Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting, breathing and swallowing difficulties resulting in patient’s death in two to five years after disease onset. In amyotrophic lateral sclerosis, both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration, accounting for great clinical heterogeneity of the disease. Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis. Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials. Since amyotrophic lateral sclerosis has low incidence rates, conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging. This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods, highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease. We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease. Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups, based on the disease pathophysiology and spatiotemporal pattern. Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups, we provide proof that instrumental studies could provide valuable insights in the disease pathology.

Рассеянный склероз (РС) — хроническое воспалительное заболевание центральной нервной системы (ЦНС), которое приводит к формированию очагов первичной демиелинизации в белом и сером веществе и диффузному поражению аксонов и нейронов. Несмотря на значительный прогресс в разработке лекарственных средств для ремиттирующего РС, влияние на прогрессирование заболевания остается недостаточным. Диффузная и компартментализованная лимфоцитарная и макрофагальная инфильтрация ткани ЦНС ингибирует дифференцировку миелинизирующих зрелых олигодендроцитов и нарушает процессы ремиелинизации. Хроническое воспаление, которое возникает при сохранном гематоэнцефалическом барьере (ГЭБ), вызывает активацию микроглии, что усиливает повреждение аксонов и нейронов и, как следствие, запускает хронический оксидантный стресс и гистотоксическую гипоксию. В настоящее время является актуальным уточнение механизмов, лежащих в основе нейродегенерации, которая на поздних этапах РС обусловлена хроническим нейроаксональным поражением, нарушением регенеративных возможностей и в значительной степени определяет исход заболевания.

Aims: The study aims to raise medical specialists’ awareness regarding the severity of possible complications of levamisole administration, and demonstrate the role of accurate medical history collection in a differential diagnosis. Background: Levamisole, an anthelmintic drug with immunomodulatory effects, has long been used worldwide till the early 2000s, when its association with demyelinating leukoencephalopathy was established. However, in the developing countries, it is still widely used for the prevention and treatment of helminthic invasion in humans. The actual prevalence of levamisole-induced multiple inflammatory leukoencephalopathy (LEV-induced MIL) in Russia remains unknown, and therefore, the study of its frequency and characteristics is indisputably important. Objectives: The objective of this study is to determine the clinical features and MRI findings of levamisole- induced MIL in the Russian population, and to analyse the frequency of diagnostic errors at the initial assessment. Methods: A single-center retrospective analysis of total 30 patients who were diagnosed with LEV- induced MIL and attended the Research Center of Neurology was conducted. Inclusion criteria were 1) clinically: acute or subacute polysymptomatic onset of neurological disturbances, 2) MRI: multifocal demyelinating lesion with no evidence of dissemination in time, 3) anamnestic data: levamisole exposure from 2 to 8 weeks before symptoms onset as well as monophasic disease course (absence of relapses according to follow up assessments up to 3 years). Results: Clinically, presentation with constitutional symptoms including headache, fever, fatigue and myalgia, focal motor disturbances and dysarthria prevailed in our cohort. On the brain MRI, multiple foci of demyelination with simultaneous gadolinium enhancement were observed. The link between neurological symptoms and levamisole intake has often been detected only during follow- up assessments. Patients were most often misdiagnosed with acute disseminated encephalomyelitis, stroke and multiple sclerosis. In most cases, LEV-induced MIL was successfully treated with intravenous corticosteroids and/or plasma exchange (PLEX), however, residual neurologic symptoms were preserved in some patients. Additionally, two detailed clinical cases of patients being initially misdiagnosed are presented in the article. Conclusion: The differential diagnosis remains difficult for suspected cases of LEV-induced MIL that could lead to delayed therapy initiation, and consequently incomplete recovery. Growing evidence suggests that a single administration of levamisole even in low doses might potentially lead to severe neurological deficit or death. Therefore, changes in medication management policies are required in order to prevent the uncontrolled use of levamisole.

Cognitive impairment (CI) is a relatively common manifestation of multiple sclerosis (MS), which can occur with any type of the disease course and activity. The largest CI prevalence and severity are observed in progressive MS. In relapsing-remitting MS the most prominent deterioration of cognitive functions is seen during relapses; however, in some patients it can continue also throughout remission. In a small number of patients CI can be the most significant symptom of the disease; in addition, it sometimes can be the only clinical feature of the relapse. Despite this, in clinical practice CI remains out of the focus of attention, and is not evaluated when assessing the disease severity and/or activity, while CI is not included into EDSS. Nonetheless, a number of specialized neuropsychological tests and batteries has been developed recently, which can be used for both screening and detailed assessment of CI in MS, as well as for assessment of its changes over time. CI has a negative impact on MS patients' quality of life, their social interactions, daily and occupational activities. The influence of disease-modifying agents on CI has been poorly investigated; however, there is evidence that they can reduce the degree of CI. The optimal choice of pathogenetic treatment in patients with CI remains understudied. There is no convincing evidence of the effectiveness of symptomatic pharmacological treatment of CI in MS, and cognitive rehabilitation is the only approach with confirmed effectiveness. Considering the limitations of this technique (its availability, quite a big number of sessions), there is a need to search for other methods to increase its efficacy, including non-invasive neuromodulation (in particular, transcranial direct current stimulation or transcranial magnetic stimulation). This article is focused on a brief review of the main diagnostic methods of CI in MS, its pathogenetic and symptomatic treatment, and cognitive rehabilitation techniques, as well as on the results of the studies on non-invasive neuromodulation.

Background/Objectives: Gut dysbiosis has been implicated in multiple sclerosis (MS), but microbial signatures remain inconsistent across studies. Machine learning (ML) algorithms based on global microbiome data integration can reveal key disease-associated microbial biomarkers and new insights into MS pathogenesis. This study aimed to investigate gut microbial signatures associated with MS and to evaluate the potential of ML for diagnostic applications. Methods: Fecal samples from 29 relapsing–remitting MS patients during exacerbation and 27 healthy controls were analyzed using 16S rRNA gene sequencing. Differential abundance analysis was performed, and data were integrated with 29 published studies. Four ML models were developed to distinguish MS-associated microbiome profiles. Results: MS patients exhibited reduced levels of Eubacteriales (p = 0.037), Lachnospirales (p = 0.021), Oscillospiraceae (p = 0.013), Lachnospiraceae (p = 0.012), Parasutterella (p = 0.018), Faecalibacterium (p = 0.004), and higher abundance of Lachnospiraceae UCG-008 (p = 0.045) compared to healthy controls. The Light Gradient Boosting Machine classifier demonstrated the highest performance (accuracy: 0.88, AUC-ROC: 0.95) in distinguishing MS microbiome profiles from healthy controls. Conclusions: This study highlights specific microbiome dysbiosis in MS patients and supports the potential of ML for diagnostic applications. Further research is needed to elucidate the mechanistic role of these microbial alterations in MS progression and their therapeutic utility.