.³ for ischemic stroke (5.0 ± 4.4 improvement on the FMA-UE). Work by Wagner et al.¹² has demonstrated that a FMA-UE improvement of 5.2 is necessary for a reliable minimal detectable change, indicating true improvement in motor function that can be assessed with kinematic assessment. Shelton et al.¹³ has also demonstrated that a 10-point improvement on the FMA-UE leads to a clinically meaningful 1.5-point improvement in the Functional Independence Measure of self-care. Thus the FMA-UE improvement of 14 in our case with VNS plus rehabilitation for ICH represents both a reliably detectable and clinically meaningful improvement. Although preliminary, our results in the first documented patient with VNS for ICH suggest VNS paired with rehabilitation may be a promising approach to enhance recovery after ICH. Further prospective trials are necessary to confirm the utility of VNS for functional recovery after ICH.

Author Contributions

Conception and design: Cummins, Kalagara, Downes, Tosto-Mancuso, Putrino, Panov, Kellner. Acquisition of data: Cummins, Tosto-Mancuso, Panov, Kellner. Analysis and interpretation of data: Cummins, Putrino, Panov, Kellner. Drafting the article: Cummins, Kalagara, Putrino, Panov. Critically revising the article: Kalagara, Putrino, Panov, Kellner. Reviewed submitted version of manuscript: Cummins, Kalagara, Downes, Park, Tosto-Mancuso, Putrino. Approved the final version of the manuscript on behalf of all authors: Cummins. Administrative/technical/material support: Park, Tosto-Mancuso, Putrino, Kellner. Study supervision: Tosto-Mancuso, Panov, Kellner. Medical illustrations: Park.