Delayed cerebral edema and fatal coma after minor head trauma Role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.код для вставкиСкачать
Delayed Cerebral Edema and Fatal Coma after Minor Head Trauma: Role of the CACNA1A Calcium Channel Subunit Gene and Relationship with Familial Hemiplegic Migraine Esther E. Kors, MD,1 Gisela M. Terwindt, MD, PhD,1 Frans L.M.G. Vermeulen,2 Robin B. Fitzsimons, MBBS, BSc(Med), PhD, FRACP,3 Philip E. Jardine, MD, FRCPCH,4 Peter Heywood , MD,5 Seth Love, MBBCh, PhD, FRCP, FRCPath,6 Arn M.J.M. van den Maagdenberg, PhD,2 Joost Haan, MD, PhD,1,7 Rune R. Frants, PhD,2 and Michel D. Ferrari, MD, PhD1 Trivial head trauma may be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval (“delayed cerebral edema”). Attacks of familial hemiplegic migraine (FHM) can be triggered by minor head trauma and are sometimes accompanied by coma. Mutations in the CACNA1A calcium channel subunit gene on chromosome 19 are associated with a wide spectrum of mutation-specific episodic and chronic neurological disorders, including FHM with or without coma. We investigated the role of the CACNA1A gene in three subjects with delayed cerebral edema. Two subjects originated from a family with extreme FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema, we found a C-to-T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A gene. The mutation was absent in nonaffected family members and 152 control individuals. Haplotype analysis excluded a common founder for both families. Neuropathological examination in one subject showed Purkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the novel S218L mutation in the CACNA1A calcium channel subunit gene is involved in FHM and delayed fatal cerebral edema and coma after minor head trauma. This finding may have important implications for the understanding and treatment of this dramatic syndrome. Ann Neurol 2001;49:753–760 Trivial head trauma is sometimes complicated by severe, even fatal, cerebral edema and coma occurring after a lucid interval, a phenomenon referred to as delayed cerebral edema. The syndrome has received particular attention in collision sports involving children and adolescents.1 Apart from young age, no other risk factors are known.1 Snoek et al described a series of 42 children who, after a lucid interval following minor head trauma, developed neurological symptoms that were mostly transient and consisted mainly of disturbances of consciousness and sometimes convulsions.2 Three of the children, however, died as a result of severe and uncontrollable brain swelling. Minor head trauma is also a recognized trigger of delayed migraine aura, also referred to as footballers migraine.3,4 Particularly in children, these aura symptoms may be dramatic, including blindness, confusion, and impaired consciousness. Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura in which attacks are associated with hemiparesis.5 Attacks of FHM can be triggered by minor head trauma, usually within 10 minutes,4 and may be associated with loss of consciousness, as in basilar migraine.6 About half of the reported FHM families are linked to chromosome 19p13 and have missense mutations in the CACNA1A gene. This gene encodes From the 1Departments of Neurology and 2Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands; 322g Macquarie Street, Sydney, Australia; 4Childrens Centre, 5Department of Neurology, and 6Department of Neuropathology, Frenchay Hospital, Bristol, UK; and 7Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands. Published online 24 March 2001. Address correspondence to Dr Ferrari, Department of Neurology, K5Q, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: M.D.Ferrari@lumc.nl Received Aug 17, 2000, and in revised form Dec 29. Accepted for publication Jan 2, 2001. © 2001 Wiley-Liss, Inc. 753 the ␣1A subunit of a neuronal calcium channel that is primarily involved in mediating the release of neurotransmitters, including monoamines and glutamate.7–9 Chromosome 19 –linked FHM families report attacks that are triggered by head trauma or are associated with coma significantly more often than do non–chromosome 19 –linked families.10 Mutations in the CACNA1A gene are associated with a wide spectrum of neurological phenotypes, ranging from relatively mild episodic disorders, such as migraine,11 FHM,7 and episodic ataxia,7 to more severe permanent symptoms, such as progressive cerebellar ataxia and severe cerebellar atrophy12,13 (see Fig 2). In tottering and leaner mice, mutations in the mouse homologue ␣1A subunit P/Q-type calcium channel gene are associated with ataxia and epilepsy.14 Because of these clinical relationships and the remarkable diversity of neurological symptoms caused by CACNA1A mutations, we postulated a role for this gene in “delayed cerebral edema.” We therefore screened the CACNA1A gene for mutations in three patients who experienced severe, in one case even fatal, cerebral edema and coma after a lucid interval following minor head trauma. Two subjects belonged to a family with severe FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. Methods The pedigrees of Families 1 and 2 are shown in Figure 1. Family 1 Family 1 is an Australian family originally reported in 1985.15 The proband (III-13) had FHM attacks and recurrent coma associated with generalized hyperreflexia, decerebrate rigidity, pinpoint pupils, hyperpyrexia, cerebrospinal fluid (CSF) pleocytosis, and hallucinations. On one occasion he required respiratory support because of respiratory arrest after cerebral angiography. His father (II-5) also had had recurrent febrile comas and psychotic episodes. His brother (III-12) had mild mental retardation and FHM attacks, which were typically triggered by trivial head injury. He once became unconscious during an attack but recovered spontaneously after 4 days. All 3 patients had progressive cerebellar ataxia, and computed tomographic (CT) scan revealed cerebellar atrophy. Two other family members (II-2 and II-6) died at the age of 5 years during “meningo-encephalitis like episodes with convulsions” following trivial head trauma in 1915 and 1926, respectively. Another sibling (III-10) had impaired consciousness for several days following minor head trauma in her twenties. She did not experience migraine attacks until her late forties, when severe headache was accompanied by increasingly slurred speech, ataxia, right-sided numbness, and fever. She has mild long-standing cerebellar ataxia that becomes worse for hours when she is tired and selective atrophy of the superior cerebellar vermis evident on CT scan. Notably, she has no history of FHM attacks. One other, more distant family member (III-7) had childhood migraine and currently has migraine attacks with preceding fortification spectra but without hemiparesis or other neurological symptoms. Family members III-9 and III-11 were unaffected. Family 2 Family 2 is a British family that has not previously been reported. The proband (III-6), a 16-year-old female, had been hypotonic since birth and was born with a convergent squint. She may have had seizures shortly after birth, but they were not well documented. Investigations at the age of 1 year, including an electroencephalogram and muscle biopsy, had normal results. Apart from recurrent falls until the age of 4, she was healthy and did not suffer from any form of migraine. To our knowledge, she never consulted a phy- Fig 1. The pedigrees of Families (a) 1 and (b) 2. The arrow indicates the proband. Coma is indicated as a black box for males and a circle for females. Familial hemiplegic migraine and ataxia is indicated by a vertical striped pattern, ataxia with or without migraine by a horizontal striped pattern, and migraine only by a black half symbol. A question mark indicates hetero-anamnestic information, and a plus indicates that DNA is available. The alleles of (in descending order) markers D19S221, D19S1150, CAG-repeat, and D19S226 are shown for each tested individual. A box encloses the haplotype co-segregating with the disease. 754 Annals of Neurology Vol 49 No 6 June 2001 sician concerning headache. At the age of 16, she was admitted to a hospital after head trauma, having been hit on her head several times without losing consciousness. In the ambulance she was orientated and alert. In the emergency room she appeared distressed and incoherent. Her initial Glasgow coma score was 12/15, but after a witnessed, generalized seizure it dropped to 7/15 an hour after admission. She became hypertonic with extensor plantar responses and was intubated and ventilated. An initial cerebral CT scan revealed no abnormalities. The CSF white cell count was slightly elevated, with normal protein and glucose levels. CSF pressure was not measured. Cytologic studies and examination of a Gramstained preparation of the CSF revealed no evidence of infection. Over the following days, her neurological condition deteriorated. Nine days after admission she was in a deep coma and had developed a pyrexia of 39°C. She exhibited no response to painful stimuli. She had fixed and dilated pupils and was not breathing spontaneously. Repeat CT scan revealed mild cerebral edema. Three days later she died. The older sister (III-5) of the proband was also hypotonic after birth and had a squint. At the age of 4 years she was still hypotonic and clumsy. In the following years, she started to suffer from intermittent unsteadiness, which became a slowly progressive problem, and now, at the age of 22, she is developing dysarthria. At neurological examination she exhibited no pyramidal or extrapyramidal signs. Cerebral magnetic resonance imaging (MRI) has not been performed. She has never suffered from any kind of migraine. The father (II-3) of the proband has always been clumsy. He suffered from attacks of headache often associated with transient hemiplegia and confusion with marked pyramidal signs, from which he recovered spontaneously. He presented to medical attention with an episode lasting 2 weeks during which he suffered intermittent headache, a fluctuating level of consciousness, vivid hallucinations concerning his own death, and marked hemiplegia. He recovered spontaneously without needing artificial ventilation. MRI of the head was unremarkable during the attack. A single-photon emission computed tomography scan showed hyperperfusion in the hemisphere contralateral to the hemiplegia. Findings of a recent neurological examination were unremarkable except for horizontal nystagmus, mild dysarthria, and a mildly ataxic gait. Neuropathological Examination Multiple blocks from both cerebral hemispheres, the cerebellum, and the brain stem from the index case of Family 2 (III-6) were taken for histologic studies and paraffin sections stained with hematoxylin-eosin, luxol fast blue–cresyl violet, Palmgren silver impregnation, and phosphotungstic acid–hematoxylin. Sections were also immunostained for neurofilament protein, glial fibrillary acidic protein, and microtubuleassociated protein 2 (MAP-2). Genomic DNA Samples Blood samples were collected from II-5, III-7, III-9, III-10, III-11, III-12, and III-13 of Family 1 and I-1, II-3, III-5, III-6, and III-7 of Family 2. Genomic DNA was isolated from leukocytes as described by Miller et al.16 Genotyping Two extragenic polymorphic microsatellite DNA markers from the Genethon linkage map, D19S221 and D19S226, which flank the CACNA1A gene, were analyzed. In addition, two intragenic polymorphisms were analyzed: marker D19S1150 in intron 7 and the CAG repeat in exon 47, using polymerase chain reaction (PCR) conditions as previously described.7 Single Strand Conformational Polymorphism (SSCP) Analysis For SSCP analysis, all 47 exons of the CACNA1A gene were amplified using exon-specific primer sets and PCR conditions as previously described.7 In brief, PCR products were radioactively labeled by incorporation of [␣32P] dCTP during PCR, denatured in formamide buffer and electrophoresed on a 8% polyacrylamide (19:1) gel containing 10% glycerol at a constant power of 28 W. PCR products revealing aberrant banding patterns on SCCP gels were purified using the QIAquick PCR Purification Kit (Qiagen Chatworth, LA). Subsequently, purified products were directly sequenced using the same PCR primers and the BigDye Terminator Cycle Sequencing Kit (PE Applied Biosystems Foster City, CA, USA) on an ABI 377 DNA automated sequencer (PE Applied Biosystems Foster City, CA USA). Carrier Detection To identify carriers of the 928 C-to-T substitution, exon 5 was amplified by PCR using primers exon 5F (5⬘-CTTGGTGGCGGGGTTT-3⬘) and exon 5R (5⬘-CTGCCTAATCCTCCCAAGAG-3⬘) and genomic DNA as template. PCR products were digested with BclI using standard protocols and electrophoresed on a 2% agarose gel. In nonaffected individuals, only one band of 291 bp is visible, whereas in heterozygous mutation carriers two additional bands of 203 and 88 bp are present. As a control, genomic DNA of 152 subjects from the general Dutch population with no history of migraine or cerebellar ataxia was tested. Results Genotyping Genetic linkage analysis to flanking and intragenic CACNA1A markers did not result in a significant Lod score due to the small size of the families, but haplotype analysis was compatible with involvement of this locus in both families. Haplotype differences between the two families excluded a common founder (see Fig 1). The number of CAG repeats in the family members was normal (ranging from 11 to 13, normal value below 1712), excluding a possible moderate expansion, as seen in episodic ataxia type 2 or spinocerebellar ataxia type 6. Mutation Analysis Mutation analysis of the CACNA1A gene was performed using SSCP analysis on genomic DNA obtained from the probands of both families (III-13 in Family 1 and III-6 in Family 2). All fragments present- Kors et al: CACNA1A Mutation and Delayed Coma 755 ing a mobility variant were checked by direct sequencing. No previously described mutations were present, but a new variant in exon 5 was found in both families, changing a C to a T at nucleotide position 928, thereby replacing a hydrophilic serine for a hydrophobic leucine residue at codon 218 (S218L). The mutation is located in the small intracellular loop between the fourth and fifth transmembrane segments of the first domain of the ␣1A subunit (Fig 2). Segregation of the mutation within the families was demonstrated by restriction enzyme digestion because the S218L mutation introduces a BclI restriction site (Fig 3). In Family 1, the S218L mutation was found in subjects II-5, III10, III-12, and III-13 and in Family 2 in subjects II-3, III-5, and III-6. It was not found in the nonaffected family members, in the family member suffering from migraine with aura (III-7 in Family 1), or in 152 normal control individuals. Neuropathological Examination Gross neuropathological examination of the brain of the index case of Family 2 (III-6) revealed bilateral, diffuse cerebral swelling with bilateral uncal herniation and cerebellar tonsillar herniation and necrosis. Apart from acute cerebral ischemic changes that were thought to be due to the agonal rise in intracranial pressure, the principal histological abnormalities were (1) cerebral edema, (2) long-standing sclerosis of the right hippocampus, and (3) chronic degenerative changes involving the cerebellar cortex. The edema diffusely affected cerebral white matter in both hemispheres and, to a lesser extent, the cerebellum. No histological abnormalities were discernible in parenchymal Fig 2. Localization of the novel S218L mutation in the ␣1A subunit of the P/Q-type calcium channel causing delayed cerebral edema and coma after a minor head trauma (arrow). The mutation is located in the small cytoplasmic between the fourth and fifth segments of the first domain of the protein. In addition, the localization of all other known CACNA1A mutations and the associated clinical phenotypes is depicted. FHM ⫽ familial hemiplegic migraine; EA-2 ⫽ episodic ataxia type 2; Progr ⫽ progressive; SCA-6 ⫽ spinocerebellar ataxia type 6. 756 Annals of Neurology Vol 49 No 6 June 2001 blood vessels. The hippocampal sclerosis was characterized by loss of pyramidal neurons from the CA1 field of the hippocampus, which exhibited dense fibrillary astrocytosis. The degenerative changes in the cerebellum consisted of mild loss of Purkinje cells, with associated proliferation of Bergmann astrocytes and cortical gliosis. Occasional “empty baskets” marked the sites of Purkinje cell loss. There was marked swelling and deformity of the dendrites of many of the remaining Purkinje cells (Fig 4). Some of the dendrites had radiating spike-like protrusions. The abnormal dendrites were moderately argyrophilic, and most were immunopositive for MAP-2. Dystrophic swellings (so-called torpedoes) of some of the Purkinje cell axons were noted within the granule cell layer. These changes were more pronounced in the vermis than in the cerebellar hemispheres and tended to spare the depths of the sulci between the folia. The deep cerebellar nuclei, inferior olives, and basal ganglia were well preserved. Discussion We describe the novel S218L missense mutation in the CACNA1A calcium channel subunit gene in three subjects with minor head trauma–triggered delayed severe cerebral edema and coma. Two subjects belonged to a family with symptoms at the very extreme end of FHM (II-5 and III-13 of Family 1). The third subject (III-6 of Family 2) was the previously completely asymptomatic daughter of a sporadic patient with hemiplegic migraine (II-3). She had never experienced migraine or hemiplegic phenomena before. Her father (II-3) is the only family member who had episodes of hemiplegic migraine. Thus, Family 2 could be regarded as family with FHM, but only retrospectively and only by assuming that the fatal event in index Patient II was her first attack of hemiplegic migraine. We hypothesize that the S218L CACNA1A mutation renders subjects at risk for a disinhibited cytotoxic edematous response to minor brain injury, mediated through dysfunction of neuronal voltage-dependent P/Q-type calcium channels. Trauma-triggered “delayed cerebral edema” can thus be added to the wide spectrum of episodic and chronic progressive neurological disorders associated with CACNA1A mutations. One might consider advising subjects with a positive family history for hemiplegic migraine or with demonstrated CACNA1A mutations to avoid sports in which head injury is common, such as contact sports. Impairment of consciousness is a known but rare associated symptom of hemiplegic migraine attacks. Apart from the S218L mutation, five other CACNA1A mutations have been associated with coma during at least some FHM attacks: V714A,11 I1811L,11 T666M,17 Y138C,18,19 and R583Q20 (see Fig 2). In addition, one family has been described in which FHM was linked to chromosome 1q, and the proband, but Fig 3. Mutation detection of the P/Q-type calcium channel ␣1A subunit gene in Families (a) 1 and (b) 2. The mutation is a C-to-T substitution at codon 218, which results in a substitution of serine for leucine (S218L). Mutation S218L results in an additional BclI restriction site. In nonaffected individuals only one band of 291 bp is visible, whereas in heterozygous mutation carriers two additional bands of 203 and 88 bp are present (88-bp band not visible in figure). not the other affected family members, had hemiplegic migraine attacks associated with coma.21 In all these families, however, the impairment of consciousness was short-lived and never as dramatic as in our patients with the S218L mutation; there also was no such dramatic delayed association with minor head trauma. The clinical presentation of Patient III-6 of Family 2, with uncontrollable cerebral edema after a lucid interval following minor head trauma, resembles that of three patients with delayed fatal detoriation in the se- ries of otherwise benign concussion in 42 children described by Snoek et al2 and of the 17 cases of delayed cerebral edema and coma in collision sports as reviewed by McCrory and Berkovic.1 Among the various explanations for these dramatic events, a migrainous mechanism was suggested but not further investigated. Screening for mutation in the mutation analysis of the CACNA1A gene in these patients might be interesting. Several pathophysiological mechanisms have been implicated in post-traumatic hemispheric swelling due Fig 4. (a) Section through cerebellar cortex. The molecular layer includes several swollen Purkinje cell dendrites (arrows). Hematoxylin-eosin, ⫻100. (b) Palmgren silver impregnation of swollen Purkinje cell dendrites in the cerebellar molecular layer. Spike-like processes radiate from one of the dendritic swellings (arrow), the center of which is relatively nonargyrophilic. ⫻200. Kors et al: CACNA1A Mutation and Delayed Coma 757 to cytotoxic edema, including traumatic depolarization (TD).22 In TD, depolarization of the neuronal cell membrane potential and activation of voltagedependent ion channels are triggered by mechanical strain on the brain. This depolarization results in massive ionic fluxes across the plasma membrane and calcium-dependent exocytotoxic release of excitatory neurotransmitters, such as glutamate and aspartate, further reinforcing the ionic perturbation and eventually causing cellular swelling.23 The ionic perturbation, the shift of the cell membrane potential, and the pivotal role of excitatory amino acid release and K⫹ in TD23 are also important mechanisms involved in cortical spreading depression (CSD). CSD is believed to be the underlying mechanism of the aura in migraine and FHM.24 This view is supported by a recent observation that the N-methyl-D-aspartate antagonist ketamine reduced the neurologic deficits in some FHM patients.25 Diffusion MRI in a sporadic patient with hemiplegic migraine carrying the Y1384C CACNA1A missense mutation showed reversible hemispheric edema and decrease of cerebral water mobility during a long-lasting attack of hemiplegic migraine associated with coma.19 Hemispheric swelling was also observed in the patients described here. The CACNA1A gene encodes for the main, ionconducting, pore-forming ␣1A subunit of voltagedependent P/Q-type neuronal calcium channels,7 which modulate neurotransmitter release.26 Like all other known CACNA1A mutations causing FHM, the S218L mutation is a missense mutation. The serine residue at position 218 is highly conserved both between the various calcium channel pore-forming subunits and across all species (Fig 5). This observation suggests that an amino acid change at this position would severely affect the function of the channel. Other missense mutations causing FHM were all found to cause either gain or loss of function.27,28,29 In tottering mice, mutations in the Cacna1a gene change the threshold for CSD30 and the release of acetylcholine at the neuromuscular junction.31 Both in lethargic mice, which have mutations in the Cacnb4 gene encoding the auxiliary ␤4 subunit of P/Q-type calcium channels, and in tottering mice, the thalamic release of glutamate is impaired.32 Thus, mutations in P/Q-type calcium channel subunit genes affect neurotransmitter release. This effect on neurotransmitter release may have profound implications for the mechanisms involved in TD and CSD and could lead to an exaggerated edematous response to minor head trauma or other trigger factors. If a calcium channelopathy is indeed an underlying mechanism in “delayed cerebral edema,” treatment with acetazolamide might prove effective. This nonspecific carbonic anhydrase inhibitor has shown to be effective in a number of other cerebral Fig 5. Alignment of relevant parts of a diverse set of pore-forming calcium channel subunits. The arrow indicates the serine residue on codon 218 (dark gray box). Both human dihydropyridine-sensitive (L-type) and -nonsensitive (non–L–type) calcium channel subunits are included. In addition, various orthologous channels of human CACNA1A and CACNA1B are presented. Variations from the human CACNA1A are indicated by light gray boxes. Amino acid residues that are not variable are indicated by a horizontal line at the bottom of the figure. The following accession numbers were used for the alignment: human CACNA1A (X99897), CACNA1B (M94172), CACNA1C (L04569), CACNA1D (M76558), CACNA1E (L29384), CACNA1F (AJ224874), and CACNA1S (L33798); mouse CACNA1A (U76716); rat CACNA1A (M64373); rabbit CACNA1A (X57688); Drosophila melanogaster DMCA1A (P91645); and Discopyge ommata DOE-4 (P56698). 758 Annals of Neurology Vol 49 No 6 June 2001 channelopathies, including the CACNA1A disorder episodic ataxia type 2.33 The pathological features of the cerebellar degeneration associated with a missense mutation in the CACNA1A gene have not been reported previously. Neligan et al noted multiple infarcts in the cerebral cortex and basal ganglia of a patient with FHM who had died 4 months after experiencing a respiratory arrest.34 Ataxia was not recorded for this patient, and genetic status is unknown. Histologic studies of the cerebellum revealed widespread loss of Purkinje cells, but this was attributed by the authors to the single anoxic episode. Although the patient whose brain was examined neuropathologically in the present study (III-6 of Family 2) had not manifested hemiplegic migraine, her father has typical clinical features of this disorder. We found the pathological abnormalities to be of similar distribution to those in spinocerebellar ataxia type 6 (SCA-6) but less severe.35,36 In cases of SCA-6 that have been studied neuropathologically, the principal abnormality has been Purkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei, the basal ganglia, and other parts of the brain. As in the present case, the cerebellar cortical abnormalities in SCA-6 tend to be more marked in the vermis than in the hemispheres. Prominent dendritic abnormalities have not been noted in descriptions of SCA6, although the dendritic abnormalities in the current study resemble those in several other types of cerebellar cortical degeneration, including Menkes’ disease.37 A potential complicating factor in the interpretation of the neuropathological findings in the cerebellum in the present case is the development of agonal ischemic changes associated with the brain swelling. These changes were, however, relatively acute and could not account for the loss of Purkinje cells, development of dystrophic axonal swellings, or cerebellar gliosis. Furthermore, the effects of ischemia on Purkinje cells do not include the formation of swollen and misshapen dendrites and tend to be most severe in the depths of sulci between folia, the least severely affected part of the cerebellar cortex in our case. In conclusion, the novel S218L mutation in the P/Q-type neuronal calcium channel ␣1A subunit gene CACNA1A and possibly other similar CACNA1A mutations are involved in a delayed disinhibited, sometimes even fatal, cytotoxic cerebral edematous response to minor head trauma after a lucid interval. This finding could offer new avenues for the understanding and treatment of this dramatic syndrome. This work was supported by the Netherlands Organisation for Scientific Research (NWO, no. 903–52-291), Migraine Trust, and Asclepiacie Association. References 1. McCrory PR, Berkovic SF. Second impact syndrome. Neurology 1998;50:677– 683. 2. Snoek JW, Minderhout JM, Wilmink JT. Delayed detoriation following mild head injury in children. Brain 1984;107:15–36. 3. Matthews WB. Footballer’s migraine. Br Med J 1972;2:326 – 327. 4. Solomon S. Posttraumatic migraine. Headache 1998;38:772– 778. 5. International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1–96. 6. Haan J, Terwindt GM, Ophoff RA, et al. Is familial hemiplegic migraine a hereditary form of basilar migraine? Cephalalgia 1995;15:477– 481. 7. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2⫹ channel gene CACNL1A4. Cell 1996; 87:543–552. 8. Catterall WA. Structure and function of neuronal Ca2⫹ channels and their role in neurotransmitter release. Cell Calcium 1998;24:307–323. 9. Hill MP, Brotchie JM. Control of glutamate release by calcium channels and kappa-opioid receptors in rodent and primate striatum. Br J Pharmacol 1999;127:275–283. 10. Terwindt GM, Ophoff RA, Haan J, et al. Familial hemiplegic migraine: a clinical comparison of families linked and unlinked to chromosome 19. Cephalalgia 1996;16:153–155. 11. Terwindt GM, Ophoff RA, Haan J, et al. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 1998;50:1105–1110. 12. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the 1A-voltage-dependent calcium channel. Nat Genet 1997;15:62– 69. 13. Tournier-Lasserve E. CACNA1A mutations: hemiplegic migraine, episodic ataxia type 2, and the others. Neurology 1999; 53:3– 4. 14. Fletcher CF, Lutz CM, O’Sullivan TN, et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 1996;87:607– 617. 15. Fitzsimons RB, Wolfenden WH. Migraine coma: meningitic migraine with cerebral oedema associated with a new form of autosomal dominant cerebellar ataxia. Brain 1985;108:555– 557. 16. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16. 17. Ducros A, Denier C, Joutel A, et al. Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 1999;64:89 –98. 18. 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. 19. Chabriat H, Vahedi K, Clark CA, et al. Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene. Neurology 2000;54:510 –512. 20. Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 1999;53:38 – 43. 21. Echenne B, Ducros A, Rivier F, et al. Recurrent episodes of coma: an unusual phenotype of familial hemiplegic migraine with linkage to chromosome 1. Neuropediatrics 1999;30:214 – 217. 22. Bauer R, Walter B, Fritz H, Zwiener U. Ontogenetic aspects of Kors et al: CACNA1A Mutation and Delayed Coma 759 23. 24. 25. 26. 27. 28. 29. 30. 760 traumatic brain edema: facts and suggestions. Exp Toxicol Pathol 1999;51:143–150. Katayama Y, Maeda T, Koshinaga M, et al. Role of excitatory amino acid-mediated ionic fluxes in traumatic brain injury. Brain Pathol 1995;5:427– 435. Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory. Brain 1994;117:199 –210. Kaube H, Herzog J, Kaufer T, et al. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000;55:139 –141. Randall A, Benham CD. Recent advances in the molecular understanding of voltage-gated Ca(2⫹) channels. Mol Cell Neurosci 1999;14:255–272. Kraus RL, Sinnegger MJ, Glossmann H, et al. Familial hemiplegic migraine mutations change alpha 1A Ca2⫹ channel kinetics. J Biol Chem 1998;273:5586 –5590. Kraus RL, Sinnegger MJ, Koschak A, et al. Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2⫹) channel kinetics. J Biol Chem 2000;275:9239 –9243. Hans M, Luuisetto S, Williams ME, et al. Functional consequences of mutations in the human alpha A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci 1999;19:1610 –1619. Ayata C, Shimizu-Sasamata M, Lo EH, et al. Impaired neurotransmitter release and elevated threshold for cortical spreading Annals of Neurology Vol 49 No 6 June 2001 31. 32. 33. 34. 35. 36. 37. depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels. Neuroscience 2000;95:639 – 645. Plomp JJ, Vergouwe MN, Van den Maagdenberg AM, et al. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2⫹) channel mutation. Brain 2000;123:463– 471. Caddick SJ, WangC, Fletcher CF, et al. Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(Lh)) and tottering (Cacna1atg) mouse thalami. J Neurophysiol 1999;81:2066 –2074. Bain PG, O’Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992;31:147–154. Neligan P, Harriman DG, Pearce J. Respiratory arrest in familial hemiplegic migraine: a clinical and neuropathological study. Br Med J 1977;2:732–734. Tsuchiya K, Ishikawa K, Watabiki S, et al. A clinical, genetic, neuropathological study in a Japanese family with SCA 6 and a review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy. J Neurol Sci 1998;160:54 –59. Ishikawa K, Watanabe M, Yoshizawa K, et al. Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6). J Neurol Neurosurg Psychiatry 1999;67:86 – 89. Ellison D, Love S. Neuropathology: a reference text of CNS pathology. London: 1998.