Potential role of vitamin D levels in amyotrophic lateral sclerosis cognitive impairment.

Cognitive impairment (CI) is common in amyotrophic lateral sclerosis (ALS): a keystone is identifying factors that could potentially modify the CI course. In recent years, vitamin D is becoming a potential modificatory factor for CI in many neurological disorders. This study aimed to highlight if vitamin D deficiency correlated with CI and clinical features in a cohort of ALS patients. We included 55 ALS patients with a neuropsychological evaluation (classified with the Strong Criteria) and a vitamin D dosage at the diagnosis. We also reviewed medical records and completed data for medical history, physical and neurological examination, and functional scales. At the diagnosis, 30 patients (54%) had CI. Most patients (82%) displayed low vitamin D levels (19.87 ± 9.80 ng/ml). Comparing the vitamin D level between patients with and without CI, we observed significantly lower values in the first group (15.8 ± 8.2 vs. 22.0 ± 9.7 ng/ml, p: 0.04). In the spinal female subgroup (n = 15), we found an inverse correlation between vitamin D and bizarreness score in the cognitive estimates test (r = 0.58; p: 0.04) and a positive correlation with the Corrected Raven's Standard Progressive Matrices (r = 0.53, p: 0.04). Conversely, in the bulbar female group, we observed a correlation with the corrected direct span (r = 0.84, p: 0.03). With the log-rank survival analysis, we found that the patients with vitamin D < 10 ng/ml had a shorter disease duration (Chi: 5.78, p: 0.02). Our results indicate that levels of vitamin D can influence the cognitive status of people living with ALS and that severe deficits might be an adverse prognostic survival factor.

Acetyl-L-carnitine and Amyotrophic Lateral Sclerosis: current evidence and potential use.

BACKGROUND: The management of neurodegenerative diseases can be frustrating for clinicians, given the limited progress of conventional medicine in this context. AIM: For this reason, a more comprehensive, integrative approach is urgently needed. Among various emerging focuses for intervention, the modulation of central nervous system energetics, oxidative stress, and inflammation is becoming more and more promising. METHOD: In particular, electrons leakage involved in the mitochondrial energetics can generate reactive oxygen-free radical-related mitochondrial dysfunction that would contribute to the etiopathology of many disorders, such as Alzheimer's and other dementias, Parkinson's disease, multiple sclerosis, stroke, and amyotrophic lateral sclerosis (ALS). RESULTS: In this context, using agents, like acetyl L-carnitine (ALCAR), provides mitochondrial support, reduces oxidative stress, and improves synaptic transmission. CONCLUSION: This narrative review aims to update the existing literature on ALCAR molecular profile, tolerability, and translational clinical potential use in neurodegeneration, focusing on ALS.

The Potential Role of Peripheral Oxidative Stress on the Neurovascular Unit in Amyotrophic Lateral Sclerosis Pathogenesis: A Preliminary Report from Human and In Vitro Evaluations.

Oxidative stress, the alteration of mitochondrial function, and changes in the neurovascular unit (NVU) could play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. Our aim was to analyze the plasma redox system and nitric oxide (NO) in 25 ALS new-diagnosed patients and five healthy controls and the effects of plasma on the peroxidation/mitochondrial function in human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. In plasma, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and nitric oxide (NO) were analyzed by using specific assays. In HUVEC/astrocytes, the effects of plasma on the release of mitochondrial reactive oxygen species (mitoROS) and NO, viability, and mitochondrial membrane potential were investigated. In the plasma of ALS patients, an increase in TBARS and a reduction in GSH and NO were found. In HUVEC/astrocytes treated with a plasma of ALS patients, mitoROS increased, whereas cell viability and mitochondrial membrane potential decreased. Our results show that oxidative stress and NVU play a central role in ALS and suggest that unknown plasma factors could be involved in the disease pathogenesis. Quantifiable changes in ALS plasma related to redox state alterations can possibly be used for early diagnosis.

Accelerated Early Progression of Amyotrophic Lateral Sclerosis over the COVID-19 Pandemic.

During the COVID-19 pandemic and the related lockdowns, outpatient follow-up visits for patients with chronic neurological diseases have been suspended. Managing people affected by amyotrophic lateral sclerosis (ALS) has become highly complicated, leaving patients without the standard multidisciplinary follow-up. This study aimed to analyze the impact of the COVID-19 lockdown on ALS disease progression. We compared the clinical data and progression in the first year following diagnosis for patients who received ALS diagnosis during 2020 (G20, N = 34), comparing it with a group of diagnosed in 2018 (G18, N = 31). Both groups received a comparable multidisciplinary model of care in our Tertiary Expert ALS Centre, Novara, Italy. The monthly rate of ALSFRS-R decline during the lockdown was significantly increased in G20 compared to G18 (1.52 ± 2.69 vs. 0.76 ± 0.56; p-value: 0.005). In G20, 47% required non-invasive ventilation (vs. 32% of G18). Similarly, in G20, 35% of patients died vs. 19% of patients in G18 (p-value: 0.01). All results were corrected for gender, age, site of onset, and diagnostic delay. Several factors can be implicated in making ALS more severe, with a faster progression, such as reduced medical evaluations and the possibility of therapeutic changes, social isolation, and rehabilitation therapy suspension.

The first case of the TARDBP p.G294V mutation in a homozygous state: is a single pathogenic allele sufficient to cause ALS?

Here, we described the first amyotrophic lateral sclerosis patient presenting the c.881 G > T p.G294V TARDBP mutation in homozygous status. The patient belongs to a large pedigree from Morocco. Except for one older affected brother his parents and remaining 8 sibs are referred to be healthy and do not show any neurological sign or symptom. The lack of evidence of TARDBP deletions of any sizes, together with the presence of several AOH segments, strongly suggests that the homozygosity status of p.G294V in the proband derived from parental consanguinity. A revision of the literature and our cohorts indicates that the p.G294V mutation has been detected in only 15 additional ALS patients in heterozygosity and, except for one additional Moroccan patient, all were of Italian origin. The analysis of microsatellite markers surrounding the TARDBP gene in 8 individuals carrying the p.G294V mutation showed that the haplotypic context of the Moroccan proband is shared with most patients of European origin indicating that they carry the p.G294V mutation inherited from a common ancestor. The analysis of the 15 ALS pedigrees (from literature data and present study), strongly suggests a reduced penetrance of the p.G294V mutation since for 13 of the 15 described p.G294V ALS cases the parents did not show any neurological symptoms. This result has potentially important implications in genetic counseling, since genetic testing of a reduced penetrance mutation on pre-symptomatic individuals proves very difficult to predict the outcome based on the genotype.

Masses of the Paranasal Sinuses After Treatment of Nasopharyngeal Carcinoma: A Case Report.

The development of a new mass in the field of irradiation of a previously treated Nasopharyngeal carcinoma is generally considered a sign of recurrence. We report a case of a 46-year-old male, with a past history of undifferentiated NPC, with an expansive lesion discovered during radiological follow-up that occupied nasal cavity and paranasal sinuses. The endoscopic sinuses surgery was necessary in order to analyze and remove the mass with intraoperative frozen sections to highlight mucosa free from disease. The presence of non-malignant masses in the paranasal sinuses are rare complications after radiotherapy at the skull base, but represent an eventuality that must be considered in the differential diagnosis of a suspected recurrence or with a secondary malignancies after radiation therapy. It is therefore required a final diagnosis based on biopsy, follow-up and an eventual endoscopic surgical treatment.

Phonosurgical Resection Using Submucosal Infusion Technique for Early Glottic Lesions: Diagnostic and Therapeutic Procedure?

OBJECTIVES:: The aim of this study was to assess the feasibility of the submucosal infusion combined with microflap dissection via laser CO2 as both a diagnostic and therapeutic procedure for superficial glottic lesions. To define a safe surgical procedure in terms of local control, a morphometric study of surgical margins was performed. METHODS:: From January 2011 to January 2016, we treated 122 patients with early glottic lesions with phonomicrosurgery. Patients with effective hydrodissection underwent a microflap and type I-II diagnostic cordectomy. In the others, a biopsy was carried out, and in the case of a malignant lesion, a type III to VI cordectomy was performed. Disease-free survival (DFS) for all the lesions was also determined according to comparative assessments of surgical margins. The Voice Handicap Index was used to evaluate functional outcomes. RESULTS:: In 27 cases (32%), hydrodissection was effective; specifically, 24 (88.8%) were premalignant lesions, and 3 (11.2%) had a carcinoma. In 56 patients (68%), hydrodissection was not adequate, and a biopsy was performed: 9 (16%) were premalignant and 47 (84%) malignant lesions. The DFS analysis suggests that margins >0.7 mm resulted in a cutoff that can guarantee a safe procedure in the case of effective hydrodissection ( P < .05). CONCLUSION:: Phonomicrosurgery may be both a diagnostic and therapeutic option with oncological efficacy for superficial glottic lesions of undetermined nature when surgical margins exceed 0.7 mm. In case of inadequate hydrodissection, the hypothesis of an infiltrative carcinoma warrants a wider cordectomy.

Metastasizing Maxillary Ameloblastoma: Report of a Case with Molecular Characterization.

BACKGROUND: Ameloblastoma is a benign odontogenic tumour that may exhibit aggressive biological behaviour with local recurrence and metastasis following initial surgical resection. Surgery is the most acceptable modality of treatment, even if a biological approach is currently on study. We report a case of maxillary ameloblastoma with development of neck and brain metastases after repeated local recurrences. Molecular analysis was performed with the aim to better characterize this neoplasm and its peculiar behaviour. METHODS: We investigated the status of tumour protein p53 (TP53), epidermal growth factor receptor (EGFR), B-Raf proto-oncogene (BRAF) and human epidermal growth factor receptor 2 (HER2) genes with immunohistochemical, fluorescent in situ hybridization and/or direct sequencing in order to clarify their possible role in the development of this neoplasm and the possibility of a targeted treatment. RESULTS: The histological appearance of the tumour was the same in the primary lesion, in the recurrence and in the metastases. EGFR positivity was present in the recurrence and the brain metastasis, while HER2 was negative in all samples tested. Fluorescent in situ hybridization analysis for EGFR showed disomy of neoplastic cells. Direct DNA sequencing of TP53 gene exons 5 - 9 was carried out in tumour samples from the infratemporal recurrence and brain metastasis, with no mutational alteration detected. Similarly, sequencing analysis of BRAF exon 15 (V600) and EGFR gene showed wild type results in all samples tested. CONCLUSIONS: Further studies are needed to identify molecular pathways that may provide an opportunity of alternative treatments and/or new potential predictive markers of local and distant spread of this rare tumour.

Psychological distress and health-related quality of life among head and neck cancer patients during the first year after treatment.

PURPOSE: Patients treated for head and neck cancer present some of the most significant posttreatment morbidity of any group of patients with cancer. Our aim is to describe quality of life and psychological distress after different treatments among head and neck cancer patients during the first year after treatment. METHODS: A total of 86 patients treated for head and neck cancer were evaluated within 1 year of the end of treatment by means of the Distress Thermometer (DT) and EORTC C30 and H&N35 questionnaires. Type of treatment was classified into 3 groups: surgery, chemo-/radiotherapy, and combined treatment. RESULTS: Forty-one percent of patients showed a high level of distress (DT >5). Distress was higher in patients with a tracheotomy or with previous cancer in another district. Quality of life was homogeneous across treatment types after adjustment for stage and time since end of treatment, except for higher levels of suffering related to sensory problems, social eating, and dry mouth among patients treated with combined therapy. CONCLUSIONS: The DT and EORTC questionnaires proved to be effective and easy tools to monitor distress and quality of life in patients with head and neck cancer. Monitoring the quality of life perceived by each patient during his/her course of treatment could be useful in planning the rehabilitation process while performing follow-up visits.

Sclerosing paraganglioma of the carotid body: a potential pitfall of malignancy.

Paragangliomas (PGs) of the head and neck region are typically benign, slow-growing neuroendocrine tumours. At times, they may exhibit unusual histological features, such as prominent stromal sclerosis (sclerosing PG), which may raise concerns of malignancy. We describe a case of sclerosing PG of the carotid body, emphasizing the value of immunohistochemical stains for differential diagnosis. A 43-year-old woman presented with a painless lump on the neck. A magnetic resonance imaging scan demonstrated a hypervascular lesion of the carotid body, which was surgically excised. Grossly, the lesion measured 1.8 cm at maximum diameter. On microscopic examination, irregular nests and tiny bundles of neoplastic cells were found between thick bands of fibrous tissue. Focal nuclear cytomegaly and marked pleomorphism were noted. Neoplastic cells proved to be immunoreactive for chromogranin, synaptophysin and neuron specific enolase, but negative for cytokeratins, smooth muscle actin and CD34. Ultrastructurally, numerous mitochondria, rough endoplasmic reticulum structures and endocrine granules were seen in the cytoplasm of the tumour cells. On consideration of the above-mentioned clinico-pathological and ultrastructural findings a diagnosis of sclerosing PG was established. Sclerosing PG is a rare entity which may mimic a malignant neoplasm. The recognition of this unusual morphological variant of PG, together with appropriate immunostains, leads to the correct diagnosis.

Which classification for ethmoid malignant tumors involving the anterior skull base?

BACKGROUND: The purpose of this study was to compare three systems of classification for malignant ethmoidal tumors in patients undergoing anterior craniofacial resection. METHODS: A radiologic locoregional evaluation of 241 patients with malignant ethmoid tumors was performed before patients underwent an anterior craniofacial resection. Disease in each case was staged according to the American Joint Committee on Cancer-Union Internationale Contre le Cancer (AJCC-UICC) 1997 classification, the AJCC-UICC 2002 classification, and the Istituto Nazionale Tumori (INT) classification. Kaplan-Meier curves and Cox models were used to investigate the prognostic value of each classification system on disease-free survival (DFS) and overall survival (OS). The classifications were compared in terms of prognostic discrimination capability, measured by use of an index of agreement between each classification and DFS or OS time. RESULTS: All three classification systems yielded statistically significant results in the Cox analysis, both for DFS and OS. In the AJCC-UICC 2002 system, minor differences were observed between T1 and T3 tumors. The INT classification showed a progressive worsening of the prognosis with increasing stage. The index of prognostic discrimination favored the INT classification over both the 1997 and 2002 AJCC-UICC classifications. CONCLUSIONS: Both the 1997 and 2002 AJCC-UICC classifications seemed to have limited prognostic value. By contrast, the INT classification satisfied one of the main goals of tumor staging, demonstrating the progressive worsening of prognosis with different tumor classes.