Diagnosis Of Small Fiber Neuropathy Research Articles

Characterizing Acute-Onset Small Fiber Neuropathy.

Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

Small fiber neuropathy in irritable bowel syndrome.

In this study, we intend to evaluate the occurrence of small fiber neuropathy in patients with irritable bowel syndrome (IBS). Small fiber neuropathy (SFN) is a sensory neuropathy that results from the degeneration of small Aδ and unmyelinated C fibers. SFN manifests positive symptoms, such as tingling, burning, prickling, and aching, and negative symptoms, including numbness, tightness, and coldness. The SFN coexistence with other comorbidities (e.g., fibromyalgia, inflammatory bowel disease, celiac disease) has been reported in previous studies. We conducted a cross-sectional study to assess the coexistence of SFN and IBS. Forty-two IBS patients and forty-three healthy individuals were asked to complete the Michigan Neuropathy Screening Instrument (MNSI) questionnaire. Results greater than three (>3) were considered positive. Participants with positive MNSI questionnaire results were examined for any neuropathy signs according to the Utah Early Neuropathy Scale (UENS) examination. The participants with positive results for the questionnaire and examination were checked for the sural and the superficial peroneal nerve conduction study (NCS). Normal NCS represented intact large fibers and the diagnosis of SFN. Ten participants, 7 (16.7 %) in the IBS group and 3 (6.9 %) in the healthy group, had positive results for the questionnaire. Four participants were positive for the examination, with normal NCS, and were classified as SFN-positive. All four SFN diagnoses were from the IBS group. No one in the healthy group was diagnosed with SFN. We could find a significant statistical difference (p<0.05) between the IBS and healthy groups regarding the prevalence of SFN diagnosis. The co-occurrence of SFN and IBS suggests the possibility of a generalized neuropathy syndrome characterized by widespread neuronal impairment. Thus, any peripheral neuropathy symptom in IBS patients (and potentially other chronic pain disorders) should be evaluated for SFN since timely diagnosis and proper treatment result in a better quality of life for the patients.

Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. MAGNET quickly generates research-quality metrics during clinical examinations.

Usefulness of the skin-wrinkling test in a patient with probable small fiber neuropathy and Gaucher disease

BackgroundGaucher disease (GD) is an autosomal recessive disease characterized by an inborn metabolic error. Although pain attributed to skeletal involvement is one of the most frequent symptoms of this condition, some patients may have neuropathic pain. Therefore, recent studies have analyzed the occurrence of peripheral polyneuropathy in patients with GD. In these studies, in cases when normal neurological examination and electroneuromyography were found, small fiber neuropathy (SFN) was investigated, mainly using skin biopsy and quantitative sensory testing.Case presentationWe demonstrate the usefulness of the skin-wrinkling test performed by immersion in water for the evaluation of SFN in a 27-year-old woman with GD who presented with neuropathic pain. After excluding other causes, the main hypothesis was an association between SFN and GD, which was recently described in the literature and possibly underdiagnosed.ConclusionsAlthough only skin biopsy can confirm the diagnosis of SFN, the skin-wrinkling test can be useful for the complimentary assessment of pain in patients with GD, owing to its easy application and wide availability.

Serum Neurofilament Light Chain Levels in Small Fiber Neuropathy Patients with Skin Denervation and Ongoing Neuropathic Symptoms (P14-8.004)

<h3>Objective:</h3> To identify active axonal damage by measurement of serum neurofilament light chain (sNfL) levels in patients with small fiber neuropathy (SFN) and ongoing neuropathy symptoms. <h3>Background:</h3> SFN is associated with sensory symptoms and is evident by skin biopsy which show a reduction of the intraepidermal nerve fiber density (IENFD) indicating skin denervation. SFN patients may complain of prolonged/worsening symptoms, but it is not clear if this is associated with continuous axonal damage. <h3>Design/Methods:</h3> Blood samples were collected from 95 consecutive patients that were referred for a skin biopsy due to suspected SFN. All patients had symptoms that were consistent with a clinical diagnosis of SFN. Patients were excluded if they had clinical or imaging evidence for a central nervous system disorder, electrodiagnostic abnormalities or absence of electrodiagnostic evaluation. Following these exclusions, 34 patients were included for analysis. Skin biopsy was performed 2–3 months from symptoms onset by 4 patients, 4–12 months by 7, and after more than 12 months by 23. Severe skin denervation was defined by an intraepidermal nerve fiber density (IENFD) below the 5^th percentile per age, mild denervation when the IENFD was at the 5–20^th percentiles, and above the 20^th percentile was considered normal. <h3>Results:</h3> The majority of patients (29/34; 85%) showed normal sNfL levels and almost half of the patients showed skin denervation (15/34; 44%). Two patients with skin denervation (2/15; 13.3%) showed elevated sNfL, after 7 and more than 12 months from symptoms onset. The skin biopsy was normal in the other 3 patients with elevated sNfL, obtained 2, 8 and more than 12 months from symptoms onset. All patients with elevated sNfL had a history of chemotherapy treatment or immune-mediated disorders. <h3>Conclusions:</h3> In this cohort, a small portion of patients with SFN and skin denervation showed increased sNfL which indicated ongoing axonal damage. <b>Disclosure:</b> Dr. Zohar has nothing to disclose. Miss Qassim has nothing to disclose. Dr. Eltity has nothing to disclose. Dr. Keren has nothing to disclose. Efrat Shavit has nothing to disclose. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mapi Pharma. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Chapman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merk Serono. The institution of Dr. Chapman has received research support from Ministry Of Industry. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TEVA. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda . Dr. Dori has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medison Pharma. Dr. Dori has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medison Pharma. The institution of Dr. Dori has received research support from Biogen. The institution of Dr. Dori has received research support from Pfizer. The institution of Dr. Dori has received research support from Alnylam therapeutics. Dr. Dori has received intellectual property interests from a discovery or technology relating to health care.

Corneal Sub-Basal Nerve Plexus in Non-Diabetic Small Fiber Polyneuropathies and the Diagnostic Role of In Vivo Corneal Confocal Microscopy.

In vivo corneal confocal microscopy (IVCM) allows the immediate analysis of the corneal nerve quantity and morphology. This method became, an indispensable tool for the tropism examination, as it evaluates the small fiber plexus in the cornea. The IVCM provides us with direct information on the health of the sub-basal nerve plexus and indirectly on the peripheral nerve status. It is an important tool used to investigate peripheral polyneuropathies. Small-fiber neuropathy (SFN) is a group of neurological disorders characterized by neuropathic pain symptoms and autonomic complaints due to the selective involvement of thinly myelinated Aδ-fibers and unmyelinated C-fibers. Accurate diagnosis of SFN is important as it provides a basis for etiological work-up and treatment decisions. The diagnosis of SFN is sometimes challenging as the clinical picture can be difficult to interpret and standard electromyography is normal. In cases of suspected SFN, measurement of intraepidermal nerve fiber density through a skin biopsy and/or analysis of quantitative sensory testing can enable diagnosis. The purpose of the present review is to summarize the current knowledge about corneal nerves in different SFN. Specifically, we explore the correlation between nerve density and morphology and type of SFN, disease duration, and follow-up. We will discuss the relationship between cataracts and refractive surgery and iatrogenic dry eye disease. Furthermore, these new paradigms in SFN present an opportunity for neurologists and clinical specialists in the diagnosis and monitoring the peripheral small fiber polyneuropathies.

Functional and structural markers of peripheral microvascular autonomic neuropathy.

Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment. Fifteen patients with confirmed SFN (idiopathic neuropathy [n=10], chemotherapy-induced peripheral neuropathy [n=2], impaired glucose tolerance [n=1], hereditary transthyretin amyloidosis (hATTR) [n=1], pulmonary sarcoidosis [n=1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART). We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function. Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system.

Response of Sjogren-related Small Fiber Neuropathy to rituximab

Objective Small fiber neuropathy typically presents as loss of temperature and pain sensation and may be associated with other autonomic symptoms. Sjogren's-related ganglionopathy can selectively affect small fibers. Current treatment options for small fiber neuropathy secondary to Sjogren's syndrome include glucocorticoids, IVIG, or immunomodulatory agents such as rituximab. However, these treatments are of uncertain effectiveness and can have variable responses. We present a case of Sjogren's-related small fiber neuropathy that had complete symptom resolution with rituximab. Background A 54 year old female presented to the clinic with neuropathic pain starting in her legs, which ascended to her trunk and arms after one week. She also reported five years of dry eyes. On initial presentation, physical exam showed normal sensation but a diagnosis of small fiber neuropathy was made by skin biopsy. The neuropathy was attributed to seronegative Sjogren's syndrome diagnosed by salivary gland biopsy. She had previously failed treatment with prednisone 40 mg daily and IVIG. After presentation to the clinic, she was started on rituximab every 4 months. A log of symptoms kept by the patient clearly demonstrated a reduction in symptoms following each Rituxan dose. She achieved complete symptom resolution after 19 months with Rituxan 10 mg/mL every 4 months. Design/Methods NA. Results NA. Conclusions In summary, our patient responded dramatically to rituximab after failing treatment with glucocorticoids and IVIG. Treatment of Sjogren's-related small fiber neuropathy has consisted of empiric trials of glucocorticoids and IVIG, although response to these treatments has been variable. Rituximab has been useful in Sjogren's-related neuropathy, although it remains unclear whether it is effective in small fiber neuropathy. Our case illustrates that patients with Sjogren's-related small fiber neuropathy, even if seronegative, may respond dramatically to rituximab. We concluded that rituximab can be considered in treatment of this condition, especially in patients who don't respond to first line immunotherapies.

Sympathetic skin response, cutaneous silent period and nociceptive flexion reflex in Fabry disease

Background &amp; Objective: Fabry disease is one of the well-known causes of the small fiber neuropathy. This study aims to explore small and large nerve fiber functions in patients with Fabry disease without using any extra equipment in a standard neurophysiology laboratory. Methods: Patients with Fabry disease at our tertiary center were invited to the electrophysiology laboratory. Routine nerve conduction studies (NCS), sympathetic skin response (SSR), cutaneous silent period (CSP) and nociceptive flexion reflex (NFR) tests were performed. The same protocol was applied to matched healthy subjects. Results: Nineteen patients and 19 healthy controls were included. Carpal tunnel syndrome was diagnosed in 3 patients (15.9%). Palmar and plantar SSRs could not be obtained in 4 and 9 patients, respectively. Abnormal CSP responses in the upper and lower extremities were recorded in 2 and 7 patients, respectively. The NFR response was abnormal in 8 patients. In total, at least one of the SSR, CSP or NFR was abnormal in 73.7% of patients. Conclusions: The study showed that combining SSR, CSP and NFR tests along with NCS could help to determine any abnormality in small and large fiber functions in most patients. The overall sensitivity of all tests was approximately 70% compared with the clinical diagnosis of small fiber neuropathy. This study is unique in that it explored a combination of NCS, SSR, CSP and NFR tests in Fabry disease.

Teaching NeuroImage: Absence of Wrinkles in Small Fiber Neuropathy.

A 48-year-old woman with clinical diagnosis of small fiber neuropathy, supported by abnormal thermal thresholds using quantitative sensory testing, underwent the water immersion wrinkling test showing lack of digital wrinkles (Figure). Normally, in the glabrous skin of the distal phalanges, water penetrates the sweat ducts provoking electrolytic changes that increase the firing of sympathetic terminals leading to vasoconstriction of the glomus bodies, generating wrinkles.1 Sympathetic fiber damage is responsible for the absence of wrinkles. This test has a sensitivity of 71% (58%–82%) and a specificity of 73% (56%–85%).2 This is a simple, noninvasive, frequently forgotten bedside test that contributes to the diagnosis of small fiber neuropathy.

A Novel Algorithm for the Evaluation of Corneal Nerve Beadings by in vivo Confocal Microscopy in Patients With Type 1 Diabetes Mellitus.

PurposePeripheral neuropathy could complicate diabetes mellitus (DM). In vivo confocal microscopy (IVCM) is an ocular examination for the diagnosis of small fiber neuropathies and the detection of the earliest corneal sub-basal nerve plexus (SBP) alterations. Corneal SBP characteristics include focal enlargement along with the nerve fiber, called corneal beadings. These dilatations represent a mitochondrial accumulation induced by the reactive oxygen stress, as a consequence of hyperglycemia. For this reason, corneal beadings are considered indicative of metabolic activity. This study aimed to describe the corneal characteristics of a population of type 1 diabetes mellitus (T1DM) well metabolically controlled, using a new algorithm for the analysis of corneal beading size (BS).MethodsPatients aged ≥18 years affected by T1DM were compared with healthy subjects who underwent IVCM (Confoscan 4; Nidek Technologies Padova, Italy). Starting from the coordinates of the beadings detected by the IVCM, we implemented a new algorithm for automatically measuring BS in corneal SBP images.ResultsWe compared 20 eyes of T1DM patients with 26 healthy controls. The corneal nerves' fiber length (p = 0.008), corneal nerves' fiber length density (p = 0.008), and the number of fibers (p = 0.017) were significantly lower in the diabetic group compared with controls. There was no difference between diabetic and healthy eyes in the mean number of corneal beadings both in the frame of analysis (p = 0.606) and for 0.1 mm of SBP nerve (p = 0.145). Regarding the BS, patients with T1DM had corneal beadings larger than controls (p = 0.036).ConclusionsWe found that the corneal beadings parameters are similar in healthy and T1DM individuals. Nevertheless, measuring the BS with our algorithm, we showed that corneal beadings are enlarged in patients affected by T1DM when compared with healthy controls. Identifying beading expansion in corneal nerve fiber using IVCM should become a useful tool to predict peripheral neuropathy at an early stage.

Role of skin punch biopsy in diagnosis of small fiber neuropathy-A review for the neuropathologist.

Over the last three decades, skin punch biopsy has become the gold standard for diagnosis of small fiber neuropathies, including autonomic neuropathies commonly seen in diabetics, patients with HIV, and children with hereditary sensory autonomic neuropathies and toxin-induced neuropathy. Clinical, biochemical, electrophysiological tests are inconclusive, making it difficult to diagnose and initiate treatment. A skin punch biopsy is easy to perform in the outpatient clinic, is highly sensitive, and provides an objective diagnosis. Importantly, it helps avoid performing invasive nerve biopsy in patients with small fiber neuropathy, thereby preventing complications such as non-healing of the biopsy site, which is common in these patients. Secondly, the greatest advantage of skin punch biopsies is that they can be repeated any number of times, unlike a nerve biopsy, and are useful to evaluate disease progression and therapeutic response. More recently, its use has been expanded to the diagnosis of large fiber neuropathies, inherited demyelinating neuropathies, etc., obviating the need for a nerve biopsy. The European Federation of Neurological Societies has published guidelines for evaluation to ensure uniformity with regard to the site of biopsy, processing, and quantification. The evaluation of the skin biopsy involves morphometric assessment of the intraepidermal nerve fiber density using PGP 9.5 immunostained sections by bright-field microscopy. This review focuses on the practical aspects of skin punch biopsy and its utility for the practicing pathologist.

Toxic exposure in a clinical pathology laboratory as a potential occupational hazard causing small fibre neuropathy

Introduction. Small fibre neuropathy (SFN) is a heterogeneous condition involving the thinly-myelinated Aδ and unmyelinated C-fibres, characterised by pain and altered temperature sensation and perception. Toxins such as alcohol and chemotherapeutic agents are known causes of SFN, with research into other toxic aetiologies well underway. Pathologists are routinely exposed to a variety of organic solvents, such as xylene, acetone and methanol, which potentially lead to the development of SFN.&#x0D; Methods. We performed a retrospective review of all pathologists who were treated at the SFN clinic in our hospital between January 2020 and May 2021. Their clinical presentation, disease course, treatment and outcomes were described.&#x0D; Results. Three patients with SFN were identified. These patients experienced somatic symptoms of SFN such as burning pain, paraesthesia and autonomic symptoms including tachycardia and postural hypotension. Normal nerve conduction studies indicated intact large nerve fibres. Abnormal SFN tests including quantitative sensory testing, quantitative sudomotor axonal testing, and tilt table testing contributed to the diagnosis of SFN. Inflammatory and autoimmune markers were raised in two of the three pathologists. Toxicology screens performed later were negative, possibly indicating that blood solvent concentrations had decreased to undetectable levels over time. Administration of intravenous immunoglobulin (IVIg) resulted in an improvement in symptoms and functional outcomes.&#x0D; Conclusion. Chronic exposure to organic solvents in the routine job scope of pathologists may lead to the development of SFN. Awareness of this hazard is imperative in order to ensure occupational safety.

O-PN003. Corneal sub-basal whorl-like nerve plexus: A landmark for early and follow-up evaluation in transthyretin familial amyloid polyneuropathy

Introduction . To evaluate the quantification of corneal sub-basal whorl-like nerve plexus parameters as a sensitive and static marker in early diagnosis of small fiber neuropathy (SFN) and monitor disease progression in familial amyloid polyneuropathy (FAP) patients. Methods . Fifteen FAP patients and fifteen healthy controls underwent neurological evaluation (including clinical scales and electrophysiological tests) and corneal nerve observation. Corneal nerve fiber density (CNFD), Corneal nerve fiber branch density (CNBD), Corneal nerve fiber length (CNFL) were detected in the central cornea (conventional method) and the whorl-like inferocentral cornea (new method). The Langerhans cells (LC) density in each image was calculated. Results . Corneal parameters were significantly reduced with disease progression. Only inferior whorl length (IWL) was significantly reduced in preclinical patients (with normal SSR and CHEPs results) comparing with age matched controls. IWL, CNFL, CNBD and CNFD were significantly lower in early phase patients. LC density was significantly increased around the central whorl in early phase patients than in healthy controls (p = 0.009), and was lower in the progressive patients. Both IWL and CNFL correlated with severity of neuropathy. IWL was more significantly reduced with the progression of disease than CNFL. The area under the ROC curve to distinguish FAP with CNFL and IWL was 88.0% and 89.3%, respectively, exceeding other parameters. The coefficient of variation of the IWL value was significantly (P < 0.0001) smaller than that of the conventional method. Conclusion . The observation of corneal sub-basal whorl-like nerve plexus can detect SFN in preclinical FAP patients earlier than traditional electrophysiological methods. IWL is the most sensitive and reliable parameters and it can best discriminate FAP patients from controls. The clustering of immature LCs at the whorl area might reflect the inflammatory response of small- fiber nerves at the very early stage.

P-PN021. A case series of cryoglobulinemia with different clinical presentations and different nerve conduction studies (NCS) findings

Introduction . Neuropathy in cryoglobulinemia can be due to hyperviscosity (type I) or non obstructive immune complex mediated inflammatory vasculitis (type II and III). Methods . Case series: Our first patient was a 72-year-old gentleman with 5-month duration of severe asymmetrical neuropathic pain and rapidly progressive weakness in right peroneal and bilateral ulnar distribution associated with significant weight loss and pain, but no sphincter and autonomic dysfunction. He denied fever, arthritis, Raynaud’s phenomenon, rash and edema. His NCS revealed bilateral ulnar and right peroneal neuropathy. Left sural nerve biopsy revealed vasculitis, and cryoglobulin was found to be positive. Myeloma panel was suggestive of Kappa monoclonal gammopathy with normal flow cytometry and bone marrow. We concluded it as cryoglobulinemic vasculitis with Kappa light chain MGUS presenting with mononeuritis multiplex. Second patient was a 56-year-old man, HCV treated one year ago with undetectable viral load currently, and had generalized Myasthenia Gravis, presented with burning sensation of bilateral feet and erythematous macules, blanching papules on ankles, arms with normal power and reflexes. Nerve conduction study was normal and supported the clinical diagnosis of small fiber neuropathy due to cryoglobulinemia with treated HCV. Third case, a 70-year-old lady, presented with tingling sensation of both lower limbs with impaired sensation of up to ankles, distal toes weakness (3/5) and absent ankle reflexes for 2 months. Her NCS showed distal sensorimotor axonal polyneuropathy. She was found to be anti-HCV positive and cryoglobulinemia with viral load of 1 × 10 6 IU/ml. All our patients had no history of exposure to heavy metals, metabolic, infection screening and ENA, ANCA, anti-CCP were negative and cryoglobulin was positive. Conclusion . Nerve conduction study can add to the clinical for diagnosis of various types of polyneuropathy (mononeuritis multiplex, large fiber peripheral neuropathy, small fiber neuropathy) as depicted in our cases.

Assessment of small fiber neuropathy in patients carrying the non-classical Fabry variant p.D313Y.

The pathophysiological significance of the Fabry-related, non-classical variant p.D313Y still remains to be solved. This study assesses the involvement of the peripheral nervous system with respect to small fiber neuropathy and neuropathic pain in female patients carrying p.D313Y. This study examined nine females carrying the Fabry-related p.D313Y variant by obtaining skin punch biopsies above the right lateral malleolus. Intraepidermal nerve fiber density was determined for each patient and compared to reference values matched for the patient's decade of life and sex. Moreover, each patient was characterized by a detailed neurological examination and by pain assessment via questionnaire. Compared to sex-matched lower fifth percentile reference values per decade, intraepidermal nerve fiber density was decreased in seven out of nine patients. Four patients reported acral paresthesias and neuropathic pain with an average visual analogue scale score of 7 out of 10 points. Two patients experienced acute pain crises. Six out of seven patients diagnosed with small fiber neuropathy had a their medical history of hypo- and/or hyperhidrosis. The diagnosis of small fiber neuropathy was made in seven out of nine females carrying the non-classical variant p.D313Y. Moreover, neuropathic pain and symptoms indicative of autonomic nervous system dysfunction seem to be common findings that may be of clinical significance and may warrant therapeutic intervention.

Electrodiagnostic Testing of Small Fiber Neuropathies: A Review of Existing Guidelines.

This article reviews the literature on neurophysiological techniques for the diagnosis of small fiber neuropathy. The review is focused on clinical approach to suspected small fiber neuropathy, letting aside techniques whose clinical applicability is doubtful. We include, however, the special techniques required to examine C and Aδ fibers, which cannot be evaluated directly with conventional neurophysiological methods. The most relevant publications are summarized and recommendations for the clinical assessment of small fiber neuropathy are provided.

Associations of Small Fiber Neuropathy with Geriatric Nutritional Risk Index and Arterial Stiffness in Hemodialysis.

Background Peripheral neuropathy is a common neurological complication in uremic patients, and quantitative sensory testing (QST) is effective for diagnosis of small fiber neuropathy. Malnutrition and arterial stiffness are prevalent in patients undergoing hemodialysis (HD). The associations of small fiber neuropathy with nutritional status and arterial stiffness remain uncertain in maintenance HD patients. Methods A total of 152 HD patients were included. Geriatric nutritional risk index (GNRI), an indicator of nutritional status, was calculated by serum albumin and actual and ideal body weight. Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) > 1400 cm/s. Small fiber neuropathy was assessed by an abnormal QST threshold of cold and warm sensation in patients' hands or feet. Multivariate forward logistic regression analysis was performed to examine the associations among abnormal QST threshold, GNRI, and arterial stiffness. Results baPWV and prevalence of abnormal QST threshold were significantly higher in diabetic patients. Multivariate logistic analyses revealed that older age (OR, 1.081; 95% CI, 1.026–1.139, p = 0.003) and male gender (OR, 4.450; 95% CI, 1.250–15.836, p = 0.021) were associated with abnormal warm threshold of hands. Furthermore, diabetes (OR, 3.966; 95% CI, 1.351–11.819, p = 0.012) and lower GNRI (per 1 unit increase, OR, 0.935, 95% CI, 0.887–0.985, p = 0.012) were associated with abnormal cold threshold of feet. Arterial stiffness (OR, 5.479, 95% CI, 1.132–22.870, p = 0.020) and higher calcium-phosphorus product (OR, 1.071, 95% CI, 1.013–1.132, p = 0.015) were associated with abnormal warm threshold of feet. Conclusions Lower GNRI and arterial stiffness were significantly associated with small fiber neuropathy in patients undergoing HD. Malnutrition risk and vascular factors might play important roles in small fiber neuropathy among patients undergoing HD.

Which Method for Diagnosing Small Fiber Neuropathy?

Introduction: Small fiber neuropathies (SFN) induce pain and/or autonomic symptoms. The diagnosis of SFN poses a challenge because the role of skin biopsy as a reference method and of each neurophysiological test remain to be discussed. This study compares six methods evaluating small sensory and autonomic nerve fibers: skin biopsy, Quantitative Sensory Testing (QST), quantitative sweat measurement system (Q-Sweat), Laser Evoked Potentials (LEP), Electrochemical Skin Conductance (ESC) measurement and Autonomic CardioVascular Tests (ACVT).Methods: This is a single center, retrospective study including patients tested for symptoms compatible with SFN between 2013 and 2016 using the afore-mentioned tests. Patients were ultimately classified according to the results and clinical features as “definite SFN,” “possible SFN” or “no SFN.” The sensitivity (Se) and specificity (Sp) of each test were calculated based on the final diagnosis and the best diagnostic strategy was then evaluated.Results: Two hundred and forty-five patients were enrolled (164 females (66.9%), age: 50.4 ± 15 years). The results are as follows: skin biopsy: Se = 58%, Sp = 91%; QST: Se = 72%, Sp = 39%; Q-Sweat: Se = 53%, Sp = 69%; LEP: Se = 66%, Sp = 89%; ESC: Se = 60%, Sp = 89%; Cardiovascular tests: Se = 15%, Sp = 99%. The combination of skin biopsy, LEP, QST and ESC has a Se of 90% and a Sp of 87%.Conclusion: Our study outlines the benefits of combining skin biopsy, ESC, LEP and QST in the diagnosis of SFN.

Is sudoscan a reliable tool in detecting small fiber neuropathy in Parkinson's disease patients?

Aim: Previous studies have revealed uncertainties concerning the utility of sudoscan in identifying small fiber neuropathy in Parkinson's disease (PD). Patients& methods: We searched for asignificant reduction of electrochemical skin conductance (ESC) in 67 PD patients versus 66 controls with similar characteristics. We conducted analysis of the subgroups of PD patients without diabetes using sudoscan technology. Results: There is no discrimination between patients and controls relative to feet ESC, the modified Hoehn and Yahr Scale and/or Unified Parkinson's Disease Rating Scale. ESC in patients did not differ significantly according to the Unified Parkinson's Disease Rating Scale score. The oldest PD patients with cardiovascular risk factors have more marked small fibers dysfunction. Conclusion: The sudoscan procedure did not show advantage in the diagnosis of small fiber neuropathy. Its diagnostic value increases in some subgroups of patients with cardiovascular co-morbidity.