- Email: [email protected]
The effect of methylprednisolone treatment on cerebral reactivity in patients with multiple sclerosis
Journal of Clinical Neuroscience 13 (2006) 214–217 www.elsevier.com/locate/jocn
Clinical study
The effect of methylprednisolone treatment on cerebral reactivity in patients with multiple sclerosis ¨ zkan *, Nevzat Uzuner, Ceyhan Kutlu, Demet O ¨ zbabalık, Gazi O ¨ zdemir Serhat O Osmangazi University, Medical Faculty, Department of Neurology, Meselik Campus, 26480 Eskisehir, Turkey Received 22 November 2004; accepted 22 March 2005
Abstract We assessed the effect of intravenous high-dose methylprednisolone (IVMP) on cerebral reactivity in multiple sclerosis (MS) patients during exacerbations by means of functional transcranial Doppler imaging. Forty-eight clinically defined MS patients were evaluated with visual evoked potentials (VEP) and functional transcranial Doppler sonography (TCD) of both posterior cerebral arteries before and after 5 days of 1000 mg IVMP. After treatment, mean Expanded Disability Status Scale score, mean blood flow velocities and mean blood flow velocities at rest and at stimulation, significantly decreased (p < 0.0001, for each). The change in cerebral blood flow velocity ratio (CBFv) with visual stimulation after treatment increased slightly (p = 0.20). All TCD parameters were not significantly correlated with VEP changes. In conclusion, we observed significant changes in CBFv with a non-significant increase in vascular reactivity after treatment with IVMP in exacerbations of MS. Case-control studies are necessary to draw conclusions regarding the beneficial effects of IVMP treatment. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Multiple sclerosis; Cerebral reactivity; Transcranial Doppler; Methylprednisolone
1. Introduction There is a wide consensus that high-dose methylprednisolone administered intravenously shortens the duration of acute multiple sclerosis (MS) exacerbations and it is the most commonly used treatment for MS exacerbation.1,2 Although the efficacy of this treatment is clear, the mechanisms are still not well understood. Previous studies have suggested that they include inhibition of leukocyte diapedes through the blood-brain barrier; reduction of capillary permeability; decreased circulating T-helper cells and B-lymphocytes; and inhibition of proinflammatory cytokines causing a reduction in inflammatory edema in the brain parenchyma.3–7 The acute clinical benefit of highdose intravenous methlprednisolone (IVMP) is probably due to its effect on inflammation, rather than remyelination *
Corresponding author. Tel.: +90 222 2398080; fax: +90 222 2309696. ¨ zkan). E-mail address: [email protected] (S. O
0967-5868/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.03.023
and repair of axonal injury. Although some investigation methods, including PET, SPECT and MRI techniques show parenchymal changes during MS exacerbations, they are expensive and difficult to repeat.8–11 Transcranial Doppler sonography (TCD) is a non-invasive laboratory technique that can provide information about blood flow velocities in basal cerebral arteries. Continous recording of cerebral blood flow velocities in responsible arteries during functional tasks such as motor or visual stimulation can also provide information about the relationship between neuronal activation and vascular reactivity or ‘vasoneuronal coupling’.12–14 In our recent study, we observed a more reactive posterior circulation to visual stimulation in MS patients during exacerbations than in controls, suggesting more reactive occipital cortical neurons.15 This reactivity can be affected by changes in neuronal integrity, supportive parenchymal tissue and vascular structure, all of which participate in the inflammatory process of acute MS exacerbations.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
215
In this study, we aimed to use visually evoked functional transcranial Doppler (TCD) to asses the effect on cerebral reactivity of IVMP treatment in relapsing, remitting-type MS during exacerbations. 2. Materials and methods We studied 48 patients (19 men, 29 women) with clinically defined MS according to Poser criteria who were admitted during an exacerbation of disease to our Department of Neurology.16 An exacerbation is defined as a rapid progressive worsening of symptoms lasting at least more than one day in a region that has not experienced new symptoms within the past month. Patients with a history of optic neuritis and non-hemispheric symptoms were excluded. Mean age was 34.2 years (range, 20-50). Mean disease duration was 34.4 months (range, 1-124), mean score on the Expanded Disability Status Scale (EDSS) at admission was 2.85 (range, 16.5).17 All patients were examined clinically and routine haematological investigations were performed. Visual evoked potentials (VEP) and cerebral MRI were done for all patients. Brain stem auditory evoked potentials; somatosensory evoked potentials, and cerebrospinal fluid investigations for oligoclonal bands and myelin basic protein were performed when needed. A long-term TCD monitoring device (Multidop X4/ TCD8, DWL Elektronische Systeme GmbH, Sipplingen, Germany) was used for simultaneous recording of both posterior cerebral arteries (PCA) using bilateral 2 MHz probes that were tightly fixed by a headband. The identification of blood vessels and the details of the procedure are published elsewhere.18 Through the temporal bone the P2 segments of both PCAs (flow direction away from the probe) were insonated at a depth of 60–68 mm. As we reported previously, visual stimulation is provided by a turning cylinder at a constant speed, which has object images on it. Subjects observed an image during a 20-second stimulation period, followed by a 20-second eyes-closed period. The target image was changed for each subsequent cycle to avoid habituation. All subjects were monitored during 10 cycles to assess cerebral blood flow velocity changes (CBFv) to activated striate and extrastriate associative visual areas.19 The first TCD sonography examination and VEPs were performed in the first 2 days of acute exacerbation of disease and prior to treatment and the second examinations were performed immediately after 5 days of 1000 mg per day IVMP. Calculations were performed off-line, and individual reactivity was defined as the relative increase of blood flow velocities as a percentage change of baseline values: DBFv ¼ 100 ðVs VrÞ=Vr where BFv is blood flow velocity; Vs is maximum velocity at stimulation (eyes open and stimulus on); and Vr is minimum velocity at rest (eyes closed), which is calculated by the system software that allows trigger-related BFv averaging
Fig. 1. Averaged responses of 10 cycles recorded in the P2 segment of the left posterior cerebral artery during visual stimulus and at rest. The maximum and minimum values were calculated as a single value at stimulation and rest as marked.
during an adjustable time-period of stimulus compared with an adjustable time period of stimulus off (rest), using the procedure as shown in Fig. 1. Two-tailed t-tests for paired samples, and the Pearson correlation test were used for statistical analysis, where appropriate; p < 0.05 was accepted for statistical significance. 3. Results Mean EDSS at admission (mean ± SD = 2.85 ± 0.97; range, 1–5.5) was significantly decreased after 5 days IVMP (2.32 ± 0.91; range, 0–6.5) (p < 0.0001). When we compared all the TCD and VEP data for both sides (right and left), there were no significant differences. So, we pooled all the data as 96 measurements and analysed as before and after treatment. A recovery effect was observed in amplitudes and latencies of VEPs after treatment, but none of them reached significance (Table 1). For TCD, mean blood flow velocity (Vmean) values before treatment were significantly higher than those after treatment, similarly for mean blood flow velocities at rest (Vr) and at stimulation (Vs) (p < 0.0001, for each). When we compared the cerebral blood flow velocity change ratio Table 1 Visual evoked potentials performed before and after high-dose intravenous methylprednisolone n
Mean ± SE
p-value
P100L-1 P100L-2
96 96
164.60 ± 4.17 159.37 ± 4.26
0.64
P100A-1 P100A-2
96 96
2.13 ± 0.17 2.18 ± 0.15
0.72
Paired t-test. P100L-1 = P100 latency before the treatment, P100A-1 = Amplitude before the treatment, P100L-2 = P100 latency after the treatment, P100A-2 = Amplitude after the treatment.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
216
Table 2 Blood flow velocity and reactivity to visual stimulation before and after high-dose intravenous methylprednisolone
Vmean Vr Vs CBFv (%)
Before treatment (n = 96)(mean ± SE)
After treatment (n = 96)(mean ± SE)
p-value
41.4 ± 0.93 33.9 ± 0.78 48.7 ± 1.11 44.1 ± 1.30
38.3 ± 0.75 31.4 ± 0.67 45.4 ± 0.86 46.0 ± 1.55
< 0.0001 < 0.0001 < 0.0001 0.20
Paired t-test. Vmean = Mean blood flow velocity, Vr = Mean blood flow velocity at rest, Vs = Mean blood flow velocity at stimulation, CBFv = Cerebral blood flow velocity change.
(CBFv), we observed that, after treatment, there was a trend to higher reactivity (Table 2). There was a negative but nonsignificant correlation between the VEP latencies and cerebral blood flow velocities either before or after treatment. There was a nonsignificant positive correlation between VEP amplitudes and all TCD data (Table 3). 4. Discussion To our knowledge, this is the first study investigating vasoneuronal coupling using TCD after IVMP treatment in MS patients. We previously observed significantly lower blood flow velocities and higher reactivity in the posterior circulation of MS patients during attack-free periods than in controls, suggesting more reactive neurons in MS patients.15 In the present study, blood flow velocities decreased after treatment, in contrast to increasing reactivity. It is apparent that inflammation can cause an increase in blood flow velocities due to increased perfusion, probably as a result of secreted vasoactive amines. Therefore, increased blood flow velocities during exacerbations may be the result of inflammation. These blood flow velocity changes may suggest diffuse parenchymal changes, but with focal neurological symptoms, as we included all patients with hemisphere symptoms without any distinction
of hemispherical location and measured the velocities only at the PCAs. Secreted vasoactive amines during inflammation cause vasodilatation of arteries that can affect the reactivity of the arterial wall. Increased reactivity with decreasing blood flow velocities after treatment may suggest a negative effect of inflammation and vasoactive amines on reactivity and a positive effect on blood flow velocity. Significantly lower blood flow velocities after treatment correlate with previous hemodynamic studies performed by PET and SPECT. In a prospective regional glucose metabolism study in MS patients who were in attack-free periods, the authors reported widespread regional hypometabolism in some areas, including the mesial occipital cortex and lateral occipital cortex where the PCAs supply blood.20 In a similar SPECT study of attack-free MS patients, low blood flow in the same regions was reported.21 However, all these observations were in patients with a stable clinical status.The significant clinical improvement as assessed by EDSS with a decrease in blood flow velocity in the PCAs after treatment, may suggest a relationship between clinical improvement and decreased perfusion. Although there was increasing reactivity after treatment, we cannot conclude a definite benefit of IVMP on reactivity during exacerbations, as we had no control MS group without treatment. In a prospective case-control study, Reddy et al. followed an MS patient during an exacerbation for 12 weeks with fMRI and MRI spectroscopy after IVMP treatment.22 On the first fMRI, in the second week of the exacerbation, they observed a significantly higher volume of activation than in controls. After 12 weeks, this high volume of activation had decreased and there was recovery of relative N-acetylaspartate (NAA) concentrations on MRI spectroscopy, suggesting axonal recovery. Neuronal reactivity may be low due to demyelination and possible axonal injury in MS patients. However, these results suggest that the severity of axonal injury may cause relatively increased neuronal activation. In our study, it is hard to explain the increased reactivity after IVMP by recovery in demyelination and axonal injury in a 5-day period. Absence of correlation
Table 3 Correlations between the transcranial Doppler data, EDSS and visual evoked potentials before and after high-dose intravenous methylprednisolone treatment EDSS (before IVMP)
P100L (before IVMP)
P100A (before IVMP)
EDSS (after IVMP)
P100L (after IVMP)
P100A (after IVMP)
Vmean
Pearson correlation Significance (2-tailed) n
0.224 0.145 48
0.113 0.275 96
0.097 0.346 96
0.016 0.918 48
0.122 0.237 96
0.106 0.304 96
Vs
Pearson correlation Significance (2-tailed) n
0.216 0.159 48
0.134 0.194 96
0.096 0.353 96
0.022 0.890 48
0.175 0.087 96
0.132 0.198 96
Vr
Pearson correlation Significance (2-tailed) n
0.208 0.176 48
0.061 0.556 96
0.092 0.372 96
0.009 0.953 48
0.075 0.468 96
0.069 0.506 96
Vmean = Mean blood flow velocity, Vs = Mean blood flow velocity at stimulation, Vr = Mean blood flow velocity at rest, P100L = P100 latency, P100A = P100 amplitude, IVMP = Intravenous methylprednisolone, EDSS, Expanded Disability Status Scale.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
of VEP and TCD data also support this suggestion. Our results may be explained by the anti-inflamatory effect of IVMP, reducing vasoactive substances, which alter vasoneuronal coupling. In a transcranial magnetic stimulation study evaluating methylprednisolone treatment in MS, the authors reported significant decreases in motor threshold, central motor conduction time, silent period and disability scores with 2000 mg per day, beginning as early as the seventh day of the treatment.23 Although this study suggests an increase in the reactivity of the pyramidal neurons, it is difficult to compare with our study which assesses vascular structures affected by inflammation. The visual cortical reaction may be different from the pyramidal cortex. In conclusion, we observed significant changes in cerebral blood flow velocities in the PCAs and vaso-neuronal coupling after treatment with IVMP in exacerbations of MS. Case-control studies are necessary to prove an effect of IVMP treatment, but functional TCD examination seems to be also useful. References 1. Andersson PB, Goodkin DE. Glucocorticoid therapy for multiple sclerosis: A critical review. J Neurol Sci 1998;160:16–25. 2. Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. J Neurol Neurosurg Psychiatry 1998;65:362–5. 3. Mansuco F, Flower RJ, Perret M. Leukocyte transmigration, but not rolling or adhesion, is selectively inhibited by dexamethasone in the hamster post capillary venule. J Immunol 1995;155:377–86. 4. Burnham JA, Wright RR, Dreisbach J, Murray RS. The effect of high dose steroids on MRI gadolinium enhancement in acute demyelinating lesions. Neurology 1991;412:1349–54. 5. Warren KG, Catz I, Verona MJ, Carroll DJ. Effect of methylprednisolone on CSF IgG parameters, myelin basic protein and antimyelin basic protein in multiple sclerosis exacerbations. Can J Neurol Sci 1986;13:25–30. 6. Wajgt A, Gorny M, Jenek R. The influence of high dose prednisone medication on autoantibody specific activity and on circulating immune complex level in cerebrospinal fluid of multiple sclerosis patients. Acta Neurol Scand 1983;68:378–85. 7. Barkhof F, Frequin ST, Hommes OR, et al. A correlative triad of gadolinium-DTPA MRI, EDSS and CSF-MBP in relapsing multiple
8.
9.
10.
11.
12. 13. 14. 15.
16.
17. 18.
19.
20.
21.
22. 23.
217
sclerosis patients treated with high dose intravenous methylprednisolone. Neurology 1992;42:63–7. Lee M, Reddy H, Johansen-Berg H, et al. The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol 2000;47:606–13. Willoughby EW, Grochowsky E, Li DK, Oger J, Kastrukoff LF, Paty DW. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol 1989;25:43–9. Jansen HM, Willemsen AT, Sinnige LG, et al. Cobalt-55 positron emission tomography in relapsing-progressive multiple sclerosis. J Neurol Sci 1995;132:139–45. Schiepers C, Van Hecke P, Vandenberghe R, et al. Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis. Mult Scler 1997;3:8–17. Aaslid R. Visually evoked dynamic blood flow response of human cerebral circulation. Stroke 1987;18:771–5. Uzuner N, Yalcinbas O, Gucuyener D, Ozdemir G. Hand gripping effect on CBF in normal subjects. Eur J Ultrasound 2000;11:147–50. Sitzer M, Diehl RR, Hennerici M. Visually evoked CBF response. J Neuroimaging 1992;2:65–70. ¨ zkan S, Gu¨cu¨yener D, Ozdemir G. Cerebral blood flow Uzuner N, O velocity changes to visual stimuli in patients with multiple sclerosis. Mult Scler 2002;8:217–21. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability rating scale (EDSS). Neurology 1983;33:1444–52. Fujioka KA, Douville CM. Anatomy and freehand techniques. In: Newell DW, Aaslid R, editors. Transcranial Doppler. New York: Raven Press; 1983. p. 9–31. Sturzenegger M, Newell DW, Aaslid R. Visually evoked blood flow response assessed by simultaneous two-channel transcranial Doppler using flow velocity averaging. Stroke 1996;27:2256–61. Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. Highresolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging 1998;8:228–34. Lycke J, Wikkelso C, Bergh AC, Jacobsson L, Andersen O. Regional cerebral blood flow in multiple sclerosis measured by single photon emission tomography with tecnetium-99m hexamethylpropyleneamine oxime. Eur Neurol 1993;33:163–7. Reddy H, Narayanan S, Arnoutelis R, et al. Relating axonal injury to functional recovery in MS. Neurology 2000;54:236–9. Fierro B, Salemi G, Brighina F, et al. A transcranial magnetic stimulation study evaluating methylprednisolone treatment in multiple sclerosis. Acta Neurol Scand 2002;105:152–7.
Clinical study
The effect of methylprednisolone treatment on cerebral reactivity in patients with multiple sclerosis ¨ zkan *, Nevzat Uzuner, Ceyhan Kutlu, Demet O ¨ zbabalık, Gazi O ¨ zdemir Serhat O Osmangazi University, Medical Faculty, Department of Neurology, Meselik Campus, 26480 Eskisehir, Turkey Received 22 November 2004; accepted 22 March 2005
Abstract We assessed the effect of intravenous high-dose methylprednisolone (IVMP) on cerebral reactivity in multiple sclerosis (MS) patients during exacerbations by means of functional transcranial Doppler imaging. Forty-eight clinically defined MS patients were evaluated with visual evoked potentials (VEP) and functional transcranial Doppler sonography (TCD) of both posterior cerebral arteries before and after 5 days of 1000 mg IVMP. After treatment, mean Expanded Disability Status Scale score, mean blood flow velocities and mean blood flow velocities at rest and at stimulation, significantly decreased (p < 0.0001, for each). The change in cerebral blood flow velocity ratio (CBFv) with visual stimulation after treatment increased slightly (p = 0.20). All TCD parameters were not significantly correlated with VEP changes. In conclusion, we observed significant changes in CBFv with a non-significant increase in vascular reactivity after treatment with IVMP in exacerbations of MS. Case-control studies are necessary to draw conclusions regarding the beneficial effects of IVMP treatment. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Multiple sclerosis; Cerebral reactivity; Transcranial Doppler; Methylprednisolone
1. Introduction There is a wide consensus that high-dose methylprednisolone administered intravenously shortens the duration of acute multiple sclerosis (MS) exacerbations and it is the most commonly used treatment for MS exacerbation.1,2 Although the efficacy of this treatment is clear, the mechanisms are still not well understood. Previous studies have suggested that they include inhibition of leukocyte diapedes through the blood-brain barrier; reduction of capillary permeability; decreased circulating T-helper cells and B-lymphocytes; and inhibition of proinflammatory cytokines causing a reduction in inflammatory edema in the brain parenchyma.3–7 The acute clinical benefit of highdose intravenous methlprednisolone (IVMP) is probably due to its effect on inflammation, rather than remyelination *
Corresponding author. Tel.: +90 222 2398080; fax: +90 222 2309696. ¨ zkan). E-mail address: [email protected] (S. O
0967-5868/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.03.023
and repair of axonal injury. Although some investigation methods, including PET, SPECT and MRI techniques show parenchymal changes during MS exacerbations, they are expensive and difficult to repeat.8–11 Transcranial Doppler sonography (TCD) is a non-invasive laboratory technique that can provide information about blood flow velocities in basal cerebral arteries. Continous recording of cerebral blood flow velocities in responsible arteries during functional tasks such as motor or visual stimulation can also provide information about the relationship between neuronal activation and vascular reactivity or ‘vasoneuronal coupling’.12–14 In our recent study, we observed a more reactive posterior circulation to visual stimulation in MS patients during exacerbations than in controls, suggesting more reactive occipital cortical neurons.15 This reactivity can be affected by changes in neuronal integrity, supportive parenchymal tissue and vascular structure, all of which participate in the inflammatory process of acute MS exacerbations.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
215
In this study, we aimed to use visually evoked functional transcranial Doppler (TCD) to asses the effect on cerebral reactivity of IVMP treatment in relapsing, remitting-type MS during exacerbations. 2. Materials and methods We studied 48 patients (19 men, 29 women) with clinically defined MS according to Poser criteria who were admitted during an exacerbation of disease to our Department of Neurology.16 An exacerbation is defined as a rapid progressive worsening of symptoms lasting at least more than one day in a region that has not experienced new symptoms within the past month. Patients with a history of optic neuritis and non-hemispheric symptoms were excluded. Mean age was 34.2 years (range, 20-50). Mean disease duration was 34.4 months (range, 1-124), mean score on the Expanded Disability Status Scale (EDSS) at admission was 2.85 (range, 16.5).17 All patients were examined clinically and routine haematological investigations were performed. Visual evoked potentials (VEP) and cerebral MRI were done for all patients. Brain stem auditory evoked potentials; somatosensory evoked potentials, and cerebrospinal fluid investigations for oligoclonal bands and myelin basic protein were performed when needed. A long-term TCD monitoring device (Multidop X4/ TCD8, DWL Elektronische Systeme GmbH, Sipplingen, Germany) was used for simultaneous recording of both posterior cerebral arteries (PCA) using bilateral 2 MHz probes that were tightly fixed by a headband. The identification of blood vessels and the details of the procedure are published elsewhere.18 Through the temporal bone the P2 segments of both PCAs (flow direction away from the probe) were insonated at a depth of 60–68 mm. As we reported previously, visual stimulation is provided by a turning cylinder at a constant speed, which has object images on it. Subjects observed an image during a 20-second stimulation period, followed by a 20-second eyes-closed period. The target image was changed for each subsequent cycle to avoid habituation. All subjects were monitored during 10 cycles to assess cerebral blood flow velocity changes (CBFv) to activated striate and extrastriate associative visual areas.19 The first TCD sonography examination and VEPs were performed in the first 2 days of acute exacerbation of disease and prior to treatment and the second examinations were performed immediately after 5 days of 1000 mg per day IVMP. Calculations were performed off-line, and individual reactivity was defined as the relative increase of blood flow velocities as a percentage change of baseline values: DBFv ¼ 100 ðVs VrÞ=Vr where BFv is blood flow velocity; Vs is maximum velocity at stimulation (eyes open and stimulus on); and Vr is minimum velocity at rest (eyes closed), which is calculated by the system software that allows trigger-related BFv averaging
Fig. 1. Averaged responses of 10 cycles recorded in the P2 segment of the left posterior cerebral artery during visual stimulus and at rest. The maximum and minimum values were calculated as a single value at stimulation and rest as marked.
during an adjustable time-period of stimulus compared with an adjustable time period of stimulus off (rest), using the procedure as shown in Fig. 1. Two-tailed t-tests for paired samples, and the Pearson correlation test were used for statistical analysis, where appropriate; p < 0.05 was accepted for statistical significance. 3. Results Mean EDSS at admission (mean ± SD = 2.85 ± 0.97; range, 1–5.5) was significantly decreased after 5 days IVMP (2.32 ± 0.91; range, 0–6.5) (p < 0.0001). When we compared all the TCD and VEP data for both sides (right and left), there were no significant differences. So, we pooled all the data as 96 measurements and analysed as before and after treatment. A recovery effect was observed in amplitudes and latencies of VEPs after treatment, but none of them reached significance (Table 1). For TCD, mean blood flow velocity (Vmean) values before treatment were significantly higher than those after treatment, similarly for mean blood flow velocities at rest (Vr) and at stimulation (Vs) (p < 0.0001, for each). When we compared the cerebral blood flow velocity change ratio Table 1 Visual evoked potentials performed before and after high-dose intravenous methylprednisolone n
Mean ± SE
p-value
P100L-1 P100L-2
96 96
164.60 ± 4.17 159.37 ± 4.26
0.64
P100A-1 P100A-2
96 96
2.13 ± 0.17 2.18 ± 0.15
0.72
Paired t-test. P100L-1 = P100 latency before the treatment, P100A-1 = Amplitude before the treatment, P100L-2 = P100 latency after the treatment, P100A-2 = Amplitude after the treatment.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
216
Table 2 Blood flow velocity and reactivity to visual stimulation before and after high-dose intravenous methylprednisolone
Vmean Vr Vs CBFv (%)
Before treatment (n = 96)(mean ± SE)
After treatment (n = 96)(mean ± SE)
p-value
41.4 ± 0.93 33.9 ± 0.78 48.7 ± 1.11 44.1 ± 1.30
38.3 ± 0.75 31.4 ± 0.67 45.4 ± 0.86 46.0 ± 1.55
< 0.0001 < 0.0001 < 0.0001 0.20
Paired t-test. Vmean = Mean blood flow velocity, Vr = Mean blood flow velocity at rest, Vs = Mean blood flow velocity at stimulation, CBFv = Cerebral blood flow velocity change.
(CBFv), we observed that, after treatment, there was a trend to higher reactivity (Table 2). There was a negative but nonsignificant correlation between the VEP latencies and cerebral blood flow velocities either before or after treatment. There was a nonsignificant positive correlation between VEP amplitudes and all TCD data (Table 3). 4. Discussion To our knowledge, this is the first study investigating vasoneuronal coupling using TCD after IVMP treatment in MS patients. We previously observed significantly lower blood flow velocities and higher reactivity in the posterior circulation of MS patients during attack-free periods than in controls, suggesting more reactive neurons in MS patients.15 In the present study, blood flow velocities decreased after treatment, in contrast to increasing reactivity. It is apparent that inflammation can cause an increase in blood flow velocities due to increased perfusion, probably as a result of secreted vasoactive amines. Therefore, increased blood flow velocities during exacerbations may be the result of inflammation. These blood flow velocity changes may suggest diffuse parenchymal changes, but with focal neurological symptoms, as we included all patients with hemisphere symptoms without any distinction
of hemispherical location and measured the velocities only at the PCAs. Secreted vasoactive amines during inflammation cause vasodilatation of arteries that can affect the reactivity of the arterial wall. Increased reactivity with decreasing blood flow velocities after treatment may suggest a negative effect of inflammation and vasoactive amines on reactivity and a positive effect on blood flow velocity. Significantly lower blood flow velocities after treatment correlate with previous hemodynamic studies performed by PET and SPECT. In a prospective regional glucose metabolism study in MS patients who were in attack-free periods, the authors reported widespread regional hypometabolism in some areas, including the mesial occipital cortex and lateral occipital cortex where the PCAs supply blood.20 In a similar SPECT study of attack-free MS patients, low blood flow in the same regions was reported.21 However, all these observations were in patients with a stable clinical status.The significant clinical improvement as assessed by EDSS with a decrease in blood flow velocity in the PCAs after treatment, may suggest a relationship between clinical improvement and decreased perfusion. Although there was increasing reactivity after treatment, we cannot conclude a definite benefit of IVMP on reactivity during exacerbations, as we had no control MS group without treatment. In a prospective case-control study, Reddy et al. followed an MS patient during an exacerbation for 12 weeks with fMRI and MRI spectroscopy after IVMP treatment.22 On the first fMRI, in the second week of the exacerbation, they observed a significantly higher volume of activation than in controls. After 12 weeks, this high volume of activation had decreased and there was recovery of relative N-acetylaspartate (NAA) concentrations on MRI spectroscopy, suggesting axonal recovery. Neuronal reactivity may be low due to demyelination and possible axonal injury in MS patients. However, these results suggest that the severity of axonal injury may cause relatively increased neuronal activation. In our study, it is hard to explain the increased reactivity after IVMP by recovery in demyelination and axonal injury in a 5-day period. Absence of correlation
Table 3 Correlations between the transcranial Doppler data, EDSS and visual evoked potentials before and after high-dose intravenous methylprednisolone treatment EDSS (before IVMP)
P100L (before IVMP)
P100A (before IVMP)
EDSS (after IVMP)
P100L (after IVMP)
P100A (after IVMP)
Vmean
Pearson correlation Significance (2-tailed) n
0.224 0.145 48
0.113 0.275 96
0.097 0.346 96
0.016 0.918 48
0.122 0.237 96
0.106 0.304 96
Vs
Pearson correlation Significance (2-tailed) n
0.216 0.159 48
0.134 0.194 96
0.096 0.353 96
0.022 0.890 48
0.175 0.087 96
0.132 0.198 96
Vr
Pearson correlation Significance (2-tailed) n
0.208 0.176 48
0.061 0.556 96
0.092 0.372 96
0.009 0.953 48
0.075 0.468 96
0.069 0.506 96
Vmean = Mean blood flow velocity, Vs = Mean blood flow velocity at stimulation, Vr = Mean blood flow velocity at rest, P100L = P100 latency, P100A = P100 amplitude, IVMP = Intravenous methylprednisolone, EDSS, Expanded Disability Status Scale.
¨ zkan et al. / Journal of Clinical Neuroscience 13 (2006) 214–217 S. O
of VEP and TCD data also support this suggestion. Our results may be explained by the anti-inflamatory effect of IVMP, reducing vasoactive substances, which alter vasoneuronal coupling. In a transcranial magnetic stimulation study evaluating methylprednisolone treatment in MS, the authors reported significant decreases in motor threshold, central motor conduction time, silent period and disability scores with 2000 mg per day, beginning as early as the seventh day of the treatment.23 Although this study suggests an increase in the reactivity of the pyramidal neurons, it is difficult to compare with our study which assesses vascular structures affected by inflammation. The visual cortical reaction may be different from the pyramidal cortex. In conclusion, we observed significant changes in cerebral blood flow velocities in the PCAs and vaso-neuronal coupling after treatment with IVMP in exacerbations of MS. Case-control studies are necessary to prove an effect of IVMP treatment, but functional TCD examination seems to be also useful. References 1. Andersson PB, Goodkin DE. Glucocorticoid therapy for multiple sclerosis: A critical review. J Neurol Sci 1998;160:16–25. 2. Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. J Neurol Neurosurg Psychiatry 1998;65:362–5. 3. Mansuco F, Flower RJ, Perret M. Leukocyte transmigration, but not rolling or adhesion, is selectively inhibited by dexamethasone in the hamster post capillary venule. J Immunol 1995;155:377–86. 4. Burnham JA, Wright RR, Dreisbach J, Murray RS. The effect of high dose steroids on MRI gadolinium enhancement in acute demyelinating lesions. Neurology 1991;412:1349–54. 5. Warren KG, Catz I, Verona MJ, Carroll DJ. Effect of methylprednisolone on CSF IgG parameters, myelin basic protein and antimyelin basic protein in multiple sclerosis exacerbations. Can J Neurol Sci 1986;13:25–30. 6. Wajgt A, Gorny M, Jenek R. The influence of high dose prednisone medication on autoantibody specific activity and on circulating immune complex level in cerebrospinal fluid of multiple sclerosis patients. Acta Neurol Scand 1983;68:378–85. 7. Barkhof F, Frequin ST, Hommes OR, et al. A correlative triad of gadolinium-DTPA MRI, EDSS and CSF-MBP in relapsing multiple
8.
9.
10.
11.
12. 13. 14. 15.
16.
17. 18.
19.
20.
21.
22. 23.
217
sclerosis patients treated with high dose intravenous methylprednisolone. Neurology 1992;42:63–7. Lee M, Reddy H, Johansen-Berg H, et al. The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol 2000;47:606–13. Willoughby EW, Grochowsky E, Li DK, Oger J, Kastrukoff LF, Paty DW. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol 1989;25:43–9. Jansen HM, Willemsen AT, Sinnige LG, et al. Cobalt-55 positron emission tomography in relapsing-progressive multiple sclerosis. J Neurol Sci 1995;132:139–45. Schiepers C, Van Hecke P, Vandenberghe R, et al. Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis. Mult Scler 1997;3:8–17. Aaslid R. Visually evoked dynamic blood flow response of human cerebral circulation. Stroke 1987;18:771–5. Uzuner N, Yalcinbas O, Gucuyener D, Ozdemir G. Hand gripping effect on CBF in normal subjects. Eur J Ultrasound 2000;11:147–50. Sitzer M, Diehl RR, Hennerici M. Visually evoked CBF response. J Neuroimaging 1992;2:65–70. ¨ zkan S, Gu¨cu¨yener D, Ozdemir G. Cerebral blood flow Uzuner N, O velocity changes to visual stimuli in patients with multiple sclerosis. Mult Scler 2002;8:217–21. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability rating scale (EDSS). Neurology 1983;33:1444–52. Fujioka KA, Douville CM. Anatomy and freehand techniques. In: Newell DW, Aaslid R, editors. Transcranial Doppler. New York: Raven Press; 1983. p. 9–31. Sturzenegger M, Newell DW, Aaslid R. Visually evoked blood flow response assessed by simultaneous two-channel transcranial Doppler using flow velocity averaging. Stroke 1996;27:2256–61. Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. Highresolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging 1998;8:228–34. Lycke J, Wikkelso C, Bergh AC, Jacobsson L, Andersen O. Regional cerebral blood flow in multiple sclerosis measured by single photon emission tomography with tecnetium-99m hexamethylpropyleneamine oxime. Eur Neurol 1993;33:163–7. Reddy H, Narayanan S, Arnoutelis R, et al. Relating axonal injury to functional recovery in MS. Neurology 2000;54:236–9. Fierro B, Salemi G, Brighina F, et al. A transcranial magnetic stimulation study evaluating methylprednisolone treatment in multiple sclerosis. Acta Neurol Scand 2002;105:152–7.