Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα.

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience.

OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

REM sleep behavior disorder in a patient with frontotemporal dementia.

We describe a patient with frontotemporal dementia (FTD), a tauopathy, who also showed clinical and polysomnographic features of REM sleep behavior disorder (RBD). The patient is a 78-year-old male with a 1 year history of behavioral dysfunction involving emotion, character and social functioning. Brain imaging and the results of neuropsychological testing were consistent with a diagnosis of FTD. Sleep symptom onset occurred some years before the behavioral changes, and consisted of unpleasant dreams, vocalization, and prominent motor behaviors. A polysomnography confirmed the diagnosis of RBD. Our findings support the hypothesis that RBD, although more frequent in synucleinopathies, might be a pathological stage in the development of almost every neurodegenerative disorder in which the pathological process involves the cerebral structures that regulate muscle tone during REM sleep.

Sleep quality in caregivers of patients with Alzheimer's disease and Parkinson's disease and its relationship to quality of life.

BACKGROUND: Knowledge about sleep complaints of caregivers of patients with Alzheimer's disease (AD) and Parkinson's disease (PD) is limited, and we lack information about the relationship between caregivers' sleep problems and their quality of life (QoL). METHODS: We evaluated subjective sleep quality and its relationship to QoL in a group of 80 caregivers of patients with AD (ADCG, n = 40) and PD (PDCG, n = 40), and in 150 controls. Information about night-time complaints was collected using the Pittsburgh Sleep Quality Index (PSQI). QoL was measured using the McGill QoL Questionnaire. RESULTS: Eighteen ADCG (45%), 22 PDCG (55%), and 45 (30%) controls reported poor sleep quality. Mean global PSQI score of PDCG (6.25 ± 3.9) was not significantly different from that of ADCG (5.8 ± 3.5; p = 0.67). However, both PDCG and ADCG scored significantly higher than control group (4.3 ± 3.1; p < 0.01). ADCG frequently reported difficulties falling asleep (72.5%) and disturbed sleep (100%). PDCG reported reduced subjective sleep quality (80%) and increased sleep disturbances (100%). Poor sleep quality was associated with depressive symptoms and correlated with QoL in caregivers of both groups, particularly the psychological symptoms domain. CONCLUSIONS: Among caregivers of patients with AD and PD, poor sleep quality is frequent and significantly linked to QoL and depressive symptoms. Identifying the nature of sleep disturbances not only in patients but also in their caregivers is important as appropriate treatment may lead to a better management of the needs of families coping with these patients.

Sleep-wake disturbances in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the frequency, severity and determinants of sleep disturbances in patients with amyotrophic lateral sclerosis (ALS). METHODS: Information about night-time complaints was collected using a standardised questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS) in a group of 100 patients with ALS and in 100 control subjects matched for age and sex. Functional disability was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Sleep was studied by overnight polysomnography in 12 patients. RESULTS: Fifty-nine patients with ALS and 36 controls reported sleep disturbances. The mean global PSQI score of patients with ALS was significantly higher than the control participants (6.82 ± 4.0 vs. 4.86 ± 3.2), and three of the seven components of PSQI in patients with ALS were significantly different from controls: 'sleep latency,' 'habitual sleep efficiency' and 'sleep disturbances.' The most commonly reported night-time complaints by patients with ALS were nocturia (54%), sleep fragmentation (48%) and nocturnal cramps (45%). Poor sleep was associated with decreased ALSFRS-R score, highest depression and ESS score. After a multivariate analysis, patients' disability and daytime somnolence remained significantly associated with sleep quality. Polysomnographic studies showed decreased sleep efficiency and fragmented sleep architecture. CONCLUSION: This study demonstrated that patients with ALS have a significant poor quality of sleep, and this correlated with the severity of ALS and daytime somnolence. Increased awareness for sleep-wake problems in patients with ALS is important, as effective intervention could lead to a better management of these patients.

Restless legs syndrome in patients with amyotrophic lateral sclerosis.

We aimed to evaluate the frequency and determinants of restless legs syndrome (RLS) in a group of 76 patients with amyotrophic lateral sclerosis (ALS) and 100 control subjects. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS severity scale. RLS was significantly more frequent in patients with ALS (ALS/RLS(+)) than in control subjects (25% vs. 8%; P = 0.002). Compared with control subjects, patients with ALS/RLS(+) showed shorter history of RLS complaints and higher frequency of symptoms occurrence. Moreover, compared with those without RLS, patients with ALS/RLS(+) showed increased functional impairment and more often reported sleep complaints. Multivariate logistic regression confirmed the association between RLS and functional impairment. Our findings suggest that RLS should be considered as a possible cause of disrupted sleep in patients with ALS and should be specifically investigated in these patients.

Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients.

BACKGROUND: Despite complaints of poor sleep being very common in people with chronic obstructive pulmonary disease (COPD), restless legs syndrome (RLS) symptoms have not been extensively investigated in these patients. OBJECTIVE: To assess the prevalence and severity of RLS in patients with COPD and to investigate the factors potentially associated with RLS. METHODS: A total of 87 patients with COPD and 110 controls, matched for age and sex, were evaluated regarding the presence and severity of RLS symptoms. A diagnosis of RLS was made according to the criteria of the International RLS Study Group (IRSLSSG), and severity was assessed by the IRLSSG severity scale. Excessive daytime somnolence was assessed using the Epworth sleepiness scale (ESS). RESULTS: RLS was significantly more frequent in COPD patients than in controls (36.8% vs. 11%; p < 0.001). Compared to controls, COPD patients with RLS showed higher disease severity (mean IRLSSG severity scale score: 20.5 +/- 2.8 for COPD, and 18 +/- 3.5 for controls; p = 0.016) and more pronounced daytime somnolence (mean ESS score: 11.8 +/- 1.1 for COPD, and 8.6 +/- 3.6 for controls; p = 0.009). Moreover, compared to those without RLS, COPD patients with RLS showed increased daytime sleepiness (mean ESS score: 11.8 +/- 1.1 for COPD/RLS, and 7.3 +/- 4 for COPD/non-RLS; p < 0.001) and longer disease duration (11.9 +/- 7 years for COPD/RLS, and 8.7 +/- 6.9 years for COPD/non-RLS; p = 0.045). Multivariate analysis showed that ESS score was the only factor significantly associated with RLS in COPD patients. CONCLUSIONS: RLS is a frequent cause of disabling sleep disturbance in patients with COPD and should be specifically investigated in these patients.

Restless legs syndrome in a patient with multifocal motor neuropathy.

Restless legs syndrome (RLS) has been frequently reported in association with peripheral neuropathy, and it is especially frequent in some forms of polyneuropathy with preferential involvement of small sensory fibers. Here, we describe a patient with multifocal motor neuropathy, who developed RLS during the course of the disease. Our findings support the notion that RLS may develop in the context of immune-mediated neuropathies and it should be specifically investigated even in those patients with preferentially or exclusive motor involvement.

Outcome and attitudes toward home tracheostomy ventilation of consecutive patients: a 10-year experience.

OBJECTIVES: To describe survival, predictors of long-term outcome and attitudes in patients treated at home by tracheostomy-intermittent positive-pressure ventilation (TIPPV) for respiratory failure during a 10-year period (1995-2004). METHODS: Seventy-seven consecutive patients were treated by TIPPV at home. Patients were divided into three groups: neuromuscular, pulmonary, and non-pulmonary patients. Effects of TIPPV on survival, factors influencing outcome after TIPPV, and attitudes of patients and caregivers regarding mechanical ventilation were studied. RESULTS: Forty-one patients (53%) were neuromuscular, 19 (25%) were affected by pulmonary diseases, and 17 (22%) by non-pulmonary diseases. The median survival time after TIPPV in the group was 49 months (range 3-149 months). There was statistically significant longer survival in neuromuscular compared to pulmonary patients (p=0.006), and a trend toward longer survival for non-pulmonary when compared to pulmonary patients (p=0.048). Chronic obstructive pulmonary disease (COPD) patients (n=14) showed the poorest outlook (median survival 26 months, range 3-45 months) and the highest number of emergency readmissions to hospital. The median survival in amyotrophic lateral sclerosis (ALS) patients was 49 months (range 30-61), lower than the whole group of neuromuscular patients. Major tracheostomy complications were low: 2.6%. Multivariate analysis showed that COPD and ALS patients had a three-fold higher risk of death than patients with other diagnoses. Lastly, 64 patients (83%) were pleased they had chosen TIPPV and 69 (90%) would choose it again. Forty-two caregivers (55%) were pleased the patients had chosen home ventilation, but 29 (38%) reported major burdens. CONCLUSIONS: TIPPV is well-received by the patients, is safe, and provides survival for long periods of time. Underlying conditions (COPD and ALS) might represent important prognostic factors for survival.

The amyotrophic lateral sclerosis functional rating scale predicts survival time in amyotrophic lateral sclerosis patients on invasive mechanical ventilation.

OBJECTIVE: To determine whether the amyotrophic lateral sclerosis functional rating scale (ALSFRS), which is a validated instrument that assesses the functional status and the disease progression in patients with amyotrophic lateral sclerosis (ALS), predicts hospital length of stay and survival time in ALS patients treated with tracheostomy-intermittent positive-pressure ventilation (TIPPV). METHODS: Thirty-three consecutive ALS patients with acute respiratory failure who received therapy with TIPPV were prospectively followed up from their admission to the hospital until death. The association of ALSFRS score at hospital admission with length of hospital stay and survival after TIPPV were examined using Cox proportional hazard models, adjusting for age at baseline, sex, and symptom duration. RESULTS: The median ALSFRS score of the ALS patients at hospital admission was 11 (range, 4 to 22). The median length of hospital stay was 55 days (range, 7 to 124 days), with a hospital mortality rate of 9%. For the 30 patients (91%) discharged from the hospital, the median survival time was 37 months (range, 2 to 64 months). The total ALSFRS score (above or below the median score) was a significant predictor of length of hospital stay (hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.2 to 6.5; p = 0.003) and survival after TIPPV (HR, 3.76; 95% CI, 1.4 to 9.7; p = 0.002). The total ALSFRS score at hospital admission was also associated with length of hospital stay (HR, 2.1; 95% CI, 1.1 to 5.1; p = 0.005) and survival (HR, 0.52; 95% CI, 0.1 to 0.8; p = 0.002) when included in a Cox multivariable model together with the other demographic and clinical variables. CONCLUSION: In ALS patients with acute respiratory failure who have been treated with TIPPV, the total ALSFRS score may predict length of hospital stay and long-term survival after invasive mechanical ventilation.

Distribution and cellular localization of high mobility group box protein 1 (HMGB1) in the spinal cord of a transgenic mouse model of ALS.

Although the aetiology of amyotrophic lateral sclerosis (ALS) is still elusive, increased attention has been put forward on events related to neuroinflammation and an active participation of glial cells in the ALS pathogenesis has been suggested. However, the specific role of many proinflammatory mediators that usually accompany the inflammatory changes is still largely unknown. High mobility group box protein 1 (HMGB1) is an ubiquitous nuclear protein that exerts numerous extranuclear and extracellular functions, including a proinflammatory activity, able to induce cytokines expression and activate inflammatory cells. To investigate whether this protein may play a role in the inflammatory events in ALS, we examined both expression and localization of HMGB1 in the lumbar spinal cord of SOD1G93A transgenic mice, a well established mouse model of familial ALS, at different stages of the disease. Intense HMGB1 reactivity was detected in ventral horn motor neurons of both non-transgenic and SOD1G93A mice and there was no difference in its expression between presymptomatic SOD1G93A mice and controls. With the progression of the disease, degenerating neurons showed a reduction of HMGB1 immunoreactivity which could reflect an extracellular release of this protein. By contrast, in the reactive glial cells HMGB1 was remarkably expressed in the nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of these cells. These results suggest that HMGB1 may have a different involvement in the motor neurons and glial cells in response to the neurotoxic environment in the spinal cord of SOD1G93A mice, and it may contribute to the progression of inflammatory and neurodegenerative processes.

Development of chronic hypoventilation in amyotrophic lateral sclerosis patients.

Early prediction of respiratory muscle involvement and chronic hypoventilation (CH) in amyotrophic lateral sclerosis (ALS) patients can help to plan mechanical ventilatory aids and palliative care interventions well before respiratory failure occurs. To describe the natural history of the progressive pulmonary dysfunction leading to CH, and to identify potential parameters associated with its development in ALS, we prospectively followed 38 ALS patients up to 26 months, starting from their first presentation at our Clinic. At study entry, median FVC was 87% (interquartile range: 72-104%) and declined by 10% after 6 months (range: 2-49%), showing a very high inter-patient variability. Over the 26-months follow-up, 19 patients (50%) presented CH in the first 12 months, and eight patients (21%) developed CH in the remaining 14 months of the study. The remaining 29% of patients did not show signs of CH during the whole period of observation. In the Cox model, the category of disease progression (rapid vs. intermediate and slow), assessed using the Appel ALS Rating Scale (AARS) in the first 3 months after presentation, was the only variable associated with a significantly increased likelihood of CH. We conclude that CH can occur within 1 year from presentation in a great proportion of patients, independently from their initial respiratory status. Including the patients in specific categories of early disease progression, as assessed with the AARS, could be a sensitive method to identify patients with different risk of developing CH, and may help physicians to more efficiently plan the frequencies of respiratory evaluations, initiate mechanical ventilation and discuss advance directives with the patients and their caregivers.

Cognitive impairment and stroke in elderly patients.

We reviewed current knowledge about the interaction between stroke and vascular risk factors and the development of cognitive impairment and dementia. Stroke is increasingly recognized as an important cause of cognitive problems and has been implicated in the development of both Alzheimer's disease and vascular dementia. The prevalence of cognitive impairment after stroke is high, and their combined effects significantly increase the cost of care and health resource utilization, with reflections on hospital readmissions and increased mortality rates. There is also substantial evidence that vascular risk factors (such as hypertension, diabetes, obesity, dyslipidemia, and tobacco smoking) are independently associated with an increased risk of cognitive decline and dementia. Thus, a successful management of these factors, as well as optimal acute stroke management, might have a great impact on the development of cognitive impairment. Notwithstanding, the pathological link between cognitive impairment, stroke, and vascular risk factors is complex and still partially unclear so that further studies are needed to better elucidate the boundaries of this relationship. Many specific pharmacological treatments, including anticholinergic drugs and antihypertensive medications, and nonpharmacological approaches, such as diet, cognitive rehabilitation, and physical activity, have been studied for patients with vascular cognitive impairment, but the optimal care is still far away. Meanwhile, according to the most recent knowledge, optimal stroke care should also include cognitive assessment in the short and long term, and great efforts should be oriented toward a multidisciplinary approach, including quality-of-life assessment and support of caregivers.

Individual and health-related quality of life assessment in amyotrophic lateral sclerosis patients and their caregivers.

We performed a cross-sectional study aimed to address the quality of life (QoL) and putative associated variables in amyotrophic lateral sclerosis (ALS) patients and their respective caregivers, using both health-related (WHOQOL-BREF) and individual (SEIQoL-DW) QoL instruments. Further, we sought to investigate concordance within patient-caregiver pairs for ratings of respective QoL. Thirty-seven patient-caregiver pairs were included in the study. QoL was rated low by both patients and caregivers, and there was no significant difference between them on scores of overall QoL, even if caregivers showed higher scores on the physical and psychological WHOQOL-BREF domains compared to patients. No correlation could be found between QoL of both patients and caregivers and all the examined socio-demographic variables. Moreover, concordance between patients and respective caregivers was low for ratings of QoL, suggesting that their QoL is not necessarily interrelated, and that these couples do not actually represent a unique psychological entity. Interestingly, physical dysfunction, measured with the ALS-FRS, was not significantly correlated with caregivers' individual QoL scores. The most frequently nominated SEIQoL-DW cues were related to health (physical and psychological) and family for both patients and caregivers, and there was high agreement for the choice of areas important for subject's QoL. Interestingly, patients and caregivers who endorsed spirituality as a significant domain reported better QoL. Our study confirms that ALS has a negative impact on QoL in both patients and caregivers. However, caregivers who present lower QoL levels are not always those who have to look after the most physically or psychologically impaired patients. Major attention on QoL issues of both patients and caregivers, family status, and health perception, integrated with the medical evaluation, could lead to a better understanding of the problems related to the caregiving experience, and could help couples dealing with this life-threatening disease.

Echocardiographic assessment of 537 dogs with mitral valve prolapse and leaflet involvement.

In this work we investigated which mitral valve leaflet was most often involved in mitral valve prolapse with degenerative mitral valve disease and whether there was an association with breed, age, gender, or weight. Five hundred and thirty-seven dogs with mitral valve prolapse-degenerative mitral valve disease were assessed; the cross-breed dog was the most represented breed (248 dogs, 46.2%). Mitral valve prolapse was more common in male dogs, and the average age was 11.3 +/- 2.8 years. Prolapse of the anterior leaflet was present in 48.4% of dogs, prolapse of the the posterior leaflet in 7.1%, and bileaflet prolapse was present in 44.5%; this distribution is different than that typically found in humans. There was a significant correlation between severity of mitral regurgitation and severity of mitral valve prolapse or ISACHC class, and between severity of mitral valve prolapse and ISACHC class. There was no relationship between the particular affected leaflet(s) and severity of mitral regurgitation, severity of mitral valve prolapse, or ISACHC class. Our findings suggest that the susceptibility to the mitral valve prolapse-degenerative mitral valve disease is not confined to a specific breeds and that the specific leaflet prolapsing is different in dogs compared with humans.