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INTRODUCTION
Herpes zoster (HZ) is the reactivation of the latent varicella-zoster virus within the sensory ganglia, resulting in a vesicular rash accompanied by pain. Postherpetic neuralgia (PHN) is the most prevalent complication of HZ, characterized by pain persisting for more than 3 months following the onset of the rash [1]. The incidence of HZ is approximately 4–5 cases per 1,000 individuals, with around 20% of HZ patients progressing to develop PHN, a risk that increases with advancing age [2,3]. PHN is frequently associated with severe burning and needle-like pain, significantly disrupting patients’ sleep and often co-occurring with anxiety, depression, and other psychiatric disorders [4,5]. This condition can lead to work disability and substantial medical expenses [2,6]. Treatment of acute HZ with antivirals can diminish the incidence and severity of associated complications [7]. However, it does not prevent the occurrence of PHN [8]. Consequently, finding effective ways to reduce the incidence of PHN has emerged as a significant clinical challenge.
Herpes zoster ophthalmicus (HZO) is a special type of HZ, which refers to recurrent infection of the first branch of the trigeminal nerve (ophthalmic nerve) by HZ virus latent in the trigeminal ganglion [9]. In addition to ophthalmic complications such as herpetic conjunctivitis, keratitis, and corneal ulceration, neuropathic pain remains the predominant symptom [10,11]. HZO accounts for approximately 10% to 20% of all HZ [12,13]. A previous study revealed that the closer the location of HZ is to the head, the higher the probability of developing PHN [14]. Besides, the incidence of HZO increases significantly over the age of 60 [15,16]. Compared to non-HZO, HZO has a higher propensity to progress to PHN [12]. In order to prevent the occurrence of refractory PHN, HZO ought to be treated with surgical intervention without delay when medication management is inadequate.
HZ-related pain is presently managed predominantly with opioid, antiepileptic, and antidepressant medications [6]. However, the effectiveness of such treatments remains a subject of debate, and side effects are unavoidable [6,17]. Neuromodulation is typically used to relieve neuropathic pain when medications are intolerable or ineffective [17]. Dorsal root ganglion pulsed radiofrequency (PRF) and spinal cord stimulation (SCS) are frequently utilized in the treatment of PHN in the spinal area [18]. Regrettably, high cervical SCS has been infrequently utilized in the treatment of trigeminal herpetic neuralgia [19]. Currently, supraorbital nerve PRF, trigeminal ganglion stimulation, trigeminal ganglion PRF, and peripheral nerve stimulation (PNS) are implemented to treat HZO [20,21]. Trigeminal ganglion stimulation or PRF has risks for the elderly and thus should not be the preferred surgical options [21]. So, which surgery should be recommended for elderly acute HZO patients with a high-risk of PHN? To answer this question, a multi-center retrospective study was conducted to determine the clinical efficacy of short-term PNS or supraorbital nerve PRF in the treatment of elderly patients with acute HZO.
MATERIALS AND METHODS
1. Study design and patients
This study was approved by the ethics committee of The First Affiliated Hospital of Nanchang University (approval number: IIT2024183). According with the Declaration of Helsinki, all patients confirmed the informed consent, and all clinical data were kept confidential. This multi-center retrospective study collected elderly acute HZO patients treated with PNS or supraorbital nerve PRF at the Department of Pain Medicine of The First Affiliated Hospital of Nanchang University, the Department of Pain Medicine of The Second Affiliated Hospital of Nanchang University and the Department of Pain Medicine of Zhejiang Provincial People’s Hospital from October 2022 to October 2023. The inclusion criteria were as follows: 1) HZO; 2) course of disease < 1 month with the herpes having subsided and the skin was fully repaired; 3) age ≥ 60; 4) no serious ocular complications; and 5) Visual Analog Scale (VAS) score ≥ 5 after regular medication. Exclusion criteria: 1) non-HZO; 2) course of disease ≥ 1 month; 3) age < 60; and 4) serious ocular complications or skin infection. All patients were followed up for 12 months.
2. Surgical methods
1) Peripheral nerve stimulation
The patients were placed in a supine position with a pillow under the scapula to tilt the head back. The head was tilted to the opposite side of the surgery and a film was applied to protect the eyes. The skin entry point was the intersection point 2–3 cm lateral of the outer canthus and 2–3 cm above the lateral canthus. After sterilization and anesthesia with 1% lidocaine at the level of the supraorbital ridge and superficial temporal fascia, a 14-gauge Tuohy needle was inserted transcutaneously and directed along a semilunar trajectory towards a supra-periosteal tissue plane located above the eyebrow. X-ray-guided transcranial surface puncture was performed to the cranial midline (Fig. 1A). A stimulation lead with eight electrodes (Model 3873; Medtronic) was inserted through the Tuohy needle under X-ray with the tip of the lead crossing the midline. The patient was returned to the ward and the neurostimulator (Model 37022; Medtronic) was connected to implantable electrodes after the anesthetic had worn off. The stimulation amplitude was 0.5–5.0 mV, 0–3 (–), 4–7 (+) for all patients. The stimulation frequency was 40–100 Hz and the pulse width was 500 µS. The electrical stimulation voltage was adjusted according to the pain severity and the patient’s tolerance to electrical stimulation. The duration of the stimulation was 10 days.
2) Supraorbital nerve pulsed radiofrequency
The application of supraorbital nerve PRF in treating acute HZO patients was applied under local infiltration anesthesia. Using ultrasound, a radiofrequency needle with a 5-mm exposed tip was inserted into the supraorbital notch. Upon reaching the expected position, a high-frequency (50 Hz, 500 μs width, < 0.2 V) stimulation test was conducted, which could induce forehead pain. Subsequently, the X-ray was used to confirm the placement of the needle tip (Fig. 1B). The PRF parameters were set at PRF mode (42°C, 2 Hz) for 600 seconds.
3. Outcomes
1) Demographic information
Demographic information was obtained from medical records. All patients were followed up for 12 months by outpatient.
2) Visual Analog Scale
The VAS scores were used to measure the pain (0 represented no pain and 10 represented the highest pain) before surgery and at 1, 5, and 10 days, and 1, 3, and 12 months after surgery. At 3 months after surgery, clinically significant PHN was defined as VAS ≥ 3 [22], and the incidence of PHN in both groups was recorded. At 12 months after surgery, the pain relief was estimated by the Barrow Neurological Institute (BNI) pain score [21] (BNI grade I: no pain, no medications; II: occasional pain, no medications required; III: some pain, adequately controlled with medications; IV: some pain, not adequately controlled with medications; and V: severe pain or no pain relief).
3) Pittsburgh Sleep Quality Index
Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) [23]. The PSQI consists of 7 different components, and each component was quantified from 0 to 3, with the total score being from 0 to 21, with higher scores indicating worse sleep quality. The PSQI score was measured before surgery and at 1, 3, and 12 months after surgery.
4. Statistical analyses
The numerical values are presented in the form of the mean ± standard deviation. Two-way repeated measures ANOVA was employed to conduct a comparison of VAS, PSQI, and medication. The chi-squared test (or Fisher’s exact test) was used to analyse categorical variables. All data were analyzed and expressed using GraphPad Prism 10 (GraphPad Software). The significance level was set at P < 0.05.
RESULTS
1. Demographic information
A total of 65 elderly acute HZO patients who were being treated with PNS or PRF were gathered. The surgeries were performed as soon as the patient’s HZ has healed. Fifty-six patients were selected in this study according to the inclusion and exclusion criteria, and four patients in the PRF group who had persistent pain and subsequently underwent PNS surgery were excluded from the 12-month follow-up. Additionally, two patients were lost to follow-up. Finally, 50 patients completed 12 months of follow-up in this retrospective study (Fig. 2). Twenty-eight patients were from the Department of Pain Medicine of The First Affiliated Hospital of Nanchang University, 12 patients were from the Department of Pain Medicine of The Second Affiliated Hospital of Nanchang University and 10 patients were from the Department of Pain Medicine of Zhejiang Provincial People’s Hospital. Twenty-seven patients were treated with PNS and 23 were treated with PRF. The demographic information of the patients, including age, sex, course of disease, side, VAS and PSQI scores are shown in Table 1.
2. Follow-up
The pain intensity of all patients was significantly relieved after surgery. For the PNS group, the VAS scores statistically reduced compared to the PRF group at 5 and 10 days, and at 1, 3, and 12 months after surgery (F(6, 128) = 21.32, P < 0.001). The VAS score of the PNS group was relieved further at 10 days after the surgery, and the difference was statistically significant compared to the VAS at 5 days after the surgery (t(2.75), P = 0.018) (Fig. 3A). The PSQI of the PNS group was significantly relieved compared to the PRF group at 1, 3, and 12 months after surgery (F(3, 62) = 7.61, P < 0.001) (Fig. 3B). At 3 months after surgery, 2 of the 27 (7.41%) patients in the PNS group and 7 of the 23 (30.43%) patients in the PRF group had VAS scores of ≥ 3 (P = 0.063) (Fig. 4A). At 12 months after surgery, there were 15 cases of BNI grade I, 10 cases of BNI grade II, 2 cases of BNI grade III, and 0 cases of BNI grade IV in the PNS group, and 5 cases of BNI grade I, 11 cases of BNI grade II, 5 cases of BNI grade III, and 2 cases of BNI grade IV in the PRF group (P = 0.039) (Fig. 4B).
3. Medication
Following surgery, the dosages of pregabalin and tramadol administered significantly declined in both groups. The dosages of pregabalin and tramadol were significantly lower in the PNS group than those in the PRF group at 1, 3, and 12 months after surgery (F(3, 78) = 3.04, P = 0.034 for pregabalin and F(3, 78) = 4.61, P = 0.005 for tramadol) (Fig. 5). There were no serious adverse events reported in this study.
DISCUSSION
In this study, the authors revealed that both short-term PNS and PRF for acute-phase HZO in the elderly can relieve pain. However, PNS may be better in providing pain relief, improving quality of life, and contributing to a downward trend in the incidence of PHN than PRF.
HZO was second only to thorax HZ, with an incidence 20 times higher than that of mandible or maxilla HZ [12,24]. Borkar et al. [25] found that 21% of patients with HZO eventually progressed to PHN. PHN was a condition characterized by abnormal pain and nociceptive hypersensitivity, which could worsen over time. It could lead to central sensitization, which involved changes in brain connectivity and abnormal neuronal excitability [26]. These factors made the treatment of PHN more challenging. The risk of PHN increased rapidly with age, and was particularly pronounced among those aged between 50 and 79 [12,15]. In HZO patients above the age of 65 years, the risk of PHN was 2.5 times higher [9,12,25]. Thus, early and aggressive treatment of HZO in the elderly population is crucial for reducing the incidence of PHN.
Following HZ infection, the virus impairs sensory ganglia which triggers inflammatory stimuli leading to changes in ion channel expression and function in sensory neurons [12]. As time progresses, patients with HZ experience altered brain function and developed central sensitization, which could lead to the development of PHN and make its treatment more challenging [27,28]. Previously, PHN was defined as persistent pain in the area affected by herpes that lasted for 3 months. However, clinicians have come to realize that this definition might cause a delay in the treatment of PHN. To provide more precise treatment, pain occurring within 1 month from the herpes was defined as acute herpetic neuralgia. Pain present between 1–3 months was defined as subacute herpetic neuralgia. Previous research revealed that PRF and SCS were more effective in treating acute HZ than PHN [29]. In this study, all patients were followed up and the results showed that more than 50% experienced significant pain relief postoperatively, improved sleep quality, and a reduction in the incidence of PHN. Therefore, it is crucial to alleviate acute or subacute HZ and prevent it from progressing to PHN. In this study, the surgical treatment of HZO was optimized, and PNS or PRF was performed promptly after the herpes wound healed to minimize nerve damage.
Pharmacotherapy and nerve blocks have been applied to treat neuropathic pain, yet they presented poor efficacy and intolerable side effects [30]. Neuromodulation has been gradually used for neuropathic pain, which included transcranial magnetic stimulation, PRF, SCS, PNS, and deep brain stimulation [31]. PRF and SCS were primarily used to treat PHN, which could significantly alleviate pain in PHN [18,32]. Some studies have shown that SCS was more effective and safer than PRF [33]. However, HZO was difficult for SCS to control [12,34]. Supraorbital nerve PRF, PNS, or trigeminal ganglion radiofrequency were usually the preferred methods for treating HZO [12]. Han et al. [35] revealed that 80% (12/15) of patients with subacute HZO-related pain experienced > 50% pain relief after PNS, but in this study, all PNS patients had pain relief > 50% at the 12-month follow-up. Previous research included HZ patients with multi-branch trigeminal nerves [35], but all patients in the present study had HZO. The authors believe that trigeminal ganglion PRF or stimulation should be used in patients with multi-branch trigeminal herpetic neuralgia [21,36]. Previous studies indicated that PRF could lower the incidence of PHN and slow the course of neuropathic alterations brought on by acute herpetic neuralgia [37,38]. Furthermore, compared to PRF, electric stimulation may offer superior pain alleviation and quality of life [39–41]. Consequently, four PRF group patients who experienced ongoing pain later received PNS surgery in this study. For HZO may extend to the tip of the nose, indicating involvement of the nasociliary branch and increasing the likelihood of ocular involvement due to shared innervation [11]. PRF only operates on the supraorbital nerve and cannot cover areas of fine nerve branches such as the supratrochlear nerve. In contrast, PNS could completely cover the first branch of the trigeminal nerve. Moreover, PRF functions by generating electric fields that have no impact on the nerve’s structural integrity and acts as a transient modulator [42], whereas PNS is a long-term continuous stimulation that can be more effective. Consistent with this, PNS patients showed a constant decrease in VAS scores during the stimulation period in this study. As per the gate-control theory, the authors speculated ectopic activity of nociceptive primary afferents (Aδ and C-fibers) caused by HZ may be inhibited by PNS [43,44].
In conclusion, the findings of this study suggest that early application of short-term PNS may offer superior pain management, enhance quality of life, and contribute to a downward trend in the incidence of PHN compared to PRF. However, this is a small sample multicenter retrospective study that lacks strictly randomized control. The authors are looking forward to multi-center prospective studies to validate their findings.
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