"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.

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.

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.

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.

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.

Assessment of the Clinical Utility of Cervical and Ocular Vestibular Evoked Myogenic Potential Testing in Elderly Patients.

OBJECTIVES: To assess whether patient age or sex was predictive of a bilaterally absent cervical or ocular vestibular evoked myogenic potential (cVEMP or oVEMP). STUDY DESIGN: Retrospective case review. SETTING: Tertiary center. PATIENTS: Patients presenting with normal vestibular tests (i.e. normal caloric and rotational chair) who underwent cVEMP and/or oVEMP testing. Patients with conductive hearing loss were excluded as were those with unilaterally abnormal VEMP results because they presented with evidence of a possible unilateral vestibular impairment. A total of 895 patients met criteria for cVEMPs and 297 for oVEMPs. MAIN OUTCOME MEASURES: The presence or absence of cVEMP and oVEMP responses elicited with a 500-Hz 125-dB pSPL air conduction stimulus. RESULTS: A logistic regression was performed including odd ratios and confidence intervals. Compared with adults in their 20s, the odds of bilaterally absent cVEMP responses are 6 times greater for patients in their 50s and 60s and over 22 times greater for patients in their 70s and 80s. A bilaterally absent oVEMP response is 6 times more likely for patients in their 40s, 50s, and 60 and 13 times greater for patients in their 70s. CONCLUSIONS: VEMPs in response to air conduction stimuli are bilaterally absent in a large percentage of older patients complaining of dizziness who otherwise have normal vestibular and auditory testing for their age. In combination with other abnormal vestibular findings, an absence of VEMP responses may be of value. However, the functional consequence of an isolated bilaterally absent VEMP is not known and may provide minimal information to an older patient's diagnostic picture. In cases where the response is bilaterally absent, a more intense AC stimulus should be used or bone conducted vibration should be considered.

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.

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.

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 (18)F 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.

The history and future of neuro-otology.

PURPOSE OF REVIEW: The field of neuro-otology has advanced substantially over the past 150 years. The function of the vestibular system was presumed to be audiologic prior to the groundbreaking work of Prosper Ménière in the late 1800s. Since that time, scientific discovery has advanced our knowledge of the physiology and the pathophysiology of the vestibular system. This article describes where we have been, where we are now, and where we need to go from here. RECENT FINDINGS: Some of the important recent advances include: (1) improved imaging of the brain and inner ear, (2) development of new eye movement recording and analysis techniques, (3) development of new tests of otolith function, (4) particle repositioning maneuvers for all types of benign paroxysmal positional vertigo, and (5) improved bedside diagnosis and treatment of vestibular neuritis. SUMMARY: The cause and treatment for some common neuro-otologic disorders is now well delineated. The diagnosis and management of less common disorders has improved as well. Future work is still required to advance the science of vestibular physiology and pathophysiology and ultimately to discover new ways to improve the health of patients with these disorders.

Opsoclonus: clinical and immunological features.

BACKGROUND: Opsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. METHODS: We recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. RESULTS: In all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4-10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. CONCLUSIONS: The clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus.

A prescription for the Epley maneuver: www.youtube.com?

OBJECTIVES: Video-sharing Web sites are being used for information about common conditions including dizziness. The Epley maneuver (EM) is a simple and effective treatment for benign paroxysmal positional vertigo (BPPV) of the posterior canal. However, the maneuver is underused in routine care. In this study, we aimed to describe and analyze the available information about the EM on youtube.com. METHODS: A YouTube search was performed on August 31, 2011, for videos that demonstrated the entire EM. Detailed data were abstracted from each video and corresponding Web site. Videos were rated on the accuracy of the maneuver by 2 authors, with differences resolved by adjudication. Comments posted by viewers were assessed for themes regarding video use. RESULTS: Of the 3,319 videos identified, 33 demonstrated the EM. The total number of hits for all videos was 2,755,607. The video with the most hits (802,471) was produced by the American Academy of Neurology. Five of the videos accounted for 85% of all the hits. The maneuver demonstration was rated as accurate in 64% (21) of the videos. Themes derived from the 424 posted comments included patients self-treating with the maneuver after reviewing the videos, and providers using the videos as a prescribed treatment or for educational purposes. CONCLUSION: Accurate video demonstration of the Epley maneuver is available and widely viewed on YouTube. Video-sharing media may be an important way to disseminate effective interventions such as the EM. The impact of video Web sites on outcomes and costs of care is not known and warrants future study.

Episodic ataxias 1 and 2.

The episodic ataxias are autosomal dominant disorders usually beginning in the first two decades of life. Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia, typically lasting seconds, and interictal myokymia, while episodic ataxia type 2 (EA2) is manifested by longer episodes of ataxia (hours) with interictal nystagmus. The EA1 gene (KCNA1) codes for the six transmembrane segments (S1 to S6) of the Kv1.1 potassium channel subunit and the EA2 gene (CACNA1A) encodes for the Ca(v)2.1 subunit of the P/Q calcium channel complex. EA1 mutations are always missense while most EA2 mutations disrupt the reading frame. Studies of the biophysical properties of the mutant Kv1.1 and Ca(v)2.1 channels in Xenopus oocytes and mammalian cell lines demonstrate clear physiologic consequences of the genetic mutations although no consistent pattern for genotype-phenotype correlation has emerged. Genetic testing for EA1 and EA2 is available, but since no single mutation is prominent for either KCNA1 or CACNA1A, all of the coding regions of the genes need to be screened for mutations. Acetazolamide can be dramatic in controlling episodes of ataxia with EA2 but is typically less beneficial with EA1.

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.

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.

Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2.

Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.