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Impairment of neuromuscular transmission in a subgroup of migraine patients
Neuroscience Letters 276 (1999) 201±203 www.elsevier.com/locate/neulet
Impairment of neuromuscular transmission in a subgroup of migraine patients Anna Ambrosini, Alain Maertens de Noordhout, Giovanna Alagona, Francesca Dalpozzo, Jean Schoenen* Department of Neurology, Headache Unit, University of LieÁge, CHR Citadelle, Blvd du XIIeÁme de Ligne, 1-B-4000 LieÁge, Belgium Received 29 September 1999; received in revised form 7 October 1999; accepted 7 October 1999
Abstract Neuronal voltage-dependent P/Q Ca 21 channels are genetically abnormal in many cases of familial hemiplegic migraine and possibly associated with the more common forms of migraine with and without aura. Besides the brain, these channels are found in motor nerve endings where they control stimulation-induced acetylcholine release. Using single ®ber EMG recordings we were able to demonstrate subclinical abnormalities of neuromuscular transmission in a subgroup of patients suffering from migraine with aura. This could be related to genetic abnormalities of P/Q Ca 21 channels in certain patients suffering from migraine with aura, which needs to be explored by proper genetic analyses. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine; P/Q Ca 21 channels; Single ®ber electromyography; Neuromuscular transmission; Familial hemiplegic migraine
Mutations in the a 1A-subunit gene of the neuronal P/Q Ca 21 channel (CACNA1A on chromosome 19p13) have been found in familial hemiplegic migraine as well as in episodic ataxia type II and spino-cerebellar ataxia type 6 [6]. Sib-pair [4] and linkage [5] analyses have provided indirect evidence that the same locus may also be linked to the more frequent forms of migraine, especially to migraine with aura. Voltage-dependent P/Q-type Ca 21 channels are widely distributed in the central nervous system, but they are also found on presynaptic motor axons at the neuromuscular junctions, where they control stimulation-induced acetylcholine release [10]. We hypothesized that subclinical dysfunctions of neuromuscular transmission might be detectable in patients suffering from migraine with aura, if P/Q-type Ca 2t channels are abnormal in this disorder. Therefore, we used single ®ber electromyography (SFEMG), which is the most sensitive in vivo method to detect dysfunctions at the neuromuscular junction and routinely used for this purpose in neuromuscular disorders [8]. In order to avoid inclusion of subjects affected by, or at risk of migraine, we studied a proper control group of * Corresponding author. Tel.: 132-4225-6391; fax: 132-42256451. E-mail address: [email protected] (J. Schoenen)
subjects (healthy volunteers: HV) without any known personal or familial history of recurrent headaches nor any other neurological disorder (n 14; six males, eight females; mean age ^ SD: 36.4 ^ 10.8 years). They were compared with a group of 19 migraine with aura patients (MA) diagnosed according to the International Headache Society criteria [3] (IHS code: 1.2; six males, 13 females; mean age: 33.6 ^ 12.3, mean attack frequency: 3.3 ^ 3.7/ month). All migraineurs but four had a family history for migraine and none of them had other coexisting headache types. None of controls or migraineurs were taking drugs on a regular basis, nor had taken any drug within 3 days before the recordings. Migraineurs were examined interictally at an interval of at least 3 days from an attack by one of us (A.A.) who was blinded to the detailed clinical history. Single muscle ®ber activity was recorded with 25 mm long single ®ber needles (Medelec w Neurodiagnostic Accessories, ref.: 16829) and the motor nerve was stimulated with Nicolet w te¯on-insulated monopolar needles. A Nicolet w Viking IV device was used for all neurophysiological recordings. We stimulated the motor branch of the radial nerve and assessed the variability in latency, i.e. the jitter, of single ®ber action potentials in m. extensor digitorum communis (EDC) of the right arm. Stimulation rate was 10 Hz and on average we recorded 18 EDC muscle ®bers per patient. As usual in SFEMG studies, results
0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 82 0- 4
202
A. Ambrosini et al. / Neuroscience Letters 276 (1999) 201±203
were expressed as the `mean value of consecutive differences' (MCD) of successive interpotential intervals. According to published normative data [9], mean MCD may not exceed 25 ms and no more than 10% of ®bers are allowed to have an MCD superior to 40 ms; in more severe impairments of neuromuscular transmission, nerve impulses may fail to elicite an action potential, producing intermittent ®ber blocking. Results obtained in the two groups of subjects were compared by the Mann±Whitney U-test. Secondary analyses in MA patients subgroups were performed by the x 2 test for observed versus expected frequencies. MCD was on average signi®cantly greater in migraine with aura patients (20.66 ^ 4.89 ms) than in healthy volunteers (17.04 ^ 2.84 ms) (P 0:034) (Fig. 1). No single ®ber with increased jitter or impulse blocking was detected in the control group. By contrast, ten out the 19 migraine with aura patients had one or several abnormal ®ndings on SFEMG: in six patients MCD exceeded the mean value of controls plus 2SD, eight had an abnormal jitter on average in 10.24% of ®bers and ®ve had intermittent impulse blocking in an average of 12.08% of ®bers. These 10 patients with SFEMG abnormalities did not differ from the other migraineurs according to monthly attack frequency (3.1 ^ 3.9 vs. 3.5 ^ 3.6) or positive family history for migraine (8/10 vs. 7/9). A retrospective more detailed analysis of the clinical records in the migraine with aura group disclosed that 14 out of the 19 patients had some notable clinical features: unilateral sensorimotor symptoms and/or aphasia and/or vertigo associated with or following the visual symptoms during the aura (n 11), sensorimotor aura symptoms and/ or vertigo without visual symptoms (n 3). Ten out of these 14 patients had abnormal SFEMG ®ndings which was statistically signi®cant (x 2 test: P 0:001). Among them, four patients ful®lled the IHS criteria for migraine with prolonged aura (code IHS: 1.2.2) and one the criteria
for basilar migraine (code IHS: 1.2.4). The six remaining patients with abnormal SFEMG quali®ed for IHS code: 1.2.1, i.e. migraine with typical aura, as did all the other migraineurs with normal SFEMG ®ndings. This study is the ®rst to demonstrate a subclinical impairment of neuromuscular transmission in patients suffering from migraine with aura according to IHS criteria (code 1.2). SFEMG abnormalities, however, were found only in patients characterized by peculiar clinical features. Five patients had slight unilateral motor de®cits during the aura, but no prolonged hemiparesis and no known family history of familial hemiplegic migraine (code 1.2.3). In two patients the aura was accompanied by vertigo and dizziness, but only one of them quali®ed for a diagnosis of basilar migraine (code 1.2.4). Ictal motor symptoms and disequilibrium are hallmarks of human P/Q-type Ca 21 channelopathies such as familial hemiplegic migraine and episodic ataxia type II [11]; ataxia and epilepsy are also found in mice with spontaneous genetic abnormalities of the P/Q Ca 21 channel [1,2]. The subtle impairment of neuromuscular transmission detected by SFEMG could thus be due to dysfunctioning P/Q Ca 21 channels on presynaptic motor endings. Whether this is a consequence of an abnormal CACNA1A gene, is being tested by appropriate genetic analyses. Interestingly, tottering mice which present natural mutations in the CACNA1A gene also have dysfunctions of neuromuscular transmission according to a recent preliminary report [7]. If it can be established that SFEMG abnormalities are related to mutations in the CACNA1A gene, this would con®rm that this gene is also involved in migraine with typical (code 1.2.1) or prolonged aura (code 1.2.2) and in basilar migraine (code 1.2.4), and that the common subtype of migraine with typical aura is genetically heterogeneous. SFEMG could thus be useful to select migraine patients for genetic analyses and hopefully for novel therapeutic strategies.
Fig. 1. Distribution of mean value of consecutive differences (MCD; on the y-axis) in HV and MA patients. Different symbols identify migraine with aura patients qualifying for different 3rddigit code levels in the IHS classi®cation. The vertical arrows indicate patients who had ®bers with increased jitter and/or impulse blocking. The range of MCD in healthy volunteers (mean ^ 2SD) is comprised between the dotted lines.
[1] Doyle, J., Ren, X., Lenin, G. and Stubbs, L., Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration and ataxia in tottering and leaner mutant mice. Mamm. Genome., 8 (1997) 113± 120. [2] Fletcher, C.F., Lutz, C.M., O'Sullivan, T.N., Shaughnessy Jr., J.D., Hawkes, R., Frankel, W.N., Copeland, N.G. and Jenkins, N.A., Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell, 87 (1996) 607±617. [3] Headache Classi®cation Committee of the International Headache Society, Classi®cation and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia, 8 (Suppl. 7) (1988). [4] May, A., Ophoff, R.A., Terwindt, G.M., Urban, C., van Eijk, R., Haan, J., Diener, H.C., Lindhout, D., Frants, R.R., Sandkuijl, L.A. and Ferrari, M.D., Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Hum. Genet., 96 (1995) 604±608. [5] Nyholt, D.R., Lea, R.A., Goadsby, P.J., Brimage, P.J. and Grif®ths, L.R., Familial typical migraine: linkage to chromo-
A. Ambrosini et al. / Neuroscience Letters 276 (1999) 201±203 some 19p13 and evidence for genetic heterogeneity. Neurology, 50 (1998) 1428±1432. [6] Ophoff, R.A., Terwindt, G.M., Vergouwe, M.N., van Eijk, R., Oefner, P.J., Hoffman, S.M., Lamerdin, J.E., Mohrenweiser, H.V., Bulman, D.E., Ferrari, M., Haan, J., Lindhout, D., Van Ommen, G.J., 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 21 channel gene CACNL1A4. Cell, 87 (1996) 543±552. [7] Plomp, J.J., Vergouwe, M.N., Ferrari, M.D., Frants, R.R. and Molenaar, P.C., Abnormal acetylcholine release at neuromuscular junctions of mice carrying the tottering a1A Ca 21 channel gene mutation. Cephalalgia, 19 (1999) 304±305. [8] Sanders, D.B. and Stalberg, E.V., AAEM minimonograph
203
#25: single-®ber electromyography. Muscle Nerve, 19 (1996) 1069±1083. [9] Stalberg, E. and Trontelj, J.V., The study of normal and abnormal neuromuscular transmission with single ®bre electromyography. J. Neurosci. Methods, 74 (1997) 145± 154. [10] Sugiura, Y., Woppmann, A., Miljanich, G.P. and Ko, C.P., A novel omega-conopeptide for the presynaptic localization of calcium channels at the mammalian neuromuscular junction. J. Neurocytol., 24 (1995) 15±27. [11] Terwindt, G.M., Ophoff, R.A., Haan, J., Sandkuijl, L.A., Frants, R. and Ferrari, M.D., Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group. Eur. J. Hum. Genet., 6 (1998) 297±307.
Impairment of neuromuscular transmission in a subgroup of migraine patients Anna Ambrosini, Alain Maertens de Noordhout, Giovanna Alagona, Francesca Dalpozzo, Jean Schoenen* Department of Neurology, Headache Unit, University of LieÁge, CHR Citadelle, Blvd du XIIeÁme de Ligne, 1-B-4000 LieÁge, Belgium Received 29 September 1999; received in revised form 7 October 1999; accepted 7 October 1999
Abstract Neuronal voltage-dependent P/Q Ca 21 channels are genetically abnormal in many cases of familial hemiplegic migraine and possibly associated with the more common forms of migraine with and without aura. Besides the brain, these channels are found in motor nerve endings where they control stimulation-induced acetylcholine release. Using single ®ber EMG recordings we were able to demonstrate subclinical abnormalities of neuromuscular transmission in a subgroup of patients suffering from migraine with aura. This could be related to genetic abnormalities of P/Q Ca 21 channels in certain patients suffering from migraine with aura, which needs to be explored by proper genetic analyses. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Migraine; P/Q Ca 21 channels; Single ®ber electromyography; Neuromuscular transmission; Familial hemiplegic migraine
Mutations in the a 1A-subunit gene of the neuronal P/Q Ca 21 channel (CACNA1A on chromosome 19p13) have been found in familial hemiplegic migraine as well as in episodic ataxia type II and spino-cerebellar ataxia type 6 [6]. Sib-pair [4] and linkage [5] analyses have provided indirect evidence that the same locus may also be linked to the more frequent forms of migraine, especially to migraine with aura. Voltage-dependent P/Q-type Ca 21 channels are widely distributed in the central nervous system, but they are also found on presynaptic motor axons at the neuromuscular junctions, where they control stimulation-induced acetylcholine release [10]. We hypothesized that subclinical dysfunctions of neuromuscular transmission might be detectable in patients suffering from migraine with aura, if P/Q-type Ca 2t channels are abnormal in this disorder. Therefore, we used single ®ber electromyography (SFEMG), which is the most sensitive in vivo method to detect dysfunctions at the neuromuscular junction and routinely used for this purpose in neuromuscular disorders [8]. In order to avoid inclusion of subjects affected by, or at risk of migraine, we studied a proper control group of * Corresponding author. Tel.: 132-4225-6391; fax: 132-42256451. E-mail address: [email protected] (J. Schoenen)
subjects (healthy volunteers: HV) without any known personal or familial history of recurrent headaches nor any other neurological disorder (n 14; six males, eight females; mean age ^ SD: 36.4 ^ 10.8 years). They were compared with a group of 19 migraine with aura patients (MA) diagnosed according to the International Headache Society criteria [3] (IHS code: 1.2; six males, 13 females; mean age: 33.6 ^ 12.3, mean attack frequency: 3.3 ^ 3.7/ month). All migraineurs but four had a family history for migraine and none of them had other coexisting headache types. None of controls or migraineurs were taking drugs on a regular basis, nor had taken any drug within 3 days before the recordings. Migraineurs were examined interictally at an interval of at least 3 days from an attack by one of us (A.A.) who was blinded to the detailed clinical history. Single muscle ®ber activity was recorded with 25 mm long single ®ber needles (Medelec w Neurodiagnostic Accessories, ref.: 16829) and the motor nerve was stimulated with Nicolet w te¯on-insulated monopolar needles. A Nicolet w Viking IV device was used for all neurophysiological recordings. We stimulated the motor branch of the radial nerve and assessed the variability in latency, i.e. the jitter, of single ®ber action potentials in m. extensor digitorum communis (EDC) of the right arm. Stimulation rate was 10 Hz and on average we recorded 18 EDC muscle ®bers per patient. As usual in SFEMG studies, results
0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 82 0- 4
202
A. Ambrosini et al. / Neuroscience Letters 276 (1999) 201±203
were expressed as the `mean value of consecutive differences' (MCD) of successive interpotential intervals. According to published normative data [9], mean MCD may not exceed 25 ms and no more than 10% of ®bers are allowed to have an MCD superior to 40 ms; in more severe impairments of neuromuscular transmission, nerve impulses may fail to elicite an action potential, producing intermittent ®ber blocking. Results obtained in the two groups of subjects were compared by the Mann±Whitney U-test. Secondary analyses in MA patients subgroups were performed by the x 2 test for observed versus expected frequencies. MCD was on average signi®cantly greater in migraine with aura patients (20.66 ^ 4.89 ms) than in healthy volunteers (17.04 ^ 2.84 ms) (P 0:034) (Fig. 1). No single ®ber with increased jitter or impulse blocking was detected in the control group. By contrast, ten out the 19 migraine with aura patients had one or several abnormal ®ndings on SFEMG: in six patients MCD exceeded the mean value of controls plus 2SD, eight had an abnormal jitter on average in 10.24% of ®bers and ®ve had intermittent impulse blocking in an average of 12.08% of ®bers. These 10 patients with SFEMG abnormalities did not differ from the other migraineurs according to monthly attack frequency (3.1 ^ 3.9 vs. 3.5 ^ 3.6) or positive family history for migraine (8/10 vs. 7/9). A retrospective more detailed analysis of the clinical records in the migraine with aura group disclosed that 14 out of the 19 patients had some notable clinical features: unilateral sensorimotor symptoms and/or aphasia and/or vertigo associated with or following the visual symptoms during the aura (n 11), sensorimotor aura symptoms and/ or vertigo without visual symptoms (n 3). Ten out of these 14 patients had abnormal SFEMG ®ndings which was statistically signi®cant (x 2 test: P 0:001). Among them, four patients ful®lled the IHS criteria for migraine with prolonged aura (code IHS: 1.2.2) and one the criteria
for basilar migraine (code IHS: 1.2.4). The six remaining patients with abnormal SFEMG quali®ed for IHS code: 1.2.1, i.e. migraine with typical aura, as did all the other migraineurs with normal SFEMG ®ndings. This study is the ®rst to demonstrate a subclinical impairment of neuromuscular transmission in patients suffering from migraine with aura according to IHS criteria (code 1.2). SFEMG abnormalities, however, were found only in patients characterized by peculiar clinical features. Five patients had slight unilateral motor de®cits during the aura, but no prolonged hemiparesis and no known family history of familial hemiplegic migraine (code 1.2.3). In two patients the aura was accompanied by vertigo and dizziness, but only one of them quali®ed for a diagnosis of basilar migraine (code 1.2.4). Ictal motor symptoms and disequilibrium are hallmarks of human P/Q-type Ca 21 channelopathies such as familial hemiplegic migraine and episodic ataxia type II [11]; ataxia and epilepsy are also found in mice with spontaneous genetic abnormalities of the P/Q Ca 21 channel [1,2]. The subtle impairment of neuromuscular transmission detected by SFEMG could thus be due to dysfunctioning P/Q Ca 21 channels on presynaptic motor endings. Whether this is a consequence of an abnormal CACNA1A gene, is being tested by appropriate genetic analyses. Interestingly, tottering mice which present natural mutations in the CACNA1A gene also have dysfunctions of neuromuscular transmission according to a recent preliminary report [7]. If it can be established that SFEMG abnormalities are related to mutations in the CACNA1A gene, this would con®rm that this gene is also involved in migraine with typical (code 1.2.1) or prolonged aura (code 1.2.2) and in basilar migraine (code 1.2.4), and that the common subtype of migraine with typical aura is genetically heterogeneous. SFEMG could thus be useful to select migraine patients for genetic analyses and hopefully for novel therapeutic strategies.
Fig. 1. Distribution of mean value of consecutive differences (MCD; on the y-axis) in HV and MA patients. Different symbols identify migraine with aura patients qualifying for different 3rddigit code levels in the IHS classi®cation. The vertical arrows indicate patients who had ®bers with increased jitter and/or impulse blocking. The range of MCD in healthy volunteers (mean ^ 2SD) is comprised between the dotted lines.
[1] Doyle, J., Ren, X., Lenin, G. and Stubbs, L., Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration and ataxia in tottering and leaner mutant mice. Mamm. Genome., 8 (1997) 113± 120. [2] Fletcher, C.F., Lutz, C.M., O'Sullivan, T.N., Shaughnessy Jr., J.D., Hawkes, R., Frankel, W.N., Copeland, N.G. and Jenkins, N.A., Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell, 87 (1996) 607±617. [3] Headache Classi®cation Committee of the International Headache Society, Classi®cation and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia, 8 (Suppl. 7) (1988). [4] May, A., Ophoff, R.A., Terwindt, G.M., Urban, C., van Eijk, R., Haan, J., Diener, H.C., Lindhout, D., Frants, R.R., Sandkuijl, L.A. and Ferrari, M.D., Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Hum. Genet., 96 (1995) 604±608. [5] Nyholt, D.R., Lea, R.A., Goadsby, P.J., Brimage, P.J. and Grif®ths, L.R., Familial typical migraine: linkage to chromo-
A. Ambrosini et al. / Neuroscience Letters 276 (1999) 201±203 some 19p13 and evidence for genetic heterogeneity. Neurology, 50 (1998) 1428±1432. [6] Ophoff, R.A., Terwindt, G.M., Vergouwe, M.N., van Eijk, R., Oefner, P.J., Hoffman, S.M., Lamerdin, J.E., Mohrenweiser, H.V., Bulman, D.E., Ferrari, M., Haan, J., Lindhout, D., Van Ommen, G.J., 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 21 channel gene CACNL1A4. Cell, 87 (1996) 543±552. [7] Plomp, J.J., Vergouwe, M.N., Ferrari, M.D., Frants, R.R. and Molenaar, P.C., Abnormal acetylcholine release at neuromuscular junctions of mice carrying the tottering a1A Ca 21 channel gene mutation. Cephalalgia, 19 (1999) 304±305. [8] Sanders, D.B. and Stalberg, E.V., AAEM minimonograph
203
#25: single-®ber electromyography. Muscle Nerve, 19 (1996) 1069±1083. [9] Stalberg, E. and Trontelj, J.V., The study of normal and abnormal neuromuscular transmission with single ®bre electromyography. J. Neurosci. Methods, 74 (1997) 145± 154. [10] Sugiura, Y., Woppmann, A., Miljanich, G.P. and Ko, C.P., A novel omega-conopeptide for the presynaptic localization of calcium channels at the mammalian neuromuscular junction. J. Neurocytol., 24 (1995) 15±27. [11] Terwindt, G.M., Ophoff, R.A., Haan, J., Sandkuijl, L.A., Frants, R. and Ferrari, M.D., Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group. Eur. J. Hum. Genet., 6 (1998) 297±307.