Abstract
Objective: To compare clinical characteristics of patients with sporadic hemiplegic migraine (SHM) with those of patients with migraine with typical aura (MA) and patients with familial hemiplegic migraine (FHM).
Methods: The authors used a computer search of Denmark’s National Patient Register to screen the population for patients with migraine with aura with motor weakness, and also examined case records from headache clinics and private practicing neurologists and placed advertisements. The authors screened patients and their relatives with a semi-structured validated telephone interview. All recruited patients were then interviewed by a physician and given a neurologic examination.
Results: A total of 105 patients with SHM were identified. Seventy-two percent had four typical aura symptoms: visual, sensory, aphasic, and motor. All had at least two symptoms present during SHM attacks. A gradual progression and sequential appearance of aura symptoms was typical; compared with MA, the duration of each aura symptom was usually prolonged and bilateral motor symptoms were more frequent. Of the patients with SHM, 72% fulfilled the criteria for basilar migraine during SHM attacks. The aura was usually followed by headache, as is common in FHM but not MA.
Conclusions: Patients with sporadic hemiplegic migraine had clinical symptoms identical to familial hemiplegic migraine and significantly different from migraine with typical aura. Sporadic hemiplegic migraine is a separate entity, and should be classified with familial hemiplegic migraine.
Familial hemiplegic migraine (FHM) is recognized as a distinct subtype of migraine with aura because of its dominant mode of inheritance.1 However, patients with similar clinical symptoms but without other affected family members have been reported,2-13⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ and the term sporadic hemiplegic migraine (SHM) has been used.2,7,9,11,12⇓⇓⇓⇓ Currently, these patients are classified as having migraine with typical aura (MA) or migraine with prolonged aura according to the classification of the International Headache Society (IHS classification).
We examined the similarity of the clinical characteristics of SHM to those of MA and those of FHM by comparing SHM with our data on FHM14 and with a historical group of patients with MA.15
Materials and methods.
Data collection.
We conducted a systematic search using three search strategies in the Danish population of 5.2 million: performing a computer search of the National Patient Register, screening over 27,000 case records from headache clinics and private practicing neurologists, and placing advertisements for people with hemiplegic migraine. Recruited persons were screened by a semi-structured validated16-18⇓⇓ telephone interview run by a physician (see appendix 1 at www.neurology.org) and diagnosed according to the diagnostic criteria of the IHS.1 To analyze SHM and MA separately, it was necessary that probands and relatives diagnosed with MA had attacks of migraine with aura that did not include motor weakness.
The operational diagnostic criteria of the IHS were used. Each of the three sources identified patients with migraine with motor weakness; in addition, to classify these as patients with either SHM or FHM, their relatives were also screened. All first-degree relatives over 15 years of age were screened; first-degree relatives aged 15 years or younger were contacted for a telephone interview only if suspected of having had headache or aura symptoms. In families without a positive family history according to the proband, all second, third, or more distant relatives suspected of having had migraine or aura symptoms were screened, whereas in families with a positive family history according to the proband, all second, third, and more distant relatives were screened.14
All patients with SHM had a face-to-face interview and a physical and neurologic examination conducted by a physician. Relatives of probands with SHM were screened by three medical students.
We identified 2,448 persons (1,914 recruited persons, 534 relatives [798 male, 1,650 female]); 139 (63 male, 76 female) were noncontactable, and 76 (43 male, 33 female) relatives were not contacted because they had no history of headache or aura symptoms. Those interviewed by telephone were labeled participants (1,836 persons [561 male, 1,275 female]) and those not interviewed were labeled nonparticipants (397 persons [131 male, 266 female]). The participation rate among recruited persons was 79% (1,446/1,828), and among relatives 96% (390/405). The study design, representativeness of the population, characteristics of the nonparticipants, and results of the physical and neurologic examination have been published.19
The project was approved by the Danish ethical committees.
We defined patients with migraine with aura that includes some degree of motor weakness/hemiparesis without similarly affected relatives as having SHM.
Basilar-type symptoms were defined as simultaneous bilateral paresis or paresthesiae, simultaneous visual symptoms in both the temporal and nasal fields of both eyes, dysarthria, vertigo, diplopia, tinnitus, decreased level of hearing, decreased level of consciousness, loss of balance when walking, drop attacks, crossed symptoms, and symptoms changing from one side of the body to the other during the attack.
Basilar migraine was confirmed in patients with at least two of the following symptoms: simultaneous bilateral paresis/paresthesiae, simultaneous visual symptoms in both the temporal and nasal fields of both eyes, dysarthria, vertigo, diplopia, tinnitus, decreased level of hearing, or decreased level of consciousness. Loss of balance when walking is not necessarily ataxia, and was therefore not used to diagnose basilar migraine. Thus, our definition of basilar migraine was partly based on the IHS criteria for basilar migraine.1
Data processing and statistical analysis.
All data were processed and statistical analyses were done using SPSS Base System 10.0 (Chicago, IL) for Windows 98. The χ2 test, Fisher exact test, Kruskal-Wallis test, t-test for independent samples, and 95% CI were used as appropriate depending on the type of data. A level of significance of 0.05 was used in single tests. When testing for multiple symptoms a 0.001 level of significance was chosen to compensate for mass significance.
Results.
We identified 105 (20 male, 85 female) patients with SHM and 534 (272 male, 262 female) relatives: 483 (253 male, 230 female) first-degree relatives, 49 (19 male, 30 female) second-degree relatives, and 2 (2 female) third-degree or more distant relatives.
Age.
The age distribution and age at onset of SHM are shown in figure 1.
Figure 1. Age distribution and age at onset in patients with sporadic hemiplegic migraine (SHM). Black bars = men; white bars = women.
The mean age was lower in men compared to women (24 years [95% CI 19 to 30] vs 33 years [95% CI 31 to 36] [p = 0.002, t-test]) and the mean age at onset was lower in men compared to women (16 years [95% CI 12 to 21] vs 21 years [95% CI 19 to 23] [p = 0.040, t-test]).
In patients with SHM who had had no attacks in the last 2 years (n = 16), the mean age at the last attack was 28 years (95% CI 22 to 33) with no sex difference.
Attack frequencies.
The lifetime number of SHM attacks varied from two attacks in a lifetime to more than 100 attacks with no sex difference (p = 0.162, Kruskal-Wallis test) (see table E-1 at www.neurology.org).
The majority (85%; 89/105; 15 male, 74 female) had had SHM attacks within the last 2 years, and of these only 3% (3/89) were above age 52. Among the 15% (16/105; 5 male, 11 female) without attacks within the last 2 years, none had SHM attacks after age 52.
There was no difference in lifetime number of attacks among SHM, FHM, and MA (p = 0.001, Kruskal-Wallis test; p = 0.052, χ2 test) (see table E-1 at www.neurology.org).
Aura symptoms.
In SHM, the presence of motor aura symptoms is essential. The most common other aura symptoms were sensory (98%), visual (91%), and aphasia (81%). Additionally, 72% of patients with SHM had co-occurrence of basilar migraine, with basilar-type symptoms during SHM attacks. The distribution of the various combinations of aura symptoms during SHM attacks is similar to those experienced by patients with FHM (figure 2).
Figure 2. Venn diagram illustrates the distribution of the various aura symptoms in 105 patients with sporadic hemiplegic migraine (bold) and 147 persons with familial hemiplegic migraine (not bold).
The four typical aura symptoms (motor, sensory, visual, and aphasic) were all frequently present during SHM attacks (n = 76) and, if not, a combination of three aura symptoms was nearly always experienced (n = 27). Motor aura symptoms were rarely combined with only sensory or visual aura symptoms (n = 2), never exclusively appeared with aphasia, and never occurred alone.
Among the 58% (61/105) of patients with SHM who experienced all four aura symptoms and co-occurrence of basilar migraine during SHM attacks, the majority (90%; 55/61) reported that the aura symptoms occurred in succession, whereas 10% (6/61) were uncertain. The most frequent temporal succession of the aura symptoms was visual, sensory, motor, aphasic, and basilar (77%), followed by sensory, motor, visual, aphasic, and basilar (8%), or sensory, visual, motor, aphasic, and basilar (8%). However, some patients reported that the succession of the aura symptoms could vary from attack to attack.
The aura symptoms were usually unilateral, but 16% reported that motor and sensory aura symptoms shifted from one side of the body to the other during an attack and 13% occasionally had sensory or motor symptoms or both with simultaneous bilateral progression. Bilateral simultaneous visual symptoms were reported in 44% during SHM attacks compared to 31% previously reported during MA attacks (p = 0.446, χ2 test).15
The lifetime occurrence of aura symptoms during SHM attacks is shown in table E-2 (www.neurology.org). The lifetime occurrence of the different aura symptoms in patients with SHM is similar to those experienced by patients with FHM and different from the lifetime occurrence of aura symptoms in patients with MA (see table E-2).
Motor aura symptoms.
The characteristics of the motor aura symptoms are shown in table 1.
Table 1 Characteristics of the sporadic hemiplegic migraine aura symptoms
The presence of motor aura symptoms is essential during SHM attacks. Fifty percent of patients with SHM had a hemiparetic distribution of the motor aura symptoms (in both arm and leg on the ipsilateral side). The other 50% had lateralized motor symptoms but with a nonhemiparetic distribution of the motor aura symptoms (in either arm or leg on the ipsilateral side). Sixty-four percent of the persons reported that the hemiparesis always affected the limbs on the same side. The right side was affected in 64% of these persons whereas the left was affected in 36%. Thirty-six percent of patients with SHM experienced a side shift of motor or sensory aura symptoms from attack to attack.
A total of 98% (103/105) of patients with SHM experienced motor aura symptoms in association with sensory aura symptoms, and in these patients the motor aura symptoms affected only those parts of the body also affected by sensory aura symptoms.
The mean gradual progression time of the motor aura symptoms was 28 minutes (95% CI 14 to 43 minutes). Forty-nine percent had prolonged aura (>60 minutes), but only 8% (8/105) had aura symptoms that lasted more than 24 hours. The mean duration of the motor aura symptoms was 7 hours 5 minutes (95% CI 271 to 578 minutes).
The distribution of the motor aura symptoms was similar in SHM, FHM, and MA (p = 0.603 face, p = 0.341 tongue, p = 0.102 hand, p = 0.877 arm, p = 0.316 foot, p = 0.370 leg, and p = 0.017 body, Kruskal-Wallis test).
Sensory aura symptoms.
The characteristics of the sensory aura symptoms are shown in table 1.
The mean gradual progression time of the sensory aura symptoms was 30 minutes (95% CI 16 to 44 minutes), typically (96%; 99/103) within 60 minutes; 48% (49/103) had prolonged (>60 minutes) sensory aura symptoms. The mean duration was 4 hours 54 minutes (95% CI 171 to 418 minutes), typically less than 12 hours (89%; 92/103), and seldom above 24 hours (4%; 4/103).
The distribution of the sensory aura symptoms in SHM, FHM, and MA was similar in the hand, tongue, and body (p = 0.063 hand, p = 0.003 tongue, and p = 0.067 body, Kruskal-Wallis test) but different in the face (p < 0.001), arm (p < 0.001), foot (p < 0.001), and leg (p < 0.001). Thus, the sensory aura symptoms were equally frequently present in the face, arm, foot, and leg during SHM and FHM attacks, but more rarely present at these locations during MA attacks.
Visual aura symptoms.
Overall visual aura symptoms were experienced by 91% of persons (96/105) during SHM attacks: 60% (58/96) with visual aura symptoms had unilateral visual aura symptoms, 84% (81/96) flickering light, 81% (78/96) a scotoma, 50% (48/96) zig-zag/fortification lines, and 98% (94/96) without preserved central vision, starting either in the periphery or the center of the visual field.
The mean gradual progression time of visual aura symptoms was 22 minutes (95% CI 13 to 32 minutes). Twenty-six percent (25/95) had prolonged (>60 minutes) visual aura symptoms. The mean duration of the visual aura symptoms was 2 hours 4 minutes (95% CI 67 to 180 minutes).
When comparing SHM, FHM, and MA the composition of the visual aura symptoms was similarly frequently unilateral (p = 0.447) and consisting of flickering light (p = 0.510), but different regarding starting centrally (p < 0.001), starting peripherally (p < 0.001), the presence of scotoma (p < 0.001), the presence of zig-zag lines (p < 0.001), and preserved central vision (p < 0.001) (Kruskal-Wallis test). In SHM and FHM, the visual aura symptoms equally frequently started peripherally and consisted of a scotoma, only rarely were associated with a preserved central vision, and were different from MA, which starts centrally and more frequently consists of zig-zag lines.
Aphasic aura symptoms.
Aphasic symptoms were experienced by 81% (85/105) during SHM attacks. Only those with problems finding the right words, impaired production of language (not due to dysarthria), or impaired comprehension of language were included as having aphasia. Eight patients with dysarthria and no aphasia were not included as having aphasia. Among the patients with SHM with aphasia, 89% (76/85) had problems articulating speech, 52% (44/85) had problems finding the right words, 5% (4/85) had problems understanding what was said, and 94% (80/85) had problems in the production of language.
The mean duration of the aphasic aura symptoms was 3 hours 19 minutes (95% CI 95 to 302). A total of 31% (26/85) had prolonged (>60 minutes) aphasic aura symptoms.
When comparing SHM, FHM, and MA, patients with aphasia had a similar frequency of problems in finding the right words (p = 0.032, χ2 test) but were different with regard to articulating speech (p < 0.001, χ2 test), problems in being understood (p < 0.001 χ2 test), and problems in understanding what was said (p < 0.001 χ2 test). In SHM and FHM, problems articulating speech and problems in understanding what was said were more frequent than during MA attacks, where problems in understanding what was said by others were more frequent.
Basilar-type symptoms and basilar migraine.
Basilar-type symptoms were simultaneous bilateral paresis or paresthesia or both in 13%, simultaneous bilateral visual symptoms in 44%, dysarthria in 69%, vertigo in 54%, diplopia in 28%, tinnitus in 17%, reduced level of hearing in 20%, reduced level of consciousness in 19%, reduced ability to balance in 54%, drop attacks in 12%, crossed symptoms in 7%, and change of symptoms from side to side in 16% (the percentages are calculated as percent of the entire SHM population [n = 105]). Of the 105 patients with SHM, 76 (72%) fulfilled the criteria for basilar migraine during SHM attacks and the basilar-type symptoms experienced by these patients are shown in table E-3 (available online at www.neurology.org).
In the previous study of MA, patients were not asked about basilar-type symptoms.15 There was no difference with regard to basilar-type symptoms in SHM compared to FHM (p = 0.204 bilateral pareses/paresthesia, p = 0.433 bilateral visual symptoms, p = 0.135 dysarthria, p = 0.819 vertigo, p = 0.174 vertigo, p = 0.628 tinnitus, p = 0.033 reduced level of hearing, p = 0.719 reduced level of consciousness, p = 0.772 reduced ability to balance, χ2 test; p = 0.01 crossed symptoms and p = 0.048 change of symptoms from side to side, Fisher exact test).
Gradual progression time and duration of aura symptoms.
The gradual progression time and duration of the different aura symptoms during SHM, FHM, and MA is shown in table 2.
Table 2 Gradual progression and duration of aura symptoms in sporadic hemiplegic migraine (SHM), familial hemiplegic migraine (FHM), and migraine with typical aura (MA)
The gradual progression time did not differ between SHM, FHM, and MA (p = 0.015 visual aura symptoms, p = 0.868 sensory aura symptoms, p = 0.39 motor aura symptoms, Kruskal-Wallis test). The duration of the visual and sensory aura symptoms did not differ in SHM compared to FHM (p = 0.267 sensory, p = 0.832 visual, χ2 test) but was prolonged in SHM and FHM compared to MA (p < 0.001 visual aura symptoms, p < 0.001 sensory aura symptoms, Kruskal-Wallis test). The duration of the motor aura symptoms and aphasic aura symptoms did not differ in SHM, FHM, and MA (p = 0.147 motor aura symptoms, p = 0.005 aphasic aura symptoms, Kruskal-Wallis test).
Headache phase.
The characteristics of the headache phase during SHM attacks are shown in table 3.
Table 3 Characteristics of headache phase (nontreated or insufficiently treated) during attacks of sporadic hemiplegic migraine, familial hemiplegic migraine (FHM), and migraine with typical aura
No sex difference was found regarding headache characteristics (p = 0.612 unilateral, χ2 test; p = 0.736 pulsating, Fisher exact test; p = 1.0 moderate/severe, Fisher exact test; p = 1.0 aggravation, Fisher exact test; p = 1.0 nausea, Fisher exact test; p = 0.187 vomiting, χ2 test; p = 0.368 photophobia, Fisher exact test; p = 1.0 phonophobia, Fisher exact test) and headache duration (p = 0.109, Kruskal-Wallis test).
When comparing SHM, FHM, and MA, headache characteristics were similar regarding location (p = 0.386 unilateral, Kruskal-Wallis test), character (p = 0.464 pulsating, Kruskal-Wallis test), intensity (p = 0.251 moderate/severe, Kruskal-Wallis test), and accompanying symptoms such as nausea (p = 0.042, Kruskal-Wallis test), vomiting (p = 0.001, Kruskal-Wallis test), photophobia (p = 0.361, Kruskal-Wallis test), and phonophobia (p = 0.003, Kruskal-Wallis test). Headache was more frequently aggravated by routine physical activity in SHM compared to MA (p < 0.001, Kruskal-Wallis test) but did not differ in FHM compared to MA (p = 0.002, Kruskal-Wallis test).
Succession of aura and headache.
Headache followed the visual aura symptoms in 78% (79/102) and came before the visual aura symptoms in 15% (15/102); both occurred simultaneously in 8% (8/102). Information was missing for three patients.
Discussion.
Our comparison among SHM, FHM, and MA based on Danish epidemiologic studies using a similar validated semi-structured telephone interview16,17⇓ showed that SHM has clinical symptoms identical to FHM and different from MA.
When comparing the aura and headache characteristics of SHM to those of FHM,14 we found similar clinical characteristics regarding frequency of each aura symptom, combinations of aura symptoms, sequence of the various aura symptoms, the gradual progression time and total duration of each aura symptom, headache characteristics, and accompanying symptoms; additionally, the aura was virtually always followed by headache in both conditions.
When studying the relation between SHM and basilar migraine, we found that 72% of the patients with SHM fulfilled the IHS criteria for basilar migraine during SHM attacks. FHM has the same high frequency of basilar-type symptoms,14,20⇓ whereas such symptoms are rare in MA.20 A more detailed discussion of basilar-type symptoms is given elsewhere.14
When comparing the aura and headache characteristics of SHM to those of MA, the types of aura symptoms in SHM were similar to those seen in MA; the order of symptoms was also the same. However, most other characteristics were different. Thus, motor, sensory, and aphasic aura symptoms were all more frequently present and the duration of each symptom (including both visual and sensory) was usually prolonged in SHM compared to MA.15 SHM was always associated with migraine headache, whereas in MA, typical aura often occurred alone15; additionally, the headache was more often aggravated by routine physical activity during SHM compared to MA (p < 0.001).
Previously, we reported that sporadic cases of hemiplegic migraine occur with approximately the same prevalence as familial cases.19 This study shows that SHM and FHM have the same clinical characteristics and have a similar frequency of basilar-type migraine symptoms present during hemiplegic attacks, whereas basilar-type symptoms are rare during MA attacks.20 Therefore, the current data strongly indicate that SHM should be separated from migraine with typical aura or migraine with prolonged aura. Thus, all cases with motor weakness should be classified as either FHM or SHM, both being subforms of hemiplegic migraine. Moreover, motor weakness should not be included as a criterion for migraine with typical aura or migraine with prolonged aura.
Cases with both motor weakness and basilar-type symptoms should be diagnosed as FHM or SHM owing to the high frequency of basilar-type symptoms in these syndromes. Based on these considerations, we suggest explicit diagnostic criteria for the separate entity SHM, which should be similar to the previously proposed revised diagnostic criteria for FHM14; however, there should be no relatives affected with hemiplegic migraine, as shown in table E-4 (available at www.neurology.org). This necessitates a clarification of the sensitivity and specificity of our proposed criteria, which should be done in future prospective studies, ideally using headache diaries.
As well as improving classification and diagnostic criteria, our data may also help to sharpen the differential diagnosis of SHM. We have shown that patients with SHM have typical aura symptoms and always have at least two aura symptoms per attack. Also, headache almost always occurs in close temporal relation to the aura. Hemiplegic aura often includes visual disturbances, and SHM has an age at onset before age 45 years (97%), whereas patients with SHM seldom have attacks beyond age 50.
The most typical differential diagnoses of SHM include epilepsy (postictal weakness following seizures or Todd phenomenon), TIA, and stroke.21 Metabolic abnormalities associated with focal deficits (i.e., hypercapnia, hyponatremia, hypocalcemia, hepatic failure, and renal failure), meningitis/encephalitis,22 carotid dissection,23 antiphospholipid syndrome,24 systemic lupus erythematosus,25 and ornithine transcarbamylase deficiency26 should also be considered as differential diagnoses together with other reported conditions that mimic SHM.11,27-30⇓⇓⇓⇓ Inherited disorders associated with migraine headache that may include hemiparesis are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy31; mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes32; hereditary hemorrhagic telangiectasia,33 a form of hereditary amyloid angiopathy34; familial cerebral cavernous malformation35; and benign familial infantile convulsions.36 Because the description of so-called migraine symptoms in persons with these other syndromes is limited, it is unknown if their migraine symptoms fulfill the diagnostic criteria for SHM or FHM proposed by us. However, we recommend that the SHM diagnosis should always be based on a thorough evaluation of the reported experienced symptomatology combined with an “appropriate workup” to eliminate other disorders with a similar symptomatology.
Acknowledgments
Supported by grants from the Cool Sorption Foundation of 1988, the Foundation for Research in Neurology, the Danish Headache Society, The AP Møller Foundation for advancement of medical science, the Novo Nordisk Foundation, and the IMK-Almene Foundation.
Acknowledgment
The authors thank the patients with SHM and their relatives; the medical students S.F. Roemer, M.K. Eriksen, and I. Andersen; and many other colleagues for excellent collaboration.
Footnotes
-
See also page 536
-
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 25 issue to find the title link for this article.
- Received March 12, 2002.
- Accepted October 16, 2002.
References
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