Efficiency of long-term vinpocetine administration in the treatment of dizziness and associated statodynamic disorders in patients with chronic cerebrovascular insufficiency (EDELWEISS study)

Complaints of dizziness are common in patients diagnosed with chronic cerebrovascular insufficiency (CCVI). Effective therapy of these patients is one of the most urgent problems of outpatient neurological practice.

Objective: to evaluate the efficiency and safety of long-term administration of vinpocetine (Cavinton Comforte) in the treatment of dizziness in patients with CCVI.

Patients and methods. A total of 139 patients took part in an open-label parallel-group clinical study. Vinpocetine (Cavinton Comforte) and vestibular exercises were prescribed in Group 1 (n=69); vestibular exercises were used in Group 2 (n=70). The efficiency of treatment was evaluated using a visual analog scale (VAS) in assessing vertigo and dizziness, the Dizziness Handicap Inventory (DHI), the Drug Attitude Inventory (DAI), the Montreal Cognitive Assessment (MoCA), the 5-point Likert scale, and videonystagmographic tests. Plasma brain-derived neurotrophic factor (BDNF) concentrations were analyzed before and after treatment. The total duration of the investigation was 8 months (6 months of therapy and 2 months of follow-up after therapy discontinuation).

Results and discussion. The administration of vinpocetine significantly decreased the subjective intensity of vertigo and dizziness (on the VAS) and improved daily activities in patients (on the DHI) and a number of parameters according to the video nystagmographic tests: pursuit and saccadic eye movement tests. According to the DNI scores, the improvement changes in the patients' condition significantly correlated with increased plasma BDNF expression throughout the follow-up (Pearson's correlation coefficient>0.5). The use of vinpocetine could improve cognitive functions (on the MoCA and the 5-point Likert scale) and increase patient adherence to the therapy performed (on the DAI). The clinically significant effect in improving the statodynamic function was shown by vinpocetine at 2 months of its administration and was highest at 5 months; there was a significant improvement in cognitive function at 6 months. The long-term use of vinpocetine was not associated with the risk of serious adverse events.

Conclusion. The findings allow vinpocetine to be recommended for long-term (at least 5 months) treatment of vertigo, dizziness, and cognitive impairment in patients with CCVI, in this case, the clinical effect is achieved through stimulating neuroplasticity, inducing BDNF synthesis in particular.

1. Barin K, Dodson EE. Dizziness in the elderly. Otolaryngol Clin North Am. 2011 Apr;44(2): 437-54, x. doi: 10.1016/j.otc.2011.01.013.

2. Ekvall Hansson E, Magnusson M. Vestibular asymmetry predicts falls among elderly patients with multi-sensory dizziness. BMC Geriatr. 2013 Jul 22;13:77. doi: 10.1186/1471-2318-13-77.

3. Vaz Garcia F. Disequilibrium and its management in elderly patients. Int Tinnitus J. 2009; 15(1):83-90.

4. Mueller M, Strobl R, Jahn K, et al. Burden of disability attributable to vertigo and dizziness in the aged: results from the KORA-Age study. Eur J Public Health. 2014 Oct;24(5):802-7. doi: 10.1093/eurpub/ckt171. Epub 2013 Nov 8.

5. Parfenov VA, Zamergrad MV. Dizziness in neurological practice. Nevrologicheskii zhurnal. 2005;(1):4-12. (In Russ.)

6. Parfenov VA, Neverovskii DV. Outpatient management of patients with dyscirculatory encephalopathy. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2015;7(1): 37-42. (In Russ.). doi: 10.14412/2074-2711-2015-1-37-42

7. Antonenko LM. Neurological aspects of diagnosis and rehabilitation of patients with dizziness and instability. Autoref. dis. doct. med. sci. Moscow; 2018. 48 p.

8. Zakharov VV, Vakhnina NV. Differential diagnosis and treatment of cognitive impairment. Russkii meditsinskii zhurnal. 2013;21(10):518-23. (In Russ.)

9. Baezner H, Blahak C, Poggesi A, et al. Association of gait and balance disorders with age-related white matter changes. The LADIS study. Neurology. 2008 Mar 18;70(12):935-42. doi: 10.1212/01.wnl.0000305959.46197.e6.

10. Belova LA. Venous cerebral discirculation in chronic brain ischemia: clinic, diagnosis, treatment. Nevrologicheskii vestnik. 2010;XLII(2): 62-7. (In Russ.)

11. Guskiewicz KM, McCrea M, Marshall SW, et al. Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA Concussion Study. JAMA. 2003 Nov 19;290(19):2549-55.

12. Iverson GL, Gaetz M, Lovell MR, Collins MW. Cumulative effects of concussion in amateur athletes. Brain Inj. 2004 May;18(5): 433-43.

13. Li C, Layman AJ, Geary R, et al. Epidemiology of vestibulo-ocular reflex function: data from the Baltimore longitudinal study of aging. Otol Neurotol. 2015 Feb;36(2):267-72. doi: 10.1097/MAO.0000000000000610.

14. Rasmussen K, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018 Nov;17(11):1016- 1024. doi: 10.1016/S1474-4422(18)30318-1.

15. Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015 Aug 5;35(31):11034-44. doi: 10.1523/JNEUROSCI.1625-15.2015.

16. Zhivolupov SA, Samartsev IN, Yakovlev EV, et al. The effectiveness of Vinpocetine (Cavinton Comfort) in the treatment of dizziness in patients with dyscirculatory encephalopathy and its effect on the concentration of brain neurotrophic factor (BDNF) in plasma. Klinicheskaya farmakologiya i terapiya. 2016;(1):48-53. (In Russ.)

17. Bittar RS, Pedalini ME, Lorenzi MC, Formigoni LG. Treating vertigo with vestibular rehabilitation: results in 155 patients. Rev Laryngol Otol Rhinol (Bord). 2002;123(1):61-5.

18. Liu C, Miller BI, Cummings JL, et al. A quantitative study of vascular dementia. Neurology. 1992 Jan;42(1):138-43.

19. Yunkerov VI, Grigor'ev SG. Matematiko-statisticheskaya obrabotka dannykh meditsinskikh issledovanii [Mathematical and statistical processing of medical research data]. Saint-Petersburg: VMedA; 2005. 292 p.

20. Altman DG. Practical statistics for medical research. London: Chapman and Hall; 1991. 263 p.

21. Mahlknecht P, Kiechl S, Bloem BR, et al. Prevalence and burden of gait disorders in elderly men and women aged 60-97 years: a population-based study. PLoS One. 2013 Jul 24;8(7): e69627. doi: 10.1371/journal.pone.0069627. Print 2013.

22. Pinter D, Ritchie SJ, Doubal F, et al. Impact of small vessel disease in the brain on gait and balance. Sci Rep. 2017 Jan 30;7:41637. doi: 10.1038/srep41637.

23. Zamergrad MV. Age aspects of diagnosis and treatment of dizziness. Autoref. dis. doct. med. sci. Moscow; 2015. 48 p.

24. Woollacott M, Shumway-Cook A. Attention and the control of posture and gait: a review of an emerging area of reaserch. Gait Posture. 2002 Aug;16(1):1-14.

25. Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013 Jan;14(1):7-23. doi: 10.1038/nrn3379.

26. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009 Jun;5(6):311-22. doi: 10.1038/nrneurol.2009.54.

27. Robinson RC, Radziejewski C, Stuart DL, Jones EY. Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. Biochemistry. 1995 Apr 4;34(13):4139-46.

28. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996 Nov 29;274(5292): 1527-31.

29. Litvinenko IV. Bolezn' Parkinsona [Parkinson's disease]. Moscow: Miklosh; 2006. 216 p.

30. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995 Mar;15(3 Pt 1):1768-77.

31. Seferlisa F, Chimonaa T, Papadakisa C, et al. Age related changes in ocular motor testing in healthy subjects. J Vestib Res. 2015;25(2):57-66. doi: 10.3233/VES-150548.

32. Shepard N, Schubert M. Background and technique of ocular motility testing. In: Jacobson G, Shepard N, editors. Balance function assessment and management. San Diego: Plural; 2008. P. 133-46.

33. Spooner J, Sakala S, Baloh R. Effect of aging on eye tracking. Arch Neurol. 1980 Sep; 37(9):575-6.

34. Warabi T, Kase M, Kato T. Effect of aging on the accuracy of visually guided saccadic eye movement. Ann Neurol. 1984 Oct;16(4):449-54.

35. Abel LA, Troost BT, Dell’Osso LF. The effects of age on normal saccadic characteristics and their variability. Vision Res. 1983;23(1):33-7.

36. Wilson SJ, Glue P, Ball D, Nutt DJ. Saccadic eye movement parameters in normal subjects. Electroencephalogr Clin Neurophysiol. 1993 Jan;86(1):69-74.

37. Muszbek N, Brixner A, Benedict A, et al. The economic consequences of noncompliance in cardiovascular disease and related conditions: a literature review. Int J Clin Pract. 2008 Feb; 62(2):338-51. doi: 10.1111/j.1742-1241.2007.01683.x.

38. Tabeeva GR, Kalimeeva EYu, Koberskaya NN, Gereeva SI. Possibilities of therapy for early manifestations of chronic cerebral ischemia: results of the PROFILE program. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2017;9(3): 36-41. (In Russ.). doi: 10.14412/2074-2711-2017-3-36-41

39. Vakhnina NV, Milovanova OV. Neurological disorders in patients with hypertension and their correction. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2016;8(4):32-7. (In Russ.). doi: 10.14412/2074-2711-2016-4-32-37

40. Shavlovskaya OA, Lokshina AB, Grishina DA. Cavinton comforte in correcting cognitive impairment in chronic brain ischemia. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018;118(8):61-5. (In Russ.).

41. Mannia L, Nikolova V, Vyagova D, et al. Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. Int J Cardiol. 2005 Jun 22;102(1):169-71.

42. Pikula A, Beiser AS, Chen TC, et al. Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham study. Stroke. 2013 Oct;44(10): 2768-75. doi: 10.1161/STROKEAHA.113.001447. Epub 2013 Aug 8.

43. Norton S, Matthews F, BarnesD, et al. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014 Aug;13(8):788-94. doi: 10.1016/S1474-4422(14)70136-X.

44. Gallaway PJ, Miyake H, Buchowski MS, et al. Physical Activity: A Viable Way to Reduce the Risks of Mild Cognitive Impairment, Alzheimer’s Disease, and Vascular Dementia in Older Adults. Brain Sci. 2017 Feb 20;7(2). pii: E22. doi: 10.3390/brainsci7020022.

45. Szatmari S, Whitehouse P. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev. 2003;(1):CD003119