[Autoimmune encephalitis: psychiatric aspects]. / Autoimmunnye entsefality: psikhiatricheskie aspekty.

Autoimmune encephalitis is a group of diseases researched by both neurologists and psychiatrists. Despite a large number of studies and practical recommendations, the differential diagnosis and early diagnostics still remains an important issue. The most difficult to diagnose are cases that debut as mental disorders and/or occur without neurological symptoms. The literature review presents the current state of the problem with an emphasis on the practice of a psychiatrist.

Levamisole-associated multifocal inflammatory encephalopathy: clinical and MRI characteristics, and diagnostic algorithm.

Levamisole-associated multifocal inflammatory encephalopathy (LAMIE) is a devastating adverse effect of levamisole (LEV) treatment. In Russia, people often use LEV without a doctor's prescription for anthelmintic prophylaxis. LAMIE often misdiagnosed as the first episode of MS or acute disseminated encephalomyelitis (ADEM). The aim of our study was to describe clinical, laboratory and morphological characteristics of LAMIE, magnetic resonance imaging (MRI) patterns and create an algorithm for the differential diagnosis. This study was a prospective observational study with retrospective analysis of cases. It was performed at two hospitals with ambulatory service for MS. We included 43 patients with LAMIE with follow-up was from 1 year to 5 years. Age was 19-68 y.o. with female predominance. The most typical manifestations of LAMIE were cerebellar, pyramidal and cognitive symptoms, and majority of patients had biphasic course of the disease. Three main types of MRI patterns were described: ADEM-like, MS-like, atypical demyelination. About 40% of patients had CSF specific oligoclonal bands synthesis, but only 20 % of them converted to MS during the period from 1 month until 2 years. The CSF albumin levels and immunoglobulin G index were elevated in LAMIE patients compared to reference values. We described results of brain biopsy in two cases. Therefore LAMIE should be considered in patients with demyelinating or inflammatory conditions with biphasic onset of the disease and variable MRI presentation.

[Neuropsychiatric presentations of amyotrophic lateral sclerosis]. / Neiropsikhiatricheskie proyavleniya bokovogo amiotroficheskogo skleroza.

Neuropsychiatric presentations are observed in a substantial number of patients with amyotrophic lateral sclerosis (ALS). Severe behavioral disorders develop in ALS combined with frontotemporal dementia, which are considered to be a disease continuum. Psychiatric disorders in ALS with predominantly motor symptoms are less prominent and mostly presented with apathy. Psychiatric disorders in ALS by their origin could be psychogenic, reflecting the patients' reactions on severe disease, and organic, developing as a result of degeneration of central motor neurons and disconnection between fronto-subcortical and frontotemporal loops. An important role in the development of psychiatric disorders in ALS belongs to genetic factors, in particular to hexanucleotide expansion in the C9orf72 gene. During the first months after establishing the diagnosis of ALS, there is the high risk of developing depressive disorders, which in severe cases can lead to suicide. More research is needed in this area.

[Autoimmune encephalitis in psychiatric institution (clinical case)]. / Autoimmunnyi entsefalit v praktike psikhiatra (klinicheskii sluchai).

Currently there is a new concept of «molecular neuropsychiatry¼ which aim is identification of biomarkers and biological substrates for mental disorders. Autoimmune encephalitis can start with psychiatric symptoms in 60% of cases. In this article we described a clinical case of a patient, 31 years old, with GABAb-associated AE started with acute polymorphic psychosis. AE was diagnosed and treated in time with a good clinical effect. According to the frequency of psychiatric symptoms in AE patients it should be reasonable to include antineuronal test in CSF and serum in patients with first acute psychosis if «red flags¼ or atypical course of the disease.

[Peripheral vertigo as onset of an immune-mediated disorder]. / Sistemnoe golovokruzhenie kak debyut immuno-oposredovannogo zabolevaniya.

In this article we present a clinical case of a female patient, 45 years old, with autoimmune encephalitis with antibodies to glutamate decarboxylase (GAD) beginning clinically with vertigo. According to high frequency of vestibular symptoms at the beginning and high frequency of admission to otoneurologist GAD-associated pathology should be included in differential diagnosis in complicated clinical cases with vertigo. These patients should be sent to neurologist.

[Acute disseminated encephalomyelitis]. / Ostryi rasseyannyi entsefalomielit.

Acute disseminated encephalomyelitis (AEM) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS), usually single-phase. In WREM, multiple lesions of the central nervous system of an inflammatory-demyelinating nature accompanied by extremely polymorphic neurological disorders develop acutely or subacutely. The review considers the issues of epidemiology, trigger factors of the inflammatory process, clinical manifestations, differential and molecular diagnostics of WECM, and outlines the ways for further study of this pathology.

Stress load and neurodegeneration after gastrostomy tube placement in amyotrophic lateral sclerosis patients.

Dysphagia and progressive swallowing problems due to motoneuron death is one of amyotrophic lateral sclerosis (ALS) symptoms. Malnutrition and body weight loss result in immunological disturbances, fatigability and increase risk of secondary complications in ALS patients, percutaneous endoscopic gastrostomy tube (PEG) placement representing a well-recognized method for malnutrition correction and potentially increasing life expectancy. However, despite nutritional correction, occasional rapid neurological deterioration may develop after PEG placement. We have hypothesized that this decline can be a result of exteroceptive stress during PEG placement and promote neurodegeneration in ALS patients. Intravenous sedation may decrease stress during invasive procedures and it is safe during PEG placement in ALS patients. The aim of the study was comparing different PEG placement protocols of anesthesia (local anesthesia or local anesthesia plus intravenous sedation) in ALS from perspectives of stress load and neurological deterioration profile. During 1.5 years 94 ALS patients were admitted; gastrostomy was performed in 79 patients. After screening according to inclusion and exclusion criteria, 30 patients were included in the prospective consecutive study. All patients were divided in two groups, with local anesthesia and with combination of local anesthesia and intravenous sedation. Routine biochemical indices, neurodegeneration and stress markers were measured. The age of ALS patients was 61 ± 10 years; 20 patients were included at stage 4A and 10 at stage 4B (King's College staging). PEG was placed at average14 months after the diagnosis and 2.2 years after first symptoms. Mean ALS Functional Rating Scale-Revised was 27.8, mean forced vital capacity of lung 46.3% (19-91%). After one year of observation only 8 patients survived. Mean life duration after PEG was 5 months (5 days-20 months). Comparison of two PEG placement protocols did not reveal differences in survival time, stress load and inflammation level. Higher saliva cortisol levels, serum cortisol, glucose, C-reactive protein and interleukin-6 were detected after PEG placement, confirming considerable stress response. PEG is a stressful factor for ALS patients, PEG placement representing a natural model of exteroceptive stress. Stress response was detected as increased cortisol, C-reactive protein, interleukin-6, and glucose levels. Intravenous sedation did not increase the risk of PEG placement procedure, however, sedation protocol did not affect stress load.

Neurosyphilis in the modern era: Literature review and case series.

The term of neurosyphilis (NS) refers to infection of central nervous system by Treponema pallidum. Classically, it has been divided into early (meningitis, meningovascular) and late forms (general paresis and tabes dorsalis). The availability of penicillin and high sensitivity of Treponema pallidum to this antibiotic has led to a widely held perception about rarity of syphilitic forms with central nervous system involvement. However, patient can exhibit atypical clinical presentation. Recently different clinical cases with autoimmune encephalitis-mimicking presentation or atypical movement disorders were described. In this article we presented clinical case series with different clinical and MRI presentation and discuss diagnostic and treatment challenges. During our screening period at neurological department we revealed 6 NS cases. Three of them have an atypical presentation. The first patient was misdiagnosed as acute disseminated encephalomyelitis, the second patient had hippocampal sclerosis and epileptic seizures. Another patient had cognitive decline and autoimmune encephalitis-like MRI lesions. We put an emphasis on widening of indication for lumbar puncture and NS tests in patients with syphilitic anamnesis and neurological manifestations.

Neuronal damage and neuroinflammation markers in patients with autoimmune encephalitis and multiple sclerosis.

Inflammatory diseases of the central nervous system (CNS) are a diagnostic challenge to clinicians. Autoimmune encephalitis (AE) is an important diagnostic consideration in patients with CNS inflammatory disorders; despite of a wide range of neuropsychiatric symptoms it should be diagnosed as soon as possible and the patient transferred to the neurologist. We studied a group of AE patients (n = 24) as compared to multiple sclerosis (MS, n = 61) and control (n = 19) groups. Detailed clinical pictures of patients are presented. We focused on relevant cerebrospinal fluid (CSF) tests like protein levels, cytosis and oligoclonal bands, neuroinflammation indices (interleukin-6, soluble receptor of IL-6, neopterin, anti-ribosomal proteins antibodies) and markers of neurodegeneration (phosphorylated neurofilament heavy chain, pNfh). Elevated neopterin level was found in AE group as compared to the MS and control groups, while protein and pNfh were increased in both AE and MS groups. In the MS group, the cytosis and soluble receptor of IL-6 were higher as compared to the control group. Anti-ribosomal proteins antibodies were increased in a single patient with AE. High levels of protein were predictive of mortality in AE patients, while IL-6 and pNfh were elevated in severe AE patients. AE patients with paraneoplastic etiology demonstrated oligoclonal bands positivity. Taken together, our results suggest the neopterin as an additional marker of autoimmune brain inflammation. Though higher levels of protein, IL-6 and pNfh were found in patients with severe disease progression and death, prognostic values of these markers should be validated in larger cohorts of patients.

[Clinical case of levamisole-induced multifocal inflammatory leukoencephalopathy]. / Levamizol-indutsirovannaia vospalitel'naia leikoéntsefalopatiia.

Levamisole is an immunomodulatory drug which can trigger development of levamisole-induced multifocal inflammatory leukoencephalopathy (LIMIL) in patients treated for helminthic invasion, aphthous stomatitis, cancer, or cocaine users. LIMIL clinical case in patient 45 years old after single dose of levamisole (taken without any medical prescription) was described. We presented clinical history and clinical picture, MRI and laboratory data and treatment results during 1-year observation. According to similarity of LIMIL with acute disseminating encephalomyelitis or debut of multiple sclerosis and high frequency of levamisole usage in Russia (usually without medical prescription) LIMIL should be included in differential diagnosis in demyelinating disorders and treated according to current clinical recommendation.

[The Edinburgh Cognitive and Behavioral ALS Screen (ECAS): a Russian version.] / Édinburgskaia shkala otsenki stepeni narusheniia kognitivnykh funktsii i povedeniia u patsientov s bokovym amiotroficheskim sklerozom (ECAS) - russkoiazychnaia versiia.

AIM: To translate into Russian and adapt the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) for patients with amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: Medical care for ALS patients requires participation of a multidisciplinary team. More than one third of patients with ALS suffer from cognitive and behavioral disturbances, and it influences decisions of the team, patients and family. The scale for measuring of these disturbances should be rapid and understandable for evaluation and take into account the specificity of cognitive and behavioral impairments in ALS. RESULTS AND CONCLUSION: ECAS met these criteria and allows screening examination of patients with ALS at different stages of movement impairment.

[Results of a randomized double blind parallel study on the efficacy and safety of tolpersione in patients with acute nonspecific low back pain]. / Rezul'taty randomizirovannogo dvoinogo slepogo parallel'nogo issledovaniia éffektivnosti i bezopasnosti primeneniia tolperizona u patsientov s ostroi nespetsificheskoi bol'iu v nizhnei chasti spiny.

AIM: To evaluate the efficacy and safety of tolpersione injection and oral formulations combined with NSAID over NSAID monotherapy in acute non-specific low back pain. MATERIAL AND METHODS: In this randomized double blind study 239 patients were included in the per protocol analysis. The first 5 days of treatment, patients received tolpersione or placebo injection which was followed by per os administration of tolpersione/placebo tablet up to 14 days. NSAID diclofenac tablet was used in both groups through the study. Functionality assessed by the Roland Morris Disability Questionnaire (RMDQ) at day 5 was the primary endpoint. Secondary endpoints were RMDQ at other time points, pain level change at rest and on movement assessed by the Visual Analogue Scale (VAS), the Clinical Global Impression of Improvement/Patient Global Impression of Improvement (CGI-I and PGI-I), change in the range of motion assessed by the distance from the fingertips to the floor, period of disability days, relative (%) changes in the daily dose of diclofenac from the 7th to the 14th day of therapy. RESULTS AND CONCLUSION: The primary and secondary endpoints clearly demonstrated the significant superiority of tolpersione added to NSAID monotherapy over NSAID monotherapy. The safety assessment revealed no statistically significant differences between the two groups. Based on the results, tolpersione injection and per os formulations can be considered an effective and safe drugs in the combined therapy for patients with acute nonspecific back pain.

[Experimental approach to the gene therapy of motor neuron disease with the use of genes hypoxia-inducible factors].

Motor neuron disease (MND), or amyotrophic lateral sclerosis, is a fatal neurodegenerative disorder characterized by a progressive loss of motor neurons in the spinal cord and the brain. Several angiogenic and neurogenic growth factors, such as the vascular endothelial growth factor (VEGF), angiogenin (ANG), insulin-like growth factor (IGF) and others, have been shown to promote survival of the spinal motor neurons during ischemia. We constructed recombinant vectors using human adenovirus 5 (Ad5) carrying the VEGF, ANG or IGF genes under the control of the cytomegalovirus promoter. As a model for MND, we employed a transgenic mice strain, B6SJL-Tg (SOD1*G93A)d11 Gur/J that develops a progressive degeneration of the spinal motor neurons caused by the expression of a mutated Cu/Zn superoxide dismutase gene SOD1. Delivery of the therapeutic genes to the spinal motor neurons was done using the effect of the retrograde axonal transport after multiple injections of the Ad5-VEGF, Ad5-ANG and Ad5-IGF vectors and their combinations into the limbs and back muscles of the SOD1(G93A) mice. Viral transgene expression in the spinal cord motor neurons was confirmed by immunocytochemistry and RT-RCR. We assessed the neurological status, motor activity and lifespan of experimental and control animal groups. We discovered that SOD1(G93A) mice injected with the Ad5-VEGF + Ad5-ANG combination showed a 2-3 week delay in manifestation of the disease, higher motor activity at the advanced stages of the disease, and at least a 10% increase in the lifespan compared to the control and other experimental groups. These results support the safety and therapeutic efficacy of the tested recombinant treatment. We propose that the developed experimental MND treatment based on viral delivery of VEGF + ANG can be used as a basis for gene therapy drug development and testing in the preclinical and clinical trials of the MND.

[Natalizumab in the treatment of patients with relapsing-remitting multiple sclerosis: the preliminary results of the observational program "Sovet"].

The post marketing observational program "Sovet" has been launched in 2011. Sixty-nine patients with relapsing-remitting multiple sclerosis (MS) treated with natalizumab (NZ), a second generation DMD, have been examined. NZ infusions were carried out during 1h every 4 weeks for 12 months. After treatment, there were a significant reduction in the frequency of relapses from 2.22±0.98 to 0.18±0.42 per year and a trend towards the decrease in EDSS scores from 3.69±1.00 to 3.37±1.17. Adverse effects were noted in 11 patients, with each patient having no more than one side-effect. One patient discontinued treatment due to a generalized allergic reaction. These findings are in line with literature results on the positive effect of NZ on the course and symptoms of MS. It has been concluded, that the strict selection of patients and their correct management during the treatment with NZ may provide the positive balance between advantages and potential risks.

Gene therapy of amyotrophic lateral sclerosis.

Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy.