Fabio Bandini

The diagnostic value of vestibular evoked myogenic potentials in multiple sclerosis.

Sirs: The diagnostic value of evoked potentials (EPs) in multiple sclerosis (MS) depends mainly on their ability to detect clinically “silent” lesions. Their use has been recently reduced by the development of MRI, which is considered to be the single most sensitive test for MS [7, 8]. MRI, however, is not specific for the disease [10], and multimodal EPs have been shown to yield clinically undetected lesions in a significant percentage of patients [1]. Furthermore, current diagnostic criteria allow MS suspects to be reclassified into definite MS categories if visually evoked potentials (VEPs) are able to identify subclinical lesions in the optic pathway [7]. Thus the development of a new, potentially diagnostic test, could enhance the utility of EPs in detecting functional CNS dysfunction. The Vestibular Evoked Myogenic Potentials (VEMPs) are a neurophysiological technique which is based upon the modulation of tonic electromyogram (EMG) activity of the sternocleidomastoid (SCM) muscle, induced by vestibular (saccular) activation. VEMPs are beginning to be applied clinically, and some encouraging reports in neurological diseases, such as spinocerebellar degeneration [15] and MS [12, 17], suggest that VEMPs may be a useful method for the diagnosis of brainstem (BS) lesions. In the present study, we were interested in evaluating VEMPs sensitivity in detecting “silent” demyelinating lesions of BS structures; we also wanted to compare it with conventional brain MRI and pattern VEPs, which are considered, together with the oligoclonal bands of the CSF, the ‘gold standard’ techniques for the diagnosis of MS [7]. Finally, we wanted to correlate VEMPs measures with the clinical staging and the duration of the disease. To accomplish this, we chose to study only patients with clinically definite MS. Thirty-six clinically definite MS patients [11], followed as outpatients at our Department of Neurosciences, University of Genoa, were enrolled in the study. There were 15 males and 21 females. The mean age was 38.8 ± 10.8 years and the mean disease duration was 84.8 ± 100.3 months. The mean EDSS clinical score [5] was 3.6 ± 2.2. Twenty-one patients had a relapsing-remitting (RR) subtype of MS, while the remaining 15 had a secondary progressive (SP) subtype. All patients with RR subtype of MS were relapse free at the time of the investigation. No patients were taking steroids. The healthy controls were 21 age-matched individuals (12 males and 9 females). Exclusion criteria for all subjects were either the history or the presence of ophthalmological or otolaryngological disorders and of any pathology affecting the SCM. All the subjects underwent pure tone audiometry, VEPs and VEMPs. MS patients underwent brain MRI. Both the neurophysiological and neuroimaging examinations were carried out within 4 weeks from the clinical evaluation. The electrophysiological data were interpreted without knowledge of the MRI findings, and vice versa. As already mentioned, our main goal was to verify the diagnostic sensitivity of VEMPs, and compare it with MRI and VEPs; we therefore chose not to consider other methods for the assessment of BS functions (e. g. caloric responses, electrooculography, brainstem trigeminal and acoustic EPs), which are no longer recommended for the diagnosis of MS [3, 7]. All subjects gave informed consent prior to their inclusion in the study. Brain MRI studies were performed with gadolinium by means of a 1.5 T scanner (Magnetom Vision, Siemens, Germany): spinecho proton density and T2weighted, spin-echo T1-weighted, flow-attenuated inversion recovery and post-contrast spin-echo T1 sequences were acquired in axial, coronal and sagittal planes. The section thickness was 5 mm, with gap interslice (50 % for flow-attenuated inversion recovery, 10 % for the other images), FOV 260, matrix 256x256, RECFOV 62–75 %. MRI scans were evaluated by an expert neuroradiologist, blinded as to the aim of the study, who counted the number of T2-weighted hyperintense BS lesions. For VEMPs recording, the MS patients were divided in two groups, depending on the presence (16 patients) or absence (20 patients) of either history or signs/symptoms of BS dysfunction. The mean EDSS score was 4 ± 2.3 in the first group and 3.4 ± 2.1 in the second group. VEMPs were evoked by square wave rarefaction clicks (duration 0.1 ms, loudness 100 dB nHl [normal hearing level]) produced by an evoked potentials stimulator (Dantec Keyboard® Portable) and delivered unilaterally to the ear by a pair of calibrated headphones, at a stimulation of 5 LETTER TO THE EDITORS

Gabapentin as Treatment for Hemifacial Spasm

Hemifacial spasm, a life-long condition characterized by involuntary unilateral contractions of the facial muscles, is a disabling disorder often resulting in patient irritation and social embarassment. Its probable etiology is neurovascular compression of the facial nerve at its root exit zone. The current medical treatment consists of either baclofen or anticonvulsant drugs, with limitation due to side effects or low efficacy. In recent years botulinum toxin injection and microvascular decompression of the facial nerve have been shown to be highly successful. However, both procedures share some complications and require special techniques. We present 5 patients affected by hemifacial spasm who responded well to the novel anticonvulsant drug gabapentin. Gabapentin was administered at a dose ranging from 900 to 1,600 mg daily, with rapid and clear improvement of spasms and absence of any remarkable adverse effects. Our findings suggest that gabapentin may be an effective treatment for patients with hemifacial spasm with a very good ratio of therapeutic effects to side effects when compared with other drugs currently used.

Electroretinographic assessment in major depressed patients receiving duloxetine: might differences between responders and non-responders indicate a differential biological background?

INTRODUCTION Despite intense research efforts, still too little is known about the biological determinants of depression, thus soliciting diverse study approaches. Among others, the electroretinography (ERG) has been proposed even as a putative proxy (retinal) measurement of central dopaminergic activity for Major Depressive Disorder (MDD) both in drug-naïve patients and subjects receiving antidepressant treatments. Nonetheless, current evidences are merely preliminary, essentially considering just older classes of antidepressants, thus requiring confirmation studies even with newer agents as duloxetine. METHOD Twenty MDD subjects and 20 matched controls received duloxetine 60 mg/day for 12 weeks, being monitored both by standard ERG recording and by administration of the Hamilton scales for Depression and Anxiety and the Young Mania Rating Scale at baseline and week 12 (end of the study). RESULTS ERG mean rod b-wave amplitude significantly reduced from baseline to week 12 in those depressed subjects achieving final response (p=.024), decreasing from the highest rank values to the ones, substantially unmodified, seen among non-responders and controls. LIMITATIONS Small sample size and lack of multiple assessments. CONCLUSIONS At least some MDD patients responding to duloxetine might exhibit a peculiar ERG pattern, hypothetically indicating a specific biological background. If confirmed by larger-sampled studies, these results might shed further light in the understanding of the biological determinants of different subtypes of depression, ideally showing alternative patterns of response upon different treatment interventions.

Dramatic rebounds of MS during pregnancy following fingolimod withdrawal

In MS, discontinuation of some therapies may result in a transitory, possibly overwhelming, increase in disease activity.1–4 We report 2 cases of severe clinical rebound after fingolimod suspension occurring in 2 patients following pregnancy. Clinical rebound was defined as the occurrence of new severe neurologic symptoms together with a significant increase of new or enlarging T2-weighted or gadolinium-enhancing T1-weighted lesions exceeding baseline activity, on treatment discontinuation.4 The first patient was diagnosed with MS in 2005. In the subsequent 3 years, she experienced several relapses and progressive increase of MRI lesion load despite the sequential introduction of weekly interferon-β1a, thrice weekly interferon-β1a and then glatiramer acetate. Natalizumab (NTZ) was then started (EDSS 3.0, JCV antibodies negative status), resulting in no evidence of disease activity for the following 40 months. On seroconversion, NTZ was interrupted in August 2011 beacause of the potential risk of progressive multifocal leukoencephalopathy (PML) and fingolimod was started. In March 2013, fingolimod was suspended as disease was stable (figure, A) and due to desire of pregnancy and potential risks of fetal exposure to fingolimod.5 Lymphocyte count was 0.34 × 109/L. In April 2013, she resulted pregnant. In July (eleventh week of pregnancy), she abruptly developed quadriplegia and signs of severe cognitive impairment (EDSS: 9.0). Lymphocyte count was 1.54 × 109/L. One gram of methylprednisolone was administered IV for 5 days with partial recovery (EDSS 7.0). One month later, she developed locked-in syndrome (EDSS 9.5). Brain MRI showed a dramatic increase of white-matter abnormalities with many gadolinium-enhancing lesions (figure, B). PML was excluded by CSF analysis. IV methylprednisolone followed by IV immunoglobulins were administered with no success. Plasma exchange was not considered because of the possible adverse effects on maternal hemodynamics and limited experience on pregnant patients with MS. On therapeutic abortion, she received IV cyclophosphamide (2 g/m2), improving clinically (EDSS 7.0) and radiologically (figure, C). One month later, her clinical condition deteriorated (EDSS 8.0) with worsening of brain MRI (figure, D). She was treated again with IV cyclophosphamide (1 g/m2), but a few days later, she developed septic shock and died.

The effect of cannabinoids on the stretch reflex in multiple sclerosis spasticity

The aim of this observational study was to assess the efficacy of a tetrahydrocannabinol–cannabidiol (THC : CBD) oromucosal spray on spasticity using the stretch reflex in patients with multiple sclerosis (MS). Numeric rating scale (NRS) for spasticity, modified Ashworth scale (MAS), and the stretch reflex were assessed before and during treatment in 57 MS patients with spasticity eligible for THC : CBD treatment. A significant reduction in stretch reflex amplitude as well as significant reductions of NRS and MAS scores were observed. There was a low concordance between the three measures (stretch reflex, NRS, and MAS), likely related to the different aspects of muscle hypertonia assessed. Stretch reflex responders were taking a significantly higher number of puffs, whereas no differences were found in the responders by the other scales, suggesting that a higher dosage would add benefit if tolerated. The present study confirms the efficacy of cannabinoids in reducing spasticity in patients with MS, suggesting a higher sensitivity and specificity of the stretch reflex compared with other measures. As an objective and quantitative measure of spasticity, the stretch reflex is particularly useful to assess the effects of cannabinoids on spinal excitability and may play a role in future pharmacological studies.

Crossed Aphasia: Analysis of a Case with Special Reference to the Nature of the Lesion

We report a case of crossed aphasia in a strongly right-handed woman due to a parieto-occipital tumor in the right hemisphere, documented by CT and MR images. Neuropsychological assessment was conducted on four different occasions: results revealed an uncommon feature in our case, because of the nature of the lesion and the evolution of the clinical picture. These findings are discussed in relation to the literature.

Resting state in Alzheimer's disease: a concurrent analysis of Flash-Visual Evoked Potentials and quantitative EEG

BackgroundTo investigate to what extent Alzheimers Disease (AD) affects Resting State activity, the possible impairment of independent electrophysiological parameters was determined in Eye-open and Eye-closed Conditions. Specifically, Flash-Visual Evoked Potential (F-VEP) and quantitative EEG (q-EEG) were examined to establish whether abnormalities of the former were systematically associated with changes of the latter.MethodsConcurrently recorded F-VEP and q-EEG were comparatively analysed under Eye-open and Eye-closed Conditions in 11 Controls and 19 AD patients presenting a normal Pattern-Visual Evoked Potential (P-VEP). Between Condition differences in latencies of P2 component were matched to variations in spectral components of q-EEG.ResultsP2 latency increased in 10 AD patients with Abnormal Latency (AD-AL) under Eye-closed Condition. In these patients reduction of alpha activity joined an increased delta power so that their spectral profile equated that recorded under Eye-open Condition. On the opposite, in Controls as well as in AD patients with Normal P2 Latency (AD-NL) spectral profiles recorded under Eye-open and Eye-closed Conditions significantly differed from each other. At the baseline, under Eye-open Condition, the spectra overlapped each other in the three Groups.ConclusionUnder Eye-closed Condition AD patients may present a significant change in both F-VEP latency and EEG rhythm modulation. The presence of concurrent changes of independent parameters suggests that the neurodegenerative process can impair a control system active in Eye-closed Condition which the electrophysiological parameters depend upon. F-VEP can be viewed as a reliable marker of such impairment.

CATATONIC FEATURES IN MAJOR DEPRESSION RELIEVED BY ELECTROCONVULSIVE TREATMENT: PARALLEL EVALUATION OF THE STATUS OF PLATELET SEROTONIN TRANSPORTER

The aim of this research was to follow parallelly the clinical status of a patient and the dynamics of the serotonin transporter (SERT), a likely player in the effect of electroconvulsive treatment (ECT), a powerful tool against deep depression. A patient affected by major depression with catatonic features, not responding to pharmacological therapy, underwent ECT. Evaluations of the binding of labelled paroxetine to venous blood platelet SERT were parallel to the assessments of clinical improvements. The density of platelet SERT, starting from a low level before ECT, displayed an initial steep increase peaking the day after the third electroconvulsive session (5 days after the start of ECT). This was followed by a rapid decrease, which seemed to precede the process of clinical recovery. These results were found in a case of unavoidable ECT treatment. If generalizable, they suggest interesting ideas about the still mysterious mechanism of ECT antidepressant action.

Electroretinographic modifications induced by agomelatine: a novel avenue to the understanding of the claimed antidepressant effect of the drug?

Background Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs. Objective and methods The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG. Results As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin. Conclusion Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between 5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.

Interhemispheric subdural haematoma from ruptured aneurysm: a case report.

Sirs: Interhemispheric subdural haematoma (ISH) is a relatively rare subtype of acute subdural haematoma (ASDH) and it is almost invariably due to head trauma [1]. Here we describe a case of a non traumatic ISH from ruptured aneurysm without bleeding into the subarachnoid space. A 62-year-old hypertensive woman started to complain of a flu-like illness together with a dull widespread headache. Three days later her headache suddenly worsened. Pain was localized on the left side of the head, spreading both to the occipital region and to the eyebrows and increasing with strain and Valsalva manoeuvre. Mild nausea and an episode of vomit followed. Four days later the patient experienced diplopia and left eyelid droop. She was admitted to our Department nine days after the onset of the symptoms. Her past neurological history was unrevealing and there was no history of head trauma, blood clot disturbances or anticoagulant therapy. There were no concomitant medications. Her blood pressure was 169/95 mmHg. The neurological examination revealed a complete left third nerve palsy, but no other signs were observed. No abnormalities were observed in routine blood counts, blood chemistry and coagulation studies. Cranial CT and MRI revealed a collection of blood along the cerebral falx, over the left tentorium and temporal fossa and posterior to the clivus. Both examinations did not reveal any evidence of a component of subarachnoid or intraparenchymal haemorrhage (Fig. 1 A, B, C). Cerebrospinal fluid (CSF) examination was entirely normal but for the presence of 10 white cells/mm3 (normal value < 5). Spectrophotometry confirmed the absence of blood pigments. MR angiography (MRA) revealed a left internal carotid artery wide-based aneurysm located in the supra-clinoid portion of the carotid siphon, close to the posterior communicating artery, at the internal carotid – posterior communicating artery junction (IC-PC) (Fig. 1 E). The aneurysm measured 10 x 6 mm, projected infero-posterolaterally and was confirmed by an angiography. The patient underwent an endovascular embolization treatment, which was only partial because of the wide neck (Fig. 1 D). Two days after the embolization, cranial CT showed a reduction of the subdural haematoma. The left oculomotor nerve palsy remained unchanged during the following weeks. When last examined, six months after the onset of the symptoms, the patient had a normal neurological examination and the left third nerve palsy had completely recovered. Non traumatic cerebral aneurysm rupture usually involves the subarachnoid space, thus causing a subarachnoid haemorrhage (SAH). The concomitant involvement of the subdural space is much less frequent [2]. Three mechanisms for the occurrence of subdural bleeding have been hypothesized. First, previous small bleedings allow adhesion of the aneurysm to the adjacent arachnoid membrane and the final rupture occurs into the subdural space. Second, a high pressure haemorrhage may lead to pia-arachnoid rupture, thus causing extravasation of blood into a subdural or parenchymal location. Third, a rapid accumulation of blood distends the subarachnoid space causing a tear of the arachnoid membrane [2]. Among the above mentioned hypotheses, only the first can account for a pure ASDH, without either SAH or parenchymal haemorrhage. ISH is a quite rare subtype of ASDH, which occurs almost invariably after head trauma. To the best of our knowledge, there are only four previously reported cases of spontaneous ISH in the absence of SAH [3, 4, 6]. Given that our patient did not undergo a clipping of the IC-PC aneurysm, we are aware that an unequivocal demonstration of the relation between the subdural bleeding and the aneurysm is impossible. However, the absence of head trauma and congenital or acquired coagulopathy, the occurrence of a complete left third nerve palsy (which is known to be related to IC-PC aneurysm rupture [5]), the closeness of the aneurysm and the subdural bleeding (Fig. 1 B, E), the extravasation of the blood along the left tentorium and the interhemispheric space, already reported for IC-PC aneurysms [3, 4], and the irregular shape of the aneurysm posterior wall on MRA imaging (possible bleeding point) strongly all suggest a causal association. In summary, our report indicates that, although uncommon, rupture of an intracranial aneurysm should be kept in mind as a cause of spontaneous ISH. Importantly, this can be the case even in the absence of subarachnoid bleeding and of a history of head injury. LETTER TO THE EDITORS