Federica Assenza

Transcranial Magnetic Stimulation Studies in Alzheimer's Disease

Although motor deficits affect patients with Alzheimers disease (AD) only at later stages, recent studies demonstrated that primary motor cortex is precociously affected by neuronal degeneration. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries, thereby maintaining motor performances in daily living. Effectively several transcranial magnetic stimulation (TMS) studies have demonstrated that cortical excitability is enhanced in AD and primary motor cortex presents functional reorganization. Although the best hypothesis for the pathogenesis of AD remains the degeneration of cholinergic neurons in specific regions of the basal forebrain, the application of specific TMS protocols pointed out a role of other neurotransmitters. The present paper provides a perspective of the TMS techniques used to study neurophysiological aspects of AD showing also that, based on different patterns of cortical excitability, TMS may be useful in discriminating between physiological and pathological brain aging at least at the group level. Moreover repetitive TMS might become useful in the rehabilitation of AD patients. Finally integrated approaches utilizing TMS together with others neuro-physiological techniques, such as high-density EEG, and structural and functional imaging as well as biological markers are proposed as promising tool for large-scale, low-cost, and noninvasive evaluation of at-risk populations.

The Ineffective Role of Cathodal tDCS in Enhancing the Functional Motor Outcomes in Early Phase of Stroke Rehabilitation: An Experimental Trial

Transcranial direct current stimulation (tDCS) is a noninvasive technique that could improve the rehabilitation outcomes in stroke, eliciting neuroplastic mechanisms. At the same time conflicting results have been reported in subacute phase of stroke, when neuroplasticity is crucial. The aim of this double-blind, randomized, and sham-controlled study was to determine whether a treatment with cathodal tDCS before the rehabilitative training might augment the final outcomes (upper limb function, hand dexterity and manual force, locomotion, and activities of daily living) in respect of a traditional rehabilitation for a sample of patients affected by ischemic stroke in the subacute phase. An experimental group (cathodal tDCS plus rehabilitation) and a control group (sham tDCS plus rehabilitation) were assessed at the beginning of the protocol, after 10 days of stimulation, after 30 days from ending of stimulation, and at the end of inpatient rehabilitation. Both groups showed significant improvements for all the assessed domains during the rehabilitation, except for the manual force, while no significant differences were demonstrated between groups. These results seem to indicate that the cathodal tDCS, provided in an early phase of stroke, does not lead to a functional improvement. To depict a more comprehensive scenario, further studies are needed.

Cathodal transcranial direct current stimulation reduces seizure frequency in adults with drug-resistant temporal lobe epilepsy: A sham controlled study

One-third of epilepsy patients develop drug resistance, and half of them can benefit from the surgical removal of epileptic focus (EF). Neuromodulation represents the only hope to ameliorate the quality of life of the remaining patients [1]. Cathodal transcranial direct current stimulation (ctDCS) is a techniques able to noninvasively inhibit cortical excitability [2], which is abnormally increased in epilepsy [3]. Preliminary results of ctDCS of Epileptic focus (EF) of focal drug-resistant epilepsy (DRE) are promising [4], but several technical issues could be optimized to achieve a clinically relevant effect. In this proof-of-principle study, we evaluated the efficacy of a novel symmetric ctDCS approach vs sham-tDCS in temporal lobe DRE. We enrolled ten patients affected by temporal lobe DRE (4 males; 42 ± 15.7 years old; 4 symptomatic and 6 cryptogenic; 5 right EF, 5 left EF). Inclusion criteria: Age>18 years; temporal DRE; mean seizure frequency (SF) 2/week in the last 3 months; patients or caregivers are able to reliably provide seizure diary. Exclusion criteria: psychogenic seizures; multifocality; major psychiatric or neurological disorders other than epilepsy; electrical medical devices. All patients signed a written informed consent approved by local ethical committee. Clinical data are summarized in supplementary Table e1. We designed a double-blind, randomized, sham-controlled, crossover, monocentric study. After a week of seizure diary (days 1e7), patients were randomized to either first-ctDCS or first-sham-ctDCS treatment. On day 8, patients underwent the assigned stimulation. On day 38, patients underwent the single-session opposite stimulation. 7 days after the second session, the study was concluded. Patients were asked to not modify their therapy during the entire study. ctDCS was delivered with a battery-driven stimulator (Schneider Electronic, Gleichen, Germany-Newronika) connected to a saline-soaked pair of surface sponge conductive electrodes (5 cm 7 cm). The cathode was placed over the EF, localized by means of EEG interictal and ictal activity, and the anode over the contralateral homologous region. The real stimulation consisted of 20-min 1mA ctDCS. The sham-ctDCS stimulation consisted of delivering current for only 10 s, both at the beginning and at the end of the 20-min session [5]. Immediately before and after stimulation, a one-hour resting state closed-eyes 19-electrodes video-EEG recording was acquired. EEG was then evaluated for the presence and duration of interictal epileptiform activity (EA). EA was then described as follows: EA

A novel c132‐134del mutation in Unverricht‐Lundborg disease and the review of literature of heterozygous compound patients

Unverricht‐Lundborg disease or progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disease caused by mutation of the cystatin B gene (CSTB), located on chromosome 21q22.3. The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG), whereas other types of mutations are rare. Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition. We report two siblings affected by heterozygous compound mutations carrying a novel mutation of the deletion of three nucleotides in exon 2 of the gene in position 132–134 of the coding sequence (c.132‐134del) in the allele not including the dodecamer repetition. This mutation results in the loss of two amino acid residues and insertion of an asparagine in position 44 (p.Lys44_Ser45delinsAsn). Our patients presented a very different clinical picture. The male patient had a severe myoclonus, drug‐resistant epilepsy and psychiatric comorbidity, while his affected sister had only very rare seizures and sporadic myoclonic jerks at awakening. The revision of literature about heterozygous compound EPM1 patients confirms this gender phenotypic expressivity, with female patients carrying less severe symptoms than male patients. These data lead to the hypothesis of complex gender‐specific factors interacting with CSTB expressivity in EPM1 patients.

Hyperventilation induces sympathetic overactivation in mesial temporal epilepsy

OBJECTIVE Hyperventilation (HV) during electroencephalography (EEG) is a standard clinical procedure to trigger seizures in patients affected by mesial temporal lobe epilepsy (MTLE). Despite the pathophysiology of this susceptibility to HV is not definitively understood, it may be hypothesized to be related to ictal and interictal sympathetic nervous system abnormalities, the presence of which is well known in MTLE patients. In order to test this hypothesis we investigated the HV effect on heart rate variability (HRV) in a group of MTLE patients, compared to a matched group of healthy controls. MATERIAL AND METHODS Forty patients affected by MTLE and 40 age- and sex-matched controls were enrolled in the study. In those subjects, a standard electroencephalographic recording has been acquired and the high and the low frequency components (HF, LF) of heart rate variability (HRV) and their ratio (LF/HF) have been analyzed at rest and during the HV. Indeed, LF/HF is a reliable index of sympathetic tone modulation. RESULTS HRV did not differ between MTLE and healthy subjects at rest, whereas HV induced a significant LF/HF increase only in MTLE. Within the MTLE group, males showed higher LF/HF increase during HV respect to females, while no differences related to the side of the epileptic focus were found. DISCUSSION MTLE patients showed an increased sympathetic response to HV compared to healthy subjects. HRV analysis points towards an autonomic overactivation as a pathophysiological pathway subtending seizure triggered by hyperventilation in MTLE. Autonomic susceptibility in MTLE may help to explain the increased prevalence of arrhythmic events in these patients, potentially predisposing to Sudden Unexpected Death in Epilepsy (SUDEP).

Osteomalacic myopathy: An uncommon side effect of antiepileptic drugs

366:2294–2304. 2. Rosen BA. Guillain-Barr e syndrome. Pediatr Rev 2012;33:164–170. 3. Antoine JC, Mosnier JF, Absi L, Convers P, Honnorat J, Michel D. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999;67:7–14. 4. Lagrange E, Veran O, Besson G. Pure motor relapsing Guillain-Barr e syndrome associated with anti-GM1 antibodies revealing urinary bladder cancer. Eur J Neurol 2007;14:e7. 5. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135–1140. 6. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucinerich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 2010;133:2734–2748. 7. Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72:241–255. 8. Hart IK, Waters C, Vincent A, Newland C, Beeson D, Pongs O, et al. Autoantibodies detected to expressed K1 channels are implicated in neuromyotonia. Ann Neurol 1997;41:238–246. 9. Lancaster E, Huijbers MG, Bar V, Boronat A, Wong A, MartinezHernandez E, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011;69:303–311. 10. T€ uz€ un E, K€ urt€ unc€ u M, Lang B, Ic€ oz S, Akman-Demir G, Eraksoy M, et al. Bickerstaff’s encephalitis and Miller Fisher syndrome associated with voltage-gated potassium channel and novel anti-neuronal antibodies. Eur J Neurol 2010;17:1304–1307.

Calcium metabolism serum markers in adult patients with epilepsy and the effect of vitamin D supplementation on seizure control

PURPOSE To evaluate serum markers of calcium metabolism in adult patients with epilepsy (PWE) treated with antiepileptic drugs (AEDs) and the effect of vitamin D supplementation on seizure frequency. METHODS Serum levels of calcium, phosphate, intact parathyroid hormone (iPTH) and 25-hydroxyvitamin D (25[OH]D) were compared in 160 PWE on chronic therapy with AEDs and 42 matched controls. Blood concentrations were analyzed taking into account the different features of epilepsy and treatment. Finally, the effect of vitamin D supplementation on seizure control was assessed in a subgroup of 48 drug resistant epileptic patients. RESULTS PWE showed lower serum levels of 25[OH]D compared to control subjects (p < .001). Only 25% PWE showed normal 25[OH]D levels, whereas 41,9% had a vitamin D failure and 33,1% a vitamin D deficiency (p < .001). 25[OH]D serum levels depended on treatment duration, number of medications and enzyme-inducing AEDs (p < .001, p < .001, p = .013, respectively). Polytherapy and enzyme-inducing AEDs showed more detrimental effects on the 25[OH]D and calcium serum levels. The administration of vitamin D failed to significantly improve seizure control. CONCLUSIONS PWE show deficiency of vitamin D. The serum levels of 25[OH]D depend on the features and duration of AEDs treatment. Vitamin D administration in drug resistant epilepsy patients does not result in a reduction of seizure frequency.

Frequency and clinical implications of hypercoagulability states in a cohort of patients with migraine with aura

Migraine is the most common neurological disorder, affecting 12% of the adult population. Migraine with aura (MA) accounts for 15% of all migraines and its typical symptoms include temporary visual or sensory of aphasic disturbances that usually strike before clinical migraine symptoms. Migraine auras can be confused with transient ischemic attack (TIA), where there are stroke symptoms passing in a short time. However, patients affected by MA present a higher cerebrovascular risk with respect to general population, in particular for cardioembolic or criptogenetic stroke. This was pointed out by a study [1] with 1.622 migraineurs compared to nonheadache participants: there was a significant association between migraine with visual aura and ischemic stroke (hazard ratio 1.7, 95% confidence interval 1.2–2.6, p = 0.008). This incidence of stroke in patients with MA may be only in part linked to the higher prevalence of patent foramen ovale (PFO) in these patients [2]. Few studies reported controversial findings about the association of MAwith hypercoagulability states (HS), but a study [3] on 154 patients with stroke, of whom 59 with a history of migraine, showed that HS were more frequent in the migraine than in the non-migraine group (38.6 vs. 16.4%, p < 0.01). In the current study, we aim at evaluating the frequency of hypercoagulability state in patients with MA in our Headache Center; moreover, we look at evidencing if there are differences in PFO frequency in patients with MAwith or without HS and, finally, if there are differences in the characteristics of aura between MA patients with or without HS. We retrospectively screened our Center patient files and included MA patients who underwent medical examination at our Headache Center between January 2012 and July 2017 with a complete thrombophilic screening (MTHR C677T and A1298C mutations, factor V mutation, factor II mutation, lupus anticoagulant (LAC) panel, protein C and S dosage). A headache questionnaire was administered to all participants. International Classification of Headache Disorders (ICHD III beta) diagnostic criteria were used to characterize migraine with visual, visual, paresthesic, or aphasic aura. Individuals with non-migraine headaches according to ICHD-3 were excluded from analysis. In a subgroup of these patients, we performed transcranial Doppler (TCD) for PFO screening; we then compared the rate of PFO in patients with and without hypercoagulability states. Further, we examined if a hypercoagulability state could influence frequency, type, and duration of aura. We found 45 MA patients with complete thrombophilic screening: there was only a male subject. The mean age of the study participants was 36 years (range 16–75 years). Of these, 26 patients (57.8%) presented at least one hypercoagulability state; six patients presented 2 contemporary procoagulant factors. The distribution of procoagulant factors was 14 patients with homozygosis for MTHFR C667T (31.1%), 3 patients with heterozygosis for MTHFR A1298C (6.7%), 2 patients with heterozygosis for factor V mutation (4.4%), 1 patient with heterozygosis for factor II mutation (2.2%), 5 patients with LAC positivity (11.1%), and 6 patients with protein C or S deficiency (13.3%). The incidence of MTHFR C677Hom and LAC positivity in our patients looked like the incidence of the same mutation in patient with stroke [3] (MTHFR C677T Hom 21% and LAC positivity 9.7–12.5%). The deficiency of protein C or S in our patients was present in 13.3%, compared with 1% of similar adult population with inherited deficiencies. Out of the 26 patients with procoagulant factors, 19 underwent TCD, and 11 present a PFO (57.9%); of the remaining 19 patients without procoagulant factors, 13 underwent TCD, and 7 present a PFO (53.8%). Both groups * Gianluca Cecchi g.cecchi@unicampus.it

Daith Piercing in a Case of Chronic Migraine: A Possible Vagal Modulation

Daith piercing is an ear piercing located at the crus of the helix, bilaterally. It is getting great consent on social media as alternative treatment in chronic migraine. No data about its efficacy and action are available in scientific literature so far. We present the case of a 54-year-old male patient suffering from refractory chronic migraine with medication-overuse, who substantially improved after bilateral ear daith piercing. His migraine was refractory to symptomatic as well as prophylactic therapies. He used to treat headaches with up to five symptomatic drugs per attack and had attempted several pharmacological preventive therapies, including Onabotulinumtoxin A. He also underwent detoxification treatments with intravenous steroids and diazepam, without durable benefit. At the time of daith piercing, the headache-related disability measures showed a HIT-6 score of 64, a MIDAS-score of 70, and a 11-point Box scale of 5. On his own free will, he decided to get a “daith piercing.” After that, he experienced a reduction of migraine attacks, which became very rare, and infrequent, less disabling episodes of tension-type headache (HIT-6 score of 56; MIDAS score of 27, 11-point Box scale of 3). Painkiller assumption has much decreased: he takes only one tablet of indomethacin 50 mg to treat tensive headaches, about four times per month. Beyond a placebo effect, we can speculate a vagal modulation as the action mechanism of daith piercing: a nociceptive sensory stimulus applied to trigeminal and vagal areas of the ear can activate ear vagal afferents, which can modulate pain pathways by means of projections to the caudal trigeminal nucleus, to the locus coeruleus and to the nucleus raphe magnus. Currently, daith piercing cannot be recommended as migraine treatment because of the lack of scientific evidence, the unquantified rate of failure and the associated risks with insertion. However, given the increasing but anecdotal evidence, we think that the mechanism needs testing by means of a controlled clinical trial in a population of chronic migraineurs.

Canonical cortical circuits: current evidence and theoretical implications

Neurophysiological and neuroanatomical studies have found that the same basic structural and functional organization of neuronal circuits exists throughout the cortex. This kind of cortical organization, termed canonical circuit, has been functionally demonstrated primarily by studies involving visual striate cortex, and then, the concept has been extended to different cortical areas. In brief, the canonical circuit is composed of superficial pyramidal neurons of layers II/III receiving different inputs and deep pyramidal neurons of layer V that are responsible for cortex output. Superficial and deep pyramidal neurons are reciprocally con - nected, and inhibitory interneurons participate in modulating the activity of the circuit. The main intuition of this model is that the entire cortical network could be modeled as the repetition of relatively simple modules composed of relatively few types of excitatory and inhibitory, highly interconnected neurons. We will review the origin and the application of the canonical cortical circuit model in the six sections of this paper. The first section (The origins of the concept of canonical circuit: the cat visual cortex) reviews the experiments performed in the cat visual cortex, from the origin of the concept of canonical circuit to the most recent developments in the modelization of cortex. The second (The canonical circuit in neocortex) and third (Toward a canonical circuit in agranular cortex) sections try to extend the concept of canonical circuit to other cortical areas, providing some significant examples of circuit functioning in different cytoarchitectonic contexts. The fourth section (Extending the concept of canonical circuit to economic decisions circuits) reviews the experiments conducted in humans by using transcra- nial magnetic stimulation to demonstrate the validity of the canonical cortical circuit model. The fifth section (Extending the concept of canonical circuit to economic decisions circuits) explores the hypothesis that also complex human behaviors such as economic decision-making could also be explained in terms of canonical cortical circuit. The final section (Conclusion) provides a critical point of view, evidencing the limits of the available data and tracking direc-