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Small fiber neuropathy (SFN) is dominated by neuropathic pain and autonomic complaints.
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The biopsychosocial model is essential in the treatment of chronic pain in SFN.
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Patients with SFN will benefit from an interdisciplinary treatment approach managed by nurse practitioners.
Abstract
Small fiber neuropathy (SFN) is a peripheral nerve condition causing neuropathic pain and autonomic complaints. Skin biopsy is an important diagnostic tool for diagnosing SFN. SFN is associated with conditions like diabetes mellitus and autoimmune diseases, but in 53% of the patients, the etiology remains unknown. Treating the underlying condition is the first-line treatment, but most patients will also need symptomatic treatment based on the biopsychosocial model. SFN can be managed by several health care professionals, including nurse practitioners, neurologists, pain specialists, and physiatrists. This article provides evidence-based information on the diagnostics of SFN and offers guidance for interdisciplinary treatment.
Furthermore, the treatment of neuropathic pain in SFN is often disappointing because effective pain reduction occurs in less than 50% of the patients and (often severe) side effects are common.
This article discusses the clinical presentation, diagnostic criteria, etiology, pathophysiology, the role of nurse practitioners (NPs), and the interdisciplinary treatment options of SFN in order to improve the recognition and treatment of painful SFN.
Case Presentation
A 32-year-old male patient presented to the outpatient neurology clinic with symptoms of pain in the hands and arms. He reported complaints of burning and tingling, which began 8 years earlier without an underlying etiology or triggers. The pain was progressive and extended to his feet, legs, hips, and shoulders. In addition to the severe pain, the patient also showed signs of autonomic dysfunction. He complained of a dry mouth and increased sweating and had intermittent palpitations. Physical exercise (eg, walking) caused an increase of pain, and because of allodynia of the fingers, working on his computer was more difficult. Moreover, his sleep was disturbed by the pain, causing restlessness at night and fatigue during the day. Only relaxation exercises, such as breathing, provided some relief. Because of these complaints, the patient was severely limited in his daily functioning and was unable to report to his work. Polyneuropathy was suspected because of the involvement of the feet and hands (eg, the stocking-glove pattern). Neurologic examination and nerve conduction studies (NCSs) showed no abnormalities, excluding large nerve fiber involvement. Skin biopsy showed a decreased intra-epidermal nerve fiber density (IENFD) compared with age- and sex-matched normative values,
and his sense of heat and cold was disturbed according to quantitative sensory testing (QST). An extensive laboratory assessment, including DNA testing, revealed the variant c.4585G>A (p.[Ala1529Thr]) in the SCN10A gene, which encodes the voltage-gated sodium channel Nav1.8. The pathogenicity of this variant was not confirmed, and the variant was classified as a variant of unknown clinical relevance.
Patients with SFN-related complaints may visit NPs in secondary care. The clinical presentation of SFN includes spontaneous and evoked pain, pruritic sensation, and paresthesia (Table 1).
Symptoms most often have a nerve length–dependent stocking-glove pattern, starting distally at the lower extremities and progressively ascending to more proximal sites.
Table 1Diagnostic Criteria for Small Fiber Neuropathy
Clinical Signs and Symptoms
Required
Supportive
Medical history
Neuropathic pain (burning sensation, pins and needles, shooting), usually in a length-dependent pattern.
Autonomic dysfunction, including sicca syndrome, accommodation problems, orthostatic complaints, hypohidrosis or hyperhidrosis, hot flashes, gastroparesis, palpitations, diarrhea or constipation, urinary incontinence or retention, impotence, and decreased ejaculation or lubrication
Neurologic examination
Signs of dysfunction of the small nerve fibers, including loss of pinprick sensation, thermal sensory loss, allodynia, and hyperalgesia
No signs of large nerve fiber dysfunction: normal muscle strength, reflexes, and vibration sense
Diagnostic Tests
Required
Supportive
NCS
No abnormalities
Skin biopsy
Decreased intraepidermal nerve density in skin biopsy (10 cm above the lateral malleolus)
QST (temperature threshold testing with the method of levels)
At least 1 deviating heat and/or cold temperature threshold measured bilaterally on the thenar eminence and foot dorsum
Adapted with permission from Geerts M, Faber CG, Merkies ISJ, Hoeijmakers JGJ. Small fiber neuropathy: what can we offer the patient? Dutch J Neurol Neurosurg. 2022;123:297-304.
Patients with SFN can also complain of autonomic dysfunction, including dry mouth, dry eyes (sicca syndrome), accommodation problems, orthostatic complaints, hypohidrosis or hyperhidrosis, hot flashes, intestinal problems, gastroparesis, impotence, decreased ejaculation or lubrication, and palpitations (Table 1).
However, these symptoms can also be a manifestation of comorbidity or a side effect of medication (such as neuropathic pain treatment). Therefore, they should be carefully evaluated in relation to the clinical context and prescribed medication. Physical examination requires an accurate neurologic examination in which loss of pinprick sensation, thermal sensory loss, allodynia, or hyperalgesia can be demonstrated.
Muscle strength, tendon reflexes, and vibration sense are normal in pure SFN because those are large nerve fiber modalities. Some patients also suffer from erythromelalgia, a severe painful redness and increased skin temperature of the extremities, that is triggered by heat or exercise (Figure 1).
Figure 1Erythromelalgia. Red discoloration of the skin, as can be seen in primary erythermalgia, but also as a symptom in patients with small fiber neuropathy.
Peripheral sensory neuropathies can be caused by various pathophysiological mechanisms, but in more than 50% of the patients with pure SFN, the etiology remains unknown despite thorough additional examinations such as blood and urine analyses.
The most common underlying conditions are autoimmune diseases, sodium channel gene mutations, diabetes mellitus (including glucose intolerance), and vitamin B12 deficiency,
A chest X-ray is necessary to identify possible signs of autoimmune illnesses such as sarcoidosis (a systemic inflammatory disease of unknown cause often with radiographic changes in the lungs and the presence of thoracic lymphadenopathy).
Sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway, especially NaV1.7, NaV1.8, and NaV1.9.
Gain-of-function sodium channel gene mutations cause electrophysiological changes of the channel and have been associated with several pain conditions, including SFN.
Gain-of-function sodium channel gene mutations can cause painful human pain conditions (eg, erythromelalgia and SFN). Erythromelalgia is more common in patients with SFN and pathogenic SCN9A mutations than in patients with SFN with no mutations or another mutation.
Furthermore, there is supporting evidence that some SFN-associated gene variants of NaV1.7 contribute to impaired regeneration and/or degeneration of sensory axons in idiopathic SFN.
The small fiber neuropathy NaV1.7 I228M mutation: impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole.
The diagnosis of SFN can be difficult to establish because complaints are nonspecific and may vary substantially. Because of the similarity of clinical symptoms, cases of undiagnosed SFN could be falsely labeled as polyneuropathy,
A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: implications for a new paradigm in fibromyalgia etiopathogenesis.
If SFN is suspected, first an NCS should be performed to exclude large nerve fiber involvement (Figure 2). An NCS is an electrodiagnostic test that is performed by a neurologist at the neurophysiology department. The NCS examines the functioning of the large distal motor and sensory nerve fibers by electrically stimulating these nerves and can classify a possible neuropathy and specify these as an axonal or demyelinating. If the NCS is abnormal, the diagnosis of polyneuropathy can be confirmed, which may have small nerve fiber involvement, as in mixed small and large fiber neuropathy.
Consequently, additional diagnostics for underlying pathology are essential, but no further diagnostic tests specific for SFN are needed.
Figure 2A flowchart approach for a patient with possible small fiber neuropathy (SFN). ACE, angiotensin-converting enzyme; ANA, antinuclear antibody; ENA, extractable nuclear antigen; IENDF, intraepidermal nerve fiber density; QST, quantitative sensory testing. (Adapted with permission from Geerts M, Faber CG, Merkies ISJ, Hoeijmakers JGJ. Small fiber neuropathy: what can we offer the patient? Dutch J Neurol Neurosurg. 2022;123:297-304.)
In close collaboration with international referral centers for patients with SFN-related complaints, SFN patient-centered care was improved by assessing normative values for IENFD, updating the temperature threshold test (TTT) protocol, and developing a standardized comprehensive diagnostic SFN workup.
A diagnosis of definite SFN requires at least 1 characteristic sensory small nerve fiber symptom, at least 2 small nerve fiber signs, a normal NCS, and an abnormal IENFD.
A skin biopsy is performed using a 3-mm disposable punch under a sterile technique after topical anesthesia with lidocaine at the leg 10 cm above the lateral malleolus (Figure 3A).
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For evaluation of the most distal sensory endings, the nerve endings are stained immunohistochemically and counted under a light microscope (Figure 3B). There are international age- and sex-based normative data for identifying abnormality in IENFD. A pathological characteristic of SFN is Aδ- and C-fiber degeneration, which can be observed as a decreased IENFD.
Figure 3(A) Skin biopsy as a nursing procedure that can be performed by a nurse practitioner. After local anesthesia of the skin, a punch biopsy of 3 mm approximately 10 cm above the lateral malleolus. (B) Intraepidermal nerve fiber in a skin biopsy. The small nerve fibers crossing the dermal-epidermal junction are indicated by the arrow. In this picture, a decreased intraepidermal nerve fiber density can be confirmed.
The TTT is a functional test and part of QST, which is performed by a neurologist at the neurophysiology department. The combination of bilateral heat and cold thresholds on the hands and feet, determined by the method of levels, leads to the highest sensitivity and specificity.
In this method, the patient receives a stimulus with a certain temperature by a thermode (a metal block) and will be asked whether or not this stimulus is felt by pressing “yes” on a switch. By changing the temperature of the stimulus, the threshold for sensing heat and cold can be determined independent of the patient’s response time. The duration of the TTT is approximately 30 minutes. The reliability of the TTT depends on the alertness and cooperation of the patient. Specificity is moderate because the TTT may be abnormal in a lesion at any level in the somatosensory nervous system. An abnormal TTT alone is not sufficient to confirm the diagnosis of SFN, but an abnormal TTT with compatible clinical signs is decisive.
Other Diagnostic Tools
A promising diagnostic tool for the future may be corneal confocal microscopy. By using a confocal microscope, the small nerve fibers in the cornea (branches of the trigeminal nerve) can be observed. Similar to skin biopsy, it is possible to visualize the small nerve fibers and to calculate the nerve fiber density.
In diabetic neuropathy or chemotherapy-induced neuropathy, a decrease in nerve density is found, and this noninvasive tool can be valuable for diagnosing and treating these conditions.
However, the small nerve density can also be reduced in other neurologic or ophthalmic disorders. The sensitivity and specificity of the test for diagnosing SFN remain uncertain.
In addition to QST, different types of nociceptive-evoked potentials, the skin wrinkling test, and the Sudoscan (Impeto Medical, Paris, France) are sometimes used in daily practice as functional tests. Compared with QST, the advantage of evoked potentials is the independence of the test on the alertness and cooperation of the patient. In contact heat-evoked potentials, heat stimuli selectively activate the Aδ and C fibers. However, contact heat-evoked potentials cannot always be generated in healthy subjects.
Laser-evoked potentials have moderate specificity, comparable to QST, because this test may be abnormal in a lesion at any level of the somatosensory system.
The stimulated skin wrinkling test is practically feasible in every health care institution. Immersion in water or the application of an eutectic mixture of local anesthetics cream on the fingertips activates the sympathetic nerve fibers in the skin. The subsequent vasoconstriction resulting in a negative pressure in the tissue causes wrinkling of the fingertips. The degree of ripple is graded visually.
The Sudoscan measures the electrochemical conductance of the skin of the hands and feet in a rapid and noninvasive manner. The electrochemical conductance of the skin is a reflection of the C-fiber sympathetic function of the sweat glands. To date, most studies with the Sudoscan have been performed in diabetic polyneuropathy,
and the value of the test in diagnosing SFN at this point is unclear.
Laboratory Testing
Laboratory screening is crucial to elucidate the most common underlying conditions of SFN (Table 2), such as autoimmune diseases, sodium channel gene mutations, diabetes mellitus (including glucose intolerance), and vitamin B12 deficiency.
Autoimmune diseases can be tested by antinuclear antibody, extractable nuclear antigen, antineutrophil cytoplasmic antibody screening, anti-RO (SSA), and anti-La (SSB) for Sjogren syndrome.
in which the exons and flanking intron sequences of 9 SCN genes (eg, SCN9A, SCN10A, and SCN11A) are examined. Diabetes mellitus or prediabetes can be examined by a fasting plasma glucose, an oral glucose tolerance test, or glycated hemoglobin. Other metabolic, endocrinologic, and infectious causes should also be tested, such as thyroid function, renal function, vitamin B, a human immunodeficiency virus test, hepatitis B and C serology, hematologic disease, serum electrophoresis and immunofixation, and complete blood count.
The treatment of SFN focuses on treating the underlying condition. However, in more than half of the patients with SFN, a causal treatment is not possible. Furthermore, treating an underlying cause does not guarantee a reduction of the complaints. In most cases, treatment will often be symptomatic, primarily aimed at reducing neuropathic pain. Before starting neuropathic pain treatment, the history of pain treatments of the patient has to be explored with attention to side effects, effectiveness, duration of therapy, doses, and comorbidity.
Additionally, any interactions with other drugs must be checked and the dosage adjusted accordingly. Patients should be informed of the potential side effects and have to be encouraged to adhere to treatment and advised to report moderate to severe side effects early.
Pharmacotherapy
Symptomatic pain treatment in SFN is based on general guidelines of neuropathic pain treatment. The use of tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants is recommended
(Figure 4). Amitriptyline as a tricyclic antidepressant is strongly recommended for neuropathic pain treatment, but it can cause anticholinergic side effects and should therefore be avoided in patients older than 65 years.
However, pharmacotherapy in neuropathic pain is often disappointing, with a pain reduction of 50% being achieved in less than half of the patients. It is essential to use neuropathic pain medicines for a sufficient time (at least 3 weeks) in an adequate dose to be able to evaluate the treatment effect.
Figure 4A flowchart of pharmacotherapy in patients with small fiber neuropathy. SNRI, serotonin-norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants.
Discovering the role of sodium channel gene mutations in the pathophysiology of SFN has led to new targets for pain treatment. A clinical trial with patients with NaV1.7-related SFN showed that lacosamide had a positive effect on pain, general well-being, and quality of sleep.
; however, in patients with idiopathic SFN, intravenous immunoglobulin treatment did not have a positive effect on pain compared with treatment with placebo.
The biopsychosocial model provides NPs a perspective for understanding the interactions between biological, psychological, and socio/environmental factors in shaping a person’s overall pain experience. Assessing the patient according to the biopsychosocial model (including medical history, comorbidities, cognitive/emotional/behavioral characteristics, and social environment) is recommended for a complete overview and for understanding the effect on a person’s overall pain experience.
Psychological and sociocultural factors, such as depression, anxiety, poor coping skills, somatization, low educational level, substance abuse, and poor social support, are associated with chronic neuropathic pain
and may be factors contributing to chronification of pain. Additionally, biological factors, including genetics, age, sex, sleep, hormones, and endogenous opiate systems, contribute to chronic neuropathic pain.
The biopsychosocial model helps NPs to identify influences on SFN progression and contributes to a broad treatment strategy that includes personalized pain medicine and psychosocial and/or behavioral interventions.
Role of the NPs
The outcome of care by NPs in terms of quality of care as well as any contribution or value added to the production and efficiency of the care is regarded as high quality, effective, and safe.
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Furthermore, NPs are leading the way by demonstrating positive results in managing care for older patients and in the complexity of chronic conditions.
They have a pivotal coordinating role in the whole process and are considered the cornerstone of the diagnostic process in SFN care. All these benefits and evidence are in line with the goals of SFN care to guarantee the quality and accessibility of health care for patients with SFN-related complaints. NPs in the department of neurology in secondary care are the case managers of the patients with SFN and, furthermore, have a crucial role in the treatment of SFN. After referral, the medical triage of patients with suspected SFN is performed by NPs. In the diagnostic process, NPs take the medical history, perform the physical and initial psychiatric examinations, and collect skin biopsies. All available test results, advice tailored to the patient’s personal situation, and treatment options are discussed with the patient and their families by the NPs. Furthermore, the NPs provide patient education about the diagnosis, prognosis, and follow-up. In patients with SFN, pharmacotherapy (eg, tricyclic antidepressants, SNRIs, and anticonvulsants) is prescribed by the NPs. Nevertheless, the focus of the treatment of SFN is not only on drug therapies.
Interprofessional Team Approach
Patients are presented by the NPs in the multidisciplinary team with all potential stakeholders (neurologists, pain specialists, psychiatrists, geneticists, and physiatrists) for patient-centered advice and treatment options based on evidence-based practice, aiming to improve the patient’s QOL (Figure 5). Rehabilitation programs can be added to the pharmacologic treatment or used in the absence of efficacy of drugs. Exercises and rehabilitation programs may avoid disability and improve QOL.
Psychological treatments and psychotherapies in the neurorehabilitation of pain: evidences and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.
Promising effects of a study with an aerobic exercise and moderate- to high-intensity interval training were found on pain severity in patients with diabetic peripheral neuropathy,
Effect of different exercise training intensities on musculoskeletal and neuropathic pain in inactive individuals with type 2 diabetes - preliminary randomised controlled trial.
The effect of exercise therapy combined with psychological therapy on physical activity and quality of life in patients with painful diabetic neuropathy: a systematic review.
Psychological treatments and psychotherapies in the neurorehabilitation of pain: evidences and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.
With different levels of evidence, mindfulness interventions, cognitive behavioral therapy, hypnotic therapies, and virtual reality are described as additional treatments to improve pain.
Psychological treatments and psychotherapies in the neurorehabilitation of pain: evidences and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.
Figure 5An interprofessional team approach of small fiber neuropathy (SFN). Assessment with the biopsychosocial model is necessary for understanding the overall pain experience and an optimal pain treatment in SFN. NCS, nerve conduction study; QST, quantitative sensory testing.
Extensive wait lists and delayed access to care because of the coronavirus disease 2019 pandemic resulted in patients with SFN experiencing limited access to health care services and diagnostics, poorer QOL, lower physical health scores, and increased dysfunction of their coping mechanisms.
Nevertheless, capacity may be enhanced through a combination of investment and more efficient use of existing resources, such as e-health and self-management in teleneurology.
Teleneurology is a technology tool that enables NPs to provide remote health care, education, and monitoring to patients, such as videoconferencing with smartphones. Earlier research showed that an online care delivery model for neuropathic pain symptom management with follow-up by an NP was highly effective in reducing symptom prevalence and distress.
Chemotherapy-related neuropathic symptom management: a randomized trial of an automated symptom-monitoring system paired with nurse practitioner follow-up.
Digitization of research processes and data-driven technology enable customized health care, self-care, and remote care and are possible innovative solutions for the complexity of chronic neuropathic pain management.
Evaluation of the Case
Based on the clinical symptoms and signs, a normal NCS, an abnormal IENFD, and an abnormal QST, a diagnosis of definite SFN, possibly related to an underlying sodium channelopathy, was made. For neuropathic pain relief, pharmacologic treatment with an anticonvulsant or antidepressant was advised. Furthermore, referral to a physiatrist was chosen for improving physical exercise and endurance under supervision. If this is not successful, a rehabilitation program for improving the patient’s QOL can be considered. Future research is needed regarding e-health for improving self-management in painful SFN and outcomes on patients’ QOL. NPs need to share their evidence-based knowledge and clinical competence for improving the quality of SFN health care in the long-term by providing education in supervising NPs in training, implementing research into nursing practice, presenting their research at international conferences, and developing national e–health care networks.
Conclusion
Patients with SFN suffer from neuropathic pain and autonomic complaints with a negative impact on QOL. The neurologic examination usually shows no abnormalities in motor and large sensory nerve fiber function. Although not easy, it is possible to objectify clinical signs of SFN during the neurologic examination if extensive sensory testing can be performed. NCSs are needed to exclude large nerve fiber involvement. To diagnose definite SFN, the typical clinical picture of SFN and an abnormal IENFD in skin biopsy are necessary. A diagnosis of probable SFN can be made in case of abnormal QST and clinical signs and symptoms of SFN. The underlying etiology is not found in more than half of the patients with SFN. NPs play a central role in diagnosing, guiding, and monitoring the treatment of patients with SFN from an individual’s holistic needs, combining pharmacotherapy with the most appropriate multidisciplinary treatment options and self-management for improving the patient’s QOL.
The small fiber neuropathy NaV1.7 I228M mutation: impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole.
A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: implications for a new paradigm in fibromyalgia etiopathogenesis.
National mixed methods evaluation of the effects of removing legal barriers to full practice authority of Dutch nurse practitioners and physician assistants.
The impact of the advanced practice nursing role on quality of care, clinical outcomes, patient satisfaction, and cost in the emergency and critical care settings: a systematic review.
The effectiveness of emergency nurse practitioner service in the management of patients presenting to rural hospitals with chest pain: a multisite prospective longitudinal nested cohort study.
Psychological treatments and psychotherapies in the neurorehabilitation of pain: evidences and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.
Effect of different exercise training intensities on musculoskeletal and neuropathic pain in inactive individuals with type 2 diabetes - preliminary randomised controlled trial.
The effect of exercise therapy combined with psychological therapy on physical activity and quality of life in patients with painful diabetic neuropathy: a systematic review.
Chemotherapy-related neuropathic symptom management: a randomized trial of an automated symptom-monitoring system paired with nurse practitioner follow-up.
Margot Geerts, RN, MSc, is nurse practitioner and PhD student at the School of Mental Health and Neuroscience, Maastricht University Medical Center in Maastricht, Netherlands, and may be contacted at [email protected]
Janneke G.J. Hoeijmakers, MD, PhD, is a neurologist and assistant professor at the School of Mental Health and Neuroscience, Maastricht University Medical Center, Netherlands.
Carla M.L. Gorissen-Brouwers, MSc, is a nurse practitioner at Maastricht University Medical Center, Netherlands.
Catharina G. Faber, MD, PhD, is a neurologist and Medical Center Director and Professor in neuromuscular disorders at the School of Mental Health and Neuroscience, Maastricht University Medical Center, Netherlands.
Ingemar S.J. Merkies, MD, PhD, is a neurologist and professor in fucntional clinimetrics at Maastricht University Medical Center and Chief Medical Officer at Curacao Medical Center in Willemstad, Curacao, Netherlands.
Article info
Publication history
Published online: February 21, 2023
Footnotes
In compliance with the standard ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.
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