Essential regional nerve blocks for the dermatologist: Part 2

Following on from Part 1 of the series (regional nerve blocks for the face and scalp), we guide the clinician through the anatomy and cutaneous innervation of the digits, wrist and ankle, providing a practical step‐by‐step guide to regional nerve blockade of these areas.     

In vitro formation of organized structure between keratinocytes and dorsal‐root‐ganglion cells

We recently found that the morphology in a co‐culture system of keratinocytes and dorsal‐root ganglion‐derived cells depended on the timing of seeding of the two cell types. In skin, epidermis is formed first, followed by construction of peripheral nerve structure. Therefore, we hypothesized that formation of peripheral nerve structure in the epidermis might be driven by interaction between keratinocytes and nerve cells. In the present study, we tested this idea by incubating keratinocytes and dorsal‐root ganglion cells in a spatially separated manner and observing the morphological changes in the co‐culture system. Extension of nerve fibre‐like structures from the ganglion cells was observed, and within 3 days after seeding, many nerve fibre‐like extensions penetrated into the keratinocyte cluster, subsequently forming a network that appeared to resemble the cutaneous peripheral nervous system. Our present model may be useful for studying the formation of peripheral nerve structure in the skin.     

Report of a Turkish child with Sjören-Larsson syndrome associated with peripheral nerve involvement

Sjögren‐Larsson syndrome is a rare hereditary neurocutaneous disorder characterized by ichthyosis, spastic di‐ or tetra‐plegia, and mild to moderate mental retardation. In this article, we present a nine‐year‐old girl with the classical features of the syndrome associated with peripheral nerve involvement because of its rare presentation. To the best of our knowledge, only three cases of Sjögren‐Larsson syndrome with peripheral nerve involvement have been previously reported in the literature. We assume that Sjögren‐Larsson syndrome involves extensive disorders of the ectodermal tissues, including the peripheral nerves as well as the skin and the central nervous system.     

Teaching peripheral nerve blocks for the head and neck area to dermatologists

Background Peripheral nerve blocks in the head and neck region can be useful for a large number of surgical or otherwise painful procedures carried out by dermatologists. As anaesthesiologists cannot always be available to help dermatologists place nerve blocks in outpatient settings, training courses for these physicians are warranted. Objectives To present a method of teaching nerve blocks for the face and scalp to dermatologists during residency and/or continuing medical education programmes. Methods Half‐day courses with theoretical education, video demonstrations and supervised ‘hands‐on’ training were organized to teach supraorbital/supratrochlear, infraorbital, mental and occipital nerve blocks. The outcome and effects of these training courses were analysed with a survey amongst participants 1–2 years after the course. Results All the 20 participants who responded the survey successfully placed at least one type of nerve block during the course. Thirteen of 20 participants (65%) reported to be able to perform all the nerve block techniques at follow‐up. Conclusions Dermatologists can learn how to perform nerve blocks for the face and scalp in a safe and controlled manner through half‐day courses, including theory, video demonstrations and supervised ‘hands‐on’ training.     

Desmoplastic melanoma may mimic a cutaneous peripheral nerve sheath tumor: Report of 3 challenging cases

Desmoplastic melanoma (DM) and cutaneous malignant peripheral nerve sheath tumors (MPNST) reveal histological and immunohistochemical similarities, including S100 positivity and negative staining for conventional melanocytic markers. We present 3 cases of cutaneous S100‐positive spindle cell tumors in elderly patients, in which first findings led to initial misdiagnoses as cutaneous MPNST and benign peripheral sheath nerve tumor (neurofibroma). The identification of adjacent atypical melanocytic hyperplasia in the overlying skin along with tumor cell proliferation, also in the superficial dermis, the neurotropic component and the absence of any relationship between the tumor and a major nerve, pre‐existing neural benign tumor or the existence of stigmata suggestive of neurofibromatosis raised consideration of a DM. Careful attention should be paid to the presence of a firm dermal nodule and atypical scar lesions especially in sun‐exposed areas (mainly head and neck region) in elderly patients associated with S100‐positive spindle cell proliferation, solar elastosis and adjacent atypical melanocytic proliferation. In such cases, the possibility of a DM should be excluded with caution, especially if the tumor reveals a paucicellular morphology resembling various non‐melanocytic neoplasms including malignant or benign peripheral sheath nerve tumors.     

Idiopathic aquagenic pruritus: pathogenesis and effective treatment with atenolol

Aquagenic pruritus (AP) is a rare condition with unknown pathogenesis. We explored its pathogenesis through investigations of a patient and report the first case to be effectively treated with atenolol. A 36‐year‐old Indian female presented with idiopathic AP. Small‐fiber neuropathy involving itch/pain‐transmitting C‐fibers appears to be pathogenetically important: compared with matched controls, our patient had increased intra‐epidermal nerve fibers, raised warmth detection threshold, and marked hyperknesis to electrical stimulation. Autonomic nerve function tests and fingertips vasoconstriction response were normal, indicating integrity of other small (Aδ and C) nerve fibers. She was initially treated with propranolol with good response, but was subsequently switched to atenolol for convenient once‐a‐day dosing. Symptoms were well controlled long term with no side effect experienced. Atenolol may exert its effect in AP through blockage of over‐activated neuronal sodium channels. Through the investigations, we propose that the pathogenesis of idiopathic AP may involve the following: upon contact of the skin with water, yet‐unknown mediator/s released stimulate dysfunctional and hyper‐innervated C‐nerve fibers, which may have resulted from a sodium channel defect. Atenolol may be a preferred therapeutic option compared with propanolol, in view of its convenient once‐a‐day dosing and better side effect profile.     

Superficial malignant peripheral nerve sheath tumor with overlying intradermal melanocytic nevus mimicking spindle cell melanoma

Malignant peripheral nerve sheath tumors are rare soft tissue sarcomas with histological and immunohistochemical similarities to spindle cell melanoma. Although spindle cell melanoma is significantly more common, both tumors may express S100 and lack staining for HMB‐45, Melan‐A or MITF. Here we present a case of superficial malignant peripheral nerve sheath tumor with diffuse S100 positivity arising in a subtle neurofibroma in close proximity to an intradermal melanocytic nevus. This configuration had led to prior misdiagnosis as a desmoplastic melanoma arising in the nevus and to sentinel lymph node biopsy. Identification of the background neurofibroma, as well as CD34 positivity raised consideration of a low grade malignant peripheral nerve sheath tumor, which was confirmed via observation of Schwannian differentiation on electron microscopy. The importance of distinguishing these two tumors is stressed owing to the difference in management.     

An organotypic culture system of Merkel cells using isolated epidermal sheets

Background Merkel cells (MCs) exist in the epidermal basal layer, in contact with keratinocytes. This direct contact seems critical for maintaining MCs in vitro. Objectives To estimate the effects of nerve cells on the maintenance of MCs within epidermal sheets in a new organotypic culture system of MCs. Methods We developed a new organotypic culture system of MCs, using MC‐containing epidermal sheets embedded in collagen gel. To estimate the effects of nerve cells on the maintenance of MCs within the epidermal sheets, we cocultured nerve cells and MC‐containing epidermal sheets. In these culture assemblies, cellular behaviour was analysed by histochemistry, immunohistochemistry, electron microscopy and enzyme‐linked immunosorbent assay. Results This culture, even in the absence of neurotrophin (NT)‐3 and nerve growth factor (NGF) (which are crucial for MC biology), retained cytokeratin (CK)‐20‐positive and neuroendocrine granule‐containing MCs within the sheets for over 2 weeks. Coculture of MCs with PC‐12 nerve cells significantly increased the number of MCs within the epidermal sheets, and the keratinocytes had almost identical expression levels of CK1, CK10, CK14 and the progenitor marker p63 to those produced by keratinocytes in vivo. Uptake of the growth marker bromodeoxyuridine by MCs and levels of NT‐3 and NGF in the culture supernatants were undetectable in this system, regardless of the presence or absence of PC‐12. Conclusions The data suggest, first, that direct contact between MCs and keratinocytes may be critical for retaining MCs in vitro; second, that nerve cell‐affected maintenance of keratinocyte differentiation, but not NT‐3 and NGF, may contribute to MC maintenance; and third, that MCs are not able to grow, at least in our system. Our method would be useful for studying MC biology.     

Activation of primary sensory neurons by the topical application of capsaicin on the epidermis of a re‐innervated organotypic human skin model

Using an ex vivo skin‐nerve preparation, skin and nerve cells were reconstituted into a single unit and maintained in a nutrient medium bath until required experimentally. Our objective was to use the epidermis as a relay for the induction of an electric current to the neurons following the topical application of capsaicin on the skin epidermis of the skin explant, an agonist of the TRPV1 channel implicated in pruritus and pain. After 10–20 days of coculture to form the re‐innervated skin model, we applied a solution of capsaicin directly on the epidermis of the skin explant (4 μm ). The resulting current was recorded using a path‐clamp technique on the neuronal fibres. Following the topical application of capsaicin, spontaneous activity was triggered, as characterised by repetitive spikes with periods of 125, 225 or 275 ms. This study demonstrates that the skin explant and nerve cells preparation may receive stimuli and be used to screen molecules or to study signal transmission.     

Effect of human skin explants on the neurite growth of the PC12 cell line

The skin is a densely innervated organ. After a traumatic injury, such as an amputation, burn or skin graft, nerve growth and the recovery of sensitivity take a long time and are often incomplete. The roles played by growth factors and the process of neuronal growth are crucial. We developed an in vitro model of human skin explants co‐cultured with a rat pheochromocytoma cell line differentiated in neuron in presence of nerve growth factor (NGF). This model allowed the study of the influence of skin explants on nerve cells and nerve fibre growth, probably through mediators produced by the explant, in a simplified manner. The neurite length of differentiated PC12 cells co‐cultured with skin explants increased after 6 days. These observations demonstrated the influence of trophic factors produced by skin explants on PC12 cells.     

Neuroimmune mechanisms in patients with atopic dermatitis during chronic stress

Objective To identify pathoaetiological neuroimmune mechanisms in patients with atopic dermatitis (AD) and chronic stress, focusing at nerve density, sensory neuropeptides, and the serotonergic system. Methods Eleven patients with AD with histories of stress worsening were included. Biopsies from involved and non‐involved skin were processed for immunohistochemistry. Salivary cortisol test was done as a marker for chronic stress. Results There were more acanthosis and fewer nerve fibres in epidermis and papillary dermis of involved compared with non‐involved skin. Whereas there was no significant change in the number of substance P and calcitonin gene‐related peptide–positive nerve fibres between the involved and non‐involved skin, there was an increase in the epidermal fraction of 5‐hydroxtrytamine 1A (5‐HT1A) receptor and serotonin transporter protein (SERT) immunoreactivity in the involved skin. The number of 5‐HT2AR, CD3‐positive cells, and SERT‐positive cells, most of them being CD3 positive, was increased in involved skin. There was an increase in mast cells in the involved skin, and these cells were often located close to the basement membrane. There was a strong tendency to a correlation between 5‐HT2AR positive cells in the papillary dermis of involved skin and low cortisol ratios, being an indicator of chronic stress. Conclusion A changed innervation and modulation of the serotonergic system are indicated in chronic atopic eczema also during chronic stress.     

Microcystic pseudoglandular plexiform cutaneous neurofibroma

Glandular structures are well documented to appear in peripheral nerve sheath tumors. These epithelial elements are usually present in malignant peripheral nerve sheath tumors although a few cases of glandular benign peripheral nerve sheath tumors have also been described, most of them being schwannomas. A neurofibroma with glands is considered to be a rare type of divergent differentiation, but a neurofibroma containing gland‐like or pseudoglandular structures have not, to our knowledge, been described. We report a 33‐year‐old patient with a well‐demarcated dermal neoplasm, composed of neoplastic Schwann cells, perineurial‐like cells and fibroblasts in a matrix with collagen fibers and myxoid areas. A part of the tumor consisted of microcystic gland‐like spaces lined by flat cells. These cells were either S100 positive or negative, with no epithelial membrane antigen, cytokeratin or CD31 immunostaining. Recognition of the presence of pseudoglandular elements in neurofibromas is important to distinguish them from other tumoral lesions, some of them with malignant potential.     

Impact of mast cells in fibromyalgia and low‐grade chronic inflammation: Can IL‐37 play a role?

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low‐grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC‐derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL‐37 is an inhibitor of proinflammatory IL‐1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL‐37. Here, we propose IL‐37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL‐1 family members.     

A Rare Case of Atypical Myxoid Cellular Neurothekeoma in a 6‐Year‐Old Girl

Neurothekeoma (nerve sheath myxoma)is a benign tumor of probable nerve sheath origin. The atypical cellular variant of this tumor, showing a peculiar histologic pattern, has been very rarely reported in the literature. The atypical variant of cellular neurothekeoma is characterized by features such as large size, deep penetration extending into skeletal muscle and/or subcutaneous fat, diffuse infiltration borders, vascular invasion, high mitotic rate and marked cytologic pleomorphism. We describe a rare form of atypical myxoid cellular neurothekeoma in a 6‐year‐old girl.     

What about physical contacts between epidermal keratinocytes and sensory neurons?

Recent studies have demonstrated that keratinocytes closely participate in sensory transduction, and therefore, intra‐epidermal free nerve endings are not exclusive transducers of pain. This discovery implies the existence of close afferent communication from keratinocytes to sensory neurons. Although reciprocal interactions between keratinocytes and intra‐epidermal free nerve endings via soluble mediators are well established, little attention has been paid to physical contacts between keratinocytes and intra‐epidermal free nerve endings. This review proposes to consider the ultrastructural and functional knowledge of these contacts, in both human skin biopsies and keratinocyte‐sensory neuron cocultures to speculate on the possible existence of synaptic contacts.     

Pathogenesis of pruritus

The pathogenesis of acute and chronic (> 6 weeks duration) pruritus is complex and involves in the skin a network of resident cells (e. g., mast cells, keratinocytes, sensory neurons) and transient inflammatory cells (e. g., eosinophils). Though pruritus and pain show overlapping mechanisms, recent studies have provided evidence that pruritus and pain pathogenesis differ in important points. In the skin, the sensory C‐nerve fibers have been investigated intensively. Several classes of histamine‐sensitive or histamine‐insensitve C‐fibers have been described. Epidermal and dermal sensory nerve fibres are now assumed to be of major importance in pruritus induction. They interact with keratinocytes, inflammatory cells such as T lymphocytes, eosinophils and basophils which have been shown to release multiple pruritogenic mediators (e.g., nerve growth factor, interleukin‐31) which lead to activation, sensitization and sprouting of skin nerves. Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. Just recently, the gastrin‐releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. Chronic pruritus is notoriously difficult to treat. Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus‐specific pathophysiological mechanism. For example, kappa‐opioid receptor agonists and neurokinin‐1 antagonists have been found to relieve chronic pruritus.     

Screening for depression in adult acne vulgaris patients: tools for the dermatologist

Summary Background Adult dermatological out patients have a 40% prevalence of psychiatric co‐morbidity. If psychiatric co‐morbidity is unrecognized, undetected and untreated, the consequences may be fatal. Acne is the most common skin disorder of the second and third decades of life. Acne and its treatments may cause depression. Aims To identify a screening tool to identify depression in adult acne patients. Methods The literature was reviewed to identify validated screening instruments for depressive disorders. Questionnaires studied included the Hospital Anxiety and Depression Scale (HAD), the Brief Patient Health Questionnaire (B‐PHQ), the General Health Questionnaire‐12 item version (GHQ‐12), and the World Health Organization‐5 Well Being Index (WHO‐5). Results WHO‐5 performed best in terms of sensitivity (0.93 for a cut‐off score of 13) as well as taking least time to complete (2–5 min) and evaluate (0.5–2 min). Conclusions WHO‐5 can be recommended as part of a two‐step screening process for depression in acne patients. Step 1 is the WHO‐5. In the case of a positive score, step 2 is a detailed psychosocial assessment.     

Coculture system of keratinocytes and dorsal‐root‐ganglion‐derived cells for screening neurotrophic factors involved in guidance of neuronal axon growth in the skin

The density of peripheral nerve fibres is increased in atopic dermatitis. Moreover, reduction in the fibres in a mouse model of atopic dermatitis reduces scratching behaviour. Thus, regulation of nerve fibre extension could be an effective strategy to reduce itching in pruritus dermatosis. In this study, we established a new coculture system of keratinocytes and dorsal‐root‐ganglion‐derived cells using an apparatus, AXIS^?, which consists of two different channels connected via a set of microgrooves, through which signalling molecules and axons, but not living cells, can pass. When we seeded keratinocytes in one chamber, extension of nerve fibres was observed from dorsal root ganglion cells seeded in the other chamber. Addition of anti‐BDNF antibody in the keratinocyte‐seeded chamber significantly reduced the extension. Application of Semaphorin 3A also reduced the extension by approximately 50%. We suggest that this coculture system may be useful for screening of anti‐itching drugs.     

Benign Nerve Sheath Myxoma in an Infant Misdiagnosed as Infantile Digital Fibromatosis

Herein we present the case of a 16‐month boy, clinically diagnosed with infantile digital fibromatosis, but 9 months after continued growth, the mass was excised and the histopathologic diagnosis was that of a benign nerve sheath myxoma. We present this case to emphasize that nerve sheath myxomas (also known as myxoid neurothekeoma) should be included in the differential diagnosis of dermal nodules in infants.