Development and Validation of a Neurological Disability Scale for Patients with HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): The IPEC-1 Scale (P03.258)

Schmidt, Felipe da Rocha; Oliveira, André Luiz dos Anjos de; Araújo, Abelardo de Queiroz Campos

doi:10.1212/wnl.78.1_meetingabstracts.p03.258

Cited by 7 publications

(5 citation statements)

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“…The IPEC-2 scale is a variation of IPEC-1 disability scale, which was previously validated ( 42 ), and differentiated only by separated assessment of lumbar pain and lower limb pain. IPEC-2 scale assesses motor impairment in addition to sensory, urinary, and intestinal alterations in HAM/TSP.…”

Section: Methodsmentioning

confidence: 99%

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression

et al. 2021

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Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

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Section: Methodsmentioning

confidence: 99%

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression

et al. 2021

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“…Correlation matrix (Figure 3A) relates these new, optimized MS progression outcomes to traditional scales of cognitive (i.e., SDMT and Paced Auditory Serial Addition Test [PASAT] (18)) and physical disability (EDSS, Scripps Neurological Rating Scale [SNRS] (19), Instituto de Pesquisa Clinica Evandro Chagas [IPEC] scale (20), and Ambulation Index [AI] (21)). Strong positive correlations demonstrate that CombiWISE successfully captures all traditional measures of physical disability.…”

Section: Resultsmentioning

confidence: 99%

“…Neurological exams have been recorded directly (after 9/2017) or transcribed retrospectively from structured medical records neurological examination form (before 9/2017) into NeurEx™ App (47) that automatically calculates traditional MS disability outcomes –EDSS (9), SNRS (19), Hauser AI (21), IPEC disability scale (20). CombiWISE was calculated from EDSS, SNRS, T25FW and nondominant hand of 9HPT, as described (14).…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype

Kósa

Lumbard

Wang

et al. 2022

Preprint

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While current treatments of multiple sclerosis (MS) effectively inhibit formation of focal lesions and relapses, most patients experience progression independent of relapse activity (PIRA). To understand PIRA, we analyzed nine prospectively acquired clinical and imaging outcomes in 176 relapsing-remitting and 215 progressive MS patients and 45 healthy volunteers, along with matched cellular and >5000 protein data in 1,042 cerebrospinal fluid (CSF) samples. Regressing out physiological aging and sex effects identified MS-related processes. Among these, compartmentalized inflammation and its effector mechanisms such as pyroptosis showed the strongest association with MS severity, irrespective of clinical categorization of patients. However, molecular processes affected localization of CNS injury: patients with predominant brain damage had proportionally higher neuroinflammation, while fibrosis and tissue hypoxia were linked to principal involvement of spinal cord. We did not identify inflammation-unrelated neurodegeneration; instead, CNS-related processes were beneficial, such as synaptogenesis. Machine learning-based CSF biomarker models predicted nine clinical and volumetric imaging outcomes in the independent cohort with accuracy exceeding published MS models. These data show intra-individual diversity of putative disease mechanisms in MS and implicate processes related to compartmentalized neuroinflammation as leading candidate mechanisms of PIRA. Future drug development should include CNS-penetrant anti-inflammatory agents.

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“…The patients received raltegravir 400 mg orally twice daily in an initial 6‐month treatment phase, followed by a 9‐month post‐treatment phase. Patients were evaluated clinically at each study time point (baseline/month 0, month 3, month 6, month 9, and month 15), with full neurological evaluations and clinical measures [Expanded Disability Status Scale (EDSS), 14 Scripps Neurologic Rating Scale (SNRS), 15 Timed 25 Foot Walk, 16 Insituto de Pesquisa Clinica Evandro Chagas scale (IPEC), 17 Ambulation Index (AI), 18 9‐Hole Peg Test 19 ] performed at each clinic visit. Of the 18 patients, 2 patients withdrew prior to the end of the treatment period, 1 due to skin reaction (possibly related to treatment) and 1 due to inability to travel for study visits (not related to treatment), and therefore both patients were not included in the final trial analysis.…”

Section: Methodsmentioning

confidence: 99%

Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP

Enose-Akahata

Billioux

Azodi

et al. 2021

Ann Clin Transl Neurol

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Objective Human T‐cell lymphotropic virus 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell‐free and cell‐to‐cell transmission of HTLV‐1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients. Methods Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6‐month treatment phase, followed by a 9‐month post‐treatment phase. HTLV‐1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients. Results While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients’ neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4+CD25+ T cells and spontaneous lymphoproliferation. Interpretation Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients. Clinical Trial Registration Number NCT01867320.

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Development and Validation of a Neurological Disability Scale for Patients with HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): The IPEC-1 Scale (P03.258)

Cited by 7 publications

References 0 publications

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression

Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype

Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP

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