Brachioradial Pruritus

Brachioradial pruritus is a neurogenic itch syndrome of the upper extremities. It is typically localized to the skin on the dorsolateral forearm overlying the proximal head of the brachioradialis muscle, but involvement of the upper arms and shoulders is also common.[1, 2] It may be unilateral or bilateral. Scratching reportedly only makes the discomfort worse, and most patients discover that application of cold packs is often the only therapy that provides symptomatic relief.[3] Brachioradial pruritus was first described in Florida in 1968 by Waisman[4] and has since been reported from subtropical areas such as South Africa[1] and Hawaii.[5] It is seen less frequently, but still with regularity, in temperate climes.[6]

The condition appears to represent a primary neuropathy.[7] Abnormalities in cutaneous innervation have been documented among patients with brachioradial pruritus. Massey and Massey[8] reported altered sensation to temperature and pinprick in the distribution of the posterior cutaneous nerve of the forearm, which supplies the skin over the brachioradialis muscle that is typically pruritic. Among patients with brachioradial pruritus, cold or heat hyperalgesia in the C5-C6 distribution[9] and pinprick hyperesthesia in the C5-C8 distribution[10, 11] have been reported.

Wallengren and Sundler[12] used neuronally directed antibodies to show that patients with brachioradial pruritus have reduced numbers of dermal and epidermal nerve fibers, and, moreover, that this reduction in cutaneous innervation only occurs during symptomatic flares.[13] De Ridder et al demonstrated selective C-fiber dysfunction at C6-8 using quantitative sensory testing in a patient with brachioradial pruritus, with improvement of C-fiber functionality after intralaminar C6-7 steroid injection.[14] Increased skin perfusion on the affected forearm as measured by Doppler imaging has also been reported.[11]

The pruritus experienced by patients with brachioradial pruritus is believed to be a variant of pain.[8] However, the anatomic location of the neural injury or irritation producing this pain is controversial. Two prevailing hypotheses are proposed. The first postulates that brachioradial pruritus is caused by injury to peripheral cutaneous nerves from sunlight exposure. The second suggests that nerves are damaged at the level of the cervical spine. Both mechanisms appear to be active in many patients.

Evidence supporting the solar hypothesis

Many patients with brachioradial pruritus have a history of chronic sun exposure.[2, 15, 16] Kestenbaum and Kalivas[17] postulated that histamine release from mast cells in response to chronic sun exposure might play a pathophysiologic role; they reported a patient with brachioradial pruritus and an elevated serum histamine level.

In some cases, sun exposure has been reported to exacerbate symptoms and photoprotection has been reported to provide amelioration.[4, 18, 19, 20]

A photoallergic reaction to varenicline mimicking brachioradial pruritus has been reported in one patient.[21]

Patients typically only describe symptoms on the sun-exposed dorsal surface of the arms and shoulders.[2, 5]

Left-sided symptoms are more common than right-sided symptoms in the United States, which may be the result of cumulative sun exposure to the arm from driving.[5] In South Africa, where drivers sit on the right-hand side of cars, the distribution is more often on the right arm.[1]

Symptoms among patients living in temperate climates often remit in the late fall and recur in the summer.[2, 4] Patients living in tropical climates, where it is sunny year round, tend to report symptoms that are more stable.[5]

Biopsy of affected skin typically shows atrophy and signs of sun damage.[2, 9]

The reduction in epidermal and dermal nerve fibers seen in brachioradial pruritus patients is also seen after serial phototherapy.[9]

Challenges to the solar hypothesis

If the dorsal surfaces of the arms are affected because they are exposed to the sun, then why is the sun-exposed face unaffected?

Why does no lower extremity equivalent of brachioradial pruritus occur in people who wear shorts?

If brachioradial pruritus is a manifestation of sun-induced nerve damage, why are children, who are typically very sensitive to the sun, never affected?

Evidence supporting the cervicogenic hypothesis

Several authors have reported a higher prevalence of cervical spine disease (eg, arthritis, osteochondrosis, spondylolytic changes) among patients with brachioradial pruritus.[1, 9, 22, 23] Marziniak et al performed magnetic resonance tomography of the cervical spine in 41 patients with brachioradial pruritus.[24] Thirty-three of 41 of these patients had stenosis of the intervertebral foramen or protrusions of the cervical disk, leading to nerve compression.

Cervical disk herniation with compression of the C6 nerve root has been reported in association with brachioradial pruritus, with rapid resolution of symptoms after ventral C5-C6 discectomy, C5-C6 vertebral fusion, and C6 nerve root decompression.[11]

Treatment of cervical spine arthritis has been reported to provide relief in patients with brachioradial pruritus.[1, 25] Epidural cervical steroid injections at the C6-7 level were reported to lead to disappearance of itch in a patient with brachioradial pruritus.[14]

Cervical spine tumors,[26] cervical ribs, hypertrophic cervical transverse processes,[27] and cervical osteophytes[28] have all been reported in case series to cause upper extremity pruritus.

Electrophysiological studies on patients with brachioradial pruritus have shown bilateral delay of F responses of median and ulnar nerves.[29]

Criticisms of the cervicogenic hypothesis

Cervical spinal disease is generally a permanent disorder and, as such, should produce a continuous neuropathic itch, rather than relapsing and remitting symptoms.

Cervical nerve blocks have been reported to be unhelpful. This may suggest that the location of the lesion is either more central (dorsal horn) or more peripheral (sensory nerve endings in the arm).

Degenerative cervical spinal changes are found in 70% of asymptomatic women and 95% of asymptomatic men older than 65 years[30] ; thus, without age-matched controls, implicating cervical spinal disease as the cause of brachioradial pruritus is erroneous.[31] In a large retrospective case series, symptoms of brachioradial pruritus were attributed to cervical spine abnormalities among only 25% of patients.[32]

Conventional electrophysiological testing may not be appropriate in investigating the pathophysiology of brachioradial pruritus because it measures conduction of myelinated fibers, while the afferent nerves that transmit itch are actually unmyelinated.[9]

Exposure of the affected areas to sun and wind may precipitate an episode, as may radiculopathy of the cervical spine. These are speculative, and the authors believe the etiology is multifactorial. In some cases, an emotional component to the symptoms seems apparent.

Frequency

United States

The prevalence of brachioradial pruritus is unknown. Brachioradial pruritus was initially described as a disease of the tropics; however, in more recent years, it has also been documented in temperate climates.

Brachioradial pruritus is typically sporadic, although an autosomal dominant inheritance pattern has been reported in one family, with 11 members across two generations experiencing symptoms.[15]

Brachioradial pruritus has been reported among patients in California,[10] Massachusetts,[3, 23] North Carolina,[8] Kansas,[17] Florida,[4] and Hawaii.[5]

International

Brachioradial pruritus has been described among patients in South Africa,[1] Ireland,[22] Sweden,[15] France,[33] Denmark,[2, 16] Belgium,[9] Turkey,[26, 31] Israel,[29] and Australia.[25]

Race

Brachioradial pruritus has been reported among patients with all skin types, but whites (Fitzpatrick skin types I-III) appear to be affected more often than darker-skinned individuals.[5]

Sex

Brachioradial pruritus was first reported among middle-aged male outdoor workers[4] ; however, more recently, cases have been widely documented among both men and women.[2, 15, 23]

Age

The onset of symptoms in persons with brachioradial pruritus typically occurs in the fourth to sixth decades of life. The youngest patient reported to have symptoms is an 18-year-old woman whose mother, sister, and 2 aunts also had brachioradial pruritus.[15]

Most patients with brachioradial pruritus have remissions, but a small percentage have chronic disease. Emotional or psychiatric factors likely play a role in prognosis.

Education regarding sun protection and avoidance of peak sunlight hours is worthwhile.

The itch of brachioradial pruritus is described as intense, burning, and prickling. It is localized to the dorsolateral aspects of the bilateral upper arms, forearms, and shoulders. Scratching is reported to make the discomfort worse, and many patients find that the only therapy that brings relief is the application of ice packs or cold, wet towels.[3, 9, 23] The discomfort is typically worse at night and, for some patients, may interfere with falling asleep.[4] The median duration of symptoms has been reported as 4.5 years,[2] but patients have reported a continuation of symptoms from this condition for as long as 18 years.[1] Rarely, patients may initially experience symptoms typical of brachioradial pruritus, followed by the onset of generalized pruritus.[34]

Despite the severity of symptoms, no associated erythema or skin eruption is seen. Evidence of excoriation or lichenification may be present in the affected areas.

Altered sensation to pinprick and temperature in the distribution of the posterior cutaneous nerve of the forearm, which supplies the skin over the proximal brachioradialis muscle, may be observed.[8] Pronounced heat hyperalgesia in the C5 and C6 dermatomal distribution[9] and pinprick hyperesthesia in the C5-C8 distribution[10] may be seen.

Psychiatric symptoms (eg, anxiety, depression) may develop over time in patients with unremitting symptoms. The intense tingling, burning, and itching associated with the disease often keeps patients awake at night.[4] Frustration from a lack of relief of symptoms with conventional antipruritis agents is common.

If herpes zoster is suspected, consider direct immunofluorescence with fluorescein-tagged antibody or polymerase chain reaction studies to detect varicella-zoster virus.

Among patients who do not respond to conventional treatments or whose symptoms progressively worsen despite treatment, consider cervical spine MRI to rule out tumor or cervical rib and to evaluate for cervical radiculopathy.[32]  In those with spinal cord injury, brachioradial pruritus may point to underlying syrinx formation.[35]

Electromyography or nerve conduction velocity studies may show delay of F responses of median and ulnar nerves and may assist in diagnosis in ambiguous cases.[8]

Biopsy of skin reveals atrophy and signs of sun damage, along with reduced numbers of both dermal and epidermal nerve fibers. Evidence exists that this reduction in cutaneous innervation occurs only during symptomatic flares, with innervation normalizing during symptom-free periods; thus, biopsy should ideally be performed when patients are actively experiencing symptoms.[12]

No staging system currently exists for brachioradial pruritus.

The best reported outcomes have been with antidepressant and anticonvulsant medications that affect nerve conduction. Gabapentin and pregabalin are commonly used.[36, 37, 38, 39]

Patients with brachioradial pruritus need time, sympathy, and understanding. They appreciate being told that they have a defined entity and that treatment options are available. Ice packs are helpful for immediate symptomatic relief, and other treatments can be tried in an outpatient setting. Frequent follow-up is often helpful emotionally for patients. Most cases remit in weeks to months.

Cervical nerve blocks have been reported to be unhelpful,[9] but cervical spine manipulation is effective in some patients.[1, 25] Cutaneous field stimulation has also been used. In one study, patients receiving 20 minutes of this treatment to affected areas once daily reported significant symptomatic improvement after 5 weeks.[40]

Acupuncture may be helpful for symptomatic relief. Stellon[41] performed a retrospective case series of 16 patients with brachioradial pruritus using deep intramuscular stimulation acupuncture to the paravertebral muscles in the dermatomal segments of the body affected by the pruritus. Treatment was also given to other segments of the body not affected by the pruritus if paravertebral spasm and tenderness was detected. After a median of 4 treatments, 12 of 16 patients reported complete resolution of symptoms and 4 patients reported partial resolution. Relapse occurred in 6 patients within 1-12 months of cessation of acupuncture.

One report describes dramatic improvement after injections with botulinum toxin A (100 IU/3 mL saline) in a 59-year-old white woman with longstanding brachioradial pruritus.[42] This patient received 4 series of injections and experienced significant improvement for 6 months following each series of injections. The authors point out that acetylcholine has been shown to be a mediator of itch in patients with atopic dermatitis, and they suggest that reduction in acetylcholine release mediated by botulinum toxin A may explain its helpfulness in the setting of brachioradial pruritus. They also postulate that botulinum toxin A may reduce histamine-mediated itch.

A compounded mixture of amitriptyline hydrochloride 1.0%, ketamine hydrochloride 0.5%, and Vanicream applied 2-3 times daily was reported to provide complete relief to an adult patient with a 5-year history of brachioradial pruritus unresponsive to conventional treatments.[43]

Compounded topical amitriptyline hydrochloride and ketamine hydrochloride can be helpful in brachioradial pruritus unresponsive to conventional treatments.[43, 44]

Aprepitant, a neurokinin-1 receptor inhibitor, can also be effective, even in long-standing disease refractory to conventional treatments.[45, 46]

Surgical care is generally not indicated unless the patient has a documented cervical radiculopathy, cervical rib, or fibrous band impinging on the brachial plexus.

Relief after physical therapy has been reported in case series, so consultation with a physical therapist or a chiropractor may be considered, particularly in patients with radiographic evidence of cervical spinal disease. Heyl[1] reported a case of one patient whose brachioradial pruritus developed after a neck injury, and symptoms were relieved by neck traction.

The authors have not found consultation with a neurologist or pain specialist to be of value.

Consultation with an acupuncturist may be helpful.

Some patients have psychiatric disorders that predispose to brachioradial pruritus, while others may develop anxiety, depression, obsessions/compulsions, or delusions of parasitosis in response to the exasperating symptoms.

No dietary modifications have been reported to alleviate symptoms.

Patients who notice exacerbation of symptoms with sunlight exposure benefit from restricting their time outdoors during peak sunlight hours (10 am to 2 pm). Often, wearing long-sleeved shirts when outdoors provides relief equal to that achieved with more sophisticated interventions. Sunscreens are typically less effective.

Strict photoprotection with sunscreen and long-sleeved shirts can prevent recurrence of symptoms in some patients.

Frequent outpatient follow-up of patients with brachioradial pruritus is often helpful.

Treatment of brachioradial pruritus remains a challenge. Most patients find relief with the application of cold packs that numb the skin; hence, a positive "ice-pack sign" is almost pathognomonic for this condition.[3] Oral antihistamines and topical corticosteroids are only occasionally of value. If potent or superpotent topical corticosteroids are used, care must be taken to avoid cutaneous atrophy from overzealous use. Occasionally, patients are helped with topical anesthetics (eg, lidocaine cream or gel) or with 5% topical doxepin.

Substance P is a neurotransmitter important in the transmission of pain and itch neural signals. Topical capsaicin cream (0.025-0.05%) is a natural plant product that depletes substance P from cutaneous nerve endings.[47]  It has been reported by a number of authors to provide relief of brachioradial pruritus within weeks.[16, 22, 48, 49, 50]  Capsaicin patches have also been used.[51, 52]

Numerous oral medications have been tried with varying success. Case reports describe sustained symptomatic relief with gabapentin (1800 mg/d),[33] lamotrigine (200 mg/d),[9] amitriptyline (25-150 mg qhs),[22] and pimozide (1-2 mg/d). Oxcarbemazepine has proven effective in several patients reported by Savk and Savk.[31] Risperidone has been used with some success in certain patients. No medication works predictably. When using psychotropic medications, obtaining a psychiatric opinion is advisable unless the treating physician commonly prescribes these agents.

Capsaicin topical (Zostrix High Potency, Trixaicin HP, Zostrix Sports)

Capsaicin is a natural chemical derived from plants of the Solanaceae family. It penetrates deep for temporary relief of minor aches and pains of muscles and joints associated with inflammatory reactions. Capsaicin may render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons. It has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain.

Doxepin cream (Prudoxin, Zonalon)

Doxepin is a TCA that has potent H1-blocking activity, making it quite useful for urticaria. However, it has very potent sedative and anticholinergic effects. It can be quite effective if used at bedtime because the sedative effects can help a patient with pruritus sleep. Widespread use produces sedation, as does use in areas of high percutaneous absorption (eg, genitals). Many individuals develop an allergy to topical doxepin.

Lidocaine (Topicaine, Senatec)

Lidocaine decreases permeability to sodium ions in neuronal membranes. This results in the inhibition of depolarization, blocking the transmission of nerve impulses

Gabapentin (Gabarone, Neurontin)

Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter GABA, which paradoxically is thought not to exert effect on GABA receptors. It appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels. Gabapentin is used to manage pain and provide sedation in neuropathic pain.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. Pregabalin binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. This agent is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, or fibromyalgia. It is also indicated as adjunctive therapy in partial-onset seizures.

Amitriptyline (Elavil)

Amitriptyline is an analgesic for certain chronic and neuropathic pain. It blocks the reuptake of norepinephrine and serotonin, which increases concentration in the CNS. It decreases pain by inhibiting spinal neurons involved in pain perception. Amitriptyline is highly anticholinergic. It is often discontinued because of somnolence and dry mouth.

Cardiac arrhythmia, especially in overdose, has been described; monitoring QTc interval after reaching target level is advised. Up to 1 month may be needed to obtain clinical effects.