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Abstract

Sporadic hemiplegic migraine (SHM) is defined as migraine attacks associated with some degree of motor weakness/hemiparesis during the aura phase and where no first degree relative (parent, sibling or child) has identical attacks. The present review deals with recent scientific studies according to which: The SHM prevalence is estimated to be 0.005%; SHM patients have clinical symptoms identical to patients with familial hemiplegic migraine (FHM) and significantly different from patients with migraine with typical aura (typical MA); SHM affected had no increased risk of migraine without aura (MO), but a highly increased risk of typical MA compared to the general population; SHM patients only rarely have mutations in the FHM gene CACNA1A; SHM attacks in some cases can be treated with Verapamil. The reviewed data underlie the change in the International Classification of Headache Disorders 2nd edition where SHM became separated from migraine with typical aura or migraine with prolonged aura. All cases with motor weakness should be classified as either FHM or SHM.

Keywords

Sporadic hemiplegic migraine migraine with typical aura clinical characteristics genetics pathophysiological considerations

Introduction

Migraine aura that includes some degree of hemiparesis has been known for ages and a dominantly inherited type called familial hemiplegic migraine (FHM) was defined in the international headache classification (1). If no family history of similar attacks is evident, the term sporadic hemiplegic migraine (SHM) has been suggested (2–13). However, SHM has not previously been recognized as a distinct subtype of migraine with aura but is in the recent second edition of the international headache classification (14). Previously, persons suffering from these attacks were classified as migraine with typical aura (typical MA) or migraine with prolonged aura. From a pathophysiological point of view it is unclear whether SHM reflects severe attacks of typical MA that just includes motor symptoms in addition to the well known visual, sensory and speech symptoms or whether it represent a separate type of migraine with aura.

In the present review we present and discuss the latest scientific evidence suggesting that SHM is equally frequent to FHM, that SHM likely should be regarded as a separate subtype of migraine, that SHM ethiologically is a heterogeneous disorder, that SHM only rarely is caused by mutations in the FHM gene CACNA1A and an effective treatment for SHM has not been demonstrated.

Epidemiology of SHM

Until recently the literature described about 100 FHM families (2, 3, 7, 8, 12, 15–54) and about 215 SHM cases (2–13,55–60) worldwide (Table 1). A recent study used several systematic, nation-wide case-finding methods in order to estimate the prevalence and sex ratio of sporadic and familial hemiplegic migraine in the entire Danish population of 5.2 million inhabitants (59). Affected patients were identified from three different recruitment sources: The National Patient Register, case records from private practising neurologists and advertisements. Recruited persons were screened by a semistructured validated telephone interview (61–63) run by a physician, and diagnosed according to the diagnostic criteria of the International Headache Society (1). A total of 1828 patients from the three recruitment sources were contacted. Based on the observed number of affected patients from each case-finding method, it was attempted to estimate the total number of affected patients by means of the statistical method known as capture-recapture. Two hundred and ninety-one affected patients were identified, 147 were FHM from 44 different families, 105 were SHM and 39 hemiplegic migraine patients could not be further classified.

Table 1

Studies of Sporadic hemiplegic migraine (SHM)

Study/reference	No. of sporadic hemiplegic migraine cases	IHS 1988 applied yes/no	CACNA1A- mutations investigated yes/no	Comments
Bradshaw et al. (1965) [2]	37	No	No	Study includes some patient with only one attack of HM.
				The symptomatology ranges from brief paraesthesiae through moderate numbness and weakness to profound hemiplegia.
				Describes clinical symptoms of FHM and SHM cases together.
Heyck (1973) [3]	20	No	No	Symptomatology ranges from paraesthesiae through moderate
Heyck (1973) [3]	20	No	No	Numbness and weakness to profound hemiplegia. Study describes clinical characteristics of FHM and SHM cases together. 2/45 cases are familial hemiplegic migraine cases.
Gilbert et al. (1974) [4]	1	No	No	A case report describing first patient with SHM and retinal
Gilbert et al. (1974) [4]	1	No	No	Nonpigmentary degeneration. Suggesting a mutual pathogenesis.
Centonze et al. (1983) [5]	2	No	No	Two case study. One patients has exclusively sensory symptoms and the other patient has motor symptoms during HM attacks. Describing a possible effect of Naloxone iv. on HM attacks.
Muneshige et al. (1987) [55]	1	No	No	Demonstration a possible effect of Flunarizine at a dose of 10 mg/day on SHM attacks. Regional CBF during attack was about 10–15% lower in the affected hemisphere.
Meaney et al. (1996) [6]	1	?	No	Describing transient unilateral cerebral oedema during SHM attacks. MR imaging
Carrera et a. (1999) [7]	7	Yes	Yes	7 SHM cases with no cerebellar signs were investigated for CACNA1A-mutations. No mutations were found.
Ducros et al. (1999) [8]	3	Yes	Yes	3 SHM cases with cerebellar signs were investigated for CACNA1A-mutations. A T666-mutation was identified in one SHM case.
Razavi et al. (2000) [9]	1	Yes	No	SHM attacks induced by exertion.
Vahedi et al. (2000) [56]	1	Yes	Yes	A novel phenotype associated with mutations in the CACNA1A-gene.
Ng et al. (2000) [10]	1	?	No	Verapamil iv. may have a possible effect on intra cerebral vasospasm associated with migraine paresis.
Dora et al. (2001) [11]	1	?	No	Possible relation between sporadic hemiplegic migraine and Sturge–Weber Syndrome.
Ducros et al. (2001) [12]	3	Yes	Yes	In 2/3 SHM patients with cerebellar signs they identified a CACNA1A-mutation.
Barbour et al. (2001) [13]	1	?	No	SHM during pregnancy. SPECT scan showed hyperperfusion of affected hemisphere.
Terwindt et al. (2002) [58]	27	Yes	Yes	2/27 SHM patients had a CACNA1A-mutation. A T666 and R583Q mutation were identified. The first SHM patient without cerebellar signs with a mutation was identified. No detailed clinical characterization of SHM was presented.
Yu et al. (2003) [57]	4	Yes	No	Study demonstrates a possible effect of Verapamil either orally or iv. on SHM attacks.
Thomsen et al. (2002) [59]	105	Yes	No	Study estimating the prevalence of familial and sporadic hemiplegic migraine.
Thomsen et al. (2003) [60]	105	Yes	No	Study describes the clinical characteristics in details of 105 SHM cases identified in a population based search in the Danish population.

The SHM sex ratio (M: F) was 1 : 4,5. Based on the identified number of affected patients the prevalence of HM ultimo 1999 was estimated to be 0.01% in Denmark, the familial and sporadic forms being equally frequent.

Despite limitations regarding the capture-recapture method, it is believed that it may provide a useful approximation of the total number of affected subjects.

Clinical characteristics of SHM

The clinical characteristics of SHM have previously been described in selected materials or case reports (2, 7, 9, 11, 12, 18). However, population-based studies are important in order to analyse the full spectrum of the disorder.

In an approximation to a population-based study, most SHM patients had all four ‘typical’ aura symptoms (visual, sensory, aphasic and motor symptoms) and all had at least two of these aura symptoms during SHM attacks. All SHM patients had at least one other typical aura symptom in addition to motor symptoms during SHM attacks. Motor weakness in SHM was always unilateral and twice as likely to be present in the upper limbs as in the lower limbs (64). Symptoms evolved over at least minutes(93%), with 7% coming on in less than 1 minute. These shorter episodes must obviously be regarded as transient ischaemic attacks until repeated episodes have taken place and extensive investigations have been normal. About two thirds had symptoms lasting only an hour, whereas one third lasted longer, in 8% more than a day. All but two SHM patients had sensory symptoms. A further useful clinical pointer is that visual aura was almost always present, and that motor symptoms never was the only aura symptom during SHM attacks.

SHM and FHM (65) displayed similar frequency of each aura symptom, combination of aura symptoms, sequence of the various aura symptoms, progression time of symptoms and total duration of each aura symptom, headache characteristics and accompanying symptoms. Additionally, the aura was virtually always followed by headache in both conditions.

Of the SHM affected 72% fulfilled the IHS criteria for basilar migraine (BM) during SHM attacks. FHM has the same high frequency of Basilar-type symptoms (39, 65) while such symptoms are rare in typical MA (39).

The combination and order of aura symptoms in SHM were similar to those in typical MA. However, most other characteristics were different. Thus, motor, sensory and aphasic aura symptoms were all more frequently present and the duration of each symptom was usually prolonged in SHM compared to typical MA (66). This includes a longer duration of both the visual and sensory aura symptoms.

SHM was always associated with migraine headache while in typical MA, typical aura often occurred alone (66); additionally, the headache was significantly more often aggravated by routine physical activity during SHM compared to typical MA (P < 0.001). The comparison between SHM, FHM and typical MA clearly showed that SHM has clinical symptoms identical to FHM and different from typical MA.

SHM in headache classification

These data 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 HM. Accordingly, motor weakness should no longer be included in the criteria 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 due to the high frequency of Basilar-type symptoms in these syndromes. Based on these considerations, explicit diagnostic criteria for the separate entity SHM has been suggested (60). With modifications, these criteria have been adopted in the second edition of the international headache classification (14).

SHM and migraine diagnosis

As a consequence of the above considerations patients suspected of SHM should undergo imaging if there is no visual aura during SHM attacks and investigations should be more aggressive if the length of the aura extends over 60 min and the age at onset increases above 45 years of age. However, one should have in mind, that prolonged aura does exist and is a benign phenomena.

The most typical differential diagnoses of SHM include epilepsy (post ictal weakness following seizures or Todds phenomenon), transient ischaemic attack (TIA) and stroke (67). The motor symptoms during epileptic attacks and TIAs neither have a gradual progression nor a postictal typical headache phase. Furthermore, metabolic abnormalities associated with focal deficits (i.e. hypercapnia, hyponatremia, hypocalcemia, hepatic failure and renal failure), meningitis/encephalitis (68), carotid dissection (69), antiphospholipid syndrome (70), systemic lupus erythematosus (71) and ornithine transcarbamylase deficiency (72) should also be considered as differential diagnoses together with other causes mimicking SHM which have been reported in the literature (11, 73–76). The SHM diagnosis should always be based on a thorough evaluation of the reported/experienced symptomatology combined with an appropriate workup.

SHM is aetiologically a heterogeneous disorder

In order to better understand SHM and particularly its relation to FHM, migraine without aura (MO) and typical MA, a recent study investigated the occurrence of MO and typical MA among probands with SHM and their first-degree relatives (77).

The data showed that, compared to the general population, SHM probands had no increased risk of MO but a highly increased risk of typical MA. First-degree relatives of all SHM probands including those with other types of migraine attacks had an increased risk of both MO and typical MA, whereas first-degree relatives of probands with exclusively SHM attacks had no increased risk of MO but an increased risk of typical MA. The interpretation of these data was that some SHM affected represents exaggerated attacks of typical MA and others have a different aetiology.

SHM genetics

At least three different genes have been implicated in FHM: The CACNA1A gene on chromosome 19p13 in half of the families (78), and the ATP1A2 gene on chromosome 1 in a few families (44, 79, 80). A few families could not be linked to either chromosome 19 or chromosome 1 (44, 46) and therefore at least a third gene most be involved.

In SHM the cause is unknown. Initially 3 patients with SHM who had cerebellar signs were analysed for mutations in the FHM gene CACNA1A. In these patients two mutations were found, a T666M mutation in a patient with SHM and cerebellar ataxia and a Y1384C mutation in a woman with mental retardation, SHM, coma, seizures and permanent cerebellar ataxia and atrophy (81). At the same time 8 SHM patients who had no cerebellar ataxia were analysed, but no mutation was found (7, 8, 12). Recently another 27 SHM patients were examined (58). In these patients two mutations were found, a T666M mutation in a patient with SHM and cerebellar ataxia and a R583Q mutation in a patient with SHM but without cerebellar ataxia. No mutations were identified in the remaining 25 SHM patients.

Thus, so far three different missense mutations in the CACNA1A-gene have been demonstrated to cause SHM, where off two mutations cause both SHM and FHM. The role of the ATP1A2 and other yet unknown FHM genes in the pathophysiology of SHM is still unknown.

Pathophysiological considerations

It is striking that the aura symptoms in SHM (60) and FHM (65), except for motor weakness, were of exactly the same type as in typical MA (62, 66, 82). The spread of symptoms was similar to typical MA with a slow march of symptoms, usually starting with visual, then sensory and finally motor and aphasic symptoms. Thus, both the slow spread of the individual symptom as well as the temporal succession of symptoms clearly indicated a phenomenon spreading contiguously in the cerebral cortex. The only known phenomenon that can spread in this fashion is a cortical spreading depression of Leao, the mechanism thought to underlie typical MA (83–86). The described clinical findings therefore support that SHM symptoms are caused by a cortical spreading depression.

In contrast to typical MA, there were not only more cortically derived symptoms but the aura was associated with basilar-type symptoms indicating either spread to the brain stem or bilateral hemispheric involvement. There was always more than one aura symptom in SHM, usually all four typical aura symptoms. In contrast, typical MA usually has only visual symptoms. Thus, the cortical spread of the symptoms was more extensive in SHM and even more distinctive was the often prolonged (>60 min) duration of each individual aura symptom in SHM(49% motor aura, 48% sensory aura, 26% visual aura and 31% aphasic aura symptoms), and a statistically significantly longer duration of otherwise typical visual and sensory disturbances.

SHM was more often followed by migrainous headache than typical MA, where aura without headache or aura followed by headache that phenomenonlogically fulfils criteria for tension-type headache are frequent (66, 82). This could indicate a genetic difference between SHM and typical MA, but it could also simply be a consequence of the larger area of brain affected by the SHM aura. It is interesting that, despite the higher frequency of headache after the SHM aura and the longer duration of the headache phase during SHM attacks compared to typical MA attacks, all other headache characteristics were similar. Given these similarities, how can it be explained that SHM attacks are more severe and shows a trends to be less frequent (60) than in typical MA? Clearly, the threshold for the cortical (spreading depression) phenomenon must remain relatively high in SHM as compared to typical MA. Thus, if both types of migraine are channelopathies as has been previously suggested (87, 88), they either must be caused by different ion-channels or, if it is the same channel, its function must be affected differently in the two conditions. This is even more obvious when considering the much larger cortical spread in SHM and the fact that symptoms may invade the brain stem or the opposite hemisphere as well as the fact that each individual symptom is considerably more long lasting. Thus, while the threshold for the cortical spreading phenomenon is lowered less in SHM than in typical MA, once it is starts it seems to spread more readily and the restorative process that makes cortical spreading depression self-limiting is more affected in SHM. Also, the defect present in SHM seems to be more widespread in the brain and to perhaps involve the brain stem and cerebellum.

Treatment strategies of SHM

Current therapeutic recommendations are based on isolated case reports: propranolol (73), flunarizine (89), naloxone (5) and verapamil (9, 10, 57). All reports suggest a positive effect of the therapeutic agent in the treatment of SHM attacks. However, due to the natural fluctuation of migraine attack frequency and attack severity over time, the studies are too small to show a statistically significant effect and publication bias can not be ruled out.

Conclusion

It may be concluded that SHM should be classified together with FHM, and that both should be classified as separate subforms of migraine with aura (MA). The reviewed data also underline the need for a better separation of hemiplegic migraine from Basilar Migraine (BM). Future genetic and pathophysiological studies are however, likely to further improve the distinction and give a more rationally based classification of the different subforms of MA.

Such studies are also likely to improve our understanding of the involved mechanism and thereby open possibilities for more rational future treatments.

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