[Mental disorders in blepharospasm]. / Psikhicheskie rasstroistva pri blefarospazme.

OBJECTIVE: To analyze mental disorders in blepharospasm (BS) before and after botulinum therapy (BT). MATERIAL AND METHODS: We examined 25 patients with BS (9 men and 16 women), aged 50 to 85 years (mean 64.1±18.5), with BS (main study group). The control group consisted of 20 healthy individuals (7 men and 13 women, mean age 63.5±8.5). Patients were examined before and after BT (after 3 weeks) using a diagnostic structured interview Mini International Neuropsychiatric Interview, GAD-7, PHQ-9, fear of negative assessment (short version) and The Liebowitz Social Anxiety Scale (LSAS). RESULTS: Fifty-six percent of patients with BS, as assessed by the GAD-7, showed a high level of anxiety, while depression, measured by the PHQ-9 and found in 52% of patients, was mainly manifested by mild disorders. In the group of patients with BS, the mean scores were higher on the GAD-7, PHQ-9, fear of negative assessment (p<0.001) and LSAS (p<0.05) than in the control group. After treatment with BT, the levels of anxiety and depression in patients with BS decreased slightly and remained higher compared with the control group. Psychiatric examination in the majority (64%) of patients revealed mental disorders that could not be explained by the occurrence of BS. The remaining 36% of patients had adaptation disorders (nosogenic reactions) caused by BS. Affective mental pathology (recurrent depressive disorder and dysthymia) and anxiety disorders (social phobia and adjustment disorders) were more often observed in the main study group compared with the control group (24% versus 5% and 68% versus 10%, respectively). CONCLUSION: A significant proportion of patients with BS have anxiety and depressive disorders, the severity of which does not depend only on the severity of motor symptoms and does not significantly decrease after successful BT, but is caused by mental disorders that preceded the manifestation of BS. Identification of mental disorders to varying degrees associated with BS, not only on the basis of psychometric scales, but also consultation with a psychiatrist, will allow, in addition to the correction of motor symptoms of BS, to differentiate the therapeutic approach through psychotherapy and psychopharmacotherapy.

[The factors impact on the urgent daytime sleepiness degree in the Parkinson's disease]. / Faktory, vliyayushchie na stepen' imperativnosti dnevnykh zasypanii pri bolezni Parkinsona.

One of the main manifestations of excessive daytime sleepiness (EDS) among patients with Parkinson's disease is sudden-onset sleep (SOS). The SOS episodes could dramatically increase the traumatic ratio among those patients. The factors of SOS among PD patients are not well understood. OBJECTIVE: Describe the clinical and physiological features of patients with different types of SOS for detection of influencing factors of urgent EDS. MATERIAL AND METHODS: 32 patients SOS positive (17 female) were included. The median age was 66.5±7.8; the median PD duration was 9.2±4.3 years (2.66±0.5 Hoehn-Yahr). The patients received the levodopa - dopamine receptors agonist combined medications. Moreover, the Unified Parkinson's disease rating scale (UPDRS parts II, III in an «on¼ state of dopaminergic medication), the diary of the assessment of the waking period, the Epworth Sleepiness Scale, the Parkinson Disease Sleep Scale I (PDSS I), the Scales for Outcomes of Parkinson's disease-Cognition (SCOPA-Cog), the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Apathy Scale, the Stroop test, objective sleep-wake assessment: standard nocturnal video-polysomnography (PSG), multiple sleep latency tests (MSLT) were used. Besides, we compare patients' clinical and neuropsychological characteristics (especially EDS sense) before the SOS. RESULTS: 36% of patients describe the SOS without preexisting sleepiness (group 1). The short-time period of sleepiness notes approximately 64% SOS patients before the sleeping period (group 2). Group 1 has the less prominent activity of daily living compared to group 2. Moreover, group 1 patients have significantly lower subjective and objective severity of night sleep disorders (higher total score value of SOS BP, longer 3rd stage of sleep duration), lesser severity of the Epworth and apathy scale (p<0.05). The group 2 patients with a low ability to resist the onset of SOS (less than 5 minutes) differed from patients with greater resistance. Firstly, by a greater degree of disturbances in daily activities (ASOBP, section 2), shorter latent periods 1, 3 stages, shorter duration of 1 stage of night sleep; more prominent anxiety, depression and impaired attention (p<0.05). The narcoleptic-like falling asleep syndrome was diagnosed in 9 (28%) cases with SOS, without significant difference between the groups. CONCLUSION: SOS among patients without EDS are an independent manifestation of PD. The degree of SOS urgency is affected by the severity of the activity of daily living, anxiety, depression, and attention disorders.

[Development of early diagnosis of Parkinson's disease and comprehensive economic analysis of the effect of its implementation]. / Razrabotka rannei diagnostiki bolezni Parkinsona i kompleksnyi ekonomicheskii analiz effekta ot ee vnedreniya.

The paper summarizes the literature and author's data on the development of early (preclinical) diagnosis of Parkinson's disease (PD). Implementation of this diagnosis will promote the use of preventive therapy and change investments in diagnosis and treatment of patients. The paper declares that at present the only approach to early diagnosis of PD is positron-emission tomography of the nigrostriatal dopaminergic system, but it cannot be used for preventive examination due to its high cost. The authors consider that a less specific, but more promising approach to the development of early diagnosis of PD is the search for markers in body fluids, mainly in the blood, in patients at the prodromal stage of PD. Indeed, a number of markers as changes in the level of metabolites of monoamines, sphingolipids, urates, and indicators of oxidative stress were found in patients selected for the risk group of the prodromal stage of PD, according to characteristic premotor symptoms. In addition, it is assumed that the search for blood markers at an earlier - pre-prodromal stage is possible only in animal models of PD at the early preclinical stage. This approach can also be used to verify blood markers identified in patients at the clinical stage of PD. It is also evident that the complex socio-economic factors influencing the incidence of PD is different in developed versus developing countries. The societal and medical costs of Parkinson's are huge and efforts to improve early preclinical diagnosis of PD will lead to considerable economical and societal benefits. For instance this will allow efficient selection of patients for preclinical diagnostic tests. To assess the effectiveness of this strategy considering the uncertainty of socio-economic issues, a modification of the «cost-utility¼ analysis is proposed. For the first time, a Markov model of PD including preclinical diagnostic tests and possible neuroprotective therapy was developed and studied. Analytical outcomes of this process suggest that the idea of developing a new multimodal strategy is promising from a socio-economic point of view.

Molecular Mechanisms and Clinical Manifestations of Catecholamine Dysfunction in the Eye in Parkinson's Disease As a Basis for Developing Early Diagnosis.

This review provides information on the non-motor peripheral manifestations of Parkinson's disease (PD) associated with a pathology of the visual analyzer and the auxiliary apparatus of the eye. The relationship between neurodegenerative processes that take place in the brain and in the eye opens new prospects to use preventive ophthalmologic examination to diagnose PD long before the characteristic motor symptoms appear. This will encourage the use of neuroprotective therapy, which stops, or at least slows down, neuronal death, instead of the current replacement therapy with dopamine agonists. An important result of an eye examination of patients with PD may be a non-invasive identification of new peripheral biomarkers manifesting themselves as changes in the composition of the lacrimal fluid.

[Development of early diagnosis of Parkinson's disease based on the search for biomarkers such as premotor symptoms and changes in blood]. / Razrabotka rannei diagnostiki bolezni Parkinsona na osnove biomarkerov v vide premotornykh simptomov i izmenenii v krovi.

OBJECTIVE: To determine changes in the chemical composition of blood plasma in subjects at risk of Parkinson's disease (PD) at the prodromal stage compared with age control. MATERIAL AND METHODS: Subjects at risk were selected for the presence of characteristic premotor symptoms, including impairments of sleep, olfaction and constipation.The risk group included 12 people, the control group - 8 people. RESULTS: Among seven catecholamines and their metabolites detected in the blood, only the concentration of L-dioxiphenylalanine (L-DOPA) changed (decreased) in subjects at risk compared with the control. A decrease in the concentration of L-DOPA is considered as a manifestation (marker) of selective degeneration of central and peripheral catecholaminergic neurons in PD. In contrast to L-DOPA, the concentration of seven of the twelve detected sphingomyelins in the blood of the subjects at risk increased. Given that a change in the metabolism of sphingomyelins is associated with processes such as apoptosis, autophagy, and synucleinopathy, an increase in their concentration in the blood of patients at risk is considered as a manifestation of systemic general degeneration of central and peripheral neurons. Finally, in the blood of subjects at risk, we found a trend towards a decrease in the concentration of urates, which are endogenous neuroprotectors. CONCLUSION: The changes in the level of L-DOPA, sphingmyelins and urates in the blood of subjects at risk may serve as diagnostic markers of PD at the prodromal stage.

Tear Fluid Catecholamines As Biomarkers of the Parkinson's Disease: A Clinical and Experimental Study.

An important approach to an early diagnosis of Parkinson's disease (PD) is screening for peripheral biomarkers in patients at the early clinical stage. In this study, we evaluated catecholamine concentration changes in the tear fluid of untreated PD patients as biomarkers. Norepinephrine and dopamine concentrations in the tear fluid of patients were found to increase compared to those in age controls, which was especially pronounced on the side where motor symptoms appeared. On the contrary, the epinephrine concentration in the tear fluid of patients was reduced bilaterally. Since there was no reason to consider the markers found in the clinical stage of PD as markers of the preclinical stage, we additionally studied the tear fluid composition in mouse neurotoxic models of PD preclinical and clinical stages. The norepinephrine concentration in the tear fluid of mice from the clinical stage model was found to be higher than that in controls; in the preclinical stage model, the norepinephrine concentration had a tendency to increase. Therefore, both PD patients and mice from PD preclinical and clinical stage models manifest unidirectional changes in their tear fluid compositions, which may be considered as promising biomarkers for the development of early diagnosis.

[Non-motor disorders in patients with muscular dystonia]. / Nedvigatel'nye narusheniia u patsientov s myshechnoi distoniei.

Non-motor disturbances represented by sensory, affective, obsessive-compulsive disorders, cognitive dysfunction, sleep disturbances are often found in patients with dystonia and have a negative impact on their quality of life. The prevalence of sensory and affective disorders and sleep disturbances is above 50% in patients with cervical dystonia and is 25% in patients with blepharospasm, writing spasm; cognitive dysfunction is found in more than 25% of patients with focal dystonia. The relationship of non-motor, in particular psychiatric disorders, with the impairment of social and everyday life and worsening of quality of life in whole was shown. Common pathophysiological mechanisms of non-motor disorders as well as approaches to treatment of these disorders are discussed. The authors present the results on the positive effect of botulinum toxin therapy that reduces cognitive dysfunction, sensory disorders and depressive syndrome. Non-medication treatment of non-motor disorders in patients with dystonia is considered.

[Syndrome of rapid eye movement sleep behavior disorder and nocturia in Parkinson's disease]. / Sindrom narusheniia povedeniia v faze sna s bystrymi dvizheniiami glaz i nikturiia pri bolezni Parkinsona.

AIM: Parasomnia, a syndrome of rapid eye movement sleep behavior disorder (RBD), is a common non-motor impairment in patients with Parkinson's disease (PD). The relationship between RBD with other symptoms of PD affecting night sleep, in particular, nocturia, is understudied. An aim of the study was to determine the symptoms related to night sleep disturbances in PD patients with RBD and assess the dynamics of these disturbances with the disease progression taking into account RBD onset. MATERIAL AND METHODS: One hundred and forty patients (72 male and 68 female) with PD without dementia (mean age 61.98±0.79 years, PD stage - 2.35±0.05, duration 5.82±90.65 years) were examined. Motor disorders were assessed with the unified Parkinson's disease rating scale (UPDRS), sleep disturbances and frequent night urinations were evaluated with the Parkinson's Disease Sleep Scale (PDSS). The diagnosis of probable RBD was based on reports of patients or their relatives on the dream-related motor activity and vocalization. Quality-of-life was evaluated with the Parkinson's Disease Questionnaire (PDQ-39). Patients were followed up after 2.5 years. RESULTS: Probable RBD was diagnosed in 46.43% of patients, including 30.77%, who developed the syndrome before the manifestation of motor symptoms, 16.92% patients with simultaneous development of RBD and motor symptoms and 52.31% with RBD development >2 years after motor disorders. Patients with RBD differed from those without parasomnia by the higher severity of nocturia. After 2.5 years of follow-up, the severity of disease was greater in patients with RBD assessed by UPDRS, quality-of-life indices, severity of nocturia and episodes of nocturia. The highest frequency of episodes of nocturia was noted in patients with early onset of RBD before the manifestation of motor symptoms. CONCLUSION: RBD in patients with PD is associated with the rapid progress of nocturia, higher degree of worsening of daily activities and deterioration of quality of life. The relationship between RBD and progression of nighttime urination suggests common pathophysiological mechanisms of their development, which include the structural changes in the brain stem nuclei. The diagnosis of RBD is one of the markers of spreading of neurodegenerative pathology into the brain stem that resulted in the unfavorable disease course.

[REM-sleep behavior disorder and sleepwalking in a patient with Parkinson's disease and essential tremor]. / Rasstroistvo povedeniia v faze bystrogo sna i snokhozhdenie u patsienta s nachal'noi bolezn'iu Parkinsona i éssentsial'nym tremorom.

REM-sleep behavior disorder (RBD), a form of parasomnia, is characterized by motor and/or speech activity during sleep corresponding to the dream content. RBD is currently considered as a marker of onset of neurodegenerative diseases (sinucleinopathies) and as a most specific early symptom of Parkinson's disease (PD). The authors describe a clinical case of a patient with the combination of essential tremor, initial signs of PD and RBD. A polysomnographic study has confirmed clinical signs of RBD and determined the disturbances of sleep architecture: the increase in falling asleep, number of awakenings, wakefulness during sleep, the absence of deep slow-wave sleep. The particular features of the patient were essential tremor and sleep walking.

[Optimal time for beginning treatment with levodopa].

Because an optimal time for beginning treatment with levodopa is not clarified so far, an aim of the study was to specify key risk factors for the development of motor fluctuations and dyskinesias and to study correlations between their manifestation and time for beginning treatment with levodopa. Forty patients (mean age 57,86+/-8,02 years; mean illness duration 6,38+/-3,2 years) with Parkinson's disease (PD) with phenomenon of "dose exhaustion' were included. Spearman correlation analysis was used to assess correlations between the development of movement disorders and clinical features of PD. Effects of different variables on fluctuations and dyskinesias were calculated using discrimination analysis. If the treatment with levodopa was started during the first four years after disease onset, the phenomenon of "dose exhaustion' developed on average after 4,6+/-2,4 years. In case of beginning the treatment during five and more years after PD onset, signs of motor fluctuations manifested after 2,26+/-1,56 years (p< or =0,05). The stage of disease predicted the development of motor fluctuations, while the daily dose of levodopa and stage of disease predicted the development of dyskinesias. It has been concluded, that disease severity and its impact on daily activities of a patient, but not potential risk of fluctuations and dyskinesias, should be first of all taken into account in the choice of therapeutic tactics.

[Effects of the dopamine agonist mirapex (pramipexole) therapy on sleep disorders in Parkinson's disease].

Disorders of initiation and maintenance of sleep (DIMS), excessive daytime sleepiness (EDS) are common and clinically significant in patients with Parkinson's disease (PD). The aim of the study was the evaluation of the effects of the dopamine agonist pramipexole on DIMS and EDS in PD. Sixty-seven patients with PD (mean age 63.2+/-9.9 years old, mean illness duration 6.5+/-4.2 years) were enrolled in the study. Forty patients received pramipexole as add-on to the other antiparkinsonian medications in mean daily dosage 2.64+/-0.6 mg. Clinical symptoms were assessed using the UPDRS, the PDSS, the PSO, the ESS, the Beck Depression Inventory (BDI), the Spielberger's State Anxiety Inventory, the SCOPA-Cog, the PDQ-39. The most common sleep complaints were sleep fragmentation and early awakening. DIMS, EDS were the main factors which negatively influenced the overall quality of sleep. The administration of pramipexole significantly improved the overall quality of sleep, decreased sleep initiation difficulties and sleep fragmentation, night and early morning dystonia, early morning tremor; restlessness, troublesome sensations in extremities, nocturia. We speculate that the effects of therapy on DIMS are caused by the decrease of nocturnal PD motor (hypokinesia, dystonia, tremor) and nonmotor (nocturia, sensor disturbances) symptoms; 15% of patients had moderate ESS in the early treatment period.

[Fatigability in Parkinson's disease].

Forty-five patients with Parkinson's disease (PD) without dementia were studied. Duration of disease was 6,02+/-3,47 years. The following scales were used: PFS-16, UPDRS part 2, the Beck Depression Scale, PDSS and the Epworth Sleepiness Scale. Fatigability is thought to be one of three presentations of PD that restrict daily activities in 64% of patients. The integrated assessment of fatigability was significantly correlated with the total depression score and PDSS scores. The treatment with mirapex resulted in the reduction of fatigability that was not correlated with changes in motor functioning, depression, sleep disorders. Fatigability is a symptom that significantly disturbs daily activities of patients. The author suggests that fatigability is more associated with nervous and psychiatric symptoms than with a severity of movement disorders. The lack of significant association between dynamics of fatigability and changes in other parameters of nervous and psychiatric functions during the therapy plausibly implies the separate genesis of this symptom.

[Mirapex (pramipexole) in the treatment of non-motor disturbances in Parkinson's disease].

The effect of the dopamine receptor antagonist mirapex on emotional disorders (anxiety, depression), cognitive disturbances and sleep disorders has been studied in 66 patients with Parkinson's disease. Mirapex has been administered in addition to levodopa and other antiparkinsonian drugs in dosage 3,5+/-1,1 mg daily to 36 patients with emotional and cognitive disorders and in dosage 2,9+/-0,96 mg daily to 30 patients with sleep disorders. Patient's state has been assessed using a number of psychometric scales and neuropsychological tests. The effectiveness of Mirapex in all disorders studied has been shown.