Current and emerging treatments for amyotrophic lateral sclerosis

Stefano Zoccolella1, Andrea Santamato2, Paolo Lamberti31Azienda Ospedaliero-UniversitariaOspedali Riuniti, Department of Medical and Neurological Sciences, Clinic of Nervous System Diseases, University of Foggia, Italy; 2Department of Physical Medicine and Rehabilitation, University of Foggia, OORR, Italy; 3Department of Neurology and Psychiatry, University of Bari, ItalyBackground: Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration.Objective: We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis.Methods: A Medline literature search was performed to identify all studies on ALS treatment published from January 1st, 1986 through August 31st, 2009. We selected papers concerning only disease-modifying therapy.Results: Forty-eight compounds were identified and reviewed in this study.Conclusions: Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.Keywords: amyotrophic lateral sclerosis, therapy, drug, surviva

A 71-nucleotide deletion in the periaxin gene in an Italian patient with late-onset slowly progressive demyelinating CMT

Background: Charcot-Marie-Tooth disease (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in the periaxin (PRX) gene cause CMT4F with an autosomal recessive early-onset demyelinating neuropathy and are extremely rare in a non-Romani white population. Methods: We report on a 66-year-old Italian man presenting with slowly progressive and late-onset demyelinating CMT. The molecular analysis was performed using a custom panel containing 39 genes associated with the CMT phenotype. Results: The patient harbored a homozygous PRX 71-nucleotide deletion (c.3286_3356del71, I1096fsX17). Conclusions: This is the first report that describes such a genetic mutation in a population of non-Romani origin

Hyperhomocysteinemia in L-dopa treated patients with Parkinson's disease: potential implications in cognitive dysfunction and dementia?

Abstract: Background: Hyperhomocysteinemia has been associated with cognitive dysfunction and dementia. The incidence of dementia in Parkinson’s Disease (PD) patients is higher than in the general population and plasma Homocysteine concentrations are increased in L-dopa treated PD patients. Objective: We evaluated the possible correlations between L-Dopa related hyperhomocysteinemia and cognitive dysfunction in PD. Methods: A Medline literature search was performed to identify all published studies on Homocysteine and cognitive dysfunction and dementia during the course of PD from 1966 to 31/03/2010. Results: Sixteen studies were found for review; ten studies focused on homocysteine and cognitive dysfunction in PD patients, five on homocysteine and PD dementia and two on homocysteine and markers of neurodegeneration in PD. The design of the study was retrospective in 14 studies, while 2 had a prospective design, with a variable follow-up period (from 24-weeks to 2 years). In most of the studies plasma homocysteine levels significantly correlated with cognitive functions, dementia and markers of neurodegeneration in PD patients. However, some studies did not confirm these findings. Several factors may concur to explain these partially conflicting results, including the retrospective design of the studies, their small sample size, their high percentage of excluded patients, and the use of a wide range of neuropsychological tasks in assessment of cognitive dysfunctions across the available studies. Conclusions: Available data seem to indicate a potential role of L-dopa related hyperhomocysteinemia on cognitive impairment and dementia during the course of PD

Inclusion of motor evoked abnormalities in amyotrophic lateral sclerosis: a diagnostic algorithm to early classify lower motor neuron phenotypes

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Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration during COVID-19 Pandemic: Results from Southern Italy

Background: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. Objective: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. Methods: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched. Results: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. Conclusion: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency

Motor-evoked potentials in amyotrophic lateral sclerosis: potential implications in detecting subclinical UMN involvement in lower motor neuron phenotype

Background: In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN) damage still lacks. Aim of the study was to estimate the role of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) as marker of subclinical UMN involvement. Methods: Clinical evidence of UMN damage was prospectively compared to MEPs in 176 ALS patients diagnosed between 2011 and 2014, and classified according to existing diagnostic criteria. Finally, we evaluated the appearance of clinical UMN signs and the level of diagnostic certainty in ALS after 1 year of follow-up. Results: At presentation, abnormal MEPs were found in 80% of patients with clinical evidence of UMN damage and in 72% of patients without clinical involvement of UMN. Among these latter, 61% showed appearance of UMN clinical signs after 1 year. Approximately 70% of patients with clinical lower motor neuron (LMN) phenotype showed MEP abnormalities, while they were considered not classifiable ALS according to Airlie house or Awaji criteria. Furthermore, abnormal MEPs in absence of clinical UMN signs at baseline were found in 80% of spinal ALS that after 1-year developed UMN signs at limbs, compared to 50% of bulbar ALS. Conclusions: TMS is a reliable marker of subclinical UMN damage particularly among LMN phenotype and ensure an early ALS diagnosis in ~ 70% of such cases

Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease. © 2013 Mezzapesa et al

Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study

Background and Objectives: Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years. Methods: Cognitive performances were examined by the Rao’s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient’s selfreported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively. Results: After 1 year of treatment the percentage of CI patients decreased from 29 % (29/100) at baseline to 19 % (19/100) (p = 0.031) and the mean baseline values of CII (13.5266.85) and FSS (4.0161.63) scores were significantly reduced (10.4867.12, p,0.0001 and 3.6161.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years. Conclusions: These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performance