Familial hemiplegic migraine, neuropsychiatric symptoms, and Erdheim-Chester disease

We report the occurrence of unilateral cerebral hemisphere edema with subsequent cortical laminar necrosis in the setting of familial hemiplegic migraine (FHM) and permanent neurologic sequelae after resolution of an attack in 1 patient. Contemporaneous with this severe attack of FHM, the patient was found to exhibit multiple systemic and neurological symptoms referable to Erdheim-Chester disease (a rare non-Langerhans cell histiocytosis) that was confirmed by bone biopsy. This case demonstrates the severity possible with a migrainous infarction associated with FHM. The co-occurrence of two such rare entities in 1 patient suggests a possible relationship.     

Familial hemiplegic migraine with prolonged aura and multimodality imaging: a case report

We report a case of familial hemiplegic migraine with prolonged aura where multimodality imaging showed hemispheric cytotoxic edema along with evidence of hypometabolism in the affected hemisphere while there was no evidence of hypoperfusion of the affected hemisphere demonstrating that neuronal depression is a more plausible explanation in its pathogenesis.     

Familial hemiplegic migraine in pediatric patients: A genetic,clinical, and follow-up study

Objective

The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype–phenotype correlations may suggest prognostic factors associated with severe phenotypes.

Background

Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts.

Methods

We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years.

Results

We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3–10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2).

Conclusion

The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.     

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.     

Familial hemiplegic migraine presenting as recurrent encephalopathy in a Native Indian family

BACKGROUND: Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, which can result from mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. Typically, FHM presents with an aura of hemiplegia accompanied by a moderate-to-severe headache. FHM can be associated with other neurological findings including coma and seizures. METHODS: We describe the clinical and genetic features of a two-generation, seven-member Native Indian family with recurrent encephalopathy and FHM. RESULTS: Two of the three affected family members presented initially with encephalopathy, the third family member presented with classic episodes of migraine and hemiparesis. The CACNA1A gene locus was excluded in this family by haplotype analysis and no mutations were identified in the coding region of the ATP1A2 gene by direct sequencing. CONCLUSIONS: This emphasizes the genetic and clinical heterogeneity in familial hemiplagic migraine FHM and highlights the need to consider the diagnosis of FHM in cases of recurrent encephalopathy.     

Familial hemiplegic migraine: a clinical comparison of families linked and unlinked to chromosome 19

We compared the clinical characteristics of 50 patients from three unrelated families with familial hemiplegic migraine (FHM) linked to chromosome 19, with those of 20 patients from two families with FHM not linked to chromosome 19. We found no significant differences for age at onset, frequency and duration of attacks, duration of the paresis, and occurrence of basilar migraine symptoms. In the linked families, significantly more patients reported unconsciousness during attacks (39%, vs 15%; p<0.05) and provocation of attacks by mild head trauma (70% vs 40%; p< 0.05). In one linked family patients also displayed chronic progressive cerebellar ataxia, whereas in one unlinked family benign infantile convulsions occurred in addition to FHM. Interestingly, so far an association with cerebellar ataxia was only described in chromosome 19-linked families. FHM linked to chromosome 19 and FHM unlinked to chromosome 19 do not differ with respect to clinical features.     

Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine

Familial hemiplegic migraine type 2 (FHM-2) and common types of migraine show phenotypic similarities which may indicate a common neurobiological background. The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that ATP1A2 mutations in patients with FHM-2 are associated with hypersensitivity to NO-cGMP pathway. Eight FHM-2 patients with R202Q, R763C, V138A and L764P mutations and nine healthy controls received intravenous infusions of 0.5 mug kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded the following variables: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by ultrasound. The primary end-points were differences in incidence of migraine headache and area under the curve (AUC) for headache score during an immediate phase (0-120 min) and a delayed phase (2-14 h) after start of infusion. We found no difference in the incidence of reported migraine between FHM-2 patients, 25% (two out of eight), and controls, 0% (0 out of nine) (95% confidence interval -0.06, 0.56) (P = 0.21). The AUC(headache) in the immediate (P = 0.37) and delayed (P = 0.09) phase was not different between patients and controls. The GTN infusion resulted in a biphasic response in patients. During the immediate phase, the median peak headache occurred at 30 min and tended to be higher in patients, 1 (0, 3.8), than in controls, 0 (0, 1) (P = 0.056). During the delayed phase, the median peak headache occurred 4 h after the start of the infusion and was significantly higher in patients, 2.5 (0, 3), than in controls, 0 (0, 0) (P = 0.046). We found no difference in the AUC(VmeanMCA) (P = 0.77) or AUC(STA) (P = 0.53) between FHM-2 patients and controls. GTN infusion failed to induce more migraine in FHM-2 patients than in controls. The pathophysiological pathways underlying migraine headache in FHM-2 may be different from the common types of migraine.     

Non-familial hemiplegic migraine responsive to naloxone

Two cases of non-familial hemiplegic migraine are described. Naloxone reversed the neurological deficits accompanying attacks, whereas the pain was uninfluenced. The possibility that the opiate-antagonist naloxone facilitates regression of neurological symptoms associated with migraine attacks in general is voiced.     

Sporadic hemiplegic migraine

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.     

Neuropsychologic phenotypes in familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare autosomal dominant-type migraine with aura. Attacks are characterised by hemiparesis in addition to other aura and migraine symptoms. Few studies have examined the influence of FHM on cognitive functions. This study was aimed to investigate neuropsychological functions in 3 adolescent siblings suffering from FHM assessed six months after the last attack. No relevant deficits were found on a battery of multisectorial tests exploring cognitive functions. Sporadic FHM attack therefore seems not to affect cognition in these patients, at least far from the crises. Received: 9 January 2002, Accepted in revised form: 10 January 2003 Correspondence to M. Roccella     

Transcranial Doppler Sonography in familial hemiplegic migraine

A patient affected by familial hemiplegic migraine underwent Transcranial Doppler Sonography twice: the first during a spontaneous attack with right hemiparesis and aphasia, the second during a headache-free period. During the attack the following haemodynamic changes were seen: (a) bilateral increase in the middle cerebral artery and anterior cerebral artery blood flow velocities (this increase was more pronounced on the left side), (b) decreased systo-diastolic ratio and pulsatility index on the right side, (c) increased systo-diastolic ratio and pulsatility index on the left side. Our results indicate that during the attack in this familial hemiplegic migraine patient a diffuse vasoconstriction of the basal cerebral arteries developed. Moreover, Transcranial Doppler Sonography data suggest that a prolonged vasoconstriction of the peripheral arterioles could play a role in determining the neurological symptoms in this syndrome.     

Is familial hemiplegic migraine a hereditary form of basilar migraine?

We studied aura symptoms in 83 patients from 6 unrelated families suffering from familial hemiplegic migraine. Fifty-five of the patients reported symptoms that allowed us to categorize them as basilar migraine (BM) patients, in accordance with the International Headache Society (IHS) criteria. In a control group of 33 patients suffering from migraine with aura and 33 patients suffering from migraine without aura, 9 patients complained of vertigo, and only one patient of diplopia during one of her attacks. None of these control patients fulfilled the IHS criteria for BM We suggest that familial hemiplegic migraine and BM may share certain pathophysiologic mechanisms, which may consist of a (genetically determined) disturbance of basilar artery blood flow.     

An epidemiological survey of hemiplegic migraine

The objective of the present study was to use systematic nation-wide case-finding methods to establish the prevalence and sex ratio of hemiplegic migraine (HM) in the entire Danish population of 5.2 million inhabitants. Affected patients were identified from three different recruitment sources: the National Patient Register, case records from private practising neurologists and advertisements. 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 familial HM from 44 different families, 105 were sporadic HM and 39 were unclassifiable HM. The HM sex ratio (M:F) was 1:3. Based on the identified number of affected patients the prevalence of HM at the end of 1999 was estimated to be 0.01% in Denmark, where the familial and sporadic form were equally frequent.     

Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

BackgroundThe mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted.Case presentationWe describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members.ConclusionsCo-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.     

Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder

In order to better understand sporadic hemiplegic migraine (SHM) and particularly its relation to familial hemiplegic migraine (FHM), migraine without aura (MO) and typical migraine with aura (typical MA), we investigated the occurrence of MO and typical MA among probands with SHM and their first-degree relatives. The pattern of familial aggregation of MO and typical MA was assessed by population relative risk calculations. A total of 105 SHM probands and 483 first-degree relatives were identified in the Danish population. Compared with 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 had an increased risk of both MO and typical MA, whereas first-degree relatives of probands with exclusively SHM had no increased risk of MO but an increased risk of typical MA. Our data suggest that SHM is a genetically heterogeneous disorder.     

Familial hemiplegic migraine: follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAO-SPECT in a patient with prolonged hemiplegic aura

Familial hemiplegic migraine (FHM) is a rare inherited autosomal dominant disorder. Migraine aura may last up to several weeks and then resolve without sequel. We report a 21-year-old male with FHM since the age of 3 years. Diffusion-weighted magnetic resonance imaging (DWI), perfusion-MR imaging (P-MRI) and [99mTc] hexamethyl-propyleneamine-oxime-single photon emission tomography (HMPAO-SPECT) were performed on day 2, when he was somnolent with right-sided hemiplegia, on day 9 when a mild hemiparesis was still present and on day 24 after recovery. The right central region showed normal findings in DWI, whereas P-MRI and SPECT revealed hyperperfusion on day 2, less marked on day 9, and normal findings on day 24. In conclusion, this case report indicates for the first time, by means of SPECT, P-MRI and DWI studies, that even extremely long-lasting migraine aura is not associated with cerebral ischaemia. Therefore, it supports the revised International Headache Society criteria where the term 'persistent' aura is proposed.     

Adult-onset hemiplegic migraine with cortical enhancement and oedema

We present genetically identical twin patients who experienced late-onset migraine with visual and somatosensory auras and later developed hemiplegic migraines associated with severe cortical oedema and enhancement. Both positron emission tomography and electroencephalography showed an increase in activity contralateral to the hemiplegic side. Brain biopsy during the attack showed reactive astrogliosis and microgliosis. Mutations in CACNA1A, ATP1A2, SLC1A3 and NOTCH3 were ruled out by sequencing. This report shows the clinical and genetic evaluation of a severe form of familial hemiplegic migraine as well as the evolution of the imaging changes.     

Cerebral hemodynamics in familial hemiplegic migraine

Clinical findings of four female members from one family with familial hemiplegic migraine are briefly summarized. Cerebral blood flow (CBF) studies using the xenon 133 inhalation method were carried out during and between hemiplegic attacks in two of the family members. CBF was significantly lower over the affected hemisphere during attacks, while equal flow on both sides was seen in headache free periods. The findings indicate that cerebral perfusion is altered, but not necessarily decreased during attacks of familial hemiplegic migraine.     

Motor cortex excitability in patients with migraine with aura and hemiplegic migraine

We studied the excitability of the motor cortex using transcranial magnetic stimulation (TMS) in 12 patients with migraine with aura (MA) and nine patients with familial hemiplegic migraine (FHM). Motor thresholds at rest, the duration of the cortical and peripheral silent period and intracortical inhibition and facilitation using paired-pulse TMS at intervals of 2 to 15 ms were measured with patients free of attacks for at least 48 h. In contrast to previous reports we could not find any significant differences between patient groups and compared to controls (n=17) in the parameters tested. The results suggest that there are no interictal changes of excitability of the motor cortex in migraine. This study does not support the concept of general cortical hyperexcitability in migraine secondary to a genetic predisposition or a structural alteration of inhibitory interneurones in the cortex due to repeated parenchymal insults during attacks.