A real-world, observational study of erenumab for migraine prevention in Canadian patients.

OBJECTIVES: To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments. BACKGROUND: In randomized controlled trials, erenumab demonstrated efficacy for migraine prevention in patients with ≤4 prior ineffective prophylactic migraine therapies. The "Migraine prevention with AimoviG: Informative Canadian real-world study" (MAGIC) assessed real-world effectiveness of erenumab in Canadian patients with migraine. METHODS: MAGIC was a prospective open-label, observational study conducted in Canadian patients with chronic migraine (CM) and episodic migraine (EM) with two to six categories of prior ineffective prophylactic therapies. Participants were administered 70 mg or 140 mg erenumab monthly based on physician's assessment. Migraine attacks were self-assessed using an electronic diary and patient-reported outcome questionnaires. The primary outcome was the proportion of subjects achieving ≥50% reduction in monthly migraine days (MMD) after the 3-month treatment period. RESULTS: Among the 95 participants who mostly experienced two (54.7%) or three (32.6%) prior categories of ineffective prophylactic therapies and who initiated erenumab, treatment was generally safe and well tolerated; 89/95 (93.7%) participants initiated treatment with 140 mg erenumab. At week 12, 32/95 (33.7%) participants including 17/64 (26.6%) CM and 15/32 (48.4%) EM achieved ≥50% reduction in MMD while 30/86 (34.9%) participants including 19/55 (34.5%) CM and 11/31 (35.5%) EM achieved ≥50% reduction in MMD at week 24. Through patient-reported outcome questionnaires, 62/95 (65.3%) and 45/86 (52.3%) participants reported improvement of their condition at weeks 12 and 24, respectively. Physicians observed improvement in the condition of 78/95 (82.1%) and 67/86 (77.9%) participants at weeks 12 and 24, respectively. CONCLUSION: One-third of patients with EM and CM achieved ≥50% MMD reduction after 3 months of erenumab treatment. This study provides real-world evidence of erenumab effectiveness, safety, and usage for migraine prevention in adult Canadian patients with multiple prior ineffective prophylactic treatments.

Unilateral pallidal deep brain stimulation in a patient with dystonia secondary to episodic ataxia type 2.

BACKGROUND/AIMS: This paper describes the use of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the treatment of secondary dystonia caused by expisodic ataxia type 2 (EA2). METHODS: We present the case of a patient with EA2, an autosomal dominant condition, who developed late-onset cervical and right upper limb segmental dystonia. The patient underwent left GPi DBS. RESULTS: Within 4 months of commencing stimulation of the left GPi, the patient had resolution of his neck pain and was able to keep the head straighter for longer time intervals. There was also improvement in right arm segmental dystonia. There was an improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS 21.5) of 55% at 4 months and of 51% at 22 months. CONCLUSION: The treatment of secondary dystonia is difficult and the results with GPi DBS are less favourable compared with primary dystonia. This case illustrates the successful treatment of secondary dystonia caused by EA2.

PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.

OBJECTIVE: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). METHODS: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. RESULTS: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. CONCLUSIONS: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Chasing the dragon - characterizing cases of leukoencephalopathy associated with heroin inhalation in British Columbia.

An association between leukoencephalopathy, a disease of the white matter of the brain, and smoking heroin is well recognized. This paper describes 27 cases of leukoencephalopathy identified in two cities in British Columbia, Canada 2001-2006; the largest number of geographically and temporally defined reported cases in North America.Twenty cases of leukoencephalopathy were identified in and around Vancouver with onset dates December 2001 to July 2003; seven further cases were identified in Victoria September 2005-August 2006. Twenty (74%) of all cases were male, two couples were reported and eleven cases (55%) had Asian ethnicity. One case reported smoking heroin on a single occasion and developed mild symptoms; all other cases were hospitalized. Thirteen (48%) cases died; all had smoked heroin for a minimum of 3 years. Testing of one available heroin sample identified no substance other than common cutting agents.Although a specific etiology was not identified our study supports the theory of an intermittent exposure to a toxic agent added to the heroin or a combustion by-product. It also suggests a dose response effect rather than genetic predisposition. Collaboration with public health, health professionals, law enforcement and persons who use illegal drugs, will facilitate the early identification of cases to enable timely and complete follow-up including obtaining samples. Testing of implicated heroin samples may allow identification of the contaminant and therefore prevent further cases. It is therefore important to ensure key stakeholders are aware of our findings.

Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies.

Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit unique spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming alpha(1)-subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in two predominant splice variants of the neuronal Ca(V)2.1 P/Q-type channel. All three FHM-1 mutations cause a greater hyperpolarizing shift in voltage-dependent properties when expressed in the short carboxyl terminus variant (Ca(V)2.1 Delta47) compared to the long variant (Ca(V)2.1 +47). Furthermore, the FHM-1 mutations also exhibit differential splice variant-specific effects on recovery from inactivation and accumulation of inactivation during tonic and burst firing. Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies.

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.

Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia.

BACKGROUND: Episodic ataxia type 2 (EA2) is an autosomal dominant condition that results from mutations in the CACNA1A gene. It is characterized by episodes of ataxia and nystagmus that typically last hours. OBJECTIVE: To describe the clinical and genetic features of 2 unrelated patients who developed EA2 in childhood and late-onset dystonia. DESIGN: Pedigree study. SETTING: University academic teaching hospital. PATIENTS: Two unrelated patients with childhood-onset EA2 and adult-onset dystonia were identified through a neurogenetics clinic. The CACNA1A gene was screened by heteroduplex analysis and sequencing for mutations. MAIN OUTCOME MEASURE: Mutations in the CACNA1A gene. RESULTS: Novel mutations in the pore-forming subunit of the P/Q-type calcium channels were found in both pedigrees. None of the family members carried an expansion of the CAG sequence that is found in the carboxy terminus of the CACNA1A gene. CONCLUSIONS: Truncating mutations are the most common mutations to cause EA2. We have identified 2 novel truncating mutations that are associated with interictal dystonia. The dystonia is a late feature in this disease and may be a manifestation of a degenerative cerebellar process.

Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic.

BACKGROUND: The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations. OBJECTIVES: 1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population. METHODS: A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed. RESULTS: A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative. CONCLUSION: A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.

Malaysian siblings with friedreich ataxia and chorea: a novel deletion in the frataxin gene.

BACKGROUND: Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype. OBJECTIVE: To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1. SETTING: Tertiary referral university hospital setting. PATIENTS AND METHODS: A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact. RESULTS: Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele. CONCLUSIONS: We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.

Functional implications of a novel EA2 mutation in the P/Q-type calcium channel.

Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients.

Fatal familial insomnia: the first account in a family of Chinese descent.

BACKGROUND: Fatal familial insomnia (FFI) is an autosomal dominant disease linked to a mutation in the prion protein gene. Fatal familial insomnia is characterized by sleep disturbance and loss of neurons, with gliosis in the thalamic nuclei. OBJECTIVE: To describe the clinical, neurophysiological, radiological, and neuropathological data in a Chinese family with FFI. SETTING: Tertiary referral university hospital setting. PATIENTS: Patient 1 was a 36-year-old man who presented with insomnia and myoclonus. In the subsequent 9 months, he developed ataxia and dementia, followed by death. Patient 2 was the aunt of patient 1, and presented at the age of 47 years with insomnia, myoclonus, and dementia; her condition declined during a 12-month period. Genetic analysis was performed, followed by neuropathological and biochemical analysis of the disease-associated form of the prion protein PrPSc on the postmortem brain specimen. RESULTS: Molecular analysis demonstrated an aspartic acid to asparagine mutation at codon 178 and homozygosity for methionine at codon 129. Both patients showed severe neuronal loss and prominent gliosis in the thalamus and brainstem involvement, with evidence of astrogliosis in the inferior olivary nucleus. Patient 1 also had neuronal loss and astrogliosis in the region of the superior colliculus and in the periaqueductal region. PrPSc was detected on Western blot analysis, and had a wide distribution. The strongest signals were present in the amygdala, hypothalamus, caudate, parahippocampal gyrus, periaqueductal gray matter, and mediodorsal thalamus. CONCLUSIONS: To our knowledge, this is the first report of FFI in a family of Chinese descent. This supports the worldwide distribution of FFI, and despite differences in genetic background, the clinical and pathological findings are similar to those found in white patients with FFI.

Pseudomigraine with lymphocytic pleocytosis: a calcium channelopathy? Clinical description of 10 cases and genetic analysis of the familial hemiplegic migraine gene CACNA1A.

OBJECTIVE: To report the clinical findings of 10 patients diagnosed with pseudomigraine with lymphocytic pleocytosis and the results of mutational analysis of the CACNA1A gene in 8 of these patients. BACKGROUND: Pseudomigraine with lymphocytic pleocytosis, also referred to as headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is characterized by episodic transient neurologic dysfunction associated with moderate to severe headache and cerebrospinal fluid lymphocytic pleocytosis. Episodes are recurrent and the condition is self-limiting. The etiology of this sporadic condition remains unknown, but the episodic nature and its ability to be triggered by angiography is somewhat reminiscent of the phenotypic features of familial hemiplegic migraine, a condition caused by mutations in the CACNA1A gene. DESIGN/METHODS: Utilizing retrospective chart review, we describe the clinical features of pseudomigraine with lymphocytic pleocytosis in 10 patients. Whole blood was taken from 8 patients (2 were lost to follow-up) and used for DNA testing. The CACNA1A gene was screened for mutations using heteroduplex analysis and direct DNA sequencing. RESULTS: Clinical features of pseudomigraine with lymphocytic pleocytosis included transient episodes of weakness, sensory and visual symptoms, aphasia, and confusion lasting minutes up to 4 hours. Sensory symptoms, typically affecting the face and arm, were the most common presentation. Localization of symptoms did not conform to vascular territories. Headache was typically throbbing and most often bilateral. Genetic analysis did not identify any mutations in the CACNA1A gene. CONCLUSIONS: Similarities between familial hemiplegic migraine and pseudomigraine with lymphocytic pleocytosis include recurrent headache with reversible neurologic deficit, cerebrospinal fluid lymphocytic pleocytosis, and triggers such as angiography. Even so, heteroduplex analysis and DNA sequencing failed to identify any sporadic mutations or shared polymorphisms in the exons or the intron/exon boundaries of the CACNA1A gene. These results do not support a role of the CACNA1A gene in the etiology of pseudomigraine with lymphocytic pleocytosis.

Neuroimaging features of heroin inhalation toxicity: "chasing the dragon".

OBJECTIVE: Our objective was to illustrate the dramatic neuroimaging findings of toxic leukoencephalopathy caused by heroin vapor inhalation. CONCLUSION: Symmetric abnormality involving the cerebellar white matter and posterior limb of the internal capsule is characteristic of heroin vapor inhalation toxicity, although involvement may be more extensive, depending on the severity of the condition. MR imaging and CT appear to be essential for making this diagnosis because clinical history is often unreliable and findings at physical examination are nonspecific.

Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: evidence for a third EKD gene.

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous.