# Predictors of Response to Occipital Nerve Stimulation in Patients with Refractory Chronic Cluster Headache: Protocol for a Prospective Observational Study

## TL;DR

This study aims to find factors that predict which patients with chronic cluster headaches will benefit from occipital nerve stimulation, using a range of tests and biomarkers.

## Contribution

The study introduces a multidimensional assessment panel to identify predictors of response to occipital nerve stimulation in refractory chronic cluster headache.

## Key findings

- A combination of MRI, serum neuropeptides, and sensory testing may predict ONS outcomes.
- TENS is explored as a non-invasive preoperative screening tool for ONS response.
- Identifying predictive biomarkers could improve patient selection and reduce unnecessary surgeries.

## Abstract

What are the main findings?
This prospective study protocol introduces a multidimensional assessment panel—including structural magnetic resonance imaging (MRI), serum neuropeptides (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide 38 (PACAP38), vasoactive intestinal peptide (VIP)), neuropsychological evaluation, auditory evoked potentials, and quantitative sensory testing—to identify predictors of response to occipital nerve stimulation (ONS) in refractory chronic cluster headache.Transcutaneous electrical nerve stimulation (TENS) is evaluated as a potential non-invasive preoperative screening tool to predict ONS outcomes.

This prospective study protocol introduces a multidimensional assessment panel—including structural magnetic resonance imaging (MRI), serum neuropeptides (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide 38 (PACAP38), vasoactive intestinal peptide (VIP)), neuropsychological evaluation, auditory evoked potentials, and quantitative sensory testing—to identify predictors of response to occipital nerve stimulation (ONS) in refractory chronic cluster headache.

Transcutaneous electrical nerve stimulation (TENS) is evaluated as a potential non-invasive preoperative screening tool to predict ONS outcomes.

What are the implications of the main findings?
Identification of reliable predictive biomarkers would enable precision patient selection for ONS, reducing unnecessary surgical complications and optimizing healthcare resource allocation.This multidimensional approach may also help us understand the biological basis of ONS response mechanisms and serve as a starting point for larger validation studies.

Identification of reliable predictive biomarkers would enable precision patient selection for ONS, reducing unnecessary surgical complications and optimizing healthcare resource allocation.

This multidimensional approach may also help us understand the biological basis of ONS response mechanisms and serve as a starting point for larger validation studies.

Background: Occipital nerve stimulation (ONS) is an effective therapy for patients with refractory chronic cluster headache (rCCH); however, it is not without complications, and to date, there are no conclusive findings regarding factors that would allow the prediction of treatment response. The primary objective of this study is to identify such factors to improve patient selection. Methods: This single-center prospective observational study will be conducted at the Department of Neurology, Hospital Universitario La Paz (Madrid, Spain). Given the low prevalence of rCCH, a convenience sampling approach will be adopted, with an expected enrollment of a minimum of 15 patients over 24 months of the study. The study is structured into three periods: Pre-ONS (pre-implantation), ONS (implantation), and Post-ONS (follow-up at 12 months). During the pre-implantation phase, patients will undergo a multidimensional assessment encompassing structural 3T brain magnetic resonance imaging (MRI), blood analysis (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide 38 (PACAP38), and vasoactive intestinal peptide (VIP)), neuropsychological evaluation, auditory evoked potentials, algometry (pressure pain threshold, temporal summation, conditioned pain modulation), and transcutaneous electrical nerve stimulation (TENS). Follow-up visits will be conducted at 3, 6, and 12 months post-implantation. Results: This study aims to identify biomarkers or their combinations capable of reliably predicting patients who would benefit from ONS. Conclusions: Through this multidimensional assessment, this study seeks to identify predictive factors of response to ONS, thereby improving patient selection, optimizing healthcare resources, and advancing the understanding of treatment response mechanisms.