Inflammatory Cytokine Patterns Associated with Neurological Diseases in Coronavirus Disease 2019.

Patients with coronavirus disease 2019 (COVID-19) can present with distinct neurological manifestations. This study shows that inflammatory neurological diseases were associated with increased levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, chemokine (C-X-C motif) ligand 8 (CXCL8), and CXCL10 in the cerebrospinal fluid. Conversely, encephalopathy was associated with high serum levels of IL-6, CXCL8, and active tumor growth factor ß1. Inflammatory syndromes of the central nervous system in COVID-19 can appear early, as a parainfectious process without significant systemic involvement, or without direct evidence of severe acute respiratory syndrome coronavirus 2 neuroinvasion. At the same time, encephalopathy is mainly influenced by peripheral events, including inflammatory cytokines. ANN NEUROL 2021;89:1041-1045.

Zika virus-associated neurological disorders: a review.

Zika virus, an arbovirus transmitted by mosquitoes of the Aedes species, is now rapidly disseminating throughout the Americas and the ongoing Brazilian outbreak is the largest Zika virus epidemic so far described. In addition to being associated with a non-specific acute febrile illness, a number of neurological manifestations, mainly microcephaly and Guillain-Barré syndrome, have been associated with infection. These with other rarer neurological conditions suggest that Zika virus, similar to other flaviviruses, is neuropathogenic. The surge of Zika virus-related microcephaly cases in Brazil has received much attention and the role of the virus in this and in other neurological manifestations is growing. Zika virus has been shown to be transmitted perinatally and the virus can be detected in amniotic fluid, placenta and foetus brain tissue. A significant increase in Guillain-Barré syndrome incidence has also been reported during this, as well as in previous outbreaks. More recently, meningoencephalitis and myelitis have also been reported following Zika virus infection. In summary, while preliminary studies have suggested a clear relationship between Zika virus infection and certain neurological conditions, only longitudinal studies in this epidemic, as well as experimental studies either in animal models or in vitro, will help to better understand the role of the virus and the pathogenesis of these disorders.

Putative role of HLA polymorphism among a Brazilian HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) population.

Around ten million people are infected with HTLV-1 worldwide, and 1-4% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by an important degeneration of the spinal cord, which can lead to death. Distinct HLA alleles have been associated with either HAM/TSP susceptibility or protection. However, these HLA alleles set may change according to the population studied. Brazil is the second country in the number of HTLV-1-infected people and there are few reports addressing the HLA influence on HTLV-1 infection as well as on disease outcome. The objective of this study was to evaluate the influence of HLA alleles as a risk factor for HAM/TSP and the proviral load (PVL) levels, clinical progression, and death outcomes in an admixed Brazilian population. The HLA-A, -B, -C, and -DRB1 were genotyped in 375 unrelated HTLV-1-infected individuals divided into asymptomatic carriers (AC) (n = 165) and HAM/TSP (n = 210) in a longitudinal cohort from 8 to 22 years of follow-up. Because locus B deviated from Hardy-Weinberg Equilibrium for the study groups, the results represented for HLA-B alleles were inconclusive. The alleles HLA-A*68 and -C*07 were related to HAM/TSP risk in multivariate analysis. The alleles HLA-A*33, and -A*36 were associated with protection against disease progression in HAM/TSP patients, while -C*12, -C*14, and -DRB1*08 were associated with increased risk of death. In the AC group, the presence of, -C*06 and -DRB1*15 alleles influenced an increased PVL, in an adjusted linear regression model, while -A*30, -A*34, -C*06, -C*17 and -DRB1*09 alleles were associated with increased PVL in HAM/TSP group compared to HAM/TSP individuals not carrying these alleles. All these alleles were also related to increased PVL associated with clinical progression outcome. Increased PVL associated with the death outcome was linked to the presence of HLA-A*30. PVL has been associated with HLA, and several alleles were related in AC and HAM/TSP patients with or without interacting with clinical progression outcomes. Understanding the prognostic value of HLA in HAM/TSP pathogenesis can provide important biomarkers tools to improve clinical management and contribute to the discovery of new therapeutic interventions.

Meningeal Sporotrichosis Due to Sporothrix brasiliensis: A 21-Year Cohort Study from a Brazilian Reference Center.

Meningeal sporotrichosis is rare and occurs predominantly in immunosuppressed individuals. This retrospective study explored clinical and laboratory characteristics, treatment, and prognosis of patients with disseminated sporotrichosis who underwent lumbar puncture (LP) at a Brazilian reference center from 1999 to 2020. Kaplan-Meier and Cox regression models were used to estimate overall survival and hazard ratios. Among 57 enrolled patients, 17 had meningitis. Fifteen (88.2%) had HIV infection, and in 6 of them, neurological manifestations occurred because of the immune reconstitution inflammatory syndrome (IRIS). The most frequent symptom was headache (88.2%). Meningeal symptoms at first LP were absent in 7/17 (41.2%) patients. Sporothrix was diagnosed in cerebrospinal fluid either by culture or by polymerase chain reaction in seven and four patients, respectively. All but one patient received prolonged courses of amphotericin B formulations, and seven received posaconazole, but relapses were frequent. Lethality among patients with meningitis was 64.7%, with a higher chance of death compared to those without meningitis (HR = 3.87; IC95% = 1.23;12.17). Meningeal sporotrichosis occurs mostly in people with HIV and can be associated with IRIS. Screening LP is indicated in patients with disseminated disease despite the absence of neurological complaints. Meningitis is associated with poor prognosis, and better treatment strategies are needed.

High frequencies of functionally competent circulating Tax-specific CD8+ T cells in human T lymphotropic virus type 2 infection.

Human T lymphotropic virus type 2 (HTLV-2) is characterized by a clinically asymptomatic persistent infection in the vast majority of infected individuals. In this study, we have characterized for the first time ex vivo specific CTL responses against the HTLV-2 Tax protein. We could detect CTL responses only against a single HLA-A*0201-restricted Tax2 epitope, comprising residues 11-19 (LLYGYPVYV), among three alleles screened. Virus-specific CTLs could be detected in most evaluated subjects, with frequencies as high as 24% of circulating CD8(+) T cells. The frequency of specific CTLs had a statistically significant positive correlation with proviral load levels. The majority of virus-specific CD8(+) T cells exhibited an effector memory/terminally differentiated phenotype, expressed high levels of cytotoxicity mediators, including perforin and granzyme B, and lysed in vitro target cells pulsed with Tax2((11-19)) synthetic peptide in a dose-dependent manner. Our findings suggest that a strong, effective CTL response may control HTLV-2 viral burden and that this may be a significant factor in maintaining persistent infection and in the prevention of disease in infected individuals.

Neurological Aspects of HIV-1/HTLV-1 and HIV-1/HTLV-2 Coinfection.

Simultaneous infection by human immunodeficiency viruses (HIV) and human T-lymphotropic viruses (HTLV) are not uncommon since they have similar means of transmission and are simultaneously endemic in many populations. Besides causing severe immune dysfunction, these viruses are neuropathogenic and can cause neurological diseases through direct and indirect mechanisms. Many pieces of evidence at present show that coinfection may alter the natural history of general and, more specifically, neurological disorders through different mechanisms. In this review, we summarize the current evidence on the influence of coinfection on the progression and outcome of neurological complications of HTLV-1/2 and HIV-1.

SARS-CoV-2: Should We Be Concerned about the Nervous System?

The COVID-19 pandemic has proved to be an enormous challenge to the health of the world population with tremendous consequences for the world economy. New knowledge about COVID-19 is being acquired continuously. Although the main manifestation of COVID-19 is SARS, dysfunction in other organs has been described in the last months. Neurological aspects of COVID-19 are still an underreported subject. However, a plethora of previous studies has shown that human CoVs might be neurotropic, neuroinvasive, and neurovirulent, highlighting the importance of this knowledge by physicians. Besides, several neurological manifestations had been described as complications of two other previous outbreaks of CoV diseases (SARS ad Middle East respiratory syndrome). Therefore, we should be watchful, searching for early evidence of neurological insults and promoting clinical protocols to investigate them. Our objectives are to review the potential neuropathogenesis of this new CoV and the neurological profile of COVID-19 patients described so far.

HTLV-1 Associated Neurological Complex. What is Hidden below the Water?

The human T-cell lymphotropic virus type 1 (HTLV-1) infects 5-10 million people worldwide and causes fatal and disabling diseases in a significant proportion of them. A chronic myelitis named HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the typical neurological manifestation of HTLV-1. However, other neurological syndromes can be either associated with HAM/TSP or occur in isolation in the HTLV-1 infected individual. Although this fact has been widely described over the years, it has been somewhat neglected by the mainstream literature, which has been largely focused on HAM/TSP. Cognitive dysfunction, encephalopathy, neurogenic bladder, motor neuron disease, inflammatory myopathies, polyneuropathy, and dysautonomia can also occur in the HTLV-1 infected patient and may remain unnoticed to the unsuspecting physician. In the present review, we intend to draw attention, primarily to the infectious disease specialist and to the general practitioner, to the fact that HTLV-1 has a broader neurological spectrum than the designation HAM/TSP suggests and that infected individuals may harbor other neurological syndromes in addition to HAM/TSP.

HTLV-I alters the multidrug resistance associated protein 1 (ABCC1/MRP1) expression and activity in human T cells.

The human T cell lymphotropic/leukaemia virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The multidrug resistance associated protein 1 (ABCC1) plays multiple functions in physiopathologic responses. The expression and activity of ABCC1 was studied in T lymphocytes from uninfected and HTLV-I-infected individuals (both asymptomatic and symptomatic/HAM/TSP). ABCC1 expression and activity was reduced to nearly half in T lymphocytes from infected patients compared to control lymphocytes. Only 51.6% of CD4(+) cells from HAM/TSP patients expressed ABCC1 whereas this was seen in 60.3% from asymptomatic individuals, compared to an expression of around 86% in controls. Our results suggest that ABCC1 is negatively regulated in HTVL-I infection, supplying a novel target to investigate the pathogenesis of HTLV-I.

Hepatitis C virus and human T-cell lymphotropic virus type 1 co-infection: impact on liver disease, virological markers, and neurological outcomes.

OBJECTIVES: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with neurological abnormalities, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and peripheral neuropathy (PN). Hepatitis C virus (HCV) infection is the leading cause of chronic liver disease worldwide, and causes PN in approximately 9% of patients. Because the interplay between these potentially neuropathogenic viruses in the same individual is still poorly understood, the clinical and laboratory outcomes of co-infected patients were evaluated and compared with those of controls. METHODS: The prevalence rates of neurological and laboratory abnormalities were evaluated in HCV/HTLV-1 co-infected patients (n=50), and in subjects with single HCV (n=46) or HTLV-1 (n=150) infection. RESULTS: A higher frequency of isolated PN was present in HCV-infected patients; this was not associated with cryoglobulinemia. No difference was found in the frequency of PN or HAM/TSP when co-infected subjects were compared to singly infected subjects. Hepatic involvement was present in HCV-infected subjects, as shown by increased levels of serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin, in addition to thrombocytopenia. On the other hand, HCV/HTLV-1 co-infected individuals presented a better prognosis for hepatic involvement when compared with singly HCV-infected subjects. CONCLUSIONS: These data suggest that HCV/HTLV-1 co-infection does not mutualistically alter the outcome with regard to neurological manifestations. Nonetheless, changes in the immunological environment induced by HTLV-1 infection could lead to a reduction in hepatic damage, even without significant HCV clearance.

The HTLV-1 neurological complex.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about 20 million people worldwide and causes immune-mediated diseases of the nervous system. The classic neurological presentation of HTLV-1 infection is a myelopathy called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, HAM/TSP is not the only neurological outcome that can result from HTLV-1 infection. In this Personal View, we show that HTLV-1 has a broader neurological spectrum than the names HAM/TSP suggest and that people infected with this virus can present with various isolated or assorted syndromes.

Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM).

After the first description of TSP/HAM in 1985 and the elaboration of WHO's diagnostic criteria in 1988, the experience of the professionals in this field has increased so that a critical reappraisal of these diagnostic guidelines was considered timely. Brazilian neurologists and observers from other countries met recently to discuss and propose a modified model for diagnosing TSP/HAM with levels of ascertainment as definite, probable, and possible, according to myelopathic symptoms, serological findings, and/or detection of HTLV-I DNA and exclusion of other disorders.

Update on Neurological Manifestations of HTLV-1 Infection.

The human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects 10-20 million persons around the world. Initially associated with the hematological malignancy adult T cell leukemia/lymphoma (ATLL), HTLV-1 is also the cause of a chronic progressive myelopathy named "HTLV-1-associated myelopathy/tropical spastic paraparesis" (HAM/TSP). HAM/TSP arises as the tip of the iceberg of an assortment of neurological syndromes triggered by the virus such as inflammatory myopathies, polyneuropathies, amyotrophic lateral sclerosis (ALS)-like syndromes, dysautonomia, and cognitive impairment. HAM/TSP typifies a chronic progressive spastic paraparesis with neurogenic bladder and minimal sensory signs. The neuropathology of HAM/TSP is concentrated in the thoracic spinal cord and is typically biphasic. Initially, there is a perivascular lymphocytic cuffing and mild parenchymal mononuclear infiltrates. Subsequently, this is replaced by gliosis and scarring. The neuropathogenesis of HTLV-1 is still partially understood. At present, the therapy of HAM/TSP remains basically symptomatic.

Dermatological findings of human T lymphotropic virus type 1 (HTLV-I)-associated myelopathy/tropical spastic paraparesis.

Dermatological findings for patients with human T lymphotropic virus type 1(HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were investigated and were compared with dermatological findings for a control group. Only xerosis, cutaneous candidiasis, and palmar erythema were significantly associated with HAM/TSP. Histopathological patterns of cutaneous lymphoma were seen in 25% of 32 patients who underwent biopsy, and, thus, the cutaneous alterations in HAM/TSP can be classified into nonspecific lesions, infectious lesions, immune-inflammatory-mediated lesions, and premalignant or malignant lesions.

Peripheral neuropathy in HTLV-I infected individuals without tropical spastic paraparesis/HTLV-I-associated myelopathy.

Tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM) is the classical neurological manifestation of HTLV-I. Only a few studies have described isolated peripheral neuropathy (PN) among HTLV-I infected individuals. 335 infected individuals without TSP/HAM were evaluated for the presence of PN and 45 of them showed evidences of peripheral nervous system involvement. Of these 21 patients had isolated PN, defined by clinical and/or electrophysiological criteria. Sural nerve biopsies revealed inflammatory infiltrates in 2, axonal degeneration in 2 and segmental demyelination in 1. Therefore, peripheral neuropathy can be found as an isolated manifestation of HTLV-I infection. We conclude that HTLV-I infection should be investigated in patients with PN of unknown origin.

Neurological manifestations in HTLV-I-infected blood donors.

The human T-cell lymphotropic virus type 1 (HTLV-I) causes a neurological disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals. Although other neurological outcomes have been described their prevalence is presently unknown. To evaluate the frequency and characteristics of neurological involvement in a population of HTLV-I-infected blood donors we investigated 196 HTLV-I positive and 196 negative blood donors from a blood center of Rio de Janeiro, Brazil. Individuals with abnormalities at the neurological examination were examined by three neurologists, and when pertinent, additional neurological investigations were performed. Descriptive analysis, Student's t-test and chi2 test were employed for statistical analysis. Neurological abnormalities were found in 71 (36.2%) of the HTLV-I positive blood donors and in only 29 (14.8%) of the HTLV-I negative donors (OR = 2.54, 95% CI = 1.67-3.59, p = 0.000002). Cases of myelopathy, motor neuron disease and myopathy were only found in the HTLV-I positive group. In addition, peripheral neuropathy (PN) was significantly more frequent in the positive group (p = 0.015). In summary, our data suggest that HTLV-I-infected individuals exhibit a wide variety of neurological manifestations apart from the classical picture of HAM/TSP.

Neurologic complications of HTLV-1: a review / Complicações neurológicas do HTLV: uma revisão HTLV-1

O vírus linfotrópico de células T humanas tipo 1 (HTLV-1) é um retrovírus que infecta cerca de 20 milhões de pessoas em todo o mundo e causa doenças imunomediadas do sistema nervoso. A apresentação neurológica clássica da infecção pelo HTLV-1 é a chamada paraparesia espástica tropical / mielopatia associada ao HTLV-1 (HAM/TSP). HAM / TSP,no entanto, não é o único desfecho neurológico que pode resultar da infecção pelo HTLV-1. Nesta revisão, é feita uma atualização sobre vários aspectos desta importante condição neurológica, o complexo neurológico do HTLV-1.