Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration

Part IOverview and Assessments of Small Fiber Neuropathy

© Springer Nature Singapore Pte Ltd. 2019

Sung-Tsang Hsieh, Praveen Anand, Christopher H. Gibbons and Claudia Sommer (eds.)Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegenerationhttps://doi.org/10.1007/978-981-13-3546-4_1

1. Overview of Small Fiber Neuropathy

Ming-Tsung Tseng¹  , Chun-Liang Pan² and Sung-Tsang Hsieh¹, ³, ⁴, ⁵, ⁶

(1)

Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan

(2)

Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

(3)

Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan

(4)

Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

(5)

Center of Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

(6)

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

Ming-Tsung Tseng

Email: [email protected]

Abstract

Small fiber neuropathy (SFN) results from impairment of small-diameter myelinated Aδ- and unmyelinated C-fibers. This debilitating condition usually leads to alterations in nociceptive processing, thermal sensations, and autonomic functions. The most common clinical feature of SFN is neuropathic pain, which is often described as burning, shooting, tingling, and even pruritic. Usually, symptoms have a length-dependent distribution, but they may also present in a non-length-dependent manner. The natural course of SFN is highly variable, and, in some cases, large fiber neuropathy may develop. Despite being regarded as a distinct nosologic entity, SFN is either idiopathic or associated with a heterogeneous group of diseases. The pathogenesis of the development and maintenance of SFN is not completely understood. Recently, gain-of-function mutations of the sodium channels have been found to enhance the excitability of dorsal root ganglion neurons, which may explain the presence of neuropathic pain symptoms in patients with SFN. However, the underlying mechanisms leading to the axonal degeneration of small-diameter sensory nerves remain unclear. On neurological examination, impaired small fiber sensations can be detected, including thermal or pinprick hypoesthesia or hyperalgesia, and allodynia to mechanical stimulations. At present, the diagnosis of SFN relies upon clinical signs of small fiber damage, abnormality in small fiber neurophysiological testing, and reduced intraepidermal nerve fiber density. Non-length-dependent SFN is underdiagnosed due to the absence of a typical topographic pattern. In conclusion, patients having chronic pain and autonomic dysfunctions with unclear causes warrant a diagnostic consideration of SFN. After the diagnosis is confirmed, underlying etiologies that are potentially treatable should be investigated.

Keywords

Painful neuropathyAutonomic neuropathyNeuropathic painPruritusSkin biopsyIntraepidermal nerve fiberClinical presentationsPain evoked potential (pain-related evoked potential)Dysautonomia

1.1 Introduction

Small fiber neuropathy (SFN) is characterized by the impairment of small-diameter myelinated Aδ- and unmyelinated C-fibers. The term SFN commonly involves painful neuropathy and autonomic neuropathy, and frequently neuropathic pain or autonomic symptoms dominate the clinical picture, respectively [1, 2]. From clinical and research’ points of view, SFN is defined according to a set of criteria at three levels of diagnostic certainty after exclusion of large fiber involvement: (1) clinical symptoms/signs, (2) abnormal psychophysical and/or neurophysiological examinations, and (3) reduced skin innervation as pathological evidence (see Sect. 1.4 and Sect. 2.​8 for details in Chap. 2) [1–4]. Although Paul Langerhans described the presence of small-diameter sensory nerves in the epidermis in 1868 [5], evaluating the integrity of small-diameter sensory nerves, especially the intraepidermal nerve fibers (IENFs) systematically and quantitatively at the light microscopic level, was not feasible until the 1990s, when immunohistochemical procedures using pan-neuronal markers (particularly protein gene product 9.5) were established [6, 7].

SFN accounts for approximately 50% of sensory neuropathy [1]. The precise prevalence of SFN remains unclear, because routine nerve conduction and evoked potential studies fail to detect the integrity of small nerve fibers. Moreover, different diagnostic criteria have been used in different studies, and the confirmation of reduced skin innervation requires taking consideration of age- and gender-adjusted normative values for interpreting IENF density (IENFD). SFN has been reported to affect at least 52.95 cases per 100,000 populations per year [8].

1.2 Clinical Manifestation

Typical symptoms of SFN stem from impairment in nociceptive processing, thermal sensation, and autonomic function (Table 1.1) [2, 9]. The most prominent clinical feature of SFN is neuropathic pain, which is noted in more than 80% of patients [1, 2, 8]. Pain quality in SFN is commonly described as burning, shooting, tingling, and even pruritic. Among different characters of pain, burning pain is a frequent symptom, affecting about two-thirds of patients, which is followed by sharp pain. In addition to spontaneous pain, patients with SFN may also complain of allodynia (i.e., pain elicited by a stimulus that does not normally provoke pain) evoked by static light touch, dynamic mechanical stimulation, or innocuous heat. Most patients complain of both spontaneous and evoked pain, although some may have either of them alone.

Table 1.1

Presentations of small fiber neuropathy

Pruritus has been reported to occur frequently in patients with SFN, involving up to 68.3% of patients [10]. It is usually accompanied by neuropathic pain and rarely occurs alone, given that pruriceptors and nociceptors are usually coexpressed in the same peripheral nerve fibers [11]. It is more severe in the evening and often present in a distal-to-proximal gradient. Like allodynia and hyperalgesia in neuropathic pain, alloknesis (itch sensation provoked by non-itching stimuli such as light touch) and punctate hyperknesis (itch sensation provoked by punctate mechanical stimuli) may occur in SFN patients with neuropathic pruritus [12]. It remains unknown why some SFN patients manifest pain but others had pruritus. An interesting observation is that herpes zoster is associated with a high incidence of neuropathic pruritus [13].

During the disease course, about half of the patients exhibit manifestations related to the autonomic nervous system. The most common autonomic presentation is hypohidrosis or anhidrosis, occurring in about 25% of patients [1]. Other autonomic symptoms include dysfunctions in the cardiovascular (orthostatic hypotension), gastrointestinal (diarrhea, constipation, dysphagia, gastroparesis, increased gastric motility, and early satiety), and genitourinary systems (retention, incontinence, and sexual dysfunction) [9]. Some patients may also complain of blurred vision, light hypersensitivity, skin discoloration, dry eyes, dry mouth, and dizziness. Although small-diameter sensory fibers mediate both somatosensory and autonomic functions, no evidence suggests a clear relationship between manifestations attributed to these two classes of small fiber nerve functions [14, 15], suggesting that the involvement of autonomic and somatic functions could be independent.

Other SFN symptoms include dysesthesia, numbness, and coldness sensations. Restless legs syndrome is present in about 40% of patients with painful neuropathy [16]. Negative symptoms can include thermal and pinprick hypoesthesia and insensitivity to pain. Symptoms usually present in a length-dependent distribution, i.e., stocking-glove pattern, starting from the toes and slowly progressing to the distal legs, at which point the distal parts of the upper extremities may also become affected [17]. However, symptoms may also develop in a non-length-dependent distribution, involving face, trunk, or proximal limbs in the early phase of disease. Patchy involvement of small fibers has been proposed to be the underlying etiology for some focal burning pain syndromes, such as burning mouth syndrome [18] and notalgia paresthetica [19]. Compared to length-dependent SFN, patients with non-length-dependent SFN appear to have younger age of onset, report more pruritic symptoms and allodynia, and have more immune-mediated but less dysglycemic etiologies [20, 21].

SFN is now considered as a distinct nosologic entity after exclusion of large fiber dysfunctions. Symptoms and signs of large fiber dysfunctions, such as imbalance, abnormal joint position sense, weakness, and muscle wasting, may develop together with above described clinical presentation of SFN. Furthermore, small fiber pathology may coexist with a disease status such as fibromyalgia [22, 23] or neurodegenerative disease of Parkinson’s disease [24]. A general nomenclature of small fiber pathology or syndrome [23] is designated for small fiber nerve degeneration and corresponding functional impairments on a background of larger fiber neuropathy (described in Chap. 9) or pain syndromes (discussed in Chap. 11) and neurodegenerative disease (described in Chap. 13). In many systemic diseases, such as diabetes (please see Chap. 6), amyloidosis (detailed in Chap. 8), paraneoplastic syndromes, etc., pure SFN may be rare or variable in frequency depending on study populations. Damage of small fibers is frequently encountered in some forms of neuropathies at the early stage, such as amyloid neuropathy and large fiber involvement developed at the late stage. About 10% of patients with a first diagnosis of SFN will develop symptoms and signs indicating the involvement of large fibers in the following 2 years [1].

The natural course of SFN is highly variable. Clinical symptoms may remain stationary, remit spontaneously, or deteriorate during the disease course [1]. In patients with idiopathic SFN and SFN associated with diabetes or impaired glucose intolerance, recent evidence suggests that the small fiber degeneration progresses in a non-length-dependent manner at a 2–3-year follow-up [25].

1.3 Etiology

Although many conditions are associated with SFN (Table 1.2), the largest proportion of patients is categorized as idiopathic [2]. In a large case series, up to 41.8% of SFN patients have no identifiable cause, and the underlying causes could only be confirmed in 25% of SFN patients during a follow-up period of 2 years [1]. For SFNs secondary to other causes, diabetes and impaired glucose tolerance are the most common causes, accounting for about 36% of SFN patients in total [1].

Table 1.2

Etiology of small fiber neuropathy

AL light chain amyloidosis, BMS burning mouth syndrome, CIDP chronic inflammatory demyelinating polyneuropathy, DM diabetes mellitus, GBS Guillain–Barré syndrome, IGT impaired glucose tolerance, MGUS monoclonal gammopathy of undetermined significance, NP notalgia paresthetica, SCM sodium channel mutations, SLE systemic lupus erythematosus, SS Sjögren’s syndrome

The pathogenesis of the development and maintenance of SFN is not completely understood. For SFN associated with hyperglycemia, evidence indicates that dysregulated axonal transport and reduced vascular growth play important roles in the impairment of axonal regeneration [26, 27]. With regard to immune-related SFN, evidence suggests that both autoantibodies and proinflammatory cytokines are elevated in patients with SFN [28, 29], and vasculitis contributes to the degeneration of small-diameter nerve fibers [30, 31]. In alcohol-related SFN, the direct neurotoxic effects of ethanol or its metabolites had been implicated [32]. Recently, altered nerve excitability due to gain-of-function mutations in Nav1.7, Nav1.8, and Nav1.9, three voltage-gated sodium channels, had been reported in painful neuropathy [33–35]. Mutations of these sodium channels have been found in up to 30% of carefully selected cases diagnosed as idiopathic SFN. Gain-of-function mutations of Nav1.7, Nav1.8, and Nav1.9 enhance the excitability of dorsal root ganglion neurons, which likely contributes to pain in SFN. Nevertheless, whether and how these mutations lead to axonal degeneration of small-diameter sensory nerves remains unclear.

1.4 Diagnosis

On neurological examination, the major findings are sensory deficits related to small fiber dysfunction. About half of the patients demonstrate thermal and/or pinprick hypoesthesia, 10–20% with hyperalgesia, and about half of them with allodynia to mechanical stimulation [1, 8]. Large fiber motor (muscle strength and deep tendon reflexes) and sensory functions (light touch, vibration, and proprioception) are relatively preserved. With regard to dysautonomia, common manifestations include sluggish or absent light reflexes, orthostatic hypotension, skin color changes, and warmth or coldness of the skin. Patients with suspected dysautonomia should receive a complete assessment of the autonomic nervous system, including the cardiovascular adrenergic (blood pressure response to postural changes), gastrointestinal (constipation, gastroparesis), genitourinary (libido, erectile function), sudomotor (sweat output), and pupillary functions (light reflex) [36].

Irrespective of the underlying causes, a diagnosis of SFN can be made when at least two of the following criteria are met [1–4]:

1.

Clinical symptoms and signs of small fiber damage (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia), with a length-dependent or non-length-dependent distribution

2.

Abnormal warm and/or cooling threshold in the foot based on quantitative sensory testing, or abnormalities in small fiber neurophysiological testing, such as nociceptive evoked potential (pain evoked potential or pain-related evoked potential, which will be discussed in Chap. 3) by laser, electrical, or contact heat stimulators [37, 38]

3.

Reduced IENFD in the distal leg

Clinically, these criteria are used to define three levels of diagnostic certainty:

1.

Possible SFN: the presence of length-dependent symptoms and/or clinical signs of small fiber damage

2.

Probable SFN: the presence of length-dependent symptoms, clinical signs of small fiber damage, and normal sural nerve conduction study

3.

Definite SFN: the presence of length-dependent symptoms, clinical signs of small fiber damage, normal sural nerve conduction study, and reduced IENFD at the ankle and abnormal quantitative sensory testing thermal thresholds in the foot and/or abnormal small fiber neurophysiological findings [17, 39]

These graded diagnostic criteria were developed for length-dependent SFN and also applicable for non-length-dependent SFN. Note that, due to the absence of a typical topographic pattern of symptoms in non-length-dependent SFN, it is conceivable that non-length-dependent SFN is an underdiagnosed condition. Serious comorbidities may complicate the diagnosis of isolated SFN. Moreover, malfunctions of the small fibers, especially overactivity, can occur even without evidence of loss of function or reduction of IENFs on skin biopsies.

1.5 Treatment

Treatment of SFN should be aimed at the underlying etiology if identifiable [40]. Nevertheless, whether and how disease-modifying therapy halts small fiber degeneration remains unclear. In diabetes-related SFN, persistent glycemic control appears to reduce SFN symptoms [39], but rapid improvement in glycemic control paradoxically induces painful neuropathy [41]. In Fabry disease, although preliminary evidence suggests that enzyme replacement therapy improves clinical manifestations of SFN [42, 43], its effects on small-diameter sensory nerves remain to be clarified. For idiopathic SFN, treatment is mainly directed to the relief of symptoms, especially the control of neuropathic pain, which will be detailed in Chap. 15 of this monograph. Antidepressants and antiepileptic drugs that have shown their efficacy for neuropathic pain in general (pregabalin, gabapentin, tricyclics, duloxetine, etc.) are considered as first-line treatment. Other options include opioids, lidocaine, and capsaicin patches [44, 45]. Nav1.7 and Nav1.8 blockers are potential therapeutic options in the future. With regard to the autonomic neuropathy, most symptoms are mild to moderate and do not require medical treatment [1, 14]. There might be regional variations in the degree of dysautonomia. For severe postural hypotension affecting quality of life, inotropic agents (midodrine and pyridostigmine) and mineral corticosteroids (fludrocortisone) are effective, although patients usually need additional non-pharmacological management to raise their standing blood pressure (e.g., postural adjustment and compression garments) [46–48]. For gastrointestinal mobility disorders, traditional prokinetic drugs can enhance cholinergic function, and new medications, such as new-generation serotonin 5-HT4 receptor agonists and secretagogues, are under development [49, 50].

Currently, available pharmacological treatment for SFN is often partially effective in managing pain and dysautonomia. Future studies investigating the pathophysiology of neuropathic pain and autonomic dysfunctions in SFN will facilitate the development of new therapeutic strategies.

1.6 Conclusion

SFN is a commonly encountered clinical entity that significantly compromises patients’ overall quality of life [51]. Patients with SFN are heterogeneous in clinical presentation, underlying causes, and pathophysiology. The presence of symptoms and/or signs of small fiber damage warrants a thorough evaluation for SFN. Furthermore, a diagnosis of SFN should also be considered in patients with chronic pain and autonomic dysfunction of unclear cause. Since currently the diagnosis of SFN mainly relies upon clinical presentation, quantitative sensory testing, specialized neurophysiology, and the evaluation of IENFD, future researches should evaluate the diagnostic value of these and of newer or neglected techniques, such as assessment of corneal nerve fiber density by corneal confocal microscopy [52] or axon reflex flare [53]. For idiopathic SFN, treatment mainly focuses on symptomatic relief, especially of neuropathic pain. Up to now, the treatment of neuropathic pain in SFN is generally inadequate and awaits new technology and molecular targets for specific etiology, pathophysiology, and mechanisms tailored individually from the perspective of precision medicine.

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© Springer Nature Singapore Pte Ltd. 2019

Sung-Tsang Hsieh, Praveen Anand, Christopher H. Gibbons and Claudia Sommer (eds.)Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegenerationhttps://doi.org/10.1007/978-981-13-3546-4_2

2. Pathology of Small Fiber Neuropathy: Skin Biopsy for the Analysis of Nociceptive Nerve Fibers

Claudia Sommer¹  

(1)

Universitätsklinikum Würzburg, Würzburg, Germany

Claudia Sommer

Email: [email protected]

Abstract

Reduced skin innervation as shown by immunostaining in skin biopsies is a sensitive and specific indicator of small fiber neuropathy (SFN). Standard methods for staining and quantification have been established, and normative values are available. However, not every condition with reduced skin innervation is a SFN, and not all types of disorders with pathological small fiber function manifest with reduced skin innervation. Identification of nociceptor subpopulations in humans in the skin is only beginning to yield data. Detection of inflammatory cells and pathologic deposits are additional diagnostic benefits of skin biopsy.

Keywords

Skin biopsySmall fiber neuropathyProtein gene product 9.5Intraepidermal nerve fiber densitySubepidermal nerve fibersRanvier nodesAmyloidosisFabry disease

2.1 Introduction

Reduced skin innervation is the hallmark of small fiber neuropathy (SFN). In recent years, methods have been refined, normative cohorts have been published, and the techniques have found widespread clinical use. Immunostaining with antibodies against the pan-neuronal ubiquitin hydrolase protein gene product 9.5 (PGP 9.5) has become the standard technique. Usually, the number of epidermal nerve fibers per length of epidermis, i.e., the intraepidermal nerve fiber density (IENFD), is assessed. Some laboratories offer additional analyses from the skin biopsies, e.g., amyloid stains, immunohistochemistry for inflammatory cells, or the analysis of subepidermal nerve fibers. Some new questions have arisen, for example, whether SFN can be diagnosed with normal skin innervation as assessed by PGP 9.5 immunostaining. Also, the question of the importance of morphological changes in the intraepidermal nerve fibers (IENF), for example, axonal swellings or branching, has been discussed. This chapter will give an overview of currently used methods for the analysis of small nerve fibers in the skin and will summarize current findings on SFN and skin innervation.

2.2 Normal Innervation of the Skin

Nerve fibers deriving from neurons in the dorsal root ganglia as well as the sympathetic and parasympathetic ganglia terminate in the skin, innervating the epidermis as free nerve endings, the mechanoreceptors such as Meissner’s corpuscles and Merkel cells, and the sweat glands, hair follicles, and blood vessels. The majority of the axons in the skin are unmyelinated (C-fibers); others are thinly myelinated (Aδ-fibers) and may lose their myelin at their distal endings [1]. C-fibers transmit the sensation of warmth, heat, and slow pain, and Aδ-fibers transmit sharp pain and the sensation of cold. Several C-fibers are wrapped into single Schwann cells, forming the Remak bundles, that can be visualized by electron microscopy [2].

In the epidermis, the IENF meander between keratinocytes, with which they are closely associated and probably connected by chemical synapses. These fibers are derived from the subepidermal nerve plexus that can be observed as horizontally oriented nerve fiber bundles located just below the epidermis. From here, the IENF traverse the epidermal basement membrane and ascend vertically between the keratinocytes. The IENF can be easily seen after immunoreaction with antibodies to PGP 9.5 (Fig. 2.1). This ubiquitin hydrolase is considered a pan-axonal marker, i.e., all axons are supposed to stain positively. However, there remains the possibility that some axons do not express PGP9.5 in a sufficient amount to be detectable by immunostaining, which could only be solved by parallel assessment of the same section with immunostaining and electron microscopy. Below the epidermis, thick nerve bundles including unmyelinated and myelinated nerves run horizontally to the surface. These are particularly numerous in glabrous skin, where the mechanoreceptors are innervated [3]. Blood vessels, arrector pilorum muscles (in hairy skin), and sweat glands are also densely innervated.

Fig. 2.1

Skin innervation in small fiber neuropathy (SFN). Photomicrograph showing immunofluorescence for PGP 9.5 in a 50-μm section of the skin from the upper leg of a patient with SFN. Note the subepidermal nerve plexus and some intraepidermal nerve fibers traversing the basement membrane, most with numerous branches, which may be a sign of pathological sprouting

2.3 Standard Methods

2.3.1 Biopsy, Choice of Site, and Method

Biopsies are usually performed by disposable circular punch devices with diameters between 2 mm for the fingertip and up to 6 mm for the back. The most commonly used 3-mm punches taken at the lower and upper leg yield enough tissue for reliable IENFD quantification [4–6]. Biopsies are performed under sterile conditions and with local anesthesia. Local infections, severe wound healing deficits, and bleeding disorders including anticoagulation are contraindications. The resulting wound may be closed by a suture or a tight adhesive, and patients are advised to avoid strain of the area or bathing until the wound has closed, which usually occurs within 7–10 days. In the diagnostic workup of SFN, biopsies are usually taken from the lateral distal