To determine the prevalence of occipital pain in people with multiple sclerosis (pwMS), assess the differences between occipital neuralgia (OcN) and central neuropathic pain (CNP), and examine their association with upper cervical cord demyelinating lesions.

While trigeminal neuralgia (TN) is a well-known symptom in pwMS, the association between OcN and MS remains less recognized, and epidemiological data are lacking. Previous studies have suggested a correlation between upper cervical cord lesions and OcN. Unlike trigeminal pain, the International Classification of Headache Disorders (ICHD-3) does not differentiate OcN from CNP secondary to MS. 

A total of 658 participants were included, of whom 18 (2.7%) had TN and 33 (5.0%) occipital pain: 17 (2.6%) OcN, 6 (0.9%) CNP, and 10 (1.5%) OcN+CNP. TN co-occurred in 5.9% of OcN cases and in none of CNP. Ipsilateral-to-pain C1-3 lesion prevalence differed significantly among the occipital pain groups (p = 0.043), showing higher frequencies in OcN+CNP (100%) and OcN (64.7%), than in CNP (50%).

Occipital pain occurred in 5% of pwMS, with OcN showing a comparable prevalence to TN, highlighting its relevance. The presence of clinical and radiological differences between OcN and CNP supports their distinction as separate conditions. Specifically, higher frequencies of upper cervical lesions in OcN than CNP suggest different pathophysiological substrates, likely involving demyelination at the nerve root entry zone and within central pathways. Distinct diagnostic evaluation is suggested to improve recognition and treatment.