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.     

神经肌肉促进技术在偏瘫上肢康复训练中的临床应用

目的:探讨神经肌肉促进技术在偏瘫上肢康复训练中的临床应用方法,并观察其疗效。方法:36例脑血管意外后的偏瘫患者被随机分成神经肌肉促进技术组(治疗组)与一般康复治疗组(对照组),其中治疗组17例,对照组19例,两组均接受每日1次、每周5次的治疗10-40次。采用Fugl-Meyer评价法的上肢主动运动功能积分及Barthel指数作为评定指标。结果:两组患者的Fugl-Meyer上肢主动运动功能积分和Barthel指数积分经治疗后都有明显提高(P<0.001),但治疗组的改善情形明显优于对照组(P<0.001或<0.01)。结论:本文所介绍的神经肌肉促进技术在偏瘫上肢康复训练中的临床应用方法对改善偏瘫上肢运动功能及患者日常生活活动能力方面(尤其是偏瘫上肢运动功能方面)有一定的疗效。     

La mesure d'indépendance fonctionnelle (MIF) a-t-elle une valeur prédictive dans les accidents vasculaires cérébraux?

Objective: Assessment of the predictive value of functional independence measure (FIM) for hemiplegie patients after ischemic stroke. Method: Comparison between functional status at admittance and at discharge, this status being assessed by FIM. Population: From 11/01/92 to 04/30/93, 172 hemiplegic patients, admitted after ischemic brain lesion (30 to 94 years old, mean 72; 92 male and 80 female), were included in this study. Motor and/or cognitive deficit had been regressive for 51 patients (29.8%). Lesion was hemispheric in 119 cases: 54% right, 45% left. Results: Total regressive deficits were associated with the highest admittance FIM (a-FIM) and discharge FIM (d-FIM), 100 and 114 respectively. For partially regressive deficits with sequelae, the benefit was 22, and for the most severe deficit, it was only 4. Hemispheric lesions had lower a-FIM and d-FIM than non-hemispheric brain lesions, and benefit was lower. If right hemiplegic patients had lower scores than left, it was due to aphasia, and benefit was not significantly different between these two groups. Discussion: FIM appears to be a good indicator for discharge status, but successful discharge to home is very unprobable when a-FIM is close to 40. Correlation between FIM and the real load of nursing would have to be evaluated.     

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.     

Familial hemiplegic migraine: linkage to chromosome 14q32 in a Spanish kindred

We sought to map the disease-causing gene in a large Spanish kindred with familial hemiplegic migraine (FHM). Patients were classified according to the ICHD-II criteria. After ruling out linkage to known migraine genetic loci, a single nucleotide polymorphism-based, 0.62-cM density genome-wide scan was performed. Among 13 affected subjects, FHM was the prevailing migraine phenotype in six, migraine with aura in four and migraine without aura in three. Linkage analysis revealed a disease locus in a 4.15-Mb region on 14q32 with a maximum two-point logarithm of odds (LOD) score of 3.1 and a multipoint parametric LOD score of 3.8. This genomic region does not overlap with the reported migraine loci on 14q21–22. Sequence analysis of three candidate genes in the region, SLC24A4, ATXN3 and ITPK1, failed to show disease-causing mutations in our patients. Genetic heterogeneity in FHM may be greater than previously suspected. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel

The dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a model system, residual calcium (Ca(2+)) in presynaptic terminals can act through neuronal Ca(2+) sensor proteins to cause Ca(2+)-dependent facilitation (CDF) of P/Q-type channels and induce short-term synaptic facilitation. However, whether this is a general mechanism of plasticity at intact central synapses and whether mutations associated with human disease affect this process have not been described to our knowledge. In this report, we find that, in both exogenous and native preparations, gain-of-function missense mutations underlying Familial Hemiplegic Migraine type 1 (FHM-1) occlude CDF of P/Q-type Ca(2+) channels. In FHM-1 mutant mice, the alteration of P/Q-type channel CDF correlates with reduced short-term synaptic facilitation at cerebellar parallel fiber-to-Purkinje cell synapses. Two-photon imaging suggests that P/Q-type channels at parallel fiber terminals in FHM-1 mice are in a basally facilitated state. Overall, the results provide evidence that FHM-1 mutations directly affect both P/Q-type channel CDF and synaptic plasticity and that together likely contribute toward the pathophysiology underlying FHM-1. The findings also suggest that P/Q-type channel CDF is an important mechanism required for normal synaptic plasticity at a fast synapse in the mammalian CNS.     

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.     

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family

Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.     

Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura inherited with an autosomal dominant pattern. Here, we report the genetic analysis of four families and one sporadic case with hemiplegic migraine (HM) in whom we searched for mutations in the three genes associated with the disease CACNA1A, ATP1A2 and SCN1A. Two novel amino acid changes p.Arg65Trp and p.Tyr9Asn, in the Na,K-adenosine triphosphatase (ATPase) alpha-2 subunit encoded by the ATP1A2 gene, were found in one FHM family and in the sporadic case, respectively. These mutations are peculiar for their location in the extreme N-terminus, an uncommon mutation target in this protein. Low frequency of migraine attacks in all our mutant patients with low complexity of the associated aura symptoms in the sporadic case is also observed. Besides the two novel mutations, the data here reported confirm the involvement of ATP1A2 gene in the sporadic form of HM, while the negative results on the other families tested for all genes known in HM strengthen the hypothesis of the existence of at least another locus involved in FHM.     

Assessment of shoulder pain in hemiplegia: Sensitivity of the ShoulderQ

Background.?The ShoulderQ is a structured questionnaire designed to assess timing and severity of hemiplegic shoulder pain (HSP), in order to target pain relief effectively. It includes both verbal and visual graphic rating scale questions, simply presented for patients with language/visuo-spatial deficits following stroke.

Objective.?To assess the sensitivity of the ShoulderQ to clinical improvement in shoulder pain following multi-disciplinary intervention.

Design and setting.?Retrospective analysis of serial questionnaires collected in the course of clinical treatment in an in-patient neurological rehabilitation unit.

Subjects and interventions.?Thirty consecutive adults with cognitive and communicative deficits, presenting with hemiplegic shoulder pain following acquired brain injury. Multi-disciplinary treatment was delivered through an integrated care pathway, and ShoulderQs recorded fortnightly, including at baseline and end of treatment.

Results.?Changes on visual graphic rating scale (VGRS) were associated with verbal reports of improvement (rho 0.665, p < 0.001). Patients were divided retrospectively on the basis of their overall clinical response into responders (n = 18) and non-responders (n = 12). Responders showed significant change in both VGRS and verbal scores, whereas the non-responder group did not. A change in summed VGRS score of ≥3 showed 77% sensitivity and 91.3% specificity for identifying the responders, with a positive predictive value of 93.3%. Summed VGRS scores of ≤2 had a negative predictive value of 73.3%.

Conclusion.?In this preliminary evaluation of clinical data, the ShoulderQ appears to provide a sensitive measure of shoulder pain which is responsive to change in pain experience for those able to complete the questionnaire, despite the difficulties that many of this group of patients may have in reporting their symptoms. Set alongside previously reported test-retest reliability, the results support the utility of the ShoulderQ as a simple and practical tool for evaluation of shoulder pain in patients with severe complex disabilities.