Neuropathic Pruritus: An Underrecognized and Often Misdiagnosed and Difficult to Treat Medical Condition

Abstract

It is estimated that approximately 8% of chronic pruritic cases are of neuropathic origin. Common neuropathic pruritic syndromes include different clinical presentations such as postherpetic pruritus, trigeminal trophic syndrome, anogenital pruritus, scalp dysesthesia, nerve compression syndromes (e.g., notalgia paresthetica, brachioradial pruritus), small-fiber neuropathy (secondary to various metabolic, infectious, autoimmune, and genetic diseases), and disorders affecting the central nervous system (occupying lesions, iatrogenic, infectious, neurodegenerative, or demyelinating diseases). Although general practitioners are most likely to see the itchy cases first and consider referring them to further medical advice, it would be a better approach for the physicians to cooperate with dermatologists and neurologists and physiotherapists in particular especially in chronic persistent itchy conditions. Neuropathic pruritus must first be differentiated from other possible etiologies of pruritus by medical history and physical examination, laboratory tests, skin biopsy, and radiological and functional evaluations. It often does not respond to classical antipruritic treatments and different treatment options such as neuroleptics, topical capsaicin, epidural steroid injections, botulinum injections, nerve blocks, and neurostimulation techniques have been tried with variable success responses. This chapter provides a comprehensive overview of the characteristics and clinical presentations of neuropathic pruritus and the diagnostic and therapeutic management used in such patients.

1. Introduction

Itching (also called “pruritus” as a medical term) is defined as an unwanted sensation that occurs in the skin and mucous membranes (especially in the conjunctiva), stimulating the scratching reflex or desire. The multifactorial and complex pathogenesis of pruritus, which is a common and distressing symptom arising from various skin disorders and systemic diseases, makes it difficult to determine the underlying etiology [1, 2, 3]. Each patient should be evaluated and treated individually, as it may be a manifestation of diseases of different etiologies and prognoses [1]. A complete medical history, clinical examination, and laboratory and radiological evaluation are important in the management of pruritus [2].

While the cause of acute pruritus can be understood more clearly, it is often more difficult to find the etiological factor in chronic pruritus. There is no single and definite classification in the categorization of itching [1]. There are two different classifications in the literature for this purpose [3, 4]. Twycross et al. grouped pruritic disorders into four categories based on their neuropsychological origin: (a) cutaneous origin: pruritoceptive, (b) neuronal origin: neuropathic, (c) originating from central mediators without neural damage: neurogenic, and (d) somatoform: psychogenic [3]. In the International Forum for the Study of Itch, it has been gathered under three main headings: itching on the skin with primary inflammation, itching on the normal skin, and itching on the skin with secondary scratching lesions of unknown origin. These three main groups are divided into six subgroups under the headings of dermatological, systemic, neurological, psychogenic, mixed, and others by clinical and laboratory evaluation [4]. Pruritus with an unknown origin or no dermatological/systemic cause, without skin damage or with only secondary scratching lesions, is defined as “idiopathic” pruritus. The fact that there are many diseases that need to be eliminated when evaluating a patient with idiopathic pruritus is challenging for both the patient and the physician. Therefore, the patient should be informed in detail about this long process [5, 6].

In every patient with pruritus, comorbidities, drug use or abuse, traveling, presence of itching in close family members, home and workplace conditions, presence of skin lesions, and contact with animals or other potential allergens should be questioned. The time of onset of symptoms (acute pruritus if less than six weeks, chronic pruritus if longer), localization of pruritus, whether it shows diurnal changes, and exacerbating causes should also be included in the medical history. The patient’s own view of the etiology of pruritus should also be taken into account, as it may aid the diagnosis [1]. While the cause of acute pruritus can be easily determined by the history, the history alone is often not sufficient in chronic pruritus. Systemic diseases that may cause chronic pruritus include thyroid diseases, iron deficiency, kidney failure, cholestasis, hematological diseases (lymphomas, leukemia, multiple myeloma, paraproteinemia, polycythemia vera), malignancies, HIV and HCV infections, rheumatological diseases (Sjögren’s syndrome, dermatomyositis), anorexia nervosa, and drug hypersensitivity [2]. While the cause can be found in 10–50% of patients with chronic pruritus, it cannot be found in 8–35% of them [2, 5]. Pruritus can also be of multifactorial origin (mixed), and this probability increases with age. Because of the subjective nature of itching, comprehensive evaluation is important. Although complex, successful treatment largely depends on identifying the cause of pruritus, so the etiology should be carefully investigated in each patient [1, 2, 5].

Pruritus, the mechanism of which is also quite complex, is increased or decreased by various mediators, receptors, and inhibitors at the levels of peripheral nerve endings, dorsal root ganglia, and central nervous system [1, 7, 8, 9]. Different activation mechanisms of different receptors and ion channels determine the subtype of itching sensation. The skin has a complex network of cells and mediators involved in the induction, perception, treatment, and control of pruritus. Histamine, neuropeptides, neurotrophins, amines, cytokines, proteases, and prostaglandins are only a small part of the factors that cause pruritus by activating specific receptors in certain anatomical parts [1]. Therefore, factors that collectively participate in different mediator and receptor compositions play a role in pruritus that occurs in various diseases [1, 2].

As a neuroimmunoendocrine organ, the skin is closely related to the peripheral sensory nervous system, the autonomic nervous system, and the central nervous system [7]. The sensation of itching is conveyed by primary afferent sensory neurons located in the dermis and epidermis and associated with various skin cells. The cell bodies of these neurons are localized in the cranial and dorsal root ganglia. After activation, itching begins as information is transmitted to the itch center via the spinal cord and the contralateral spinothalamic tract. The primary neurons pass through the ipsilateral dorsal spinal root ganglion, synapse with the secondary neuron in the substantia gelatinosa, and reach the thalamus by entering the contralateral anterolateral spinothalamic tract. Microneurographic studies have also shown the lamina 1 spinothalamic sub-neuron class specific for pruritus in neurons that were previously thought to perform only contralateral conduction. Here, tertiary neurons originating from the posterolateral thalamic nucleus cross the internal capsule and terminate in the sensory cortex in the postcentral gyrus. The sense of itching also stimulates the motor cortex to initiate scratching. Studies with the positron emission technique have shown that the central center of pruritus is the left primary sensory cortex. In the brain, factors possibly affecting the anterior cingulate cortex provide a reduction and modulation of itching sensation [8, 9, 10]. Although hundreds of itch-related mediators and receptors have been identified today, there are undoubtedly some waiting to be discovered. As our knowledge about cutaneous neuroimmunoendocrinology increases, including itch mediators and neuronal pathways involved in itch transmission, new strategies may be developed in the diagnosis and treatment of various pruritic diseases [7, 11].

Unlike neurogenic pruritus, in which the neural structure is considered normal but abnormally stimulated, neuropathic pruritus (NP) is related to a pathology located at any point in the afferent pathway of the nervous system [11, 12, 13, 14]. Pruritus due to these neurological disorders may precede diagnosis and may be transient, persistent, or paroxysmal. Typically, various paresthetic sensations such as pain, tingling, burning, and numbness accompany the pruritus [11, 12]. Damage to any part of the peripheral (nerve fibers, nerve plexuses, and ganglia) and central (spinal cord, brainstem, thalamus, or cortex) somatosensory system can lead to NP [13, 14]. In this context, NP may occur in many metabolic, infectious, autoimmune, neurodegenerative, orthopedic, malignant, and iatrogenic entities [15]. Although it is estimated that approximately 8% of chronic pruritic cases are of neuropathic origin, epidemiological studies investigating the prevalence and incidence of NP are insufficient in the literature [16].

In this chapter, case reports, clinical trials, cohort studies, systematic reviews, and meta-analyses associated with NP published up until now have been evaluated. The Medline literature database was searched through PubMed using the keywords, individually and in combination: “pruritus,” “itching,”, “dysesthesia,” “neuropathic,” and “neural damage.” Only articles available in original or translated English were reviewed. This article is intended to provide a comprehensive overview of the characteristics and clinical presentations of NP, and the diagnostic and therapeutic management used in such patients.

2. Clinical disorders causing neuropathic pruritus

2.1 Postherpetic neuralgia/pruritus

It is the most common complication of herpes zoster and is associated with persistent and resistant neuropathies. It is estimated that up to 30% of people with postherpetic neuralgia have pruritus [17, 18]. Postherpetic pruritus is also a common cause of NP in the dermatomal area affected by the peripheral nerve region damaged by the varicella zoster virus [19, 20, 21].

2.2 Trigeminal trophic syndrome (TTS)

A rare complication of trigeminal nerve injury and a rare cause of NP, it is characterized by facial ulceration, anesthesia, and paresthesia in the same trigeminal dermatome. While it most commonly appears as unilateral ulceration of the nasal area, it can also be found on the scalp in the frontoparietal and auriculotemporal region, when nerve damage occurs in the V1 and V3 distribution, respectively. Trigeminal nerve damage can be caused by various causes such as iatrogenic causes, herpes zoster, brain infarction, trauma, malignancy, multiple sclerosis, and infectious diseases. Although the exact cause is unknown, it is predominantly seen in women [13, 14]. Because pruritus associated with TTS is often described as crawling and tickling, some patients are misdiagnosed as delusional about parasitic infestation. The intensive, persistent, and subconscious desire to scratch, which usually occurs during sleep, causes chronic and deep excoriations on the scalp. The resulting wounds can sometimes even reach the bones [20, 21, 22]. These patients often refer to dermatologists, but neurologists should be consulted to identify and treat the underlying cause [14, 16].

In the literature review by Sawada et al., the mean age of patients with TTS was found to be 53.3 ± 19.7 years (range, 6–91). It was seen more frequently on the right side of the face (57%); the most common area was the nasi (79%), followed by the cheek (28%). The importance of ophthalmology consultations was emphasized because of the detection of corneal lesions in 18% of the cases. Major etiological factors were determined as trigeminal nerve ablation (30%) and cerebrovascular accidents (30%), and the latent period was observed to range from days to 30 years [23].

2.3 Entrapment syndromes of specific peripheral nerves

Nerve compression syndromes such as notalgia paresthetica, brachioradial pruritus, cheiralgia paresthetica (radial nerve), meralgia paresthetica (lateral femoral cutaneous nerve), and gonalgia paresthetica (infrapatellar branch of the saphenous nerve) present with pruritus localized to a specific anatomical area along the corresponding dermatome [15, 16]. Two typical syndromes caused by spinal nerve-root injury (radiculopathy) are notalgia paresthetica (dorsal branches of T2-T6 spinal nerves) and brachioradial pruritus (radiculopathy in C3-C8) [13].

2.3.1 Notalgia paresthetica

Pruritus that occurs classically on the midscapular line in the T2-T6 dermatomal area may also be accompanied by sensory changes such as pain, paresthesia, numbness, and stinging. It is usually unilateral. The skin initially appears normal, but in chronic cases, pruritus may be accompanied by secondary skin changes, a hyperpigmented patch, or signs of macular amyloidosis. It occurs more frequently in women and in late adulthood [15, 24]. Although the pathophysiology is unclear, the mechanism is thought to be a sensorineural neuropathy. It is widely believed that it is caused by the damage of the cutaneous branches of the posterior parts of the spinal nerves as a result of compression due to degenerative diseases of the spine or spasm of the paraspinal muscles [14]. In some individuals, conditions such as intervertebral disc herniation and degenerative disc diseases that may cause compression on nerves in the spine have been described. The localization of pruritus is often correlated with radiological findings of the vertebrae and decreased intraepidermal nerve fiber density (IENFD) in the skin. Movements that compress the nerve may also precipitate notalgia paresthetica [24, 25].

2.3.2 Brachioradial pruritus

It is a pruritic condition described in the sun-exposed parts of the upper arm, wrist, and forearm in middle-aged and fair-skinned people. It is mainly localized neuropathic dysesthesia of the dorsolateral upper extremity, although occasionally the shoulders, back, anterior chest, and neck may also be involved [13]. It is bilateral at a rate of 75% and may become more generalized over time. The skin may develop excoriations, prurigo papules, mild atrophy, and signs of sun damage in the later stages. It is reported more frequently in women and people who engage in activities such as golf and tennis in sunny weather. This disorder occurs in people with fair skin, and the age range is quite wide. Typically, there is no itching on non-sun exposed areas of the arm. It regresses in the winter [14, 26]. Although the etiology is unknown, it is thought that cervical spine diseases that cause compression on the cervical nerves predispose to brachioradial pruritus, and the sun plays a triggering role [26, 27].

Cervical neuropathies and especially C3-C8 spinal nerve injuries have been demonstrated in most patients with brachioradial pruritus [27, 28]. In these people, a decrease in epidermal and dermal nerve fibers has been detected, and the nerves return to their normal state in symptom-free periods. Most of the patients stated that their complaints increased with sun exposure. Relief of pruritus with ice cube/cold application is diagnostic [29]. Although cervical spine pathologies (especially degenerative joint disease) are detected in the majority of patients with brachioradial pruritus, pruritus is not usually associated with neuropathy in these patients. Therefore, if cervical spine disease is strongly suspected or in patients whose symptoms worsen despite treatment, it is recommended to perform examinations such as MRI and to consult a neurologist in patients with accompanying neurological symptoms [27, 28, 29]. However, it should be kept in mind that brachioradial pruritus may occur due to compression of spinal tumors, especially in elderly individuals [30].

2.4 Small-fiber neuropathy (SFN)

In SFN arising from damaged small, unmyelinated C-, and thin-myelinated A-delta fibers, pruritus and pain may be localized (mostly in the distal extremities) or generalized [13]. It may occur secondary to various metabolic, infectious, autoimmune, and genetic diseases, mainly diabetes mellitus, sarcoidosis, amyloidosis, vitamin B12 deficiency, and viral infections. In addition, drugs (e.g., chemotherapy) and alcohol use can also induce SFN [31]. Chronic pruritus (≥6 weeks), normal-appearing skin, and the presence of reduced IENFD were reported as obligatory criteria for SFN-related chronic generalized itching by Pereira et al. [32].

2.5 Post-burn or post-surgery scars and keloids

These scar tissues are usually associated with pruritus, possibly due to damage to the cutaneous nerves. Neurophysiological studies have revealed functional abnormalities in small nerve fibers. Scar tissue is prone to prolonged itching and is often characterized by a burning and piercing sensation [33, 34, 35]. In one study, it was observed that approximately two-thirds of patients discharged from burn units complained of pruritus. Responses to sensory stimulation on burn-skin grafts were reduced or absent in the vast majority of patients [34]. The majority of patients with keloids also complained of pruritus, especially around the keloid margins [35].

2.6 Anogenital pruritus

It is defined as localized itching of the anus and perianal and/or genital skin. It is usually a symptom of underlying skin/mucosa disorder or anorectal pathology. Most patients are associated with an inflammatory dermatosis (e.g., contact dermatitis, psoriasis, lichen planus), infectious disease (e.g., fungal infection), or anorectal disease (e.g., perianal fissure). When no demonstrable cause is found, it is usually defined as idiopathic (primary) anogenital pruritus. In a significant proportion of idiopathic cases, degenerative changes (sclerosis, anterior and posterior osteophytes, narrowing of the intervertebral space) in the lower spine and sacrum radiographs and lumbosacral radiculopathy leading to nerve or nerve-root compression at the level of the L4-S2 vertebrae have been detected in nerve conduction studies [36]. Since Koh et al. reported a case of ipsilateral neuropathic scrotal pruritus secondary to direct nerve compression by an inguinal hernia, it may be recommended to perform investigations for inguinal hernia in the presence of anogenital pruritus [37]. Vulvar pruritus constitutes 66% of cases that apply to gynecologists due to vulvar problems and 73% of cases that apply to dermatologists. It can occur at any age. There is growing evidence to suggest that neurogenic factors may contribute to vulvar pruritus [38]. Several studies have shown increased expression of the transient receptor potential vanilloid 1 ion channel, which is well known for its role in modulating pain and itching signals in the vulvovaginal epithelium in patients with vulvodynia [39]. Although vulvodynia is classically considered a form of neuropathic pain, it may be accompanied by itching and burning in 20 and 70% of cases, respectively [40]. Vulvar pruritus can also be caused by nerve or nerve-root compression at the L4 to S2 vertebral levels due to spinal injuries or lumbosacral arthritis. In addition, 8.4% of herpes zoster cases affect the dermatomes that innervate the vulva, and long-term damage to the affected nerves can cause persistent pain and/or itching of the vulvar skin [41].

2.7 Scalp dysesthesia

It is a neuropathic phenomenon where itching is usually accompanied by paresthesia, hyperesthesia, and hypoesthesia. Neuropathic etiologies of scalp pruritus are often associated with cervical spine degenerative disc disease, TSS, and postherpetic neuralgia. In addition, it may be associated with brain malignancy (such as brainstem tumors, tumors infiltrating the trigeminal ganglion, cervical intramedullary glioma), multiple sclerosis, and stroke. Diabetic and geriatric patients have also been found to have higher rates of scalp pruritus [21, 42]. Cosmetic procedures such as face and brow lift can also cause NP when they cause local nerve damage. Paresthesia and dysesthesia are the most common complications in open and endoscopic brow lift procedures, with rates up to 5.4 and 6.2%, respectively. It was observed that the scalp dysesthesia, which appeared 1–2 weeks after the procedure, regressed after an average of 3 months. The occurrence of pruritus and paresthesia is relatively common but usually minimal, and patients report that dysesthesia is not significant enough to prevent them from undergoing reoperation [43, 44]. In addition, postinfectious trichodynia (58.4%), which is generally associated with telogen effluvium and defined as pain, pruritus, burning, and/or paresthesia on the scalp with light hair touching or brushing, has been reported after COVID-19 infection. Symptoms of trichodynia appeared an average of 1–2 weeks after the diagnosis of COVID-19, lasting 4–5 weeks, and regressed in 44% of patients. These patients reported relief of trichodynia with sleeping, cold water washing, application of superpotent topical steroids, combing, massage, and scratching [21, 45].

2.8 Elderly dysesthesia

The high prevalence of pruritus in the geriatric age group (between 7 and 45.9%) tends to increase with age. Geriatric patients are more likely to have diseases and conditions that predispose them to pruritus, such as shingles and postherpetic neuralgia, stroke, diabetes mellitus, and TTS. Age-related neuropathic changes and disruption of pruritus-inhibiting fibers, as well as the frequent occurrence of degenerative spine diseases in geriatric patients, make these individuals prone to neurogenic pruritus [46]. In these patients, besides the secondary lesions due to scratching, complaints such as burning, stinging, and numbness called dysesthesia may also be encountered [21, 46].

2.9 Disorders affecting the central nervous system

Central space-occupying lesions such as abscess, cysts, tumors, vascular malformations, or syringomyelia may cause neuropathic pruritus. Neural damage induced by trauma (accidents or iatrogenic) or infectious diseases (meningitis, encephalitis, prion disease) has also been associated with the occurrence of pruritus [16, 47, 48, 49]. It has also been reported that unilateral pruritus develops after ischemic/hemorrhagic stroke or hemicraniectomy (e.g., due to ruptured arteriovenous malformation) [50]. Posterior inferior cerebellar artery stroke, also known as Wallenburg syndrome, is often associated with neuropathic pain and pruritus in the ipsilateral trunk and extremities and the contralateral trigeminal region. Lateral medullary infarction usually causes 20% of TTS resulting from vertebrobasilar strokes and most commonly presents as NP with V2–V3 distribution [21].

Paroxysmal pruritus associated with neuroinflammatory conditions (demyelinating diseases) such as multiple sclerosis and neuromyelitis optica is clinically an acute onset and recalcitrant pruritus that is usually triggered by the onset of movement and has frequent attacks during the day. It has been theorized that transversely diffused ephatic activation of partially demyelinating pain-transmitting neurons causes paroxysmal pruritus [51, 52, 53]. In the study of Ingrasci et al., pruritus was reported in 35% of a total of 77 multiple sclerosis patients. It was frequently characterized as acute (74%), paroxysmal (59%), and tingling (55%). The most common triggering factor was temperature increase (52%), while cold temperatures had no effect. Multiple sclerosis patients with pruritus had significantly more fatigue, heat sensitivity, cognitive impairment, and signs of depression or anxiety, as well as more T2 hyperintensity in the posterior cervical cord and anterior pons/ventromedial medulla. Again, T2 hyperintensities in the anterior pons/ventromedial medulla were strongly associated with localized pruritus on the face or scalp. As a result, paroxysmal NP localized to the extremities, face or scalp, most frequently, is seen in multiple sclerosis patients. Patients with pruritus are more likely to have multiple sclerosis-related comorbidities and demyelinating lesions in the spinal cord or brainstem [51]. Muto et al. have suggested that most of the opticospinal form of multiple sclerosis is neuromyelitis optica, and it was found that paroxysmal pruritus was more prominent in these cases [52].

3. Diagnosis of neuropathic pruritus

NP must first be differentiated from other possible underlying etiologies of pruritus. The diagnosis and management of NP are very difficult, especially due to its multidimensional nature in terms of its clinical presentation and possible underlying causes [11, 12, 15].

Laboratory tests and other further investigations recommended for pruritus due to systemic diseases are summarized in the European guideline. In this guideline, lumbar puncture and MRI in the case of suspected neurological disorder, cerebrospinal fluid analysis (oligoclonal bands) and brain MRI (CT) in multiple sclerosis, histopathology and cerebrospinal fluid analysis and brain MRI (CT) in brain tumors, thoracic spine MRI (CT) in notalgia paresthetica, and thoracic and cervical spine MRI for brachioradial pruritus have been recommended [2].

3.1 Medical history and physical examination

NP is difficult to diagnose and may be missed in routine history, examination, and tests. A detailed medical history is required to diagnose NP and exclude other possible etiologies that may cause chronic pruritus [14, 15]. The characteristics of the pruritus, its onset and possible associated events, and the appearance of the skin at the onset of symptoms should be questioned in detail [13]. NP should be suspected in patients with chronic pruritus that begins in normal-appearing skin without an associated systemic condition causing pruritus. Patients with NP are not expected to have a primary skin disease or lesion, but secondary excoriations or chronic scratch lesions (e.g., chronic nodular prurigo, lichenification) may develop due to the chronic itch-scratching cycle [14, 16]. In addition, the distribution pattern of pruritus at the onset and during the course of the disease (e.g., dermatomal in post-herpetic neuralgia or brachioradial pruritus, stocking, and glove distribution in SFN) may provide more clues for the diagnosis of NP and the localization of pathology within the somatosensory system [13, 15]. Although the affected area of the somatosensory system is crucial for pruritus localization, NP that is initially localized may become generalized later on [26, 54].

The severity of pruritus, accompanying sensory symptoms, fluctuation of pruritus during the day, and alleviating factors should be evaluated. Although clinical sensory symptoms such as the presence of additional dysesthesias including stinging and tingling, pruritus occurring with attacks rather than being continuous, and relief with cold packs or cold application have been suggested as diagnostic criteria for SFN-related pruritus, it may not completely exclude non-neuropathic pruritic conditions [31, 32]. For example, in atopic dermatitis, sensory symptoms such as crawling, tickling, and stinging may accompany itching [55]. In NP, there may be alloknesis (induction of itching after application of a non-itchy stimulus, e.g., a perception of intense itching after a light touch on the skin with cotton wool or a brush) and hyperknesis (exaggerated itching response to an itchy stimulus). These phenomena reflect neuronal sensitization processes that contribute to the chronicity of pruritus [56]. A general medical history of comorbidities and concomitant medications can also help inform patients about the ultimate limitations of therapeutic options [1, 14].

Although standardized questionnaires have been successfully developed to screen for neuropathic pain, questionnaires used for NP are very limited. A Neuropathic Pruritus 5 (NP5) score was proposed by Huguen et al. to differentiate NP from non-NP based on patient-reported results. The presence of two of the five independent factors for NP (presence of sudden sharp localized pain, no burning, worsening of pruritus with activity, not worsening with stress, and relief of pruritus with cold weather) has been shown to provide 76% sensitivity and 77% specificity in distinguishing NP from non-NP [57]. Also, for small-fiber polyneuropathy, there is also a patient-centered questionnaire study with questions on itchy skin [58].

3.2 Laboratory tests, skin biopsy, and radiological and functional evaluations

Certain laboratory tests are necessary to exclude other conditions that cause chronic pruritus, such as renal insufficiency, cholestasis, and hematooncological diseases [1, 2]. In addition, disease-specific testing should be performed in selected patients with a suspected neurological condition (such as cerebrospinal fluid analysis for suspected brain tumor, oligoclonal bands for multiple sclerosis diagnosis) [15, 16]. In patients diagnosed with SFN, evaluation of glycosylated hemoglobin, vitamin B12 and folate serum levels, HIV and hepatitis B and C serology, TSH, and antinuclear antibodies is necessary to detect possible causes [31].

Skin biopsy may provide important clues for the determination of neurocutaneous morphological changes and examination of epidermal neural architecture in neuropathic pruritic conditions [13]. Decreased IENFD, which is the gold standard in the diagnosis of SFN, is also observed in neuropathic compression and radiculopathy syndromes such as brachioradial pruritus. Clinically, the magnitude of the reduction in IENFD seems to affect the perception of dysesthesia [29, 31]. To determine IENFD, after staining a skin sample from non-lesional itchy skin via punch biopsy with an axonal marker (e.g., protein gene product 9.5), nerve fibers crossing the basement membrane from the dermis to the epidermis are counted and divided by the length of the dermoepidermal junction. The lateral lower leg should be selected for biopsy, as reference values are currently only available for the innervation region of the sural nerve. If another body area is affected, a skin sample should be taken from an unaffected symmetrical area for comparison [59].

MRI and CT play an important role in detecting space-occupying lesions (such as tumors, abscesses, and vascular or inflammatory lesions) and their anatomical relationship with peripheral or central neural structures [30, 36, 60], as well as in the diagnosis of neurological conditions such as stroke, meningitis, or degenerative neuroinflammatory diseases that can cause NP [49, 50, 51, 52, 53]. In the diagnostic study of itchy neuropathic compression syndromes, MRI, CT, high-resolution sonography, or MR neurography are also used to identify underlying pathologies such as compression of the nerve roots or spinal cord, disc prolapse or herniation, degenerative vertebral changes, osteophytes, or neuroforaminal stenosis [25, 27]. While there is a correlation between MRI findings and localization of dysesthesias in brachioradial pruritus, such a relationship is not clear for notalgia paresthetica [29].

Morphological examinations of neuroanatomical changes associated with small unmyelinated C fibers and thin myelinated A-delta fibers transmitting itching can be performed with functional assessments. In quantitative sensory testing, a validated test battery using thermal and mechanical standardized stimuli can determine perception and pain thresholds and a possible gain or loss of function of different nerve fibers by measuring the response to suprathreshold stimuli. Although this non-invasive method provides a comprehensive neurophysiological profile of sensory neuropathies, it is time consuming and requires expert staff and patient collaboration [61]. Although large myelinated sensory fibers are not involved in itch transmission, SFN may occur as part of a polyneuropathy with the involvement of large fibers. Therefore, patients with SFN-related NP should seek the opinion of a neurologist for nerve conduction studies or electromyography [31, 32]. Pathological nerve conduction studies can also be demonstrated in patients with pruritic compression diseases (as reported in brachioradial pruritus and anogenital neuropathic pruritus) [29, 36]. Evaluation of evoked potentials and microneurography are methods of investigating selective nerve fiber dysfunction and are mostly performed in research studies but may only be considered in selected clinical cases [62, 63].

4. Treatment and management of neuropathic pruritus

NP may become more difficult to manage by negatively affecting the patient’s quality of life, especially in chronic conditions that were misdiagnosed and could not be diagnosed despite multiple tests. While it is ideal to target the cause of pruritus, such as decompression of the spine or resection of the tumor, these interventions are often incurable and rarely practical. Therefore, treatment is usually directed toward symptomatic therapy to improve quality of life [14, 16, 20].

More rapid therapeutic relief can be achieved with local anesthetics and antipruritics, especially in patients with localized mild acute pruritus. A topical 5–10% ketamine, 5% amitriptyline, and 5% lidocaine combination, topical ketamine combined with amitriptyline, and 8% topical capsaicin patches have been shown to be effective at varying rates against NP [64, 65, 66, 67]. Other topical treatments that can relieve mild pruritus include topical menthol, pramoxine, and lidocaine [14, 16]. The local combination of the calcineurin inhibitor tacrolimus and gabapentin has been shown to be effective against TTS and not associated with systemic effects [68].

High doses of anticonvulsant drugs such as gabapentin, pregabalin, phenytoin, and carbamazepine and low doses of antidepressants such as tricyclic antidepressant amitriptyline are frequently used in moderately severe NP. The combination of selective serotonin and norepinephrine inhibitor mirtazapine and gabapentin used to treat neuropathic pain may also be beneficial for NP. Kappa opioids, which are particularly beneficial for chronic resistant pruritus, may be effective against NP [11, 16, 34]. In particular, fMRI studies of butorphanol have been shown to reduce activity in areas of the brain associated with itching activity, such as the claustrum, insula, and putamen [69].

Those with severe NP may benefit from more invasive treatments such as botulinum toxin A injections, nerve blocks, transcutaneous electrical nerve stimulation, IV ketamine, and IV phenytoin [70, 71, 72, 73, 74]. Botulinum toxin A, which is used to prevent cholinergic transmission and reduce substance P along the itch pathways, is injected into several points at 1–2 cm intervals along the affected area. Although outcomes are variable, it has been shown to improve NP in persistent postherpetic pruritus, brachioradial pruritus, notalgia paresthetica, and keloids [70, 71]. IV phenytoin provides rapid relief of neuropathic dysesthesias and is an acute rescue therapy for trigeminal neuralgias [73]. Recently, Morin et al. reported three cases of severe localized NP refractory to treatment that was successfully and rapidly treated with dronabinol, an oral synthetic formulation of delta-9-tetrahydrocannabinol [74].

As in TTS, patient education and counseling are necessary to prevent and reverse repetitive manipulation of self-induced ulcerations at the itch site. Cognitive behavioral therapy, such as habit reversal and relaxation training, can be used to control the itch-scratch cycle and improve quality of life [20, 23]. Again, an exercise regimen consisting of physical rehabilitation and spinal range of motion exercises, mild mobilization, and muscle stretching has been found to be beneficial in patients with scalp dysesthesia [21].

5. Conclusion

The diagnosis of NP is difficult due to its different clinical presentations and complex etiological factors. In addition to a thorough medical history and physical examination, some laboratory tests, skin biopsy, and radiological examinations are necessary to detect typical signs and symptoms and rule out other possible causes for chronic pruritus. In special cases, neurology expert opinion may be considered for functional evaluations such as quantitative sensory tests and nerve conduction studies. In general, the treatment of NP is difficult, and there is often no response to classical antipruritic treatments such as antihistamines and corticosteroids. Instead, local or systemic treatments suppressing neuronal stimulation and agents repairing the skin barrier are given. Although there are no controlled studies on the treatment of NP, anticonvulsants such as carbamazepine and phenytoin; neuroleptics such as gabapentin and pregabalin; low-dose antidepressants; regional, intrathecal, or paravertebral nerve blocks; cervical epidural steroid injections; intravenous anesthetics; botulinum injections; topical capsaicin; topical anesthetics; topical amitriptyline/ketamine mixture; and topical menthol and neurostimulation techniques are applied with variable success responses depending on the underlying cause of neuropathy.

In conclusion, despite the different options available for diagnosis and treatment, neuropathic pruritic syndromes still remain a clinical challenge in routine clinical practice. Although itchy cases usually refer to dermatologists, it would be a better approach for dermatologists to cooperate with neurology and physical therapy departments in terms of the possibility of neuropathic origin, especially in chronic, persistent itchy conditions that are resistant to treatment.