Subcortical lesions due to cobalamin deficiency: an unusual MRI lesion pattern.

We present a 44-year-old male patient with new onset of right focal epilepsy and bilateral hand hypesthesia. Cerebral MRI showed bilateral T2w/DWI hyperintense subcortical lesions in the cingulate gyrus, insula, and amygdala, whereas spinal MRI revealed a cervical posterior column lesion, corresponding to subacute combined degeneration. Laboratory workup revealed a cobalamin deficiency due to type A gastritis, and no evidence of antibodies associated with limbic encephalitis. After sufficient cobalamin substitution, the cerebral and spinal lesions gradually regressed. Our case represents a unique cerebral subcortical MRI lesion pattern in a patient with epilepsy and cobalamin deficiency. Thus, the latter represents an important differential diagnosis for autoimmune encephalitis.

Acute binocular diplopia: peripheral or central?

OBJECTIVES: Acute diplopia is a diagnostic challenge for clinicians, in particular in the emergency department. The most common cause of acute diplopia are ocular motor nerve palsies (OMP). In this prospective study, we focused on identifying the most crucial signs and symptoms for differentiating between peripheral and central OMP. METHODS: We prospectively evaluated 56 non-consecutive patients who presented at our emergency department with acute binocular diplopia (≤ 10 days). The patient history was taken using a standardized questionnaire and patients underwent a neurological, neuro-ophthalmological and neuro-otological examination, including measurement of the subjective visual vertical (SVV), Harms tangent screen test, and cranial MRI. RESULTS: Forty-six out of 56 patients were diagnosed with an ocular motor cranial nerve palsy (OMP), 21 of peripheral and 23 of central origin; in two patients, the etiology remained unknown. The following features were different in peripheral and central OMP: (1) the presence of vertigo/dizziness was more frequent in central (43.5%) than in peripheral (9.5%) OMP. (2) Central ocular motor signs, such as saccadic smooth pursuit, additional internuclear ophthalmoplegia, skew deviation, and saccade palsies, were also found more frequently in the central than in the peripheral group (86.7% vs. 33.3%). (3) Further, a pathological SVV deviation by monocular testing of the non-affected eye was also more common in central (77.3%) than in peripheral OMP (38.9%). The presence of all three factors has a positive predictive value of 100% (CI 50-100%) for the presence of a central lesion. CONCLUSIONS: In acute diplopia due to central OMP, the most important accompanying symptom is vertigo/dizziness, and the most important clinical signs are central ocular motor disorders (which require examination of the non-paretic eye) and an SVV deviation in the non-paretic eye.

An algorithm as a diagnostic tool for central ocular motor disorders, also to diagnose rare disorders.

BACKGROUND: Recently an increasing number of digital tools to aid clinical work have been published. This study's aim was to create an algorithm which can assist physicians as a "digital expert" with the differential diagnosis of central ocular motor disorders, in particular in rare diseases. RESULTS: The algorithm's input consists of a maximum of 60 neurological and oculomotor signs and symptoms. The output is a list of the most probable diagnoses out of 14 alternatives and the most likely topographical anatomical localizations out of eight alternatives. Positive points are given for disease-associated symptoms, negative points for symptoms unlikely to occur with a disease. The accuracy of the algorithm was evaluated using the two diagnoses and two brain zones with the highest scores. In a first step, a dataset of 102 patients (56 males, 48.0 ± 22 yrs) with various central ocular motor disorders and underlying diseases, with a particular focus on rare diseases, was used as the basis for developing the algorithm iteratively. In a second step, the algorithm was validated with a dataset of 104 patients (59 males, 46.0 ± 23 yrs). For 12/14 diseases, the algorithm showed a sensitivity of between 80 and 100% and the specificity of 9/14 diseases was between 82 and 95% (e.g., 100% sensitivity and 75.5% specificity for Niemann Pick type C, and 80% specificity and 91.5% sensitivity for Gaucher's disease). In terms of a topographic anatomical diagnosis, the sensitivity was between 77 and 100% for 4/8 brain zones, and the specificity of 5/8 zones ranged between 79 and 99%. CONCLUSION: This algorithm using our knowledge of the functional anatomy of the ocular motor system and possible underlying diseases is a useful tool, in particular for the diagnosis of rare diseases associated with typical central ocular motor disorders, which are often overlooked.

Positive interictal epileptiform discharges in adults: A case series of a rare phenomenon.

OBJECTIVE: Positive interictal epileptiform discharges (IEDs) are rarely recorded from surface EEG, due to the orientation of the cortex and its neurons. Their frequency and significance in adults is unknown, and has only been studied as a phenomenon of the neonatal period and childhood. We aimed to evaluate the frequency and characteristics of positive epileptiform discharges in a large cohort of patients. METHODS: We retrospectively reviewed 24,178 reports from 18,060 patients of non-invasively recorded EEGs for various indications. RESULTS: Positive IEDs were recorded in six patients (eight EEGs - 0.033%), all of which had epileptic seizures. Brain surgery was the most common reason for recording positive and not negative IEDs. Cortical malformation was the most probable etiology in the remaining patients. CONCLUSIONS: Positive IEDs seem to be of lower frequency in adults than in children and are highly associated with epilepsy. They appear more often, but not exclusively, in adult patients with skull defects. SIGNIFICANCE: This is the first adult series reported. Positive IEDs must be identified for the correct diagnosis and clearly differentiated from normal variants.

Beyond Dizziness: Virtual Navigation, Spatial Anxiety and Hippocampal Volume in Bilateral Vestibulopathy.

Bilateral vestibulopathy (BVP) is defined as the impairment or loss of function of either the labyrinths or the eighth nerves. Patients with total BVP due to bilateral vestibular nerve section exhibit difficulties in spatial memory and navigation and show a loss of hippocampal volume. In clinical practice, most patients do not have a complete loss of function but rather an asymmetrical residual functioning of the vestibular system. The purpose of the current study was to investigate navigational ability and hippocampal atrophy in BVP patients with residual vestibular function. Fifteen patients with BVP and a group of age- and gender- matched healthy controls were examined. Self-reported questionnaires on spatial anxiety and wayfinding were used to assess the applied strategy of wayfinding and quality of life. Spatial memory and navigation were tested directly using a virtual Morris Water Maze Task. The hippocampal volume of these two groups was evaluated by voxel-based morphometry. In the patients, the questionnaire showed a higher spatial anxiety and the Morris Water Maze Task a delayed spatial learning performance. MRI revealed a significant decrease in the gray matter mid-hippocampal volume (Left: p = 0.006, Z = 4.58, Right: p < 0.001, Z = 3.63) and posterior parahippocampal volume (Right: p = 0.005, Z = 4.65, Left: p < 0.001, Z = 3.87) compared to those of healthy controls. In addition, a decrease in hippocampal formation volume correlated with a more dominant route-finding strategy. Our current findings demonstrate that even partial bilateral vestibular loss leads to anatomical and functional changes in the hippocampal formation and objective and subjective behavioral deficits.

Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction?

Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ (2) test, p < 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (χ (2) test, left eye and right eye: p < 0.0001), associated with horizontal gaze-evoked nystagmus (χ (2) test, p < 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease.

Vestibular loss and balance training cause similar changes in human cerebral white matter fractional anisotropy.

Patients with bilateral vestibular loss suffer from severe balance deficits during normal everyday movements. Ballet dancers, figure skaters, or slackliners, in contrast, are extraordinarily well trained in maintaining balance for the extreme balance situations that they are exposed to. Both training and disease can lead to changes in the diffusion properties of white matter that are related to skill level or disease progression respectively. In this study, we used diffusion tensor imaging (DTI) to compare white matter diffusivity between these two study groups and their age- and sex-matched controls. We found that vestibular patients and balance-trained subjects show a reduction of fractional anisotropy in similar white matter tracts, due to a relative increase in radial diffusivity (perpendicular to the main diffusion direction). Reduced fractional anisotropy was not only found in sensory and motor areas, but in a widespread network including long-range connections, limbic and association pathways. The reduced fractional anisotropy did not correlate with any cognitive, disease-related or skill-related factors. The similarity in FA between the two study groups, together with the absence of a relationship between skill or disease factors and white matter changes, suggests a common mechanism for these white matter differences. We propose that both study groups must exert increased effort to meet their respective usual balance requirements. Since balance training has been shown to effectively reduce the symptoms of vestibular failure, the changes in white matter shown here may represent a neuronal mechanism for rehabilitation.

Ocular VEMPs indicate repositioning of otoconia to the utricle after successful liberatory maneuvers in benign paroxysmal positioning vertigo.

CONCLUSIONS: This study showed a transient increase of ocular vestibular evoked myogenic potential (oVEMP) amplitudes in the affected ear after successful liberatory maneuvers and no changes in cervical VEMP (cVEMP) amplitudes. These findings support the hypothesis that successful liberatory maneuvers can lead to a repositioning of otoconia to the utricle. OBJECTIVES: To evaluate whether oVEMP amplitudes increase after successful liberatory maneuvers in patients with posterior semicircular canal benign paroxysmal positioning vertigo (pc-BPPV), while cVEMP amplitudes do not change. These findings may indicate a successful repositioning of dislodged otoconia to the utricular macula, but not to the saccular macula. METHODS: Thirty patients with unilateral pc-BPPV were prospectively examined with bone-conducted oVEMP and air-conducted cVEMP at four time points: before, after, 1 week after, and 1 month after the liberatory maneuvers (Sémont maneuvers). RESULTS: At the 1-week follow-up, 20 of 30 patients were asymptomatic (responders); BPPV could still be induced in the other 10 (non-responders). In responders the mean n10 amplitude on the affected side increased from 12 ± 6.5 µV at baseline (before the treatment) to 15.9 ± 7.1 µV at 1 week after treatment; this increase was significantly (p = 0.001) higher in responders than in non-responders. cVEMP did not differ significantly.

Clinical testing of otolith function: perceptual thresholds and myogenic potentials.

Cervical and ocular vestibular-evoked myogenic potential (cVEMP/oVEMP) tests are widely used clinical tests of otolith function. However, VEMP testing may not be the ideal measure of otolith function given the significant inter-individual variability in responses and given that the stimuli used to elicit VEMPs are not physiological. We therefore evaluated linear motion perceptual threshold testing compared with cVEMP and oVEMP testing as measures of saccular and utricular function, respectively. A multi-axis motion platform was used to measure horizontal (along the inter-aural and naso-occipital axes) and vertical motion perceptual thresholds. These findings were compared with the vibration-evoked oVEMP as a measure of utricular function and sound-evoked cVEMP as a measure of saccular function. We also considered how perceptual threshold and cVEMP/oVEMP testing are each associated with Dizziness Handicap Inventory (DHI) scores. We enrolled 33 patients with bilateral vestibulopathy of different severities and 42 controls to have sufficient variability in otolith function. Subjects with abnormal oVEMP amplitudes had significantly higher (poorer) perceptual thresholds in the inter-aural and naso-occipital axes in age-adjusted analyses; no significant associations were observed for vertical perceptual thresholds and cVEMP amplitudes. Both oVEMP amplitudes and naso-occipital axis perceptual thresholds were significantly associated with DHI scores. These data suggest that horizontal perceptual thresholds and oVEMPs may estimate the same underlying physiological construct: utricular function.

Pharmacotherapy of vestibular disorders and nystagmus.

Vertigo and dizziness are with a life-time prevalence of ~30% among the most common symptoms and are often associated with nystagmus or other oculomotor disorders. The prerequisite for a successful treatment is a precise diagnosis of the underlying disorder. In this overview, the current pharmacological treatment options for peripheral and central vestibular, cerebellar, and oculomotor disorders including nystagmus are described. There are basically seven groups of drugs that can be used (the "7 As"): antiemetics; anti-inflammatory, anti-Menière's, and antimigraine medications; antidepressants, anticonvulsants, and aminopyridines. In acute vestibular neuritis, recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Menière's disease, a long-term high-dose treatment with betahistine-dihydrochloride (at least 48 mg three times daily) had a significant effect on the frequency of the attacks; the underlying mode of action is evidently an increase in inner-ear blood flow. The use of aminopyridines is a well-established therapeutic principle in the treatment of downbeat and upbeat nystagmus as well as episodic ataxia type 2 and cerebellar gait disorders. As was shown in animal experiments, these potassium channel blockers increase the activity and excitability and normalize irregular firing of cerebellar Purkinje cells. They evidently augment the inhibitory influence of these cells on vestibular and deep cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus; gabapentin and memantine improve pendular and infantile nystagmus. However, many other eye-movement disorders such as ocular flutter, opsoclonus, central positioning, and see-saw nystagmus are still difficult to treat. Although substantial progress has been made, further state-of-the-art trials must still be performed on many vestibular and oculomotor disorders, namely Menière's disease, vestibular paroxysmia, vestibular migraine, and many forms of central eye-movement disorders.

Semicircular canal, saccular and utricular function in patients with bilateral vestibulopathy: analysis based on etiology.

The diagnosis of bilateral vestibulopathy (BV) is typically established based on bilateral semicircular canal dysfunction. The degree to which both otolith organs-the saccule and utricle-are also impaired in BV is not well-established, particularly with respect to the etiology and severity of BV. The aim of this study was to evaluate semicircular canal, saccular and utricular function in patients with BV due to aminoglycoside ototoxicity and bilateral Menière's disease, and with different severities of BV. Caloric and head impulse testing were used as measures of canal function. Cervical vestibular-evoked myogenic potentials (cVEMP) and ocular VEMPs (oVEMP) were used as measures of saccular and utricular function, respectively. We enrolled 34 patients with BV and 55 controls in a prospective case-control study. Patients with BV were less likely to have saccular (61 %) or utricular (64 %) dysfunction relative to canal dysfunction (100 %). Utricular function differed significantly between patients by etiologic group: the poorest function was found in patients with BV due to aminoglycoside toxicity, and the best function in Menière's disease patients. Canal and saccular function did not vary according to etiology. Further, utricular but not saccular function was significantly correlated with canal function. Saccular and utricular function had the strongest association with Dizziness Handicap Inventory scores relative to canal function. These data suggest that when a patient with BV is identified in a clinical context, oVEMP testing is the most sensitive test in distinguishing between aminoglycoside toxicity and bilateral Menière's disease. Both cVEMP and oVEMP testing may be considered to evaluate the functional impact on the patient.

False-positive head-impulse test in cerebellar ataxia.

The objective of this study was to compare the findings of the bedside head-impulse test (HIT), passive head rotation gain, and caloric irrigation in patients with cerebellar ataxia (CA). In 16 patients with CA and bilaterally pathological bedside HIT, vestibuloocular reflex (VOR) gains were measured during HIT and passive head rotation by scleral search coil technique. Eight of the patients had pathologically reduced caloric responsiveness, while the other eight had normal caloric responses. Those with normal calorics showed a slightly reduced HIT gain (mean ± SD: 0.73 ± 0.15). In those with pathological calorics, gains 80 and 100 ms after the HIT as well as the passive rotation VOR gains were significantly lower. The corrective saccade after head turn occurred earlier in patients with pathological calorics (111 ± 62 ms after onset of the HIT) than in those with normal calorics (191 ± 17 ms, p = 0.0064). We identified two groups of patients with CA: those with an isolated moderate HIT deficit only, probably due to floccular dysfunction, and those with combined HIT, passive rotation, and caloric deficit, probably due to a peripheral vestibular deficit. From a clinical point of view, these results show that the bedside HIT alone can be false-positive for establishing a diagnosis of a bilateral peripheral vestibular deficit in patients with CA.

Effects of unilateral midbrain lesions on gaze (eye and head) movements.

The rostral midbrain, especially the rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) and the interstitial nucleus of Cajal (INC), plays an important role in the control of eye movements. Although the effect of midbrain lesions on eye movements is well investigated, little is known about its effect on head movements. In this study, we measured eye and head (gaze) movements in five patients with unilateral, acute midbrain lesions and nine healthy controls. In all patients, vertical eye velocity was reduced as a result of the lesion compared to healthy subjects, whereas peak head velocity was not affected. Further, most patients displayed an increased contralesional torsion in peripheral head positions, independently of whether they presented a head tilt in the straight-ahead position or not. Our results indicate that midbrain lesions affect the control of eye and head differently and independently.

Clinical, electrophysiological, and MRI findings in patients with cerebellar ataxia and a bilaterally pathological head-impulse test.

A significant number of patients with bilateral vestibulopathy suffer from cerebellar ataxia and central vestibular symptoms and vice versa. We examined 31 patients presenting with the combination of gait and stance ataxia, cerebellar ocular motor signs, and a bilaterally pathological head-impulse test (HIT). Tests included neuro-orthoptical examination, electromyography and neurography, caloric irrigation, pure-tone audiogram, vestibular-evoked myogenic potentials, and volumetric magnetic resonance imaging (MRI). Only 17 of 31 patients had a pathological caloric irrigation. Twenty-three patients had evidence of polyneuropathy (predominantly mixed sensorimotor involving axonal loss and demyelination) and twenty of hypoacusis (1 unilateral and 19 bilateral). Voxel-based morphometry comparing local gray matter brain volume between patients and controls revealed cerebellar atrophy involving both the vermis and the hemispheres. We conclude that there is a clinically relevant combination of cerebellar ataxia with cerebellar atrophy, bilaterally pathological HIT, polyneuropathy, and hypoacusis. This multisensory syndrome is most likely caused by a neurodegenerative disorder affecting different systems, leading to severe impairment of affected patients.