General Considerations and Diagnostic Approach

Chapter 1

Abstract

Merkel's cells

3

1. Introduction

The Cutaneous Biopsy for the

Corpuscles and Merkel's Cells

Jorge García-Piqueras, Giuseppina Salvo, Juan L. Cobo,

Cutaneous biopsy is a complementary method, alternative to peripheral nerve biopsy, for the analysis of nerve involvement in peripheral neuropathies, systemic diseases, and several pathologies of the central nervous system. Most of these neuropathological studies were focused on the intraepithelial nerve fibers (thinmyelinated Aδ fibers and unmyelinated C fibers), and few studies investigated the variations in dermal innervation, that is, large myelinated fibers, Merkel's cellneurite complexes, and Meissner's corpuscles. Here, we updated and summarized the current data about the quantitative and qualitative changes that undergo MCs and MkCs in peripheral neuropathies. Moreover, we provide a comprehensive rationale to include MCs in the study of cutaneous biopsies when analyzing the

Elda Alba, Ramón Cobo, Jorge Feito and José A. Vega

peripheral neuropathies and aim to provide a protocol to study them.

Keywords: skin biopsy, peripheral neuropathy, Meissner's corpuscles,

Since the last half of the past century, the analysis in the cutaneous biopsy of nerves, Merkel's cells (MkCs), and sensory corpuscles, especially Meissner's corpuscles (MCs), become a complementary method to diagnose peripheral neuropathies [1] and a reliable alternative to peripheral nerve biopsy. Nevertheless, it has been during the last decade that numerous studies have provided consistent evidence to support this technique as a valuable tool to understand the etiologies of some neurological diseases and to follow up clinical trials [2–4] (Figures 1 and 2). Most of the neuropathological studies on cutaneous biopsies were focused on intraepithelial nerve fibers, which are thin-myelinated Aδ fibers or unmyelinated C fibers [2, 3, 5–9]. Conversely, few studies have investigated the large myelinated fibers (although it can offer notable advantages over the unmyelinated ones [10]). Also, the quantitative and qualitatively changes in MCs and MkCs associated to peripheral neuropathies are poorly known although the study of MCs has gained interest [11–13].

s

Diagnosis of Peripheral

Neuropathies: Meissner'

Olivia García-Suárez, Yolanda García-Mesa,

#### Chapter 1

### The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner' s Corpuscles and Merkel' s Cells

Olivia García-Suárez, Yolanda García-Mesa, Jorge García-Piqueras, Giuseppina Salvo, Juan L. Cobo, Elda Alba, Ramón Cobo, Jorge Feito and José A. Vega

#### Abstract

Cutaneous biopsy is a complementary method, alternative to peripheral nerve biopsy, for the analysis of nerve involvement in peripheral neuropathies, systemic diseases, and several pathologies of the central nervous system. Most of these neuropathological studies were focused on the intraepithelial nerve fibers (thinmyelinated Aδ fibers and unmyelinated C fibers), and few studies investigated the variations in dermal innervation, that is, large myelinated fibers, Merkel's cellneurite complexes, and Meissner's corpuscles. Here, we updated and summarized the current data about the quantitative and qualitative changes that undergo MCs and MkCs in peripheral neuropathies. Moreover, we provide a comprehensive rationale to include MCs in the study of cutaneous biopsies when analyzing the peripheral neuropathies and aim to provide a protocol to study them.

Keywords: skin biopsy, peripheral neuropathy, Meissner's corpuscles, Merkel's cells

#### 1. Introduction

Since the last half of the past century, the analysis in the cutaneous biopsy of nerves, Merkel's cells (MkCs), and sensory corpuscles, especially Meissner's corpuscles (MCs), become a complementary method to diagnose peripheral neuropathies [1] and a reliable alternative to peripheral nerve biopsy. Nevertheless, it has been during the last decade that numerous studies have provided consistent evidence to support this technique as a valuable tool to understand the etiologies of some neurological diseases and to follow up clinical trials [2–4] (Figures 1 and 2).

Most of the neuropathological studies on cutaneous biopsies were focused on intraepithelial nerve fibers, which are thin-myelinated Aδ fibers or unmyelinated C fibers [2, 3, 5–9]. Conversely, few studies have investigated the large myelinated fibers (although it can offer notable advantages over the unmyelinated ones [10]). Also, the quantitative and qualitatively changes in MCs and MkCs associated to peripheral neuropathies are poorly known although the study of MCs has gained interest [11–13].

#### Figure 1.

Meissner's corpuscles (arrows) and Merkel's cells in the first toe skin of nondiabetic (nd) and diabetic (d) subjects as observed using immunohistochemistry for S100 protein (S100P) and cytokeratin-20 (CK20), specific markers for lamellar cells and Merkel's cells, respectively.

The evaluation of the dermal innervation, including large fibers, MCs, and MkCs, is not currently included within the routine analysis of skin biopsies because of the lack of a validated protocol. Changes in the density and size of MC and MkCs (i.e., variations in number/unit of surface, atrophy and/or hypertrophy, protein expression, etc.), can reflect quantitative or qualitative variations in the number of sensory neurons or nerve fibers innervating them or in the cells forming MCs themselves. Even more, they might also reflect pathologies of the central nervous system, and in these cases, the cutaneous biopsy becomes a method to study diseases difficult to be analyzed without invasive surgery.

This chapter is aimed to update the current data about the quantitative and qualitative changes in MCs and MkCs in peripheral neuropathies, as well as to provide a comprehensive rationale to include them in the study of cutaneous biopsies when analyzing the peripheral neuropathies. Furthermore, our purpose is to provide a technical protocol for analyzing MCs and MkCs in cutaneous biopsies. We have excluded from this review the intraepidermic nerve fibers because they have been extensively studied in peripheral neuropathies, and standardized method has been proposed and accepted [4, 9].

#### 2. State of the art: a review and update of the literature

#### 2.1 Why do we study Meissner's corpuscles and Merkel's cells for clinical purposes

The cutaneous MCs are sensory structures placed just beneath the epidermis within the dermal papillae in areas especially sensitive to light touch, like the fingertips, palms, soles, lips, and male and female genital skin [14–16]. They show an ellipsoid morphology with the main axis perpendicular to the skin surface and a size largely variable (length of 80–150 μm and diameter of 20–40 μm). Structurally, they consist of an axon that runs between the stacked nonmyelinating Schwann-like cells (the so-called lamellar cells) and habitually lacks a differentiated capsule [14, 16, 17]. The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner's Corpuscles… DOI: http://dx.doi.org/10.5772/intechopen.81687

#### Figure 2.

Meissner's corpuscles (arrows) of the palmar aspect of the fingers of patients diagnosed of Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as observed using immunohistochemistry for S100 protein (S100P). The samples were obtained during necropsy and in compliance with Spanish law.

MCs are particularly abundant in the fingers and palm hand, which are two zones easily accessible for biopsy. Nevertheless, the analysis of MCs from these zones has many problems. First of all, the normal density (MCs/mm<sup>2</sup> ) at this localization should be determined to compare normal and pathological conditions. The most ancient studies established that the density of MCs in the human hand is ˜10–<sup>24</sup> MCs/mm<sup>2</sup> [18–20], it is higher in the fingertip (2.7/mm<sup>2</sup> ° 0.68) than in the palm (1.33/mm<sup>2</sup> ° 0.6), and it does not change significantly with age [21]. Nolano et al. [22] found 33.02/mm<sup>2</sup> ° 13.2 in the fingertip of digit III and 45/mm<sup>2</sup> in the digit V; Herrmann et al. [12] determined that the density of MCs on the palmar side of digit <sup>V</sup> is 12/mm<sup>2</sup> ° 5.3, whereas in the skin of the thenar eminence, it is 5.1/mm<sup>2</sup> ° 2.2.

The second trouble for the use of MCs in the diagnosis of neuropathies is whether or not MCs change in density and characteristic with aging. A reduction in number and size of MCs in elderly is generally assumed [18, 23–25], but detailed studies are not available. Preliminary data from our laboratory demonstrate that aging is accomplished of a reduction in the number and size of digital MCs, as well as changes in their architecture and immunohistochemical properties (García-Piqueras et al., unpublished). However, the variations in the corpuscular size and morphology of MCs are difficult to evaluate because of their large variability within the same skin sample. Therefore, in the absence of evident atrophy, hypertrophy, or corpuscular disruption, the evaluation of these parameters must be cautiously considered when evaluating cutaneous biopsies.

The main constituents of MCs, that is, the axon and lamellar cells, contain specific proteins as widely demonstrated using immunohistochemistry [17, 26, 27]. These studies reported a large volume of information, but they are purely descriptive and do not consent to quantify those proteins and their possible variations in neuropathies. The central axon displays immunoreactivity for general neuronal markers (neuronspecific enolase, protein gene product 9.5, neurofilament subunit proteins). They also express Ca2+-binding proteins such as calbindin D28k, parvalbumin, calretinin, and neurocalcin, which presumably regulate the axonic Ca2+ homeostasis and therefore participate in the mechanoelectric transduction. Recently, our research's group detected axonic TRPC6, TRPV4, ASIC2, and Piezo2 ion channels that work as putative mechanoproteins [28–30]. Regarding lamellar cells, the vimentin is the intermediate filament filling their cytoplasm, while the glial fibrillary acidic protein is always absent. They strongly express S100 protein colocated with parvalbumin or calbindin D-28 kDa. The lamellar cells also display immunoreactivity for TrkB, the signaling receptor for the neurotrophins BDNF/NT-4 [31]. Apart from axon- or lamellar cellspecific proteins, there are some others shared by both corpuscular constituents. They include p75NTR and TrkA (low-affinity pan-neurotrophin receptor and the highaffinity receptor for nerve growth factor, respectively; [32, 33]), the epidermal growth factor receptor [34], or cell death protein Bcl-2 [35]. The presence of some ion channels in the lamellar cells has been also reported [28–30]. It is possible that some of these proteins undergo changes during peripheral neuropathies, but limited information is so far available in this topic (see [17]). The proteins present in human MCs are summarized in Table 1.

The cutaneous MkCs are special epidermal cells placed in the basal layer of the epidermis, isolated or forming clusters, in both the glabrous and hairy skin. They are innervated by Aβ sensory axons connected through synapse-like contacts forming the so-called MkCs-neurite complexes. MkCs are involved in fine touch working as a part of slowly adapting type I low-threshold mechanoreceptors and express specific mechanoproteins [16, 30, 36–39]. MkCs have an epithelial origin and do not originate from the neural crest, as classically accepted [40–42].

Using immunohistochemistry, diverse proteins have been detected in the MkCneurite complexes. They include low-molecular-weight cytokeratins and a repertory of synaptic vesicles-related proteins (chromogranin A, synaptophysin), different neuropeptides as well as neurotransmitter receptors, neurotrophin receptors, ion channels (ASIC2 and Piezo2), and neuron-specific enolase [28, 43–46]. The axon of the MkC-neurite complexes displays immunoreactivity for general neuronal markers (Table 1).

The density of MCs varies from an anatomical region to another, and it is directly related to the sensibility of those zones [47]. In terms of density as far as we know, no age-dependent changes have been communicated. Recently, we have found significant reduction in of digital MkCs with aging (García-Piqueras et al., unpublished). On the other hand, whether or not MkCs, or the nerve fibers innervating them, are involved in peripheral neuropathies has been poorly studied, but this possibility should be explored because the easily accessibility to MkCs-neurite complexes.

#### 2.2 Variations in MCs and MKCs in peripheral neuropathies

Data reporting changes in MCs in peripheral neuropathies are scarce and are restricted to diabetes and other rare inheretary neuropathies, HIV infection, mechanical or traumatic nerve entrapment, and a miscellaneous group of systemic diseases with neurological symptoms.

Meissner's corpuscles Merkel's cell-neurite complex Protein Ax LC Ax MC Axonal proteins Neuron-specific enolase Protein gene product 9.5 β-Arrestin 1 GAP-43 Ca2+-binding proteins S100 protein Calbindin D28K Calretinin Neurocalcin Cytoskeletal proteins Neurofilament proteins Vimentin Growth factor receptors p75NTR (pan-neurotrophin receptor) TrkA (NGF receptor) TrkB (BDNF/NT4 receptor) EGF receptor Putative mechanoproteins (ion channels) ASIC2 Piezo2 TRPC6 TRPV4 TRPM8 Cell death-live proteins Bcl-2 Neuropeptides and bioactive amines Serotonin Bombesin Vasoactive intestinal polypeptide Substance P CCK8 Calcitonin gene-related peptide Neuropeptide receptors NMDA Synaptic vesicle-associated proteins Chromogranin A Synaptophysin

The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner's Corpuscles… DOI: http://dx.doi.org/10.5772/intechopen.81687

#### Table 1.

Proteins detected in human Meissner's corpuscles and Merkel's cell neurite complexes using immunohistochemistry. Red: positivity for a protein in the axon of Meissner's corpuscles; Blue: positivty for a protein in the lamellar cells (LC) of Meissner's corpuscles.

#### 2.2.1 Diabetic neuropathy

Distal symmetric peripheral neuropathy is one of the most common complications of diabetes [48] and involves motor, autonomic, and sensory nerve fibers. The histopathological studies have provided evidence that both the thin unmyelinated C fibers and the large myelinated ones are affected in on diabetic neuropathy. Consistently, the two most prominent complaints are peripheral pain and changes in touch [13, 49–52]. The intraepidermic nerve fibers as well as the nerve apparatus of the dermis are reduced in the diabetic neuropathy, and the reduction of the dermic nerves involves MCs. Importantly, although some authors have argued their interest in studying MCs and MkCs to better understand the diabetic neuropathy [53], only few studies have approached this topic.

In cutaneous biopsies, it was shown that the density of MCs is significantly reduced in diabetic patients with respect to the controls (10.2 ˜ 8.4 vs. 16.2 ˜ 9.4/mm2 , more evidently in type I than in type II diabetes), and this correlated with a reduction in median and ulnar nervessensory amplitude; moreover,some MCs were hypertrophic or showed anomalies in their architecture (disorganization of the lamellar cells and increase in the irregularity of the axons) [54]. Similar findings as those obtained from cutaneous biopsy were observed using in vivo reflectance confocal microscopy at the thenar eminence and digit V [55]. We have recently communicated that long-term diabetic neuropathy courses with a reduction in the number and size of MCs and changes in their immunohistochemical profile [56] (Figure 1).

Nevertheless, the number and size of MCs are probably related with the time of evolution of the neuropathy. In fact, in an animal model of diabetes that develop neuropathy, MCs were found more abundant and hypertrophic during the first few years of hyperglycemia, whereas after a long time, the hypertrophy declines but the number of corpuscles remained higher than in age-matched nondiabetic subjects; furthermore, the MCs from the diabetic animals found had abnormal structure and immunochemistry properties [57].

On the other hand, as far as we know, the only study reporting a reduction in the number of immunohistochemically demonstrable MkCs in diabetic neuropathy was from our laboratory [56].

#### 2.2.2 Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is a common inherited neuromuscular disorder characterized by neuropathies without known metabolic alterations. In the skin of patients with common and rare forms of CMT caused by different mutations, the density of MCs is reduced compared with normal controls [58–60]. Similar findings were reported by Almodovar et al. [61] using in vivo reflectance confocal microscopy.

#### 2.2.3 Human immunodeficiency virus (HIV) neuropathy

HIV-sensory neuropathy is a common complication of HIV infection and may be associated with significant morbidity due to neuropathic pain [62]. Several approaches exist for quantitative assessment of human HIV-associated distal sensory polyneuropathy, and some of them have analyzed both unmyelinated and myelinated nerve fibers, as well as MCs. Using in vivo reflectance confocal microscopy, it was found a marked reduction in MCs [12, 63] in HIV+ subjects with and without distal sensory neuropathy [64].

The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner's Corpuscles… DOI: http://dx.doi.org/10.5772/intechopen.81687

#### 2.2.4 Entrapment neuropathies

Surprisingly, little is known about the impact of entrapment neuropathy on target innervation. More than 20 years ago, we reported that human digital MCs survive to entrapment or section of peripheral nerves for more than 10 years, and although its number remains relatively stable, denervated MCs lack some antigens or change the pattern of expression of some others [65–67]. These data were confirmed recently in subjects undergoing carpal tunnel syndrome [68].

#### 2.2.5 Miscellaneous

A reduction in density or loss of MCs has also been reported in the skin of patients suffering from Ross syndrome (a rare disorder of sweating associated with areflexia and tonic pupil) [69], POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) [70], systemic sclerosis [71], pachyonychia congenita (in contrast, MkC densities are higher) [72], chronic inflammatory demyelinating polyradiculoneuropathy [73], and systemic lupus erythematosus [12].

#### 2.3 MCs are also altered in central nervous system disorders

In addition to the abovementioned peripheral neuropathies, changes in MCs have been reported in Parkinson's disease associated or not with dementia [74–76], spinobulbar muscular atrophy [77], Friedreich's ataxia [78], amyotrophic lateral sclerosis [79], or Guillain-Barré syndrome [73]. Furthermore, altered cutaneous innervation also has been observed in some psychiatric disorders [80] and mental deficiencies [81] (Figure 2).

#### 3. Proposal of a method to systematically study MCs and MkCs in cutaneous biopsies

MCs are only present in glabrous skin, and therefore fingers or toes are appropriate regions to take cutaneous biopsies focused to evaluate them; in spite of the discrepancies regarding their density in these places, they are abundant enough.

In our opinion, the palmar aspect of fingertip IV would be an ideal region to be biopsied, because it is not involved in handling; the lateral borders should be excluded to avoid damaging the digital nerves and the formation of neuromas. On the other hand, toe pad biopsies can be also useful, but they contain a lower density of MCs than fingers [82].

The Joint Task Force EFNS/PNS [9] recommends to perform a 3 mm punch skin biopsy (including epidermis and the subpapillary and reticular dermis), using a sterile technique and under local anesthesia. A sample of these dimensions does not need sutures, heal completely within 1 week, and this normally guaranties no side effects or complaints. Informed consent is required, and information on the possible risks must be always provided. The fixation of the skin samples is recommended in 2% PLP (2% paraformaldehyde, 0.075 M lysine, 0.037 M sodium phosphate, 0.01 M periodate) or Zamboni's solution. We have also obtained excellent structural results and good antigen preservation using Bouin's fixative and buffered 10% formaldehyde. Conversely, 4% paraformaldehyde masked most of the antigens present in MCs. The thickness of the sections is also important. The Joint Task Force EFNS/

PNS especially recommends 50-μm thick sections to perform 3D reconstructions of MCs. Nevertheless, our experience demonstrates that to demonstrate the occurrence of most antigens present in the axon or in the lamellar cells of Meissner's corpuscles, 8 or 10 μm sections are appropriate.

There are different techniques for identification and assessment of MCs (silver impregnation techniques, electron microscopy, immunohistochemistry, and immunofluorescence), but the ideal one should allow to the quantification and specific immunostaining, distinguishing the different MCs constituents. In routine studies, at least one marker for the axon and one for the lamellar cells should be used. Indirect immunofluorescence, especially when associated with confocal microscopy, provides an opportunity to investigate multiple neuronal and nonneuronal proteins within the same MC and also to perform its 3D reconstruction using appropriate computerized image analysis systems. Ideally, double immunostaining for both axon and lamellar cells, associated or not with labeling of the nuclei, provides a global image of the morphology and size of the corpuscle, as well as of the arrangement of corpuscular constituents (Figure 3).

To quantify MCs, we use the method proposed by Verendeev et al. [83] to establish the density of MCs in the fingertips of primates. Briefly, 10-μm-thick sections, 200 μm apart, processed for S100 protein immunohistochemistry, are used. The sections are scanned by SCN400F scanner (Leica, Leica Biosystems™) and computerized using SlidePath Gateway LAN software (Leica, Leica Biosystems™). Then, in each section, MCs are identified and counted by two independent observers. The average numerical values were corrected applying the Abercrombie's formula: N = n\*T/(T + H), where N is the corrected average number of MCs, n is the counted average number of MCs in all sections of a fingertip, T is the average section's thickness, and H is the average diameter of the counted MCs. Through a specific tool of the abovementioned software, the average MCs diameter was determinate measuring the horizontal axis by drawing a straight line approximately in the central region of each corpuscle. The longitudinal epidermis of each section (mm) is measured with the same tool, and the average length was multiplied by the section's thickness (mm) to give the measured surface area (mm<sup>2</sup> ). Finally, the average number of Meissner corpuscles (N) was divided by the surface area (mm<sup>2</sup> ) that is the density of MCs by squared millimeter of skin (number of MCs/mm<sup>2</sup> ) (Figure 4). To establish the density of digital Merkel's cells, we used the same method immunostaining Merkel's cells for cytokeratin.

#### Figure 3.

3D reconstruction of a Meissner's corpuscle in a finger of a 25-year-old male. The axon is labeled in red, and the lamellar cells in green. The cell nuclei were labeled with DAPI. Scale bar = 20 μm.

The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner's Corpuscles… DOI: http://dx.doi.org/10.5772/intechopen.81687

#### Figure 4.

Schematic representation of the technical procedure to quantify Meissner's corpuscles in sections of human digital skin immunostained for the detection of S100 protein.

#### 4. Final remarks and future prospectives

Peripheral neuropathies are diverse and require a multidimensional approach for detection and monitoring clinical and research setting. The minimal invasiveness of skin biopsy makes it a useful tool not only for diagnostics but also for following the progression or the effects of a treatment in neuropathies.

Pathophysiological studies in patients with large nerve fiber polyneuropathies are limited because the difficulty in obtaining nerve samples due to the invasive nature of the procedure. For this reason, some authors utilized skin biopsies to obtain morphological and molecular information from large dermal myelinated nerve fibers. The development of new methods to evaluate skin innervation, including MCs, through noninvasive techniques, that is, in vivo reflectance confocal microscopy, may contribute to better understand the changes in sensory corpuscles in neuropathies [12, 55, 61, 84–86].

Nevertheless, to use MCs as a complementary method in the diagnosis of neurological diseases, more studies are still necessary. Firstly, the density of MCs must be mapped in the specific areas where they are abundant and easily accessible to cutaneous biopsy, especially the hand glabrous skin. Secondly, the physiological age-related changes in the number and protein composition of MCs of these selected areas must be established. Quantitative data, apart from qualitative, on

#### Demystifying Polyneuropathy - Recent Advances and New Directions

changes in protein composition of MCs with aging are necessary as a baseline for possible pathological changes. In addition to immunohistochemical studies, skin biopsy is amenable to the extraction of mRNA, RT-PCR, or microarrays for genes involved in neuropathies, and these methods should be used and standardized to study MCs. Finally, future studies should include not only neuropathies such as neurofibromatosis [85], or other rare metabolic neuropathies such as Gaucher type 1 disease [86], but also central nervous system diseases such as Alzheimer's disease.

### Author details

Olivia García-Suárez<sup>1</sup> , Yolanda García-Mesa<sup>1</sup> , Jorge García-Piqueras<sup>1</sup> , Giuseppina Salvo<sup>1</sup> , Juan L. Cobo1,2, Elda Alba3 , Ramón Cobo<sup>1</sup> , Jorge Feito1,4 and José A. Vega1,5\*

1 Departamento de Morfología y Biología Celular, Grupo SINPOS, Universidad de Oviedo, Spain

2 Servicio de Cirugía Máxilofacial, Hospital Universitario Cental de Astrias, Oviedo, Spain

3 Servicio de Neurología, Hopital Universitario "La Paz", Madrid, Spain

4 Servicio de Anatomía Patológica, Complejo Hospitalario de Salamanca, Salamanca, Spain

5 Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago de Chile, Chile

\*Address all correspondence to: javega@uniovi.es

© 2018 The Author(s). Licensee IntechOpen. This chapteris distributed underthe terms oftheCreative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner's Corpuscles… DOI: http://dx.doi.org/10.5772/intechopen.81687

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Section 2

Etiologies and Pathogenesis

**21**

<50 CD4+ T cells/mm3

**Chapter 2**

**Abstract**

**1. Introduction**

complications of HIV infection.

Indonesia when patients received stavudine [8].

Neuropathy

*and Patricia Price*

HIV-Associated Sensory

*Fitri Octaviana, Ahmad Yanuar Safri, Darma Imran*

models are needed to confirm the roles of the encoded proteins.

**Keywords:** HIV sensory neuropathy, inflammation, neuronal repair

As advances in the treatment of HIV are now allowing patients a longer life span, further comorbidities become apparent. This includes sensory neuropathy (HIV-SN) which can affect a patient's quality of life. Here, we review factors influencing HIV-SN in patients receiving antiretroviral therapy that promotes this condition and in the modern era when these therapies have been withdrawn. This has halved the incidence of HIV-SN, but the condition remains significant in the lives of many sufferers. Genetic polymorphisms that influence pathogenesis of HIV-SN have indicated likely mechanisms, but studies of skin biopsies and animal

Management of HIV patients is now focused on their quality of life as antiretroviral therapy (ART) increases life expectancy. However, with longer lives, a growing number of patients experience a neurological disorder that predominantly affects small fibers. HIV-associated sensory neuropathy (HIV-SN) may arise not only as a result of HIV infection itself but also as a side effect of ART. The clinical pictures triggered by HIV infection or ART are very similar and include neuropathic pain, tingling sensation, and numbness [1–3]. HIV-SN is one of the most common

The incidence and prevalence of HIV-SN vary widely—perhaps because most studies do not distinguish between neuropathy due to HIV itself and due to ART regimens with different risk profiles. Cross-sectional studies including patients receiving ART identify HIV-SN in 16–50% of HIV patients [4–6]. ART that includes the non-nucleotide reverse transcriptase inhibitor (NNRTI), stavudine (d4T), is associated with high prevalence of HIV-SN. The prevalence in Melbourne was up to 42%, whereas in Kuala Lumpur and Jakarta, the reported level was lower, 19 and 34%, respectively [7]. Stavudine is no longer in first-line therapy, and the prevalence of HIV-SN is almost halved (14.2%) compared to data from the same clinic in

In untreated patients, the risk factors for HIV-SN were severe HIV disease marked by low numbers of CD4+ T cells and high viral loads (HIV RNA) in plasma. In the era of ART (including stavudine), the risk factors of HIV-SN included older age, height,

, malnutrition, and concurrent diabetes [1, 7, 9, 10]. HIV-SN

#### **Chapter 2**

## HIV-Associated Sensory Neuropathy

*Fitri Octaviana, Ahmad Yanuar Safri, Darma Imran and Patricia Price* 

#### **Abstract**

As advances in the treatment of HIV are now allowing patients a longer life span, further comorbidities become apparent. This includes sensory neuropathy (HIV-SN) which can affect a patient's quality of life. Here, we review factors influencing HIV-SN in patients receiving antiretroviral therapy that promotes this condition and in the modern era when these therapies have been withdrawn. This has halved the incidence of HIV-SN, but the condition remains significant in the lives of many sufferers. Genetic polymorphisms that influence pathogenesis of HIV-SN have indicated likely mechanisms, but studies of skin biopsies and animal models are needed to confirm the roles of the encoded proteins.

**Keywords:** HIV sensory neuropathy, inflammation, neuronal repair

#### **1. Introduction**

Management of HIV patients is now focused on their quality of life as antiretroviral therapy (ART) increases life expectancy. However, with longer lives, a growing number of patients experience a neurological disorder that predominantly affects small fibers. HIV-associated sensory neuropathy (HIV-SN) may arise not only as a result of HIV infection itself but also as a side effect of ART. The clinical pictures triggered by HIV infection or ART are very similar and include neuropathic pain, tingling sensation, and numbness [1–3]. HIV-SN is one of the most common complications of HIV infection.

 The incidence and prevalence of HIV-SN vary widely—perhaps because most studies do not distinguish between neuropathy due to HIV itself and due to ART regimens with different risk profiles. Cross-sectional studies including patients receiving ART identify HIV-SN in 16–50% of HIV patients [4–6]. ART that includes the non-nucleotide reverse transcriptase inhibitor (NNRTI), stavudine (d4T), is associated with high prevalence of HIV-SN. The prevalence in Melbourne was up to 42%, whereas in Kuala Lumpur and Jakarta, the reported level was lower, 19 and 34%, respectively [7]. Stavudine is no longer in first-line therapy, and the prevalence of HIV-SN is almost halved (14.2%) compared to data from the same clinic in Indonesia when patients received stavudine [8].

In untreated patients, the risk factors for HIV-SN were severe HIV disease marked by low numbers of CD4+ T cells and high viral loads (HIV RNA) in plasma. In the era of ART (including stavudine), the risk factors of HIV-SN included older age, height, <50 CD4+ T cells/mm3 , malnutrition, and concurrent diabetes [1, 7, 9, 10]. HIV-SN

was also more common in African-Americans [3] and Hispanics [11]. Genetic polymorphisms may alter risk for HIV-SN in Africans [12–14], Asians [15], and Caucasians [16]. These factors are discussed in more detail here.

#### **2. Clinical features and diagnostic criteria**

There are two forms of HIV-SN—distal symmetrical polyneuropathy in HIV (DSP) and antiretroviral toxic neuropathy (ATN). DSP arises at later stages of HIV infection, while ATN is caused by neurotoxic effects of antiretroviral drugs [10, 17]. These two forms cannot be distinguished clinically, so they are grouped as HIV-SN when seen in patients receiving ART.

The most frequent symptoms of HIV-SN are pain, numbness, and burning sensations. The symptoms can be progressive, predominantly affecting the soles of the feet and may become more severe at night. Physical examination may reveal hyperalgesia and allodynia, with absent physiological reflexes and sensory loss in the distal limb segments, including sensitivity to vibration [1, 9–11]. Clinical symptoms usually occur first on the lower limbs for several months but may spread upward. Since HIV-SN predominantly affects small nerve fibers, the clinical signs can also manifest as autonomic neuropathy with postural hypotension and urinary dysfunction [18]. Guidelines for the diagnosis and management of HIV-SN are available [e.g., https://www.hiv.va.gov/provider/manual-primary-care/peripheralneuropathy.asp] but require adaptation to accommodate differences between patient populations, structures of medical care, and available resources.

 Perhaps, the optimal tool to screen HIV-SN is AIDS Clinical Trial Group Brief Peripheral Neuropathy Screening Test (ACTG BPNST). This test has been used in many countries including Australia, the USA, India, South Africa, and Indonesia. It is relatively inexpensive, is fairly easy to do, and takes less than 10 minutes to perform but has low sensitivity. A study comparing BPNST to modified Total Neuropathy Scores (mTNS) in HIV patients on ART (including d4T, ddI, ddC) found that the sensitivity of BPNST was 49%, whereas the specificity was high at 88% [17]. Peripheral neuropathy can be diagnosed if there is ≥1 symptom assessed in the BPNST list and one of the following signs: decreased Achilles reflexes or decreased sensibility to vibration when a tuning fork is held on a toe. This definition means that patients with two abnormal signs but no symptoms are not considered to have HIV-SN. This may contribute to variations in the prevalence of peripheral neuropathy in HIV reported in various studies. Some studies consider this intermediate group as asymptomatic peripheral neuropathy with the assumption that they can become symptomatic in time. Ellis et al. defined peripheral neuropathy as a decrease in Achilles tendon reflexes or decreased perception of vibration in both legs. The sensitivity increased by 80% but the specificity decreased to 59% [19].

Clinically, peripheral neuropathy can also be classified as small- or large-fiber neuropathy. The latter manifests as the loss of joint position and vibration sense and sensory ataxia, whereas small-fiber neuropathy manifests as neuropathic pain, impairment of temperature sensing, and autonomic function. A nerve conduction study (NCS) can include sensory and motor nerve conduction and help in documenting sensory motor deficits that mainly affect large-fiber nerves [20]. As HIV-SN is a predominately small-fiber neuropathy, NCS is often normal [21]. In HIV-SN patients, ATN- and HIV-associated DSP often cannot be distinguished since patients can have both types at same time. However, there are some evidences that ATN primarily impairs small-fiber nerves, whereas HIV-associated neuropathy (DSP) has been linked to large-fiber nerves [22, 23].

#### *HIV-Associated Sensory Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.81176*

 Stimulated skin wrinkling (SSW) test is a method to assess small nerve fiber function using exposure to eutectic mixture of local anesthetic. It has been shown to correlate with intraepidermal nerve fiber density (IENFD) in patients with a sensory neuropathy [24] and has high sensitivity compared to other assessments of small-fiber neuropathy in diabetic patients [25]. Skin wrinkling occurs as a result of vasoconstriction in the glabrous skin, mediated by postganglionic sympathetic fibers [26]. Other assessments that have been used to detect smallfiber neuropathy in HIV-SN patients include quantitative sudomotor axon reflex tests (QSART) [27], quantitative sensory tests (QST) [18], and sympathetic skin responses (SSR) [22, 23].

Skin biopsies are the gold standard for the detection of damage to small-diameter sensory nerves, including non-myelinated and myelinated intraepidermal nerve fibers. Lower nerve fiber densities have been demonstrated in patients with HIV-SN [18]. Studies have used several different techniques. The European Federation of Neurological Societies recommended a biopsy of the skin to a depth of 3 mm by using a skin punch biopsy on the distal limbs to calculate the linear density or nerve fibers with a minimum of 50 μm-thick slices, fixed in a 2% solution of paraformaldehyde-lysine-periodate (2% PLP). Immunohistochemical staining techniques recommended are bright-field immunohistochemistry and indirect immunofluorescence [28]. PGP9.5 immunofluorescence allows nerves to be visualized using a confocal microscope [29]. Smaller intraepidermal nerve fiber densities (IENFD) in HIV-SN patients correlated with the clinical and electrophysiological severity [30]. Skin biopsies can also be used to identify cells and mediators that contribute to SN. These are discussed later in this chapter.

### **3. Clinical factors influence the risk of HIV-SN**

 Analyses of the risk factor of HIV-SN require that we consider the condition in three distinct eras—(1) pre-ART, (2) the use of combination ART that included stavudine (d4T), and (3) the use of non-neurotoxic ART. In the pre-ART era, the risk factors for developing HIV-SN included HIV disease severity, low CD4+ T-cell counts, high viral load, and older age [31, 32]. In the second era, the risk factors are older age, height, low nadir CD4+ T-cell counts, HIV duration, malnutrition, diabetes mellitus, dyslipidemia, and the use of neurotoxic drugs (usually stavudine; see **Table 1**; [7, 14, 15, 33, 34]). Stavudine is no longer recommended by the WHO as first-line ART and is now rarely used anywhere in the world, but HIV-SN has


#### **Table 1.**

*Genetic and demographic risk factors affecting HIV-SN in patients receiving ART.* 

not disappeared. The risk factors of HIV-SN in patients on ART without stavudine are almost the same as in the pre-ART era—high plasma viral load and older age [8]. Isoniazid is widely used as therapy for tuberculosis and has been recognized as a risk factor for neuropathy for a long time. It remains weakly associated with HIV-SN even though patients receiving isoniazid are also given B6 supplementation to prevent neuropathy. Protease inhibitor (PI) exposure may be a risk factor of HIV-SN. Lopinavir, indinavir, and ritonavir, but not nelfinavir, were associated with neuropathy in one study [35].

#### **4. Genetic risk factors**

The risk of HIV-SN cannot be correlated with a single genetic variant, so candidate genes are discussed separately (see **Table 1**). It is of interest to determine if any aligns with the greater sensitivity of individuals of African descent [13, 14, 36].

#### **4.1 Genes in linkage disequilibrium with TNF or encoding components of pathways regulated by TNF**

 In patients receiving stavudine, haplotypic combinations of alleles of singlenucleotide polymorphisms (SNP) spanning the tumor necrosis factor (TNF) block in the central major histocompatibility complex (MHC) associate with variations in the prevalence of HIV-SN, but the associations were different in Africans and Asians [12]. For example, a polymorphism in intron 10 of BAT1 (marking an MHC haplotype associated with several inflammatory disorders) and a polymorphism in the promoter region of the *TNFA* gene (TNF-1031) were associated with an increased risk of HIV-SN in Caucasians [37]. TNF-1031\*2 is associated with an increased risk of HIV-SN in Indonesian HIV-positive patients who receive stavudine [15, 16]. However, in Africans, different SNP alleles were found in linkage disequilibrium with TNF-1031\*2, so TNF-1031\*2 was not associated with HIV-SN. These findings link HIV-SN with an unknown SNP in the TNF block marked by (but distinct from) TNF-1031. The link between HIV-SN and inflammation was supported by studies linking *IL4* genotypes with HIV-SN in Africans receiving stavudine [13].

#### **4.2 The** *P2X7R***,** *P2X4R***, and** *CAMKK2* **gene cluster: Inflammation and neuronal repair**

 Goullee et al. linked SNP in three genes *P2X7R*, *P2X4R*, and *CAMKK2* with HIV-SN in African patients treated with stavudine. In a logistic regression model which included demographic analyses, SNP in *CAMKK2*, and to a lesser extent *P2X7R* and *P2X4R*, demonstrated independent associations with HIV-SN (p < 0.0001; R2 = 0.19) [14].

The P2X7R receptor is expressed by microglia and may be involved in neuropathic pain, as its ablation or inhibition in animal models of neuropathy can reduce responses to painful stimuli [38]. Conversely, stimulation of P2X7R will increase the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα [39] as well as pro-inflammatory chemokines such as CXCL2 and CCL3, which have been implicated in neuropathic pain [40, 41].

 In animal studies, P2X4R was activated in spinal microglial cells in rats with induced pain [42]. Mice with disrupted *P2X4R* genes showed reduced pain response in two models of chronic pain (inflammatory and neuropathic) [43]. P2X4R is upregulated after peripheral nerve injury which results in increased activity of

#### *HIV-Associated Sensory Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.81176*

 mitogen p38 [44]. This process initiates the release of brain-derived neurotropic factor (BDNF). BDNF induces neuronal hyperexcitability through interaction with the TrkB receptor [45, 46].

The *CAMKK2* gene encodes calcium-/calmodulin-dependent protein kinase 2 (CaMKK2), which acts as a pervasive second messenger of Ca2+ in many cellular functions such as energy balance, neuronal differentiation, and inflammation [47]. CaMKK2 plays a role in neural plasticity and neurite growth by activating another protein kinase CaMKI [48]. *CAMKK2* and *P2X4R* polymorphisms affect TNFα production in vitro. This suggests a mechanism for their impact on HIV-SN [49]. Hence, polymorphisms in *CAMKK*2 may affect inflammation or neuronal growth.

#### **4.3 Mitochondrial haplotypes and iron metabolism**

The process of mitochondrial toxicity induced by ART is not a simple drug toxicity, but mitochondrial DNA (mtDNA) SNP has a role in developing HIV-SN in patients receiving NRTI. SNP in African mtDNA haplogroup L1c and European haplogroup J is associated with decreased prevalence of HIV-SN compared with all other haplogroups [36]. Moreover, Thai persons belonging to mtDNA haplogroup B were more likely to develop HIV-SN [50].

 HIV-1 *Nef* protein may influence iron levels via interactions with the hemochromatosis protein HFE in humans [51]. In an observational prospective study, Kallianpur et al. suggested that disruption of iron homeostasis due to HIV infection might damage neurons and potentially lead to HIV-SN. They presented evidence that the *HFE* C282Y mutation may be a protective factor in HIV patients using NRTI [52]. They subsequently linked polymorphisms in iron management genes with increased risk (*TF, CP, ACO1, BMP6, B2M*) and reduced risk (*TF, TFRC, BMP6, ACO1, SLC11A2, FXN*) of HIV-SN [53].

#### **5. The pathophysiology of HIV-SN**

 The pathophysiology of HIV-SN is not completely understood, but there are several promising theories. It remains unclear whether HIV inflicts direct damage in the nerve body of dorsal root ganglia (DRG) or damages nerve fibers; both will lead to the development of distal axonopathies. HIV causes distal axon degeneration, reduction of nerve fiber in DRG, infiltration of inflammation cells, and reduction of the intraepidermal nerve fiber (IENFD) count [2]. As HIV itself cannot directly infect nerve bodies, destruction of neuron in HIV-SN may be caused by neurotoxic agents released by activated macrophage and satellite glial cells (TNF-α, IL-1β, chemokines), viral proteins with neurotoxic properties (gp41, gp120, Tat, Vpr), infection of perineural cells, or combinations of these processes [54–58]. A study in simian immunodeficiency virus macaque model confirmed that HIV infection activates perineuronal inflammatory cells (including macrophages and lymphocytes) in trigeminal ganglia and DRG during the early stage of infection. In the later stage, neuronal damage becomes evident, and regenerative capacity of small epidermal nerve is impaired [59].

HIV infection may cause macrophages to respond to the axonal degeneration (even in mild cases) causing inflammation of the nerves and DRG. Proinflammatory mediators were released by Schwann cells at DRG and may accumulate adjacent to peripheral nerves, activate apoptotic pathways and cause damage to the nerves directly or indirectly (reviewed in [55]). The gp120 virus protein may act directly on chemokine receptors expressed on neurons and cause pain [60]. A histopathology study of skin biopsies from HIV-SN patients on ART without stavudine confirmed the presence of inflammatory macrophages and T cells expressing some chemokine receptors (CX3CR1, CCR2, CCR5), along with reduced IENFD [61].

HIV protein gp120 is a component of the viral glycoprotein sheath. The entry of the HIV virus into cells requires the interaction of gp120 with CD4 glycoprotein and a chemokine receptor (usually CXCR4 and/or CCR5) which may be expressed on neurons or infiltrating inflammatory cells. Several chemokine receptors, such as CCR2, CCR5, and CXCR4, and CX3CR1 (fractalkine receptor) are located in primary afferent neurons or secondary neurons of the spinal dorsal horn. Chemokines and gp120 can cause pain through direct effects on chemokine receptors expressed by nociceptive neurons [62]. For example, binding of gp120 to CXCR4 receptors increases the release of CCL5, which binds CCR5 and triggers the release of TNFα and other neurotoxic substances. These interactions activate an influx of Ca2+, kinase cascades, and STAT3 signaling leading to the signs and symptoms of HIV-SN. The pathways have been reviewed previously [61, 63].

The pathophysiology of HIV-SN in patients on stavudine may reflect damage to the mitochondria of neurons and axons via damage to mitochondrial DNA (mtDNA) [64]. Inhibition of mtDNA gamma polymerase, mtDNA intercalation, and damage in stress response of mitochondria has been demonstrated in vitro in cultures of T-lymphoblastoid cells [65]. This finding is further supported by differences in haplotypes or SNP in mtDNA in Europeans, Hispanics, and Africans that may contribute to differences in the prevalence of HIV-SN [36, 52, 66, 67].

#### **6. Therapeutic options**

Management of HIV-SN aims to avoid further nerve damage and minimize the patients' symptoms especially neuropathic pain. Some studies showed that smoked cannabis is effective and has analgesic value to relieve pain in HIV-SN patients [68, 69]. However, due to legal issues in many countries, the recommendation of smoked cannabis has been controversial. Other pharmacological treatments recommended for neuropathic pain are amitriptyline, pregabalin, and gabapentin [70]. However, these medications were not superior to the placebo in HIV-SN patients [71–73]. Another option is non-pharmacological treatment such as acupuncture and hypnosis. However, acupuncture was not superior to the placebo to improve pain in HIV patients [74]. A small study showed that hypnosis showed benefit to reduce the pain score in HIV-SN patients [75].

#### **7. Conclusions and future directions**

Despite the withdrawal of the most toxic drugs from recommended ART regimens, HIV-SN remains a common neurological complication of HIV disease. The risk factors of HIV-SN have changed with changes in ART from the patient's age and height to the efficacy of ART and the use of protease inhibitors. Genetic polymorphisms that influence pathogenesis of HIV-SN will provide candidate molecules, which may contribute to pathogenesis, but studies of skin biopsies from patients are needed to confirm the roles of the encoded proteins. Animal models may reveal mechanisms for neuropathy and pain by HIV proteins but do not mimic the complexities of HIV disease in patients.

*HIV-Associated Sensory Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.81176* 

### **Author details**

Fitri Octaviana1,2\*, Ahmad Yanuar Safri1,2, Darma Imran1,2 and Patricia Price1,3,4

1 Neurology Department, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

2 Neurology Department, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

3 School of Biomedical Sciences, Curtin University, Bentley, Australia

4 School of Physiology, University of Witwatersrand, Johannesburg, South Africa

\*Address all correspondence to: fitri.octaviana@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## Peripheral Neuropathy in Connective Tissue Diseases

*Mouna Snoussi, Faten Frikha and Zouhir Bahloul* 

#### **Abstract**

 Connective tissue diseases are characterized by different organ disorders due to loss of immune system tolerance to autoantigens. Peripheral neuropathy is one of the features of these diseases with variable frequency; it is more prevalent in Sjögren syndrome. Peripheral neuropathy is often seen in the course of the disease. Nonetheless, it may be also a presenting sign or the unique feature of immune system dysfunction. Neuropathies in connective tissue diseases are related mainly to vasculitic disorder. It requires prompt diagnosis and treatment to improve its outcome. Peripheral neuropathy in connective tissue diseases could be multifocal and asymmetric, or confluent and symmetrical. This chapter reviews the clinical, diagnostic and therapeutic features of neuropathies associated with the common diffuse connective tissue diseases.

**Keywords:** peripheral neuropathy, vasculitis, connective tissue disease, treatment, electromyography, nerve biopsy

#### **1. Introduction**

 Connective tissue diseases (CTDs) are defined as a group of acquired diseases resulting from persistent immune-mediated inflammation. They are generally the consequence of autoimmune dysregulation resulting in generation of autoreactive T cells or autoantibodies [1]. Immune disorders can affect any organ of the human body responsible for multisystem involvement. The CTDs classily include systemic lupus erythematosus (SLE), Sjögren syndrome (SS), systemic sclerosis (SSc), dermatomyositis and polymyositis (PM/DM), undifferentiated CTD (UTCD) and overlap syndromes such as mixed CTD (MCTD). Most clinicians do not include systemic necrotizing vasculitis, e.g. polyarteritis nodosa, Churg-Strauss syndrome and Wegener's granulomatosis in the category of CTD [1]. Peripheral neuropathies (PN) may complicate many different systemic autoimmune diseases. PN in CTD large clinical, histopathological and pathogenic spectrum [2]. We aim in this chapter to precise the epidemiology, the pathogenesis, the diagnosis and the treatment of neuropathies in CTD including systemic lupus erythematosus (SLE), Sjögren syndrome (SS), dermatomyositis and polymyositis (PM/DM), systemic sclerosis (SSc) and mixed CTD (MCTD).

#### **2. Epidemiology of peripheral neuropathy associated with connective tissue diseases and its topographic distribution**

PN is one of the clinical features of CTD with variable frequency and prognosis. It is often seen in the course of the disease. However, it may also be a presenting


#### **Table 1.**

*Types of neuropathies associated with CTD (adapted from neuropathies in connective tissue disease/Richard K) [12].* 

sign or the unique feature of immune system dysfunction [3]. The prevalence of PN is different in the literature series depending on the type of CTD and the means of diagnosis. The incidence of PN in SS is 10–60%, and many of these patients (40–93%) present with neuropathy as the sentinel symptom [4]. PN in SLE patients ranges from 25 to 50% based on electrodiagnostic studies. Curiously, the incidence drops to only 5% based on clinical criteria [5, 6]. Finally, PN is rarely associated with the other CTD, namely, SSc, MCTD, DM and PM [4].

PN refers to the part of a spinal nerve distal to the root and plexus. It is a damage or a disease affecting nerves [7–9]. Neuropathy affecting one nerve is called "mononeuropathy" and neuropathy affecting multiple nerves in the same areas on both sides of the body is named "symmetrical polyneuropathy". When separate nerves in disparate areas of the body are affected, the neuropathy is called mononeuritis multiplex, multifocal mononeuropathy or multiple mononeuropathy [8, 10, 11]. Types of neuropathies that are associated with CTD are outlined in **Table 1**.

#### **3. Pathogenesis of peripheral neuropathy in connective tissue diseases**

The principal components in the pathogenesis of peripheral nerve lesions in diffuse CTD are ischemia due to vasculitis and immune abnormalities. Generally, most of patients have a combination of the ischemic, immunological and metabolic mechanisms of damage to the peripheral nervous system. Nevertheless, one component may be predominant in a different stage of the disease. In systemic scleroderma, the greater role is played by ischemic mechanisms, mainly in the initial states of the disease, while SLE may involve the participation of immunological mechanisms, especially in acute and subacute disease with high level of autoimmune activity [13].

#### **3.1 Vasculitic neuropathy**

The immunopathogenesis of vasculitis in CTD is still unclear. The accumulation of immune complexes in the vasa nervorum initiates the leukocytoclastic reaction, which is characterized by segmental fibrinoid necrosis and transmural inflammatory cell infiltration. Vasculitis induces the occlusion of vasa nervorum at the

*Peripheral Neuropathy in Connective Tissue Diseases DOI: http://dx.doi.org/10.5772/intechopen.82271* 

epineurial arteries and produces nerve infarction. Nerve infarcts typically lead to axonal degeneration [14]. Demyelination and conduction block may occur transiently but are usually not a predominant or persistent finding [15]. The clinical and electrophysiological features of neuropathies correlate with the rapidity of onset of ischemia. Acute ischemia induces the development of mononeuropathy, while prolonged circulatory insufficiency is associated with chronic polyneuropathy. The compression-ischemic mechanism leads to the formation of tunnel syndromes [13, 14, 16, 17]. The Peripheral Nerve Society task force has recently proposed a classification that categorizes vasculitic neuropathy into primary systemic vasculitides, secondary systemic vasculitides including CTD and nonsystemic or localized vasculitis on the basis of disease associations [18].

#### **3.2 Autoimmune disorders**

Patients with diffuse CTD may have IgG and IgM anticardiolipin antibodies in their serum, which are associated with severe signs of neural lesions, as demonstrated by electromyogram [13]. Moreover, serum levels of anti-nerve growth factor (NGF) antibodies are greater than normal in 32.1% of patients with diffuse CTD. Increased serum levels of anti-NGF are associated with high disease activity and more severe nervous system involvement [13].

#### **3.3 Metabolic disorder**

Peripheral nervous system abnormalities in CTD are also explained by metabolic disorder secondary to aggressive therapy, multiorgan pathology and endocrine abnormalities in these patients. Metabolic disorder may induce a reaction of demyelization and axon dystrophy in severe cases [13].

#### **4. Clinical practice guidelines of peripheral neuropathy in CTD**

In CTD neuropathic symptoms often start gradually and then get worse. Deep proximal aching pain is the first sign in the affected limb. Burning pain in the cutaneous distribution of the affected nerve is frequent. Weakness and numbness usually appear over several hours to several days after the pain. The delay of the former symptoms is explained by the nerve infarction. On physical examination, most patients have pain and temperature sensory loss in the distribution of the affected nerve. A few patients have impairment of vibration and position sense. Hyporeflexia is also rare except in the ankles. In fact, tendon reflexes other than at the ankle are lost only if the femoral, musculocutaneous, or radial nerves are affected proximally [12, 18, 19]. The quantitative sensory testing (QST) is a tool to analyse the perception in response to external stimuli of controlled intensity. It has been used for the early diagnosis and follow-up of small fibre neuropathies. Although the QST is time-consuming and it is modified also in non-neuropathic pain as in rheumatoid arthritis and inflammatory myalgia, it cannot be taken alone as a conclusive demonstration of PN [20]. The QST is helpful to quantify the effects of treatments on allodynia and hyperalgesia and may reveal a differential efficacy of treatments on different pain components (grade A) [20]. According to EFNS international guidelines, to evaluate hyperalgesia in PN, it is recommended to use simple tools such as a brush and at least one high-intensity weighted pinprick or von Frey filament. The evaluation of pain in response to thermal stimuli

is best performed by using the thermotest which is recommended for pathophysiological research or treatment trials. The DN4 may be a useful instrument for the daily diagnostic of PN in CTD [21].

#### **5. Diagnosis and clinical results**

In patient with multiorgan involvement and mononeuropathy multiplex, the diagnosis of vasculitic neuropathy is usually easy. However, the diagnosis may be more difficult in less typical presentations of CTD or when peripheral neuropathy is the unique manifestation of the disease. The diagnosis of peripheral neuropathy in CTD particularly in atypical situation is based first on clinical and physical examinations. Electromyography confirms even an underlying axonal neuropathy. The most characteristic electromyographic finding in vasculitic neuropathy described in the previous series is axonal degeneration with multifocal distribution. The typical feature is a low sensory nerve and compound muscle action potential amplitudes in a non-length-dependent distribution with normal or minimally reduced conduction velocities [15, 17, 22, 23]. A partial conduction block is rare, and it is seen transiently and early in stage of nerve ischemia [12]. Laboratory tests may be helpful in establishing the presence of systemic vasculitis or identifying previously undiagnosed connective tissue disease. Evaluation of patients with suspected neuropathy in CTD should include liver and kidney function tests, erythrocyte sedimentation rate, urinalysis as well as a complete blood count. The choice of immunological test including rheumatoid factor, antinuclear antibody, cryoglobulins, antineutrophil cytoplasmic autoantibody and serum complement depends on the clinical presentation of the patient. Nerve biopsy may be helpful in demonstrating vasculitic process. A concomitant muscle specimen is useful to increase diagnostic yield because of the patchy distribution of vasculitic lesions [18].

#### **6. Particularity of PN in each CTD**

#### **6.1 Peripheral neuropathy in Sjögren syndrome**

Sjögren syndrome is a CTD more prevalent in women at the age of menopause. It is characterized by sicca syndrome and other extra-glandular symptoms. Peripheral nervous involvement in Sjögren syndrome (SS) is reported with variable frequency because of diverse methods for detection of neuropathy and may precede the onset of the disease or be the initial diagnostic clue [24]. The most common feature is symmetrical distal sensory neuropathy, autonomic neuropathy and trigeminal sensory neuropathy. Mononeuritis multiplex, chronic inflammatory demyelinating neuropathy and motor neuropathy are less common [8].

#### *6.1.1 Ganglionopathies*

 Sensory ganglionopathy is characterized by an impairment of kinesthetic awareness. Patients have the profound handicap of proprioceptive sense affecting larger joints. Electromyogram shows unelicitable sensory nerve action potentials, with preservation of compound motor action potentials [25]. When MRI is performed, it can reveal T2 hyperintensities limited to the gracile and cuneatus tracts of the dorsal spinal cord with sensory neuronopathies [26]. There are two mechanisms evoked in the pathogenesis of gangliopathies in SS. First, the cellular autoimmunity, confirmed by the infiltration of mononuclear and predominantly T cells in

#### *Peripheral Neuropathy in Connective Tissue Diseases DOI: http://dx.doi.org/10.5772/intechopen.82271*

the dorsal root ganglia, is associated with cellular degeneration in the absence of vasculitis [25, 27, 28]. Second, recent studies have suggested that the presence of antibodies against the G-bodies, which are a subcellular aggregation of noncoding RNA intermediates and proteins, is associated to neuropathy [29, 30]. Moreover, It was reported that antineuronal antibodies were seen more frequently in Sjögren patients with severe peripheral neuropathy (PN) complications [25].

#### *6.1.2 Small fibre neuropathies*

 Small fibre neuropathy is the most common PN manifestation of SS. It is a painful, sensory neuropathy affecting the nociceptive A-alpha and unmyelinated C-fibres. Small fibre neuropathy is reported with variable frequency. In the Hopkins Green Sjögren cohort, it was described as the most frequent manifestation [31]. The onset of small fibre neuropathy is usually subacute to chronic, occurring over weeks to months, although cases with hyperacute evolution of hours to days have been reported [27]. The cardinal clinical symptom of isolated small fibre neuropathy is an excruciating burning pain. The physical examination reveals a selective impairment in small-fibre modalities of pinprick and temperature, with relatively preserved vibratory sense and proprioception. The diagnosis of small fibre neuropathy is based on skin biopsy, which assesses the low density of intraepidermal nerve fibres [25, 32].

#### *6.1.3 Sensorimotor polyneuropathies*

The majority of studies reported that axonal polyneuropathies as the most frequent type of PN in SS. The onset of sensorimotor polyneuropathy is usually subacute or chronic. The axonal sensory neuropathies are characterized by proprioceptive sensory loss and motor reflexes, and there are diminished sensory nerve action potentials in electromyogram [25]. The sensory symptoms, however, are gradually accompanied by muscle weakness in a distal, symmetrical distribution [32].

#### *6.1.4 Multiple mononeuropathy*

 It is the transduction of vasculitic neuropathy, and it is very uncommon in SS reported in 0–5% in previous studies. It is usually associated with extra-glandular manifestations [25, 27, 33–35]. Patients with SS and presenting mononeuritis multiplex should be assessed for cryoglobulinemia polyclonal (types II and III) rather than monoclonal (type I) mainly when there is high-titer rheumatoid factor positivity or when there is disproportionate C4 hypocomplementemia, with normal levels of C3. When nerve biopsy is performed, it may show a lymphocytic or necrotizing vasculitis [32].

#### *6.1.5 Cranial neuropathies*

 The most common cranial neuropathy in SS is the trigeminal neuropathy, which is usually progressive and can be bilateral and requires symptomatic treatment. Motor dysfunction of cranial nerves is less common, and the facial nerve is the most cranial nerve targeted. The acute onset of cranial neuropathy is due to vasculitic mechanism especially when associated with equally rapid development of multiple mononeuropathies in the extremities [25].

#### *6.1.6 Demyelinating neuropathies*

Demyelinating neuropathy is a rare manifestation of SS [32, 33]. Cases of chronic idiopathic demyelinating polyneuropathy have been the subject of case reports in Sjögren patients but have not been substantially described in larger case series. The most common neurophysiologic finding in demyelinating neuropathies was demyelination of the motor nerves [36–38]. The onset of this neuropathy is subacute and characterized by severe proximal and distal weakness and proprioceptive sensory deficit. Treatment with steroid and sometimes with intravenous immune globulins may be effective [32, 39].

#### *6.1.7 Autonomic neuropathy*

Autonomic neuropathy is the rarest type of peripheral nerve involvement in SS because it is usually underdiagnosed. The clinical manifestations of autonomic neuropathy will vary depending on the organs which are affected. Symptoms range from urinary symptoms to severe disabling postural hypotension [27, 32, 38]. In recent studies, autonomic dysfunction is associated with the severity of fatigue in patients with primary SS. However, no association was detected between autonomic dysfunction and exocrine function in these patients [32, 40].

#### **6.2 Peripheral neuropathy in systemic erythematosus lupus**

 Systemic lupus erythematosus is a multisystem autoimmune disorder with a broad spectrum of clinical presentations as cutaneous, renal and articular manifestations (**Figure 1**). Affected patients typically have subacute or chronic distal symmetrical polyneuropathies with predominant sensory symptoms. Distal symmetrical axonal degeneration is the major feature of most cases, although other types of peripheral neuropathy have been described [12, 41]. Oomatia reported the subtypes of peripheral neuropathy (PN) attributable to SLE in a group of 82 patients out of 2097 and detailed in **Table 2** [42]. Other features such as Guillain-Barré syndrome, plexopathy and autonomic neuropathy are very low in all series

**Figure 1.**  *Butterfly rash in systemic lupus erythematosus.* 

*Peripheral Neuropathy in Connective Tissue Diseases DOI: http://dx.doi.org/10.5772/intechopen.82271* 


#### **Table 2.**

*Type of peripheral neuropathy in SLE (adapted from peripheral neuropathies in systemic lupus erythematous/ Oomatia et al.) [42].* 

[41]. In recent data, small fibre neuropathy is more frequent in SLE, and the decreased intraepidermal nerve fibre density of unmyelinated fibres is a diagnostic test [42]. The mechanisms of peripheral neuropathy in SLE are unclear. Several factors have been reported particularly small-vessel vasculitis and lesions induced by autoimmune antibodies and immune complexes. In series, where nerve biopsy is performed, the anatomopathologic aspect was perivascular mononuclear cell infiltration and variable intimal thickening without necrotizing vasculitis. The presence of necrotizing vasculitis is possible and constitutes a prognostic factor of the disease [12, 41, 43]. Endoneurial mononuclear cell infiltration and increased class II antigen expression were also noticed [12, 43].

#### **6.3 Peripheral neuropathy in systemic sclerosis**

Systemic sclerosis is a rare connective tissue disease with a prevalence of 1 in 10,000 [44]. It is characterized by symmetrical, widespread thickening of the skin (**Figure 2**) [45]. The prevalence of peripheral neuropathy is unknown with reported ranges in retrospective studies varying from 0.01 to 14% of patients [46, 47]. Vascular-dependent neuropathy is the principal mechanism inducing a distal symmetric, mainly sensory polyneuropathy as in other connective tissue diseases [13, 46, 47]. Cranial mononeuropathies can also occur, mainly the trigeminal nerve, leading to numbness and dysesthesias in the face. Rarely the seventh and ninth cranial neuropathies are affected [11]. The electrophysiological features are those of sensory axonopathy [11]. Rare cases of mononeuritis multiplex have been mentioned in the course of limited SSc (CREST: calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) and are due to a necrotizing vasculitis [11].

#### **6.4 Peripheral neuropathy in mixed connective tissue disease**

Mixed connective tissue disease is defined as the overlap of SLE, SSc and PM, with a high titer of extractable nuclear antigen and its ribonucleoprotein component [48]. Mild distal axonal polyneuropathy was exceptionally reported in 2 of 20 patients with mixed connective tissue disease, but there has not been a detailed study of the neuropathy or its treatment [48].

**Figure 2.**  *Sclerosis of the face in systemic sclerosis.* 

#### **6.5 Peripheral neuropathy in dermatomyositis and polymyositis**

Nerve involvement in patients with DM is mediated through membrane attack complex (MAC) formation, leading to nerve injury. This entity called "neuromyositis" was first reported in 1890 [49]. Further studies showed a frequency of 7.5% in DM or PM patients with polyneuropathy [50]. Neuropathy due to DM is difficult to diagnose due to necessity of excluding other comorbid etiologic conditions and heterogeneity of muscular manifestations [49]. Nerve biopsy may reveal endothelial vascular injury, and immunohistochemical stains revealed increased expression of perivascular VEGF and demyelinization associated or not with inflammation [51].

#### **7. Treatment of peripheral neuropathy in CTD**

#### **7.1 General approach**

 There are no treatment guidelines specific to each CTD. In general, the management of PN is based on symptomatic treatment of pain as in other causes of neuropathies. Typically, patients with painful polyneuropathies respond to drugs known to be effective for neuropathic pain, including tricyclic antidepressants and a variety of antiepileptic drugs as gabapentin and pregabalin, which is preferred because of its better bioavailability [52]. Concerning the antidepressants, international guidelines provide the same level of recommendation for nonselective tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs). Most clinical trials showed that the efficacy of SNRIs is lower than that of tricyclic antidepressants. However, tricyclic antidepressants have more side effects in elderly and are contraindicated in patients with glaucoma, prostate hypertrophy or some cardiac conduction disturbances. Venlafaxine is a SNRI who has shown efficacy in painful polyneuropathies of different origins [53]. In CTD, PN is mainly due to vasculitic

*Peripheral Neuropathy in Connective Tissue Diseases DOI: http://dx.doi.org/10.5772/intechopen.82271* 

 and immune abnormalities. So when vasculitic neuropathy is diagnosed, corticosteroids should be promptly introduced to recover sensory and motor deficits [3]. Most authors recommend starting oral prednisone at high dose of 1 mg/kg per day. In severe cases, intravenous pulses of methylprednisolone of one 1 g for 3–5 days might be appropriate for initial treatment. This treatment should be maintained during the subacute phase, and after 6 to 8 weeks, the treatment should be tapered progressively. Immunosuppressant therapy is associated to corticosteroids in severe forms of vasculitic neuropathy or in systemic vasculitic PN. Cyclophosphamide seems to be the most effective drug for induction of remission and improvement of survival in non-viral systemic vasculitides [18]. Most patients need 3–12 months of cyclophosphamide induction therapy before they can be switched to a maintenance immunosuppressant [54]. Immunosuppressant used as a maintenance therapy is azathioprine, methotrexate and mycophenolate mofetil [55]. Intravenous immunoglobulin is a safe treatment used in serious systemic PN with clinical benefit [18].

#### **7.2 Particularities of treatment in each CTD**


Therapeutic strategies of small fibre neuropathy in SS are still unclear. Carbamazepine is generally the first-line agent for trigeminal neuralgia. The use

*PNS: peripheral nervous system; SNRI: serotonin-norepinephrine reuptake inhibitors; IVIG: intravenous immunoglobulins; PEX: plasma exchange; GBS: Guillain Barré Syndrom.* 

#### **Table 3.**

*Treatment options available for peripheral nervous system involvement in patients with SLE (adapted from PNS involvement in SLE/A. Bortoluzzi et al.) [60].* 

 of other antiepileptic agents such as gabapentin should be prescribed with slow titration to minimize its side effects particularly over somnolence and fatigue. The duration of therapeutic trial should be at least 3 months. The secondary amine tricyclic antidepressants such as nortriptyline and desipramine have fewer anticholinergic side effects and a proven efficacy in neuropathic pain, and so they may be slowly prescribed in patients with SS. The use of new immunosuppressant agents mainly monoclonal antibody directed against CD20 antigen on B cells as rituximab and the tumour necrosis factor (TNF)-alpha inhibitors such as adalimumab has been reported to be efficient in the small fibre neuropathies occurring in SS [25]. The management of axonal polyneuropathy is based on a symptomatic treatment; corticosteroids and immunosuppressors are discussed in the case of motor neuropathy with rapid progression [25]. In the case of multiple mononeuropathy, the presence of vasculitis is associated with a good response to immunosuppressive therapy [34]. There is evidence supporting the use of immunoglobulin therapy in Sjögren-associated sensorimotor and nonataxic sensory neuropathy from retrospective and observational cohorts and case reports [56, 57].

 In SLE, there are no clear guidelines on the treatment of peripheral neuropathy. Induction treatments with glucocorticoids with or without immunosuppressant agents are indicated in the situation of active vasculitic neuropathy [58]. In the case of necrotizing vasculitis, treatment with plasmapheresis, steroids and immunosuppressant has led to improvement [59, 60]. The definitions of response to treatment are variable between studies. Overall, the rate of global response (complete or partial) is more than 50% [41] (**Table 3**).

In SSc, there is not enough data regarding the response of scleroderma-associated neuropathy to immunosuppression [11, 61]. However, this therapy seems to be effective in mononeuritis multiplex and sensorimotor polyneuropathy with inflammatory process [11]. In DM/PM the treatment of PN is based on corticosteroids and immunosuppressant agents depending on the severity of the clinic presentation [51].

PNS, peripheral nervous system; SNRI, serotonin-norepinephrine reuptake inhibitors; IVIG, intravenous immunoglobulins; PEX, plasma exchange; GBS, Guillain-Barré syndrome.

#### **8. Conclusion**

#### **8.1 Final considerations**

PN is one of the possible neurologic manifestations encountered by physicians in CTD. Coexistence of both conditions is explained by immune-mediated factors particularly a vasculitis of peripheral nerve. Therefore, it is important to take a detailed medical history and examination and then adequate investigations to assess for an underlying systemic autoimmune diseases that may be associated with the neuropathy. Pure sensory and sensorimotor neuropathies are the most common PN features in these disorders. Acute to subacutely evolving multifocal or asymmetric neuropathy suggests a vasculitic cause. This situation constitutes a prognostic factor of the disease and requires prompt treatment with steroids and immunosuppressant agents. The treatment of PN in CTD progresses in three fronts: first, to identify the type of PN through the medical history and physical exam; second, to precise the pathogenic mechanism of neuropathy via clinical presentation, electromyographic data and in unclear situation the nerve biopsy and finally, the efficient control of pain. Corticosteroids remain the mainstay of treatment for vasculitic neuropathy in CTD.

#### **8.2 Futures directions**

Although much is known about the PN in CTD, particularly its pathogenesis and its clinical aspects, further experience needs to be gained especially in the treatment with prospective trials to identify indications and precise efficacy for cytotoxic agents, intravenous immunoglobulin, plasma exchange and new biological drugs. In future, we need also further studies to precise clear guidelines to diagnose PN related to CTD such as more specific features in the electromyogram and neuromuscular biopsy. Moreover, in the treatment approach of PN in CTD, we need further researches to identify curative drugs targeting the pathogenesis pathways rather than the symptomatic and the previous conventional therapy.

### **Conflict of interest**

There is no conflict of interest.

### **Author details**

Mouna Snoussi\*, Faten Frikha and Zouhir Bahloul Department of Internal Medicine, Medical School of Sfax, Tunisia

\*Address all correspondence to: mounasnoussi23@yahoo.fr

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**49**

**1. Inclusion**

**Chapter 4**

**Abstract**

*Gökhan Özdemir*

Working Hand Syndrome: A

Polyneuropathy Condition

work-ups of the upper extremity are enough to make a diagnosis.

Polyneuropathies (PNP) are disorders of the peripheral nervous system that indicates any disorder of the peripheral nervous system. Polyneuropathy is one of the most prevalent neurologic conditions. Polyneuropathy has an estimated prevalence of 5–8% in the general population. However, if there are one or more risk factors involved, this rate can increase to 12–17%. Various systemic diseases, exposure to toxicity, drugs, infections, and hereditary diseases are considered causes. Young patients are much more likely to have a polyneuropathy on a genetic basis, elderly patients are much more likely to have idiopathic polyneuropathy, and middle-age patients are more likely to have acquired polyneuropathy. It needs to be done that family history and other important details of the individual's history and examination. Family history should focus on illnesses associated with neuropathy, such as diabetes mellitus, hypothyroidism, renal failure, hepatic disorder,

**Keywords:** working hand syndrome (WHS)

New Definition of Nonclassified

The aim of this chapter was to define an unexplained nonclassified polyneuropathy condition as a new neurological disease. This new diagnosis of occupationrelated polyneuropathy has been named as "working hand syndrome (WHS)." This study collected and compared clinical and electrophysiological analyses data from healthy controls, WHS patients, carpal tunnel syndrome (CTS) patients, and polyneuropathy patients. The WHS patients presented to the clinic with pain, numbness, tingling, and burning sensations in their hands that increased significantly during rest and nighttime. However, there was no weakness in the muscles, and the deep tendon reflexes were normal in this disease. The patients had all been working in physically demanding jobs requiring the use of their hands/arms for at least 1 year, but no vibrating tools were used by the patients. All of the cases were men. I suppose that overload caused by an action repeated chronically by the hand/arm may impair the sensory nerves in mentioned hand/arm. In patients with these complaints, for a definitive diagnosis, similar diseases must be excluded. Nonetheless, the specific electrophysiological finding that the sural nerves are normal on the lower sides, as well as the occurrence of sensory axonal polyneuropathy in the sensory nerves without a significant effect on velocity and latency in the

#### **Chapter 4**

## Working Hand Syndrome: A New Definition of Nonclassified Polyneuropathy Condition

*Gökhan Özdemir*

#### **Abstract**

 The aim of this chapter was to define an unexplained nonclassified polyneuropathy condition as a new neurological disease. This new diagnosis of occupationrelated polyneuropathy has been named as "working hand syndrome (WHS)." This study collected and compared clinical and electrophysiological analyses data from healthy controls, WHS patients, carpal tunnel syndrome (CTS) patients, and polyneuropathy patients. The WHS patients presented to the clinic with pain, numbness, tingling, and burning sensations in their hands that increased significantly during rest and nighttime. However, there was no weakness in the muscles, and the deep tendon reflexes were normal in this disease. The patients had all been working in physically demanding jobs requiring the use of their hands/arms for at least 1 year, but no vibrating tools were used by the patients. All of the cases were men. I suppose that overload caused by an action repeated chronically by the hand/arm may impair the sensory nerves in mentioned hand/arm. In patients with these complaints, for a definitive diagnosis, similar diseases must be excluded. Nonetheless, the specific electrophysiological finding that the sural nerves are normal on the lower sides, as well as the occurrence of sensory axonal polyneuropathy in the sensory nerves without a significant effect on velocity and latency in the work-ups of the upper extremity are enough to make a diagnosis.

**Keywords:** working hand syndrome (WHS)

#### **1. Inclusion**

Polyneuropathies (PNP) are disorders of the peripheral nervous system that indicates any disorder of the peripheral nervous system. Polyneuropathy is one of the most prevalent neurologic conditions. Polyneuropathy has an estimated prevalence of 5–8% in the general population. However, if there are one or more risk factors involved, this rate can increase to 12–17%. Various systemic diseases, exposure to toxicity, drugs, infections, and hereditary diseases are considered causes. Young patients are much more likely to have a polyneuropathy on a genetic basis, elderly patients are much more likely to have idiopathic polyneuropathy, and middle-age patients are more likely to have acquired polyneuropathy. It needs to be done that family history and other important details of the individual's history and examination. Family history should focus on illnesses associated with neuropathy, such as diabetes mellitus, hypothyroidism, renal failure, hepatic disorder,

human immunodeficiency virus infection, and dysproteinemic disorders (10% of peripheral neuropathies are associated with dysproteinemias) and in those receiving chemotherapy and cancer. In the developed world, the most common cause of peripheral neuropathy is diabetes mellitus. Patients with cancer may develop neuropathy depending to nutritional deficiency and chemotherapy side effects. But the etiology of 20–25% of these neuropathies remains uncertain [1–3].

 The clinical manifestations of peripheral neuropathy vary widely that weakness, fatigue, hypesthesia, ataxia, autonomic symptoms, and positive symptoms include cramps, twitching, and myokymia. Sensorimotor peripheral neuropathies are the most common form of neuropathy. Usually, there is a progression from distal to proximal. Diminished deep tendon reflexes, distal muscle weakness, and atrophy are common in advanced cases. Most neuropathies are chronic and progressive. Peripheral neuropathy may be symmetrically generalized, multifocal, or focal. Most neuropathies are symmetric and length-dependent. Chronic symmetrical polyneuropathy is the most common type of polyneuropathy and usually evolves over months. Sensory or motor symptoms in a more diffuse, involving both proximal and distal limbs in lengthindependent pattern. In these cases reflexes are globally reduced or absent. The earliest symptoms of polyneuropathy are usually sensory abnormalities. Sensory symptoms start in the feet, which are supplied by the longest axons. Pathologic mechanisms in peripheral neuropathy are distal axonopathy, myelinopathy, and neuronopathy. The symptoms ascend insidiously up the leg. The upper limb involvement may never occur. Development of symptoms in the hands and feet at the same time is atypical for a length-dependent neuropathy and may indicate coexisting disorder [2, 3].

One of the most common causes of neuropathic pain in the hands is physical compression of the nerves, known as compression neuropathy. Carpal tunnel syndrome (CTS) and cubital tunnel syndrome are examples. Direct injury to a nerve, interruption of its blood supply, or inflammation may also cause neuropathic pain.

Anamnesis, neurological checkup, and electrophysiological work-up are recommended for diagnosis [1–3].

#### **2. Working hand syndrome**

 Working hand syndrome patients have neuropathic pain in their hands, and axonal neuropathy is detected only in the sensorial neurons of the upper extremity. The common trait for these patients is the fact that they used their hands/arms during heavy labor. I think that a significant number of patients as this should not to be underestimated in the general population. Common traits among the patients include man sex, use of the arms and hands in heavy labor, neuropathic pain in their

#### *Working Hand Syndrome: A New Definition of Nonclassified Polyneuropathy Condition DOI: http://dx.doi.org/10.5772/intechopen.81966*

hands, and axonal polyneuropathy in the sensory median and ulnar nerves. The average age of the patients is 45.7 ± 20.4 years in working hand syndrome (WHS).

 None of the WHS cases have systemic disease, and all of the cases are men. The use of the upper extremity while working a physically demanding job (construction worker, farmer, forester, crushing, tire repairer) requiring the use of the hands/ arms for at least 1 year; presentation with pain, numbness, tingling and burning sensations (neuropathic) in the hands and fingers that increases significantly during rest and nighttime in the WHS [1].

#### **3. Etiopathogenesis**

 Pathology in the sensory nerves can cause neuropathic pain. Sensory polyneuropathy is one of the most common causes of neuropathic pain. It is believed that WHS is likely a sensory neuropathy with such a mechanism as axonal polyneuropathy, because the ulnar nerve is more affected than the median nerve in the upper extremities in polyneuropathies. I posit that an overload caused by an action repeated chronically by the hand/arm may impair the sensory nerves in the said hand/arm. Not only the peripheral nervous system but also the local vessels may be affected. This process may result in vasoconstriction of the local vessels. This situation leads to hypoxia and a lack of nutrition in the sensory nerves. However, there is not a clear relation between WHS and its pathology. However, in my opinion, genetics, ergonomics, emotional stress, and biodynamic status play an important role in WHS, because this disease does not occur in everyone who is doing the same job [1].

#### **4. Diagnosis**

 WHS is a polyneuropathy and occupational disease. Patients with WHS present with pain, numbness, tingling, and burning sensations in their hands that increases significantly during rest and nighttime. They also use their arms/hands for jobs that require heavy labor. The neurological examinations of patients with WHS are normal. Only the sensory nerves in the upper extremities are affected.



#### **Table 1.**

*Electrophysiological findings of working hand syndrome and similar diseases.* 


#### **Table 2.**

*Differential diagnosis of working hand syndrome.* 

For a definitive diagnosis:


*Working Hand Syndrome: A New Definition of Nonclassified Polyneuropathy Condition DOI: http://dx.doi.org/10.5772/intechopen.81966* 

4. Specific electrophysiological findings that the sural nerves are normal, as well as the occurrence of sensory axonal polyneuropathy in the sensory nerves without being greatly affected by speed and latency in the work-ups of the upper extremity, are enough to make a diagnosis [1].

#### **5. Nerve conduction studies**

 The electromyographer plays an important role in the evaluation of patients with polyneuropathy. The results of nerve conduction studies and electromyography are useful in analyzing the underlying pathophysiology. The recording and measurement of the terminal latency, amplitude, duration of the evoked potential, and the conduction velocity. Nerve conduction studies are also valuable in differentiating whether a demyelinating process is acquired or inherited. Nerve conduction studies can identify the predominant pathophysiology (axonal loss or segmental demyelination) and establish whether sensory or motor findings predominate. In addition, the studies provide quantitating the severity and the distribution of the neuropathy. Electrophysiological work-ups show axonal damage (axonal neuropathy), demyelination (demyelinating neuropathy), and both (mix neuropathy). In the electrophysiological work-ups that involve distal latency, the amplitude, shape, and velocity of the motor and sensory nerves are checked. Axonal degeneration causes a decrease in amplitude, while demyelinating polyneuropathy causes delays in distal latencies and decreases in velocity. Acute axonal damage in the motor nerves can cause spontaneous activities in muscle fibers when checked with electromyography, where dilution in voluntary activity and chronic neurogenic motor unit potentials (MUP) are seen [1, 4].

The electrophysiological work-ups in the WHS are completed with standardized supramaximal percutaneous stimulation techniques. In the upper sides, a sensorial check-up is completed of the median and ulnar nerves. The sural nerves are used for a lower extremity sensory evaluation. For the median motor nerve evaluation, a 6–7 cm proximal of the abductor pollicis brevis muscle is supramaximally stimulated; the ulnar motor nerve is recorded from the abductor minimi muscle; the median sensorial nerve is recorded from the second finger; and the ulnar sensorial nerve is recorded from the fifth finger. For the sural nerves, the active electrode was placed between the lateral malleolus and the heel, and the reference electrode was placed 30 mm distally at the lateral edge of the foot. Supramaximal stimuli are applied at 13 cm proximal to the active electrode, just lateral to the midline of the calf. Amplitudes below 16 uV for the sensorial nerves in the upper sides and amplitudes below 10 uV for the sensorial nerves in the lower sensory sides (sural nerves) are considered the limits of sensory axonal neuropathy to assess its sensitivity and specificity. The use of an infrared lamp ensured that the temperature of the extremities during measurement has been done at 34°C or higher. In the electrophysiological findings of the WHS according to the normal, the distal latency and velocity of the median and ulnar sensorial nerves are similar in both hands. However, both the median sensory and ulnar sensory nerve amplitudes are decreased (P < 0.05). The motor nerve conduction work-ups of the upper and lower sides are similar in all differential diagnosis. The sural nerve results are similar on the lower sides in the normal, CTS, and WHS. The sural nerve results are significantly affected in the polyneuropathy (P < 0.05).

#### **6. Clinical results**

The deep tendon reflex polyneuropathy patients have a significantly decreased reflex when compared with all differential diagnosis (P < 0.05, Duncan). Regarding the presence of atrophy when all cases are compared with the WHS, there is no significant difference. In terms of hand complaints, polyneuropathy has a higher complaint score (1.3 ± 1.33; P < 0.05) when compared with the healthy normal group. However, the WHS (3.00 ± 0.00) and CTS (3.00 ± 0.00) groups exhibit an increase in hand complaints when compared with both the healthy and polyneuropathy.

#### **7. Other comorbid diseases in the WHS**

In terms of diabetes mellitus, hypertension, cardiovascular diseases, hyperlipidemia, cigarette smoking, and the presence of atrophy, when all cases are compared with the WHS, there is no significant difference according to Fisher exact test.

#### **8. Differential diagnosis in the WHS**

The use of a vibrating tool by the patients and the presence of a nervous system disease, such as polyneuropathy, CTS, or hand-arm vibration syndrome (HAVS). The diagnosis of distal axonal sensory polyneuropathy is extracted from nerve conduction work-up reports based on the presence of bilateral, symmetric, and distal lower and upper extremity neuropathic pain. The motor nerves are unaffected, and there is no muscle weakness in this condition. Only the hands experience neuropathic pain in the WHS, while there is neuropathic pain in both the feet and hands in the polyneuropathy. Sensory nerve conduction work-ups of the median, ulnar, and sural nerves are widely used in the electrodiagnosis of sensory polyneuropathy. The long nerves are most commonly affected by polyneuropathy. Thus, the sural sensory nerve action potential (SNAP) amplitude is likely the most useful parameter for differentiating normal subjects from those with distal sensory polyneuropathy. Even the sural SNAP is most sensitive in the diagnosis of early distal sensory polyneuropathy. The sural nerve results are significantly affected in the polyneuropathy, while the WHS have normal sural nerve conduction work-ups.

Several diseases affect the nerves of the hand, the most common being CTS, which is caused by median nerves in the carpal tunnels becoming stuck. It is characterized by neuropathic complaints in the first four fingers and the palm of the hand. Its symptoms manifest usually during rest hours or nighttime, and the cases identified in the WHS are similar in that regard. This means the entirety of their hand and the fingers have neuropathic pain. Women are more commonly affected by CTS, and rheumatism, pregnancy, and diabetes are among the known risk factors for CTS. All of the WHS cases are men, and they have no known CTS risk factors. Characteristic electrophysiological findings of CTS include a progressively delayed sensory peak latency, and amplitude becomes smaller in the median nerve. In medium cases, similar findings appear in the motor nerves. In advanced cases, SNAP and compound muscle action potential (CMAP) values decrease, which means that in CTS, a delayed distal latency and decrease in velocity are pronounced in the median nerve. The ulnar nerve conduction work-ups in CTS are normal. In the WHS, according to the normal, distal latency and velocity are close to normal, but both the median sensory and ulnar sensory nerve amplitudes are decreased. Motor values are completely normal.

Guyon canal and cubital tunnel entrapment neuropathies can cause neuropathic pain, as well [8], but neuropathic pain is seen only in the ulnar nerve tract. In nerve conduction studies, distal latency and velocity are affected in the ulnar nerve. In all of the cases herein, neuropathic pain is identified in every region of the hand. Not only the ulnar nerve but also the median nerve is affected.

#### *Working Hand Syndrome: A New Definition of Nonclassified Polyneuropathy Condition DOI: http://dx.doi.org/10.5772/intechopen.81966*

 The mechanical energy created by vibrating tools, which enters the body through the fingers or palms, is called hand-arm vibration. These tools are generally used in the production, stone working, mining, construction, agriculture, and forestry sectors. HAVS is a clinical condition that occurs after exposure to hand-arm vibration. Symptoms of HAVS include numbness, pain, and reduced dexterity, strength, and sensation in the hands. In HAVS, the peripheral and central nervous systems are affected, which can lead to vascular, bone and joint, and tendon and muscle diseases. There is a direct correlation between the disease and the magnitude and duration of hand-arm vibration and cold temperatures. In the cases here in, no vibrating tools are used by the patients, but they engage in taxing labor using their hands (using such tools as a sledgehammer, hammer, saw, and carry stones). It is argued that the usage of beta-blockers and cigarettes and a decrease in blood circulation due to exposure to the cold lead to an increase in HAVS symptoms. According to the anamnesis of the patients in the WHS, their symptoms do not change in cold temperatures or after smoking. CTS is often observed in people with HAVS who engage in breaking stones, plating, and forestry. This means that HAVS itself can cause CTS. Electrophysiological studies aimed at defining the nature of a vibration injury have provided conflicting results. Usually, electrophysiological findings related to HAVS are similar to those related to CTS, and the effect on velocity is pronounced. These conditions can be seen together often.

 The ulnar nerve is rarely affected in HAVS, but both the ulnar and median nerves are affected in the WHS. Especially, the ulnar nerve is affected. In HAVS, slowed sensory nerve conduction velocities are often observed in the hands. In the WHS, especially, the amplitude is low without being greatly affected by speed and latency. In vibration-associated neuropathies, conceivable target structures could be peripheral sensory receptors, large or thin myelinated nerve fibers, and small-caliber, nonmyelinated C fibers. Pathological studies by cutaneous biopsy have demonstrated demyelinating neuropathy in the digital nerves of individuals with HAVS [5–8].

#### **9. Treatment options**

In treatment of polyneuropathy, the primary goal in the evaluation of neuropathy is to identify the etiology and if possible treat the underlying cause. Medical causes such as diabetes mellitus, renal insufficiency, hypothyroidism, vitamin B-12 deficiency, and Guillain-Barré syndrome need specific treatments. But, there is no specific treatment for many chronic neuropathies such as chronic idiopathic axonal polyneuropathy or the hereditary neuropathies. One of the most limiting symptoms is neuropathic pain. The neuropathic pain can be effectively treated with an algorithmic approach. In the WHS, there is no specific treatment yet. However, I gave 75 mg pregabalin.

#### **10. Conclusion and future directions**

The WHS is a new disorder. It is also an occupational disease. I think that a significant number of patients as this should not to be underestimated in the general population. We only considered it previously as a sensory polyneuropathy in upper limbs. For this reason, we need to examine it more in detail from the etiopathogenesis to its treatment. This disorder is suggested to serve as a resource for patients, healthcare professionals, and members of the neurology community at large.

*Demystifying Polyneuropathy - Recent Advances and New Directions* 

#### **Author details**

Gökhan Özdemir Department of Neurology, Selcuk University Medical Faculty, Konya, Turkey

\*Address all correspondence to: noro.ozdemir@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Working Hand Syndrome: A New Definition of Nonclassified Polyneuropathy Condition DOI: http://dx.doi.org/10.5772/intechopen.81966* 

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Section 3

Management and New

Clinical Applications

Section 3
