Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Clinical, histologic, and immunologic signatures of Small Fiber Neuropathy in Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVES: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. METHODS: We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. RESULTS: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. DISCUSSION: This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated.

The role of antibodies in small fiber neuropathy: a review of currently available evidence.

Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and in vitro and in vivo studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.

[Neuropathy in pruritus medicine : Recommended diagnostics and therapy]. / Neuropathie in der Pruritusmedizin : Empfohlene Diagnostik und Therapie.

Chronic itch is a frequent and debilitating condition that greatly affects the quality of life of those affected. In a subset of patients, damage to the peripheral or central nervous system constitutes the cause of the itch. Small-fiber neuropathy, nerve compression syndromes, post-herpetic neuralgia, scars and burns are possible conditions affecting the peripheral nervous system potentially causing itch, whereas space-occupying lesions affecting the spinal cord and stroke are examples of conditions that may induce central itch. Neuropathic itch starts on normal appearing skin, is often accompanied by pain sensations and other dysesthesias, and usually relieved by local cold application. Its distribution depends on the affected site of the somatosensory system. A comprehensive medical history is paramount to reach the diagnosis, while complementary diagnostics with skin biopsies for the investigation of cutaneous neuromorphological alterations or medical imaging to rule out nerve impingement may be advised in selected cases. Topical agents such as capsaicin or local anesthetics as well as systemic drugs such as gabapentinoids, antidepressants and opioid receptor modulators are used in the treatment of neuropathic itch. This review article provides an overview of the clinical features, underlying causes, diagnostic workup and therapeutic approach in neuropathic itch.

Pathological evaluation of the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy.

Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto-Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.

YAP Ultralate Laser-Evoked Responses in Fibromyalgia: A Pilot Study in Patients with Small Fiber Pathology.

Background: The investigation of C-fiber-evoked ultralow-level responses (ULEPs) at somatic sites is difficult in clinical practice but may be useful in patients with small fiber neuropathy. Aim: The aim of the study was to investigate changes in LEPs and ULEPs in patients with fibromyalgia affected or not by abnormal intraepidermal innervation. Methods: We recorded LEPs and ULEPs of the hand, thigh and foot in 13 FM patients with a normal skin biopsy (NFM), 13 patients with a reduced intraepidermal nerve fiber density (IENFD) (AFM) and 13 age-matched controls. We used a YAP laser, changing the energy and spot size at the pain threshold for LEPs and at the heat threshold for ULEPs. Results: ULEPs occurred at a small number of sites in both the NFM and AFM groups compared to control subjects. The absence of ULEPs during foot stimulation was characteristic of AFM patients. The amplitude of LEPs and ULEPs was reduced in patients with AFM at the three stimulation sites, and a slight reduction was also observed in the NFM group. Conclusions: The present preliminary results confirmed the reliability of LEPs in detecting small fiber impairments. The complete absence of ULEPs in the upper and lower limbs, including the distal areas, could confirm the results of LEPs in patients with small fiber impairments. Further prospective studies in larger case series could confirm the present findings on the sensitivity of LEP amplitude and ULEP imaging in detecting small fiber impairments and the development of IENFD in FM patients.

Small fiber neuropathy in irritable bowel syndrome.

Aim: In this study, we intend to evaluate the occurrence of small fiber neuropathy in patients with irritable bowel syndrome (IBS). Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Polyneuropathy as an initial manifestation of Hereditary Transtyretin Amyloidosis (ATTRV) in a young patient: Case report of a diagnostic challenge.

We report the case of a 27-year-old man with transthyretin amyloidosis secondary to the p.Val142Ile mutation with an atypical clinical presentation of predominantly lower limb polyneuropathy without cardiac involvement. p.Val142Ile is mainly associated with cardiopathy, whereas the neuropathic phenotype is mainly associated with p.Val50Met. Our patient belongs to a non-endemic region and due to his lack of support network a possible familial component is unknown. His case represents a diagnostic challenge given the wide heterogeneity of clinical manifestations associated with the disease, with other possible diagnoses of polyneuropathy being reasonably excluded according to prevalence and frequency. The particularly unusual genotype-phenotype association distinguishes this case from the classic description of transthyretin amyloidosis secondary to p.Val142Ile.

Age-dependent small fiber neuropathy: Mechanistic insights from animal models.

Small fiber neuropathy (SFN) is a common and debilitating disease in which the terminals of small diameter sensory axons degenerate, producing sensory loss, and in many patients neuropathic pain. While a substantial number of cases are attributable to diabetes, almost 50% are idiopathic. An underappreciated aspect of the disease is its late onset in most patients. Animal models of human genetic mutations that produce SFN also display age-dependent phenotypes suggesting that aging is an important contributor to the risk of development of the disease. In this review we define how particular sensory neurons are affected in SFN and discuss how aging may drive the disease. We also evaluate how animal models of SFN can define disease mechanisms that will provide insight into early risk detection and suggest novel therapeutic interventions.

Serum neurofilament light chain levels correlate with small fiber related parameters in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

BACKGROUND: Recent evidence suggests that both serum neurofilament light chain (sNfL) levels and small fiber related diagnostic variables may be valuable disease biomarkers of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Our study aimed to explore the relations between sNfL and small fiber related skin biopsy and quantitative sensory testing (QST) parameters in a cohort of ATTRv-PN patients and pre-symptomatic carriers. METHODS: We retrospectively analyzed data from 13 ATTRv patients and 21 pre-symptomatic carriers who underwent sNfL dosage, skin biopsy, and QST, and analyzed correlations between sNFL, intraepidermal nerve fiber density (IENFD), and cold (CDT) and warm detection thresholds (WDT). RESULTS: Both sNfL and small fiber related parameters significantly differed between carriers and patients (sNfL: p < 0.0001; IENFD: p = 0.0008; CDT, WDT: < 0.0001). sNFL levels were normal in all carriers, altered in 85% of patients, negatively correlated with distal IENFD (r = -0.47, p = 0.005), and significantly correlated with CDT (r = -0.68; p < 0.0001) and WDT (r = 0.57; p < 0.0001). CONCLUSIONS: Our study showed that sNfL reliably discriminates symptomatic ATTRv-PN patients from pre-symptomatic carriers, and found significant relations between sNfL, skin biopsy, and QST small fiber related parameters, suggesting that sNfL might be a valuable biomarker of peripheral nerve involvement in ATTRv-PN and a supportive criterion for symptomatic disease transition.

[Sequence variants of unknown significance in small fiber neuropathy : Characterization of a heterogeneous patient population]. / Sequenzvarianten unklarer Signifikanz bei Small-Fiber-Neuropathie : Charakterisierung einer heterogenen PatientInnenpopulation.

BACKGROUND: In almost half of patients suffering from small fiber neuropathies (SFN), the etiology remains elusive. For these patients with "idiopathic SFN", symptomatic analgesic therapy is the only option. Reports on a potential genetic background of neuropathic pain syndromes are increasing and particularly in SFN patients, several genetic variants were found mainly located in genes encoding voltage-gated sodium channels. Although up to 30% of SFN patients show genetic alterations, most of these remain of "unknown pathogenic significance" and little is known about "genetic SFN". OBJECTIVES: The study aimed to determine clinical characteristics of SFN patients carrying a rare genetic variant of unknown significance in pain-associated genes. MATERIALS AND METHODS: From 2015 to 2020, 66 patients with primarily idiopathic SFN were examined and rare gene variants of unknown significance detected in 13/66 (20%) of these. A detailed medical history with focus on pain was recorded and patients filled in standardized questionnaires to assess physical and emotional burden due to pain. RESULTS: The authors found 13/66 (20%) patients with rare variants of unknown significance located in pain-associated genes who reported pain refractory to analgesic treatment, a higher number of external factors influencing clinical symptoms, and a higher level of physical impairment and emotional stress due to pain compared with patients without such genetic variants. CONCLUSIONS: Early genetic assessment is recommended to optimize the management of patients with potentially hereditary SFN. Early access to rehabilitation and mental support as well as a consequent elimination of external triggering factors should be granted.

Neurofilament Light Chains in Systemic Amyloidosis: A Systematic Review.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.

Transient Locked-in Syndrome after Aneurysmal Subarachnoid Bleeding due to Spasm Hypoxemia?

How to cite this article: Finsterer J. Transient Locked-in Syndrome after Aneurysmal Subarachnoid Bleeding due to Spasm Hypoxemia? Indian J Crit Care Med 2024;28(1):86.

Gastrointestinal manifestations seen in pediatric patients diagnosed with small fiber neuropathy.

OBJECTIVES: Small fiber neuropathy (SFN) affects the fibers involved in cutaneous and visceral pain and temperature sensation and are a crucial part of the autonomic nervous system. Autonomic dysfunction secondary to SFN and autoimmune receptor antibodies is being increasingly recognized, and gastrointestinal (GI) manifestations include constipation, early satiety, nausea, vomiting, and diarrhea. Enteric nervous system involvement may be a possible explanation of abnormal GI motility patterns seen in these patients. METHODS: Children suspected to have SFN based on symptoms underwent skin biopsy at the Child Neurology clinic at Arnold Palmer Hospital for Children, which was processed at Therapath™ Neuropathology. SFN was diagnosed using epidermal nerve fiber density values that were below 5th percentile from the left distal leg (calf) as reported per Therapath™ laboratory. RESULTS: Twenty-six patients were diagnosed with SFN. Retrospective chart review was performed, including demographic data, clinical characteristics, and evaluation. A majority of patients were white adolescent females. Autonomic dysfunction, including orthostasis and temperature dysregulation were seen in 61.5% of patients (p = 0.124). Somatosensory symptoms, including pain or numbness were seen in 85% of patients (p < 0.001). GI symptoms were present in 85% of patients (p < 0.001) with constipation being the most common symptom seen in 50% of patients. This correlated with the motility testing results. CONCLUSIONS: Pediatric patients with SFN commonly have GI symptoms, which may be the main presenting symptom. It is important to recognize and look for symptoms of small fiber neuropathy in children with refractory GI symptoms that may explain multisystemic complaints often seen in these patients.

Discontinuity third harmonic generation microscopy for label-free imaging and quantification of intraepidermal nerve fibers.

Label-free imaging methodologies for nerve fibers rely on spatial signal continuity to identify fibers and fail to image free intraepidermal nerve endings (FINEs). Here, we present an imaging methodology-called discontinuity third harmonic generation (THG) microscopy (dTHGM)-that detects three-dimensional discontinuities in THG signals as the contrast. We describe the mechanism and design of dTHGM and apply it to reveal the bead-string characteristics of unmyelinated FINEs. We confirmed the label-free capability of dTHGM through a comparison study with the PGP9.5 immunohistochemical staining slides and a longitudinal spared nerve injury study. An intraepidermal nerve fiber (IENF) index based on a discontinuous-dot-connecting algorithm was developed to facilitate clinical applications of dTHGM. A preliminary clinical study confirmed that the IENF index was highly correlated with skin-biopsy-based IENF density (Pearson's correlation coefficient R = 0.98) and could achieve differential identification of small-fiber neuropathy (p = 0.0102) in patients with diabetic peripheral neuropathy.

Investigation of small fiber neuropathy in patients with diabetes mellitus by corneal confocal microscopy.

OBJECTIVES: Corneal confocal microscopy (CCM) is a non-invasive technique that examines the corneal cellular structure. Its use in the detection of small fiber neuropathy is being researched. In our study, we examined the role of CCM in the detection of small fiber neuropathy in diabetic patients, as well as the differences between CCM findings in diabetic patients with and without overt polyneuropathy with neuropathic symptoms. METHODS: 56 Diabetes Mellitus (DM) patients and 18 healthy controls were included in the study. The individuals included in the study were divided into three groups. Patients with diabetes who were found to have polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 1, patients with diabetes and neuropathic symptoms without overt polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 2, and healthy individuals were classified as Group 3. Electrophysiological examination and corneal imaging with CCM were performed in all groups. RESULTS: The CNFD and CNFL values of individuals in the diabetic group were discovered to be lower. CNFD values differ statistically between the groups (p = 0.047). Group 1-Group 3 differs from Group 2-Group 3 (respectively; p = 0.018, p = 0.048). CONCLUSION: Our study demonstrates that CCM can be used in patients with neuropathic symptoms and no polyneuropathy detected in EMG and thought to have small fiber neuropathy. CCM provides an opportunity for early diagnosis in small fiber neuropathy.

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

OBJECTIVES: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. METHODS: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. RESULTS: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST. CONCLUSIONS: Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).

Cognitive, behavioral, and psychological phenotypes in small fiber neuropathy: A case-control study.

OBJECTIVE: Small fiber neuropathy (SFN) is a well-defined chronic painful condition causing severe individual and societal burden. While mood disorders have been described, cognitive and behavioral profiles of SFN patients has not been investigated. METHODS: Thirty-four painful SFN patients underwent comprehensive cognitive, behavioral, psychological, quality of life (QoL), and personality assessment using validated questionnaires. As control samples, we enrolled 36 patients with painful peripheral neuropathy (PPN) of mixed etiology and 30 healthy controls (HC). Clinical measures of neuropathic pain, duration, frequency, and intensity of pain at the time of assessment were recorded. Between-group and correlation analyses were performed and corrected for multiple comparisons. RESULTS: No differences in clinical measures were found between SFN and PPN, and all groups had similar cognitive profiles. SFN patients showed higher levels of anxiety and alexithymia (p < .005) compared to PPN and HC, considering also pain intensity. Maladaptive coping strategies characterized both patient groups, but only SFN revealed higher levels of acceptance of pain (p < .05). Pain intensity and neuropathic symptoms were associated with mood, low QoL and catastrophism (p < .001), particularly, the higher the perceived pain intensity, the higher the use of maladaptive coping strategies (p < .001). The personality assessment revealed significant feelings of worthlessness and somatization traits both in SFN and PPN (p < .002 vs HC). DISCUSSIONS: our results suggest that SFN patients had a normal-like cognitive profile, while their behavioral profile is characterized by mood disorders, alexithymia, maladaptive coping strategies, and poor QoL, as other chronic pain conditions, possibly related to pain intensity. Personality assessment suggests that somatization and feelings of worthlessness, which may worsen the neuropsychological profile, deserve clinical attention when considering patients' therapeutic approaches. At the same time, the high level of acceptance of pain is promising for therapeutic approaches based on psychological support.

Abnormal quantitative sudomotor axon reflex test results in patients with tinnitus as a possible indicator of small fiber neuropathy.

A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN has not been studied. This study investigated a possible relationship between SFN and patients with TN (PwTNs) using autonomic function tests (AFTs) including quantitative sudomotor axon reflex tests (QSART). We performed QSARTs and other AFTs such as the Sympathetic skin response (SSR), Valsalva ratio (VR), and heart rate variability (HRV). The QSART results, obtained at seven hospitals using same protocols, were compared between PwTNs and healthy controls. We confirmed the abnormalities in SSR, VR, and HRV in PwTNs, although those parasympathetic AFTs were not performed in healthy controls. Additionally, we checked Tinnitus handicap inventory (THI) scores for PwTNs and ~50% of PwTNs had low-grade disability, whereas 9.3% had high-grade disability. Data from 57 PwTNs and 122 healthy controls were analyzed. The sweat volumes of QSART in the older age group tended to be higher in the PwTNs than in age-matched healthy controls, and significant differences between the PwTN and control groups were observed in the feet in both sexes (p < 0.001) and in the arms in women (p = 0.013). In the younger age group, the sweat volumes in the feet of men were higher in PwTNs than in healthy controls (p = 0.017). No association was observed between THI and QSART scores. In this study, the sweat volumes in QSARTs were higher in PwTNs than in healthy controls. However, abnormal SSR, HRV, and VR results were not commonly observed in PwTNs. Although the results should be interpreted with caution because of limitations in study, PwTNs might also have SFN apart from dysautonomia. This is the first study to perform QSART with other parasympathetic AFTs in PwTNs. However, larger and more rigorously controlled studies will be needed to reveal the relationship between SFN and TN in the future.