[The effectiveness of non-invasive lung ventilation in lateral amyotrophic sclerosis].

OBJECTIVE: Lateral amyotrophic sclerosis (LAS) is a very severe neurodegenerative disease with progressive course and terminal respiratory insufficiency. Non-invasive lung ventilation (NLV) is a main method of treatment. We studied the effectiveness of NLV in LAS and assessed patient's adaptation to NLV, life expectancy, compliance and an effect of NLV on spirometric parameters. MATERIAL AND METHODS: NVL was administered to 28 patients, mean age 56.2 ± 9.4 years, including 10 patients with bulbar onset and 16 with spinal onset. The rapid progression of the disease was observed in 15 patients, slow progression in 13 patients. RESULTS AND CONCLUSION: NLV used in regime S extended the life of patients, in particular, patients with spinal onset. The adjustment to the NLV device plays a crucial role. Two types of the adjustment were established: gradual (13 patients) and accelerated (4 patients). The causes of the latter were not found. It should be emphasized that several questions related to the details of NVL regime should be specified in further research in the field.

[A specific phobia of amyotrophic lateral sclerosis (ALS phobia)].

A specific phobia of amyotrophic lateral sclerosis (ALS phobia) was not previously described in the literature. We examined 21 patients, 11 men and 10 women, aged 28-72 years, with symptoms of this phobia. Only 23% of patients had a history of the psychiatric disorder in the past. The duration of phobia symptoms was significantly higher in patients with moderate and severe phobia than in mild cases (1.5±0.6 and 5.0±1.1 months respectively; р<0.05). The severity of ALS phobia was correlated with its duration (r= -0.5; p=0.004). The primary character of phobia was established in 52.4% of patients basing on the regression of phobia symptoms assessed by the Hamilton anxiety scale after psychotherapy and pharmacotherapy (17±4 and 3±1 scores before and 3 months after treatment, respectively; p<0.05).

[The study of chronic partial denervation and quality of life in patients with motor neuron disease treated with semax].

The study of chronic partial denervation (CPD) and quality of life was carried out in 27 patients with definite, probable and possible diagnosis of motor neuron disease (MND) treated with semax (1% solution). The needle electromyography (EMG) was performed thrice with short-term 2 month interval (60 days before enrollment and on day 1 and day 48 of the study) in three muscles on bulbar, cervical and lumbosacral levels on the less affected side. According to Revised El-Escorial Criteria (1998) the needle EMG for diagnostic purposes was also performed in two muscles on the cervical and lumbosacral levels on the more affected side along with stimulation electroneuronmyography of motor and sensory fibers of the peripheral nerves of neck, upper and lower extremities. The open-label clinical trial of Semax (1% solution) was conducted in sequential groups of patients. The drug was administered intranasally in two 10-day-long courses with 2-weeks break in daily dose of 12 mg. Sixty days before enrollment, and on days 1, 10, 24, 34 and 48, patients were assessed by the Norris ALS, the ALS Functioning Rating Scale and the ALSAQ-40 quality of life in the ALS scale. It was shown that CPD on the early as well as on the late stages was characterized by forward-backward, but not unidirectional course, that did not allow to recommend the follow-up needle EMG with short-term interval for evaluation of drug efficacy monitoring. Early CPD stages were characterized by forward-backwards fluctuations reflecting the compensatory reinnervation process (a phenomenon of exchange of muscle fibers, more rational in view of reinnervation, between adjacent motor units) whereas on the late CPD stages these forward-backwards CPD fluctuations reflected the processes of progressive deterioration of muscle fibers and secondary demyelination of large motor axons. Semax (1% solution) does not influence either the course of CPD or the dynamics of clinical estimates, in particular the terms of ensuing marked functional deficits on bulbar, cervical and lumbosacral levels of segmental innervation. However, 1% semax significantly improves the total estimate of life quality due to the improvement of emotional state and motivation in MND patients with the maximal effect on day 10. This finding suggests that it is feasible to administer 1% semax in complex MND palliative therapy.

[Analysis of the possible involvement of the glutamate transporter gene EAAT2 and the glutamate receptor genes GRIA1 and GRIA2 in pathogenesis of motor neuron disease in the Russian population].

Polymorphisms of the genes of the glutamatergic system EAAT2, GRIA1, and GRIA2 have been analyzed in patients with sporadic motor neuron disease (MND) from Russia. The disease is not associated with polymorphic alleles of the genes studied, which indicates that EAAT2, GRIA1, and GRIA2 play an insignificant role in the pathogenesis of sporadic MND.

[The study of denervation-reinnervation process in motor neuron disease and benign neuron disorders].

To study peculiarities of chronic partial denervation (CPD), needle electromyography (EMG) of the neck, upper and lower extremity muscles on the less affected side was performed in 25 patients with definite motor neuron disease (MND) and in 9 patients with benign motor neuron disorders (BMND) with 2-month-long follow-up interval. Normal values of EMG parameters for muscle studied and test-retest correlation coefficient were calculated in 35 healthy volunteers. In MND on the early stages (1 and 2) of CPD, duration and amplitude of motor unit potentials (MUPs) correlated negatively while on the later stages (3A, SB, 4 and 5) the correlations were positive, but only in muscles within the site of onset. There was no significant predominance of duration and amplitude of MUPs in those muscles. MUPs amplitude was significantly higher in patients with MND with predominant lower motor neuron involvement (p < 0.05). In muscles with MUPs duration higher than--20% and increased amplitude, MUPs duration decreased within the site of onset up to the second study. In BMND, MUPs duration and amplitude never decreased in follow-up. These parameters were significantly higher in BMND than in MND (p < 0.0001) in less affected muscles (without paresis). In contrast to BMND, no lag of paresis behind the CPD stage was observed in MND. The data obtained suggest a recurrent and forward mode of CPD on late stages and allow to differentiate slowly progressive MND and BMND in the single as well as in repeated study after a short period of time.

[Detoxication gene polymorphism and susceptibility to sporadic motor neuron disease in Russian population].

Motor neuron disease (MND) is caused by selective degeneration of motor neurons of the cerebral cortex, brain stem and spinal cord. Many genetic systems are thought to be involved in pathogenesis of this complex disease. A significant etiological factor of MND may be oxygen free radicals, which damage neuronal cells when they are present in high concentrations. Detoxication processes resulting in the formation of free radicals, which subsequently transformed into nontoxic products, are also critical for the disease development. The major participants of these processes are cytochromes P-450 (CYP2E1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT2). To investigate a role of genes of detoxication system in development of MND, we study polymorphisms in these genes in 72 patients with MND from Moscow and controls from Russia. Significant statistical differences have been found in frequency of the alleles CYP2E1*1D, CYP2D6*4 and GSTM1(0/0) and genotypes homozygous for GSTM1 (0) between the study and control groups. The analysis of GSTT1, GSTP1 and NAT1 gene polymorphisms has revealed no between-group differences in distribution of different alleles and genotypes. The GSTP1*A/ GSTP1*A genotype was associated with a classical upper and lower motor neuron involvement and the GSTP1*A allele with predominant lower and upper motor neuron involvement.

[Sleep-related breathing disturbances in motor neuron disease].

Presented are the results of the study of respiratory parameters, together with standard polysomnography, in 18 patients with motor neuron disease (13 males, 5 females, mean age 61,5 +/- 10,6 years). AHI =10 epis./h was found in 10 (56%) cases. Other 4 patients demonstrated a low level (less 94%) of average blood saturation during sleep. The highest number of obstructive episodes was observed in patients with progressive bulbar palsy and amyotrophic lateral sclerosis (ALS) with bulbar signs. The lowest level of nighttime saturation was registered in patients with ALS without bulbar signs. Mean saturation (less than 94%) was associated with more pronounced limb muscle weakness, rapid disease progression and worse survival.

[Pharmacological therapy of sialorrhea in patients with motor neuron disease].

A comparative trial of amithryptiline and dysport (botulinic toxin type A) in the treatment of sialorrhea in patients with motor neuron disease (MND) was conducted in 10 MND patients with sialorrhea, of whom 5 were treated with subcutaneous injections of Dysport and 5 with Amithriptiline, and 6 controls without salivary dysfunction. Gravimetry and scintigraphy of salivary glands were used before and after treatment. Compared to controls, saliva production was significantly decreased in MND patients. Both amithryptilin and dysport used in mean therapeutic doses decreased sialorrhea with similar effect. However, 3 patients, receiving amythryptiline in dosage 50 mg/day, experienced side effects (constipation, accommodation disturbances, dry mouth, sleepiness and poor concentration). Reducing of amithryptiline dose, along with prescribing dysport, removed the side-effects in these patients, while sialorrhea did not increase. The authors concluded that due to high efficacy and low cost of amithryptiline therapy of sialorrhea proved to be a golden standard of palliative care in MDN. However, in these terms dysport can not be an alternative to amithryptiline in sialorrhea therapy. Nevertheless, in cases when amithryptiline treatment is accomplished with side-effects, the drug dosage can be reduced and combined with dysport.

[Analysis of the glutathione S-transferase P1 gene Ile105Val polymorphism in the patients with sporadic motor neuron disease from Russia]. / Analiz Ile105Val polimorfizma gena glutation-S-transferazy P1 u bol'nykh so sporadicheskoi formoi bolezni dvigatel'nogo neirona iz Rossii.

Ile105Val polymorphism in exon 5 of glutathione S-transferase (GSTP1) gene was examined in a group of patients with motor neuron disease (MND) and control sample. No statistically significant differences in the allele and genotype frequency distributions between the samples examined were demonstrated. We conclude that Ile105Val polymorphism is not associated with the risk of the disease development in the patients from Russia with sporadic form of MND.

[Peculiarities of sporadic motor neuron disease associated with D90A and G12R mutations in Russian population]. / Osobennosti sporadicheskoi bolezni dvigatel'nogo neirona, assotsiirovannoi s mutatsiiami D90A i G12R, v rossiiskoi populiatsii.

Fifty-one blood samples of Russian patients with sporadic motor neuron disease were examined for mutations in Cu/Zn superoxide dismutase (SOD-1) gene. One female patient with amyotrophic lateral sclerosis (ALS) was heterozygous for G12R mutation. This patient suffered from ALS with cervical cord onset, pyramidal variant and fast progression. Mutation was also detected in her healthy son. Earlier, such mutation was described in 5 Italian patients with slow progressive ALS. Also, D90A SOD-1 gene associated haplotypes of the female ALS patients previously examined by the authors have been analyzed. A homozygous female patient with ALS was characterized by typical lumbar onset and extremely slow progression, as well as a female patient with heterozygous mutation and moderate progression carried so-called "Scandinavian" haplotype. To our knowledge, it is the first report on the finding of the haplotype considered as a "protective" one in the subjects heterozygous for D90A mutation with clinical symptoms of ALS. Mechanisms of "protective" influence of this haplotype on ALS course are not yet elucidated. Our finding suggests that the presence of "Scandinavian" haplotype does not completely protect from the disease development in patients exposed to other more pathogenic causative factors. This assumption is in line with modern conceptions on motor neuron disease as a complicated multifactor disorder.

[Association of homozygosity for short allele (S) of heavy neurofilament subunit gene with motor neuron disease and oxidative stress development]. / Assotsiatsiia gomozigotnosti po korotkomu alleliu (S) gena tiazhelykh neirofilamentov s bolezn'iu dvigatel'nogo neirona i razvitiem oksidantnogo stressa.

We analyzed distribution of heavy neurofilament (NF-H) gene S/L-polymorphic variants in 51 patients with idiopathic motor neuron disease (MND) vs control group and in relation to superoxide dismutases (SODs) activity and thiobarbituric acid reactive substances (TBARS) level in cerebrospinal fluid (CSF), erythrocytes and blood serum. We found that individuals with homozygosity for NF-H gene short allele (S/S-genotype carriers) in MND group predominate significantly over those in control one (p < 0.001). We revealed significant increase of oxidative markers in CSF and blood serum in MDN patients vs controls (p < 0.05), but not in patients with spondylogenic myelopathy, conforming non-specific role of oxidative stress in MND pathogenesis. There were no differences between TBARS level in CSF and serum in relation to the rate of MND progression, suggesting that oxidative stress does not influence the MND course. We showed normal SOD-1 activity in erythrocytes and CSF of MND patients that argued for the absence of these antioxidant enzymes deficiency in MND without SOD-1 gene mutations. We found significant association between homozygosity for short allele (S) and increased TBARS level in CSF (p < 0.02). These findings specify the role of NF-H with lower molecular weight in MND pathogenesis and make expedient antioxidants administration to MND patients homozygous for S-allele of NF-H gene.

[Polymorphism of glutathione S-transferase genes M1 and T1 in patients with motor neuron disease from the city of Moscow]. / Polimorfnye markery genov gliutation-S-transferazy M1 i T1 i bolezn' dvigatel'nogo neirona u patsientov iz g. Moskvy.

Comparison of the frequency distributions of alleles, genotypes, and genotype combinations of genes GSTM1 and GSTT1 did not show statistically significant differences between patients with motor neuron disease (MND) and a random sample from the Moscow population. Apparently, these genes are not involved in MND pathogenesis in these patients.

[Sporadic amyotrophic lateral sclerosis associated with Asp90Ala CuZn-superoxide dismutase mutations in Russia]. / Sporadicheskii bokovoi amiotroficheskii skleroz u patsientov s Asp90Ala mutatsiei med'-tsinksoderzhashchei superoksiddismutazy v Rossii.

16 blood samples from Russian patients (Moscow) with idiopathic motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Two patients (12.5%) with amyotrophic lateral sclerosis (ALS) were found to have a disease related mutation. One patient appears to have autosomal recessive adult-onset ALS associated with homozygosity for Asp90Ala and presents the characteristic phenotype of very slowly ascending paresis with both lower and upper motor neuron signs. The other patient heterozygous for Asp90Ala presents ALS with lumbar onset and rapid progression. Both of cases are apparently sporadic.