**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

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

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, 47–49]. 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 [51–53]. 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].

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

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 [49–53]. 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 [64–67]. 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 [70–74]. 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

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

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.
