Lithium is the most effective therapy for bipolar and schizoaffective disorders. Despite its efficacy, lithium has a narrow therapeutic index and adverse effects are frequent. Lithium intoxication ...(LI) generally affects brain, but less frequently can affect kidneys, thyroid, and parathyroid.Here, we report the case of a patient with lithium neurotoxic effects complicated by parathyroid and renal adverse effects. The patient was a 52-year-old woman treated with lithium, who was recently diagnosed with hypercalcemia and hyperparathyroidism.She was admitted for severe agitation, confusion, and diffuse tremor. Despite serum lithium and calcium normalization, laboratory tests revealed a life-threatening hypernatremia caused by nephrogenic diabetes insipidus (NDI). Hemodialysis was started, but after the first treatment the patient died for cardiac arrest.Neurological symptoms of LI may occur even if the dosage is close to the normal therapeutic range. Hypercalcemia and NDI are rare, but should be promptly diagnosed and treated. In case of poor clinical outcome, hemodialysis should be performed independently of lithium serum level.
We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer ...acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries.
The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity.
First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (
signed-rank < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio HR 0.36, 95% confidence interval CI 0.28-0.47;
< 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93;
= 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups.
This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients.
This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA.
Background: Theory of mind (ToM) is the ability to understand and interpret another person's beliefs, intentions (cognitive ToM) and emotions (affective ToM). Objective: To explore affective and ...cognitive ToM and their neuropsychological correlates in patients affected by multiple sclerosis (MS). Material and Method: Forty MS patients and 40 matched control individuals underwent tasks assessing cognitive (the ToM Pictures Sequencing Task and the Advanced Test of ToM) and affective ToM (the Reading the Mind in the Eyes Task and the Emotion Attribution Task), in both verbal and nonverbal modality, a comprehensive neuropsychological battery, and questionnaires for behavioral disorders. Results: MS patients performed significantly worse than controls on tasks assessing cognitive and affective ToM, in verbal and nonverbal modality. Moreover, MS patients achieved significantly lower scores on tests assessing visuospatial learning and speed of spatial information processing, and significantly higher scores on scales for alexithymia and depression with respect to controls. After covarying for cognitive and behavioral variables different in the 2 groups, the differences between patients and controls on ToM tasks remained significant. ToM abilities were significantly related to executive functions, but not to depressive, anxious and apathetic symptoms. Higher alexithymia scores were associated with poor recognition of others' mental states. Conclusion: The findings demonstrated that both affective and cognitive aspects of ToM are impaired in nondemented and mildly to moderately disabled MS and suggest that impaired social cognition can occur independently from behavioral disorders.
General Scientific Summary
Patients with multiple sclerosis are impaired in comprehending others' mental states. Such defect is related to cognitive dysfunctions and not to behavioral symptoms. This defect might contribute to impaired social cognition in patients with Multiple Sclerosis.
Background
Prospective memory (PM) deficits are often reported in multiple sclerosis (MS), but their relationship with neuropsychological characteristics and personality traits remains to be ...explored.
Objective
To systematically investigate both time-based and event-based PM abilities in a sample of MS without clinically relevant disability or global cognitive decline and to explore cognitive, neuropsychiatric characteristics and personality traits associated with PM deficits.
Methods
Thirty-three patients with MS and 33 healthy individuals were enrolled in the study. All participants underwent a standardized measure of PM to evaluate both time-based and event-based PM. Moreover, patients with MS completed the Brief Repeatable Battery to assess cognitive functioning, the Beck Depression Inventory-II and the Dimensional Apathy Scale to assess neuropsychiatric characteristics, and the NEO Personality Inventory-3 to assess personality traits.
Results
Individuals with MS demonstrated impaired time-based PM compared to healthy individuals. The regression analysis showed that poor performance in time-based PM was significantly related to lower extroversion and openness traits, whereas poor performance in event-based PM was significantly related to lower visuospatial memory abilities.
Conclusions
Low levels of openness and extroversion traits are associated with a greater risk of developing time-based PM deficit. Therefore, personality assessment and behavioural interventions should be encouraged in MS clinical practice.
A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of ...secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0) versus non-progressive patients 1.8 (1.2, 1.9). This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early MS ...is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >/= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline (HR = 1.19; 95CI 1.13-1.25, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.44; 95CI 1.28-1.61, p < 0.001), longer disease duration at baseline (HR = 1.56; 95%CI 1.28-1.90, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95CI 0.88-0.96, p < 0.001), lower number of relapses before the event (HR = 0.76; 95CI 0.73-0.80, p < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95CI 0.81-0.93, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95CI 1.35-1.79, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95CI 0.89-0.99, p = 0.017), higher number of relapses before the event (HR = 1.04; 95CI 1.01-1.07, p < 0.001). Longer exposure to disease modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (p < 0.001). This study provides evidence that in early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.
Background Multiple sclerosis (MS) is frequently associated with depressive symptoms and major depression. Objective We assessed psychometric properties of the Hamilton Depression Rating Scale (HDRS, ...17-item version) for assessing depressive symptomatology in a sample of MS patients. Methods Seventy patients (aged 43.3 ± 10.3 years) completed the HDRS and a thorough clinical and neuropsychological assessment, including diagnosis of major depression according to the established clinical criteria. Results HDRS was easy to administer and acceptable, and showed fair internal consistency (Cronbach's alpha = 0.8). The HDRS showed good convergent validity with respect to neuropsychiatric inventory (NPI) subdomain of depression (rrho = .85) and good divergent validity with respect to remaining NPI subdomains (rrho < .30). Moreover, HDRS's total score correlated moderately with functional disability and apathetic symptomatology, and poorly with general cognitive status. Receiver operating characteristics curve analysis demonstrated that a cutoff >14.5 can identify clinically relevant depressive symptoms with good sensitivity (93 %) and specificity (97 %) with respect to the diagnosis of major depression. Such a cutoff identified clinically relevant depressive symptoms in 42 % of our MS sample, whereas 44.2 % patients met established clinical criteria for major depression. Conclusion The HDRS can be considered as an easy, reliable, and valid tool to assess depressive symptomatology for clinical and research purposes in non-demented MS patients.
Objective
To identify predictors of 10‐year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse‐onset multiple sclerosis.
Methods
Using data obtained ...from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease‐modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10‐year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.
Results
We identified 2,466 patients followed up for at least 10 years reporting post‐baseline disability scores. Patients were treated an average 83% of their follow‐up time. EDSS scores increased by a median 1 point (interquartile range = 0–2) at 10 years post‐baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10−22). On‐therapy relapses carried greater burden than off‐therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = −0.86, p = 1.3 × 10−9). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10‐year observation period (coeff = −0.36, p = 0.009).
Interpretation
We provide evidence of long‐term treatment benefit in a large registry cohort, and provide evidence of long‐term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on‐treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89–100
Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on ...progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.
Tumefactive demyelinating lesions (TDLs) are atypical presentations of various demyelinating diseases. They can mimic brain tumors in their clinical and radiological features and usually respond ...favorably to corticosteroid therapy. We report a case of a 17-year-old girl with a single TDL suddenly increasing in size even under steroid therapy. She underwent very strict follow-up examinations with conventional magnetic resonance and diffusion-weighted imaging, perfusion-weighted imaging, proton-magnetic resonance spectroscopy. The behavior of the lesion during the different follow-up sessions posed a diagnostic challenge as it expanded its size during the final examination, in stark contrast to what we forecast. Diagnosis of TDL was initially hypothesized, but the aggressive behavior of the lesion required biopsy.
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