Small fibre neuropathy frequently underlies the painful long-COVID syndrome.

ABSTRACT: Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case-control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. Clinical data, quantitative sensory testing, and skin biopsies were collected from 26 selected patients with painful long-COVID syndrome. We also examined 100 individuals with past COVID-19 infection, selecting 33 patients with painless long-COVID syndrome, characterized mainly by symptoms such as brain fog and fatigue, and 30 asymptomatic post-COVID-19 controls. Demographic and clinical variables were compared among these groups. Among the 26 patients with painful long-COVID syndrome, 12 had skin biopsy and/or quantitative sensory testing abnormalities compatible with small fibre neuropathy. Demographic and clinical data did not differ across patients with small fibre neuropathy, patients with painless long-COVID syndrome, and asymptomatic post-COVID-19 controls. This case-control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post-COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy.

An overview of diagnosis and assessment methods for neuropathic pain.

Neuropathic pain, defined as pain arising as a consequence of a lesion or disease affecting the somatosensory nervous system, requires precise diagnostic assessment. Different diagnostic tools have been devised for the diagnosis of neuropathic pain. This review offers insights into the diagnostic accuracy of screening questionnaires and different tests that investigate the somatosensory nervous system, in patients with suspected neuropathic pain. Thus, it illustrates how these tools can aid clinicians in accurately diagnosing neuropathic pain.

Autonomic Small-Fiber Pathology in Patients With Fibromyalgia.

In this clinical and skin biopsy study, we aimed to investigate whether fibromyalgia-associated small-fiber pathology (SFP), consisting of an intraepidermal nerve fiber loss, implies damage of dermal autonomic nerve fibers and how this damage is associated with autonomic symptoms that patients with fibromyalgia syndrome experience. Using skin biopsy, we investigated intraepidermal nerve fiber density, piloerector muscle, and sweat gland nerve fiber density (SGNFD) in 138 participants, that is, 58 patients with fibromyalgia syndrome, 48 healthy subjects, and 32 patients with small-fiber neuropathy. In patients with fibromyalgia-associated SFP, we also investigated how the different skin biopsy variables correlated with autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 questionnaire. We found that in patients with fibromyalgia-associated SFP, the piloerector muscle and SGNFD were lower than that in healthy subjects. However, the autonomic small-fiber damage had no correlation with autonomic symptoms severity. In patients with SFP, the intraepidermal, piloerector muscle, and SGNFD were higher than that in patients with small-fiber neuropathy. Our clinical and skin biopsy study shows that patients with fibromyalgia have a reduction of dermal autonomic small fibers paralleling the intraepidermal nerve fiber loss, thus indicating that SFP also implies autonomic small nerve fiber damage. However, the autonomic small-fiber damage we found had no correlation with the severity of autonomic symptoms, and thus its clinical impact is still undetermined. PERSPECTIVE: In patients with fibromyalgia, SFP also affects autonomic fibers. These novel data provide additional insights into the pathophysiology of fibromyalgia syndrome, highlighting the complex role of small-fiber damage in the clinical picture of fibromyalgia.

Trigeminal neuropathy presenting secondary to SARS-CoV-2 infection.

Introduction: A 58-year-old woman presented to a multidisciplinary facial pain clinic in October 2021 complaining of a constant pain in the right side of her face since contracting coronavirus SARS-CoV-2 18 months earlier. The pain extending from the right temple down to her right cheek extraorally and including the maxillary teeth and right side of tongue intraorally. This was accompanied by anosmia, diplopia on lateral gaze, and dizziness. Methods: Clinical examination was supplemented with several neurophysiological tests to confirm the diagnosis including an MRI brain scan, quantitative sensory testing, electrophysiological blink reflex testing, corneal confocal microscopy, and pain and short-form anxiety and depression questionnaires. Results: Quantitative sensory testing showed unilateral loss of perception in thermal and mechanical sensibility and bilateral hyperalgesia indicating central sensitization. Bilateral corneal confocal microscopy showed an abnormally reduced corneal nerve fibre length on the right side. MRI, blink reflex, and masseter inhibitory testing findings were normal. Conclusion: This case study is the first case of trigeminal neuropathy related to SARS-CoV-2 infection reported in the literature. It also discusses the successful management of the patient's trigeminal neuropathic pain.

Considerations When Using Gabapentinoids to Treat Trigeminal Neuralgia: A Review.

Despite the exemplary efficacy of voltage-gated sodium channel blockers as a first-line treatment of trigeminal neuralgia, the pharmacological management of this excruciating facial pain condition remains a major issue, as these first-line drugs produce intolerable side effects in a significant portion of patients. In addition, in patients with concomitant continuous pain, the efficacy of these drugs may drop, thus suggesting the opportunity to test the efficacy of different drug categories. The aim of this review is to provide current, evidence-based, knowledge about the use of gabapentin and other α2δ ligands in patients with trigeminal neuralgia. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), considering publications up to April 2023. Two authors independently selected studies for inclusion and data extraction. The efficacy of α2δ ligands, gabapentin and pregabalin, has been assessed in seven controlled or open-label studies. Despite the low quality of evidence, the favorable tolerability profile and the possible action on concomitant continuous pain make this drug category of interest for future trials in trigeminal neuralgia.

Sex differences in trigeminal neuralgia: a focus on radiological and clinical characteristics.

BACKGROUND: It is well established that trigeminal neuralgia is more prevalent in females than in males. Neurovascular compression with morphological changes of the trigeminal root represents the most recognized etiological factor. However, other factors may play a role in the framework of a multi-hit model. The primary aim of this study was to investigate sex differences in radiological and clinical characteristics of trigeminal neuralgia to better understand the multifactorial origin of this peculiar neuropathic pain condition. METHODS: In this cross-sectional study patients with a definite diagnosis of primary trigeminal neuralgia were consecutively enrolled. Each patient underwent 3T MRI with sequences dedicated to the study of neurovascular compression. Major morphological changes of the trigeminal root were quantitatively assessed. Clinical characteristics were systematically collected through a dedicated questionnaire. A logistic regression model was implemented to predict radiological and clinical characteristics based on sex. RESULTS: A total of 114 patients with classical (87) or idiopathic trigeminal neuralgia (27) were enrolled. Female sex was predictive for idiopathic trigeminal neuralgia. Male sex was predictive, among the comorbidities and clinical characteristics, for hypertension, the involvement of the left side and the second trigeminal division, alone or with the ophthalmic division. DISCUSSION: The preponderance of TN in the female sex and the association between idiopathic TN and the female sex suggest the role of additional etiological factors in the framework of a multi-hit model. The identification of clinical variables predicted by sex suggests the possibility that distinct phenotypes, with peculiar pathophysiological and therapeutic aspects, may occur in females and males.

Anti-LGI1 encephalitis: A family affair.

Here we describe the second ever-reported case of familial anti-leucine-rich glioma-inactivated protein 1 (LGI1) limbic encephalitis (LE). Two elderly Caucasian sisters presented with psychiatric symptoms and cognitive impairment, followed by faciobrachial dystonic seizures. Anti-LGI1 antibodies were detected in their serum. Considering they had been living in distant regions for decades, environmental factors could be ruled out. Human leukocyte antigen (HLA) genotyping revealed that both carried HLA-DRB1*07, found in 90% of anti-LGI1 encephalitis patients, HLA-DQA1*02:01 and HLA-DQB1*03:03, commonly associated with DRB1*07:01. Considering the exceptional nature of familial cases, as-yet-unknown genetic contributors other than HLA might play a role in our siblings.

Pain associated with COVID-19 vaccination is unrelated to skin biopsy abnormalities.

Introduction: Previous clinical observations raised the possibility that COVID-19 vaccination might trigger a small-fibre neuropathy. Objectives: In this uncontrolled observational study, we aimed to identify small fibre damage in patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination. Methods: We collected clinical data, including a questionnaire for assessing autonomic symptoms (Composite Autonomic Symptom Score-31), and investigated quantitative sensory testing (QST) and skin biopsy in 15 prospectively enrolled patients with generalized sensory symptoms and pain after COVID-19 vaccination. Nine patients complaining of orthostatic intolerance also underwent cardiovascular autonomic tests. Results: We found that all patients experienced widespread pain, and most of them (11 of 15) had a fibromyalgia syndrome. All patients had normal skin biopsy findings, and in the 9 patients with orthostatic intolerance, cardiovascular autonomic tests showed normal findings. Nevertheless, 5 patients had cold and warm detection abnormalities at the QST investigation. Conclusions: In our study, most patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination had clinical and diagnostic test findings compatible with a fibromyalgia syndrome. Although the abnormal QST findings we found in 5 patients might be compatible with a small-fibre neuropathy, they should be cautiously interpreted given the psychophysical characteristics of this diagnostic test. Further larger controlled studies are needed to define precisely the association between small fibre damage and COVID-19 vaccination.

The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy.

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non-specialist centers are warranted to identify patients who require second-level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN-SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN-SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN-SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second-level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials.

Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain.

OBJECTIVE: In this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain. METHODS: We enrolled 65 patients with a definite diagnosis of primary trigeminal neuralgia. Patients were grouped according to whether they experienced purely paroxysmal pain (36) or also had concomitant continuous pain (29). All participants underwent trigeminal reflex testing to assess the function of large non-nociceptive myelinated fibres and laser-evoked potentials to assess the function of small myelinated Aδ and unmyelinated C fibres. Neurophysiological examiners were blinded to the affected side. RESULTS: The only neurophysiological abnormality distinguishing the two groups of patients was the side asymmetry of C fibre-related laser-evoked potential amplitude (p = 0.005), which was higher in patients with concomitant continuous pain than in patients with purely paroxysmal pain (indicative of a reduced C fibre-related laser-evoked potential amplitude in the affected side of patients with concomitant continuous pain). CONCLUSIONS: Our clinical and neurophysiological study indicates that in patients with trigeminal neuralgia concomitant continuous pain is associated with unmyelinated C fibre damage as assessed with laser-evoked potentials. SIGNIFICANCE: Our findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.

Real-world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia.

BACKGROUND: It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long-term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined. METHODS: In this retrospective, real-world study, we assessed the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical (254 patients), secondary (60 patients) and idiopathic (40 patients) trigeminal neuralgia. We analysed data using a propensity score analysis to account for selection bias; frequencies of side effects associated with carbamazepine and oxcarbazepine were calculated by adjusting data with the inverse probability of treatment weighting. RESULTS: The initial proportion of responders was 88.3% with carbamazepine, and 90.9% with oxcarbazepine. The number of refractory patients was significantly higher in idiopathic (15%) and secondary forms (27%) than in classical trigeminal neuralgia (6%; p < .05). In 53 patients treated with carbamazepine (29.6%) and in 22 treated with oxcarbazepine (12.6%), major side effects caused treatment interruption or dosage reduction to an unsatisfactory level. Side effects occurred more frequently in patients treated with carbamazepine (43.6%) than with oxcarbazepine (30.3%, p < .0001). The frequency of treatment discontinuation was higher in patients with secondary and idiopathic forms than in those with classical trigeminal neuralgia (p < .05). CONCLUSIONS: Our real-world study shows that carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia; nevertheless, side effects are still a major issue, particularly in patients with secondary and idiopathic trigeminal neuralgia. SIGNIFICANCE: Although carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia, their side effects are still a major issue, thus necessitating the development of better-tolerated drugs.

Concomitant continuous pain in patients with trigeminal neuralgia is associated with trigeminal nerve root atrophy.

INTRODUCTION: Trigeminal neuralgia is an exemplary neuropathic pain condition characterized by paroxysmal electric-shock-like pain. However, up to 50% of patients also experiences concomitant continuous pain. In this neuroimaging study, we aimed to identify the specific anatomical features of trigeminal nerve root in patients with concomitant continuous pain. METHODS: We enrolled 73 patients with a definitive diagnosis of classical and idiopathic trigeminal neuralgia and 40 healthy participants. The diagnosis of trigeminal neuralgia was independently confirmed by two clinicians. Patients were grouped as patients with purely paroxysmal pain (45 patients) and patients also with concomitant continuous pain (28 patients). All participants underwent a structured clinical examination and a 3T MRI with sequences dedicated to the anatomical study of the trigeminal nerve root, including volumetric study. Images analysis was independently performed by two investigators, blinded to any clinical data. RESULTS: In most patients with concomitant continuous pain, this type of pain, described as burning, throbbing or aching, manifested at the disease onset. Demographic and clinical variables did not differ between the two groups of patients; the frequency of neurovascular compression and nerve dislocation were similar. Conversely, trigeminal nerve root atrophy was more severe in patients with concomitant continuous pain than in those with purely paroxysmal pain (p = 0.006). CONCLUSIONS: Our clinical and neuroimaging study found that in patients with trigeminal neuralgia, concomitant continuous pain was associated with trigeminal nerve root atrophy, therefore suggesting that this type of pain is likely related to axonal loss and abnormal activity in denervated trigeminal second-order neurons.

Pharmacotherapeutic Options for Managing Pain in Multiple Sclerosis.

Pain is a major matter for patients with multiple sclerosis; treatment response is frequently inadequate, with a significant impact on quality of life. The estimated prevalence of pain in multiple sclerosis ranges widely (26-86%), and different subtypes of pain, mediated by specific pathophysiological mechanisms, are described. The aim of this narrative review, performed using a systematic search methodology, was to provide current, evidence-based, knowledge about the pharmacological treatment of the different kinds of pain in multiple sclerosis. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Clinical Trials database (ClinicalTrials.gov), considering publications up to November 2019. Two authors independently selected studies for inclusion, data extraction, and bias assessment. A total of 27 randomized controlled trials were identified, but in only a few cases, patients with different pain qualities were stratified. Following a mechanism-based approach, treatment of paroxysmal pain and painful tonic spasms should be based on sodium-channel blockers, whereas treatment of ongoing extremity pain should be based on gabapentinoids and antidepressants.

Adverse Psychiatric Effects Associated with Herbal Weight-Loss Products.

Obesity and overeating are among the most prevalent health concerns worldwide and individuals are increasingly using performance and image-enhancing drugs (PIEDs) as an easy and fast way to control their weight. Among these, herbal weight-loss products (HWLPs) often attract users due to their health claims, assumed safety, easy availability, affordable price, extensive marketing, and the perceived lack of need for professional oversight. Reports suggest that certain HWLPs may lead to onset or exacerbation of psychiatric disturbances. Here we review the available evidence on psychiatric adverse effects of HWLPs due to their intrinsic toxicity and potential for interaction with psychiatric medications.

Extreme high prevalence of a defective mannose-binding lectin (MBL2) genotype in native South American West Andean populations.

Mannose-binding lectin (MBL) is one of the five recognition molecules in the lectin complement pathway. Common variant alleles in the promoter and structural regions of the human MBL gene (MBL2) influence the stability and serum concentration of the protein. Epidemiological studies have shown that MBL2 variant alleles are associated with susceptibility to and the course of different types of infectious and inflammatory conditions. However, it has been suggested that these alleles are maintained in different populations due to selected advantages for carriers. We investigated the MBL2 allelic variation in indigenous individuals from 12 different West Central South America localities spanning from the desert coast, high altitude Andean plates and the Amazon tropical forest within the territories of Peru (n = 249) (Departments of Loreto, Ucayali, Lambayeque, Junin, Ayacucho, Huancayo and Puno), and Ecuador (n = 182) (Region of Esmeraldas and Santo Domingo de los Colorados). The distribution of MBL2 genotypes among the populations showed that the defective variant LYPB haplotype was very common. It showed the highest frequencies in Puno (Taquile (0.80), Amantani (0.80) and Anapia (0.58) islander communities of the Lake Titicaca), but lower frequencies of 0.22 in Junin (Central Andean highland) and Ucayali (Central Amazonian forest), as well as 0.27 and 0.24 in the Congoma and Cayapa/Chachis populations in the Amazonian forest in Ecuador were also observed. Our results suggest that the high prevalence of the MBL2 LYPB variant causing low levels of functional MBL in serum may mainly reflect a random distribution due to a population bottleneck in the founder populations.

Haplotypes in SLC24A5 Gene as Ancestry Informative Markers in Different Populations.

Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator's ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population.

Genetic polymorphisms in autochthonous Basques from northern Navarre.

This survey reports primary results of classical allele frequencies on ten protein loci in a Basque population sample from northern Navarre, the less known from an anthropological and genetic point of view than the populations of the other Basque territories of Spain. Since ancient times this has been a zone of Basque population settlement, and the Basque language (Euskera) still remains deeply rooted among its autochthonous population. A total of 122 blood samples from unrelated northern Navarrese with autochthonous ascendants to the third generation were typed for GC, HP, PI, TF, ACP1, AK1, CA2, ESD, PGD and PGM1 genetic systems. Basque surnames and birthplaces were the criteria used to define family origins. Genetic structure was analyzed on different population hierarchical levels. Northern Navarre seems to be the most genetically deviated area in comparison with other Basque groups. The highest level of differentiation is observed between Navarrese and Alava Basques whereas Guipúzcoa province, the territory adjacent to northern Navarre, presents the lowest genetic distance from the study area. Northern Navarrese show some distinguishing genetic characteristics in relation to other Basque relative samples, which include high frequencies for PI*M1 and TF*C1 and low levels of PGD*C and PGM1*2 alleles. When the genetic data reported here are analyzed jointly with GM allotypes frequencies, the results significantly reinforce the relative position of Navarrese Basques as well as the topology of the Basque cluster on genetic maps. The analysis of relationships among the genetic structures of Basque population samples leads us to ask ourselves which of them fits in best with the ancient Basque population. Classical geographers placed the tribe of the Vascones in the geographical region currently known as Navarre, so extant Navarrese Basques might be considered firm candidates to denote the anthropological and genomic distinctiveness of the ancient Basques.

Restriction fragment length polymorphisms of type I collagen locus 2 (COL1A2) in two communities of African ancestry and other mixed populations of northwestern Ecuador.

Restriction fragment length polymorphisms are good anthropological markers for discriminating geographically distinct populations at both the allele and the haplotype level. Two communities of African ancestry and ladinos, mestizos, and mulattoes living in the Esmeraldas province in northwestern Ecuador were analyzed for three RFLPs (EcoRI, RsaI, and MspI) of the COL1A2 gene. Also, the same markers were studied in a population sample from Spain to compare the allele and haplotype frequencies of the Esmeraldas populations with those of their representative European parental population. Data for the native American and sub-Saharan African founder components were available from the literature. No significant levels of differentiation between the two African Ecuadoran communities emerged from either the frequency analysis of each single marker and all three RFLP markers together or from the AMOVA. The ladinos and mestizos also showed a rather similar distribution of allele and haplotype frequencies, confirming that the two ethnic terms do not correspond to genetically different populations. The comparison with the supposed founding European, sub-Saharan African, and native American populations indicated a large presence of African genes in the gene pool of both communities, with a higher proportion of the Amerindian component in Viche than in Rio Cayapas. The present findings confirm the previous genetic admixture estimates based on nuclear and mitochondrial DNA markers and the demographic data.