Small-fiber Polyneuropathy Research Articles

Small fiber polyneuropathy as a potential therapeutic target in interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) and fibromyalgia (FM) are frequently co-occurring medical diagnoses in patients referred to the urology clinic for secondary and tertiary treatment options. Abundant literature has shown that many patients with FM have small fiber polyneuropathy (SFPN) that can be confirmed via skin punch biopsy and immunological staining to measure nerve density. This finding of SFPN provides a therapeutic target for FM and in this article we hypothesize and provide rationale for the idea that this same phenomenon (SFPN) might explain, in some IC/BPS patients, the finding of widespread pain and likewise provide a therapeutic target for these patients.

A Postmortem Study of a Patient with Low Titer Nicotinic Acetylcholine Receptor Ganglionic Antibody: Implications for Clinical Neurologic Disease

Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic efferent function in the skin. A patient with low serum titers of neuronal acetylcholine receptor ganglionic antibodies and autonomic failure had symptomatic small fiber polyneuropathy late in life in the setting of autoimmune dementia and encephalopathy and prostate cancer. Large and small fiber polyneuropathy and dysautonomia were detected in routine electrodiagnostic and autonomic laboratory studies, and epidermal nerve fiber analysis of the calf and thigh. Clinical improvement for one year concomitant with intravenous immune globulin therapy preceded a clinical decline in neurocognitive function and death. Postmortem examination showed typical features of Alzheimer disease with neuropathic neuropathological changes in the peripheral nervous system, and viable autonomic ganglia consistent with a channelopathy mechanism involving postsynaptic neuronal nAChRs.

Case Report: Length-dependent Small Fiber Polyneuropathy Caused by Coxsackie and Influenza Virus Co- Infection

Case Report: Length-dependent Small Fiber Polyneuropathy Caused by Coxsackie and Influenza Virus Co- Infection

Neurological and electroneurography findings in patients with systemic sclerosis and symptoms of neuropathic pain in extremities.

To analyze neurological and electroneurography (ENG) findings in patients with systemic sclerosis (SSc) and symptoms of neuropathic pain in upper and lower extremities. Using the PainDetect questionnaire, 42 consecutive patients with SSc (38 women and 4 men) were screened for the presence of neuropathic pain in upper and/or lower extremities. Patients with previously diagnosed diabetes or other metabolic diseases, malignancy, other autoimmune disorders, or any neurological or psychiatric disease, were not included. Neurological examination, ENG, and laboratory analyses (glycated hemoglobin-HbA1C, and vitamin B12) were performed in SSc patients with neuropathic pain in extremities. Methods of descriptive statistics were used to summarize the data. Eleven patients (26.2%) had significant symptoms of neuropathic pain in extremities. Neurological examination indicated polyneuropathy in 10/11 (90.9%) of patients. Symmetrical hyperesthesia in the lower and/or upper extremities was found in ten patients. Symmetrical hyporeflexia was found in 7/11 (63.6%) of patients in the arms, and 6/11 (54.4%) of patients in the legs. Proprioception was diminished in 3/11 (27.3%), whilst pallhypesthesia was present in all patients. However, polyneuropathy could be confirmed by ENG only in four out of ten SSc patients, who had typical neurological findings for polyneuropathy. Hypoesthesia in a specific lumbar root dermatome, suggesting radiculopathy, was found in 6/11 (54.5%) of patients. Asymmetrical hyporeflexia was noticed in 2/11 (18.1%) of patients in the lower limbs. Seven patients (63.6%) had signs of radiculopathy in at least one root dermatome on ENG. A significant number of SSc patients with neuropathic pain in the upper and/or lower extremities have symptoms and signs of polyneuropathy undetectable by ENG, which indirectly suggests the presence of small-fiber polyneuropathy in these patients. In some patients, radiculopathy cannot be excluded as possible co-morbid non-scleroderma condition associated with neuropathic pain.

Pain Syndromes Other Than Headache

Pain is experienced within a complex biologic, emotional, psychological, and social context that may defy physical examination, diagnostic procedures, and laboratory tests. This chapter aims to empower internists to improve their medical practices in pain management. It provides a scientific background that covers nociception and how sensory processing occurs at multiple levels in the body. Clinical assessment is detailed, as well as diagnostic categories that include mixed or uncertain chronic pain syndromes (back pain, fibromyalgia, postamputation pain, pain from cancer and bone) and neuropathic pain syndromes (polyneuropathy, mononeuropathy multiplex, ganglionopathy, genetic disorders, focal and regional syndromes). Treatment of chronic pain can be surgical or interventional. Pharmacologic treatment for acute and chronic nociceptive pain includes special considerations for geriatric and terminal patients. For treatment of neuropathic pain, medications are the major component. One tables lists iatrogenic nerve injuries that can cause posttraumatic neuralgia and complex regional pain syndrome. Other tables detail stepwise pharmacologic management of neuropathic pain and cite recommendations on opioid use from the Centers for Disease Control and Prevention. One figure illustrates how pain transducers monitor and influence tissue conditions. Other figures show sensory processing in the spinal cord dorsal horn, physical findings in the feet of patients with bilateral foot pain from small-fiber polyneuropathy, illustrate how examination can identify specific nerve injuries causing chronic pain, and provide classification of chronic pain syndromes. This chapter contains 82 references.

What gnaws at the heart and gets on the nerves

Transthyretin is atransport protein for thyroxine and retinol-binding protein, which is mainly produced in the liver. Hereditary transthyretin-related amyloidosis (ATTR) is caused by one of more than 120 point mutations in the transthyretin gene and inherited as an autosomal dominant disorder. The mutations cause areduction in the stability of the tetrameric structure and dissociation into dimers and monomers as the rate-limiting step in amyloid formation is promoted. Clinical symptoms are related to the specific mutation, the age of onset, the ethnic background and environmental factors. The nerves, heart, eyes and intestines are paticularly affected. In general, two different age peaks are observed. An accumulation occurs at the age of 25-35years with predominantly neurological symptoms. The second peak occurs between the ages of 55 and 65 years and is commonly associated with cardiac involvement with or without polyneuropathy. Characteristic for the nerve involvement are the symmetrical small fiber polyneuropathy and an autonomous polyneuropathy. The typical picture of cardiac involvement is biventricular hypertrophy with diastolic dysfunction finally resulting in restrictive cardiomyopathy. In addition to the symptomatic treatment for the alleviation of individual organ disorders, for many years liver transplantation was the only causal therapy of ATTR amyloidosis. Since 2011 tafamidis, ahighly selective transthyretin stabilizer, has been the first drug approved for treatment of ATTR resulting in reduction of the progression of polyneuropathic symptoms. Other therapeutic approaches to reduce amyloid formation (patisiran and inotersen) effectively reduce transthyretin blood levels, leading to areduction in polyneuropathy and improved quality of life. The approval is expected in 2018.

Platform Session – Electromyography: Preconscious and conscious responses to thermoalgesic stimulation in healthy subjects and patients with small fibre polyneuropathy

Functional evaluation of small fibers is still a challenging task for neurophysiologists. Adelta fibers function may be evaluated by nociceptive evoked potentials but there is no known neurophysiological method to evaluate a potential dysfunction of unmyelinated type C fibers. We have used a quantitative psychophysical method to demonstrate disturbance in pain and temperature assessment in patients with small fiber polyneuropathy (SFPNP). In 16 healthy volunteers and 16 patients with SFPNP, we applied the thermode of a Thermotest (Somedic, Sweden), already heated at either 41, 43 and 45 °C, over the skin of the ventral forearm for the subjects to mark the first preconscious pain sensation, and the later conscious evaluation of the temperature sensation on an electronic VAS system consisting of graded manipulandum lever of 10 cm long. Subjects were warned that the thermode could be either hot, cold or at neutral temperature and instructed to continue marking their sensation during 40 s after the initial sensation. Only the results of heat stimulation are reported here. We measured two aspects: The first initial straight lever displacement, which indicated the reaction to the first sensation, and the degree of adaptation to the thermode temperature during 40 s. The initial reaction was larger in healthy subjects than in patients but the maximum level of pain was not different between healthy subjects and patients. Adaptation was present in all temperatures in healthy subjects, with a decrease of the sensation of more than 20% of the maximum level at 20 s. In contrast, patients expressed significantly less adaptation at all temperatures, with only 12% ± 5% decrease at 40 s. Patients with SFPNP have reduced initial sensation and late adaptation to constant temperature stimuli. Our results show a quantitative novel method for the assessment of functions of temperature and pain fibers.

Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy.

ABSTRACT Introduction: Pain mechanisms in fibromyalgia syndrome (FMS) are not clearly understood. Growing evidence appears to suggest a role for small fiber polyneuropathy (SFPN) in some FMS patients, as measured by epidermal nerve fiber density (ENFD). We aimed to better characterize and distinguish the subset of patients with both fibromyalgia and small fiber, early or mild sensory polyneuropathy (FM‐SFSPN). Methods: 155 FMS patients with neuropathic symptoms completed a Short Form McGill Questionnaire and visual analog scale in addition to having skin biopsies, nerve conduction studies (NCS), and serologic testing. Results: Sural and medial plantar (MP) response amplitudes correlated with ENFD, with markers of metabolic syndrome being more prevalent in this subset of patients. Pain intensity and quality did not distinguish patients. Discussion: The FM‐SFSPN subset of patients may be identified through sural and MP sensory NCS and/or skin biopsy but cannot be identified by pain features and intensity. Muscle Nerve 58: 625–630, 2018

Small Fiber Polyneuropathy in Patients with Neurofibromatosis, Type 1 (S31.008)

Small Fiber Polyneuropathy in Patients with Neurofibromatosis, Type 1 (S31.008)

Small Fiber Polyneuropathy Is Prevalent in Patients Experiencing Complex Chronic Pelvic Pain.

To demonstrate the prevalence of small fiber polyneuropathy (SFPN) in patients with refractory chronic pelvic pain (CPP). Retrospective study of prospective database. Participants were complex CPP patients recruited from subspecity referral clinics defined as those who were refractory to initial treatment and/or exhibited comorbid pain syndromes at initial presentation. Comprehensive treatment history for CPP was obtained, and participants referred as above; 3-mm punch biopsies were obtained of the lower extremity and sent to diagnostic reference labs to evaluate for SFPN. The reported lab sensitivity and specificity for SFPN are 78-92% and 65-90%, respectively. Twenty-five of 39 patients (64%) were positive for SFPN. Comorbid conditions noted in our population included gastroesophageal reflux disease (46%), migraine (38%), irritable bowel syndrome (33%), lower back pain (33%), fibromyalgia (38%), endometriosis (15%), interstitial cystitis (18%), vulvodynia (5%), and other chronic pain syndromes (36%). The prevalence of SFPN in our specialty referral patients with complex CPP is remarkably high vs published general population prevalence data (53/100,000). Identification of SFPN in this complex population shifts the focus from undefined syndromes to symptom complexes with linked potentially treatable mechanisms (e.g., SFPN, central sensitization). Most CPP patients with SFPN are undiagnosed. Considering the diagnosis may expand treatment options beyond conventional or so-called adjuvant analgesics. Treatment may expand to therapies such as IV lidocaine, IVIG, or other immunomodulatory options. In addition, the value to the patient of receiving a diagnosis for a multisystem or refractory pain syndrome, often attributed to negative psychologic factors, cannot be underestimated. Identifying SFPN should be contemplated in CPP patients who present with multisystem pain or who have not responded to initial evaluation and management.

IVIg for apparently autoimmune small-fiber polyneuropathy: first analysis of efficacy and safety.

Objectives:Small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. We have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barré and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this ‘apparently autoimmune SFPN’ (aaSFPN), but intravenous immunoglobulin (IVIg), first-line for Guillain-Barré and CIDP, is prescribed off-label for aaSFPN despite very high cost. This project aimed to conduct the first systematic evaluation of IVIg’s effectiveness for aaSFPN.Methods:With IRB approval, we extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution and other potential causes excluded. IVIg needed to have been dosed at ⩾1 g/kg/4 weeks for ⩾3 months. We chose two primary outcomes – changes in composite autonomic function testing (AFT) reports of SFPN and in ratings of pain severity – to capture objective as well as patient-prioritized outcomes.Results:Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62% of skin biopsies, and 89% of composite AFT. Evidence of autoimmunity included 27% of patients having systemic autoimmune disorders, 20% having prior organ-specific autoimmune illnesses and 80% having ⩾1/5 abnormal blood-test markers associated with autoimmunity. A total of 73% had apparent small-fiber-restricted autoimmunity. IVIg treatment duration averaged 28 ± 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89% at baseline to 55% (p ⩽ 0.001). Sweat production normalized (p = 0.039) and the other four domains all trended toward improvement. Among patients with pre-treatment pain ⩾3/10, severity averaging 6.3 ± 1.7 dropped to 5.2 ± 2.1 (p = 0.007). Overall, 74% of patients rated themselves ‘improved’ and their neurologists labeled 77% as ‘IVIg responders’; 16% entered remissions that were sustained after IVIg withdrawal. All adverse events were expected; most were typical infusion reactions. The two moderate complications (3.6%) were vein thromboses not requiring discontinuation. The one severe event (1.8%), hemolytic anemia, remitted after IVIg discontinuation.Conclusion:These results provide Class IV, real-world, proof-of-concept evidence suggesting that IVIg is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provide rationale for prospective trials, inform trial design and indirectly support the discovery of small-fiber-targeting autoimmune/inflammatory illnesses.

Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy.

Multiple studies now confirm that ∼40% of patients with fibromyalgia syndrome meet diagnostic criteria for small-fiber polyneuropathy (SFPN) and have objective pathologic or physiologic evidence of SFPN, whereas 60% do not. Given possibilities that tens or hundreds of millions globally could have SFPN, developing screening tools becomes important. This analysis explored whether specific symptoms might help distinguish these fibromyalgia endophenotypes. With institutional review board approval, all adults tested for SFPN by distal-leg skin biopsy or autonomic function testing at Massachusetts General Hospital in 2014 to 2015 were queried about symptoms. Inclusion required a physician's fibromyalgia syndrome diagnosis plus meeting the American College of Rheumatology 2010 Fibromyalgia Criteria. The primary outcome was the validated Small-fiber Symptom Survey, which captures severity of all known SFPN-associated symptoms. The Composite Autonomic Symptom Score-31, Short-Form Health Survey-36, and Short-Form McGill Pain Questionnaires provided secondary outcomes. Among the 39 participants, 14 had test-confirmed SFPN (SFPN+) and 25 did not (SFPN-). Their pain severity did not differ. Paresthesias ("tingling") were different (worse) in the SFPN+ group (3.14 ± 0.9 vs 2.28 ± 1.1; P = 0.16). Their component subscore for dysautonomia symptoms was also worse (10.42 ± 4.0 vs 7.16 ± 4.0; P = 0.019). Receiver operating characteristic analyses revealed that each item had fair diagnostic utility in predicting SFPN, with areas under the curve of 0.729. No secondary questionnaires discriminated significantly. Among patients with fibromyalgia, most symptoms overlap between those with or without confirmed SFPN. Symptoms of dysautonomia and paresthesias may help predict underlying SFPN. The reason to screen for SFPN is because-unlike fibromyalgia-its medical causes can sometimes be identified and definitively treated or cured.

Diabetic Neuropathy

The diabetic polyneuropathy (DN) is a common disorder with diverse clinical presentations depending on the type and duration of diabetes, number of nerve fibers affected and its glycemic control. They progress in length-dependent pattern causing severe sensory-motor deficit, more common in distal lower limbs than in upper limbs. In addition, small fiber polyneuropathy has been identified in vast majority of patients affecting sensory and autonomic system in distal limbs. Excruciating pain, trophic changes in the feet, abnormal sweating and numbness are the main manifestations of small fiber DN. Occasionally diabetic neuropathy can present with focal and multifocal neuropathies of cranial, truncal and peripheral nerves among patients with long standing diabetes and age over 50. The length dependent DN hardly improves over period of time when compared to focal or multifocal neuropathy which is usually self-limiting after a course of few relapses. Therefore, adequate attention should be paid on early clinical diagnosis, identifying sub types and complications to tailor the appropriate treatment or to initiate preventive measures to avoid the devastating consequences of DN.

Validation and continuing development of a patient-reported survey of small-fiber polyneuropathy symptoms (P4.317)

Validation and continuing development of a patient-reported survey of small-fiber polyneuropathy symptoms (P4.317)

(399) Small Fiber Polyneuropathy: A Big Clue to Etiology and Management of Chronic Pelvic Pain (CPP)

(399) Small Fiber Polyneuropathy: A Big Clue to Etiology and Management of Chronic Pelvic Pain (CPP)

What's in the Literature?

In this edition of this column, we review new studies concerning the pathophysiology, treatment, and outcomes of patients with necrotizing myopathy, genetic testing in congenital myopathies, and limb girdle muscular dystrophies, and the incidence of polyneuropathy in the myotonic dystrophies. Various studies in myasthenia gravis, including those concerning antibody testing, clinical features, and quality of life are also reviewed as are recent findings in congenital myasthenic syndromes. Finally, 2 studies concerning polyneuropathy are discussed, including one on the association of polyneuropathy in patients with the metabolic syndrome and one on laboratory testing in patients with otherwise idiopathic small fiber polyneuropathy.

Initial Development and Validation of a Patient-Reported Symptom Survey for Small-Fiber Polyneuropathy.

This article reports the initial development and early psychometric validation of a new patient-reported outcome measure intended to capture the wide range of multisystem symptoms of SFPN. When further developed, it could potentially help clinicians diagnose and monitor patients, and help advance research.

Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy.

Small-fiber polyneuropathy (SFPN) causes non-specific symptoms including chronic pain, cardiovascular, gastrointestinal, and sweating complaints. Diagnosis is made from history and exam in patients with known risk factors such as diabetes, but objective test confirmation is recommended for patients without known risks. If tests confirm SFPN, and it is "initially idiopathic" (iiSFPN), screening for occult causes is indicated. This study's aim was to evaluate the 21 widely available, recommended blood tests to identify the most cost-effective ones and to learn about occult causes of iiSFPN. Records were reviewed from all 213 patients with SFPN confirmed by distal-leg skin biopsy, nerve biopsy, or autonomic-function testing in our academic center during 2013. We determined the prevalence of each abnormal blood-test result (ABTR) in the iiSFPN cohort, compared this to population averages, and measured the costs of screening subjects to obtain one ABTR. Participants were 70% female and aged 43.0±18.6years. High erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA; ≥1:160 titer) were most common, each present in 28% of subjects. The ABTR ≥3 ×more prevalent in iiSFPN than in the total population were high ESR, high ANA, low C3, and Sjögren's and celiac autoantibodies. Together, these suggest the possibility of a specific association between iiSFPN and dysimmunity. ABTR identifying diabetes, prediabetes, and hypertriglyceridemia were less common in iiSFPN than in the population and thus were not associated with iiSFPN here. The six most cost-effective iiSFPN-associated blood tests-ESR, ANA, C3, autoantibodies for Sjögren's and celiac, plus thyroid-stimulating hormone-had estimated cost of $99.57/person and 45.6% probability of obtaining one abnormal result. Angiotensin-converting enzyme was elevated in 45%, but no patients had sarcoidosis, so this test was futile here.

Small Fiber Neuropathy Following Vaccination.

To identify clinical and quantitative relationship between vaccinations and small fiber neuropathy (SFN). SFN refers to damaged unmyelinated or thinly myelinated sensory and/or autonomic fibers. Diagnosis is primarily based on clinical presentation. Intraepidermal nerve fiber density can provide diagnostic confirmation with a sensitivity of 88% and a specificity of 91%. However, the possible association between vaccination and small fiber polyneuropathy is not well defined. Case study. Fourteen-year-old white adolescent girl presented with intractable generalized pain for 1.5 years. Burning dysesthetic pain began in the lower back and progressed to all extremities 9 days following human papillomavirus vaccination. The pain persisted despite various pain medications. Examination was significant for allodynia of right scapula (T4-T6) and decreased pinprick sensation in feet. MRI Brain with and without contrast, MR Face, Orbit with and without contrast, and MR Cervical, Lumbar spines with and without contrast were all normal. Nerve Conduction Studies/Electromyogram studies were unremarkable, and skin biopsy of the right thigh and foot showed low intraepidermal nerve fiber density with normal sweat gland nerve fiber density. This case report describes an acute onset of non-length-dependent SFN potentially related to human papillomavirus vaccine administration. Literature review includes several similar case studies, and various pathological processes have been proposed for vaccine-associated polyneuropathies. Some theories describe immune-mediated hypersensitivity to the solvents/adjuvants and/or invasion of nervous system through a prolonged, less virulent infection. However, the lack requires that evidence must be carefully reviewed.

Pain Syndromes Other Than Headache

Pain is experienced within a complex biologic, emotional, psychological, and social context that may defy physical examination, diagnostic procedures, and laboratory tests. This chapter aims to empower internists to improve their medical practices in pain management. It provides a scientific background that covers nociception and how sensory processing occurs at multiple levels in the body. Clinical assessment is detailed, as well as diagnostic categories that include mixed or uncertain chronic pain syndromes (back pain, fibromyalgia, postamputation pain, pain from cancer and bone) and neuropathic pain syndromes (polyneuropathy, mononeuropathy multiplex, ganglionopathy, genetic disorders, focal and regional syndromes). Treatment of chronic pain can be surgical or interventional. Pharmacologic treatment for acute and chronic nociceptive pain includes special considerations for geriatric and terminal patients. For treatment of neuropathic pain, medications are the major component. One tables lists iatrogenic nerve injuries that can cause posttraumatic neuralgia and complex regional pain syndrome. Other tables detail stepwise pharmacologic management of neuropathic pain and cite recommendations on opioid use from the Centers for Disease Control and Prevention. One figure illustrates how pain transducers monitor and influence tissue conditions. Other figures show sensory processing in the spinal cord dorsal horn, physical findings in the feet of patients with bilateral foot pain from small-fiber polyneuropathy, illustrate how examination can identify specific nerve injuries causing chronic pain, and provide classification of chronic pain syndromes. This chapter contains 82 references.