Correspondence *Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts University of Kiel, Schittenhelmstrasse 10, 24105 Kiel, Germany

Email a.binder@neurologie.uni-kiel.de

The case

A 64-year-old woman presented to an outpatient clinic with itching and burning sensations in her right dorsal forearm. The itch had started subacutely 2 years previously, showed no seasonal dependency, and had become progressively more intense. The itch intensity fluctuated throughout the day and regularly kept the patient awake at night. In addition, a persistent redness was present within the affected itchy area. The mean intensity of the itch sensation was scored 6 on an 11-point numerical analog scale (0 = no itch, 10 = the most severe itch that can be imagined). Concurrently, the patient felt transient paresthesias within the same area. The itch could be relieved by scratching the skin and by warm ambient temperature, whereas cold temperatures exacerbated the itch—an unusual finding given that cold commonly helps to relieve itch. The patient had not experienced any additional skin changes, such as rash, pain or other neurological deficits, during the course of this disease. No trauma to the affected extremity or the spine had occurred, and there was no family history of comparable symptoms. There was no history of prolonged sun exposure as a result of traveling or sunbathing, or of continuous exposure to the sun in daily life, before the symptoms developed.

A review of the patient's medical history revealed a cervical disc herniation at the C5–C6 level and intervertebral osteochondrosis without any accompanying neurological deficits. The disc herniation had been a coincidental finding on an MRI scan of the cervical spine conducted 2 years previously, before surgery was performed to decompress the median nerve bilaterally to relieve symptomatic carpal tunnel syndrome. The surgery did not leave the patient with any residual symptoms. In addition, 6 years before her presentation to the outpatient clinic, the patient had experienced sciatica in the left lower extremity that subsided completely within a few weeks. No further relevant medical conditions had been reported, and a systems review revealed no further pathologies. The patient did not take any medications, drugs or alcohol on a regular basis, and she had not experienced any allergies or skin diseases.

On examination, the patient was severely distressed as a consequence of the itching and burning sensations. Her vital signs were normal. A dermatological assessment showed redness of the right dorsal forearm, with a few discrete papulous skin lesions within the same area, but no further abnormalities. Thorough neurological assessment showed that the area of itching and redness corresponded to part of the C6 dermatome. Both of the scars from the previous carpal tunnel syndrome surgery had completely healed, and the Hoffmann–Tinel sign was negative on both scars. The patient's cranial nerves were functioning normally, and she had very good muscle bulk and strength. Her muscle tendon reflexes were normal, apart from an absent left achilles tendon reflex, which was probably a residual effect of irritation of the S1 nerve root that had caused the sciatica reported 6 years previously. Sensation to light touch, sharp stimuli and vibration, and awareness of proprioception were intact. The patient's gait, posture and coordination were all normal.

The diagnostic work-up included a skin biopsy, MRI scans of the cervical spine, quantitative sensory testing (QST) and laser Doppler imaging. QST was performed on the right dorsal forearm according to the protocol of the German Research Network on Neuropathic Pain (Box 1).¹ The thermal tests were performed by use of a TSA-II NeuroSensory Analyzer (Medoc Advanced Medical Systems, Ramat Yishai, Israel) with a 30 30 mm thermode and a computerized test paradigm. All parameters were determined by repeated measurements, as outlined in the standardized and validated QST protocol.

Within the affected area, compared with the corresponding unaffected area on the left forearm, a decreased mechanical detection and cold detection threshold was observed. In addition, a decreased cold pain and heat pain threshold (cold and heat hyperalgesia), and increased mechanical pain sensitivity to pinprick stimuli (pinprick hyperalgesia) were observed. No alloknesis was reported. These results indicated decreased function of A-fibers and A-fibers, in combination with sensitization of the PNS and CNS. It is possible that the heat, cold and mechanical hyperalgesia were caused by C-fiber sensitization.

Skin perfusion, as measured by laser Doppler imaging, was increased in the affected skin compared with the contralateral side (Figure 1). Histological analysis of a skin biopsy sample showed results consistent with chronic irritant eczema, but there were no further pathological findings. Skin biopsy to evaluate C-fiber density was not performed, so changes in this parameter cannot be ruled out.

Figure 1 Laser Doppler images of the affected right forearm in a patient with brachioradial pruritus.

(A) The affected right forearm. (B) Increased skin perfusion before nerve root decompression. (C) Normalization of skin perfusion after nerve root decompression.

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MRI scans of the cervical spine demonstrated intervertebral osteochondrosis, which was most prominent at the C5–C6 level. In addition, a right-sided mediolateral disc herniation, along with mild compression of the spinal cord and severe compression of the right C6 nerve root, was shown (Figure 2). MRI scans of the brachial plexus were normal. X-rays of the cervical spine showed severe intervertebral osteochondrosis that was most prominent at the C5–C6 level, along with spondylarthritis.

Figure 2 MRI scan of the cervical spine in a patient with brachioradial pruritus.

The scan shows compression of the spinal cord and right sixth cervical nerve root (arrows).

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Symptomatic analgesic treatment with gabapentin was initiated. After uptitration from 300 mg to 900 mg daily, the intensity of the itching and burning sensations was almost halved. The patient was admitted to a neurosurgery department with a suspected diagnosis of brachioradial pruritus (BRP) of neuropathic origin. In the neurosurgery department, she underwent a ventral C5–C6 discectomy and C6 nerve root decompression, followed by fusion between the C5 and C6 vertebrae by use of a standard polyetheretherketone (PEEK) cage under general anesthesia. This treatment option was chosen because it had been established that nerve structures were compressed and were therefore at risk of being damaged irretrievably. Intensification of the first-line treatment for BRP—that is, pharmacological treatment of symptoms—was not tried. The patient recovered completely from the itching and burning sensations within 1 week after surgery. Administration of gabapentin medication was stopped. A clinical dermatological follow-up showed no residual pathologies. Follow-up assessment with QST demonstrated an alleviation of heat and cold hyperalgesia but not of mechanical hyperalgesia, and restoration of function with respect to cold and mechanical detection thresholds within the previously affected forearm area, indicating possible regeneration of the decompressed nerve root. Skin perfusion, as assessed by laser Doppler imaging, was normalized (Figure 1).

Discussion of diagnosis

BRP is a rare disease, usually restricted to the forearms, that was first identified in 1968.² It is most prevalent in individuals between the ages of 39 and 72 years, and it preferentially affects women.³ BRP usually develops bilaterally and involves the area overlying the brachioradial muscle, although it can spread to the back or chest.³ Patients with BRP report having an itching sensation, usually combined with a burning or painful sensation.^{2, 3} Owing to ongoing scratching, secondary skin changes such as prurigo or lichenification can develop.^{2, 4} In the present case, scratching induced papulous skin lesions, nonspecific skin changes within the skin biopsy sample, and an increase in skin blood flow—probably as a result of a flare reaction—as assessed by laser Doppler imaging.

The pathophysiology of BRP is a matter for debate. Two main mechanisms have been proposed. Initially, exposure to ultraviolet light was assumed to be the main factor leading to BRP, owing to the observation of seasonal occurrence in the summer, and to an association with outdoor activities or living in tropical or subtropical areas.^{4, 5, 6} These observations led to the alternative terms 'solar pruritus' or 'recurrent solar dermopathy'. Later, however, it was hypothesized that neuropathy might be the underlying cause of both BRP and related pruritus syndromes. This hypothesis seems to be at least partially valid in BRP, as this condition has been shown to be associated with cervical spine degeneration, spondylosis, foraminal narrowing, lowering of disc space, cervical ribs, and peripheral nerve lesions (e.g. radiculopathy or polyneuropathy).^{3, 7, 8} Moreover, spinal tumors and hemangiomas have been reported to be associated with BRP.⁷ The case of the patient presented here supports this neuropathic hypothesis, because spinal nerve decompression led to a rapid and complete recovery. A combination of sun-induced nerve damage and underlying peripheral nerve damage—the former serving as a trigger for nerve sensitization and the latter causing amplification of afferent input—might, however, contribute to the variable degrees of BRP between different patients.⁴ This hypothesis was substantiated by the demonstration that epidermal and dermal innervation by nociceptors is reduced in BRP.⁹ Skin biopsy results after phototherapy reveal similar changes in innervation.¹⁰ It can, therefore, be hypothesized that photodamaged nociceptive afferents induce abnormal nerve activity, and, consequently, itch. A predisposing peripheral or central nerve injury will facilitate this pathological input, thereby contributing to BRP. It remains unclear, however, whether peripheral input is needed, or whether a proximal nerve injury can induce BRP by itself.

The diagnosis of BRP is made on the basis of clinical symptoms and signs. Applying an ice pack to the affected area might provide itch relief in patients with BRP, and this 'ice-pack sign' is often diagnostic for BRP.¹¹ The clinician should look for a history of sun exposure, possible peripheral nerve or spinal injury, or a family history of BRP. Dermatological examination, including skin biopsy, might reveal damage that could be attributed to ultraviolet light, or a reduction in epidermal and dermal nociceptor innervation. Neurological assessment, including electrophysiological work-up if necessary, should identify any nerve lesions. MRI scans of the related radicular nerves and spine, along with X-rays if applicable, are needed to exclude nerve entrapment or lesions of the spinal cord.

Differential diagnosis

In view of the fact that BRP is diagnosed on the basis of its unique presentation, there are few potential differential diagnoses. Herpes zoster, in particular zoster sine herpete, should be considered, although this condition usually presents with pain, and itch is the predominant symptom in only a minority of cases. It is also important to exclude localized dermatological diseases. In addition to idiopathic forms of BRP, as was seen in the patient presented here, a possible X-linked familial form of BRP has recently been described.¹²

Treatment and management

Owing to the low prevalence of BRP, no controlled studies are available to provide evidence-based treatment options. When exposure to ultraviolet light is a contributing factor, sun protection could provide rapid recovery, or the itch intensity could be eased by topical local anesthetics or local cooling (although application of an ice pack might be counterproductive in the long term).^{3, 11}

Conservative symptomatic treatment is the standard first-line treatment in BRP. In line with the assumed neuropathic etiology of BRP, capsaicin cream, carbamazepine, oxcarbazepine, lamotrigine, NSAIDs and gabapentin have shown efficacy in some cases.^{4, 6, 13, 14, 15, 16} These compounds are all known to be effective in the treatment of other neuropathic pain syndromes.^{15, 17}

In the patient presented here, decompression of nerve structures was performed on the basis of substantiated evidence of compression of nerve structures. Cause-based treatment of this type should be evaluated as a therapeutic option, as it can produce complete recovery and replace symptomatic treatment, although this invasive approach also puts the patient at risk from surgery-related complications. If cause-based treatment fails, symptomatic therapy is insufficient, or invasive interventions are impossible, the treatment guidelines for neuropathic pain, involving the administration of various classes of drugs and combination therapies, could be followed. Physiotherapy might be beneficial as an add-on therapy.¹³

Conclusions

BRP has a unique presentation of symptoms and signs that are most probably related to nerve damage and are, therefore, neuropathic. In order to optimize treatment, thorough dermatological and neurological work-up, including a search for a possible lesion within the PNS or CNS, is required. Symptomatic treatment follows the guidelines for neuropathic pain and can include protection of the skin from the sun, local cooling and physiotherapy. Cause-based treatment, for example radicular decompression, can lead to full recovery in some cases.

Acknowledgments

A Binder, J Koroschetz, M Stengel and R Baron were supported by the Federal Ministry of Education and Research, the German Research Network on Neuropathic Pain (grant 01 EM 0504) and an unrestricted educational grant from Pfizer, Germany. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Pain