Notalgia paresthetica: a study on pathogenesis

BACKGROUND: Notalgia paresthetica is a sensory neuropathy involving the dorsal spinal nerves. The characteristic symptom is pruritus on the back, occasionally accompanied by pain, paresthesia, and/or hyperesthesia, which results in a well-circumscribed hyperpigmented patch in the symptomatic area. The etiology of this condition has not yet been completely defined. OBJECTIVE: Possible mechanisms that could explain the pathogenesis of notalgia paresthetica were investigated through clinical examination and various diagnostic tests. METHODS: Ten cases of notalgia paresthetica underwent dermatologic, neurologic, and orthopedic examination. This was followed by skin biopsy, electrodiagnostic investigation, and radiography of the spine. RESULTS: All patients had a typical symptomatology and dermatologic picture. Neurologic examination and standard electrodiagnostic investigation results were normal in all cases. Histopathology was compatible with postinflammatory hyperpigmentation; there were no amyloid deposits. In seven cases, degenerative changes in the vertebrae were observed and, in all of these cases, these changes were most prominent in the vertebrae which corresponded to the dermatome of the cutaneous lesion. CONCLUSIONS: The striking correlation of notalgia paresthetica localization with degenerative changes in the spine suggests that spinal nerve impingement may contribute to the pathogenesis of this entity.     

Localized pruritus-notalgia paresthetica.

Notalgia paresthetica, possibly an isolated sensory neuropathy involving the posterior primary rami of thoracic nerves T2 through T6, and appearing as pruritus of the back, is apt to be encountered by both dermatologists and neurologists. Two cases illustrate this disorder.     

Notalgia Paresthetica and Multiple Endocrine Neoplasia Syndrome 2A: A Case Report

Notalgia paresthetica is characterized by a hyperpigmented macular pruritic skin lesion most commonly localized unilaterally in the middle and upper back region. This condition has been reported in association with multiple endocrine neoplasia syndrome type 2A (MEN 2A) in several families; it rarely affects children and it may serve as an early marker of MEN 2A. We report a 9‐year‐old girl diagnosed with MEN 2A and notalgia paresthetica.     

Neuropathic Itch of the Back: A Case of Notalgia Paresthetica

Notalgia paresthetica refers to an isolated mononeuropathy involving chronic localized itch or paresthesia most often at the skin of the scapula or surrounding regions. There are no specific skin manifestations except those arising from chronic scratching and rubbing. The specific etiology remains unknown; however, it has been theorized that the neuropathic itch is caused by sensory nerve entrapment involving the posterior rami of the T2 to T6 nerve root. The entrapment is due to degenerative changes in the vertebrae. We report here a particular case of notalgia paresthetica in a 55-year-old woman. The patient visited our hospital for tingling pain around the left inferior angle of the scapula. Pruritus was first reported seven years ago with tingling pain developing only four months ago. There were no specific skin lesions observed except for excoriation and vague hyperpigmentation. A skin biopsy revealed only epidermal thinning with pigmentary incontinence. The patient was treated with 600 mg of gabapentin daily as well as capsaicin cream. The response was deemed unsatisfactory.     

Symptoms of notalgia paresthetica may be explained by increased dermal innervation.

Notalgia paresthetica is a sensory neuropathy characterized by infrascapular pruritus, burning pain, hyperalgesia, or tenderness. To assess whether the symptoms may be caused by alterations in the cutaneous innervation, skin from the affected area of patients (n = 5) was compared with controls (n = 10) comprising the contralateral unaffected area from the same patients and site-matched biopsies of normals, using immunohistochemistry. Frozen sections were immunostained with antisera to the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, and neuropeptide with tyrosine, and to the general neural marker PGP 9.5 and the glial marker S-100 to show the overall innervation and glial cells, respectively. No discernible change in the distribution of neuropeptide-immunoreactive axons was found, but all of the specimens from the affected areas had a significant increase in the number of intradermal PGP 9.5-immunoreactive nerve fibers compared with unaffected areas from the same patients and normal controls. Epidermal dendritic cells immunoreactive for S-100, possibly Langerhans cells, were substantially increased. It is concluded that there is an increase in the sensory epidermal innervation in the affected skin areas in notalgia paresthetica, which could contribute to the symptoms, and that neural immunohistochemistry of skin biopsies could be helpful in the diagnosis of the disease.     

Paresthetic notalgia and multiple endocrine neoplasia type 2a (Sipple's syndrome): 3 cases]

INTRODUCTION: Notalgia paresthetica is an isolated sensory mononeuropathy. Patients have a pruritus in the mid-upper back. Its association with multiple endocrine neoplasia type IIA has been reported in a few cases. We report three cases of this association. CASE REPORTS: Case n(o) 1: A 45 year-old woman had multiple endocrine neoplasia type IIA with a medullary thyroid carcinoma and a primary hyperparathyroidism; she had a mid-upper back pigmented lesion. Histological examination showed dermal melanosis and deposits of amyloid in the dermis. Case n(o) 2: A woman had a multiple endocrine neoplasia type IIA which was diagnosed at the age of 60; she had a surgical treatment for a pheochromocytoma, a medullary thyroid carcinoma, and a primary hyperparathyroidism; she had dermatological examination for a pruriginous lesion of the mid-upper back. Case n(o) 3: The daughter of the patient n(o) 2 had had a surgical cure for a medullary thyroid carcinoma and a pheochromocytoma at the age of 31; she had a papulous and pruriginous lesion in the left scapular area. Her daughter and her sister had a multiple endocrine neoplasia type IIA without notalgia paresthetica. DISCUSSION: Notalgia paresthetica is a benign cutaneous disorder which can be associated with multiple endocrine neoplasia type IIA. It can be considered that notalgia paresthetica is an early clinical marker of multiple endocrine neoplasia type IIA. Patients with a familial history of notalgia paresthetica or with an onset of notalgia paresthetica in childhood should be screened for multiple endocrine neoplasia type IIA. Patients with multiple endocrine neoplasia must also been screened for notalgia paresthetica because its finding is an argument for a familial form of multiple endocrine neoplasia type IIA. Dermatologists should be aware of this association.     

Efficacy of gabapentin in the improvement of pruritus and quality of life of patients with notalgia paresthetica

BACKGROUND

notalgia paresthetica is a subdiagnosed sensory neuropathy presenting as a condition of intense itching and hyperchromic macule on the back that interferes with daily habits.

OBJECTIVES

To determine the efficacy of treatment of notalgia paresthetica using oral gabapentin, assessing the degree of improvement in itching and influence on quality of life. Moreover, to evaluate the signs and symptoms associated with notalgia paresthetica.

METHODS

We conducted an experimental, non-randomized, parallel, non-blinded study including 20 patients with clinical and histopathological diagnosis of notalgia paresthetica. After application of the visual analogue scale of pain adapted for pruritus and of the questionnaire of dermatology life quality index (DLQI), ten patients with visual analogue scale > 5 were given treatment with gabapentin at the dose of 300 mg/day for four weeks. The other ten were treated with topical capsaicin 0.025% daily for four weeks. After the treatment period, patients answered again the scale of itching.

RESULTS

The use of gabapentin was responsible for a significant improvement in pruritus (p=0.0020). Besides itching and hyperchromic stain on the back, patients reported paresthesia and back pain. It was observed that the main factor in the worsening of the rash is heat.

CONCLUSION

Gabapentin is a good option for the treatment of severe itching caused by nostalgia paresthetica.     

Notalgia paresthetica: a review for dermatologists

Notalgia paresthetica (NP) is an underdiagnosed condition that presents with unilateral pruritus medial to the scapula on the midback with or without an associated hyperpigmented or hypopigmented macule. There is a paucity of recent reviews on this chronic cutaneous neuropathy in peer‐reviewed journals. Current theories propose the condition is likely multifactorial, including spinal entrapment and muscular compressive neuropathy. An extensive literature review was performed by searching the MEDLINE database to review all published works on notalgia paresthetica. This review will provide a useful update for clinicians on the pathogenesis, clinical features, biopsy features, risk factors, and management options for this condition including pharmacological and nonpharmacological methods detailing published treatment options to date for this difficult to treat condition.     

Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis

In order to evaluate more fully the role of neuropeptides in the pathogenesis of psoriasis, skin biopsies were obtained from 36 patients with psoriasis to identify substance P (SP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP). Lesional and nonlesional skin was examined from these biopsies and the results compared with those from biopsies taken from patients with a variety of other inflammatory dermatoses, including lichen planus, lichen simplex chronicus, spongiotic dermatitis, and seborrheic dermatitis. Also studied was a series of nine biopsies taken from patients with no known skin disorders. We found an increase in the number of SP-positive nerve fibers within the epidermis in biopsies from lesional skin of psoriasis patients (8.4 nerves per 3-mm biopsy) compared with nonlesional psoriatic skin (2.6 nerves per 3-mm biopsy) and normal skin (2.0 nerves per 3 mm biopsy). Other inflammatory disorders also demonstrated fewer SP-positive nerves than lesional psoriatic skin; lichen planus (0 nerves per 3 mm biopsy) and lichen simplex chronicus (1.3 nerves per 3 mm biopsy). The difference in SP-positive nerve expression between lesional psoriatic skin and the group comprising nonlesional skin, normal skin, lichen planus, and lichen simplex chronicus attained statistical significance ( P < 0.013). SP-positive intraepidermal nerve fibers in lesional psoriatic specimens were fewer than in spongiotic dermatitis (17.4 nerves per 3 mm biopsy). There was no significant difference in numbers of VIP- or CGRP-immunopositive intraepidermal nerve fibers between psoriatic skin and the group comprising all other material tested. However, in five patients with psoriasis, there was a marked increase in the expression of intraepidermal CGRP (up to 10.7 nerves per 3-mm biopsy) and VIP (up to 8.3 nerves per 3-mm biopsy) which was not observed in control groups. These findings suggest that neuropeptides SP, CGRP, and VIP play a role in the pathogenesis of psoriasis. Received: 3 March 1997     

Notalgia paresthetica: clinical, physiopathological and therapeutic aspects. A study of 12 cases

Notalgia paresthetica (NP) is a common but often unrecognized neurocutaneous condition, with very few cases reported to date. It is characterized by pruritus localized in an area between D2 and D6 dermatomes, sometimes accompanied by sensory neuropathies and/or electrical conductivity disorders. Cutaneous pigmented patches and friction amyloidosis can arise with irritation. Some hereditary cases have been noted mainly in young patients, associated with multiple endocrine neoplasia type 2A. However, NP mainly occurs in older patients and most are sporadic pathologies linked with musculoskeletal compression of spinal nerves. Only capsaicin has shown some (but unfortunately only transient) efficacy in relieving NP symptoms. We present observations on 12 sporadic cases of NP. Spinal X-rays revealed dorsal arthrosis or spinal static disequilibrium in nine of these patients. Six patients underwent spinal and paraspinal ultrasound or radiation (better) physiotherapy, and the symptoms subsided in four of these cases. These results highlighted that spinal disorders could be a determining factor in NP, indicating that patients could benefit from physiotherapy.     

Substance P-induction of endothelial nitric oxide synthase expression on human endothelial cells: modulation of this neurogenic inflammation by an Avena Rhealba® oatmeal extract

Recovery of sensation in grafted skin is a major concern in reconstructive surgery. Because the pilosebaceaous unit represents an important tactile organ within the skin, we developed a tissue-engineered reconstructed skin allowing the formation of complete pilosebaceous units after grafting, and we evaluated nerve regeneration. This model is based on our self-assembly approach of tissue engineering. Sheets obtained after culturing mouse fibroblasts for 35 days with ascorbic acid, which allows collagen synthesis, are superposed. Thereafter, hair buds taken from dermis of newborn mice after collagenase digestion or freshly isolated newborn mice keratinocytes were seeded on the reconstructed dermis, cultured 10 days and grafted on athymic mice. One month after grafting, complete pilosebaceous units where obtained in reconstructed skin containing initially hair buds and were maintained up to 6 months. NF150 (neurofilaments) immunostaining revealed systematical localization of nerves around the pilosebaceous units 1 month after grafting. In contrast, nerves colonization was almost always absent when hair buds were not included in the grafted reconstructed skin. However, after 6 months, the nerves were present in both skin grafted (with or without hairs). These results suggest that the presence of hairs inside the reconstructed skin promotes nerves regeneration after grafting. Furthermore, the connection of pilosebaceous units with nerves suggests that they may be functional for the detection of the tactile stimuli.     

Localized hyperpigmentation and pruritus on the upper back

This retrospective study of 28 patients with pruritus and hyperpigmentation located on the upper half of the back, without involvement of other skin areas, includes 8 cases of macular amyloidosis, four neurodermatitis and 16 compatible with what has been described as notalgia paresthetica (NP). With the exception of the amyloid deposition, we did not find histopathological data that differentiated between macular amyloidosis and NP, since in both processes we found necrotic keratinocytes and melanophages. The differential diagnosis and the current nosological situation of the hyperpigmentation localized on the upper back are reviewed. A diagnostic protocol is proposed.     

Immunohistochemical findings in notalgia paresthetica

BACKGROUND: Notalgia paresthetica (NP) is a sensory neuropathy the pathogenesis of which is not yet completely elucidated. OBJECTIVE: The aim of this study was to investigate the histopathological changes in NP with special emphasis on cutaneous innervation. METHODS: Along with site-matched biopsies from 5 healthy individuals, lesional skin biopsies from 14 cases of NP and biopsies from contralateral nonlesional skin in 9 of these cases were stained with hematoxylin-eosin and Congo red. For immunohistochemical analysis, all samples were stained with two general neural markers (S-100 protein and protein gene product 9.5) and two neuropeptides (vasoactive intestinal polypeptide and substance P). RESULTS: Light microscopy was compatible with postinflammatory hyperpigmentation. Immunohistochemistry did not reveal a significant difference in the staining pattern of lesional skin and control tissue (p > 0.05). Although not reaching statistical significance, the percentage of cases which showed no staining was higher in the group of patients with more chronic NP. CONCLUSION: The finding of less immunohistochemical staining in cases with more chronicity could be of clinical importance and is worth investigating further.     

A comparative evaluation of skin and nerve histopathology in single skin lesion leprosy

BACKGROUND: In spite of leprosy being a disease of nerves, ROM therapy for single skin lesion leprosy was based on clinical trials without much evidence-based studies of nerve pathology. The present study was undertaken to compare the histology of skin and nerve in single skin lesion leprosy, and to assess the scientific rationale and justification of single dose ROM therapy. METHODS: Twenty-seven untreated patients with single skin lesion without significantly thickened peripheral nerves were selected. Skin and nearby pure cutaneous nerve biopsies were studied under both H&E and Fite's stain. RESULTS: All the skin biopsies were negative for AFB and clinico-pathological correlation was positive in 51.85% of skin biopsy specimens. Histopathological diagnosis of leprosy was evident in 55.5% of clinically normal looking nerves, with AFB positivity in 29.6% of nerve biopsy specimens. Correlation between clinical diagnosis and nerve histopathology was poor (26%). CONCLUSIONS: Single skin lesion without thickened peripheral nerves as criteria for single dose ROM therapy is not logical, since the histological diagnosis of leprosy in normal looking nerves with presence of AFB is revealed in this study. Pure cutaneous nerve biopsy is a simple outpatient procedure, without complications. This study emphasizes the need to consider nerve pathology as an important tool for further therapeutic recommendations, than just clinical trials and skin pathology alone. Though single dose ROM therapy has been withdrawn recently, the principle holds good for any future therapeutic recommendations.     

Tratamiento de la notalgia parestésica con toxina botulínica A intradérmica

IntroductionNotalgia paresthetica is a sensory mononeuropathy that affects dorsal segments T2 to T6. It can have a significant effect on quality of life. Numerous treatments have been used with variable results.Material and methodsFive patients diagnosed with notalgia paresthetica were treated with intradermal botulinum toxin A. None had achieved relief of the pruritus with previous treatments.ResultsVariable results were observed after the administration of intradermal botulinum toxin. Complete resolution of the pruritus was not achieved in any of the patients.ConclusionsBotulinum toxin A appears to be a safe therapeutic option for patients with notalgia paresthetica. However, data currently available come from small patient series, making it difficult to draw definitive conclusions regarding the true efficacy and long-term effects of this treatment.     

A quantitative immunohistochemical study of the expression of integrins by nerves in psoriatic and normal skin

Qualitative and quantitative assessment of integrin expression by dermal nerves was made by an avidin-biotin immunoperoxidase method on snap-frozen biopsies from affected psoriatic skin, and skin from normal control subjects with no history of skin disease. Nerves expressed alpha 1, alpha 2, alpha 3, alpha 6, beta 1 and beta 4 integrin subunits, and perineural sheaths in the mid-dermis also expressed these subunits, with the exception of alpha 2. There were more upper dermal nerve segments expressing alpha 1 integrin compared with other integrins both in controls and in psoriatic skin. The greater number of nerves expressing alpha 1 integrin compared with other integrins may be due to anatomical or functional differences between groups of nerves. There were significantly more nerves expressing alpha 1, alpha 2, alpha 3, alpha 6 and beta 4 integrins in psoriatic skin compared with control skin. This generalized increase may indicate a secondary trophic effect on all nerves rather than a specific increase in one type of nerve. However, the expression of alpha 2 integrin may be significant in the pathogenesis of the psoriatic plaque, in that it was barely detectable in the normal site-matched biopsies, but much greater in psoriatic plaques. The study of the expression of adhesion molecules by neurones in psoriasis offers a new avenue for investigation of the role of neuronal hypertrophy in the initiation and maintenance of psoriatic plaques.     

Tattooing increases the number of Langerhans cells in skin: an immunocytochemical study

Abstract Tattooing is an act of permanent marking of the skin with indelible patterns by pricking and inserting pigments. Langerhans cells (LCS) are dendritic cells normally present in suprabasal layers of the epidermis of the skin. To assess whether there were any effects caused by the tattooing on Langerhans cell population and cutaneous nerves, skin from affected areas (n=15) was compared with controls (n=10). Frozen sections were immunostained with antisera to S-100. No discernible change either in distribution or in number of Langerhans cells and nerves was seen upon comparison with control skin taken from different areas, but all of the specimens taken from affected areas had a significant increase in the number of Langerhans cells (p < 0.001) even after several years of tattooing with no change in the cutaneous nerves. Thus, the study shows persistent stimulation of Langerhans cell population in tattooed skin.     

Eosinophil cationic protein- and eosinophil-derived neurotoxin/eosinophil protein X-immunoreactive eosinophils in prurigo nodularis

Abstract It is known that eosinophils are actively involved in allergy and inflammation. The granular components of eosinophils, eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin/eosinophil protein X (EDN/EPX), play an important role in such allergic and inflammatory processes. Prurigo nodularis is a chronic inflammatory skin disease with obvious cutaneous nervous involvement. To detect ECP and EDN/ EPX expression in the eosinophils and their relation to nerve fibres in prurigo nodularis, ECP and EDN/EPX single-labelling immunofluorescence, and ECP and PGP 9.5 double-labelling immunofluorescence, were performed. In prurigo nodularis lesional skin, the ECP- and EDN/EPX-containing cells, which were mainly distributed in the upper dermis, were significantly increased in number compared to their numbers in uninvolved and normal skin. The immunoreactivity of ECP and EDN/EPX in prurigo lesional skin was stronger than in uninvolved skin or control skin. The PGP 9.5-immunoreactive nerves were also increased in number in the areas where there were increased eosinophils. The nerves were in close proximity to eosinophils, and occasionally even seemed to be in contact. The present results indicate that the cutaneous nerves and the ECP- and EDN/EPX-containing eosinophils are possibly involved in the pathogenesis of the disease. The close relationship of nerves and eosinophils indicates that the cutaneous nerves may influence eosinophil function in the chronic inflammatory states of prurigo nodularis. ECP and EDN/EPX could thus be released to the local tissue and modulate the inflammation of the prurigo nodularis lesion. Received: 28 August 1999 / Received: 2 January 2000 / Accepted: 20 March 2000     

Neuropeptides in the skin of patients with atopic dermatitis

There is increasing evidence that neuropeptides may be involved in the pathogenesis of atopic dermatitis (AD). This study examines whether neuropeptide distribution in the skin of patients with AD differs from normal controls. The distribution and density of several neuro-peptides were examined in lesional and non-lesional skin of AD patients (n= 5) and in normal controls (n= 4) using indirect immunofluorescence and image analysis. Cholinergic innervation was studied using cholinesterase histochemistry. Staining with the general neuronal marker protein gene product 9·5 showed a subepidermal network of nerves with fibres penetrating the epidermis, and nerves around blood vessels, sweat glands and hair follicles. Image analysis of nerves around sweat glands showed a significantly higher nerve density in non-lesional compared with both normal controls and lesional skin (P < 0·05); lesional compared with control skin showed no significant difference. In the epidermis the density of nerves was not significantly greater in non-lesional compared with lesional skin and controls. Calcitonin gene-related peptide immunoreactivity was similar in all subjects except in three of the AD patients, where more nerves appeared to penetrate the epidermis. Substance P immunoreactivity in the papillary dermis was seen in all AD patients hut no controls. Vasoactive intestinal polypeptide and neuropeptide Y staining were similar in all groups. Acetyleholinesterase-positive nerves were found around sweat glands in all subjects, the staining being greatest in non-lesional and least in lesional skin. Occasional nerves were seen in the papillary dermis in lesional skin of two out of the four patients. We have demonstrated quantitative differences in nerve growth in clinically normal skin of AD patients, and altered cutaneous neuropeptide expression in these patients which may contribute to the pathogenesis of AD.     

Cutaneous field stimulation in the treatment of severe itch

OBJECTIVE: To evaluate the efficacy of cutaneous field stimulation of C fibers for the treatment of itchy skin and its effect on peripheral nerve fibers as shown in skin biopsy specimens. DESIGN: We conducted an open-label uncontrolled study of 19 patients with itching. Each patient applied a flexible plate containing electrodes to the itchy area for 20 minutes at a time once daily for 5 weeks to stimulate nerve fibers with a constant current (0.8 mA). Skin biopsy specimens were collected before treatment and at the end of treatment and were immunostained for calcitonin gene-related peptide and protein gene product 9.5. SETTING: University hospital in Lund, Sweden. PATIENTS: Sixteen patients with nostalgia paresthetica or brachioradial pruritus and 3 with generalized itch. INTERVENTIONS: Cutaneous field stimulation and punch biopsies of the itchy skin. MAIN OUTCOME MEASURES: Visual analog scale for assessment of itching and counting the immunoreactive nerve fibers in 3-mm biopsy specimens. RESULTS: Patients with localized itching experienced a reduction in mean values on the visual analog scale (from 78% before treatment to 42% by the end of the fifth week). The number of protein gene product 9.5- immunoreactive nerve fibers in the epidermis was reduced by 40% by the end of treatment compared with baseline values. CONCLUSIONS: Cutaneous field stimulation is an effective alternative for the treatment of localized itching. The reduction in itching is accompanied by degeneration of the epidermal nerve fibers, as evidenced by the loss of protein gene product 9.5 immunoreactivity.