Yoon-Hee Cha

Familial Clustering of Migraine, Episodic Vertigo, and Ménière's Disease

Objective: To evaluate the association between migraine, episodic vertigo, and Ménières disease in families. Study Design: Clinical report. Setting: University Neurotology Clinic. Patients: Index patients identified with Ménières disease and migraine and their family members. Intervention: Structured interview to assess a diagnosis of migraine, episodic vertigo, and Ménières disease in 6 families. Genotyping was performed on 3 sets of twins to analyze monozygosity or dizygosity. Main Outcome Measures: Clinical history of migraine, episodic vertigo, and Ménières disease. Results: Six index patients and 57 family members were interviewed either by a senior neurologist in person or over the phone by a trained study coordinator. An additional 6 family members completed questionnaires by mail. All 6 index patients had Ménières disease and migraine. Twenty-six (41%) of the 63 relatives met International Classification of Headache Disorders II criteria for migraine headaches. Thirteen (50%) of these 26 experienced migraine with aura. Three others experienced typical aura without headache. Seventeen (27%) of 63 family members experienced recurrent spells of spontaneous episodic vertigo. There was one twin pair in each of 3 families; 2 pairs were monozygotic and one was dizygotic. In each twin pair, one twin had migraine and Ménières disease, whereas the other experienced migraine and episodic vertigo without auditory symptoms. Conclusion: The frequent association of episodic vertigo, migraine, and Ménières disease in closely related individuals, including identical twins supports the heritability of a migraine-Ménières syndrome, with variable expression of the individual features of hearing loss, episodic vertigo, and migraine headaches.

Clinical features and associated syndromes of mal de debarquement

ObjectiveTo investigatethe clinical features and naturalhistory of mal de debarquement(MdD).DesignRetrospective casereview with follow-up questionnaireand telephone interviews.SetingUniversity Neurotology Clinic.PatientsPatients seen between1980 and 2006 who developed apersistent sensation of rocking orswaying for at least 3 days after exposureto passive motion.Main outcome measureClinical features,diagnostic testing, and questionnaireresponses.ResultsOf 64 patients(75 % women) identifiedwith MdD, 34 completed follow-upquestionnaires and interviews in2006. Most patients had normalneurological exams, ENGs andbrain MRIs. The average age of thefirst MdD episode was 39 ± 13years. A total of 206 episodes wereexperienced by 64 patients. Ofthese, 104 episodes (51 %) lasted> 1 month; 18 %, > 1 year; 15 %, > 2years; 12 %, > 4 years, and 11 %, > 5years. Eighteen patients (28 %) subsequentlydeveloped spontaneousepisodes of MdD-like symptomsafter the initial MdD episode.There was a much higher rate ofmigraine in patients who went onto develop spontaneous episodes(73 %) than in those who did not(22 %). Subsequent episodes werelonger than earlier ones in mostpatients who had multiple episodes.Re-exposure to passivemotion temporarily decreasedsymptoms in most patients (66 %).Subjective intolerance to visualmotion increased (10 % to 66 %)but self-motion sensitivity did not(37 % to 50 %) with onset of MdD.ConclusionThe majority of MdDepisodes lasting longer than 3 daysresolve in less than one year but theprobability of resolution declineseach year. Many patients experiencemultiple MdD episodes. Somepatients develop spontaneousepisodes after the initial motiontriggeredepisode with migrainebeing a risk factor.

Association of progesterone receptor with migraine-associated vertigo

While migraine has been demonstrated to be familial and have genetic contributions, genome-wide linkage analyses and candidate gene studies have highlighted that migraine is genetically complex. Despite substantial efforts, no consistent replication of linkage or association has been reported for common migraine syndromes. Among the candidate genes tested for association with migraine by several groups were female sex hormone genes based on the observation of a much higher incidence of migraine in females. Migraine-associated vertigo (MAV) is a migraine syndrome also much more common in females than males. Because MAV is less common in the general population than migraine or migraine with aura, it may be a better migraine syndrome to detect susceptibility alleles. In this study, we tested the association of two female hormonal genes, progesterone receptor (PGR) and estrogen receptor (ESR1), which were previously reported to be associated with migraine in women. We typed 150 MAV subjects and 145 genomic matched control subjects. One SNP (rs1042838) within PGR, which is in high linkage disequilibrium with the functional PROGINS variant, was significantly associated with MAV (p = 0.0007). Two SNPs (rs2228480 and rs1801132) within ESR1 demonstrated no significant association. No synergistic effect between ESR1 variants and PGR variants was identified.

Episodic ataxia type 1: clinical characterization, quality of life and genotype–phenotype correlation

Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean=50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.

Metabolic and functional connectivity changes in mal de debarquement syndrome.

Background Individuals with mal de debarquement syndrome (MdDS) experience a chronic illusion of self-motion triggered by prolonged exposure to passive motion, such as from sea or air travel. The experience is one of rocking dizziness similar to when the individual was originally on the motion trigger such as a boat or airplane. MdDS represents a prolonged version of a normal phenomenon familiar to most individuals but which persists for months or years in others. It represents a natural example of the neuroplasticity of motion adaptation. However, the localization of where that motion adaptation occurs is unknown. Our goal was to localize metabolic and functional connectivity changes associated with persistent MdDS. Methods Twenty subjects with MdDS lasting a median duration of 17.5 months were compared to 20 normal controls with 18F FDG PET and resting state fMRI. Resting state metabolism and functional connectivity were calculated using age, grey matter volume, and mood and anxiety scores as nuisance covariates. Results MdDS subjects showed increased metabolism in the left entorhinal cortex and amygdala (z>3.3). Areas of relative hypometabolism included the left superior medial gyrus, left middle frontal gyrus, right amygdala, right insula, and clusters in the left superior, middle, and inferior temporal gyri. MdDS subjects showed increased connectivity between the entorhinal cortex/amygdala cluster and posterior visual and vestibular processing areas including middle temporal gyrus, motion sensitive area MT/V5, superior parietal lobule, and primary visual cortex, while showing decreased connectivity to multiple prefrontal areas. Conclusion These data show an association between resting state metabolic activity and functional connectivity between the entorhinal cortex and amygdala in a human disorder of abnormal motion perception. We propose a model for how these biological substrates can allow a limited period of motion exposure to lead to chronic perceptions of self-motion.

Regional correlation between resting state FDG PET and pCASL perfusion MRI

To determine how arterial spin labeling (ASL) measured perfusion relates to baseline metabolism, we compared resting state cerebral perfusion using pseudo-continuous ASL and cerebral glucose metabolism using 18F-FDG PET in 20 normal volunteers. Greater regional metabolism relative to perfusion was observed in the putamen, orbitofrontal and temporal lobes, whereas perfusion was relatively higher in the hippocampus and insula. In a region of interest analysis limited to gray matter, the overall mean correlation between perfusion and metabolism across voxels was r=0.43 with considerable regional variability. Cross-voxel correlations between relative perfusion and metabolism in mean ASL and PET images of all 20 subjects were the highest in the striatum (caudate: r=0.78; putamen: r=0.81), and the lowest in medial temporal structures (amygdala: r=0.087; hippocampus: r=−0.26). Correlations between mean relative perfusion and metabolism across 20 subjects were the highest in the striatum (caudate: r=0.76; putamen: r=0.58), temporal lobe (r=0.59), and frontal lobe (r=0.52), but very poor in all other structures (r<0.3), particularly in caudal structures such as the hippocampus (r=−0.0026), amygdala (r=0.18), and insula (r=0.14). Although there was good overall correlation between perfusion and glucose metabolism, regional variability should be considered when using either ASL or 18F-FDG PET as surrogate markers for neural activity.

Migraine Associated Vertigo

The interrelations of migraine and vertigo are complex, eluding a simple localization either centrally or peripherally. Spontaneous episodic vertigo, benign paroxysmal positional vertigo, and Menieres disease all occur more frequently in patients with migraine than in those without. Family studies support a hereditary predisposition to migraine associated vertigo. In this review, we discuss definitions, epidemiology, associated syndromes, neurootological abnormalities, genetics and treatment for patients with migraine and vertigo.

Repetitive Transcranial Magnetic Stimulation for Mal de Debarquement Syndrome

Objective Mal de debarquement syndrome (MdDS) is a chronic disorder of imbalance characterized by a feeling of rocking and swaying. The disorder starts after prolonged exposure to passive motion such as from a boat or plane. All medical treatment is palliative and symptoms that persist beyond 6 months show low likelihood of remission. This pilot study explored the feasibility and tolerability of repetitive transcranial magnetic stimulation (rTMS) as potential treatment for MdDS. Patients/Intervention Ten subjects (8 women) with persistent MdDS lasting from 10 to 91 months were given 1 session each of 4 counterbalanced protocols: left 10 Hz (high frequency), left 1 Hz (low frequency), right 10 Hz, and right 1 Hz rTMS over the dorsolateral prefrontal cortex (DLPFC). Main Outcome Measure Reduction of rocking sensation reported on a visual analogue scale. Results 1) Right-handers improved most with 10-Hz stimulation over the left DLPFC while left-handers improved most with 10 Hz stimulation over the right DLPFC; 2) low-frequency DLPFC stimulation was associated with symptom worsening in some subjects; 3) duration of symptoms was negatively correlated with treatment response; 4) rTMS was well tolerated in MdDS subjects, showing similar rates of headache (10 of 40 sessions) as for other studies; and 5) fatigue occurred after 6 sessions usually with low-frequency stimulation. Conclusion rTMS was well tolerated in subjects with MdDS with promising short-term symptom improvement. Future studies of rTMS in MdDS may consider sequential days of stimulation, longer post-rTMS observation periods, formal measurement of post-TMS fatigue, and randomization with a sham condition.

Lasting Modulation Effects of rTMS on Neural Activity and Connectivity as Revealed by Resting-State EEG

The long-lasting neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) are of great interest for therapeutic applications in various neurological and psychiatric disorders, due to which functional connectivity among brain regions is profoundly disturbed. Classic TMS studies selectively alter neural activity in specific brain regions and observe neural activity changes on nonperturbed areas to infer underlying connectivity and its changes. Less has been indicated in direct measures of functional connectivity and/or neural network and on how connectivity/network alterations occur. Here, we developed a novel analysis framework to directly investigate both neural activity and connectivity changes induced by rTMS from resting-state EEG (rsEEG) acquired in a group of subjects with a chronic disorder of imbalance, known as the mal de debarquement syndrome (MdDS). Resting-state activity in multiple functional brain areas was identified through a data-driven blind source separation analysis on rsEEG data, and the connectivity among them was characterized using a phase synchronization measure. Our study revealed that there were significant long-lasting changes in resting-state neural activity, in theta, low alpha, and high alpha bands and neural networks in theta, low alpha, high alpha and beta bands, over broad cortical areas 4 to 5 h after the last application of rTMS in a consecutive five-day protocol. Our results of rsEEG connectivity further indicated that the changes, mainly in the alpha band, over the parietal and occipital cortices from pre- to post-TMS sessions were significantly correlated, in both magnitude and direction, to symptom changes in this group of subjects with MdDS. This connectivity measure not only suggested that rTMS can generate positive treatment effects in MdDS patients, but also revealed new potential targets for future therapeutic trials to improve treatment effects. It is promising that the new connectivity measure from rsEEG can be used to understand the variability in treatment response to rTMS in brain disorders with impaired functional connectivity and, eventually, to determine individually tailored stimulation parameters and treatment procedures in rTMS.

Phenotypic and genetic analysis of a large family with migraine-associated vertigo.

Objectives.— To describe a large multigenerational family with migraine‐associated vertigo (MAV) combining a detailed phenotypic and genetic analysis.