Can COVID-19 pandemic worsen previous neurological/psychiatric diseases?

Introduction: The SARS-CoV-2 pandemic has been affecting the world since January 2020. Although its pathogenesis is primarily directed to the respiratory tract, other organs may be affected, including the nervous system. It has also been shown that the social context (confinement, lack of treatment) has affected neurological patients during this period. The aim of the study it was to assess the subjective worsening of neurological/psychiatric diseases in the context of the SARS-Cov-2 pandemic. Methods: Three groups of neurological/psychiatric patients were included: Patients who had symptomatic COVID-19 (n = 89), patients who had asymptomatic COVID-19 (n = 40), and a control group (n = 47), consisting of neurological/psychiatric patients without a history of SARS-Cov-2 infection. Results: 30.7% of the included individuals considered that their basal pathology had worsened during the study period. This feeling was significantly more frequent (P = 0.01) in patients with symptomatic COVID-19 (39.3%) than in patients of the other 2 groups (21.8%). Worsening was not related to the severity of COVID-19. The neurological conditions that significantly worsened after COVID-19, comparing symptomatic COVID-19 with the other 2 groups, were demyelinating and degenerative diseases. Conclusions: These results confirmed the impact of the SARS-Cov-2 pandemic on patients with neurological/psychiatric diseases. Confinement, lack of medical care, and the threat of diagnosis are surely contributing factors. Although the finding of a higher frequency of worsening in symptomatic COVID-19 patients may be related to greater anxiety/depression in this group of patients, we cannot exclude the role of direct affectation of the nervous system by the virus or damage due to neuroinflammation.

Introducción: La pandemia por SARS-CoV-2 afecta al mundo desde enero de 2020. Aunque su patogenia se dirige principalmente a las vías respiratorias, otros órganos pueden verse afectados, incluido el sistema nervioso. También se ha demostrado que el contexto social (confinamiento, falta de tratamiento) ha afectado a los pacientes neurológicos durante este periodo. El objetivo del estudio fue evaluar el empeoramiento subjetivo de enfermedades neurológicas/psiquiátricas en el contexto de la pandemia por SARS-Cov-2. Métodos: Se incluyeron tres grupos de pacientes neurológicos/psiquiátricos: pacientes que tenían COVID-19 sintomático (n = 89), pacientes que tenían COVID-19 asintomático (n = 40) y un grupo control (n = 47), formado por pacientes neurológicos/psiquiátricos sin antecedentes de infección por SARS-Cov-2. Resultados: El 30,7% de los individuos incluidos consideró que su patología basal había empeorado durante el período de estudio. Este sentimiento fue significativamente más frecuente (p = 0,01) en pacientes con COVID-19 sintomático (39,3%) que en pacientes de los otros 2 grupos (21,8%). El empeoramiento no estuvo relacionado con la gravedad de COVID-19. Las condiciones neurológicas que empeoraron significativamente después de la COVID-19, comparando la COVID-19 sintomática con los otros 2 grupos, fueron las enfermedades desmielinizantes y degenerativas. Conclusiones: estos resultados confirmaron el impacto de la pandemia del SARS-Cov-2 en pacientes con enfermedades neurológicas/psiquiátricas. El encierro, la falta de atención médica y la amenaza del diagnóstico son seguramente factores contribuyentes. Aunque el hallazgo de una mayor frecuencia de empeoramiento en pacientes sintomáticos de COVID-19 puede estar relacionado con una mayor ansiedad/depresión en este grupo de pacientes, no podemos excluir el papel de la afectación directa del sistema nervioso por el virus o el daño por neuroinflamación.

Olig2 expression, GFAP, p53 and 1p loss analysis contribute to glioma subclassification.

The expression of Olig2, a basic helix-loop-helix (bHLH) transcription factor involved in oligodendroglial specification, was investigated by immunohistochemistry in a series of 146 tumours and control samples. Olig2 expression was restricted to glial tumours and nontumoral oligodendrocytes. It was higher in oligodendrogliomas as compared to astrocytomas and oligoastrocytomas, and in grade III as compared to grade II tumours. Olig 2 was absent or weakly expressed in glioblastoma (GBM), whereas strong expression was found in the oligodendroglial foci of GBM with oligodendroglial component (GBMO). Double labelling was performed on a subset of the most typical tumours, according to the WHO classification. It showed a mutual exclusion, at cell level, of Olig2 and GFAP expression. In pure oligodendrogliomas, tumour cells were Olig2+/GFAP-. In contrast, two main tumour populations, Olig2+/GFAP- and Olig2-/GFAP+, were found in both oligoastrocytomas and astrocytomas. Based on these data from selected samples, two separate entities can be established, corresponding to 'pure oligodendrogliomas' and 'astrocytomas and oligoastrocytomas'. The relevance of this subdivision is further supported by the association with 1p loss and a trend to better survival for pure oligodendrogliomas and with p53 expression and a trend to shorter survival for astrocytomas and oligoastrocytomas. Combined testing of Olig2, 1p status, GFAP and p53 expression may therefore be helpful in refining current classification and providing more homogeneous sets of gliomas for clinical studies.

Correlation between genetic alterations and growth of human malignant glioma xenografted in nude mice.

In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies.

Telomerase reactivation in malignant gliomas and loss of heterozygosity on 10p15.1.

An inhibitor of telomerase activity maps to chromosome 10p15.1. A series of 51 high-grade gliomas was analyzed for loss of heterozygosity (LOH) on chromosome 10 and for telomerase activity. In univariate analysis, LOH10p (59%) and LOH10q (61%) were associated with telomerase activity (55%; p < 0.0001 and p = 0.0006). In multivariate analysis, only LOH10p remained statistically related to telomerase activity, suggesting that the telomerase repressor gene located on 10p15.1 is inactivated in high-grade gliomas.

OLIG-1 and 2 gene expression and oligodendroglial tumours.

OLIG 1/2 genes encode basic helix-loop-helix transcription factors that play a critical role in motor neurone and oligodendrocyte fate specification during development. Two recent studies in which OLIG transcripts were detected by in situ hybridization have reported a high expression of the OLIG genes in oligodendrogliomas. This suggests that the detection of these lineage markers could become an adjunct to the classic morphological diagnosis of these tumours. There are problems in the diagnosis of oligodendroglioma. To date, all other known oligodendrocyte lineage markers have failed to label specifically neoplastic oligodendrocytes. Deletions on chromosome 1p and 19q are much more frequent in oligodendrogliomas than in astrocytomas but these molecular alterations are not constant. For the future, when routinely available, immunohistochemical techniques using anti-OLIG antibodies on paraffin embedded tissues will allow a systematic study of a large series of tumours so that we will know the specificity and sensitivity of this investigation in diagnosis. At another level, it is possible that expression of OLIG in neoplastic oligodendrocyte might participate in the oncogenesis of oligodendrogliomas. Initial work suggests that this is probably not the case. However further in vitro and in vivo studies analysing the functional consequence of OLIG overexpression in terms of proliferation and tumour progression are needed.

Nifurtimox plus pyrimethamine for treatment of murine toxoplasmosis.

In the search for novel antitoxoplasmic agents, we evaluated the efficacy of nifurtimox (3-methyl-4[5'-nitrofurfurylidene-amino]-tetrahydroe-4H-1,4- thiazine-1,1-dioxide), an antiprotozoal drug effective against trypanosomiasis, in an experimental model of acute toxoplasmosis in mice. One hundred NIH mice were inoculated intraperitoneally, each with 2,614 RH tachyzoites of Toxoplasma gondii, and randomly allocated into 5 groups (n = 19-21). Animals from each group were orally treated for 10 days either with nifurtimox 25 mg/kg/day (NF1), nifurtimox 50 mg/kg/day (NF2), pyrimethamine 60 mg/kg/day (P), the combination nifurtimox 50 mg/kg/day plus pyrimethamine 60 mg/kg/day (NF2-P), or with corn oil (controls). Survival of mice was recorded daily for 1 mo after the experimental infection. Comparisons of cumulative mortality between groups were made applying the chi2 test. Mean survival time was longer in animals from P and NF2-P groups than those from NF1, NF2, and control groups. Cumulative mortality was less in mice from the NF2-P group (25%), than that in mice from the P (65%), the NF1 (100%), the NF2 (89%), or the control (95%) groups (P < 0.01). The doses of nifurtimox used in the present study were not significantly effective against murine toxoplasmosis. However, when combined with pyrimethamine, a strong anti-toxoplasma effect was obtained in comparison with survival rates associated with pyrimethamine or nifurtimox alone. It seems feasible that nifurtimox inhibits the replication of T. gondii tachyzoites similar to that of other protozoans, e.g., Trypanosoma and Leishmania. It will be important to determine if the reduction of mortality in mice treated with the nifurtimox-pyrimethamine combination results from summation or from synergism. Further studies on the toxic mechanisms exerted by nifurtimox on T. gondii seem warranted.

Colchicine, like methylprednisolone, decreases the perilesional fibrosis secondary to a chronic brain granuloma in cats.

We studied the effects of long-term administration of colchicine on the fibrosis surrounding a granulomatous lesion previously induced by stereotactic injection of aluminum silicate into the brain parenchyma of cats. Every week the animals received a single i.m. injection of colchicine (0.25 mg), or methylprednisolone (4 mg), or saline solution (controls) for 6 months. The mean area of fibrosis in animals treated with colchicine or with methylprednisolone was smaller than that of control animals (P < 0.05). In controls, a dense capsule of procollagen and collagen fibers was found around the granuloma, and myelinated neurites were scarce, whereas in animals treated with colchicine or with methylprednisolone the capsule and fibers were thinner and more myelinated neurites remained. These changes were more evident in animals treated with colchicine. Our results suggest that chronic administration of colchicine or methylprednisolone limit the fibrosis and histological damage around a granulomatous lesion of the brain.

Lack of therapeutic effect of colchicine on murine toxoplasmosis.

In a previous report, we showed that addition of colchicine to cultures of glial cells infected with Toxoplasma gondii decreased the number of parasites by up to 80%. To provide support for potential therapeutic use of colchicine in toxoplasmosis, a murine model of T. gondii infection was used. Mice infected with pure RH T. gondii tachyzoites (from 2,233 to 25,000 parasites) were treated daily with either pyrimethamine (80 or 51 mg/kg), colchicine (10 mg/kg), pyrimethamine-colchicine, or vehicle (controls). Survival rates were lower in animals treated with colchicine (from 40% to 27%) and pyrimethamine-colchicine (from 73% to 41%) than in animals treated with pyrimethamine alone (from 100% to 73%). There was no extension of mean survival time in animals treated with colchicine compared to controls. These results demonstrate that colchicine does not improve the course of acute toxoplasmosis in mice, and it is detrimental rather than beneficial at the regimen tested.

Colchicine decreases the infection by Toxoplasma gondii in cultured glial cells.

Addition of colchicine (2.5 x 10(-8)-1.25 x 10(-6) M) to cultures of glial cells infected with Toxoplasma gondii decreased the number of parasites up to 80% (P < 0.05) in comparison with controls. Our results indicate that colchicine could interfere with the infectious, or replicative mechanisms, or both, of Toxoplasma and place it as a candidate in the search for additional antitoxoplasmic therapy for those cases where the parasitic load is massive. Further studies in vivo must be made to confirm this finding and provide support for therapeutic trials.