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.

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.

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.

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.

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.

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.

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.

SPIR MRI usefulness for steroid treatment management in Tolosa-Hunt syndrome.

A 40-year-old man underwent surgery for a right middle ear cholesteatoma. One month later, he presented with a subacute ocular pain that was followed one day later by the appearance of vertical diplopia attributable to a right superior rectus paresis, lid ptosis and hypoaesthesia in the territory of the I and the II right trigeminal branches. A fat-suppressed (selective partial inversion recovery, SPIR) gadolinium-enhanced MRI favours the detection of inflammatory pathological tissue inside the right cavernous sinus, and in this patient it suggested a diagnosis of Tolosa-Hunt syndrome. The pain disappeared quickly after steroid treatment was started whereas the ocular nerve involvement improved only slightly during the first week of treatment. After two months, the patient only complained of diplopia on up-gaze, but the therapy was discontinued two months later on the basis of both clinical signs and MRI findings. SPIR MRI may be useful not only to support a diagnosis of Tolosa-Hunt syndrome, but also to follow-up the disease course and to manage steroid treatment.

Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an autoimmune acute peripheral neuropathy. Frequently a flu-like episode or a gastroenteritis precede GBS, and the cross-reactivity between microbial and neural antigens partly explains the pathophysiology of the disease and the possible detection of antiganglioside antibodies. The weakness reaches its nadir in 2-4 weeks: the patients may be chair- or bed-bound, may need artificial ventilation and frequently experience dysautonomic dysfunction; 5-15% of the patients die and more patients are left with a disabling motor deficit and/or fatigue. Electrophysiology and cerebrospinal fluid evaluation support the diagnosis. The treatment of GBS is multidisciplinary, and both plasma exchange and high dose immunoglobulin (IVIg) are effective in reducing both the severity of the disease and the residual deficits. Finally, steroids are not effective in GBS.

Ocular motor myotonic phenomenon in myotonic dystrophy.

OBJECTIVE: To detect disconjugate ocular motor abnormalities and a possible extraocular muscle myotonic phenomenon in patients with myotonic dystrophy (MyD). METHODS: The magnetic scleral search coil technique was used to record monocularly the small (25 degrees ) and large (50 degrees ) saccades, which were paced to two interstimulus intervals (ISIs), one short (1 s), the other long (5 s). The case study comprised 20 patients with MyD, 10 patients with multiple sclerosis (MS), and 10 controls. The amplitude, duration, peak velocity, and skewness of the velocity profile (ratio between the acceleration and the deceleration periods) of each saccade were measured. The disconjugate parameters (difference between the two eyes of the same measure), and the myotonic parameter (the maximal (as absolute value) short-long ISI difference between the same measures) were considered. RESULTS: The disconjugate parameters were the same in all three groups. The mean values of myotonic parameters found in patients with MyD for duration (for both small and large target displacements) and skewness (for small target displacements only) differed from those found for both the MS and the control groups. Additionally, the occurrence of individual patients presenting with abnormal duration and skewness parameters was higher in the MyD than in the MS group. In patients with MyD, the saccade duration was longer for long than for short ISI; the effect derived from a prolongation of the acceleration period, which manifested as an increase in skewness. CONCLUSION: The results can be explained by a combination of the myotonic and the warm up phenomena. A delay in the relaxation (myotonia) of the extraocular muscle may be more evident after a long fixation period (long ISI) and it may improve by increasing saccade pacing (short ISI-warm up). This phenomenon is slight, and is unlikely to affect saccade performance significantly, but it may provide some insight into the nature of the disorder affecting extraocular and skeletal muscles in myotonic dystrophy.

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.

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.

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.

Auditory saccade impairment after central thalamus lesions.

Visual and auditory saccades were studied in three patients with an isolated lesion located in the central thalamus. Visual saccades proved to be normal, whereas for auditory stimuli, the amplitude of the first saccade was asymmetric: saccades ipsilateral to the lesion were significantly smaller than those directed to the contralateral side. The patients were able to make a corrective saccade and hence to improve gain and to decrease gain asymmetry. It is suggested that patients were able to localise auditory targets correctly, but did not correctly take into account eye position during the saccade, probably as a consequence of an inaccurate efference copy (corollary discharge) signal. The findings are in keeping with the hypothesis that the central thalamus deals with saccades that are based on extraretinal signals.

Opsoclonus in a patient with cerebellar dysfunction.

After two days of malaise, headache, nausea, and vomiting, a 26-year-old man suddenly developed opsoclonus and stance and gait ataxia, without myoclonus. Having excluded a paraneoplastic etiology, we assumed that the disorder was probably related to a viral infection. Spontaneous resolution occurred in about two months. Opsoclonus became flutter dysmetria and then resolved. Saccadic eye movement recording disclosed the occurrence of hypermetria, increased velocity, and delayed latency, which also resolved. In this patient, the correspondence between clinical and ocular motor abnormality courses suggests a transient cerebellar dysfunction as the possible pathophysiologic mechanism for opsoclonus.