Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.

BACKGROUND AND PURPOSE: Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients' management was studied, focusing on the subgroup of Ab-negative-AE. METHODS: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). RESULTS: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second-line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first-line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00-1.04). CONCLUSIONS: In-house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab-positive-AE underestimation. Notwithstanding this limitation, our findings suggest that Ab-negative-AE and Ab-positive-AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab-negative-AE patients risk worse responses due to delayed and less aggressive treatments.

After Effects of Cerebellar Continuous Theta Burst Stimulation on Reflexive Saccades and Smooth Pursuit in Humans.

The use of cerebellar repetitive transcranial magnetic stimulation has been attempted for perturbing reflexive and voluntary eye movements, but discrepancies are seen between the results of distinct studies possibly due to the different stimulation sites, intensities, and paradigms. We describe the after effects of 20 and 40 s continuous Theta Burst Stimulation (cTBS) as compared to sham stimulation, applied over the lateral cerebellar vermis and paravermis on Reflexive Saccades (RS) and Smooth Pursuit (SP) eye movements, recorded in the 30 min following stimulation. The experiments were carried out in eight healthy volunteers, and eye movements were recorded monocularly with video-oculography. The 40 s cTBS significantly increased the amplitude of ipsilateral RS and the acceleration of the ipsilateral SP, and this effect was detectable all over the 30-min recording period; 40 s cTBS did not modify the other parameters, namely the peak velocity, the duration and the latency of RS, and the latency and the velocity of SP. The 20 s cTBS was ineffective on all RS and SP parameters. Finally, we detected a significant quite-linear reduction of RS peak velocity over time, but this was independent from cTBS and was probably caused by fatigue. The effects of 40 s cTBS in our experiments mimic the disorder of ocular motility in Wallenberg's syndrome and could result from functional impairment of cerebellopontine pathways. This effect lasts 30 min at least, and can provide a useful framework for adaptive ocular motor studies.

Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial.

OBJECTIVES: Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity. METHODS: Twenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2. RESULTS: At T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016). At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group. CONCLUSIONS: tDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections. SIGNIFICANCE: This study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm.

Lamotrigine induced Brugada-pattern in a patient with genetic epilepsy associated with a novel variant in SCN9A.

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.

ICHD-II diagnostic criteria for Tolosa-Hunt syndrome in idiopathic inflammatory syndromes of the orbit and/or the cavernous sinus.

A bibliographical search was conducted for papers published between 1999 and 2007 to verify the validity of International Classification of Headache Disorders (ICHD)-II criteria for the Tolosa-Hunt syndrome (THS) in terms of (i) the role of magnetic resonance imaging (MRI); (ii) which steroid treatment should be considered as adequate; and (iii) the response to treatment. Of 536 articles, 48, reporting on 62 patients, met the inclusion criteria. MRI was positive in 92.1% of the cases and it normalized after clinical resolution. There was no evidence of which steroid schedule should be considered as adequate; high-dose steroids are likely to be more effective both to induce resolution and to avoid recurrences. Pain subsided within the time limit required by the ICHD-II criteria, but signs did not. We conclude that THS diagnostic criteria can be improved on the basis of currently available data. MRI should play a pivotal role both to diagnose and to follow-up THS.

A role for NMDAR-dependent cerebellar plasticity in adaptive control of saccades in humans.

BACKGROUND: Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated. OBJECTIVE: To test the role of cerebellar plasticity phenomena on adaptive saccade control. METHODS: We evaluated the effect of continuous theta burst stimulation (cTBS) over the posterior vermis on saccade amplitude adaptation and spontaneous recovery of the initial response. To further identify the substrate of synaptic plasticity responsible for the observed adaptation impairment, subjects were pre-treated with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. RESULTS: Amplitude adaptation was altered by cTBS, suggesting that cTBS interferes with cerebellar plasticity involved in saccade adaptation. Amplitude adaptation and spontaneous recovery were not affected by cTBS when recordings were preceded by memantine administration. CONCLUSION: The effects of cTBS are NMDAR-dependent and are likely to involve long-term potentiation or long-term depression at specific synaptic connections of the granular and molecular layer, which could effectively take part in cerebellar motor learning.

Memory guided saccades in mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural and functional damage. The incidence and the features of this damage are still a matter of debate and vary depending on the method applied. Memory guided saccades (MGSs) with a memorization delay longer than 20s can be used reliably to evaluate the parahippocampal cortex. METHODS: MGSs with 3 and 30s memorization delays were recorded with the search coil technique in six patients affected by right MTLE-HS, and in 13 healthy controls. RESULTS: The patients were not able to reduce the MGSs residual amplitude error after the first saccade with a 30s memorization delay. This finding was more evident with leftward saccades. CONCLUSIONS: MGS abnormalities suggested the functional involvement of the right parahippocampal cortex in most of the patients with MTLE-HS, and this supports the clinical and anatomopathological heterogeneity of the disease. SIGNIFICANCE: MGSs can be used in patients with right MTLE-HS to detect a possible functional involvement of the ipsilateral parahippocampal cortex.

MRI and brainstem auditory evoked potential evidence of eighth cranial nerve involvement in multiple sclerosis.

An MS patient experienced sudden hearing loss. Brainstem auditory evoked potentials, previously normal, showed substantial abnormalities that suggested the impairment of the distal part of the acoustic nerve. MRI detected a small hyperintense lesion along the acoustic nerve; the lesion decreased in size and then disappeared after steroid treatment. This demonstrates that a demyelinating lesion in the distal tract of the eighth cranial nerve may cause an acute hearing loss in MS.

Epileptic skew deviation.

We describe a 43-year-old neurologically intact patient who reported episodes of diplopia and oscillopsia associated with a right-beating nystagmus and a skew deviation. These symptoms and signs were related to a left posterior epileptic EEG discharge. We suggest that these ocular motor signs derived from an ictal activation of the vestibular cortex, which in turn activated descending projections to the vestibular nuclei, leading to both a dynamic (right-beating nystagmus) and a static (skew deviation) vestibular imbalance.

Quantitative evaluation of saccadic and smooth pursuit eye movements. Is it reliable?

PURPOSE: The authors evaluated the reliability of the coefficients of the (1) amplitude/duration and (2) amplitude/peak velocity relationships of the mean precision values and the mean latency values (saccadic eye movements) and the coefficients of the target velocity/gain relationship (smooth pursuit eye movements). They computed test-retest maximum variability limits for these parameters. METHODS: After a 1-week interval, saccadic and smooth pursuit eye movements were recorded twice from 20 healthy subjects; 12 of these subjects underwent a third recording session. The estimate of the intraclass coefficient of reliability, R, was adopted to evaluate the reliability of eye movement quantitative analysis. RESULTS: The data demonstrated that the reliability was fairly good for the amplitude/peak velocity relationship, was good for the precision, and was excellent for the amplitude/duration, the target velocity/gain relationships, and the latency. CONCLUSIONS: Quantitative analysis of both saccadic and smooth pursuit eye movements is reliable. One statistic used to estimate reliability, ie, the within-subjects mean square value, also enables the determination of test-retest normal variability values for both the variances and the differences of measurements.

Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis.

OBJECTIVES: Body cooling has been proposed as a symptomatic treatment for multiple sclerosis. This study aimed to assess the effects of body cooling and of circadian variations on clinical parameters and on visual and auditory evoked potential measures in multiple sclerosis patients. METHODS: Clinical status was assessed and VEPs, BAEPs and MLAEPs (all with two stimulus frequencies) were recorded a total of 4 times on two separate days (two times per day at 08:30 and 15:00 h each day) in 10 multiple sclerosis patients and 10 controls. On one of these days, the subjects were submitted to body cooling before the afternoon session. RESULTS: Tympanic temperature was significantly higher in the afternoon. Cooling lowered the temperature by 1.4 degrees C. No clinical effects were observed. Circadian effects were detected on VEP amplitude, which increased both in controls and in patients at low stimulus frequency (P<0.01), and increased in controls and decreased in patients at high stimulus frequency (interaction: P<0.01). Cooling determined an increase in BAEP I-V peak-to-peak time in controls, and a reduction in patients at high stimulus frequency (interaction: P<0.01). In patients, cooling also determined a great increase in MLAEP amplitude (interaction: P<0.001). We did not find cooling effects on VEP measures. CONCLUSIONS: Visual and auditory evoked potentials showed differences in circadian and cooling effects between controls and multiple sclerosis patients. These differences are consistent with the hypothesis of temperature-dependent conduction blocks in demyelinated fibers. Cooling may have a clinical effect in selected patients only.

Periodic alternating nystagmus and vestibulo-spinal system facilitating activity.

OBJECTIVE: Periodic alternating nystagmus has been associated with the instability of the velocity storage mechanism, which is known to play an important role in both the vestibulo-oculomotor and the optokinetic systems. In the present study we looked for a possible spinal equivalent to PAN. METHODS AND RESULTS: In 3 PAN patients, the H-reflex amplitude proved to be slightly but significantly influenced by nystagmus direction, in that it was greater when the nystagmus was beating toward the stimulation side. CONCLUSIONS: This finding suggests that projections from velocity storage may play a role not only in the ocular motor but also in assisting postural stability through the vestibulo-spinal system.

Saccade latency toward auditory targets depends on the relative position of the sound source with respect to the eyes.

The latency of saccadic eye movements evoked by the presentation of auditory and visual targets was studied while starting eye position was either 0 or 20 deg right, or 20 deg left. The results show that for any starting position the latency of visually elicited saccades increases with target eccentricity with respect to the eyes. For auditory elicited saccades and for any starting position the latency decreases with target eccentricity with respect to the eyes. Therefore auditory latency depends on a retinotopic motor error, as in the case of visual target presentation.

Multimodal evoked potentials in myotonic dystrophy (MyD).

By means of multimodal evoked potentials (EPs), we evaluated the central nervous system (CNS) involvement in 25 subjects suffering from myotonic dystrophy: brainstem auditory evoked potentials (BAEPs), middle-latency auditory evoked potentials (MLAEPs) and somatosensory evoked potentials (SEPs) from the upper limb were performed on all subjects, whereas only the 19 patients, whose clinical ocular abnormalities were slight, underwent pattern-electretinograms (PERGs) and pattern visual-evoked potentials (VEPs) in order to identify the site of lesion among visual pathways (retinal and/or retroretinal). PERGs were abnormal in 8/19 subjects, VEPs in 8/19 subjects (the two techniques were simultaneously abnormal in 8 eyes), BAEPs in 7/25 subjects, MLAEPs in 4/25 subjects (in one subject both BAEps and MLAEPs were abnormal) and SEPs were abnormal in 1/25 subjects. 13/25 of our subjects showed at least one EP that revealed a CNS involvement. The electrophysiological alterations were not correlated either with subject age or with disease duration. Multimodal EPs enabled us to demonstrate that CNS involvement in myotonic dystrophy is important and mainly affects the visual and auditory system.

Eye-head coordination toward auditory and visual targets in humans.

Eye-head coordination during gaze orientation toward auditory targets in total darkness has been examined in human subjects. The findings have been compared, for the same subjects, with those obtained by using visual targets. The use of auditory targets when investigating eye-head coordination has some advantages with respect to the more common use of visual targets: (i) more eccentric target positions can be presented to the subject; (ii) visual feedback is excluded during the execution of gaze displacement; (iii) complex patterns of saccadic responses can be elicited. This last aspect is particularly interesting for examining the coupling between the eyes and the head displacements. The experimental findings indicate that during gaze orientation toward a visual or an auditory target the central nervous system adopts the same strategy of using both the saccadic mechanism and the head motor plant. In spite of a common strategy, qualitative and quantitative parameters of the resulting eye-head coordination are slightly different, depending on the nature of the target. The findings relating to patterns of eye-head coordination seem to indicate a dissociation between the eyes and the head, which receive different motor commands independently generated from the gaze error signal. The experimental findings reported in this paper have been summarized in a model of the gaze control system that makes use of a gaze feedback hypothesis through the central reconstruction of the eye and head positions.

Vestibular evoked myogenic potentials: test-retest reliability.

Vestibular evoked myogenic potentials (VEMPs) are myogenic responses induced by stimulation of the saccular macula by intense sound stimuli. The responses are recordable from the sternocleidomastoid (SCM) muscles. We recorded VEMPs from normal subjects (up to three times in each subject) to identify: i) the best recording procedures, ii) the reliability, and iii) the normal limits for both individual point and test-retest evaluation. We adopted a recording setting in which the subjects were asked to simultaneously activate both SCM muscles by pushing their forehead against a load cell during a bilateral acoustic stimulation. This system enabled subjects to monitor their intensity of SCM activation and to keep intensity constant; us to record VEMPs from both sides simultaneously, and thus to minimize the duration of the recording session. For each subject we considered the mean and the difference (divided by the mean) of the values derived from the two SCM muscles of the latency of the P13 and N23 components and of the P13-N23 peak-to-peak amplitude. Reliability was evaluated by estimate of the intraclass correlation coefficient, and was good or excellent for all parameters, with the exception of the P13-N23 amplitude side-difference. To take advantage of all the data available, we computed the normal limits for both individual point and test-retest evaluation by means of the variability indices used for the evaluation of reliability. In this system, VEMP recording is simple, inexpensive and rapid. It is well tolerated by subjects, and easily implemented in laboratories equipped for evoked potential recording.

Clinical aspects of fatigue in multiple sclerosis.

We studied 100 multiple sclerosis outpatients in order to assess the frequency of fatigue and to detect its relationships with other clinical findings. Fatigue was quantified by fatigue severity scale (FSS; range 1-7); current clinical neurological status and disability level were respectively scored by Kurtzke's functional systems and expanded disability status scale (EDSS). FSS mean score was 4.12; fatigue was totally absent in 3% of the patients. Fatigue started before onset of the disease in 7 patients, at onset in 12 and within the first year in 7. Fatigue intensity and frequency were related to each other. FSS mean scores were significantly higher in the patients with fatigue worsened by heat (p < 0.01), with chronic progressive disease (p < 0.0001), with motor symptoms (p < 0.0001) and with EDSS > or = 3.5 (p < 0.0001). Multiple regression analysis showed a significant effect of EDSS on fatigue (p < 0.0001), not attributable to differences in duration of the disease.

Visual evoked potential abnormalities in dyslexic children.

Developmental reading disability (dyslexia) has traditionally been attributed to impaired linguistic skills. Recent psychophysical data suggest that dyslexia may be related to a visual perceptual deficit. A few visual evoked potential (VEP) studies have addressed this hypothesis, but their results are far from consistent. We submitted 9 dyslexic subjects and 9 age- and sex-matched normal controls to checkerboard pattern reversal VEPs. The main experimental variables were: large (0.5 cycles per degree; cpd) and small (2 cpd) checks and two reversal frequencies (2.1 Hz and 8 Hz); mean luminance and contrast (60 cd/m2 and 50%, respectively) were kept constant in all four conditions. Transient VEP (2.1 Hz) parameters did not differ between controls and dyslexics at 2 cpd. At 0.5 cpd, N70 amplitude was significantly smaller and N70 latency significantly shorter in dyslexics. Amplitudes for the fundamental frequency (8 Hz), as well as for the second and third harmonics of the steady-state VEPs were smaller in dyslexics for both stimulus sizes. A discriminant analysis correctly classified each subject. Our data confirm the hypothesis of a perceptual deficit in dyslexic subjects. The abnormalities are related to spatial and temporal stimulus frequencies: they appear when large stimuli are presented, or when the stimulation frequency is high. These data support the hypothesis of selective magnocellular dysfunction in dyslexia.

Electrophysiologic patterns of oral-pharyngeal swallowing in parkinsonian syndromes.

OBJECTIVES: To assess the presence, severity, and differences in dysphagia in Parkinson disease (PD), Parkinson variant of multiple system atrophy (MSA-P), and progressive supranuclear palsy (PSP), and to study the pathophysiology of swallowing abnormalities in these disorders. METHODS: We applied an electrophysiologic method to evaluate oral-pharyngeal swallowing. We analyzed the following measures: duration of EMG activity of suprahyoid/submental muscles (SHEMG-D); duration of laryngeal-pharyngeal mechanogram (LPM-D); duration of the inhibition of the cricopharyngeal muscle activity (CPEMG-ID); interval between onset of EMG activity of suprahyoid/submental muscles and onset of laryngeal-pharyngeal mechanogram (I-SHEMG-LPM); and swallowing reaction time (SRT). RESULTS: The prolongation of I-SHEMG-LPM was more typical in PD, whereas the most distinctive finding both in patients with PSP and MSA-P was the reduction or the absence of CPEMG-ID early in the course of the disease. CONCLUSIONS: Involvement of the peduncolo-pontine tegmental nucleus, with subsequent dysfunction of basal ganglia and of the medullary central pattern generator of swallowing, may account for the abnormalities detected in these parkinsonian syndromes. The method described was able to identify swallowing abnormalities also in patients without symptoms of dysphagia and to evaluate dysphagia severity in all patients.