Tag: small-fiber neuropathy

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19

Abstract:

Objectives: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.

Methods: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention.

Results: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02).

Discussion: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN.

Classification of evidence: This study provides Class III evidence. It is a retrospective cohort study.

Source: McAlpine L, Zubair AS, Joseph P, Spudich S. Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200244. doi: 10.1212/NXI.0000000000200244. Epub 2024 Apr 17. PMID: 38630952. https://www.neurology.org/doi/10.1212/NXI.0000000000200244 (Full text)

Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms.

Methods: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 HC. The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively. Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and healthy controls (HC), as well as, analyze the relationship of these symptoms with cognition and fatigue.

Results: Statistically significant differences were found between groups in heart rate, with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC. Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance.

Conclusions: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN.

Source: Naiara Azcue, Rocio Del Pino, Marian Acera et al. Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome, 06 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3388628/v1] https://www.researchsquare.com/article/rs-3388628/v1 (Full text)

Persistent post-COVID-19 neuromuscular symptoms

Abstract:

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue.

These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers.

Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.

Source: Abrams RMC, Zhou L, Shin SC. Persistent post-COVID-19 neuromuscular symptoms. Muscle Nerve. 2023 Jul 19. doi: 10.1002/mus.27940. Epub ahead of print. PMID: 37466117. https://onlinelibrary.wiley.com/doi/10.1002/mus.27940 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood.

We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence.

Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.

Source: Wirth KJ, Löhn M. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators? Medicina. 2023; 59(5):978. https://doi.org/10.3390/medicina59050978  https://www.mdpi.com/1648-9144/59/5/978 (Full text)

ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing

Abstract

Introduction: Mechanisms underlying exercise and orthostatic intolerance in myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS) have been uncovered by invasive cardiopulmonary exercise testing (iCPET) and
autonomic function testing (AFT), but the relationships between the two are not known. This study aims to determine
if there is overlap of cardiovascular and respiratory pathophysiology in patients who have undergone both
tests.

Methods: Between January 2017 and April 2022, 62 patients were identified with a contemporary iCPET and
AFT. Key variables from the iCPET included peak oxygen uptake (pVO2), cardiac output (pQc), right atrial pressure
(pRAP), and systemic oxygen extraction (Ca-vOy/Hgb) at peak exercise. Key variables from the autonomic testing
included epidermal and sweat gland small fiber neurite density, electrochemical skin conductance, and change in
heart rate (AH) and end tidal carbon dioxide (AETCO2) from supine to upright during the tilt table test
(TTT).

Results: All 62 patients demonstrated preload failure (pRAP < 6.5mmHg). Of this group, 54 patients (87.1%) fulfilled NAM criteria for ME/CFS, with 32 testing positive (59.3%) for small fiber neuropathy (SFN) using either morphological and/or functional testing. Significant correlations were found between pVOg and both AH (r=-0.439. P<0.05) and AETCO, (r=0.474, P<0.05) during TTT. The same tilt table variables were found to be significantly correlated with pQc (r=-0.365, P<0.05 and r=0.351, P<0.05) from the iCPET. It should be noted that 8 of the ME/CFS SFN patients (25%) fulfilled diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) based on the tilt table test.

Conclusion: Decreased oxygen uptake and cardiac output at peak exercise during iCPET correlated with a greater change in heart rate and ETCO from supine to upright during TTT. There appears to be significant overlap of cardiopulmonary pathophysiology in ME/CFS underlying exercise and orthostatic symptoms.

Source: J. Squires, K. Wichmann Madsen, M.C. Stovall, S. Al-Zayer, W. Xiao, C.-J. Chang, P. Novak, D.M. Systrom. ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing. American Journal of Respiratory and Critical Care Medicine 2023;207:A2996. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2996

Management of Post-Viral Postural Orthostatic Tachycardia Syndrome With Craniosacral Therapy

Abstract:

Postural Orthostatic Tachycardia Syndrome (POTS) is a rare disorder of the autonomic nervous system. The number of people afflicted with this dysautonomia has increased dramatically in recent years due to the long-term effects of coronavirus disease (COVID-19); however, it is largely underdiagnosed.

This case report is about a patient with post-viral neuropathic POTS.

Neuropathic POTS is believed to be due to the damage of small nerve fibers that regulate the constriction of the blood vessels in the limb and abdomen, which leads to interference with vasoconstriction, and therefore causes tachycardia.

Current literature emphasizes a treatment that is based on lifestyle modifications, such as increasing water and salt intake, and symptomatic pharmacological treatment.

In this case, the 39-year-old male patient was treated with osteopathic manipulative treatment (OMT), specifically the compression of the fourth ventricle (CV4), which has been associated with the production of hyperparasympathetic and anti-inflammatory effects and, hence, helps overcome the small-fiber neuropathy caused by the viral illness.

We found that the CV4 technique led to the successful remission of the patient’s symptoms. Therefore, we propose craniosacral therapy as a successful single management modality in patients with POTS.

Source: Tafler L, Chaudry A, Cho H, Garcia A. Management of Post-Viral Postural Orthostatic Tachycardia Syndrome With Craniosacral Therapy. Cureus. 2023 Feb 15;15(2):e35009. doi: 10.7759/cureus.35009. PMID: 36938206; PMCID: PMC10021347. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10021347/ (Full text)

Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected

Abstract:

Long COVID is an emerging problem in the current health care scenario. It is a syndrome with common symptoms of shortness of breath, fatigue, cognitive dysfunction, and other conditions that have a high impact on daily life. They are fluctuating or relapsing states that occur in patients with a history of SARS-CoV-2 infection for at least 2 months. They are usually conditions that at 3 months after onset cannot be explained by an alternative diagnosis. Currently very little is known about this syndrome.

A thorough review of the literature highlights that the cause is attributable to deposits of tau protein. Massive phosphorylation of tau protein in response to SARS-CoV-2 infection occurred in brain samples from autopsies of people previously affected with COVID-19. The neurological disorders resulting from this clinical condition are termed tauopathies and can give different pathological symptoms depending on the involved anatomical region of the brain.

Peripheral small-fiber neuropathies are also evident among patients with Long COVID leading to fatigue, which is the main symptom of this syndrome. Certainly more research studies could confirm the association between tau protein and Long COVID by defining the main role of tau protein as a biomarker for the diagnosis of this syndrome that is widespread in the post-pandemic period.

Source: Ferrara, F., Zovi, A., Masi, M. et al. Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected. Naunyn-Schmiedeberg’s Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02417-5 https://link.springer.com/article/10.1007/s00210-023-02417-5 (Full text)

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia

Abstract:

The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Source: Verma V, Drury GL, Parisien M, Özdağ Acarli AN, Al-Aubodah TA, Nijnik A, Wen X, Tugarinov N, Verner M, Klares R 3rd, Linton A, Krock E, Morado Urbina CE, Winsvold B, Fritsche LG, Fors EA, Piccirillo C, Khoutorsky A, Svensson CI, Fitzcharles MA, Ingelmo PM, Bernard NF, Dupuy FP, Üçeyler N, Sommer C, King IL, Meloto CB, Diatchenko L; HUNT-All In Pain. Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia. Pain. 2021 Sep 24:10.1097/j.pain.0000000000002498. doi: 10.1097/j.pain.0000000000002498. Epub ahead of print. PMID: 34913882; PMCID: PMC8942876. https://pubmed.ncbi.nlm.nih.gov/34913882/

A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS

Dear Editors,

As case numbers of coronavirus disease 19 (COVID-19) increase, chronic symptoms, including those of autonomic dysfunction, are being reported with increasing frequency [], leading to the diagnosis of post-acute sequelae of COVID-19 (PASC), or Long-COVID. In addition, small fiber neuropathy (SFN) has been reported after viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) []. These associations have prompted our group to systematically perform autonomic testing and skin biopsies in a cohort of patients who have developed postural tachycardia syndrome (POTS) as a consequence of PASC (Long-COVID POTS). As part of this evaluation, all skin biopsy samples undergo immunohistochemical analysis of both intraepidermal nerve fiber density (IENFD) and phosphorylated α-synuclein (p-syn) [], the pathological form of α-synuclein associated with the neurodegenerative diseases of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF), as well as isolated REM sleep behavior disorder (iRBD), a prodromal manifestation of synucleinopathy for the majority of patients.

Read the rest of this article HERE. 

Source: Miglis MG, Seliger J, Shaik R, Gibbons CH. A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS. Clin Auton Res. 2022 May 16:1–4. doi: 10.1007/s10286-022-00867-0. Epub ahead of print. PMID: 35570247; PMCID: PMC9108014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108014/ (Full text)

Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial

Rationale: One third of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have evidence of small fiber neuropathy (SFN). Neurovascular dysregulation during upright exercise may be associated with impaired venoconstriction resulting in low biventricular filling pressures and impaired arteriolar constriction resulting in a mismatch between perfusion and skeletal muscle metabolism. We hypothesize that pyridostigmine, a reversible acetylcholinesterase inhibitor, may improve vascular regulation and exercise tolerance in ME/CFS by increasing sympathetic outflow.

Methods: 45 subjects (39 women, 6 men) with ME/CFS were assessed. A baseline invasive cardiopulmonary exercise test (iCPET) was performed to confirm presence of low peak exercise RAP (<6.5mmHg). Eligible subjects were blindly administered placebo (n=22) or 60mg pyridostigmine (n=23) at a 1:1 ratio. A second iCPET was performed following a 50 minute combined rest and dosing period. Serial iCPET results were compared to assess changes in oxygen uptake at peak exercise (VO2 max). Secondary outcomes included subject ventilatory efficiency (VE/VCO2), peak hemodynamic response (RAP, PCWP, SV, Qt), systemic gas exchange (Ca-vO2/Hgb), and subjective reporting of dyspnea and fatigue. Results: 39 subjects (all women) were considered in data analysis. There was a significant increase in VO2 max between iCPET 1 and iCPET 2 in the treatment group when compared with the placebo group (p = 0.043).

There was a significant decrease in the placebo group and a significant increase in the treatment group in VO2 (p = 0.008), Qt (p = 0.039), and RAP (p = 0.045) when comparing iCPET 1 peak – rest and iCPET 2 peak – rest between groups. There were no significant differences in peak arteriovenous oxygen content difference (Ca-vO2/Hgb). 38% of subjects had objective evidence of SFN with no statistically significant difference between groups.

Conclusion: Using pyridostigmine as an investigative tool, this study suggests that neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. Additionally, we have new evidence that worsening vascular dysregulation results from prior exercise, which sheds insight into the post exertional malaise that is a hallmark of this syndrome.

Source: M. Stovall, P. Joseph, R. Pari, A. Warren, S. Miller, J. Squires, W. Xiao, A.B. Waxman, D.M. Systrom. Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial. American Journal of Respiratory and Clinical Care Medicine, Vol 205, p A2063, May 2022. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2063