**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 [1–3]. 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, 7–9]. 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].

#### *Neuropathic Pruritus: An Underrecognized and Often Misdiagnosed and Difficult to Treat… DOI: http://dx.doi.org/10.5772/intechopen.110825*

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 [8–10]. 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 [11–14]. 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 [19–21].

#### **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 [20–22]. 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

#### *Neuropathic Pruritus: An Underrecognized and Often Misdiagnosed and Difficult to Treat… DOI: http://dx.doi.org/10.5772/intechopen.110825*

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 [27–29]. 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 [33–35]. 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].
