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Multimodal functional imaging of prolonged neurological deficits in a patient suffering from familial hemiplegic migraine
Neuroscience Letters 332 (2002) 115–118 www.elsevier.com/locate/neulet
Multimodal functional imaging of prolonged neurological deficits in a patient suffering from familial hemiplegic migraine Alexander Gutschalk a,*, Rainer Kollmar a, Alexander Mohr b, Marcus Henze c, Nicole Ille a, Markus Schwaninger a, Marius Hartmann b, Stefan Ha¨hnel b, Uwe Haberkorn c, Andre´ Rupp a, Uta Meyding-Lamade a a Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany c Department of Nuclear Medicine, University of Heidelberg, 69120 Heidelberg, Germany b
Received 21 June 2002; received in revised form 7 August 2002; accepted 12 August 2002
Abstract The case of a patient with familial hemiplegic migraine (FHM) suffering from prolonged right sided hemiparesis and aphasia that persisted for more than 10 days is reported. The symptoms were accompanied by slowing of the magnetoencephalogram over the left hemisphere, which normalized parallel to the clinical improvement. Positron emission tomography obtained on the 6th day revealed glucose-hypometabolism (hemispheric difference $10%) in left hemisphere’s fronto-basal cortex, caudate nucleus, and thalamus. In contrast, magnetic resonance imaging including perfusion and diffusion weighted imaging was normal and did not show significant alterations of cortical perfusion or water mobility during the episode. We hypothesize that this finding provides evidence for a primary neuronal dysfunction causing the prolonged neurological deficits in FHM. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine aura; Functional neuroimaging; Magnetoencephalography; Positron emission tomography; Magnetic resonance imaging; Perfusion weighted imaging; Calcium channels
Many patients suffering from familial hemiplegic migraine (FHM) exhibit a missense mutation in the CACNA1A gene on chromosome 19p13, coding for the a1A-subunit of P/Q-type calcium channels [12]. Animal models with altered P/Q-type calcium currents provide evidence for altered synaptic transmission [10] in the brain. However, there is considerable clinical variability not only among different mutations in mice, but also in humans with FHM and different genotypes [6]. Neurological deficits in FHM may be of similar duration as those preceding migraine with typical aura [8], or last up to several days, sometimes including confusion and coma [6]. However, these severe clinical manifestations are rare, and there are only few reports on functional neuroimaging in hemiplegic migraine [1,3,4]. As animal models do not yet provide a valid model of migraine, studies of human patho-
* Corresponding author. Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Tel.: 149-6221-56-5191; fax: 149-6221-56-5258. E-mail address: [email protected] (A. Gutschalk).
physiology are necessary to further our understanding of FHM. This is especially interesting with respect to recent evidence of an involvement of the CACNA1A gene in migraine with typical aura and migraine without aura [16]. Here, we report a case of FHM [8] that was monitored with perfusion- and diffusion-weighted magnetic resonance imaging (MRI), magnetoencephalography (MEG), transcranial Doppler sonography, and positron emission tomography (PET) during a 2 week period of neurological deficits and follow-up studies over 3 months. The 16 year old male with known FHM [15] linked to chromosome 19p13 presented to the emergency room with mild right-sided hemiparesis, hemihypaesthesia and non-fluent aphasia. He complained about a throbbing, left-sided headache; the onset of symptoms was similar to his usual migraine auras, but hemiparesis now persisted for more than 4 h. CCT and MRI were normal; the symptoms resolved after intravenous administration of 0.5 g Aspirin, and he was discharged home being instructed to return in case of worsening symptoms. On the next morning, he presented again with moderate hemiparesis, global aphasia, and meningismus. White blood count amounted to 17/ml, body
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temperature was 39 8C. MRI was again normal; cerebrospinal fluid showed normal cell counts (1/ml) and protein (31.8 mg/dl). He was admitted to the neurology service and received intravenous Aspirin (1.0 g at the 2nd and 3rd day) and Nimodipine (300 mg per day orally from day 4– 18). Later Acetazolamid was added (500 mg per day orally from day 5–18); low molecular weight heparin was given for prophylaxis of thrombembolism. In the following days, he recovered only slowly from his neurological deficits; meningismus resolved within 3 days and white blood count was within normal limits at day 4. Hemiparesis started to decrease at day 5, and completely resolved within 10 days. The headaches subsided after about 7 days. Aphasia improved more slowly, and on day 12 he still suffered from non-fluent aphasia with paraphasic speech, impaired auditory word understanding, naming and word finding difficulties. At discharge on day 18, he still suffered from mild word finding difficulties, which resolved after 2 months of speech therapy. On physical exam he did not show any signs of cerebellar dysfunction, which were found in other members of his family [15]. Another prolonged episode comparable to the present one happened at the age of 12 years. MRI was obtained at days 1, 2, 10 and 98 on a 1.5 T scanner (EDGE, Marconi). The protocol included axial T2-weighted fast spin echo sequences, coronar T1-weighted spin echo sequences, and axial isotropic diffusion-weighted imaging EPI sequences. Additionally, at day 2 and 98 perfusion-weighted imaging was performed. Relative regional cerebral blood volume (rrCBV) and mean transit time (MTT) were calculated based on 40 data sets of axial T2*-weighted gradient echo EPI sequences (slice thickness 8 mm) acquired during the injection of 25 ml Gadolinium at 5 ml/s. Continuous MEG was recorded at days 3, 5, 12, 35, and 98 with a Neuromag 122 channel whole-head system. Recordings were performed at 400 Hz sample-rate with a lowpass of 100 Hz. Data were visually inspected to exclude artifact-contaminated epochs and evaluated by an averaged Fast Fourier Transform (FFT) over the whole 10 min recording (BESA2000, Megis Software GmbH, Munich). The FFT block size was set to 2048 samples corresponding to 5.12 s. FFT was calculated every 2.56 s and the overlapping FFTblocks were averaged. A cos 2-shaped window was applied to each data block prior to FFT, to assign equal weight to each sample. To monitor cerebral glucose metabolism, 18F-2-fluoro-2deoxy-d-glucose (FDG) PET was obtained at day 6 with a Siemens-CTI EXACT-47-scanner. Plasma-glucose level of the fasting patient was 85 mg/dl. After 10 min of transmission measurement, 100 MBq 18F-FDG were given. Then, after 30 min, emission of the brain was recorded for 20 min in 3D-mode. Image reconstruction was done iteratively, using the ordered subsets-expectation maximization algorithm. After correcting for radioactive decay (t0:5 ¼ 110 min), tracer-uptake was expressed as standardized uptake
value (SUV ¼ (tissue activity concentration [kBq/g])/ (injected dose [kBq]/bodyweight [g])). For estimation of unilateral changes in FDG-uptake, SUV-ratios were calculated using reference regions in the contralateral hemisphere. Semiquantitative measurements of bilateral changes of FDG-uptake were obtained by calculating relative SUVs normalized to the global brain metabolism, based on normal values published by Volkow et al. [17]. Structural MRI was normal during as well as after the migraine episode. Diffusion-weighted scans also did not show any asymmetry and were normal with respect to routine clinical criteria used for the diagnosis of ischemic stroke. Perfusion-weighted imaging at day 2 and 98 did not show pathological differences between hemispheres with respect to rrCBV- and MTT-maps. MEG recordings on day 3 showed prominent high amplitude delta activity over the whole left hemisphere with a maximum over the left temporal lobe, while activity in the alpha- and beta-band was strongly suppressed over the left hemisphere (Fig. 1a). The left-sided slowing degraded over the following sessions, but was not completely resolved at day 98. The lateralized suppression of alpha and beta activity was maintained until day 35 and at day 98 had returned to a symmetrical distribution over the occipital lobe. Positron emission tomography at day 6 showed moderate but significantly reduced FDG-uptake ($10% difference between hemispheres) within left hemisphere’s frontobasal cortex, caudate nucleus, and thalamus (Fig. 1b). In occipital cortex reduced FDG-accumulation was observed in both hemispheres relative to the mean standard uptake values of the other cortical regions (.10%). Transcranial Doppler was performed at day 1, 4, 6, 13 and 98. Each time, velocities were found enhanced over the anterior and the medial cerebral artery of both hemispheres. Frequencies were in the range of 3–5 kHz in ictal as well as interictal examinations with no consistent difference between hemispheres. Similar frequencies were reported 4 years ago in an interictal examination. Summarizing, our data show prolonged neuronal dysfunction reflected by focal slowing in the MEG recordings, that go along with reduced relative FDG-uptake in the affected hemisphere. These findings parallel the symptoms of the migraine aura, and the results of the repeated MEG-recordings parallel the slow improvement of neurological deficits. The bilateral slowing of occipital alpha-rhythm was similarly accompanied by bilateral reduction of FDG-uptake in the occipital cortex. However, there was no clinical correlation of these bilateral neuronal changes. Although visual aura symptoms may have been missed in the acute stage, there was no evidence of hemianopia during the further hospital course and there was no history of visual aura given by the patient. Bilateral reduction of perfusion, spreading over the occipital lobe, has been reported to precede migraine without aura [18], and bilaterally reduced FDG-uptake has been reported in migraine with and without aura after reserpine induced migraine attacks [14]. This would suggest that the bilateral reduction of brain meta-
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Fig. 1. (A) Sum of MEG amplitude at days 3, 5, 12, 35, and 98 in the delta- (1–4 Hz), theta- (4–8 Hz), alpha- (8–14 Hz), and beta-band (14–30 Hz). The FFT-maps are spline interpolated and shown in top meridian projection down to the level of the lateral rows nine and ten in the 10–20 system; the 61 gradiometer positions are plotted above as white dots. Note that the scaling for the delta-band is twice as large as for the other frequency bands. (B) 18F-FDG PET obtained at day 6, radiological convention. The chosen scans depict the reduced FDGuptake in the left frontal cortex, caudate nucleus and thalamus, as well as in bilateral occipital cortex.
bolism correlates to a pathophysiological mechanism typical for migraine that is not necessarily accompanied by visual aura symptoms. As our semi-quantitative PET-study relies on the assumption of a normal reference, we can not exclude that increased FDG-uptake in other brain regions may mimic reduced uptake in bilateral occipital and left frontal cortex. However, we consider this alternative explanation very improbable, since it would contradict the findings of reduced perfusion and metabolism found unilaterally [5,11] and bilaterally [14,18] in the majority of studies on migraine. In contrast to the PET- and MEG-findings, neither perfusion- nor diffusion-weighted MRI-scans revealed significant abnormalities. Studies recording perfusion-weighted MRI [5,7] and xenon133-SPECT [11] in typical migraine aura reported moderate hypoperfusion corresponding closely to the clinical presentation of neurological deficits. As shown by a recent functional MRI-study, this decreased perfusion is probably a consequence of cortical spreading depression [7], as it shares the characteristics of blood oxygenation level dependent signal changes derived from a cat model [9]. Hypoperfusion might also have accompanied the initiation of the migraine aura in our patient, but at this time
recording was not possible. In the further course, however, perfusion weighted MRI was normal, while FDG-PET and MEG showed continued cortical dysfunction. Although it cannot be excluded that FDG-PET is more sensitive than perfusion weighted MRI, we would have expected at least mild hemispheric differences in the perfusion weighted MRI 24 h after symptom onset, given the severe clinical presentation. For the same reasoning it is improbable that a decreased perfusion might have been found at the day of PET-scanning, since the patient had clinically improved by that time. It rather appears, that the physiological coupling of brain metabolism and perfusion becomes lost in the prolonged course of migraine aura in FHM. A similar uncoupling of brain metabolism and perfusion with decreased deoxyglucose uptake with normal perfusion has for example been observed in the vicinity of epileptic foci in the interictal interval [2]. Irrespective of this interpretation, our results provide further evidence that hypoperfusion in migraine is not responsible for prolonged neurological deficits. If it was, we would expect faster recovery of the focal slowing and hypometabolism as well as faster clinical recovery than observed in our patient.
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Two earlier cases report employing SPECT in FHM reported hyper- [1] as well as hypoperfusion of the affected hemisphere [4] during prolonged aura. Decreased water mobility, consistent with reversible cytotoxic edema, was reported applying diffusion tensor imaging to a FHMpatient with a severe attack [3]. All three cases [1,3,4] have in common a swelling of the affected hemisphere observed with standard T1- and T2-weighted MRIsequences, in two cases associated with meningeal enhancement [3,4]. Repeated MRI studies including T1-, T2-, and diffusion-weighted sequences were normal in our patient, suggesting that this case represents a less severe form of the broad clinical spectrum of FHM [6], that is closer to migraine with prolonged aura [8] in patients that do not suffer from FHM. The origin of the prolonged neuronal dysfunction in FHM remains unclear at present; while spreading cortical depression may well explain typical migraine aura [7] as well as the initiation of prolonged aura in FHM, it can hardly account for neuronal dysfunction over days and weeks. Mouse models with ablation [10] or mutation [13] in the a1A-subunit of P/Q-type calcium channels provide evidence for altered synaptic transmission due to alteration of voltage gated calcium currents. With reference to this data [13], one might speculate that dysregulation of calcium influx into excitatory synapses might result in prolonged blockage of synaptic transmission after the beginning of migraine aura triggered by spreading depression. New mouse models of FHM may further resolve these mechanisms. [1] Barbour, P.J., Castaldo, J.E. and Shoemaker, E.I., Hemiplegic migraine during pregnancy: Unusual magnetic resonance appearance with SPECT scan correlation, Headache, 41 (2001) 310–316. [2] Bruehl, C., Hagemann, G. and Witte, O.W., Uncoupling of blood flow and metabolism in focal epilepsy, Epilepsia, 39 (1998) 1235–1242. [3] Chabriat, H., Vahedi, K., Clark, C., Poupon, C., Ducros, A., Denier, C., Le Bihan, D. and Bousser, M.G., Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene, Neurology, 54 (2000) 510–512. [4] Crawford, J.S. and Konkol, R.J., Familial hemiplegic migraine with crossed cerebellar diaschisis and unilateral meningeal enhancement, Headache, 37 (1997) 590–593. [5] Cutrer, F.M., Sorensen, A.G., Weisskoff, R.M., Ostergaard, L., Sanchez del Rio, M., Lee, E.J., Rosen, B.R. and Moskowitz, M.A., Perfusion-weighted imaging defects during spontaneous migrainous aura, Ann. Neurol., 43 (1998) 25– 31. [6] Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M.G. and Tournier-Lasserve, E., The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel, N. Engl. J. Med., 345 (2001) 17–24.
[7] Hadjikhani, N., Sanchez del Rio, M., Wu, O., Schwartz, D., Bakker, D., Fischl, B., Kwong, K.K., Cutrer, F.M., Rosen, B.R., Tootell, R.B.H., Sorensen, A.G. and Moskowitz, M.A., Mechanisms of migraine aura revealed by functional MRI in human visual cortex, Proc. Natl. Acad. Sci. USA, 98 (2001) 4687–4692. [8] Olesen, J., Bes, A., Kunkel, R., Lance, J.W., Nappi, G., Pfaffenrath, V., Clifford Rose, F., Schoenberg, B.S., Soyka, D., Tfelt-Hansen, P., Welch, K.M.A. and Wilkinson, M., Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain, Cephalalgia, 8(Suppl. 7) (1988) 1–96. [9] James, M.F., Smith, M.I., Bockhorst, K.H., Hall, L.D., Houston, G.C., Papadakis, N.G., Smith, J.M., Williams, E.J., Xing, D., Parsons, A.A., Huang, C.L.H. and Carpenter, T.A., Cortical spreading depression in the gyrencephalic feline brain studied by magnetic resonance imaging, J. Physiol., 519 (1999) 415425. [10] Jun, K., Piedras-Renteria, E.S., Smith, S.M., Wheeler, D.B., Lee, S.B., Lee, T.G., Chin, H., Adams, M.E., Scheller, R.H., Tsien, R.W. and Shin, H.S., Ablation of P/Q-type Ca 21 channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the a1A-subunit, Proc. Natl. Acad. Sci. USA, 96 (1999) 15245–15250. [11] Olesen, J., Friberg, L., Skyhoj Olsen, T., Iversen, H.K., Lassen, N.A., Andersen, A.R. and Karle, A., Timing and topography of cerebral blood flow, aura, and headache during migraine attacks, Ann. Neurol., 28 (1990) 791–798. [12] Ophoff, R.A., Terwindt, G.M., Vergouwe, M.N., van Eijk, R., Oefner, P.J., Hoffman, S.M.G., Lamerdin, J.E., Mohrenweiser, H.W., Bulman, D.E., Ferrari, M., Haan, J., Lindhout, D., van-Ommen, G.J.B., Hofker, M.H., Ferrari, M.D. and Frants, R.R., Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca 1 channel gene CACNL1A4, Cell, 87 (1996) 543–552. [13] Plomp, J.J., Vergouwe, M.N., Vander-Maagdenberg, A.M., Ferrari, M.D., Frants, R.R. and Molenaar, P.C., Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering a1A Ca 21 channel mutation, Brain, 123 (2000) 463–471. [14] Sachs, H., Wolf, A., Russell, J.A.G. and Christman, D.R., Effect of reserpine on regional cerebral glucose metabolism in control and migraine subjects, Arch. Neurol., 43 (1986) 1117–1123. [15] Spranger, M., Spranger, S., Schwab, S., Benninger, C. and Dichgans, M., Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis, Eur. Neurol., 41 (1999) 150–152. [16] Terwindt, G.M., Ophoff, R.A., van-Eijk, R., Vergouwe, M.N., Haan, J., Frants, R.R., Sandkuijl, L.A. and Ferrari, M.D., Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura, Neurology, 56 (2001) 1028–1032. [17] Volkow, N.D., Wang, G.J., Fowler, J.S., Rooney, W.D., Felder, C.A. and Lee, J.H., Resting brain metabolic activity in a 4 tesla magnetic field, Magn. Reson. Med., 44 (2000) 701–705. [18] Woods, R.P., Iacoboni, M. and Mazziotta, J.C., Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache, N. Engl. J. Med., 331 (1994) 1689–1692.
Multimodal functional imaging of prolonged neurological deficits in a patient suffering from familial hemiplegic migraine Alexander Gutschalk a,*, Rainer Kollmar a, Alexander Mohr b, Marcus Henze c, Nicole Ille a, Markus Schwaninger a, Marius Hartmann b, Stefan Ha¨hnel b, Uwe Haberkorn c, Andre´ Rupp a, Uta Meyding-Lamade a a Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany c Department of Nuclear Medicine, University of Heidelberg, 69120 Heidelberg, Germany b
Received 21 June 2002; received in revised form 7 August 2002; accepted 12 August 2002
Abstract The case of a patient with familial hemiplegic migraine (FHM) suffering from prolonged right sided hemiparesis and aphasia that persisted for more than 10 days is reported. The symptoms were accompanied by slowing of the magnetoencephalogram over the left hemisphere, which normalized parallel to the clinical improvement. Positron emission tomography obtained on the 6th day revealed glucose-hypometabolism (hemispheric difference $10%) in left hemisphere’s fronto-basal cortex, caudate nucleus, and thalamus. In contrast, magnetic resonance imaging including perfusion and diffusion weighted imaging was normal and did not show significant alterations of cortical perfusion or water mobility during the episode. We hypothesize that this finding provides evidence for a primary neuronal dysfunction causing the prolonged neurological deficits in FHM. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine aura; Functional neuroimaging; Magnetoencephalography; Positron emission tomography; Magnetic resonance imaging; Perfusion weighted imaging; Calcium channels
Many patients suffering from familial hemiplegic migraine (FHM) exhibit a missense mutation in the CACNA1A gene on chromosome 19p13, coding for the a1A-subunit of P/Q-type calcium channels [12]. Animal models with altered P/Q-type calcium currents provide evidence for altered synaptic transmission [10] in the brain. However, there is considerable clinical variability not only among different mutations in mice, but also in humans with FHM and different genotypes [6]. Neurological deficits in FHM may be of similar duration as those preceding migraine with typical aura [8], or last up to several days, sometimes including confusion and coma [6]. However, these severe clinical manifestations are rare, and there are only few reports on functional neuroimaging in hemiplegic migraine [1,3,4]. As animal models do not yet provide a valid model of migraine, studies of human patho-
* Corresponding author. Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Tel.: 149-6221-56-5191; fax: 149-6221-56-5258. E-mail address: [email protected] (A. Gutschalk).
physiology are necessary to further our understanding of FHM. This is especially interesting with respect to recent evidence of an involvement of the CACNA1A gene in migraine with typical aura and migraine without aura [16]. Here, we report a case of FHM [8] that was monitored with perfusion- and diffusion-weighted magnetic resonance imaging (MRI), magnetoencephalography (MEG), transcranial Doppler sonography, and positron emission tomography (PET) during a 2 week period of neurological deficits and follow-up studies over 3 months. The 16 year old male with known FHM [15] linked to chromosome 19p13 presented to the emergency room with mild right-sided hemiparesis, hemihypaesthesia and non-fluent aphasia. He complained about a throbbing, left-sided headache; the onset of symptoms was similar to his usual migraine auras, but hemiparesis now persisted for more than 4 h. CCT and MRI were normal; the symptoms resolved after intravenous administration of 0.5 g Aspirin, and he was discharged home being instructed to return in case of worsening symptoms. On the next morning, he presented again with moderate hemiparesis, global aphasia, and meningismus. White blood count amounted to 17/ml, body
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 94 0- 0
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temperature was 39 8C. MRI was again normal; cerebrospinal fluid showed normal cell counts (1/ml) and protein (31.8 mg/dl). He was admitted to the neurology service and received intravenous Aspirin (1.0 g at the 2nd and 3rd day) and Nimodipine (300 mg per day orally from day 4– 18). Later Acetazolamid was added (500 mg per day orally from day 5–18); low molecular weight heparin was given for prophylaxis of thrombembolism. In the following days, he recovered only slowly from his neurological deficits; meningismus resolved within 3 days and white blood count was within normal limits at day 4. Hemiparesis started to decrease at day 5, and completely resolved within 10 days. The headaches subsided after about 7 days. Aphasia improved more slowly, and on day 12 he still suffered from non-fluent aphasia with paraphasic speech, impaired auditory word understanding, naming and word finding difficulties. At discharge on day 18, he still suffered from mild word finding difficulties, which resolved after 2 months of speech therapy. On physical exam he did not show any signs of cerebellar dysfunction, which were found in other members of his family [15]. Another prolonged episode comparable to the present one happened at the age of 12 years. MRI was obtained at days 1, 2, 10 and 98 on a 1.5 T scanner (EDGE, Marconi). The protocol included axial T2-weighted fast spin echo sequences, coronar T1-weighted spin echo sequences, and axial isotropic diffusion-weighted imaging EPI sequences. Additionally, at day 2 and 98 perfusion-weighted imaging was performed. Relative regional cerebral blood volume (rrCBV) and mean transit time (MTT) were calculated based on 40 data sets of axial T2*-weighted gradient echo EPI sequences (slice thickness 8 mm) acquired during the injection of 25 ml Gadolinium at 5 ml/s. Continuous MEG was recorded at days 3, 5, 12, 35, and 98 with a Neuromag 122 channel whole-head system. Recordings were performed at 400 Hz sample-rate with a lowpass of 100 Hz. Data were visually inspected to exclude artifact-contaminated epochs and evaluated by an averaged Fast Fourier Transform (FFT) over the whole 10 min recording (BESA2000, Megis Software GmbH, Munich). The FFT block size was set to 2048 samples corresponding to 5.12 s. FFT was calculated every 2.56 s and the overlapping FFTblocks were averaged. A cos 2-shaped window was applied to each data block prior to FFT, to assign equal weight to each sample. To monitor cerebral glucose metabolism, 18F-2-fluoro-2deoxy-d-glucose (FDG) PET was obtained at day 6 with a Siemens-CTI EXACT-47-scanner. Plasma-glucose level of the fasting patient was 85 mg/dl. After 10 min of transmission measurement, 100 MBq 18F-FDG were given. Then, after 30 min, emission of the brain was recorded for 20 min in 3D-mode. Image reconstruction was done iteratively, using the ordered subsets-expectation maximization algorithm. After correcting for radioactive decay (t0:5 ¼ 110 min), tracer-uptake was expressed as standardized uptake
value (SUV ¼ (tissue activity concentration [kBq/g])/ (injected dose [kBq]/bodyweight [g])). For estimation of unilateral changes in FDG-uptake, SUV-ratios were calculated using reference regions in the contralateral hemisphere. Semiquantitative measurements of bilateral changes of FDG-uptake were obtained by calculating relative SUVs normalized to the global brain metabolism, based on normal values published by Volkow et al. [17]. Structural MRI was normal during as well as after the migraine episode. Diffusion-weighted scans also did not show any asymmetry and were normal with respect to routine clinical criteria used for the diagnosis of ischemic stroke. Perfusion-weighted imaging at day 2 and 98 did not show pathological differences between hemispheres with respect to rrCBV- and MTT-maps. MEG recordings on day 3 showed prominent high amplitude delta activity over the whole left hemisphere with a maximum over the left temporal lobe, while activity in the alpha- and beta-band was strongly suppressed over the left hemisphere (Fig. 1a). The left-sided slowing degraded over the following sessions, but was not completely resolved at day 98. The lateralized suppression of alpha and beta activity was maintained until day 35 and at day 98 had returned to a symmetrical distribution over the occipital lobe. Positron emission tomography at day 6 showed moderate but significantly reduced FDG-uptake ($10% difference between hemispheres) within left hemisphere’s frontobasal cortex, caudate nucleus, and thalamus (Fig. 1b). In occipital cortex reduced FDG-accumulation was observed in both hemispheres relative to the mean standard uptake values of the other cortical regions (.10%). Transcranial Doppler was performed at day 1, 4, 6, 13 and 98. Each time, velocities were found enhanced over the anterior and the medial cerebral artery of both hemispheres. Frequencies were in the range of 3–5 kHz in ictal as well as interictal examinations with no consistent difference between hemispheres. Similar frequencies were reported 4 years ago in an interictal examination. Summarizing, our data show prolonged neuronal dysfunction reflected by focal slowing in the MEG recordings, that go along with reduced relative FDG-uptake in the affected hemisphere. These findings parallel the symptoms of the migraine aura, and the results of the repeated MEG-recordings parallel the slow improvement of neurological deficits. The bilateral slowing of occipital alpha-rhythm was similarly accompanied by bilateral reduction of FDG-uptake in the occipital cortex. However, there was no clinical correlation of these bilateral neuronal changes. Although visual aura symptoms may have been missed in the acute stage, there was no evidence of hemianopia during the further hospital course and there was no history of visual aura given by the patient. Bilateral reduction of perfusion, spreading over the occipital lobe, has been reported to precede migraine without aura [18], and bilaterally reduced FDG-uptake has been reported in migraine with and without aura after reserpine induced migraine attacks [14]. This would suggest that the bilateral reduction of brain meta-
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Fig. 1. (A) Sum of MEG amplitude at days 3, 5, 12, 35, and 98 in the delta- (1–4 Hz), theta- (4–8 Hz), alpha- (8–14 Hz), and beta-band (14–30 Hz). The FFT-maps are spline interpolated and shown in top meridian projection down to the level of the lateral rows nine and ten in the 10–20 system; the 61 gradiometer positions are plotted above as white dots. Note that the scaling for the delta-band is twice as large as for the other frequency bands. (B) 18F-FDG PET obtained at day 6, radiological convention. The chosen scans depict the reduced FDGuptake in the left frontal cortex, caudate nucleus and thalamus, as well as in bilateral occipital cortex.
bolism correlates to a pathophysiological mechanism typical for migraine that is not necessarily accompanied by visual aura symptoms. As our semi-quantitative PET-study relies on the assumption of a normal reference, we can not exclude that increased FDG-uptake in other brain regions may mimic reduced uptake in bilateral occipital and left frontal cortex. However, we consider this alternative explanation very improbable, since it would contradict the findings of reduced perfusion and metabolism found unilaterally [5,11] and bilaterally [14,18] in the majority of studies on migraine. In contrast to the PET- and MEG-findings, neither perfusion- nor diffusion-weighted MRI-scans revealed significant abnormalities. Studies recording perfusion-weighted MRI [5,7] and xenon133-SPECT [11] in typical migraine aura reported moderate hypoperfusion corresponding closely to the clinical presentation of neurological deficits. As shown by a recent functional MRI-study, this decreased perfusion is probably a consequence of cortical spreading depression [7], as it shares the characteristics of blood oxygenation level dependent signal changes derived from a cat model [9]. Hypoperfusion might also have accompanied the initiation of the migraine aura in our patient, but at this time
recording was not possible. In the further course, however, perfusion weighted MRI was normal, while FDG-PET and MEG showed continued cortical dysfunction. Although it cannot be excluded that FDG-PET is more sensitive than perfusion weighted MRI, we would have expected at least mild hemispheric differences in the perfusion weighted MRI 24 h after symptom onset, given the severe clinical presentation. For the same reasoning it is improbable that a decreased perfusion might have been found at the day of PET-scanning, since the patient had clinically improved by that time. It rather appears, that the physiological coupling of brain metabolism and perfusion becomes lost in the prolonged course of migraine aura in FHM. A similar uncoupling of brain metabolism and perfusion with decreased deoxyglucose uptake with normal perfusion has for example been observed in the vicinity of epileptic foci in the interictal interval [2]. Irrespective of this interpretation, our results provide further evidence that hypoperfusion in migraine is not responsible for prolonged neurological deficits. If it was, we would expect faster recovery of the focal slowing and hypometabolism as well as faster clinical recovery than observed in our patient.
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Two earlier cases report employing SPECT in FHM reported hyper- [1] as well as hypoperfusion of the affected hemisphere [4] during prolonged aura. Decreased water mobility, consistent with reversible cytotoxic edema, was reported applying diffusion tensor imaging to a FHMpatient with a severe attack [3]. All three cases [1,3,4] have in common a swelling of the affected hemisphere observed with standard T1- and T2-weighted MRIsequences, in two cases associated with meningeal enhancement [3,4]. Repeated MRI studies including T1-, T2-, and diffusion-weighted sequences were normal in our patient, suggesting that this case represents a less severe form of the broad clinical spectrum of FHM [6], that is closer to migraine with prolonged aura [8] in patients that do not suffer from FHM. The origin of the prolonged neuronal dysfunction in FHM remains unclear at present; while spreading cortical depression may well explain typical migraine aura [7] as well as the initiation of prolonged aura in FHM, it can hardly account for neuronal dysfunction over days and weeks. Mouse models with ablation [10] or mutation [13] in the a1A-subunit of P/Q-type calcium channels provide evidence for altered synaptic transmission due to alteration of voltage gated calcium currents. With reference to this data [13], one might speculate that dysregulation of calcium influx into excitatory synapses might result in prolonged blockage of synaptic transmission after the beginning of migraine aura triggered by spreading depression. New mouse models of FHM may further resolve these mechanisms. [1] Barbour, P.J., Castaldo, J.E. and Shoemaker, E.I., Hemiplegic migraine during pregnancy: Unusual magnetic resonance appearance with SPECT scan correlation, Headache, 41 (2001) 310–316. [2] Bruehl, C., Hagemann, G. and Witte, O.W., Uncoupling of blood flow and metabolism in focal epilepsy, Epilepsia, 39 (1998) 1235–1242. [3] Chabriat, H., Vahedi, K., Clark, C., Poupon, C., Ducros, A., Denier, C., Le Bihan, D. and Bousser, M.G., Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene, Neurology, 54 (2000) 510–512. [4] Crawford, J.S. and Konkol, R.J., Familial hemiplegic migraine with crossed cerebellar diaschisis and unilateral meningeal enhancement, Headache, 37 (1997) 590–593. [5] Cutrer, F.M., Sorensen, A.G., Weisskoff, R.M., Ostergaard, L., Sanchez del Rio, M., Lee, E.J., Rosen, B.R. and Moskowitz, M.A., Perfusion-weighted imaging defects during spontaneous migrainous aura, Ann. Neurol., 43 (1998) 25– 31. [6] Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M.G. and Tournier-Lasserve, E., The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel, N. Engl. J. Med., 345 (2001) 17–24.
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