- Email: [email protected]
Variable Manifestations of Familial Hemiplegic Migraine Associated With Reversible Cerebral Edema in Children
Pediatric Neurology 47 (2012) 201e204
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Variable Manifestations of Familial Hemiplegic Migraine Associated With Reversible Cerebral Edema in Children Sheila J. Asghar MD, MSc a, *, Alessandra Milesi-Hallé MD, PhD a, Chavvi Kaushik MD b, Charles Glasier MD b, Gregory B. Sharp MD a a b
Section of Pediatric Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas Section of Radiology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
article information
abstract
Article history: Received 22 February 2012 Accepted 9 May 2012
Three children with familial hemiplegic migraine presented with right-sided weakness, speech difficulty, altered mental status, and gait abnormalities. These persistent aura signs were accompanied by left-sided slowing and cerebral dysfunction, documented by electroencephalograms. Cranial magnetic resonance imaging revealed cortical edema restricted to the left cerebral hemisphere. Follow-up electroencephalogram and imaging studies produced normal results 1-4 months afterward. However, cognitive changes persisted. Genetic testing demonstrated variable results: one child manifested a CACNA1A mutation compatible with familial hemiplegic migraine type 1, whereas another demonstrated an ATP1A2 sequence alteration. No known mutations were evident in the third child, with minor head trauma thought to precipitate the familial hemiplegic migraine. These findings demonstrate the variable clinical and genetic heterogeneity of childhood familial hemiplegic migraine. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Familial hemiplegic migraine is defined as an atypical type of migraine with aura signs that includes some degree of hemiparesis, and may include sensory, language, or visual changes before or during the headache. Often these signs persist throughout the headache phase, and resolve with appropriate management. Confusion or severe coma may also occur as one of the multiple aura signs. The persistent aura phase is thought to be caused by hyperperfusion in the corresponding brain regions [1]. Multiple imaging modalities have been used to investigate the perfusion changes associated with familial hemiplegic migraine, including perfusion and diffusion weighed magnetic resonance imaging, single photon emission tomography [1], and positron emission tomography. In * Communications should be addressed to: Dr. Asghar; Section of Pediatric Neurology; Department of Pediatrics; University of Arkansas for Medical Sciences; Arkansas Children’s Hospital; 1 Children’s Way, Slot #512-15; Little Rock, AR 72202. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.05.006
addition, these studies demonstrated cortical edema [2], which was reversible in most cases [3]. The inherited basis of familial hemiplegic migraine makes genetic testing an important diagnostic tool. In comparison, sporadic hemiplegic migraine is defined as migraine with aura including motor weakness, without any first-degree or second-degree relative manifesting similar attacks. A definite autosomal dominant inheritance pattern with high penetrance is evident. Familial hemiplegic migraine is also genetically heterogeneous. Mutations in the CACNA1A gene on chromosome 19p13, involving the voltage-gated P/Q-type calcium channels, occur in familial hemiplegic migraine type 1 [4]. Furthermore, mutations in the ATP1A2 gene, involving sodium-potassium channels, occur in familial hemiplegic migraine type 2 [5], whereas familial hemiplegic migraine type 3 is caused by mutations in the SCN1A gene [6]. Hemiplegic migraine caused by mutations in CACNA1A, ATP1A2, and SLC1A3 has been associated with hemispheric cerebral edema [7-9]. This report describes the clinical and genetic heterogeneity of familial hemiplegic migraine in three children. The use of their medical records was approved by the
202
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204
Institutional Review Board of the University of Arkansas for Medical Sciences (Little Rock, AR). According to cranial magnetic resonance imaging, all three patients revealed reversible abnormalities compatible with unilateral cortical edema and transient cerebral blood flow abnormalities. Furthermore, despite the reversibility of cerebral edema on follow-up scans, all three children continued to exhibit neurocognitive impairment several months after the initial headache episode. Patients and Methods Patient 1 was a 13-year-old white girl, transferred to our hospital from an outside facility. She exhibited altered mental status, speech difficulties, and incontinence. She had developed a severe headache during a volleyball game 4 days earlier. The family did not report any head trauma or other type of injury. She had a history of headaches that were typically accompanied by slurred speech lasting for a few minutes to hours, often resolving with over-the-counter analgesics, without changes in mental status. Her most recent headache episode had occurred 6 months earlier. Her mother and brother also reported frequent episodes of migraine, accompanied by neurologic deficits such as confusion, aphasia, and hemiplegia. On neurologic examination, our patient demonstrated an unsteady gait, global aphasia, right-sided weakness, and ataxia. In addition, she exhibited urinary incontinence. Her initial computed tomography scan and cranial magnetic resonance imaging produced normal results. Our initial hospital electroencephalograms revealed generalized slowing between 1 and 2 Hz in the left hemisphere, which persisted more than 8 days after her onset of signs. Follow-up cranial magnetic resonance imaging 9 days after the onset of signs revealed an increased T2 signal diffusely involving the left cerebral hemisphere, and more significantly in the frontal and temporal cortical gray areas, with mild mass effect and a subtle midline shift. Slight meningeal but no cortical enhancement was observed (Fig 1). Her clinical presentation and progression, along with her family history of hemiplegic migraine, led to a diagnosis of familial hemiplegic migraine. Treatment included verapamil, a trial of valproic acid, methylprednisolone, and intravenous immunoglobulin, using current pediatric dosing recommendations. The intravenous immunoglobulin was administered in an attempt to improve her severe aphasia and impulsive behavior. The patient manifested CACNA1A gene mutations consistent with a diagnosis of familial hemiplegic migraine type 1. The mutation was located upstream 1997 bp on the CACNA1A gene, and involved a transition from C to T (threonine to methionine; analysis by Athena Diagnostics, Worcester, MA) [10]. The patient was discharged 21 days later on a prophylactic dose of verapamil, with improved gait and the resolution of weakness on the right side, but her speech had still not returned to baseline level. Cranial magnetic resonance imaging and magnetic resonance angiography at a follow-up appointment 4 months after her initial attack indicated a complete resolution of the T2 and fluid attenuated inversion recovery signal abnormalities in the left hemisphere. A repeated electroencephalogram at that time also revealed normal results. The patient had been maintained on verapamil as a prophylactic treatment, and she reported sporadic headaches that responded to ibuprofen, but denied migraine attacks with other neurologic signs. However, she reported attention and memory problems in school, and her grades had declined since her hospital admission. The results of neuropsychologic testing are pending. Our second patient was an 8-year-old white boy who presented to our emergency department with a 3-day history of lethargy, altered mental status, and gait difficulties. He had a history of migraine headaches starting at age 6 years. However, his first episode of migraine with neurologic deficits had occurred 2 months earlier, with left-sided weakness. A strong family history of migraines involved his mother, uncle, and maternal grandfather. A neurologic examination revealed ataxia, prominent weakness of the right arm, and severe expressive aphasia. His magnetic resonance images on the day of presentation revealed subtle abnormality and fullness throughout most of the cerebral cortex within the left hemisphere (Fig 2). Electroencephalograms,
Figure 1. Patient 1: Magnetic resonance imaging demonstrates diffuse increase in left cerebral cortex signal and sulcal effacement.
performed on the same day, revealed abnormal results, with slowing in the left hemisphere from 1.5-2 Hz, consistent with the magnetic resonance findings of edema. He was treated with ketorolac followed by steroids, dihydroergotamine, and verapamil. A DNA analysis revealed an
Figure 2. Patient 2: Magnetic resonance imaging demonstrates diffuse left cortical edema.
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204 ATP1A2 sequence variant. The mutation was located upstream 1025 bp on the ATP1A2 gene, and involved a transition from T to C (leucine to proline; analysis by Athena Diagnostics) [11]. He was discharged on a prophylactic dose of verapamil after 8 days of hospitalization. Repeated magnetic resonance imaging at a follow-up clinic visit 3 weeks later produced normal results. Subsequent neuropsychologic testing after 7 months revealed cognitive disorder not otherwise specified and memory disorder, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV [12]. Since then, he has been maintained on verapamil, and has not reported any further migraine attacks. Cognition and school performance have improved over a period of 4 years, but he still exhibits some mild memory problems. The third patient was a 15-year-old white boy who presented with headache, altered mental status, and slurred speech several hours after being struck on the right side of his face with a basketball. He did not exhibit loss of consciousness or other signs of concussion. He had experienced a similar episode 2 years earlier, with slurred speech and drooping right mouth after going down a water slide. His aunt had a similar history of headaches with unilateral weakness. On examination, he demonstrated pronounced right-sided weakness, affecting both his hand and leg with severe aphasia. Initial cranial magnetic resonance imaging and magnetic resonance angiography on the day of presentation revealed normal results. An electroencephalogram obtained 3 days after the onset of signs indicated left-sided slowing of 1-2 Hz. The patient continued to be disoriented, and developed a fever of up to 38.7 C. Cerebrospinal fluid studies for possible encephalitis produced negative results. Repeated cranial magnetic resonance imaging after 6 days indicated an increased T2 signal, diffuse in the left cerebral hemisphere cortical gray area and most significant in the temporal and parietal lobes (Fig 3), with minimal associated impaired diffusion. Familial hemiplegic migraine was suspected, and he received appropriate doses of verapamil, followed by methylprednisolone after being treated with appropriate antibiotics and acyclovir, until the possibility of bacterial meningitis and herpes simplex encephalitis were excluded via negative cerebrospinal fluid culture and polymerase chain reaction, respectively. Genetic testing revealed negative results for known mutations associated with familial hemiplegic migraine. Nine days after admission, he was discharged home. At a follow-up visit 4 weeks after his onset of signs, cranial magnetic resonance imaging produced normal results. He did not report any headaches but complained of problems at school, specifically with attention.
Figure 3. Patient 3: Magnetic resonance imaging demonstrates diffuse increase in left cortical signal intensity and sulcal effacement.
203
Blood samples for genetic testing were sent to Athena Diagnostics, and genetic analyses were performed by polymerase chain reaction amplification of highly purified genomic DNA, followed by automated, bidirectional DNA sequencing of the entire codon regions of CACNA1A and ATP1A2. Selected exons of the SCN1A gene were similarly analyzed. All test results were reviewed, interpreted, and reported by clinical molecular geneticists certified by the American Board of Medical Genetics.
Discussion
The International Headache Society characterizes familial hemiplegic migraine as migraine episodes with aura signs including visual disturbance, sensory loss, and dysphasia. Familial hemiplegic migraine must include motor involvement or hemiparesis, which occur together with one other sign during familial hemiplegic migraine aura [1]. The neurologic deficits may outlast the associated migrainous headache. Approximately 40-50% of families with familial hemiplegic migraine type 1 manifest cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. The diagnostic criteria for familial hemiplegic migraine involve: (1) the criteria for migraine with aura; (2) aura including some degree of hemiparesis, possibly prolonged; and (3) at least one first-degree or second-degree relative with identical attacks. The patients described here met these criteria in full, and two of the three children demonstrated known genetic alterations suggestive of a familial hemiplegic migraine phenotype. The patient with negative results of genetic testing had experienced a clearly traumatic event that appeared to precipitate the signs of migraine headache. On magnetic resonance imaging, all three children manifested diffuse cortical swelling involving the left hemisphere. Its probable mechanisms include a prolonged depolarization of neurons, causing the shift of water from the extracellular to the intracellular compartment, with a subsequent swelling of the cells and edema. Cerebral edema has been reported in status migrainous without aura as well as with aura [13], in both sporadic and familial hemiplegic migraine [14]. Reversible magnetic resonance imaging changes have been demonstrated in patients with both the CACNA1A [14] and ATP1A2 mutations [15]. Cha et al. [2] described twin brothers with familial hemiplegic migraine who developed severe, reversible cortical edema. However, these brothers did not manifest CACNA1A, ATP1A2, or SLC1A3 mutations. Cerebral blood flow is thought to be altered in familial hemiplegic migraine, with focal reduction in the hemisphere contralateral to the aura signs. Subsequent hyperperfusion in the affected hemisphere was demonstrated by Masuzaki et al., with dilatation of the arteries according to magnetic resonance angiography [16]. Attacks of hemiplegic migraine can be triggered most frequently by emotional stress and secondly by minor head trauma. Such hemiplegic migraine attacks triggered by minor head trauma were revealed to be genetically distinct in both animal and human studies, involving the p.S218L mutation in the P/Q-type Ca channel. Such minor head trauma may produce cerebral edema, which may not be reversible, as noted in the case report by Malpas et al. [17]. We have not encountered any other case reports of minor trauma preceding an attack of familial hemiplegic migraine
204
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204
with reversible changes on magnetic resonance imaging. Interestingly, our patient 3 did not test positive for any of the common mutations known to cause familial hemiplegic migraine, although he had a strong family history of familial hemiplegic migraine. In addition, the electroencephalogram recordings in all three children revealed slowing in the cerebral hemispheres, contralateral to the hemiparesis. This finding was also been reported by Chan et al. [18]. Electroencephalogram abnormalities commonly observed in hemiplegic migraine attacks mostly involve unilateral or bilateral slow waves, constituting further evidence of neuronal depression. On follow-up visits, all three patients presented with persistent neurocognitive impairments. Selected studies have indicated that migraineurs, especially those with aura, are more likely to exhibit cognitive deficits particularly affecting memory and attention, informational speed processing, and psychomotor ability. Other studies did not indicate any differences in terms of neuropsychologic and behavioral measures [19]. Karner et al. [20] described intact linguistic abilities and verbal memory, and deficits in figural memory and executive functions in some aspects of attention and in dexterity, among six patients with familial hemiplegic migraine. More importantly, our report suggests that children with attacks of familial hemiplegic migraine may need periodic neuropsychologic assessment. Furthermore, they may develop neurocognitive dysfunction even after magnetic resonance imaging abnormalities have resolved, as demonstrated by repeated magnetic resonance imaging scans that produced normal results. In conclusion, our patients represent the heterogeneity observed in familial hemiplegic migraine, adding to the complexity of its diagnosis as well as its management, in both the short and long term. References [1] Oberndorfer S, Wober C, Nasel C, et al. Familial hemiplegic migraine: Follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAOSPECT in a patient with prolonged hemiplegic aura. Cephalalgia 2004;24:533e9. [2] Cha YH, Millett D, Kane M, Jen J, Baloh R. Adult-onset hemiplegic migraine with cortical enhancement and oedema. Cephalalgia 2007;27:1166e70. [3] Gentile S, Rainero I, Daniele D, Binello E, Valfre W, Pinessi L. Reversible MRI abnormalities in a patient with recurrent status migrainosus. Cephalalgia 2009;29:687e90.
[4] Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Cell 1996;87:543e52. [5] De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A 2 encoding the Naþ/Kþ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003;33: 192e6. [6] Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371e7. [7] Chabriat H, Vahedi K, Clark CA, et al. Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene. Neurology 2000;54:510e2. [8] Dreier JP, Jurkat-Rott K, Petzold GC, et al. Opening of the bloodbrain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 2005;64:2145e7. [9] Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 2005;65:529e34. [10] Terwindt GM, Ophoff RA, van Eijk R, et al, Dutch Migraine Genetics Research Group. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001;56:1028e32. [11] Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000;55:1040e2. [12] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, text revision (DSM-IV-TR). 4th ed. Arlington, VA: American Psychiatric Association; 2000. [13] Resnick S, Reyes-Iglesias Y, Carreras R, Villalobos E. Migraine with aura associated with reversible MRI abnormalities. Neurology 2006;66:946e7. [14] Iizuka T, Sakai F, Suzuki K, Igarashi H, Suzuki N. Implication of augmented vasogenic leakage in the mechanism of persistent aura in sporadic hemiplegic migraine. Cephalalgia 2006;26:332e5. [15] Spadaro M, Ursu S, Lehmann-Horn F, et al. A G301R Naþ/KþATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 2004;5:177e85. [16] Masuzaki M, Utsunomiya H, Yasumoto S, Mitsudome A. A case of hemiplegic migraine in childhood: Transient unilateral hyperperfusion revealed by perfusion MR imaging and MR angiography. AJNR 2001;22:1795e7. [17] Malpas TJ, Riant F, Tournier-Lasserve E, Vahedi K, Neville BG. Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: A novel de novo CACNA1A gene mutation. Dev Med Child Neurol 2010;52:103e4. [18] Chan YC, Burgunder JM, Wilder-Smith E, et al. Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation. J Clin Neurosci 2008;15:891e4. [19] Calandre EP, Bembibre J, Arnedo ML, Becerra D. Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: Their relationship with the clinical manifestations of the illness. Cephalalgia 2002;22:291e302. [20] Karner E, Delazer M, Benke T, Bosch S. Cognitive functions, emotional behavior, and quality of life in familial hemiplegic migraine. Cogn Behav Neurol 2010;23:106e11.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Variable Manifestations of Familial Hemiplegic Migraine Associated With Reversible Cerebral Edema in Children Sheila J. Asghar MD, MSc a, *, Alessandra Milesi-Hallé MD, PhD a, Chavvi Kaushik MD b, Charles Glasier MD b, Gregory B. Sharp MD a a b
Section of Pediatric Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas Section of Radiology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
article information
abstract
Article history: Received 22 February 2012 Accepted 9 May 2012
Three children with familial hemiplegic migraine presented with right-sided weakness, speech difficulty, altered mental status, and gait abnormalities. These persistent aura signs were accompanied by left-sided slowing and cerebral dysfunction, documented by electroencephalograms. Cranial magnetic resonance imaging revealed cortical edema restricted to the left cerebral hemisphere. Follow-up electroencephalogram and imaging studies produced normal results 1-4 months afterward. However, cognitive changes persisted. Genetic testing demonstrated variable results: one child manifested a CACNA1A mutation compatible with familial hemiplegic migraine type 1, whereas another demonstrated an ATP1A2 sequence alteration. No known mutations were evident in the third child, with minor head trauma thought to precipitate the familial hemiplegic migraine. These findings demonstrate the variable clinical and genetic heterogeneity of childhood familial hemiplegic migraine. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Familial hemiplegic migraine is defined as an atypical type of migraine with aura signs that includes some degree of hemiparesis, and may include sensory, language, or visual changes before or during the headache. Often these signs persist throughout the headache phase, and resolve with appropriate management. Confusion or severe coma may also occur as one of the multiple aura signs. The persistent aura phase is thought to be caused by hyperperfusion in the corresponding brain regions [1]. Multiple imaging modalities have been used to investigate the perfusion changes associated with familial hemiplegic migraine, including perfusion and diffusion weighed magnetic resonance imaging, single photon emission tomography [1], and positron emission tomography. In * Communications should be addressed to: Dr. Asghar; Section of Pediatric Neurology; Department of Pediatrics; University of Arkansas for Medical Sciences; Arkansas Children’s Hospital; 1 Children’s Way, Slot #512-15; Little Rock, AR 72202. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.05.006
addition, these studies demonstrated cortical edema [2], which was reversible in most cases [3]. The inherited basis of familial hemiplegic migraine makes genetic testing an important diagnostic tool. In comparison, sporadic hemiplegic migraine is defined as migraine with aura including motor weakness, without any first-degree or second-degree relative manifesting similar attacks. A definite autosomal dominant inheritance pattern with high penetrance is evident. Familial hemiplegic migraine is also genetically heterogeneous. Mutations in the CACNA1A gene on chromosome 19p13, involving the voltage-gated P/Q-type calcium channels, occur in familial hemiplegic migraine type 1 [4]. Furthermore, mutations in the ATP1A2 gene, involving sodium-potassium channels, occur in familial hemiplegic migraine type 2 [5], whereas familial hemiplegic migraine type 3 is caused by mutations in the SCN1A gene [6]. Hemiplegic migraine caused by mutations in CACNA1A, ATP1A2, and SLC1A3 has been associated with hemispheric cerebral edema [7-9]. This report describes the clinical and genetic heterogeneity of familial hemiplegic migraine in three children. The use of their medical records was approved by the
202
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204
Institutional Review Board of the University of Arkansas for Medical Sciences (Little Rock, AR). According to cranial magnetic resonance imaging, all three patients revealed reversible abnormalities compatible with unilateral cortical edema and transient cerebral blood flow abnormalities. Furthermore, despite the reversibility of cerebral edema on follow-up scans, all three children continued to exhibit neurocognitive impairment several months after the initial headache episode. Patients and Methods Patient 1 was a 13-year-old white girl, transferred to our hospital from an outside facility. She exhibited altered mental status, speech difficulties, and incontinence. She had developed a severe headache during a volleyball game 4 days earlier. The family did not report any head trauma or other type of injury. She had a history of headaches that were typically accompanied by slurred speech lasting for a few minutes to hours, often resolving with over-the-counter analgesics, without changes in mental status. Her most recent headache episode had occurred 6 months earlier. Her mother and brother also reported frequent episodes of migraine, accompanied by neurologic deficits such as confusion, aphasia, and hemiplegia. On neurologic examination, our patient demonstrated an unsteady gait, global aphasia, right-sided weakness, and ataxia. In addition, she exhibited urinary incontinence. Her initial computed tomography scan and cranial magnetic resonance imaging produced normal results. Our initial hospital electroencephalograms revealed generalized slowing between 1 and 2 Hz in the left hemisphere, which persisted more than 8 days after her onset of signs. Follow-up cranial magnetic resonance imaging 9 days after the onset of signs revealed an increased T2 signal diffusely involving the left cerebral hemisphere, and more significantly in the frontal and temporal cortical gray areas, with mild mass effect and a subtle midline shift. Slight meningeal but no cortical enhancement was observed (Fig 1). Her clinical presentation and progression, along with her family history of hemiplegic migraine, led to a diagnosis of familial hemiplegic migraine. Treatment included verapamil, a trial of valproic acid, methylprednisolone, and intravenous immunoglobulin, using current pediatric dosing recommendations. The intravenous immunoglobulin was administered in an attempt to improve her severe aphasia and impulsive behavior. The patient manifested CACNA1A gene mutations consistent with a diagnosis of familial hemiplegic migraine type 1. The mutation was located upstream 1997 bp on the CACNA1A gene, and involved a transition from C to T (threonine to methionine; analysis by Athena Diagnostics, Worcester, MA) [10]. The patient was discharged 21 days later on a prophylactic dose of verapamil, with improved gait and the resolution of weakness on the right side, but her speech had still not returned to baseline level. Cranial magnetic resonance imaging and magnetic resonance angiography at a follow-up appointment 4 months after her initial attack indicated a complete resolution of the T2 and fluid attenuated inversion recovery signal abnormalities in the left hemisphere. A repeated electroencephalogram at that time also revealed normal results. The patient had been maintained on verapamil as a prophylactic treatment, and she reported sporadic headaches that responded to ibuprofen, but denied migraine attacks with other neurologic signs. However, she reported attention and memory problems in school, and her grades had declined since her hospital admission. The results of neuropsychologic testing are pending. Our second patient was an 8-year-old white boy who presented to our emergency department with a 3-day history of lethargy, altered mental status, and gait difficulties. He had a history of migraine headaches starting at age 6 years. However, his first episode of migraine with neurologic deficits had occurred 2 months earlier, with left-sided weakness. A strong family history of migraines involved his mother, uncle, and maternal grandfather. A neurologic examination revealed ataxia, prominent weakness of the right arm, and severe expressive aphasia. His magnetic resonance images on the day of presentation revealed subtle abnormality and fullness throughout most of the cerebral cortex within the left hemisphere (Fig 2). Electroencephalograms,
Figure 1. Patient 1: Magnetic resonance imaging demonstrates diffuse increase in left cerebral cortex signal and sulcal effacement.
performed on the same day, revealed abnormal results, with slowing in the left hemisphere from 1.5-2 Hz, consistent with the magnetic resonance findings of edema. He was treated with ketorolac followed by steroids, dihydroergotamine, and verapamil. A DNA analysis revealed an
Figure 2. Patient 2: Magnetic resonance imaging demonstrates diffuse left cortical edema.
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204 ATP1A2 sequence variant. The mutation was located upstream 1025 bp on the ATP1A2 gene, and involved a transition from T to C (leucine to proline; analysis by Athena Diagnostics) [11]. He was discharged on a prophylactic dose of verapamil after 8 days of hospitalization. Repeated magnetic resonance imaging at a follow-up clinic visit 3 weeks later produced normal results. Subsequent neuropsychologic testing after 7 months revealed cognitive disorder not otherwise specified and memory disorder, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV [12]. Since then, he has been maintained on verapamil, and has not reported any further migraine attacks. Cognition and school performance have improved over a period of 4 years, but he still exhibits some mild memory problems. The third patient was a 15-year-old white boy who presented with headache, altered mental status, and slurred speech several hours after being struck on the right side of his face with a basketball. He did not exhibit loss of consciousness or other signs of concussion. He had experienced a similar episode 2 years earlier, with slurred speech and drooping right mouth after going down a water slide. His aunt had a similar history of headaches with unilateral weakness. On examination, he demonstrated pronounced right-sided weakness, affecting both his hand and leg with severe aphasia. Initial cranial magnetic resonance imaging and magnetic resonance angiography on the day of presentation revealed normal results. An electroencephalogram obtained 3 days after the onset of signs indicated left-sided slowing of 1-2 Hz. The patient continued to be disoriented, and developed a fever of up to 38.7 C. Cerebrospinal fluid studies for possible encephalitis produced negative results. Repeated cranial magnetic resonance imaging after 6 days indicated an increased T2 signal, diffuse in the left cerebral hemisphere cortical gray area and most significant in the temporal and parietal lobes (Fig 3), with minimal associated impaired diffusion. Familial hemiplegic migraine was suspected, and he received appropriate doses of verapamil, followed by methylprednisolone after being treated with appropriate antibiotics and acyclovir, until the possibility of bacterial meningitis and herpes simplex encephalitis were excluded via negative cerebrospinal fluid culture and polymerase chain reaction, respectively. Genetic testing revealed negative results for known mutations associated with familial hemiplegic migraine. Nine days after admission, he was discharged home. At a follow-up visit 4 weeks after his onset of signs, cranial magnetic resonance imaging produced normal results. He did not report any headaches but complained of problems at school, specifically with attention.
Figure 3. Patient 3: Magnetic resonance imaging demonstrates diffuse increase in left cortical signal intensity and sulcal effacement.
203
Blood samples for genetic testing were sent to Athena Diagnostics, and genetic analyses were performed by polymerase chain reaction amplification of highly purified genomic DNA, followed by automated, bidirectional DNA sequencing of the entire codon regions of CACNA1A and ATP1A2. Selected exons of the SCN1A gene were similarly analyzed. All test results were reviewed, interpreted, and reported by clinical molecular geneticists certified by the American Board of Medical Genetics.
Discussion
The International Headache Society characterizes familial hemiplegic migraine as migraine episodes with aura signs including visual disturbance, sensory loss, and dysphasia. Familial hemiplegic migraine must include motor involvement or hemiparesis, which occur together with one other sign during familial hemiplegic migraine aura [1]. The neurologic deficits may outlast the associated migrainous headache. Approximately 40-50% of families with familial hemiplegic migraine type 1 manifest cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. The diagnostic criteria for familial hemiplegic migraine involve: (1) the criteria for migraine with aura; (2) aura including some degree of hemiparesis, possibly prolonged; and (3) at least one first-degree or second-degree relative with identical attacks. The patients described here met these criteria in full, and two of the three children demonstrated known genetic alterations suggestive of a familial hemiplegic migraine phenotype. The patient with negative results of genetic testing had experienced a clearly traumatic event that appeared to precipitate the signs of migraine headache. On magnetic resonance imaging, all three children manifested diffuse cortical swelling involving the left hemisphere. Its probable mechanisms include a prolonged depolarization of neurons, causing the shift of water from the extracellular to the intracellular compartment, with a subsequent swelling of the cells and edema. Cerebral edema has been reported in status migrainous without aura as well as with aura [13], in both sporadic and familial hemiplegic migraine [14]. Reversible magnetic resonance imaging changes have been demonstrated in patients with both the CACNA1A [14] and ATP1A2 mutations [15]. Cha et al. [2] described twin brothers with familial hemiplegic migraine who developed severe, reversible cortical edema. However, these brothers did not manifest CACNA1A, ATP1A2, or SLC1A3 mutations. Cerebral blood flow is thought to be altered in familial hemiplegic migraine, with focal reduction in the hemisphere contralateral to the aura signs. Subsequent hyperperfusion in the affected hemisphere was demonstrated by Masuzaki et al., with dilatation of the arteries according to magnetic resonance angiography [16]. Attacks of hemiplegic migraine can be triggered most frequently by emotional stress and secondly by minor head trauma. Such hemiplegic migraine attacks triggered by minor head trauma were revealed to be genetically distinct in both animal and human studies, involving the p.S218L mutation in the P/Q-type Ca channel. Such minor head trauma may produce cerebral edema, which may not be reversible, as noted in the case report by Malpas et al. [17]. We have not encountered any other case reports of minor trauma preceding an attack of familial hemiplegic migraine
204
S.J. Asghar et al. / Pediatric Neurology 47 (2012) 201e204
with reversible changes on magnetic resonance imaging. Interestingly, our patient 3 did not test positive for any of the common mutations known to cause familial hemiplegic migraine, although he had a strong family history of familial hemiplegic migraine. In addition, the electroencephalogram recordings in all three children revealed slowing in the cerebral hemispheres, contralateral to the hemiparesis. This finding was also been reported by Chan et al. [18]. Electroencephalogram abnormalities commonly observed in hemiplegic migraine attacks mostly involve unilateral or bilateral slow waves, constituting further evidence of neuronal depression. On follow-up visits, all three patients presented with persistent neurocognitive impairments. Selected studies have indicated that migraineurs, especially those with aura, are more likely to exhibit cognitive deficits particularly affecting memory and attention, informational speed processing, and psychomotor ability. Other studies did not indicate any differences in terms of neuropsychologic and behavioral measures [19]. Karner et al. [20] described intact linguistic abilities and verbal memory, and deficits in figural memory and executive functions in some aspects of attention and in dexterity, among six patients with familial hemiplegic migraine. More importantly, our report suggests that children with attacks of familial hemiplegic migraine may need periodic neuropsychologic assessment. Furthermore, they may develop neurocognitive dysfunction even after magnetic resonance imaging abnormalities have resolved, as demonstrated by repeated magnetic resonance imaging scans that produced normal results. In conclusion, our patients represent the heterogeneity observed in familial hemiplegic migraine, adding to the complexity of its diagnosis as well as its management, in both the short and long term. References [1] Oberndorfer S, Wober C, Nasel C, et al. Familial hemiplegic migraine: Follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAOSPECT in a patient with prolonged hemiplegic aura. Cephalalgia 2004;24:533e9. [2] Cha YH, Millett D, Kane M, Jen J, Baloh R. Adult-onset hemiplegic migraine with cortical enhancement and oedema. Cephalalgia 2007;27:1166e70. [3] Gentile S, Rainero I, Daniele D, Binello E, Valfre W, Pinessi L. Reversible MRI abnormalities in a patient with recurrent status migrainosus. Cephalalgia 2009;29:687e90.
[4] Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Cell 1996;87:543e52. [5] De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A 2 encoding the Naþ/Kþ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003;33: 192e6. [6] Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371e7. [7] Chabriat H, Vahedi K, Clark CA, et al. Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene. Neurology 2000;54:510e2. [8] Dreier JP, Jurkat-Rott K, Petzold GC, et al. Opening of the bloodbrain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 2005;64:2145e7. [9] Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 2005;65:529e34. [10] Terwindt GM, Ophoff RA, van Eijk R, et al, Dutch Migraine Genetics Research Group. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001;56:1028e32. [11] Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000;55:1040e2. [12] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, text revision (DSM-IV-TR). 4th ed. Arlington, VA: American Psychiatric Association; 2000. [13] Resnick S, Reyes-Iglesias Y, Carreras R, Villalobos E. Migraine with aura associated with reversible MRI abnormalities. Neurology 2006;66:946e7. [14] Iizuka T, Sakai F, Suzuki K, Igarashi H, Suzuki N. Implication of augmented vasogenic leakage in the mechanism of persistent aura in sporadic hemiplegic migraine. Cephalalgia 2006;26:332e5. [15] Spadaro M, Ursu S, Lehmann-Horn F, et al. A G301R Naþ/KþATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 2004;5:177e85. [16] Masuzaki M, Utsunomiya H, Yasumoto S, Mitsudome A. A case of hemiplegic migraine in childhood: Transient unilateral hyperperfusion revealed by perfusion MR imaging and MR angiography. AJNR 2001;22:1795e7. [17] Malpas TJ, Riant F, Tournier-Lasserve E, Vahedi K, Neville BG. Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: A novel de novo CACNA1A gene mutation. Dev Med Child Neurol 2010;52:103e4. [18] Chan YC, Burgunder JM, Wilder-Smith E, et al. Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation. J Clin Neurosci 2008;15:891e4. [19] Calandre EP, Bembibre J, Arnedo ML, Becerra D. Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: Their relationship with the clinical manifestations of the illness. Cephalalgia 2002;22:291e302. [20] Karner E, Delazer M, Benke T, Bosch S. Cognitive functions, emotional behavior, and quality of life in familial hemiplegic migraine. Cogn Behav Neurol 2010;23:106e11.