Episodic Ataxia Type 1: Natural History and Effect on Quality of Life.

Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy, due to mutations in KCNA1. Patients have childhood onset of intermittent attacks of ataxia, dizziness or imbalance. In order to quantify the natural history of EA1, its effect on quality of life and in preparation for future clinical trials, we set up an international multi-centre study of EA1. We recruited thirty-three participants with EA1: twenty-three completed 1-year follow-up and eighteen completed 2-year follow-up. There was very little accumulation of disability or impairment over the course of the 2 years of the study. The outcome measures of ataxia (SARA and functional rating of ataxia) and the activities of daily living scale were largely stable over time. Self-reported health-related quality of life (SF-36) scores were lower across all domains than controls, in keeping with a chronic condition. Physical subdomain scores appeared to deteriorate over time, which seems to be driven by the female participants in the study. This is an interesting finding and warrants further study. Attacks of EA1 reported by participants in real time via an interactive voice response system showed that symptoms were not stereotyped; however, attack duration and frequency was stable between individuals. This large prospective study is the first ever completed in subjects with EA1. We document the natural history of the disorder over 2 years. These data will enable the development of outcome measures for clinical trials of treatment.

Vestibular Migraine I: Mechanisms, Diagnosis, and Clinical Features.

Vestibular migraine (VM), also known as migrainous vertigo or migraine-associated vertigo, is characterized by recurrent vestibular attacks often accompanied by migraine headaches and other migraine symptoms. It is one of the most common presenting complaints to physicians in primary care, otolaryngology, and neurology. Epidemiologic data suggest that VM may affect 1 to 3% of the general population and 10 to 30% of patients seeking treatment for dizziness. Attacks typically last minutes to hours and range from spontaneous and positional vertigo to extreme sensitivity to self and surround motion. As with headaches, nausea, and vomiting, phonophobia and photophobia are common accompanying symptoms. The clinical spectrum of VM and its underlying pathophysiological mechanisms are just being identified, with much debate about the causal relationship of vestibular symptoms and headache, no evidence-based guidelines for clinical management, limited characterization of its disease burden, and little information about its negative impact on health-related quality of life.

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

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.

"Havana Syndrome": A post mortem.

BACKGROUND: Since 2016, an array of claims and public discourse have circulated in the medical community over the origin and nature of a mysterious condition dubbed "Havana Syndrome," so named as it was first identified in Cuba. In March 2023, the United States intelligence community concluded that the condition was a socially constructed catch-all category for an array of health conditions and stress reactions that were lumped under a single label. AIMS: To examine the history of "Havana Syndrome" and the many factors that led to its erroneous categorization as a novel clinical entity. METHOD: A review of the literature. RESULTS/CONCLUSIONS: Several factors led to the erroneous classification of "Havana Syndrome" as a novel entity including the failure to stay within the limitations of the data; the withholding of information by intelligence agencies, the prevalence of popular misconceptions about psychogenic illness, the inability to identify historical parallels; the role of the media, and the mixing of politics with science.

MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2.

In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: (1) duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; (2) age: VI, Crus II, and flocculus correlated with age in control subjects; and (3) clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.

Unusual caloric responses in a patient with a fourth ventricular ependymoma.

The caloric test is probably the most widely used clinical test of vestibular function. A unilateral decrease in response to cold and warm water reliably indicates a unilateral peripheral vestibular lesion. Central signs on caloric testing are less common but important to recognize because they are often associated with lesions of the brainstem. We describe a patient with a tumor originating in the floor of the fourth ventricle who presented with premature reversal after cold stimulation on one side and perverted nystagmus after cold stimulation of the other side.

Mal de débarquement syndrome diagnostic criteria: Consensus document of the Classification Committee of the Bárány Society.

We present diagnostic criteria for mal de débarquement syndrome (MdDS) for inclusion into the International Classification of Vestibular Disorders. The criteria include the following: 1] Non-spinning vertigo characterized by an oscillatory perception ('rocking,' 'bobbing,' or 'swaying') present continuously or for most of the day; 2] Onset occurs within 48 hours after the end of exposure to passive motion, 3] Symptoms temporarily reduce with exposure to passive motion (e.g. driving), and 4] Symptoms persist for >48 hours. MdDS may be designated as "in evolution," if symptoms are ongoing but the observation period has been less than 1 month; "transient," if symptoms resolve at or before 1 month and the observation period extends at least to the resolution point; or "persistent" if symptoms last for more than 1 month. Individuals with MdDS may develop co-existing symptoms of spatial disorientation, visual motion intolerance, fatigue, and exacerbation of headaches or anxiety. Features that distinguish MdDS from vestibular migraine, motion sickness, and persistent postural perceptual dizziness (PPPD) are reviewed. Motion-moderated oscillatory vertigo can also occur without a motion trigger, typically following another vestibular disorder, a medical illness, heightened psychological stress, or metabolic disturbance. Terminology for this non-motion triggered presentation has been varied as it has features of both MdDS and PPPD. Further research is needed into its phenomenological and biological relationship to MdDS, PPPD, and other vestibular disorders.

Clinical features and associated syndromes of mal de debarquement.

OBJECTIVE: To investigate the clinical features and natural history of mal de debarquement (MdD). DESIGN: Retrospective case review with follow-up questionnaire and telephone interviews. SETTING: University Neurotology Clinic. PATIENTS: Patients seen between 1980 and 2006 who developed a persistent sensation of rocking or swaying for at least 3 days after exposure to passive motion. MAIN OUTCOME MEASURE: Clinical features,diagnostic testing, and questionnaire responses. RESULTS: Of 64 patients(75% women) identified with MdD, 34 completed follow-up questionnaires and interviews in 2006. Most patients had normal neurological exams, ENGs and brain MRIs. The average age of the first MdD episode was 39+/-13 years. A total of 206 episodes were experienced by 64 patients. Of these, 104 episodes (51%) lasted>1 month; 18%, >1 year; 15%, >2 years; 12%, >4 years, and 11%, >5 years. Eighteen patients (28%) subsequently developed spontaneous episodes of MdD-like symptoms after the initial MdD episode.There was a much higher rate of migraine in patients who went onto develop spontaneous episodes(73%) than in those who did not(22%). Subsequent episodes were longer than earlier ones in most patients who had multiple episodes.Re-exposure to passive motion temporarily decreased symptoms in most patients (66%).Subjective intolerance to visual motion increased (10% to 66%)but self-motion sensitivity did not(37% to 50%) with onset of MdD. CONCLUSION: The majority of MdD episodes lasting longer than 3 days resolve in less than one year but the probability of resolution declines each year. Many patients experience multiple MdD episodes. Some patients develop spontaneous episodes after the initial motion-triggered episode with migraine being a risk factor.

Increased prevalence of significant recurrent headache in preclinical familial Alzheimer's disease mutation carriers.

BACKGROUND/AIMS: A previous study found a high prevalence of headaches in persons with familial Alzheimer's disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). METHODS: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by chi(2) or Fisher's exact tests. RESULTS: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. CONCLUSIONS: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.

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. BACKGROUND: Migraine-associated vertigo is said to be highly prevalent in the general population and, like other migraine syndromes, its etiology is felt to have a strong genetic component. However, so far, there have been no reports of large families with MAV. METHODS: Detailed clinical study was conducted on a large multigenerational family with MAV. Genetic study using identical-by-descent analysis with dense single nucleotide polymorphism (SNP) arrays was performed to examine consistent inheritance pattern among the affecteds. RESULTS: Clinical features of MAV were variable although most had other migraine symptoms with at least some of their attacks. We did not find a region of the genome shared by all eight subjects with MAV indicating a polygenetic inheritance for MAV even in this single large family. CONCLUSIONS: A region on 11q shared by most affected females may contain a susceptibility allele for MAV that is expressed exclusively or predominantly by women.

Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation.

We describe a family with an R1668W mutation in the CACNA1A gene who presented with a broader clinical spectrum and more variable features than previously reported. The mother had a pure progressive cerebellar ataxia of late onset with downbeat nystagmus, whereas her daughter suffered from episodic ataxia, hemiplegic migraine, and progressive cerebellar ataxia with horizontal gaze-evoked and rebound nystagmus. In both patients, treatment with acetazolamide was ineffective and worsened baseline ataxia, whereas flunarizine ameliorated episodic symptoms. Our report highlights profound phenotypic variability that can be associated with CACNA1A mutations and adds important therapeutic considerations.

Familial clustering of migraine, episodic vertigo, and Ménière's disease.

OBJECTIVE: To evaluate the association between migraine, episodic vertigo, and Ménière's disease in families. STUDY DESIGN: Clinical report. SETTING: University Neurotology Clinic. PATIENTS: Index patients identified with Ménière's disease and migraine and their family members. INTERVENTION: Structured interview to assess a diagnosis of migraine, episodic vertigo, and Ménière's 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 Ménière's 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 Ménière's 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 Ménière's disease, whereas the other experienced migraine and episodic vertigo without auditory symptoms. CONCLUSION: The frequent association of episodic vertigo, migraine, and Ménière's disease in closely related individuals, including identical twins supports the heritability of a migraine-Ménière's syndrome, with variable expression of the individual features of hearing loss, episodic vertigo, and migraine headaches.

Comprehensive Clinical Profile of Mal De Debarquement Syndrome.

BACKGROUND: There has been increasing awareness that post-motion triggered rocking self-vertigo can last for months or years, a disorder known as Mal de Debarquement Syndrome (MdDS). A similar feeling of oscillating self-motion can occur without a motion trigger in some individuals, leading to controversy about whether motion triggered (MT) and non-motion triggered (non-MT) symptoms ultimately represent the same disorder. Recognizing the similarities and differences between MT and non-MT MdDS can prevent unnecessary diagnostic testing and lead to earlier and more effective treatments. METHODS: Standardized questionnaire assessment and follow-up interviews of individuals with persistent MT or non-MT MdDS (>1 month) examined at a University Dizziness Clinic. FINDINGS: Questionnaires were available on 80 individuals with persistent MT MdDS and 42 with non-MT MdDS. Sex distribution (81% female) and age of onset (mean 43.4 ± 12.2 years MT; 42.1 ± 15.2 years non-MT) were comparable between MT and non-MT MdDS (p > 0.05). Mean duration of illness was significantly longer in the non-MT group (82.8 ± 64.2 months) than the MT group (35.4 ± 46.4 months) (p < 0.001). There was no correlation between trigger type and age of onset or duration of illness for MT MdDS. Improvement with re-exposure to motion (driving) was typical for both (MT = 89%, non-MT = 64%), but non-MT individuals more frequently had symptoms exacerbated with motion (MT = 0%; non-MT = 10%). Peri-menstrual and menstrual worsening of symptoms was typical in both MT and non-MT MdDS (each 71%). Both MT and non-MT MdDS exhibited a higher population baseline prevalence of migraine (23% and 38%, respectively). Benzodiazepines and SSRI/SNRIs were helpful in both subtypes of MdDS (>50% individuals with a positive response). Physical therapy was modestly helpful in the MT (56%) subtype but not in non-MT (15%). Vestibular therapy made as many individuals worse as better in MT and none improved in the non-MT group. CONCLUSION: General demographic characteristics and exacerbating factors are similar in MT and non-MT MdDS, but there are differences in the duration of illness, effect of motion on symptoms, and response to therapy. Recognizing clinical features of MdDS subtypes may allow for better tailoring of therapy and potentially serve as classification criteria for new clinical designations.

A new episodic ataxia syndrome with linkage to chromosome 19q13.

BACKGROUND: Multiple episodic ataxia phenotypes and genotypes have been described. OBJECTIVE: To describe a new episodic ataxia syndrome. DESIGN: Genomewide linkage analysis with dense single nucleotide polymorphism arrays. SETTING: University clinic. Patients Family with lifelong episodes of ataxia and normal interictal examination results. RESULTS: Suggestive linkage (logarithm of odds score, 3.27) to a 10-centimorgan region on chromosome 19q13. CONCLUSION: A new dominantly inherited episodic ataxia syndrome is linked to chromosome 19q.

Body lateropulsion as an isolated or predominant symptom of a pontine infarction.

BACKGROUND: Lateropulsion of the body--that is, falling to one side--is a well-known clinical feature of stroke in the posterior circulation. Body lateropulsion as an isolated or predominant manifestation of a pontine stroke has not been reported previously. OBJECTIVE: To elucidate the possible mechanisms of patients presenting with body lateropulsion as an isolated or predominant symptom of an isolated pontine infarction. METHODS: Between May 2004 and February 2006, out of 134 patients admitted with an isolated pontine stroke, we identified 8 (6%) consecutive patients in the Keimyung University Stroke Registry who had body lateropulsion as the main presenting symptom. RESULTS: All lesions were localised to the paramedian tegmentum just ventral to the fourth ventricle. All except one showed a uniform pattern of body lateropulsion, in which the direction of falling was away from the side of an infarct. In two patients body lateropulsion was the sole clinical manifestation, whereas the other patients had other neurological signs. All but one patient had contraversive tilting of the subjective visual vertical (SVV). In all cases, the direction of SVV tilt corresponded to the direction of body lateropulsion. The mean net tilt angle was 6.1 degrees. CONCLUSIONS: Based on the known anatomy of ascending vestibular pathways, SVV tilting and MRI findings, it is concluded that body lateropulsion probably results from damage to the graviceptive pathway ascending through the paramedian pontine tegmentum.

Histopathology of the vestibular end organs after intratympanic gentamicin failure for Meniere's disease.

CONCLUSION: To our knowledge, this is the first report of the histopathology of the vestibular end organs following intratympanic gentamicin for intractable Meniere's disease. There was relative sparing of the utricular macula, compared with the cristae ampullares. However, the utricular macula exhibited severe hair cell loss. Clinically, the patient has been free from vertigo spells for 3 years following labyrinthectomy. OBJECTIVE: To describe the histopathology and morphometry of the vestibular end organs from a 59-year-old Meniere's patient who underwent transmastoid labyrinthectomy for recurrent vertigo after failed intratympanic gentamicin. MATERIALS AND METHODS: Light and transmission electron microscopy were utilized; with unbiased stereology-physical fractionator for type I, type II hair cell, and supporting cell counts. Comparison with end organ histopathology in a 56-year-old with Meniere's disease without gentamicin treatment was carried out. RESULTS: Histopathological analysis of the semicircular canal cristae ampullares showed severe atrophy of the neuroepithelium with undifferentiated cells, and fibrosis and edema of the stroma. The utricular macula had some remaining type I and type II vestibular hair cells, and nerve fibers and terminals within the underlying stroma. Morphometric measures were obtained from the utricular macula: 2000 type I and 500 type II hair cells, representing 7.3% of type I hair cells and 4.9% of type II hair cells compared with normative controls, and 24 000 supporting cells were obtained.

Increased risk of death in community-dwelling older people with white matter hyperintensities on MRI.

BACKGROUND: Previous studies in subjects with a history of stroke have shown that white matter hyperintensities (WMH) on MRI are associated with increased risk of death. However, it has not been determined whether WMH are independently related to death in community-dwelling older people without stroke. METHODS: In a sample of community-dwelling people over 75 years with no history of stroke or other neurological diseases, WMH on brain MRI T2-weighted sequences were classified as grade 0, grade 1, or grade 2. Grade 2 WMH were identified in 36 subjects. Age- and sex-matched grade 0 and grade 1 WMH groups were selected for comparison to the grade 2 WMH group. All subjects underwent an initial clinical evaluation and were followed for a median of 11.8 years (interquartile range=10.7 to 12.2 years). Cox proportional-hazards analysis was used to determine the independent association between WMH and time to death from any cause. RESULTS: In an unadjusted analysis, grade 2 WMH was associated with death from any cause (hazard ratio=1.98; 95% confidence interval=1.06, 3.70). After adjustment for hypertension, high cholesterol, diabetes, and coronary artery disease, grade 2 WMH remained significantly associated with death (hazard ratio=2.31; 95% confidence interval=1.21, 4.40) in these age- and sex-matched groups. CONCLUSIONS: Severe WMH increase the risk of death, even in community-dwelling elderly without stroke or other neurological disease, independent of other covariates including hypertension, age, and coronary artery disease.