Dynamic cerebral autoregulation is impaired in glaucoma

Journal of the Neurological Sciences 220 (2004) 49 – 54 www.elsevier.com/locate/jns

Dynamic cerebral autoregulation is impaired in glaucoma Marcin Tutaj a,b,*, Clive M. Brown c, Miroslaw Brys a,b, Harald Marthol a,c, Martin J. Hecht c, Matthias Dutsch c, Georg Michelson d, Max J. Hilz a,c a

Department of Neurology, New York University, 550 First Ave. NB 7W11, New York, NY 10016, USA b Department of Neurology, Jagiellonian University, ul. Botaniczna 3, 31-503 Krakow, Poland c Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany d Department of Ophthalmology, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany Received 16 April 2003; received in revised form 5 January 2004; accepted 3 February 2004

Abstract Objectives: Autonomic and endothelial dysfunction is likely to contribute to the pathophysiology of normal pressure glaucoma (NPG) and primary open angle glaucoma (POAG). Although there is evidence of vasomotor dysregulation with decreased peripheral and ocular blood flow, cerebral autoregulation (CA) has not yet been evaluated. The aim of our study was to assess dynamic CA in patients with NPG and POAG. Materials and Methods: In 10 NPG patients, 11 POAG patients and 11 controls, we assessed the response of cerebral blood flow velocity (CBFV) to oscillations in mean arterial pressure (MAP) induced by deep breathing at 0.1 Hz. CA was assessed from the autoregressive cross-spectral gain between 0.1 Hz oscillations in MAP and CBFV. Results: 0.1 Hz spectral powers of MAP did not differ between NPG, POAG and controls; 0.1 Hz CBFV power was higher in patients with NPG (5.68 F 1.2 cm2 s 2) and POAG (6.79 F 2.1 cm2 s 2) than in controls (2.40 F 0.4 cm2 s 2). Furthermore, the MAP – CBFV gain was higher in NPG (2.44 F 0.5 arbitrary units [a.u.]) and POAG (1.99 F 0.2 a.u.) than in controls (1.21 F 0.1 a.u.). Conclusion: Enhanced transmission of oscillations in MAP onto CBFV in NPG and POAG indicates impaired cerebral autoregulation and might contribute to an increased risk of cerebrovascular disorders in these diseases. D 2004 Elsevier B.V. All rights reserved. Keywords: Glaucoma; Cerebral autoregulation; Spectral analysis; Autonomic dysfunction; Metronomic breathing; Cerebral blood flow; Cross-spectral gain

1. Introduction Glaucoma is characterised by progressive optic neuropathy resulting in optic nerve head damage and visual field loss. It is a leading cause of blindness [1]. The most common form of the disease is primary open angle glaucoma (POAG), which is associated with an elevated intraocular pressure (IOP) to above 21 mmHg. In normal pressure glaucoma (NPG), similar glaucomatous damage occurs in the absence of an elevated IOP [2,3]. Although NPG and POAG have been described as different clinical entities and vary with respect to some risk factors and clinical characteristics, there is evidence of some overlap between the two diseases. For example, NPG patients tend to have higher diurnal variations in IOP than healthy persons [2]. In contrast, some persons with IOP greater than 21 mmHg * Corresponding author. Department of Neurology, Jagiellonian University, Collegium Medicum, ul. Botaniczna 3, 31-503 Krakow, Poland. Tel.: +48-12-424-8628; fax: +48-12-411-3199. E-mail address: [email protected] (M. Tutaj). 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.02.002

do not develop glaucoma [4,5]. Indeed, some authors believe that there is no clear demarcation between normal pressure and primary open angle glaucoma [2,3]. Systemic factors are considered to play a role in the pathophysiology of the glaucomas. Impaired vascular function might contribute to normal pressure glaucoma because this disease is associated with vascular disorders such as vasospasm [6 –9] and migraine [10,11]. Moreover, hypertension [12 – 14], hypotension [14] and diabetes [12,15] have been identified as risk factors for primary open angle glaucoma. There is also evidence that blood perfusion to the optic nerve is reduced in primary open angle glaucoma [16,17]. Furthermore, in both primary open angle and normal pressure glaucoma, the peripheral vasomotor responses to baroreflex stimulation are impaired [18]. These findings not only demonstrate vascular involvement in the glaucomas but also suggest that primary open angle and normal pressure glaucoma both share a common pathophysiological mechanism. Retinal and optic nerve head circulation is dependent on local autoregulatory mechanisms, which serve to maintain

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blood perfusion independently of eye perfusion pressure changes [19 – 21]. Several studies have demonstrated altered ocular autoregulation in glaucoma, which further indicates that vascular dysregulation plays an important role in the pathogenesis of glaucomatous optic neuropathy [21 –23]. Cerebral autoregulation refers to the ability of the cerebral resistance vessels to maintain a near-constant cerebral perfusion despite changes in blood pressure [24]. Myogenic, neurogenic, neurohormonal, metabolic and local chemical factors probably contribute to cerebral autoregulation (CA) [25]. The vascular dysregulation observed in the glaucomas [6,9,18,26] might be also manifested by an impairment of cerebral autoregulation. This would explain the findings that glaucoma is associated with disorders such as vasospasm and migraine [6– 11]. Moreover, magnetic resonance imaging (MRI) studies have demonstrated diffuse small-vessel ischemic changes in the brains of normal pressure glaucoma patients [27,28]. However, cerebral autoregulation in patients with glaucoma has not yet been evaluated. The aim of our study was to assess dynamic cerebral autoregulation in patients with POAG and NPG using a simple test that can be applied in a clinical setting. We evaluated responses of the cerebral blood flow velocity (CBFV) to cyclic changes in blood pressure elicited by deep breathing at 0.1 Hz (6 cycles/min) [29]. We hypothesised that cerebral autoregulation is compromised in patients with NPG and POAG and that this might be demonstrated by an enhanced transmission of breathinginduced 0.1 Hz oscillations in blood pressure onto the cerebral blood flow velocity.

2. Materials and methods 2.1. Subjects We studied 10 patients with NPG aged 57 F 18 (mean F S.D.) years, 11 patients with POAG aged 52 F 11 years and 11 healthy controls aged 51 F 19 years. A medical history was taken, and detailed neurological and ophthalmologic examinations were performed in all study participants. The diagnosis of glaucoma had been made using standard criteria [2]. To ensure that our results were not confounded by other conditions that might influence autonomic or cerebrovascular function, we intended to exclude patients or controls from the study if they had any other concurrent cardiovascular or neurological disorder, or if they were taking any medication known to affect the autonomic or cardiovascular systems. All glaucoma patients who were taking topical medication for glaucoma discontinued the medication for 3 days prior to testing. Patients who were unable to comply with this requirement for medical reasons were not included in the study. The topical medication in NPG patients included latanoprost,

brimonidin and dorzolamid, while in POAG patients, the topical medication included latanoprost, brimonidin, dorzolamid and timolol. All procedures were approved by the local ethics committee and written informed consent was obtained from each subject prior to testing according to the Declaration of Helsinki. 2.2. Procedures The patients were sent for the testing from the Department of Ophthalmology. The investigators were blinded as to which group each patient belonged until after the data collection and analysis were completed. The subjects initially rested in a supine position for at least 30 min to ensure cardiovascular stability. They were then instructed to breathe deeply at a rate of 6 breaths per minute (5 s inspiration, 5 s expiration), following combined visual and auditory stimuli, for 3 min. This standard challenge manoeuvre of the autonomic nervous system induces sinusoidal 0.1 Hz oscillations in mean arterial pressure (MAP) that are subsequently transmitted onto the cerebral vessels and the CBFV [29]. We continuously monitored electrocardiographic RR intervals (five-lead ECG) and non-invasive beat-to-beat blood pressure at the left radial artery using applanation tonometry (ColinR Pilotk, San Antonio, TX, USA). The tonometer consists of an array of 31 equally spaced piezoresistive pressure transducers, an automated positioning system and signal conditioning and initial calibration by oscillometric cuff measurement of the brachial artery [30]. Respiratory frequency was monitored by calibrated electrical inductance plethysmography (Respitrace Calibratork, Ambulatory Monitoring, Ardsley, NY, USA) with two respiratory belts placed around the chest and abdomen. We recorded cerebral blood flow velocity using transcranial Doppler ultrasonography (Multidop XLk, DWL, Sipplingen, Germany) at the proximal segment of the middle cerebral artery (MCA), insonated through the temporal window approximately 1 cm above the zygomatic arch at a depth of 40 – 60 mm using 2-MHz probes. After optimising the Doppler signal by standard methods, the probe was attached to the skull in a fixed position using a headband with an adjustable positioning system. Expiratory air was sampled via a nasal cannula and endtidal CO2 (PETCO2) measured by infrared absorption (ColinPilotk, Colin Medical, San Antonio, TX, USA). 2.3. Data acquisition and analysis The recorded signals were digitised at a sampling rate of 300 Hz and fed to a Macintosh PowerBook computer (Apple, USA). A computer program identified all the QRS complexes in each ECG sequence and then located the peak of each R-wave. We constructed time-series of blood pressure, CBFV, respiration and PETCO2. For further

M. Tutaj et al. / Journal of the Neurological Sciences 220 (2004) 49–54 Table 1 Variables recorded during metronomic deep breathing at 0.1 Hz: mean arterial pressure (MAP), mean cerebral blood flow velocity (CBFV), endtidal CO2 (PETCO2) and the calculated values of cerebrovascular resistance (CVR), spectral powers of MAP and CBFV oscillations at 0.1 Hz, MAP – CBFV coherence and normalised MAP – CBFV gain at 0.1 Hz

MAP [mmHg] CBFV [cm s 1] CVR [mmHg s cm 1] PETCO2 [mmHg] 0.1 Hz power of MAP [mmHg2] 0.1 Hz power of CBFV [cm2 s 2] MAP – CBFV coherence MAP – CBFV gain [a.u.]

Controls (n = 11)

NPG (n = 10)

POAG (n = 11)

89.70 F 4.5 43.89 F 3.7 2.11 F 0.2 33.48 F 3.8 9.76 F 1.5

85.90 F 2.5 40.24 F 7.2 3.58 F 0.7 34.88 F 3.6 9.86 F 1.4

93.24 F 5.2 44.70 F 4.1 2.43 F 0.4 32.59 F 2.9 8.57 F 1.2

2.40 F 0.4

5.68 F 1.2*

6.79 F 2.1*

0.94 F 0.1 1.21 F 0.1

0.96 F 0.1 2.44 F 0.5*

0.93 F 0.1 1.99 F 0.2*

Values are means F S.E.M. Significant differences compared with controls are indicated by *( P < 0.05, Kruskal – Wallis with Dunn’s post-test). NPG = normal pressure glaucoma, POAG = primary open angle glaucoma.

analysis, we selected 90-s segments with the most stable PETCO2 values (between the 30th and the 150th second of the constructed time series). Oscillations in the recorded signals were characterised by autoregressive power spectrum analysis. Cerebrovascular resistance (CVR) was calculated as the ratio of MAP to CBFV [31,32]. Dynamic cerebral autoregulation can be assessed by observing the effects of changes in blood pressure on cerebral blood flow velocity [29,33]. Oscillations in blood pressure at frequencies up to 0.20 Hz are

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dampened by the cerebral vessels [29,33]. Our approach was to induce large blood pressure oscillations at 0.1 Hz by deep breathing at this frequency and to use cross-spectral analysis to evaluate the transmission of these oscillations onto the CBFV. Cross-spectral analysis allows for the comparison of pairs of oscillating signals provided the coherence is adequate [34]. The coherence function, ranging from 0 to 1, refers to the amount of linear coupling between two oscillations. Coherence values above 0.5 are considered significant [34]. To assess the transfer of 0.1 Hz MAP oscillations onto the CBFV, we calculated the MAP –CBFV gain as the square root of the ratio of the power of CBFV oscillations to the power of MAP oscillations at 0.1 Hz frequency. To account for possible differences in the cerebrovascular resistance and in the vasomotor reactivity to changes in pCO2 between the patients and controls [21,35], we normalised the individual MAP – CBFV gain by the participant’s mean CBFV and MAP [36] and expressed the normalised value in arbitrary units (a.u.). Since the ratio of MAP at the brain level to mean CBFV reflects cerebrovascular resistance, the normalised MAP – CBFV gain can be considered a measure of the dynamic CBFV responses to MAP oscillations occurring around a given CVR value [36]. Increased MAP – CBFV gain indicates a more passive behaviour of the cerebral resistance vessels resulting in an inadequate buffering of blood pressure fluctuations and is an indicator of impaired cerebral autoregulation [33]. All values reported are means F S.E.M. Mean values of the recorded signals, frequency-domain responses and parameters of cerebral autoregulation were compared be-

Fig. 1. Examples of time series of mean arterial pressure (MAP) and mean cerebral blood flow velocity (CBFV) recordings in (a) a healthy person and (b) a patient with normal pressure glaucoma. The CBFV oscillations are more pronounced in the glaucoma patient despite similar oscillations in MAP.

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Fig. 2. Normalised MAP – CBFV gain between mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP) oscillations at 0.1 Hz in patients with normal pressure glaucoma (NPG), primary open angle glaucoma (POAG) and healthy controls. MAP – CBFV gain was significantly higher in patients with normal pressure and primary open angle glaucoma than in controls, indicating compromised cerebral autoregulation in the patients. Significant differences compared with controls are indicated by *( P < 0.05, Kruskal – Wallis with Dunn’s post-test).

tween the three groups using the Kruskal – Wallis test with Dunn’s post-tests where a significant P-value was found. Pvalues were all two-sided and the level of statistical significance was set at P < 0.05.

3. Results None of the patients or controls screened for enrollment in this study had other diseases or were on any medication other than the glaucoma medication that might interfere with the autonomic cardiovascular control. Mean cardiovascular parameters and their spectral characteristics recorded during 0.1 Hz deep breathing are summarised in Table 1. Mean values of MAP, CBFV, CVR and end-tidal CO2 values did not differ significantly between controls and glaucoma patients. There was no difference in the powers of breathinginduced 0.1 Hz blood pressure oscillations between the controls and the two groups of glaucoma patients. However, the 0.1 Hz powers of CBFV oscillations were significantly higher ( P < 0.05) in normal pressure and primary open angle glaucoma patients than in the controls (e.g., Fig. 1). All subjects showed a significant (>0.5) coherence between low-frequency 0.1 Hz oscillations in MAP and CBFV during the deep breathing test. The MAP – CBFV gain between MAP and mean CBFV oscillations at 0.1 Hz was significantly higher ( P < 0.05) in NPG and POAG patients than in the healthy controls (Fig. 2).

4. Discussion Our study shows compromised cerebral autoregulation in patients with normal pressure and primary open angle glaucoma, as revealed by increased transmission of oscil-

lations in mean arterial blood pressure onto the mean cerebral blood flow velocity. These results suggest that the cerebral resistance vessels are affected in glaucoma and seem to strengthen the hypothesis that this disease might be a manifestation of a more widespread systemic disorder. Blood pressure oscillations at the respiratory frequency are predominantly due to the mechanical effects of breathing-induced fluctuations in cardiac stroke volume [37]. We found no difference in the magnitude of the 0.1 Hz blood pressure oscillations between the controls and glaucoma patients, indicating that our results were not influenced by different breathing patterns. However, the transmission of the 0.1 Hz blood pressure oscillations onto the cerebral blood flow velocity was significantly higher in the glaucoma patients than in the controls and resulted in higher 0.1 Hz CBFV oscillations and higher MAP –CBFV gain values in the patients than the controls. This finding indicates that the ability of the cerebral vascular bed to compensate for changes in perfusion pressure is impaired in both primary open angle and normal pressure glaucoma. Impaired regulation of vascular resistance has already been implicated in glaucoma because of the high prevalence of vasospastic disorders among patients with glaucoma [6– 8]. We previously demonstrated that patients with primary open angle and normal pressure glaucoma have impaired vasomotor responses to baroreceptor stimulation [18]. The present study suggests that the vascular dysregulation in glaucoma is also associated with an impairment of cerebral autoregulation. The precise pathophysiological deficits contributing to vascular dysregulation in glaucoma are unclear, but dysfunction of the vascular endothelium might be a factor. This is supported by findings of altered endothelium-mediated vasoconstriction [9] and vasodilatation [26] in glaucoma patients. However, the neural control of the blood vessels might also be affected in glaucoma, because studies have demonstrated autonomic involvement in both primary open angle and normal pressure glaucoma [18,38 –41]. Autonomic neural control probably has a role in the beat-to-beat regulation of cerebral blood flow in response to arterial pressure [42]. It is plausible that autonomic dysfunction in glaucoma could affect the ability of the cerebral blood vessels to adjust to changes in blood pressure. Clinically, vascular dysregulation might influence the progression of glaucoma. Gasser et al. [6] tested visual field changes in normal pressure glaucoma patients with and without vasospasm during sympathetic activation by hand immersion into ice-water. After the cold stimulation, the visual field deteriorated due to a prominent vasoconstriction in choroidal vessels. The vasoconstriction and the resulting visual field impairment were more pronounced in normal pressure glaucoma patients with vasospasm than those without [6]. Furthermore, ophthalmic artery perfusion is decreased in patients with advanced primary open angle glaucoma [17].

M. Tutaj et al. / Journal of the Neurological Sciences 220 (2004) 49–54

The altered cerebrovascular control might contribute to an increased risk of cerebrovascular disorders in normal pressure and primary open angle glaucoma [10,11,27,28]. This hypothesis is supported by MRI findings that patients with NPG have diffuse small-vessel ischemic changes [27,28]. Our results could also have some therapeutical relevance, as certain vasoactive agents may improve cerebrovascular and ocular resistance control. Dorzolamide, a vasodilating topical carbonic anhydrase II inhibitor, has been shown to reduce intraocular pressure and improve retinal, choroidal and optic nerve head perfusion in normal pressure and primary open angle glaucoma [43,44]. However, application of carbonic anhydrase inhibitors might be limited by systemic side effects. Certain calcium channel blockers, such as nimodipine, nilvadipine or brovincamine, have been shown to improve ocular haemodynamics and visual field in patients with NPG and POAG [21,45 – 47] and might also be effective in ameliorating cerebral haemodynamics in glaucoma. In individual patients, the assessment of cerebral autoregulation might refine any treatment regimen to improve vascular function. 4.1. Methodological considerations Several additional factors that may have influenced our results should be discussed. Firstly, we must consider the potential role of carbon dioxide levels on the cerebral vessels. Harris et al. [35] demonstrated an increased resistance of ocular arteries during normocapnia and an altered reactivity of these arteries to increases in pCO2 in NPG. These findings suggest that during similar pCO2 changes, vascular resistance of ocular and possibly also cerebral vessels may show a different response in patients with NPG than in patients with POAG or controls. However, we normalised the MAP – CBFV gain to avoid a possible influence of CVR differences on cerebral autoregulation parameters in the present study. Moreover, we found no differences in end-tidal CO2 values between patients and controls, suggesting that our findings are unlikely to have been influenced by different breathing patterns or CO2 levels. Secondly, we considered the possible role of topical medication taken by our glaucoma patients. Although a longer washout period than 3 days might have been valuable, withdrawal of medication is associated with a marked rise in intraocular pressure, even within 24 h [44,48,49]. For ethical reasons, we therefore restricted the withdrawal of medication to 3 days. However, the influence, if any, of glaucoma medication on our results is probably negligible, because the plasma concentration of topical medication is low and decreases within several hours of administration [44,48,49]. A final methodological consideration considers the possibility that changes in the diameter of the insonated MCA might have affected the results. However, several studies

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have indicated that there is only minimal or no major change in the diameter of the proximal MCA during various stimuli [50 –52].

5. Conclusion Our study showed that cerebrovascular autoregulation is compromised in normal pressure and primary open angle glaucoma. Cerebrovascular resistance regulation in glaucoma might be impaired, at least in part, by altered sympathetic and endothelial dependent vasomotor control of cerebral vessels in these patients. The assessment of cerebrovascular autoregulation before and in combination with therapy might refine the understanding of the pathophysiology of NPG as well as POAG and possibly contribute to slowing disease progression.

Acknowledgements This study was supported by grants from the Kosciuszko Foundation (recipients: Marcin Tutaj and Miroslaw Brys). We would like to thank Dr. Joanna Harazny for her valuable comments and suggestions during the preparation of this manuscript.

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