Sympathetic Skin Response Research Articles

Clinical Cues for the Early Diagnosis of Transthyretin-Related Polyneuropathy.

The estimated prevalence of hereditary transthyretin-related familial amyloid polyneuropathy (TTR-FAP) and the small number of known patients in Germany indicate that many patients with TTR-FAP remain undiagnosed, and may instead be classified as "idiopathic." The aim of this study was to identify biomarkers for detecting TTR-FAP among a cohort of patients with idiopathic polyneuropathy (PNP). Clinical evaluations (including the Neuropathy Impairment Score and Neuropathy Disability Score), nerve conduction studies (NCSs), quantitative sensory testing, and autonomic function tests were performed on 23 patients with TTR-FAP and 89 with idiopathic PNP. Discriminant analysis was then performed to identify variables useful for predicting TTR-FAP. Patients with TTR-FAP had paresis of the finger and thumb muscles, and reduced vibration perception and increased pressure pain in the upper and lower extremities. The NCSs showed that action potentials were smaller in the median, ulnar (both motor and sensory), and sural nerves in TTR-FAP. The sensory nerve conduction velocity was also reduced in the ulnar nerve. Autonomic neuropathy was confirmed by reduced sympathetic skin responses in the hands and feet in TTR-FAP. Multivariate discriminant analysis revealed that finger abduction strength, sensory ulnar nerve action potential amplitude, and vibration detection and pressure pain thresholds in the upper extremities were sufficient to correctly identify TTR-FAP in 81.3% of cases. Detailed clinical and neurophysiological investigations of standard parameters in the upper limb may help to identify the otherwise-rare TTR-FAP.

Association of hyperventilation-induced heart rate variability and sudden unexpected death in epilepsy in drug-resistant epilepsy.

Within the general epilepsy population, the incidence of Sudden Unexpected Death in Epilepsy (SUDEP) ranges from approximately 0.35 to 2.3 per 1,000 individuals per year. We aimed to evaluate the relationship between SUDEP risk factors and heart rate variability (HRV) parameters as a potential biomarker of SUDEP in patients with drug-resistant epilepsy (DRE). There were 52 patients diagnosed with DRE and under follow-up, and controls including 45 healthy subjects, included in the study. Hyperventilation-induced HRV (HRVHV) parameters, including the standard deviation of all RR intervals (SDRR), mean heart rate (HR), root mean squares of successive differences (RMSSD), SD of mean NN intervals recordings (SDANN), and HRV triangular index, were assessed during resting. To predict the risk of SUDEP, the relationship between HRV parameters and SUDEP risks was evaluated using the Risk Assessment for Sudden Death in Epilepsy (SUDEP-7) Risk Inventory. No statistically significant difference was found in sympathetic skin response (SSR) latency and amplitudes between the patient and control groups. In comparing healthy control subjects with patients experiencing DRE, we observed significant decreases in SDRRHV and hyperventilation-induced RMSSD (RMSSDHV) values, specifically within HRVHV. Notably, a significant correlation emerged concerning the RMSSDHV values (p < 0.01), when examining the correlation between the SUDEP-7 inventory and HRVHV parameters. This correlation between RMSSDHV and the SUDEP-7 Risk Inventory in patients with DRE represents a novel and consequential finding, suggesting its potential as an indicator of SUDEP risk.

Autonomic Dysfunction in Fibromyalgia Patients: Electrophysiological Evidence from a Cross-sectional Study in Kochi, India

Background: Over the decades, studies from various populations have found fibromyalgia and dysautonomia to be linked. However, recent evidence from Indian populations contradicts these findings. Methods: This cross-sectional study, conducted in a quaternary care centre in South India, recruited 30 women with fibromyalgia (2016 ACR criteria) and 30 age and sex-matched controls. We assessed all participants using Composite Autonomic Symptom Score (COMPASS-31) questionnaires, Sympathetic Skin Response (SSR) for sympathetic dysfunction and Heart Rate Variability battery of tests for parasympathetic dysfunction. Results: Median age of the women was 40 years. Fibromyalgia group reported severe levels of pain and disease impact on life. Fourteen participants (46.7%) with fibromyalgia tested positive for either sympathetic or parasympathetic dysfunction or both, while none of the control participants tested positive for either (odds ratio [OR] = 53.6, 95% confidence interval [CI] = 3–957, p = 0.0068). Conclusion: Dysautonomia is strongly associated with fibromyalgia syndrome. Further research is needed to determine causality.

The value of concomitant testing of cutaneous silent period with sympathetic skin response and heart rate variability in Type-2 diabetes patients: An electrophysiological study.

To explore the association among cutaneous silent period, sympathetic skin response and heart rate variability in diabetes patients. The case-control study was conducted at the Department of Physiology, College of Medicine, Al- Mustansiriyah University, Baghdad, Iraq, from November 1, 2020, to May 20, 2021, and comprised 24 healthy controls in Group I and 49 patients of type 2 diabetes in Group II who were recruited from the neuroelectrophysiological unit of Al-Imamain Al-Kadhmean Teaching Hospital, Baghdad, Iraq. Both groups were subjected to cutaneous silent period, sympathetic skin response and heart rate variability testing. Data was analysed using SPSS 24. Of the 73 subjects, 24(32.9%) were in Group I and 49(67.1%) were in Group II. Cutaneous silent period mean latency values were significantly increased in Group II compared to Group I (p<0.05), and a negative sympathetic skin response in the right lower limb was significantly different between the groups (p<0.001). There was no significant correlation between Cutaneous silent period and sympathetic skin response values (p>0.05). Heart rate variability was significantly increased in diabetic patients with negative sympathetic skin response compared to those with positive sympathetic skin response (p<0.05). Simultaneous measurement of cutaneous silent period, sympathetic skin response and heart rate variability should be done as there were no strong correlation among the tests in diabetic patients.

Understanding inter-individual variability of experimental pain habituation and conditioned pain modulation in healthy individuals

Although reduced experimental pain habituation is proposed as a proxy of diminished endogenous pain modulatory capacity in chronic pain, prior studies show contradictory findings. Even across healthy participants, pain habituation varies substantially, which may relate to another measure of endogenous pain modulation, i.e., conditioned pain modulation (CPM). Hence, this study investigated the relationship between pain habituation and CPM. Pain habituation was assessed in 45 healthy participants between two blocks of 15–20 contact-heat stimuli applied to the hand. Habituation of subjective pain ratings and objective neurophysiological readouts (contact-heat evoked potential (CHEP) and palmar sympathetic skin response (SSR)) was investigated. CPM was assessed by comparing heat pain thresholds before and after hand immersion in a noxious cold (9 °C) and lukewarm water bath (32 °C, to control for repeated measures effects). Pain habituation showed a large variability, with subjective but not objective pain habituation correlating with cold-induced CPM effects (r = 0.50; p = 0.025). This correlation was not observed for ‘true’ CPM effects (corrected for repeated measures effects) nor for CPM effects induced by a lukewarm water bath. These findings suggest that the observed variability in subjective pain habituation may be influenced by both descending endogenous pain modulation and peripheral adaptation processes associated with repeated measures. Objective pain habituation readouts, i.e., CHEPs and SSRs, capture different, complementary aspects of endogenous pain modulation.

The value of electrophysiological testing in the adjunctive diagnosis of premature ejaculation.

Although the four-class system of classifying premature ejaculation (PE), including lifelong PE (LPE), acquired PE (APE), natural variable PE (NPE), and subjective PE (SPE), has existed for many years, objective classification standards in clinical practice are lacking. In this study, we sought to investigate the use of electrophysiologic parameters to assist in the classification of PE, thereby guiding subsequent treatment. From July 2023 to April 2024, 187 study participants were enrolled. For each participant, the biological sensory threshold (BST), penile sympathetic skin response (PSSR), and dorsal nerve somatosensory evoked potential (DNSEP) were recorded. The differences in the PSSR latencies (PL) and DNSEP latencies (DL), the PSSR amplitudes (PA) and DNSEP amplitudes (DA), and the BST were compared among the LPE, APE, SPE, NPE, and healthy control (HC) groups. The participants were divided into the LPE (46 cases), APE (53 cases), SPE (20 cases), NPE (33 cases), and HC (35 cases) groups. The results showed shorter latencies of the PSSR (PL) and DNSEP (DL), larger amplitudes of the PSSR (PA) and DNSEP (DL), and smaller BST in the LPE group than in the NPE, SPE, APE, and HC groups (P < .05). In addition, the larger PA and shorter PL in the APE group than in the NPE and HC groups (P < .05). However, the electrophysiological parameters were not significantly different among the NPE, SPE, and HC groups (P > .05). In addition, PL <1262.0milliseconds and DL <41.85 milliseconds were strong predictors of LPE, 1262.0milliseconds < PL <1430.0milliseconds was a predictor of APE, and PL >1430.0milliseconds suggested possible SPE or NPE. Analysis of the electrophysiological parameters of PE may be helpful for classification and treatment. No previous study, to our knowledge, has analyzed the electrophysiological parameters of the four types of PE. The main limitation is the small sample size. APE is characterized by increased sympathetic excitability, whereas LPE is characterized by increased penile sensitivity and increased sympathetic excitability. However, penile sensitivity and sympathetic excitability in SPE and NPE patients may not differ significantly from normal.

Dysfunction of the autonomic nervous system in gastro-esophageal reflux disease: Consequences for the cardiovascular system

ObjectiveThe pathophysiology of gastro esophageal reflux disease (GERD) implicates autonomic dysregulation of the lower esophageal sphincter tone. Our goal is to investigate whether this dysregulation of the autonomic nervous system (ANS) function observed in isolated GERD cases can affect other systems, such as cardiovascular regulation.Methods: Twenty-five participants were included in the study, 11 patients with isolated GERD and 14 controls. All patients and 7 controls responded to a COMposite Autonomic Symptoms Score 31 (COMPASS 31) questionnaire and underwent functional explorations including EMLA test, sympathetic skin response (SSR), 24-hour heart rate recording and ambulatory blood pressure measurement (ABPM). Seven additional controls underwent a 24-hour heart rate recording only. ResultsGERD patients (Age: mean 36.81±7.82; SR= 0.22) showed high clinically dysautonomic scores (COMPASS 31) (p = 0.015), increased Heart rate variability (HRV) parameters (daytime, nighttime, 24-hour SDNN (standard deviation of the RR interval (NN)), respectively p = 0.003, p < 0.001, p = 0.001; daytime and nighttime very low frequencies (VLF) respectively p = 0.03 and p = 0.007), impaired nocturnal dipping of blood pressure (3/11 patients) and high positivity of EMLA test (7/11, p = 0.037). These outcomes were strongly correlated with clinical dysautonomic assessment. No difference was observed between patients and controls regarding SSR. ConclusionOur data suggests a high parasympathetic tone amongst patients with GERD and a dysregulation of parasympathetic and sympathetic balance in the cardiovascular system with an impairment of the peripheral sympathetic fibers of cutaneous microcirculation, assessed by the EMLA test. GERD may be an inaugural symptom of autonomic neuropathy. Further functional exploration of peripheral small fibers seems to be necessary.

Screening tools for diabetic foot ulcers: a narrative review.

The prevalence of diabetic foot ulcers (DFUs) is 4 to 10% among people with diabetes mellitus. DFUs are associated with increased morbidity and mortality as well as reduced quality of life and have a significant impact on overall healthcare expenditure. The main predisposing factors for DFU are diabetic neuropathy, peripheral arterial disease, and trauma. The fact that a range of tests can be used to identify patients at risk for DFU often causes confusion among practitioners regarding which screening tests should be implemented in clinical practice. Herein we sought to determine whether tests of somatic nerve function, such as pinprick sensation, thermal (cold/hot) test, ankle reflexes, vibration perception, 10-g monofilament, Ipswich touch test, neuropathy disability score, and nerve conduction studies, predict the development of DFUs. In addition, we examined whether sudomotor function screening tests, such as Neuropad, sympathetic skin response, and other tests, such as elevated plantar pressure or temperature measurements, can be used for DFU screening. If not treated properly, DFUs can have serious consequences, including amputation, early detection and treatment are vital for patient outcomes.

Novel neurophysiological evidence for preserved pain habituation across chronic pain conditions

ObjectiveThe present study aimed to investigate whether subjective and objective measures of pain habituation can be used as potential markers for central sensitization across various chronic pain patients. MethodsTwo blocks of contact-heat stimuli were applied to a non-painful area in 93 chronic pain patients (low back pain, neuropathic pain, and complex regional pain syndrome) and 60 healthy controls (HC). Habituation of pain ratings, contact-heat evoked potentials (CHEP), and sympathetic skin responses (SSR) was measured. ResultsThere was no significant difference in any measure of pain habituation between patients and HC. Even patients with apparent clinical signs of central sensitization showed no reduced pain habituation. However, prolonged baseline CHEP and SSR latencies (stimulation block 1) were found in patients compared to HC (CHEP: Δ-latency = 23 ms, p = 0.012; SSR: Δ-latency = 100 ms, p = 0.022). ConclusionGiven the performed multimodal neurophysiological testing protocol, we provide evidence indicating that pain habituation may be preserved in patients with chronic pain and thereby be of limited use as a sensitive marker for central sensitization. These results are discussed within the framework of the complex interactions between pro- and antinociceptive mechanism as well as methodological issues. The prolonged latencies of CHEP and SSR after stimulation in non-painful areas may indicate subclinical changes in the integrity of thermo-nociceptive afferents, or a shift towards antinociceptive activity. This shift could potentially affect the relay of ascending signals. SignificanceOur findings challenge the prevailing views in the literature and may encourage further investigations into the peripheral and central components of pain habituation, using advanced multimodal neurophysiological techniques.

The Electrophysiological Evaluation of Small Fiber Neuropathy in Symptomatic Patients with Vitamin B12 Deficiency before and after Treatment

ABSTRACT Background: Small fiber neuropathy (SFN) leads to sensory and autonomic dysfunction by affecting small-diameter myelinated A-delta and unmyelinated C fibers, with vitamin B12 deficiency identified as one of its causes. Objectives: To achieve early diagnosis of SFN in patients with vitamin B12 deficiency and to illustrate the impact of vitamin B12 replacement therapy using noninvasive electrophysiological tests. Materials and Methods: Patients aged 18 to 65 with vitamin B12 deficiency experiencing neuropathic pain or autonomic symptoms were included. A control group consisted of asymptomatic, healthy volunteers with normal B12 levels. Neurological examinations, cutaneous silent period (CSP), sympathetic skin response (SSR), and cardiovascular autonomic tests (R-R interval variability during the Valsalva maneuver [RRIV-VM] and standing [RRIV-S]) were performed at admission and six months later. Patients received 1000 mcg cyanocobalamin intramuscularly daily for one week, weekly for one month, and monthly for three months. Results: The final analyses included 25 patients and 25 controls. At admission, patients had significantly longer CSP and SSR latencies compared to controls (P = 0.047, P &lt; 0.001) and shortened CSP durations (P = 0.043). The SSR amplitude was lower in patients but not significantly (P = 0.823). Post-treatment, CSP latency, CSP duration, and SSR latency significantly improved (P &lt; 0.001, P = 0.002, P &lt; 0.001). Positive symptoms and autonomic symptoms improved significantly after treatment (P = 0.039, P = 0.016). The number of patients with neuropathic pain significantly decreased (P = 0.008). Conclusion: CSP latency, CSP duration, and SSR latency are effective, non-invasive, and cost-effective screening tests for diagnosing SFN in individuals with B12 deficiency. These tests are also valuable for monitoring the progression of SFN following vitamin B12 replacement therapy. The study supports the use of these noninvasive electrophysiological tests to enhance early diagnosis and treatment efficacy in SFN associated with vitamin B12 deficiency.

Differential diagnosis value of sympathetic skin response and cutaneous silent period on early-stage multiple system atrophy and Parkinson disease

PurposeEarly differentiation between Parkinson's disease (PD) and Multiple system atrophy (MSA), particularly the parkinsonian subtypes (MSA-P), is challenging due to similar clinical symptoms. We aimed to evaluate Sympathetic skin response (SSR) and Cutaneous silent period (CSP) parameters in patients with MSA-P and PD to identify possible biomarkers that could distinguish the two groups of patients in early stage. Methods22 individuals with early-stage MSA-P, 29 with early-stage PD, and 28 healthy controls were recruited from Guangdong Provincial People's Hospital. Demographic data was collected for all participants. Their SSR and CSP were evaluated using clinical electromyography equipment. Data were compared between different groups. The diagnostic accuracy of SSR and CSP parameters was calculated using the ROC curve. Logistic regression was used to produce an integration model to enhance diagnostic utility. ResultsFoot amplitude, CSP end latency and duration distinguished MSA-P from PD with the area under the curve (AUC) 0.770, 0.806, and 0.776, respectively. Foot and hand SSR amplitude distinguished PD from HC with the AUC 0.871 and 0.768, respectively. Foot SSR amplitude, hand SSR amplitude, and CSP end latency distinguished MSA-P from HC with the AUC 0.964, 0.872, and 0.812, respectively. The combination of SSR and CSP parameters differentiation between MSA-P and PD, PD and HC with the AUC 0.829 and 0.879, respectively. ConclusionsAnalysis of SSR and CSP parameters showed excellent diagnostic accuracy in discriminating patients with early-stage MSA-P from HC and good diagnostic accuracy in discriminating patients with MSA-P from PD with early stages.

Nerve function impairment and quality of life in patients with leprosy: a prospective, observational study.

There is a limited number of studies assessing the alterations in nerve function impairment (NFI) in leprosy over an extended period of time. To the best of our knowledge, no published study has evaluated neurological state longitudinally during treatment utilizing a combination of clinical, functional (activity limitation), electrophysiological, and patient-reported quality of life (QOL) outcomes. This prospective, observational study included leprosy patients of all spectra. Over 1 year of treatment, cutaneous and neurological examinations were done in addition to a nerve conduction study (NCS) and sympathetic skin response (SSR) assessment. QOL and activity limitation assessments using the World Health Organization Quality of Life brief version (WHOQOL-BREF) and Screening of Activity Limitation and Safety Awareness scale (SALSA), respectively, were also performed. Out of 63 leprosy patients, loss of sensation was noted in 43 (68.2%) at baseline. At the completion of treatment, proportionate change revealed no change in 18 (28.5%), restored function in 9 (14.2%), improved status in 34 (53.9%), and deteriorated NFI in only 2 (3.1%) cases. The association between NCS-SSR abnormalities was significant for a longer duration of disease at presentation (P = 0.04), in multibacillary cases [OR 9.12 (95% CI, 1.22-67.93)], in those in reaction [OR 3.56 (95% CI, 0.62-20.36)] and in those aged over 40 [OR 1.93 (95% CI, 0.28-13.41)]. There was an improvement in WHOQOL-BREF and SALSA scores at release from treatment (P = 0.005 and P = 0.01, respectively). The majority of leprosy patients on treatment show improvement in NFI at the completion of therapy. However, change is influenced by critical factors such as bacillary load, disease duration, age, and the presence of reaction(s).

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Study on the relationship between peripheral nerve fiber types and levodopa usage in Parkinson's disease.

<p>The aim of this study is to comprehensively determine the types of affected fibers in Parkinson&rsquo;s disease (PD) patients by employing nerve conduction studies (NCS), sympathetic skin response (SSR) examinations, and current perception threshold (CPT) testing and to analyze the correlation between levodopa use and nerve involvement.</p>. <p>This retrospective study included 36 clinically diagnosed PD patients who were recruited between January 2018 and April 2019. All patients underwent NCS, SSR testing, and CPT sensory examinations. Additionally, the PD patients were assessed for disease staging using the Hoehn and Yahr (H-Y) scale.&nbsp;</p>. <p>Fifteen patients were included in the tremor-dominant subtype, ten patients in the rigid-dominant subtype, and eleven patients in the mixed subtype. Eleven patients were using levodopa, while twenty-five patients had never used any anti-Parkinson&rsquo;s medication. Ten patients (28%) showed abnormal sympathetic skin responses (SSR). The CPT examination revealed sensory abnormalities in twenty-four patients (67%), with eighteen patients (75%) experiencing sensory hypersensitivity and six patients (25%) experiencing sensory hypoesthesia. Twelve patients (33%) had normal CPT results. Among the patients with abnormal CPT findings, seven cases (29%) involved large myelinated fiber damage, twenty-two cases (92%) involved small myelinated fiber damage, and nineteen cases (79%) involved unmyelinated fiber damage. The rate of sensory abnormalities was 64% (7/11) in the levodopa group and 68% (17/25) in the non-levodopa group, with no statistically significant difference between the two groups.&nbsp;</p>. <p>The incidence of abnormal CPT findings in PD patients was higher than that of abnormal SSR responses, suggesting that nerve fiber damage primarily affects small fiber nerves (SFN).</p>.

Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.

This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR). The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR. SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration. ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.

Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects.

Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs. Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested. Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure. We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.

Alcohol-related peripheral neuropathy: Clinico-neurophysiological characteristics and diagnostic utility of the neuropathy symptoms score and the neuropathy impairment score

Alcohol overconsumption is well known to cause damage to the peripheral nervous system, affecting both small and large nerve fibers. The aim of this descriptive study was to investigate peripheral nerve damage, and to correlate clinical, epidemiological and neurophysiological findings, in patients diagnosed with Alcohol Use Disorder (AUD). Ninety alcohol-dependent subjects on inpatient basis were enrolled in this prospective study over a 3-year period. Every subject was assessed by the Neuropathy Symptoms Score (NSS) questionnaire and the Neuropathy Impairment Score (NIS) clinical examination grading scale, followed by Nerve Conduction Studies, Quantitative Sensory Testing and Sympathetic Skin Response (SSR) testing. Peripheral neuropathy was diagnosed in 54 subjects (60%), by abnormal neurophysiological tests and presence of clinical signs or symptoms. Among them, pure large fiber neuropathy (LFN) was found in 18 subjects, pure small fiber neuropathy (SFN) in 12 subjects, and both large and small fiber neuropathy was diagnosed in 24 subjects. Using linear regression, we found that higher NSS and NIS scores correlated with lower amplitudes of the sural sensory nerve action potential and of the SSR. We also found a significant longer duration of alcohol abuse in subjects with neuropathy, using Student's t-test (p = 0.024). Additionally, applying NIS abnormal cut-off score ≥4, using ROC analysis, we predicted the majority of subjects with LFN, confirming 95.23% sensitivity and 93.75% specificity. Our study confirmed that peripheral neuropathy involving large and small nerve fibers, with a symmetrical length-dependent pattern, is common between patients with AUD and related to the duration of the disorder. We suggest that NSS and NIS scales could be used for the assessment of neuropathy in clinical practice, when the essential neurophysiological testing is not available.

Early Detection of Peripheral Neuropathy by Assessment of Sudomotor Function

Chronic hyperglycemia in both type 1 and type 2 diabetes commonly lead to diabetic peripheral neuropathy (DPN) which commonly affects small nerve fibers, including autonomic sudomotor nerves, of the lower limbs. DPN results from nerve damage leading to gradual onset of foot pain, tingling, numbness, muscle weakness, extreme sensitivity to touch, and heat intolerance. Peripheral neuropathy is associated with increased all-cause mortality and morbidities such as foot ulcers, poor wound healing, local and systemic infection, limb amputation, and painful neuropathic symptoms. DPN is also typically diagnosed during later stages when disease progression has already led to irreversible nerve damage and associated severe symptoms. As such, early detection of peripheral neuropathy is important in implementing early interventions and can help preserve nerve function and prevent serious complications of DPN. Non-invasive methods of testing for early DPN rely on assessment of sudomotor nerve function. One method includes quantitative sudomotor axon reflex test (QSART) which measures postganglionic sympathetic function via iontophoresis which allows quantification of sweat production, and by extension, autonomic function. In general, QSART provides a non-invasive, reproducible, and precise evaluation of autonomic function in both controls and diabetics. It can be used to evaluate a large number of autonomic diseases, and the quantitative data it generates provides a measure of the extent and location of the peripheral neuropathy in each individual. Another assessment method includes the sympathetic skin response (SSR) test which measures the change in electrical potential of the skin which itself comes from activated eccrine sweat glands. The SSR test has a well-established protocol, and the results are easily-measured, and the results are quantifiable. It can be used reliably in the diagnosis of numerous autonomic disorders including DPN where a diminished or absent response correlate with sudomotor nerve damage. SudoCheck by VitalScan is an FDA-cleared, non-invasive autonomic sdomotor assessment tool that combines QSART, SSR, BIA, and EIS to provide rapid results with a specificity of 95% and a sensitivity of 80%. It was created to enable a precise evaluation of sweat gland function, and by extension, the presence and progression of diabetic peripheral neuropathy including early sub-clinical disease

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.

Autonomic dysfunction and treatment strategies in intracerebral hemorrhage.

Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes. This review aims to provide insight and convenience for future clinical practice and research on autonomic dysfunction in ICH patients. We summarize the autonomic dysfunction in ICH from the aspects of potential mechanisms, clinical significance, assessment, and treatment strategies. The CAN structures mainly include insular cortex, anterior cingulate cortex, amygdala, hypothalamus, nucleus of the solitary tract, ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguus, parabrachial nucleus, and periaqueductal gray. Autonomic dysfunction after ICH is closely associated with neurological functional outcomes, cardiac complications, blood pressure fluctuation, immunosuppression and infection, thermoregulatory dysfunction, hyperglycemia, digestive dysfunction, and urogenital disturbances. Heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, sympathetic skin response, and plasma catecholamine concentration can be used to assess the autonomic functional activities after ICH. Risk stratification of patients according to autonomic functional activities, and development of intervention approaches based on the restoration of sympathetic-parasympathetic balance, would potentially improve clinical outcomes in ICH patients. The review systematically summarizes the evidence of autonomic dysfunction and its association with clinical outcomes in ICH patients, proposing that targeting autonomic dysfunction could be potentially investigated to improve the clinical outcomes.