Neurology -- Correspondence for Yu and Horowitz, 60 (1) 120-121

Correspondence published:

Reply to Letter to the Editor: Wengui Yu (5 March 2003)

Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil: Augusto Cezar Lastimosa (5 March 2003)

Reply to Letter to the Editor 5 March 2003

Wengui Yu
University of California-San Francisco CA
Send Correspondence to journal:
Re: Reply to Letter to the Editor

wenguiyu{at}sbcglobal.net Wengui Yu

We thank Dr. Lastimosa for his interest in our paper. [1] He raised an important question on the molecular mechanism of verapamil in hemiplegic migraine. His comments were intriguing but some of his criticisms reflect a misunderstanding of the case report and literature. Hemiplegic migraine is a heterogenous disorder. Gene mutations within the P/Q gated neuronal calcium channel a1 subunit (CACNA1A) were identified on chromosome 19p13 in half of the families with familial hemiplegic migraine (FHM). [2] At least 13 different missense mutations have been identified within the conserved functional domains of CACNA1A. In addition, an unknown gene was shown on chromosome 1 in a few families, and a third one in a different chromosome. De novo mutations or incomplete penetrance of CACNA1A have also been found in-patients with sporadic hemiplegic migraine (SHM). [2, 3, 4] Although it would have been ideal to do DNA analysis in our patients, a recent study only identified gene mutations in CACNA1A in two out of 27 patients with SHM. Our patients were diagnosed to have SHM based on International Headache Society Criteria. [5] They were treated as a clinical syndrome rather than a "homogeneous disorder." We reported the effect of verapamil on patients with SHM rather than "a grouping" based on pharmacological response. Dr. Lastimosa's question is interesting: why was an L-type calcium channel blocker verapamil effective for a disorder with a P/Q-type calcium channel dysfunction? Our case report cannot answer this. A double blind, placebo controlled study is necessary to confirm the effect of verapamil but will not give information on the molecular mechanism. It is unknown whether mutated P/Q type channel is resistant to verapamil. It is also unclear whether hemiplegic migraine is an exclusive P/Q channel dysfunction. L-type channels are up regulated in the cerebellar Purkinje cells in CACNA1A knockout mice, [6] suggesting a role for L-type channel in disorders with P/Q channel dysfunction. The antinociceptive effect of verapamil via L-type channel may be relevant in headache. Such a mechanism is highly unlikely in hemiplegic migraine because the nociceptive receptor has no role in hemiparesis, which is a distinctive feature of hemiplegic migraine.
References:
1. Yu W, Horowitz SH. Treatment of Sporadic Hemiplegic Migraine with Calcium-channel Blocker Verapamil. Neurology 2003;60:120-121.
2. Ducros A, Denier, C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. New Eng J Med 2001;345:17-24.
3. Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000;55:1040-1042.
4. Terwindt G, Kors E, Haan J, et al. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Archives Neurology 2002;59:1016-1018.
5. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7:1-96.
6. Jun K, Piedras-Renteria ES, Smith SM, et al. Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the a1-subunit. PNAS 1999;96:15245-15250.

Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil 5 March 2003

Augusto Cezar Lastimosa
Ft Worth Texas
Send Correspondence to journal:
Re: Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil

res005n3{at}gte.net Augusto Cezar Lastimosa

I enjoyed the article by Drs. Yu and Horowitz [1] and learned a new treatment for hemiplegic migraine. The rationale for using verapamil was based on both the demonstrations that familial hemiplegic migraine has gene mutations within the P/Q-type neuronal calcium channel alpha1A subunit and the assumption that sporadic hemiplegic migraine has similar calcium channel dysfunction. Based on these assumptions, they gave verapamil intravenously and orally. Their findings suggest that neuronal calcium-channel dysfunction may underlie the pathogenesis of familial and sporadic hemiplegic migraines and that verapamil is an effective therapy for both disorders. However, I believe that their conclusion is untenable because
1. Their patients were treated as homogeneous disorders with P/Q-type calcium channel<O: P</O: P defect without DNA analysis.
2. They lumped the group based on the pharmacologic response to verapamil assuming that they are targeting the P/Q-type calcium channel dysfunction when verapamil binds the alpha1 subunit of L-type calcium channel of phenylalkylamine receptor type. In addition, the P/Q type is resistant to the phenylalkylamine receptor types of calcium channel blockers [2].
3. Their conclusion is not based on a double blind, placebo- controlled study. An alternative explanation for the effectiveness of their treatment can be attributed to the antinociceptive effect of L-type voltage-gated calcium channel blockers provided by verapamil. The L-type voltage-gated calcium channel antagonists have been found to be intrinsically antinociceptive when administered systemically under conditions of both acute inflammations in the acetic acid induced abdominal constriction test and in the formalin model of acute, persistent nociception [3]. Antinociceptive effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint was also reported [4].
Furthermore, as far as the P/Q calcium-channel blocker is concerned, it should be noted that studies have failed to show significant effect by P/Q calcium channel blocker in acute tests of nociception such as rat hot plate [5]. It has no effect on tactile allodynia in a peripheral neuropathy model
I believe that they raised a valid point in suggesting verapamil as a treatment for hemiplegic migraine. However, further studies on larger number of subjects using double-blind placebo-controlled studies need to be done to confirm their result and studies need to be done to define the mechanism of the antinociceptive effect of verapamil in hemiplegic migraine
References
1. Yu W, Horowitz SH. Treatment of Sporadic Hemiplegic Migraine with Calcium-channel Blocker Verapamil. Neurology 2003;60:120-121.
2. Balser, JR, George, AL. Pharmacology of ion channels. In Rose, MR and Griggs, RC (Eds.), Channelopathies of the Nervous System, Butterworth Heinemann, Boston, 2001, chapter 3, pp. 23-45.
3. Miranda HF, Bustamente D, Kramer V, Pelissier T, Saavedra H, Paeile C, Fernandez E, Pinardi G. Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol 1992;217:137-141.
4. Neugebauer H, Vanegas J, Rumenapp P, Schaible HG. Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. J Neurophysiol. 1996;76:3740-3749.
5. Malmberg AB, Yaksh TL. Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 1994;14:4882-4890.