ORTHOSTATIC INTOLERANCE AN EXPRESSION OF AUTONOMIC DISFUNCTION IN PARKINSON S DISEASE
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1 Rev. Med. Chir. Soc. Med. Nat., Iaşi 2014 vol. 118, no. 1 INTERNAL MEDICINE - PEDIATRICS ORIGINAL PAPERS ORTHOSTATIC INTOLERANCE AN EXPRESSION OF AUTONOMIC DISFUNCTION IN PARKINSON S DISEASE Emilia-Lidia Dumbravă (Chirilă) 1, Doina-Clementina Cojocaru 2,3, Paraschiva Postolache 2,3 University of Medicine and Pharmacy Carol Davila - Bucureşti Faculty of Medicine 1. Ph.D. student University of Medicine and Pharmacy Grigore T. Popa - Iaşi Faculty of Medicine 2.I st Medical Department Rehabilitation Clinical Hospital 3. Pulmonary Rehabilitation Clinic, Iaşi ORTHOSTATIC INTOLERANCE AN EXPRESSION OF AUTONOMIC DYSFUNCTION IN PARKINSON S DISEASE (Abstract): Orthostatic intolerance syndrome is an important issue, having multiple etiologies and being the result of an inadequate response to changing in body position, namely the transition from supine to standing, a process that causes a series of responses regulated by the autonomic nervous system. Aim: The aim of this study was to create a profile of patients with Parkinson's disease and orthostatic hypotension, a form of orthostatic intolerance, identifying the risk factors for this condition. Material and methods: We conducted a study on 41 patients with Parkinson's disease selected from 200 consecutive patients with orthostatic hypotension, hospitalized in Cardiology Clinic of Colentina Clinic Hospital which met the diagnosis criteria for orthostatic hypotension. In order to meet the inclusion criteria, all patients were evaluated according to a preset protocol: medical history, clinical and paraclinical examination, including neuro-psychiatric assessment and the orthostatic tolerance test. Results and discussion: The decline in standing blood pressure was related to the presence of hypotensive neurological drugs, especially Levodopa, in chronic treatment, but it was not influenced by age or cardiovascular co morbidities. There is an improvement in blood pressure both in supine and upright position at discharge when compared to admission values. Conclusion: The degree of decrease in the standing blood pressure values was correlated with the presence of potentially hypotensive neurological drugs, particularly Levodopa treatment, with a favorable effect of administration of non-pharmacological treatment and changes made in chronic neurological treatment. Keywords: ORTHOSTATIC HYPOTENSION, ORTHOS- TATIC TOLERANCE TEST, PARKINSON S DISEASE. Orthostatic intolerance syndrome is an important issue, having multiple etiologies and being located on the border of several medical specialties, as diagnosis and treatment. After essential arterial hypertension, orthostatic hypotension is the most common disorder of blood pressure regulation in adults aged over 65 years, with prevalence between 5 and 30%, depending on the studied population and the used definition. 75
2 Emilia-Lidia Dumbravă (Chirilă) et al. Prospective studies have shown that orthostatic hypotension is a predictive factor for ischemic stroke and all-cause mortality in elderly people (1-3). This condition is one of the least understood manifestations of autonomic dysfunction, being the result of an inadequate response to changing in body position, namely the transition from supine to standing, a process that causes a series of responses regulated by the autonomic nervous system. The term autonomic dysfunction refers to any dysfunction of the autonomic nervous system - central, peripheral or secondary to other conditions (1,2). There are two types of autonomic dysfunction- acute and chronic form. Chronic form can be divided into primary and secondary, the last one being more common. However, when failure dominates the clinical picture and a clear cause is not obvious, it is called primary dysautonomia. Primary dysautonomia, in its turn, can be divided into four syndromes: isolated pure dysautonomia, systemic nerve atrophy, Parkinson's disease with autonomic dysfunction (3) and Lewy body dementia, while secondary autonomic dysfunction, involving autonomous damage and disease makes its debut in the context of diabetes mellitus, amyloidosis or various polyneuropathies (4-6). While primary and secondary autonomic dysfunctions are caused by structural damages of the autonomic nervous system (either central or peripheral), druginduced orthostatic hypotension is about functional impairment. The clinical aspects that suggest the diagnosis at initial assessment are represented by the onset of the symptoms (dizziness, syncope) after switching from supine to standing, possibly after prolonged immobilization and the existence of a temporal relationship between the onset and a change in dosage of potentially hypotensive drugs, parkinsonism, presence of autonomic neuropathy or hypovolemia. Effective treatment of orthostatic intolerance can be a challenge. The main therapeutic target consists of improving the symptoms in the transition from supine to standing position and functional status of the patient while reducing the risk of falls and syncope, being less oriented to strictly normalize the blood pressure levels. MATERIAL AND METHODS We conducted a study on 200 consecutive patients hospitalized in Cardiology Clinic of Colentina Clinic Hospital which met the diagnosis criteria for orthostatic hypotension as mentioned in the syncope guide of the European Society of Cardiology: a symptomatic reduction of the systolic blood pressure from baseline values with more than or equal to 20 mmhg or/and of the diastolic blood pressure with more than or equal to 10 mmhg, or a systolic pressure-lowering below 90 mmhg (3,5). To determine the blood pressure we used the active method (active standing), the orthostatic tolerance test being performed both on admission and at discharge, by measuring blood pressure and heart rate initially supine, then standing at 1, 3 and 5 minutes after changing position (4). In order to meet the inclusion criteria, all patients were evaluated according to a preset protocol: medical history, clinical and paraclinical examination, including neuro-psychiatric assessment. All the patients with Parkinson's disease were further selected in order to create a profile of these patients and to identify the risk factors for orthostatic hypotension. These neurological patients were investigated before and after non-pharmacological treatment, assessment and adjustment of the current drugs. 76
3 Orthostatic intolerance an expression of autonomic dysfunction in Parkinson s disease Statistical analyze was done using the Microsoft Excel 2007 and SPSS for Windows programs. RESULTS The larger selection group diagnosed with orthostatic intolerance (n= 200 patients) consists of 107 women and 93 men. The Parkinson s disease study group included 41 patients, the gender distribution showing a slightly higher percentage of male patients (18 men vs 13 women), representing 19.35% of total male patients and 12.15% of females (fig. 1). The mean age of neurological patients was years (64-86 years). Fig. 1. The frequency of patients depending on the presence of Parkinson's disease All the 41 Parkinson s disease patients were treated with neurological drugs, ten patients receiving also psychiatric medication, Levodopa being the most used agent in combined therapy (tab. I). Average supine blood pressure on admission was 129/75 mmhg versus 127/72 mmhg at discharge (p=0.265) (fig. 2), while the lowest of standing blood pressure values at admission was 75/40 mmhg and at discharge was reaching 90/60 mmhg (p<0.001) (fig. 3). TABLE I The distribution of cases according to the neurologicaltreatment Medication Number of cases Seligelinum 1 Amantadinum 1 Biperiden 1 Acidumvalproicum 1 Carbamazepinum 1 Rasagiline&Ropinirole 1 Amantadinum&Seligelinum 2 Fenobarbitalum&Carbamazepinum 1 Levodopa+benserazide 18 77
4 Emilia-Lidia Dumbravă (Chirilă) et al. Medication Number of cases Seligelinum&Levodopa+benserazide 4 Ropinirole&Levodopa+benserazide 1 Rasagiline&Levodopa+benserazide 1 Pramipexole&Levodopa+benserazide 1 Amantadinum&Levodopa+benserazide 1 Ropinirole& Levodopa &Carbidopa 1 Donepezile&Acidumvalproicum& Memantine&Levodopa+benserazide 1 Amantadinum&Levodopa&Carbidopa 1 Levodopa&Carbidopa&Amantadinum&Pramipexole 1 Levodopa&Carbidopa&Memantine&Pramipexole 1 Levodopa&Carbidopa&Entacapone&Amantadinum&Pramipexole 1 Total 41 Fig. 2. Average supine blood pressure values Fig. 3. Minimum of standing blood pressure values 78
5 Orthostatic intolerance an expression of autonomic dysfunction in Parkinson s disease Orthostatic tolerance test on admission revealed an average of 109/65 mmhg compared to 122/69 mmhg at discharge (p=0.007) (fig. 4). Fig. 4. Average of standing blood pressure values There was no significant difference between the mean age of patients with orthostatic hypotension and those with negative tolerance test at the time of discharge (p= 0.929). Patients with persistent orthostatic hypotension at discharge had a prevalent cardiovascular history, compared to their counterparts without orthostatic hypotension, but the difference did not reach the statistical significance (p= 0.789). All the patients received non-pharmacological treatment and 10% were treated with vasopressor agent Midodrine. Neurological medication is influencing the maintenance of orthostatic hypotension at discharge (p < 0.05), Levodopa having the most significant hypotensive effect (p < 0.001). DISCUSSION We used the analysis of postural changes in blood pressure values in order to find responsible modifiable factors that influence this type of pathology and to determine the frequencies for the studied group. It is known that in Parkinson's disease, the prevalence of orthostatic hypotension is between 43 % and 58 % and may reach up to 60 % in some studies (7). Two factors could explain this high prevalence: first, dopaminergic drugs that may induce or aggravate orthostatic hypotension, and, second, Parkinson's disease dysautonomia (8, 9). Our Parkinson s disease study group had a relatively homogenous gender distribution and a high mean value of age (76.41 years) which probably contribute to orthostatic hypotension. Also, the degree of decrease in the standing blood pressure values was correlated with the presence of potentially hypotensive neurological drugs, Levodopa being the most powerful contributor to this phenomenon, these findings being supported by several previous studies (7). Age and cardiovascular co morbidities were not influential over the presence of orthostatic intolerance, as we would have expected, but we had not perform a detailed analyze of these cardiovascular diseases and their hemodynamic effects. Despite these facts, the results showed a significant improvement of blood pressure values in both supine and upright position 79
6 Emilia-Lidia Dumbravă (Chirilă) et al. at discharge, compared to values determined on admission, for these neurological patients. This favorable outcome is even more relevant as it could not be explained by the use of vasopressors, as long as only 10% of patients were receiving Midodrine. The reasonable explanation for the improvements in blood pressure values both in supine and upright position at discharge, when compared to the values measured on admission, remains the adjustment of concomitant hypotensive medication and the association of non-pharmacological treatment, which were performed in all patients. CONCLUSIONS The results indicate that the degree of decrease in the standing blood pressure values was correlated with the presence of potentially hypotensive neurological drugs, particularly Levodopa-associating treatment. Our research also revealed that the administration of non-pharmacological treatment and changes made in chronic neurological treatment explain the favorable response to orthostatic tolerance test at discharge when compared with admission. We suggest that he management of orthostatic hypotension in patients with Parkinson's disease should always start with patient education, identification and, if possible, a change of the potential hypotensive neurologic therapy. ACKNOWLEDGEMENTS This study was financially supported by the project FEST "European Funding for Doctoral Studies" implemented by the "Carol Davila" University of Medicine and Pharmacy Bucharest-contract number POSDRU/88/1.5/S/ REFERENCES 1. Braunwald E, Bonow R, Mann D et al. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition, Philadelphia: Elsevier Saunders, The Consensus Comittee of the American Autonomic Society and the American Academy of Neurology.Consensus statement on the definition of orthostatic hypertension, pure autonomic failure and multiple system atrophy. Neurol 1996; 46: Goldstein DS. Cardiovascular aspects of Parkinson disease. J Neural Trans 2006; 70: Moya A, Sutton R, Ammirati F. et al. Guidelines for the diagnosis and management of syncope. Eur Heart J 2009; 30: Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neuro 2006; 13: Shibao C, Lipsitz LA, Biaggioni I. ASH Position Paper: Evaluation and Treatment of Orthostatic Hypotension. J Clin Hypertens 2013; 15: Senard JM, Rai S, Lapeyre-Mestre M, et al. Prevalence of orthostatic hypotension in Parkinson s disease. J Neurol Neurosurg Psychiatry 1997; 63: Fedorowski A, Stavenow L, Hedblad B et al. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project). Eur Heart J 2010; 31: Senard JM, Brefel-Courbon C, Rascol O, Montastruc JL Orthostatic hypotension in patients with Parkinson's disease: pathophysiology and management. Drugs Aging 2001; 18:
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