Dynamic Tests in Pituitary Endocrinology: Pitfalls in Interpretation during Aging.

Aging and age-related diseases represent hot topics of current research. Progressive damage in morphology and function of cells and tissue characterizes the normal process of aging that is influenced by both genetic and environmental factors. The ability of each individual to adapt to these stressors defines the type of aging and the onset of age-related diseases (i.e., metabolic syndrome, inflammatory disorders, cancer, and neurodegenerative diseases). The endocrine system plays a critical role in this process because of its complex relationships with brain, immune system, and skeletal muscle; thus, alterations in hormonal networks occur during aging to maintain homeostasis, with consequent under- or overactivity of specific hypothalamic-pituitary-peripheral hormone axes. On the other hand, the increase in life expectancy has led to increasing incidence of age-related diseases, including endocrine disorders, which may prompt assessment of endocrine function in aging individuals. In this context, there is growing awareness that natural changes of endocrine physiology and physiopathology occurring with increasing age may necessitate age-driven diagnostic cutoffs requiring validation in the elderly. This review aims to analyze the available literature on the hormone response to the most important dynamic tests currently used in the clinical practice for the screening of anterior pituitary-related diseases to underline pitfalls in interpretation during aging.

Exploring extra dimensions to capture saliva metabolite fingerprints from metabolically healthy and unhealthy obese patients by comprehensive two-dimensional gas chromatography featuring Tandem Ionization mass spectrometry.

This study examines the information potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOF MS) and variable ionization energy (i.e., Tandem Ionization™) to study changes in saliva metabolic signatures from a small group of obese individuals. The study presents a proof of concept for an effective exploitation of the complementary nature of tandem ionization data. Samples are taken from two sub-populations of severely obese (BMI > 40 kg/m2) patients, named metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Untargeted fingerprinting, based on pattern recognition by template matching, is applied on single data streams and on fused data, obtained by combining raw signals from the two ionization energies (12 and 70 eV). Results indicate that at lower energy (i.e., 12 eV), the total signal intensity is one order of magnitude lower compared to the reference signal at 70 eV, but the ranges of variations for 2D peak responses is larger, extending the dynamic range. Fused data combine benefits from 70 eV and 12 eV resulting in more comprehensive coverage by sample fingerprints. Multivariate statistics, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) show quite good patient clustering, with total explained variance by the first two principal components (PCs) that increases from 54% at 70 eV to 59% at 12 eV and up to 71% for fused data. With PLS-DA, discriminant components are highlighted and putatively identified by comparing retention data and 70 eV spectral signatures. Within the most informative analytes, lactose is present in higher relative amount in saliva from MHO patients, whereas N-acetyl-D-glucosamine, urea, glucuronic acid γ-lactone, 2-deoxyribose, N-acetylneuraminic acid methyl ester, and 5-aminovaleric acid are more abundant in MUO patients. Visual feature fingerprinting is combined with pattern recognition algorithms to highlight metabolite variations between composite per-class images obtained by combining raw data from individuals belonging to different classes, i.e., MUO vs. MHO.Graphical abstract.

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

AN ITALIAN SURVEY OF COMPLIANCE WITH MAJOR GUIDELINES FOR L-THYROXINE OF PRIMARY HYPOTHYROIDISM.

OBJECTIVE: The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment. METHODS: This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology. RESULTS: The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score <6), 38.6% medium (6 to <8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers. CONCLUSION: Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography.

Vitamin D and Neurological Diseases: An Endocrine View.

Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the "non-calcemic" actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vitamin D and neurological diseases.

The Role of Decompressive Craniectomy on Functional Outcome, Mortality and Seizure Onset after Traumatic Brain Injury.

BACKGROUND: Decompressive craniectomy (DC) to treat increased intracranial pressure after a traumatic brain injury (TBI) is a common but controversial choice in clinical practice. This study aimed to determine the impact of DC on functional outcomes, mortality and the occurrence of seizures in a large cohort of patients with TBI. METHODS: This retrospective study included patients with TBI consecutively admitted for a 6-month neurorehabilitation program between 1 January 2009 and 31 December 2018. The radiological characteristics of brain injury were determined with the Marshall computed tomographic classification. The neurological status and rehabilitation outcome were assessed using the Glasgow Coma Scale (GCS) and the Functional Independence Measure (FIM), which were both assessed at baseline and on discharge. Furthermore, the GCS was recorded on arrival at the emergency department. The DC procedure, prophylactic antiepileptic drug (AED) use, the occurrence of early or late seizures (US, unprovoked seizures) and death during hospitalization were also recorded. RESULTS: In our cohort of 309 adults with mild-to-severe TBI, DC was performed in 98 (31.7%) patients. As expected, a craniectomy was more frequently performed in patients with severe TBI (p < 0.0001). However, after adjusting for the confounding variables including GCS scores, age and the radiological characteristics of brain injury, there was no association between DC and poor functional outcomes or mortality during the inpatient rehabilitation period. In our cohort, the independent predictors of an unfavorable outcome at discharge were the occurrence of US (ß = -0.14, p = 0.020), older age (ß = -0.13, p = 0.030) and the TBI severity on admission (ß = -0.25, p = 0.002). Finally, DC (OR 3.431, 95% CI 1.233-9.542, p = 0.018) and early seizures (OR = 3.204, 95% CI 1.176-8.734, p = 0.023) emerged as the major risk factors for US, independently from the severity of the brain injury and the prescription of a primary prophylactic therapy with AEDs. CONCLUSIONS: DC after TBI represents an independent risk factor for US, regardless of the prescription of prophylactic AEDs. Meanwhile, there is no significant association between DC and mortality, or a poor functional outcome during the inpatient rehabilitation period.

Post-Surgical Indications to Radioiodine Treatment and Potential Risk Factors for Post-Treatment Recurrence in Patients with Intermediate-Risk Differentiated Thyroid Carcinoma.

In this multicentric retrospective observational study, we investigated the potential risk factors for radioiodine (RAI) indication and the post-treatment recurrence of intermediate-risk differentiated thyroid cancer (DTC) 1 and 3 years from diagnosis. We included 121 patients who underwent thyroidectomy for intermediate-risk DTC. The 92 patients (76.0%) who underwent RAI treatment had a higher prevalence of extra-thyroid micro-extension (mETE) (p = 0.03), pT3 staging (p = 0.03) and recourse to therapeutic central (p = 0.04) and lateral (p = 0.01) neck dissection, as well as higher numbers (p = 0.02) and greater dimensions (p = 0.01) of lymph node metastases, compared with untreated patients. Relapse was observed in 18.1% and 20.7% of cases 1 and 3 years from diagnosis, respectively, with no significant differences between groups. A lower age at diagnosis (p = 0.03) and higher levels of stimulated thyroglobulin (Tg) (p = 0.04) emerged as the only independent risk factors for tumour relapse at 1 year. Tumour relapse at 3 years was only independently predicted by the presence of tumour relapse at 1 year (p = 0.04). In conclusion, mETE, pT3 and the presence of large, multiple or clinically evident lymph node metastases represent the main indicators for referring patients to RAI treatment. Early recurrence may be considered the most relevant factor when planning further surveillance.

Free Thyroxine (fT4) as a Potential Biomarker of Neurological and Functional Outcome in Acquired Brain Injury: A Prospective Multicenter Cohort Study.

The potential involvement of thyroid hormones (THs) in the neurological and functional recovery of patients with brain damage has been hypothesized. We aimed at investigating the role of THs and their variations during the rehabilitation process as predictive biomarkers of neurological and functional outcome in patients with acquired brain injury (ABI). This prospective, multicenter cohort study included 220 patients with ABI consecutively admitted for a 6-month neurorehabilitation program. Data on the etiology of the brain injury, occurrence of seizures, neurosurgical procedures, and death during hospitalization were collected. Both at the baseline (T0) and at the end of the rehabilitation process (T1), the following variables were evaluated: thyroid function (TSH, fT4, and fT3) and outcome measure including the Glasgow Coma Scale (GCS), Glasgow Outcome Scale-Extended (GOS-E), and Functional Independence Measure (FIM) scale. During neurorehabilitation, a significant decrease in fT4 levels was documented in the population as a whole and in patients with severe ABI (p < 0.0001), whereas no significant variations were found in TSH and fT3 levels. No significant associations were found between THs and seizure occurrence, while the neurological and functional outcomes were associated with the variation in fT4 levels during rehabilitation. In particular, a higher magnitude of decrease in fT4 levels emerged as an independent predictor of more severe neurological damage (OR = 3.48, CI 95% 1.04-11.69, p = 0.04) and a lower functional recovery (ß = -0.22, p = 0.01). In conclusion, serum fT4 variation during neurorehabilitation could represent a potential biomarker of neurological and functional outcome in patients with ABI. Further studies are needed to investigate the mechanisms underlying this association.

A Data-Driven Approach to Refine Predictions of Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study.

CONTEXT: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features. OBJECTIVE: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors. METHODS: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction. RESULTS: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis. CONCLUSION: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

Impact of Cranioplasty on Rehabilitation Course of Patients with Traumatic or Hemorrhagic Brain Injury.

BACKGROUND: Some authors have hypothesized that cranioplasty after decompressive craniectomy (DC) could positively influence functional recovery through several mechanisms. However, only a few studies with small sample sizes have investigated the effects of cranioplasty on functional recovery. Our study aims at evaluating the role of post-DC cranioplasty in influencing the functional recovery in a large cohort of patients with different etiologies of acquired brain injury (ABI). METHODS: This retrospective study consecutively enrolled 253 patients with ABI, consisting of 108 adults who underwent post-DC cranioplasty and 145 adults who did not. All the subjects underwent a 6-month individual rehabilitation program. Demographic data, etiology, classification and anatomical site of brain injury, neurological and functional assessment at baseline and on discharge, and number of deaths during hospitalization were recorded. RESULTS: In our cohort, 145 patients (57.3%) and 108 patients (42.7%) had, respectively, a hemorrhagic stroke (HS) and a traumatic brain injury (TBI). Only in the patients with TBI cranioplasty emerged as an independent predictor of better functional outcome in terms of the Functional Independence Measure (FIM) total score at discharge (ß = 0.217, p = 0.001) and of the FIM variation during rehabilitation (ΔFIM) (ß = 0.315, p = 0.001). Conversely, in the case of HS, no associations were found between post-DC cranioplasty and functional recovery. CONCLUSIONS: Post-DC cranioplasty was associated with better functional recovery six months after TBI but not in the patients with HS. Although the pathophysiological mechanisms underlying HS are different from those of TBI and possibly play a role in the different outcomes between the two groups, further studies are needed to investigate the mechanisms underlying the observed differences.

Impact of seizures and their prophylaxis with antiepileptic drugs on rehabilitation course of patients with traumatic or hemorrhagic brain injury.

Objective: To determine whether, in patients undergoing rehabilitation after traumatic or hemorrhagic brain injury, seizures and the use of antiepileptic drugs (AEDs) negatively impact on functional outcome, and, in turn, whether prophylactic AED therapy can prevent the development of seizures. Design: Observational retrospective study. Setting: Highly specialized inpatient neurorehabilitation clinic. Participants: Patients with traumatic brain injury (TBI), or hemorrhagic stroke (HS) consecutively admitted to our neurorehabilitation unit between January 1, 2009, and December 31, 2018. Main measures and variables: Patients' demographic data, neurological status (Glasgow Coma Scale), and rehabilitation outcome (Functional Independence Measure scale), both assessed on admission and on discharge, associated neurosurgical procedures (craniectomy, or cranioplasty), AED use, early or late seizures occurrence, and death during hospitalization. Results: Of 740 patients, 162 (21.9%) had seizures, and prophylactic AEDs were started in 192 (25.9%). Multivariate logistic regression identified severity of brain injury as a risk factor for acute symptomatic seizures (ASS) in HS (OR = 1.800, 95%CI = 1.133-1.859, p = 0.013), and for unprovoked seizures (US) in TBI (OR = 1.679, 95%CI = 1.062-2.655, p = 0.027). Prophylaxis with AEDs reduced ASS frequency, but, if protracted for months, was associated with US occurrence (HS, p < 0.0001; TBI, p = 0.0002; vs. untreated patients). Presence of US (ß = -0.12; p < 0.0001) and prophylaxis with AEDs (ß = -0.09; p = 0.002), were associated with poor functional outcome, regardless of age, severity of brain insult, and HS vs. TBI subtype. Conclusions: Severity of brain injury and occurrence of seizures during neurorehabilitation are the main driver of poor outcome in both HS and TBI. The possible detrimental role on the epileptogenic and functional outcome played by seizures prophylaxis with AEDs, nonetheless useful to prevent ASS if administered over the first week after the brain injury, warrants further investigation.

The pattern of TSH and fT4 levels across different BMI ranges in a large cohort of euthyroid patients with obesity.

Purpose: A multifold association relates the hypothalamo-pituitary-thyroid axis to body weight. The potential underlying mechanisms are incompletely understood. Further, the mild severity of obesity and the small proportion of individuals with obesity in so far published cohort studies provide little insights on metabolic correlates of thyroid function in obesity. Methods: We retrospectively enrolled 5009 adults with obesity (F/M, 3448/1561; age range, 18-87 years; BMI range, 30.0-82.7 kg/m2), without known thyroid disease in a study on TSH and fT4 levels, lipid profile, glucose homeostasis and insulin resistance, anthropometric parameters including BIA-derived fat mass (%FM) and fat-free mass (FFM). Results: The overall reference interval for TSH in our obese cohort was 0.58-5.07 mIU/L. As subgroups, females and non-smokers showed higher TSH levels as compared to their counterparts (p<0.0001 for both), while fT4 values were comparable between groups. There was a significant upward trend for TSH levels across incremental BMI classes in females, while the opposite trend was seen for fT4 levels in males (p<0.0001 for both). Expectedly, TSH was associated with %FM and FFM (p<0,0001 for both). TSH and fT4 showed correlations with several metabolic variables, and both declined with aging (TSH, p<0.0001; fT4, p<0.01). In a subgroup undergoing leptin measurement, leptin levels were positively associated with TSH levels (p<0.01). At the multivariable regression analysis, in the group as a whole, smoking habit emerged as the main independent predictor of TSH (ß=-0.24, p<0.0001) and fT4 (ß=-0.25, p<0.0001) levels. In non-smokers, %FM (ß=0.08, p<0.0001) and age (ß=-0.05, p<0.001) were the main significant predictors of TSH levels. In the subset of nonsmokers having leptin measured, leptin emerged as the strongest predictor of TSH levels (ß=0.17, p<0.01). Conclusions: Our study provides evidence of a gender- and smoking-dependent regulation of TSH levels in obesity.

Bone Response to Weight Loss Following Bariatric Surgery.

Obesity is a global health challenge that warrants effective treatments to avoid its multiple comorbidities. Bariatric surgery, a cornerstone treatment to control bodyweight excess and relieve the health-related burdens of obesity, can promote accelerated bone loss and affect skeletal strength, particularly after malabsorptive and mixed surgical procedures, and probably after restrictive surgeries. The increase in bone resorption markers occurs early and persist for up to 12 months or longer after bariatric surgery, while bone formation markers increase but to a lesser extent, suggesting a potential uncoupling process between resorption and formation. The skeletal response to bariatric surgery, as investigated by dual-energy X-ray absorptiometry (DXA), has shown significant loss in bone mineral density (BMD) at the hip with less consistent results for the lumbar spine. Supporting DXA studies, analyses by high-resolution peripheral quantitative computed tomography (HR-pQCT) showed lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number for up to 5 years after bariatric surgery. These alterations translate into an increased risk of fall injury, which contributes to increase the fracture risk in patients who have been subjected to bariatric surgery procedures. As bone deterioration continues for years following bariatric surgery, the fracture risk does not seem to be dependent on acute weight loss but, rather, is a chronic condition with an increasing impact over time. Among the post-bariatric surgery mechanisms that have been claimed to act globally on bone health, there is evidence that micro- and macro-nutrient malabsorptive factors, mechanical unloading and changes in molecules partaking in the crosstalk between adipose tissue, bone and muscle may play a determining role. Given these circumstances, it is conceivable that bone health should be adequately investigated in candidates to bariatric surgery through bone-specific work-up and dedicated postsurgical follow-up. Specific protocols of nutrients supplementation, motor activity, structured rehabilitative programs and, when needed, targeted therapeutic strategies should be deemed as an integral part of post-bariatric surgery clinical support.

Circulating Irisin in Children and Adolescents With Prader-Willi Syndrome: Relation With Glucose Metabolism.

Irisin is a myokine involved in the browning of white adipose tissue and regulation of energy expenditure, glucose homeostasis and insulin sensitivity. Debated evidence exists on the metabolic role played by irisin in children with overweight or obesity, while few information exist in children with Prader Willi Syndrome (PWS), a condition genetically prone to obesity. Here we assessed serum irisin in relation to the metabolic profile and body composition in children and adolescents with and without PWS. In 25 PWS subjects [age 6.6-17.8y; body mass index standard deviation score (BMI SDS) 2.5 ± 0.3] and 25 age, and BMI-matched controls (age 6.8-18.0y; BMI SDS, 2.8 ± 0.1) we assessed irisin levels and metabolic profile inclusive of oral glucose tolerance test (OGTT), and body composition by dual-energy X-ray absorptiometry (DXA). In PWS, we recorded lower levels of fat-free mass (FFM) (p <0.05), fasting (p<0.0001) and 2h post-OGTT insulin (p<0.05) and lower insulin resistance as expressed by homeostatic model of insulin resistance (HOMA-IR) (p<0.0001). Irisin levels were significantly lower in PWS group than in controls with common obesity (p<0.05). In univariate correlation analysis, positive associations linked irisin to insulin OGTT0 (p<0.05), insulin OGTT120 (p<0.005), HOMA-IR (p<0.05) and fasting C-peptide (p<0.05). In stepwise multivariable regression analysis, irisin levels were independently predicted by insulin OGTT120. These results suggest a link between irisin levels and insulin sensitivity in two divergent models of obesity.

Prophylactic central neck dissection in differentiated thyroid cancer: risks and benefits in a population with a high rate of tumour recurrence.

BACKGROUND: The role of prophylactic central neck dissection (pCND) in differentiated thyroid cancer (DTC) is still controversial. METHODS: In a cohort of 274 DTC cN0 patients with a high rate of tumour recurrence, who underwent total thyroidectomy with or without pCND, clinical and histopathological features were retrospectively analysed. RESULTS: In our cohort, no clinical or histopathological features are able to predict the presence of central lymph node metastases (CLNM) at diagnosis, which instead represents the only variable significantly associated with a higher risk of long-term tumour relapse, independently from age, sex, BMI and radioiodine treatment (OR=1.03, CI95% 1.002-1.074, p<0.05). Moreover, our study demonstrates that pCND does not significantly increase the risk of post-surgical complications. CONCLUSIONS: In our setting, pCND could have a key role in the management of DTC. The risks and benefits of pCND should be evaluated for each population to make the most appropriate therapeutic choice.

Thyrotropic Axis and Disorders of Consciousness in Acquired Brain Injury: A Potential Intriguing Association?

Purpose: A potential involvement of thyrotropic axis in influencing the state of consciousness could be hypothesized. We aimed at investigating thyroid function tests as predictors of disorders of consciousness (DoC) and relating recovery in a large cohort of patients with DoC secondary to acquired brain injury (ABI). Methods: This retrospective, multicenter, cohort study included 151 patients with DoC following ABI, consecutively admitted for a 6-month neurorehabilitation program. Data on etiology of brain injury, evolution of DoC, disability and rehabilitation assessments, and death during rehabilitation were collected at baseline and on discharge. Thyroid function tests (serum TSH, fT4 and fT3 levels) were assessed on admission in all patients and at final discharge in 50 patients. Results: Lower baseline TSH levels and greater TSH increments (ΔTSH) after neurorehabilitation predicted a favorable change in DoC independent of age, sex, BMI, etiology of brain injury and initial DoC subtype (TSH: OR=0.712, CI 95% 0.533-0.951, p=0.01; ΔTSH: OR=2.878, CI 95% 1.147-7.223, p=0.02). On the other hand, neither fT4 nor fT3 or their variations appeared to play any role on DoC changes after 6-months inpatient neurorehabilitation. A lower magnitude of ΔfT4 acted as a strong predictor of improved functional disability level (ß=0.655, p=0.002) and cognitive functions (ß=-0.671, p=0.003), implying that smaller changes in fT4 were associated with higher outcomes. Conclusions: Serum TSH levels assessed in the subacute post-ABI phase and its variation during neurorehabilitation could represent a potential biomarker of DoC evolution, while variations in fT4 levels seem to be associated with rehabilitation and cognitive functions. Further studies are needed to investigate the mechanisms underlying these associations.

Post-traumatic seizures and antiepileptic therapy as predictors of the functional outcome in patients with traumatic brain injury.

Post-traumatic seizures (PTS) are a common and debilitating complication of traumatic brain injury (TBI) and could have a harmful impact on the progress of patient rehabilitation. To assess the effect of PTS and relative therapy on outcome in the initial phase after TBI, during the rehabilitation process when neuroplasticity is at its highest, we retrospectively examined the clinical data of 341 adult patients undergoing rehabilitation for at least 6 months post-TBI in our neurorehabilitation unit between 2008 and 2019. We correlated through logistic regression the occurrence of seizures and use of anti-seizure medication (ASM) with neurological and functional outcomes, respectively assessed with the Glasgow Coma Scale (GCS) and the Functional Independence Measure (FIM). PTS were documented in 19.4% of patients: early PTS (EPTS) in 7.0%; late PTS (LPTS) in 9.4%; both types in 3.0%. Patients who developed EPTS had an increased risk of developing LPTS (OR = 3.90, CI 95% 1.58-9.63, p = 0.003). Patients with LPTS had a significantly higher risk of worse neurological (p < 0.0001) and rehabilitation (p < 0.05) outcome. Overall, 38.7% of patients underwent therapy with ASM; prophylactic therapy was prescribed in 24.0% of patients, of whom 14.6% subsequently developed seizures. Mortality was associated with a lower FIM and GCS score on admission but not significantly with PTS. The use of ASM was associated with a worse rehabilitation outcome, independently of the onset of epilepsy during treatment. LPTS appear to exert a negative impact on rehabilitation outcome and their occurrence is not reduced by prophylactic therapy, whereas EPTS do not influence outcome. Our findings caution against the generic use of prophylactic therapy to prevent post-traumatic epilepsy in patients with TBI.

Insights into non-classic and emerging causes of hypopituitarism.

Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.

Obesity and Bone Loss at Menopause: The Role of Sclerostin.

Background. Peripheral fat tissue is known to positively influence bone health. However, evidence exists that the risk of non-vertebral fractures can be increased in postmenopausal women with obesity as compared to healthy controls. The role of sclerostin, the SOST gene protein product, and body composition in this condition is unknown. Methods. We studied 28 severely obese premenopausal (age, 44.7 ± 3.9 years; BMI, 46.0 ± 4.2 kg/m2) and 28 BMI-matched post-menopausal women (age, 55.5 ± 3.8 years; BMI, 46.1 ± 4.8 kg/m2) thorough analysis of bone density (BMD) and body composition by dual X-ray absorptiometry (DXA), bone turnover markers, sclerostin serum concentration, glucose metabolism, and a panel of hormones relating to bone health. Results. Postmenopausal women harbored increased levels of the bone turnover markers CTX and NTX, while sclerostin levels were non-significantly higher as compared to premenopausal women. There were no differences in somatotroph, thyroid and adrenal hormone across menopause. Values of lumbar spine BMD were comparable between groups. By contrast, menopause was associated with lower BMD values at the hip (p < 0.001), femoral neck (p < 0.0001), and total skeleton (p < 0.005). In multivariate regression analysis, sclerostin was the strongest predictor of lumbar spine BMD (p < 0.01), while menopausal status significantly predicted BMD at total hip (p < 0.01), femoral neck (p < 0.001) and total body (p < 0.05). Finally, lean body mass emerged as the strongest predictor of total body BMD (p < 0.01). Conclusions. Our findings suggest a protective effect of obesity on lumbar spine and total body BMD at menopause possibly through mechanisms relating to lean body mass. Given the mild difference in sclerostin levels between pre- and postmenopausal women, its potential actions in obesity require further investigation.

A Retrospective Study on Statins and Post-stroke Patients: What About Functional Outcome and Follow-Up in a Stroke Rehabilitation Cohort?

Objective: Statins exert pleiotropic effects by influencing several mechanisms, including synaptogenesis, neurogenesis, cerebral flow regulation, and angiogenesis. Results from in vitro and animal models suggest that statins could have beneficial effect on functional recovery and outcome after stroke events. However, results in human studies are still controversial. The aim of our study was to evaluate the role of statin in influencing functional outcome and subsequent clinical follow-up in a large cohort of post-stroke rehabilitation patients. Methods: This retrospective study consecutively enrolled 413 adult patients with stroke event, admitted to the division of Neurorehabilitation of the IRCCS ICS Maugeri, Veruno (Italy), for an individual rehabilitation program between 2015 and 2017. Follow-up lasted 3-5 years after discharge. Demographic data, etiology, classification, and anatomical site of stroke lesion, functional assessment, use and duration of statin therapy, and death during hospitalization were collected at baseline and on discharge. Clinical data on subsequent follow-up were also evaluated, considering these as variables: stroke recurrence, bone fractures, cardiovascular complications, and death. Results: In our cohort, 177 patients (42.9%) were prescribed statin therapy, of whom 50 (28.2%) before the stroke event and 127 (71.8%) at the beginning of the rehabilitation process. The use and type of statin therapy as well as the duration of treatment were not associated with recovery and functional outcome, regardless of confounders including sex, age, etiology, and site of stroke lesion, and initial functional level. For what concern post-discharge clinical follow-up, the use of statin therapy was significantly associated with a lower risk of bone fractures (OR = 0.095, CI 95%: 0.012-0.743, p = 0.01) independently from age, sex, initial and final functional level, and comorbidities. Conclusions: The use of statins does not seem to influence the functional outcome in post-stroke patients. However, they could exert a protective role against bone fractures during post-discharge follow-up, suggesting further evaluation on this topic.