Cognitive dysfunction and mortality in multiple sclerosis: Long-term retrospective review.

BACKGROUND: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple sclerosis (MS) is still a matter of debate. OBJECTIVE: The aim of this study was to explore the long-term outcome associated with neuropsychological performance in a cohort of patients with MS. METHODS: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102-192 months after T1. Demographic and clinical data regarding the last clinical appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. RESULTS: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transitioning from relapsing-remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted hazard ratio (HR) = 3.07, p = 0.006) and the progressive disease course subgroup (adjusted HR = 3.68, p = 0.007), even when adjusting for other covariates. DISCUSSION: The study results demonstrate that cognitive dysfunction in MS is predictive of poorer prognosis and mortality.

Correlated prevalence of hydrocele and microfilaremia in Amazon (Belém, 1951-2005).

BACKGROUND & OBJECTIVES: For decades, the city of Belém in Brazil's eastern Amazon was the second city in the country with highest prevalence of cases of filariasis due to Wuchereria bancrofti infection. However, this prevalence decreased over time until reaching null records, concomitantly with a decrease in frequency of recorded hydrocele cases. In this context, we analyzed cross-sectional data to evaluate the degree of correlation between prevalence of positive blood microfilariae results during surveillance screening occurred along 54 years (1951-2005) and prevalence of hydrocele cases recorded in the same time period. METHODS: The dataset regarding hydrocele cases was obtained from two local hospitals. The Endemic Diseases Control Division of the Health Surveillance Department of the Municipal Health Department of Belém provided dataset regarding positive blood microfilariae cases. Prevalence calculus and linear correlation statistics were performed. RESULTS: Both positive blood microfilariae and hydrocele cases are well correlated statistically in absolute frequency (r = 0.871, 95%CI = 0.788 to 0.923, R2 = 0.759, p < 0.0001) and in prevalence (r = 0.835, 95%CI = 0.732 to 0.901, R2 = 0.698, p < 0.0001). INTERPRETATION & CONCLUSION: We have concluded that blood microfilariae detection and hospitalized hydrocele cases are well correlated in our dataset. In addition, these results support the hypothesis that hydrocele prevalence can be useful to filariasis surveillance and control in endemic areas. However, limitations to hydrocele prevalence as an epidemiological indicator of filariasis are evidenced.

The epidemiology of multiple sclerosis in the entre Douro e Vouga region of northern Portugal: a multisource population-based study.

BACKGROUND: The prevalence of Multiple Sclerosis (MS) has been increasing worldwide and the north-south gradient of prevalence may be disappearing in the Northern hemisphere. The few previous prevalence studies performed in Portugal have reported a lower prevalence than the average for Western Europe. The aim of this study is to estimate the prevalence of MS in the Entre Douro e Vouga region, in Northern Portugal. METHODS: Multiple overlapping sources were used to ascertain all cases from the reference population: records from hospitals in the region and neighbouring regions; diagnostic databases of primary care physicians; and applications for disability benefits. The prevalence date was set at 1 January 2014. The reference population was 274,859 inhabitants. Patients' neurologists were contacted to retrieve clinical information and confirm the diagnosis based. RESULTS: A total of 177 patients were identified after eliminating duplicates from different sources. The female to male ratio was 1.9 and the mean age at disease onset was 33.5 (standard deviation: 10.3). Clinically isolated syndrome accounted for 9.0% of patients, relapsing remitting for 58.8%, secondary progressive for 20.3% and primary progressive for 11.8%. The prevalence was estimated in 64.4 patients per 100,000 (95% confidence interval: 54.9;73.9). CONCLUSIONS: In this study we report a higher point prevalence of MS than had been previously described in Portugal, but still far from the higher values recently reported in other Southern European countries.

Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine.

BACKGROUND: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients' lives. OBJECTIVE: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment. METHODS: ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score. RESULTS: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment. CONCLUSION: PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.

Cognitive reserve in multiple sclerosis: Protective effects of education.

BACKGROUND: Recent data suggest that cognitive reserve modulates the adverse effects of multiple sclerosis (MS) pathology on cognitive functioning; however, the protective effects of education in MS are still unclear. OBJECTIVE: To explore education as an indicator of cognitive reserve, while controlling for demographic, clinical and genetic features. METHODS: A total of 419 MS patients and 159 healthy comparison (HC) subjects underwent a comprehensive neuropsychological (NP) assessment, and answered the Hospital Anxiety and Depression Scale. Based on the HC data, MS patients' NP scores were adjusted for sex, age and education; and the estimated 5(th) percentile (or 95(th) percentile, when appropriate) was used to identify any deficits. Patients also performed the Mini-Mental State Examination (MMSE); and their human leucocyte antigen HLA-DRB1 and apolipoprotein E (ApoE) genotypes were investigated. RESULTS: Patients with higher education were less likely (p < 0.05) to have cognitive deficits than those with lower education, even when controlling for other covariates. Other significant predictors of cognitive deficit were: age, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), and a progressive course. No significant association was found with the HLA-DRB1*15:01 or ApoE ε4 alleles. CONCLUSIONS: These results provide support to the use of education as a proxy of cognitive reserve in MS and stress the need to take into account education when approaching cognition in MS.

Characteristics of Neuro-Behçet's Disease in a Case-Series from a Single Centre in Northern Portugal.

INTRODUCTION: Behçet's disease (BD) is a multisystem inflammatory disease of unknown etiology that may affect the CNS - Neuro-Behçet (NB). Our aim was to evaluate the frequency of neurological involvement and characterize a cohort of our NB patients. METHODS: We retrospectively revised the clinical, laboratory and imaging data of a cohort of BD patients, followed in our hospital outpatient clinic. RESULTS: We identified 138 BD patients. Twenty-five out of 138 had NB (15 female). Four patients presented with neurological symptoms. We identified a total of 37 attacks. Twenty-one attacks were classified as parenchymatous, four non-parenchymatous and 12 as other syndromes. Seventeen patients had CSF analysis performed (20 samples). Five samples were normal, 15 showed CSF pleocytosis. The most frequent finding on MRI performed in the acute phase was extensive lesions involving the brainstem. Two patients died due to the neurological involvement of BD. CONCLUSION: We found 18.1% prevalence of NB and a higher female-to-male ratio in our group than in other series. Gastrointestinal and vascular involvement was more frequent in the NB group. The fact that neurological involvement may be the first manifestation of BD with therapeutic implications and associated morbidity points out the relevance of an early diagnosis.

Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M.

BACKGROUND: Early-onset (≤40 years) and later-onset (≥50 years) cases of familial amyloid polyneuropathy (FAP) ATTRV30M are not different entities, often coexisting in the same family, and showing anticipation (earlier age-at-onset (AO) in younger generations, usually associated with more severe phenotype). Historically, anticipation has been ascribed to ascertainment biases. Our aim was to study anticipation in a very large number of FAP kindreds, removing possible biases, and gain further insight into parent-of-origin effects. METHODS: We analysed 926 parent-offspring pairs (from the Unidade Clínica de Paramiloidose roster, collected in 70 years), both clinically observed and had well-established AO, correcting for intrafamilial correlations. RESULTS: Women had a significantly higher AO, either for daughters (mean: 33.70, SD: 6.84) vs sons (29.43, 6.08); or mothers (39.57, 11.75) vs. fathers (35.62, 11.62). Also, 291 pairs showed marked anticipation (≥10 years); the transmitting parent was the mother in 203 pairs. Mother-son pairs showed larger anticipation (10.43, 9.34), while father-daughter pairs showed only a residual anticipation (1.23, 9.77). Gender of offspring and parents was highly significant (with no interaction). To remove possible biases, we repeated analyses: (1) excluding the proband; (2) removing pairs with simultaneous onset; and (3) excluding offspring born after 1960. Anticipation was found in all subsamples, with the same trend for a parent-of-origin effect. Noteworthy, parents with AO ≤40 years never had offspring with AO ≥50. CONCLUSIONS: These findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M. Acknowledgment of anticipation may have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers.

Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis.

Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) ß have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease.

Neurological Involvement in a Portuguese Cohort of IgG4-Related Disease.

INTRODUCTION: Neurological involvement in immunoglobulin G4-related disease (IgG4-RD) is increasingly recognized. Its diagnosis can be challenging due to clinical mimics and difficulty in obtaining nervous system biopsies. The aim of this study was to describe a cohort of neurological IgG4-RD patients. METHODS: Patients were recruited from a neuroimmunology tertiary center. Clinical, laboratory, neuroimaging and histological data were reviewed. RESULTS: Fifteen patients (60% women), with a median age of 53 years (48.5 - 65.0) were included: 13 (86.7%) classified as possible IgG4-RD, one (6.7%) as probable and one (6.7%) as definitive. The most common neurological phenotypes were meningoencephalitis (26.7%), orbital pseudotumor (13.3%), cranial neuropathies (13.3%), peripheral neuropathy (13.3%), and longitudinally extensive transverse myelitis (LTEM) (13.3%). Median serum IgG4 concentration was 191.5 (145.0 - 212.0) mg/dL. Seven in 14 patients had CSF pleocytosis (50.0%) and oligoclonal bands restricted to the intrathecal compartment, while most cases presented elevated CSF proteins (64.3%). Magnetic resonance imaging abnormalities included white matter lesions in four (26.7%), hypertrophic pachymeningitis in two (13.3%), and LETM in two (13.3%). Two patients had biopsy-proven IgG4-RD in extra-neurological sites. CONCLUSION: This study highlights the phenotypical variability of the neurological IgG4-RD. Biopsy inaccessibility reinforces the importance of new criteria for the diagnosis of this subset of patients.

Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant.

BACKGROUND: Cognitive dysfunction is part of the broad spectrum of clinical manifestations in older untreated hereditary transthyretin amyloidosis patients with peripheral polyneuropathy. OBJECTIVE: The objective of this study is to systematically explore cognitive dysfunction in ATTRV30M amyloidosis patients whose disease course was modified by liver transplant (LT). METHODS: A series of 269 carriers of TTRVal30Met mutation treated with LT underwent a neuropsychological assessment. Clinical charts were reviewed to identify focal neurological episodes (FNEs), cognitive complaints and laboratory results. Chi-square and Mann-Whitney tests explored potential predictors of cognitive dysfunction. RESULTS: Cognitive dysfunction was identified in 35 patients (13%)-14 (5%) had mild and 21 (8%) had moderate dysfunction. In comparison to normal cognition, both mild and moderate cognitive dysfunction patients had older age, higher mPND score and elevated NT-proBNP and Cystatin C values. Mild cognitive dysfunction was associated with longer disease duration and history of FNEs, whereas moderate dysfunction was related to older age at disease onset and more cognitive complaints and depression symptoms. CONCLUSIONS: Consistent with the natural history of the disease, older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction in ATTRV30M patients treated with LT. The level of cognitive dysfunction may depend on some clinical variables.

Effect of commercial yeasts (Saccharomyces cerevisiae) on fermentation metabolites, phenolic compounds, and bioaccessibility of Brazilian fermented oranges.

Brazil is the largest producer of oranges worldwide, as well as one of the largest producers of orange juice. Alcoholic fermented beverages have been considered a marketable alternative for oranges. In this study, four S. cerevisiae commercial yeasts were evaluated for metabolites generated during orange juice (cv. 'Pêra D9') fermentation. Alcohols, sugars, and organic acids were evaluated by HPLC-DAD-RID during fermentation, and phenolic compounds were analyzed in fermented orange. Orange juice and fermented oranges were also subjected to digestion simulations. The yeasts presented an adequate fermentation activity, based on sugar consumption, and high ethanol (>10.5%) and glycerol (4.8-5.5 g/L) contents. The yeast strains T-58 and US-05 produced high levels of lactic acid. Phenolic compounds and antioxidant activity did not differ amongst yeasts, presenting hesperidin levels between 115 and 127 mg/L, respectively. The fermented orange showed a >70% bioaccessibility, compared to juice, especially for catechin, epigallocatechin-gallate, procyanidin-B2, rutin, and procyanidin-B1.

People with Primary Progressive Multiple Sclerosis Have a Lower Number of Central Memory T Cells and HLA-DR+ Tregs.

The importance of circulating immune cells to primary progressive multiple sclerosis (PPMS) pathophysiology is still controversial because most immunotherapies were shown to be ineffective in treating people with PPMS (pwPPMS). Yet, although controversial, data exist describing peripheral immune system alterations in pwPPMS. This study aims to investigate which alterations might be present in pwPPMS free of disease-modifying drugs (DMD) in comparison to age- and sex-matched healthy controls. A multicentric cross-sectional study was performed using 23 pwPPMS and 23 healthy controls. The phenotype of conventional CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells, natural killer (NK) T cells and NK cells was assessed. Lower numbers of central memory CD4+ and CD8+ T cells and activated HLA-DR+ Tregs were observed in pwPPMS. Regarding NK and NKT cells, pwPPMS presented higher percentages of CD56dimCD57+ NK cells expressing NKp46 and of NKT cells expressing KIR2DL2/3 and NKp30. Higher disease severity scores and an increasing time since diagnosis was correlated with lower numbers of inhibitory NK cells subsets. Our findings contribute to reinforcing the hypotheses that alterations in peripheral immune cells are present in pwPPMS and that changes in NK cell populations are the strongest correlate of disease severity.

Kappa free light chains: Diagnostic performance in multiple sclerosis and utility in a clinical laboratory.

BACKGROUND: Automated, technically simple analytical methods offering objective results are highly valued in clinical laboratories. Kappa free light chains (KFLC) in cerebrospinal fluid (CSF) are promising multiple sclerosis (MS) biomarkers, particularly kappa (K) index. METHODS: KFLC were determined in CSF and serum samples of patients diagnosed with MS, clinically/radiologically isolated syndrome (N, 39), and controls (N, 152; inflammatory and non-inflammatory neurological disorders). Diagnostic performance of several KFLC parameters, previously determined oligoclonal band (OCB) testing, and IgG index, was assessed. A K index decision threshold for sample screening was identified and reduction in performed OCB analyses estimated accordingly. RESULTS: Higher KFLC parameters were detected in the MS group and K index performed best among them (AUC 0.92). At a 7.25 cut-off it showed better sensitivity (85% vs. 77%) though less specificity (88% vs. 91%) than OCBs. Comparatively, IgG index's performance was inferior (AUC 0.83). A decision K index threshold of 2.55 (97% sensitivity) would reduce OCB testing by 52% in the studied population. CONCLUSIONS: The proposed 7.25 cut-off could assist MS diagnostics and identify some false negative cases from OCB studies. Sequential algorithms using K index for the decision to perform OCB detection would improve laboratory efficiency and substantially reduce costs.

Pituitary metastasis unveiling a lung adenocarcinoma.

SUMMARY: Pituitary metastasis (PM) can be the initial presentation of an otherwise unknown malignancy. As PM has no clinical or radiological pathognomonic features, diagnosis is challenging. The authors describe the case of a symptomatic PM that revealed a primary lung adenocarcinoma. A 62-year-old woman with multiple sclerosis and no history of malignancy, incidentally presented with a diffusely enlarged and homogeneously enhancing pituitary gland associated with stalk enlargement. Clinical and biochemical evaluation revealed anterior hypopituitarism and diabetes insipidus. Hypophysitis was considered the most likely diagnosis. However, rapid visual deterioration and pituitary growth raised the suspicion of metastatic involvement. A search for systemic malignancy was performed, and CT revealed a lung mass, which proved to be a lung adenocarcinoma. Accordingly, the patient was started on immunotherapy. Resection of the pituitary lesion was performed, and histopathology analysis revealed metastatic lung adenocarcinoma. Following surgery, the patient underwent radiotherapy. More than 2 years after PM detection, the patient shows a clinically relevant response to antineoplastic therapy and no evidence of PM recurrence. LEARNING POINTS: Although rare, metastatic involvement of the pituitary gland has been reported with increasing frequency during the last decades. Pituitary metastasis can be the initial presentation of an otherwise unknown malignancy and should be considered in the differential diagnosis of pituitary lesions, irrespective of a history of malignancy. The sudden onset and rapid progression of visual or endocrine dysfunction from a pituitary lesion should strongly raise the suspicion of metastatic disease. MRI features of pituitary metastasis can overlap with those of other pituitary lesions, including hypophysitis; however, rapid pituitary growth is highly suggestive of metastatic disease. Survival after pituitary metastasis detection has improved over time, encouraging individualized interventions directed to metastasis to improve quality of life and increase survival.

Depression and anxiety in multiple sclerosis patients: The role of genetic variability of interleukin 1ß.

BACKGROUND: Mood disorders, as depression and anxiety, are frequent in Multiple Sclerosis (MS) patients. High pro-inflammatory cytokine levels (e.g. IL-1ß) have been reported in depressed individuals. OBJECTIVE: We aimed to investigate the role of the rs16944 (IL-1ß-511 C>T) polymorphism in the development of anxiety and depression symptoms in a Portuguese cohort of MS patients. METHODS: 393 MS patients answered the Hospital Anxiety and Depression Scale (HADS) at T1. This questionnaire was reapplied to a subgroup of 175 MS patients approximately three years later (T2). HADS cut-off scores for anxiety and depression were respectively ≥11 and ≥8. RESULTS: At T1, anxiety was found in 106 MS patients (27.0%) and 11 controls (16.7%); whereas depression was identified in 116 (29.5%) MS patients and 9 controls (13.6%). Persistent anxiety and depression were respectively recorded in 12% and 20% of MS patients. The rs16944TT genotype was found to be a susceptibility factor for the occurrence of depression at T1 (OR = 3.16, p=0.002) and the development of persistent depression (OR = 5.63, p=0.003) in MS. CONCLUSION: Study results support the hypothesis that inflammation is a significant factor in psychopathology development.

First report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder, seen most often in young adults and children, triggered by tumors or infections. We report a case of cryptococcal meningitis in a patient with sarcoidosis, presenting prominent neuropsychiatric symptoms, electroencephalographic features of autoimmune encephalitis and positive anti-NMDAR antibodies in the cerebrospinal fluid, raising the hypothesis of an infectious immune-mediated mechanism triggering the production of anti-NMDAR antibodies. Since anti-NMDAR encephalitis is potentially fatal and has significant morbidity, further descriptions of its etiological associations are essential to early identification and prompt treatment.

[Recommendations about Multiple Sclerosis Management during Pregnancy, Partum and Post-Partum: Consensus Position of the Portuguese Multiple Sclerosis Study Group]. / Recomendações sobre a Abordagem da Esclerose Múltipla na Gravidez, Parto e Pós-Parto: Posição de Consenso do Grupo de Estudos de Esclerose Múltipla.

Multiple sclerosis typically affects young women of reproductive age. Therefore, all healthcare professionals involved in the follow-up of multiple sclerosis patients must be prepared to discuss pregnancy and breastfeeding issues and provide the best possible counselling. However, there are still many doubts and heterogeneous clinical approaches partly due to the lack of consensus and guidelines. Concerning the handling of disease modifying therapies during pregnancy and postpartum, existing uncertainties have been complicated by the increase in the number of treatments available in recent years. This article aims to present the state-of-the-art and provide guidance based on the best level of available evidence and expert opinion regarding the management of multiple sclerosis patients at different stages: pregnancy planning, pregnancy, partum, and the postpartum period.

A esclerose múltipla afecta tipicamente mulheres jovens em idade reprodutiva. Desta forma, todo os profissionais de saúde envolvidos no seguimento destes doentes deverão estar preparados para abordar as questões relacionadas com a gravidez e amamentação e fornecer o melhor aconselhamento possível. No entanto, existem ainda muitas dúvidas e abordagens clínicas heterogéneas em parte devido à ausência de consensos e normas orientadoras. No que concerne ao manuseamento das terapêuticas modificadoras de doença durante os períodos de gravidez e pós-parto, as incertezas têm sido agravadas devido ao aumento do número de fármacos disponíveis nos últimos anos. Este artigo visa apresentar a informação mais atual e fornecer orientações baseadas no melhor nível de evidência disponível e na opinião de peritos relativamente ao seguimento das doentes com esclerose múltipla em diferentes etapas: planificação da gravidez, gravidez, parto e período pós-parto.

Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients.

Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ≈2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggest that tafamidis can cross the CSF-blood and eye-blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers or TTR lowering drugs are essential to understand the clinical effect of our observations.

The hospital anxiety and depression scale, in patients with multiple sclerosis.

PURPOSE: Multiple sclerosis (MS) is a long-lasting disabling disease with psychological implications. Hospital Anxiety and Depression Scale (HADS) is a questionnaire developed to screen anxiety and depression among patients in hospital settings. The objective of this report was to study the metric properties of the Portuguese version of HADS regarding MS. MATERIALS AND METHODS: This was a cross-sectional study. Three hundred and eighty individuals with a diagnosis of MS, according to the revised McDonald criteria, were recruited from an outpatient Neuroimmunology Clinic of the city of Porto. Participants had a mean age of 40.04 years (SD =10.86), 63.9% of them were female. HADS consists of two subscales - anxiety and depression - scored separately, with seven items each. RESULTS: The results of our study show the appropriateness of HADS for the identification of mood changes in people with MS and show good metric properties. CONCLUSION: It seems to be a useful tool for the scrutiny of mood disorders in Portuguese patients with MS. The questionnaire is also sensitive to disease when compared to people with other severe illnesses, and with people without the disease.

Age-dependent cognitive dysfunction in untreated hereditary transthyretin amyloidosis.

Central nervous system (CNS) involvement in hereditary transthyretin (TTR) amyloidosis has been described in patients whose disease course was modified by liver transplant. However, cognitive dysfunction has yet to be investigated in those patients. Moreover, CNS involvement in untreated patients or asymptomatic mutation carriers remains to be studied. A series of 340 carriers of the TTRVal30Met mutation (180 symptomatic and 160 asymptomatic) underwent a neuropsychological assessment, which included the Dementia Rating Scale-2 (DRS-2), auditory verbal learning test, semantic fluency, phonemic fluency, and trail making test. Cognitive deficits were identified at the individual level, after adjusting the neuropsychological test scores for demographic characteristics (sex, age, and education), based on large national normative data. The presence of cognitive dysfunction was determined by deficit in DRS-2 and/or multiple cognitive domains. Participants were also screened for depression based on a self-report questionnaire. The frequency of cognitive dysfunction was higher (p = 0.003) in symptomatic (9%) than in asymptomatic (2%) carriers. Among older carriers (≥ 50 years), the frequency of cognitive dysfunction was higher (p < 0.001) in symptomatic (36%) than asymptomatic (4%) individuals. Among younger participants (< 50 years), the frequency of cognitive dysfunction was not different (p = 0.631) between symptomatic patients (2%) and asymptomatic (1%) carriers. This cross-sectional study shows that cognitive dysfunction is part of the broad spectrum of clinical manifestations in older hereditary TTR amyloidosis patients with peripheral polyneuropathy, even in the early stages of the disease.