Evaluation of Next-Generation Sequencing for the Diagnosis of Infections of the Central Nervous System Caused by the Neurotropic Herpes Viruses: A Pilot Study.

BACKGROUND: There are sparse and limited studies on small sample size reporting the application of next-generation sequencing (NGS) in the detection of central nervous system (CNS) viral infections. We assessed the diagnostic performance of NGS of cerebrospinal fluid (CSF) for predicting viral infections of the CNS caused by the neurotropic herpes viruses in a pilot population. MATERIALS AND METHODS: We prospectively collected CSF samples from 24 patients with CNS viral infection from April 2017 to October 2018. Of the 24 patients, 19 patients were infected with herpes simplex virus 1 (HSV-1), 1 patient with HSV-2, and 4 patients with varicella-zoster virus (VZV). All CSF samples were screened for viral DNA using NGS technologies to detect viral CNS infections. RESULTS: Of the 24 patients with confirmed viral CNS infection caused by the neurotropic herpes viruses, 10 (10/24, 41.67%) patients exhibited positive NGS results. With the help of NGS, HSV-1 DNA was detected in the CSF of 6 patients (6/19; 31.58%). HSV-2 DNA was detected in 1 patient (1/1; 100%) and VZV DNA was detected in 3 patients (3/4; 75%). The positive rate of virus detected by NGS decreased with time. The positive rates of NGS of CSF in the first, second, and third weeks were 54.5% (6/11), 44.4% (4/9), and 0% (0/4), respectively. CONCLUSIONS: NGS method is a promising pathogen detection tool for identifying viral CNS infections. It should be recommended to sequence viral DNA of CSF in the early stage of CNS viral infections.

Corrigendum: Correlation between blood glucose and cerebrospinal fluid glucose levels in patients with differences in glucose metabolism.

[This corrects the article DOI: 10.3389/fneur.2023.1103026.].

Correlation between blood glucose and cerebrospinal fluid glucose levels in patients with differences in glucose metabolism.

Objectives: We aimed to determine a method to identify normal cerebrospinal fluid (CSF) glucose levels by examining the correlation between blood and CSF glucose levels in patients with normal and abnormal glucose metabolism. Methods: One hundred ninety-five patients were divided into two groups according to their glucose metabolism. The glucose levels were obtained from CSF and fingertip blood at 6, 5, 4, 3, 2, 1, and 0 h before lumbar puncture. SPSS 22.0 software was used for the statistical analysis. Results: In both the normal and abnormal glucose metabolism groups, CSF glucose levels increased with blood glucose levels at 6, 5, 4, 3, 2, 1, and 0 h before lumbar puncture. In the normal glucose metabolism group, the CSF/blood glucose ratio range was 0.35-0.95 at 0-6 h before lumbar puncture, and the CSF/average blood glucose ratio range was 0.43-0.74. In the abnormal glucose metabolism group, the CSF/blood glucose ratio range was 0.25-1.2 at 0-6 h before lumbar puncture, and the CSF/average blood glucose ratio range was 0.33-0.78. Conclusion: The CSF glucose level is influenced by the blood glucose level 6 h before lumbar puncture. In patients with normal glucose metabolism, direct measurement of the CSF glucose level can be used to determine whether the CSF level is normal. However, in patients with abnormal or unclear glucose metabolism, the CSF/average blood glucose ratio should be used to determine whether the CSF glucose level is normal.

Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients.

Mutations in the SH3TC2 gene cause Charcot-Marie-Tooth disease type 4C (CMT4C), characterized by inherited demyelinating peripheral neuropathy. CMT4C is a common form of CMT4/autosomal recessive (AR) CMT1. This study examined the SH3TC2 variants, investigated genotype-phenotype correlations and explored the frequency of CMT4C in Chinese patients. A total of 206 unrelated patients of Chinese Han descent clinically diagnosed with CMT were recruited. All patients underwent detailed history-taking, neurological examination, laboratory workups, and electrophysiological studies. Genetic analysis was performed via high-throughput target sequencing (NGS). Three patients, one male and two females, were found to carry five SH3TC2 mutations: patient 1 (c.3154C > T, p.R1054X; c.929G > A, p.G310E); Patient 2 (c.2872_2872del, p.S958fs; c.3710C > T, p.A1237V) and Patient 3 (c.2782C > T, p.Q928X; c.929G > A, p.G310E). The c.2872_2872del, c.3710C > T and c.2782C > T variants were not reported before. CMT4C caused by SH3TC2 mutation is a very common type of CMT4/AR CMT1. Three novel mutations, c.2872_2872del, c.3710C > T and c.2782C > T, were found in this study. Combination of clinical phenotype, nerve conduction studies, genetic analysis and bioinformatics analysis are of vital importance in patients suspected as CMT.

Contact heat evoked potentials in knowledge workers and unskilled labors.

BACKGROUND: Whether occupation has an impact on contact heat evoked potential (CHEP) results has not been investigated. In this study, we investigated the difference of CHEP parameters between knowledge workers and unskilled labors. METHODS: A total of 137 healthy participants were recruited between November 20, 2014 and December 31, 2016. All participants underwent neurologic examination, laboratory examination, and nerve conduction studies. CHEP was performed on four body sites: the upper border of the distal third of the volar forearm, the upper border of the distal third of the lateral leg, the spinous process of seventh cervical vertebrae (C7), and the spinous process of 12th thoracic vertebrae (T12). Independent t test and nonparametric test were performed using SPSS software to compare the difference of the CHEP parameters between knowledge workers and unskilled labors. RESULTS: The "N2 latency/height" (Z = -2.290, P = 0.022) and "P2 latency/height" (Z = -2.020, P = 0.043) on the volar forearm of unskilled labors significantly increased than those of knowledge workers. The "N2 latency/height" (F = 6.348, P = 0.016) and "P2 latency/height" (F = 5.920, P = 0.018) in the distal leg of unskilled labors significantly prolonged than those of knowledge workers. The N2-P2 amplitude (F = 5.797, P = 0.020) in the distal leg of unskilled labors significantly decreased than those of knowledge workers. CONCLUSIONS: Our study found that significantly prolonged N2 latency and P2 latency and significantly decreased N2-P2 amplitude in the distal leg and the volar forearm in unskilled labors as to knowledge workers.

Metagenomic Next-Generation Sequencing for Diagnosis of Infectious Encephalitis and Meningitis: A Large, Prospective Case Series of 213 Patients.

Purpose: We assessed the performance of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis. Methods: This was a prospective multicenter study. Cerebrospinal fluid samples from patients with viral encephalitis and/or meningitis, tuberculous meningitis, bacterial meningitis, fungal meningitis, and non-central nervous system (CNS) infections were subjected to mNGS. Results: In total, 213 patients with infectious and non-infectious CNS diseases were finally enrolled from November 2016 to May 2019; the mNGS-positive detection rate of definite CNS infections was 57.0%. At a species-specific read number (SSRN) ≥2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] = 0.659, 95% confidence interval [CI] = 0.566-0.751); the positivity rate was 42.6%. At a genus-specific read number ≥1, mNGS performance in the diagnosis of tuberculous meningitis (definite or probable) was optimal (AUC=0.619, 95% CI=0.516-0.721); the positivity rate was 27.3%. At SSRNs ≥5 or 10, the diagnostic performance was optimal for definite bacterial meningitis (AUC=0.846, 95% CI = 0.711-0.981); the sensitivity was 73.3%. The sensitivities of mNGS (at SSRN ≥2) in the diagnosis of cryptococcal meningitis and cerebral aspergillosis were 76.92 and 80%, respectively. Conclusion: mNGS of cerebrospinal fluid effectively identifies pathogens causing infectious CNS diseases. mNGS should be used in conjunction with conventional microbiological testing. Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800020442.

Repetitive Nerve Stimulation in Amyotrophic Lateral Sclerosis.

BACKGROUND: Nowadays, it is widely known that decremental responses in low-frequency repetitive nerve stimulation (LF-RNS) are frequently observed in patients with amyotrophic lateral sclerosis (ALS). The pathological mechanism of this phenomenon remains unknown. This study aimed to illuminate the features of RNS in Chinese patients with ALS. METHODS: Clinical and electrophysiological data of 146 probable and definite ALS patients who underwent RNS were retrospectively enrolled and analyzed. LF-RNS (3 Hz) was performed in trapezius, deltoid, abductor digiti minimi (ADM), quadriceps femoris, and tibialis anterior. High-frequency RNS (HF-RNS, 10 Hz) was performed only in ADM. The two-sample t-test and Chi-squared test were used for statistical analysis. RESULTS: Decremental responses to LF-RNS (≥10%) in at least one muscle were detected in 83 (56.8%) of the cases and were most commonly seen in trapezius and deltoid. The incidence of decremental response was higher in patients with upper limb onset. Incremental responses to HF-RNS (≥60%) in ADM were observed in 6 (5.6%) of the cases. In 106 muscles with decremental response, 62 (57.4%) muscles had a continuous decremental pattern, more than a U-shape pattern (37 cases, 34.3%). Nineteen cases showed definite decrements in LF-RNS tests in trapezius, while no abnormalities were found in the electromyography and neurological examination of the sternocleidomastoid muscle, supplied by the accessory nerve as well. CONCLUSIONS: Decremental responses in the RNS are commonly observed in ALS patients. The findings regarding the trapezius indicated that some ALS onsets could be initiated by a "dying back" process, with destruction of neuromuscular junctions (NMJs) before motor neurons. Incremental responses in the ADM implied damage of the NMJs involved both the post and presynaptic membranes.

Lamotrigine induced DIHS/DRESS: Manifestations, treatment, and outcome in 57 patients.

OBJECTIVE: To evaluate the clinical features, course, response to treatment, and outcome of lamotrigine induced drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS). METHODS: A comprehensive PubMed and Scopus search (covering the period from January 1999 through April 2014) of the English and non-English literature (with English abstract) was conducted to identify published reports of severe cutaneous adverse reactions (SCARs) associated with lamotrigine therapy. RESULTS: This study population included 57 patients, of whom 38 (66.67%) were female and 19 (33.33%) were male. The latency period varied from 9 days to 120 days, with a mean of 27.58 ± 20.65 days. Multisystem involvement was present in 97.37% (37/38) patients. Systemic corticosteroids were administered to (61.29%) 19/31 patients. 35/38 (92.11%) patients recovered completely, one patient developed liver failure and needed liver transplant, one died from septic shock and one died from multiple organ failure. CONCLUSIONS: We found a greater predominance of women with LTG-DIHS/DRESS, and 68.42% patients were >18 years of age. The presenting symptoms in most of patients were fever, skin rash, liver involvement, hypereosinophilia, and lymphadenopathy. Lamotrigine is associated to a rather high risk of severe cutaneous adverse reactions and to the risk of dying from such reactions, likes many other anticonvulsants. Early recognition and withdrawal of the suspected agent may avoid irreversible damage to the organs will be life saving.

Lamotrigine-induced severe cutaneous adverse reaction: Update data from 1999-2014.

We systematically reviewed and analyzed published patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) associated with lamotrigine therapy to identify characteristics of these reactions. We identified a total of 70 patients (42 SJS, five SJS/TEN, 23 TEN). The female to male ratio was 2.83:1 in the TEN group and 1.47:1 in the SJS group. Patients in the TEN group were younger than in the SJS group but this difference was not significant (28.35 versus 32.71 years, respectively; p=0.27). The median time to onset was 25.33 versus 18.42 days for SJS and TEN, respectively. The median dosage at onset was 36.46 versus 57.29mg, and final dosage 111.25 versus 97.92mg/day for SJS and TEN, respectively. The median final dosages did not significantly differ. Concomitant use of valproate acid was reported in 54.55% of the SJS patients and 50.00% of the TEN patients. Three fatal reactions were reported, of which two patients deteriorated rapidly and died within 12h of admission, indicating that this disease can develop rapidly before effective treatment. There was no significant difference between the SJS and TEN groups in any of the clinical factors examined which confirmed the opinion that SJS and TEN are part of a single disease spectrum.

[Relationship between socs3 mRNA expression and jak2v617f point mutation in bcr-abl negative patients with myelo-proliferative disease].

To investigate the relationship between socs3 mRNA expression and jak2v617f point mutation in bcr-abl negative patients with myelo-proliferative disease (MPD), 62 bcr-abl negative MPD patients (26 cases of PV, 26 cases of ET, 9 cases of IMF, and one case of CNL) were arranged as experiment group, and the others (20 cases of CML, 10 cases of AL and 15 healthy volunteers) were arranged as control group. All the diagnosis had been made according to the 2001 WHO criteria. jak2v617f point mutation was detected by AS-PCR and confirmed by direct sequencing. The expression level of socs3 mRNA was measured by RT-PCR. The association jak2v617f point mutation with socs3 mRNA expression in bcr-abl negative MPD patients was observed and analyzed. The results showed that among 62 bcr-abl negative MPD patients, the somatic jak2v617f point mutation was positive in 44 patients (PV 23, ET 15, IMF 5, CNL 1) while negative in the other 18 patients and control group. The expression of socs3 mRNA could be detected in 39 patients from 44 jak2v617f mutation positive patients and in 10 patients from 18 jak2v617f mutation-negative patients. There was a statistically significant difference in socs3 mRNA expression rates between jak2v617f mutation positive and negative group (chi(2) = 8.44, p < 0.005). There was a statistically significant difference in socs3 mRNA expression levels between jak2v617f mutation positive and negative groups (p = 0.035). It is concluded that there is a statistically significant difference in the expression level of socs3 mRNA in the patients between jak2v617f mutation positive group and negative group.