Journal o/the ~\euroh)gicat S,'tet~ ,'~. !*i4 c P~') i ) ".?-
32
c 1991 Elsevier Science Publishers B'~ tll)22-:~!i)X:01 S~ik.!.,
JNS 03557
Orthostatic changes of cerebral blood flow velocity in patients with autonomic dysfunction M. Daffertshofer, R.R. Diehl, G.-U. Ziems and M. Hennerici Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim (F.R.G.)
(Received 30 October, 1990) (Revised, received 18 February, 1991) (Accepted 26 February, 1991)
Key words: Orthostasis; Autonomic regulation; Cerebrovascular flow measurements; Transcranial Doppler
Summary Simultaneous registrations of intracranial blood flow velocity parameters achieved by transcranial Doppler sonography and basic cardiovascular parameters were carried out during orthostatic changes in normal controls, diabetic patients and patients with pandysautonomia. Normal subjects had a rapid increase in heart rate at a constant blood pressure and a slight decrease in cerebral blood flow velocities associated with a mild increase of the pulsatility index (PI) after being tilted from a horizontal to a vertical position. Diabetics showed a fixed heart rate reflecting the disturbed autonomic innervation but only minor changes of cerebral blood flow velocity, which is similar to normal cerebrovascular autonomic regulation. Patients with pandysautonomia had a fixed heart rate associated with a decrease of systemic blood pressure but a failure of compensatory cerebral autoregulation to maintain normal flow velocity values after standing up. The results suggest that in diabetics cerebrovascular autonomic regulation is intact in contrast to cardiac autonomic function, while in patients with pandysautonomia both functions are disturbed. Criteria for the interpretation of autonomic regulatory mechanisms involved in cerebrovascular flow measurements are discussed.
Introduction Autonomic failure occurs both in diseases of the central and peripheral nervous system and may become clinically relevant if it leads to orthostatic dysregulation with a minor brain perfusion often resulting in drop attacks and syncope. Thorough descriptions exist on peripheral disorders of cardiovascular regulation, including autonomic failures in peripheral vascular innervation (Skinhoj 1972; Kontos et al. 1976; Low 1987), which lead to orthostatic dysregulation. On the other hand, only limited knowledge exists regarding cerebrovascular regulation (CR) in orthostatic failure causing, in the case of disturbance, an additional and more circumscribed distribution mismatch in brain perfusion (Gotoh et al. 1971; Skinhoj 1972; Caronna et al. 1973; Fitch et al. 1975). Brain perfusion, physiologically, is regulated independently from systemic circulation. Cerebral blood flow is kept constant throughout a wide range of systemic blood pressure ( 5 0 - 1 5 0 m m H g ) by cerebrovascular regulation Correspondence to: Prof. Dr. M. Hennerici, Neurologische Klinik der Universitflt Heidelberg, Klinikum Mannheim. Theodor Kutzer Ufer, D-6800 Mannheim, F.R.G.
mechanisms that are not totally understood but are definitely different from mechanisms in systemic autoregulation (Low 1987). In addition to the cerebrovascular autoregulation via the reflexive decreased tension of the arterial muscle cells due to diminished wall tension, the metabolic mediated reaction (local adenosine, pH, potassium) and the distribution dynamics (Berne et al. 1981) seem to be more important than in peripheral vascular regulation. Our knowledge about the role of the autonomic nervous system in human cerebral circulation is also limited. Animal experiments showed only a minor influence of the autonomic nervous system on CR. Total sympathectomy and therapeutic blockade of the stellatum had no influence on cerebrovascular resistance (EklOfet al. 1971 ; Fitch et al. 1975). On the other hand, clinical experience shows that patients with autonomic failure but systemic blood-pressure regulation within physiological ranges sometimes have orthostatic problems. Thus one could expect that CR may also be disturbed in these patients. Further evidence is provided for this hypothesis by studies measuring cerebral blood flow in patients with central neurogenic orthostatic hypotension showing a passive blood pressure dependent change on brain perfusion (Gotoh et al. 1971; Meyer et al. 1973). Former methods for measuring cerebral perfusion are
33 invasive, of poor time resolution and focus mainly on the arteriolar regulation mechanismus. In addition, functional position test set-ups were limited (Halsey 1989). With transcranial Doppler sonography, a method exists to register instantaneous flow velocities in real-time of the main intracranial arteries with an approximation of the volume flow as an indicator of changing brain perfusion (Aaslid et al. 1989; Kontos 1989). The possibility to monitor these wtlues over a longer period compensates for the lack of quantitative data acquisition (Brunh~51zl et al. 1986; Briebach ct al. 1988). Thc aim of the present study is to analyze the reaction ofintracranial flow during orthostatic conditions in patients with different disorders of the autonomic nervous system and to obtain some additional predictors about orthostatic induced syncope. Patients with two different types of autonomic disorder are therefore analyzed: Patients with diabetes mellitus induced autonomic neuropathy, only affecting postganglionic autonomic nerve fibres, as a model for peripheral neuropathy, divided into one subgroup with and another without a history of orthostatic syncope. Patients with pandysautonomia, which additionally affects preganglionic nerve fibres, were investigated as a model for a peripheral and central autonomic dysregulation.
Patients and methods Forty-five subjects (age 44.9 + 15.8) in total, 26 men (age 48 +_ 15.7) and 19women (age 39.4 + 15.9), were investigated. All had daily measured blood-pressure levels within a normal range in the ying position throughout the week before examination and had no arteriosclerotic lesions in extra- and intracranial Doppler test. 24 normal subjects (age 41.2 + 15.6), 15 men (age 44.8 _+ 15.9) and 9 women (age 30.3 + 9.4) without any signs or symptoms of autonomic neuropathy served as controls. 17 patients with diabetic neuropathy (age 50.7 + 16.3), 8 mcn (age 50.5 +_ 14.7) and 9 women (age 50.9 _+ 18,8) with a long history of diabetes, poor metabolic adjustment and a pathological heart rate variation measurement testing the parasympathetic branches of the autonomic nervous system and infrared pupillometry testing the sympathetic branches of the autonomic nervous system (Aminoff 1989: Skinhoj 1972; Kontos et al. 1976) were investigated. An initial group of 12patients (age 4 8 . 4 + 17.2), 7 m e n (age 49.4 +_ 16.1) and 5 women (age 54.4 + 15.9), reported no history' of orthostatic syncope. A second group of 5 patients, 1 man and 4 women (age 54.4 + 15.9), reported one or more syncope after standing up in their li)rmer course. Additionally, 4 patients with pandysautonomia due
FABLE 1 CLINICAl. CRITERIA FOR PATIENTS CLASSIFICATION Normal subiects
No history' of syncope No clinical signs of diabetes mellitus HBAI, and blood glucose levels with normal values Normal heart beat variation test Normal sensible skin response
Diabetic patients (without syncope)
Clinical signs of diabetics mellitus Insufficient diabetic therapy ( H b A ~ > 10%) No history of syncope Heartbeat variation diminished Pathological sensible skin response Pathological pupillometry Neuropathic ulcera Decreased nerve conduction velocity
Diabetic patients Iwith syncope)
,Additional to criteria above - history with syncopes
Patients with pandysautonomia
History with syncopes Paresis of internal eye muscles Decreased gastrointestinal motility Increased spinal fluid protein ( > 9 0 mg/dl) Heartbeat variation diminished Pathological sensible skin response Pathological pupillometry Decreased nerve conduction velocity F-wave failures
(obligate) (obligate) (obligate) (obligate) (obligate) (obligate) (t:actdtative) ( facuh ativc ) obligate)
(obligate) (obligate) (obligate) (obligate) (obligate) (obligate) (facultative) (facultative)
34 to a Guillain-Barr6 syndrome (Young et al. 1969), 3 men and l woman (age 64.5 + 6.4), having a severe orthostatic dysregulation with multiple syncopes in their history and pathological results both in the sensible skin response and the heart rate variation test were studied. Clinical selection criteria for the three groups of patients were summarized in Table 1. Heart rate, blood pressure and intracranial flow velocity of the middle cerebral artery (MCA) measured by transcranial Doppler sonography were continuously monitored under orthostatic examination conditions. Additionally, the pulsatility index (PI) (i.e., systolic minus diastolic velocity divided by the mean velocity) was calculated (Kirkhan~ et al. 1986), which is a common measurement for changes of peripheral vascular resistances. Patients were fixed on a tilt table, and measurement started in a horizontal position. After 6 min at rest, the table was tilted in a vertical position so that the patient was standing up. After an additional 8 rain, the table was tilted again in a horizontal position, and 8 min later the investigation was finished. Changes in the position of the table were completed within 2-3 sec. All alteration of 1;
variables were transformed into relative values, using the mean value during the last three minutes in the first lying phase as reference (100%). The amount of data was then reduced by calculating for each variable 22 successive mean values (1 per rain). Inference statistically (two-tailed t-test) each time point of each parameter from the clinical subgroups were compared with the corresponding values of the normal group (significance level = 5 °., ).
Results In normal subjects, an increase in heart rate occurred after changing from a horizontal to a vertical position. Blood pressure was slightly reduced initially after standing but in general remained constant throughout the entire procedure (Fig. la). In contrast, the intracranial blood flow velocity showed a mild decrease during a standing position with normalization after lying down again (Fig. lb). PI values increased slightly after tilting the table to a vertical position. Standard deviations ranged from 30% in maximum in the pulsatility measurements to 3 % in single heart rate values. °/o
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35 The first group of patients with diabetic autonomic neuropathy but no evidence of orthostatic dysregulation revealed a similar increase in heart rate but 10°.0 lower than in normal subjects, but these differences were not significant. Blood pressure, cerebral Mood flow velocity, and pulsatility indices were normal (Fig. 2a and b). Concerning the blood flow velocities, patients in the other group with diabetic neuropathy but with a history of orthostatic syncopes did not differ significantly from those without clinical events or normal subjects. Furthermore, no significant differences in the pulsatility index were o b s e r v e d (Fig. 3). However, the heart rate was fixed, and b l o o d pressure mildly decreased during the orthostatic changes. Differences in blood pressure response, as well as in heart rate between the diabetic group and normals were statistically significant. Within the following two minutes after lying down, blood prcssure normalized (Fig. 3a). In patients with p a n d y s a u t o n o m i a , the heart rate was fixed as in patients with diabetic neuropathy. However, blood pressure when tilted to the vertical position was severely and significantly reduced (Fig. 4a). Furthermore, the cerebral blood flow velocities were also m a r k e d l y reduced in the standing position. Particularly notable are
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