Neurophysiological assessment of brachioradial pruritus patients

Abstract Background: Pruritus is a common complaint in dermatology. Wartenberg, in 1943, associated pruritus with neuropathy, relating it to the “posterior antebrachial cutaneous nerve neuropathy”. In 1968, Waisman described patients with frequent pruritus complaints in the upper limb during the summer, which he named “brachioradial summer pruritus”. Currently, this pruritus is named brachioradial pruritus (BRP). BRP is characterized by a chronic pruritus, usually localized, with a long duration, and without apparent cutaneous abnormalities. Neurological disorders both from the central and peripheral nervous systems, including multiple sclerosis, are associated with pruritus. Objective: To investigate correlations between symptomatic dermatomes and alterations in the myotomes, as evidenced by electroneuromyography (ENMG). Methods: Forty-six patients with BRP dermatological diagnoses were subjected to upper limb ENMG. Results: Among 46 patients with C5 to C8 dermatomal pruritus, we evaluated 113 symptomatic dermatomal areas. Overall, 39 (85%) patients had radicular involvement and 28 (60%) had agreement between complaint and the ENMG findings (p=0.015). A total of 80% of the patients with complaints at C7 and 47% at C6 had radicular involvement at the same level. Conclusions: Among the patients who presented complaints, 47 and 80%, respectively, had ENMG alterations in the C6 and C7 myotomes. We conclude that peripheral nervous system involvement is associated with BRP.


INTRODUCTION
Among the chronic cutaneous manifestations, pruritus is one of the most challenging in terms of propaedeutic and dermatological treatment. Considering the impact of chronic pruritus (CP) on quality of life, the investigation of its etiology is crucial to define follow-up strategies.
In the first case description in 1943, Wartenberg related the "posterior antebrachial cutaneous nerve neuropathy" to pruritus 1,2 . Waisman, in 1968, described patients with recurrent pruritus complaints, located predominantly in the upper limbs, and occurring in the summer 3 . In Waisman's study, the brachioradial muscle region was mostly affected and symptoms were described as pruritus, burning, stinging, paresthesia, or localized pain that could be relived with ice. Waisman named this pruritus as "brachioradial summer pruritus", which is currently known as brachioradial pruritus (BRP) 4 .
In 2007, the International Forum for the Study of Itch (IFSI) suggested to use the concept "Chronic Pruritus in the Absence of Skin Diseases" in order to avoid ambiguity with terms such as "essential pruritus". This definition is used to designate systemic, neurological, psychogenic, and mixed conditions that can be present along with chronic pruritus in patients without skin inflammation or lesions caused by non-specific chronic abrasion 5 . Although this condition is uncommon, it should not be overlooked. BRP is a clinical condition characterized by chronic pruritus, usually spatially restricted, which differs from most of the other causes of long-term pruritus 6 .
Wallengren and Sundler, studying skin biopsies in 2005, found a reduction in cutaneous sensory innervation during pruritus, which reverse to normal during remissions. These authors found the same results in a similar skin biopsy study after serial phototherapy application 7,8 . However, the methodology used in these studies did not allow to discriminate between myelinated and amyelinated fibers. Even so, the authors classified the sensory involvement as crucial in the pruritus pathophysiology.
Neurological disorders such as notalgia paresthetica and herpes zoster may be associated with pruritus 6 . BRP has been associated with orthopedic/radicular disorders since 1968 and has been studied mainly through image-based diagnostics 9,10,11,12,13 .
Electroneuromyography (ENMG) has been employed as complementary diagnosis for peripheral nerve lesions, both focal and diffuse, since 1950. It allows to locate the compromised radicular motor nerve to assess the gravity of the process, and avoid a lesion in upper limb peripheral nerves 14,15 . The routine ENMG has limitations in identifying pure sensory radiculopathy. Specifically, ENMG is unable to detect the involvement of amyelinic C fibers involved in pain and pruritus sensations.
The goal of the present study was to investigate the clinical profile of BRP and to correlate the symptomatic dermatome with the compromised myotomes, using upper limb ENMG in patients with BRP from the Instituto Lauro de Souza Lima (ILSL), Brazil, between 2015 and 2019.

METHODS
Patients diagnosed with BRP by the ILSL Dermatology Service were referred for evaluations to the ILSL Clinical Neurophysiology between 2015 and 2018. Neurological and ENMG examinations were carried out in every patient. Inclusion criteria were age equal to or higher than 21 years; presence of chronic pruritus (>6-week-long) with characteristic symptoms of BRP, i.e., localized pruritus, no apparent cutaneous lesion, frequently starting bilaterally, and affecting the dorsolateral region of the upper limbs and/or forearms; and negative clinical, laboratorial, and anatomopathological results for other concomitant causes of localized pruritus. Patients with chronic pruritus and skin alterations, with incomplete associated data, or that gave imprecise answers in the interview, were excluded from the analysis.
The patients, after reading and signing a term of consent, were evaluated by the neurophysiology team and the ENMG exam was carried out. A Nihon Kohden MEB-9200J electromyograph was used for the nerve conduction studies (NCS). Following the protocol, studies of motor nerve conduction, sensory, and F wave were carried out in the upper limb, followed by the electromyography for evaluating the radiculopathy. The sensory NCS analysis were performed distally and antidromically in the Superficial Radialis, Ulnaris V finger and Dorsal Cutaneous Branch, and Median in I-IV digits nerves. Motor conduction were performed in the Ulnar and Median nerves. Both techniques were performed by surface electrodes and the body temperature was controlled between 32-34°C 16 . The following muscles were examined: trapezium (C3, C4), deltoid (C5, C6), biceps (C5, C6), triceps (C6, C7, C8), pronator teres or flexor carpi radialis (C6, C7), extensor indicis or extensor digitorum (C7, C8), first dorsal interossei (C8, T1), and cervical paraspinal muscles.
Chronic neurogenic alterations were considered as such when there were more than 10-25% polyphasic potentials, i.e., with more than four phases, among the potentials measured in 3-4 sites in each muscle 13 . Radiculopathy is defined by the presence of neurogenic patterns in two or more muscles innervated by the same root belonging to different nerves 15 .
The clinical and neurophysiological results were compared using Pearson's chi-square test considering a 5% significance level.

RESULTS
Overall, 46 patients who presented symptoms within the C5-C8 dermatomes were evaluated, totaling 113 symptomatic dermatomeric areas. The mean age was 60 years (min. 41, max. 83) being 35 women and 11 men, with a mean duration of the disease of five years. Complaints were distributed as follows: 19 cases in C5, 38 in C6, 40 in C7, and 16 in C8, corresponding respectively to 17, 34, 35, and 14% of the symptomatic dermatomeric areas. Signs of radicular involvement were observed in 39 (85%) patients, and in 28 (60%) there was full concordance (p=0.015) between the complaints and the ENMG findings (Figure 1). When each root was analyzed separately, concordance between dermatological symptoms and ENMG was found in 8 cases at the root of C5, 18 cases in C6, 32 in C7, and 9 in C8, representing 7, 16, 29, and 8% of the symptomatic dermatomeric areas, respectively (Figure 2). It was noted that 80% of the patients with complaints within dermatological territory of C7 (n=32) and 47% of the patients with complaints in C6 territory (n= 8) had signs of radicular involvement at the same level as the ENMG.

DISCUSSION
The scientific literature shows that the mean age of BRP patients is 59 years, with a predominance in females, which is corroborated by our dataset. Dermatomeric complaints at the roots of C6 and C7 were the commonest ones (34 and 35%, respectively) 17 . Considering only the patients with complaints at C7 (n=40), 80% had electromyographic alterations in myotomeric distribution in C7.
Pruritus and pain are conducted by the same type of neural fiber, the amyelinic C fibers, and both have been historically considered different degrees of the same sensation. However, it is currently accepted that pruritus and pain are two distinct mechanisms with great similarity in the transduction of the signals and sharing the same pro-inflammatory mediators, neurotransmitters, and neuropeptides. Both sensations are also processed in the same regions of the brain, i.e., the amygdala, hippocampus, and hypothalamus 18 . Studies of skin biopsy have shown that cutaneous innervation reduces during occurrence of the symptoms 7 . Therefore, these findings suggest the need for a fine and wide assessment of all sensory modalities, including tactile, thermal, pain sensation and autonomic function of the symptomatic areas in pruritus evaluation. In this context, quantitative sensory test (QST) 19 would be interesting to apply in future neurophysiological studies, which could improve the knowledge on BRP pathophysiology.
Among our sample, individuals with more than 40 years old were more prone to radicular compressions. However, the presence of high frequency of radicular involvement in ENMG in individuals without BRP suggests additional associated causes. In this sense, a hereditary cause was suggested by Wallengren and Dahlbäck, who reported BRP in several members of the same family 20 . Notwithstanding, genome wide association studies were not found in our late literature search.
Some studies report either worsening or beginning of the symptoms after prolonged exposure to sun rays, but it is not known how sun exposure triggers such symptoms 8,21 . Wallengreen suggested that sun exposure could harm nerve endings 21 . The currently accepted etiology is a bicausal origin with cervical radicular involvement and ultraviolet radiation 21,22 . In this study, the C7 dermatome was the most frequently involved, which corresponds to the area more prone to be subjected to sun exposure, i.e., the latero-posterior face (extensor) of the upper limbs.
In conclusion, this study evidences the correlation between cervical radicular involvement and pruritus. The more frequent involvement of the C7 root, corresponding to the C7 dermatome, which has more solar exposure, supports the idea that solar radiation is a coadjutant factor in patients with BRP. The majority of patients with cervical radicular involvement did not present pruritus. In order to better recognize this condition (BRP), we suggest future studies aimed at investigating the putative genetic bases of this phenotype.