S44 Non-invasive presurgical evaluation of insular cortex epilepsy

Abstracts / Clinical Neurophysiology 128 (2017) e178–e303

Some mild demyelinating signs like prolonged distal latencies of motor responses, mild reduced conduction velocities and prolonged latencies of late responses may be seen due to loss of fast conducting fibers in early stages. Atypical electrophysiological findings were also reported including fasciculations, findings of bulbar involvement, chronic inflammatory demyelinating polyneuropathy and pure motor neuropathy, in patients with relevant atypical presentations. EMG is also used in follow-up of treatment. Recently, sum scores with clinical and electrophysiological findings were recommended. Discussion: EMG studies provide useful information for the diagnosis and follow-up of FAP. It is important to be aware of atypical presentations. Keywords: Familial amyloid polyneuropathy, Electromyography doi:10.1016/j.clinph.2017.07.052

S42 Familial amyloid polyneuropathy (FAP): All aspects of the disease from diagnosis to treatment: Disease management— Hacer Durmus-Tekce (Ístanbul University Ístanbul Medical Faculty, Department of Neurology, Istanbul, Turkey) Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant disorder caused by mutations of the transthyretin (TTR) gene. More than 100 different mutations of the transthyretin gene were identified worldwide, but still the first described Val30Met is the most common one. The mutant amyloidogenic transthyretin protein causes systemic accumulation of amyloid fibrils that results in organ dysfunction and death. TTR-associated FAP is a progressive and fatal disease if left untreated and should be considered in the differential diagnosis of any patient with a progressive polyneuropathy, especially with an accompanying autonomic involvement. Several medications are under investigation for TTR-FAP (TTRstabilizing agents, Tafamidis and Difluniasal; antisense oligonucleotides, that suppresses TTR mRNA expression; RNA interference therapeutics designed to suppress the expression of TTR protein); but liver transplantation, which removes the primary source of abnormal TTR, remains the gold standard for therapy. Symptomatic management is primarily focused on reducing the impact of neuropathic pain and improving gastrointestinal and other autonomic symptoms. A comprehensive and multidisciplinary approach is required to manage TTR-FAP. Keywords: Transthyretin-related familial amyloid polyneuropathy, TTR-FAP, Management doi:10.1016/j.clinph.2017.07.053

Symposium III. – Clinical investigation of insular cortex epilepsy S43 Insular semiology: From observation of cases to cortical stimulation—Jean Isnard (Hospices Civiles de Lyon, Functional Neurology and Epileptology, Lyon, France) Objectives: Stereotactic stimulations of the insular cortex through intracranial electrodes aim at characterizing the semiology of insular seizures. These stimulations, carried out in the context of StereoElectro-Encephalography (SEEG) during pre-surgical monitoring of epilepsy, reproduce the ictal symptoms observed during the development of insular seizures.

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Methods: We reviewed the results of insular stimulations performed in 222 patients admitted between 1997 and 2015 for presurgical SEEG exploration of atypical temporal or perisylvian epilepsy. Stimulations (50 Hz, trains of 5s, pulses of 0.5 ms, intensity 0.2–3.5 mA) were carried out using trans-opercular electrodes implanted orthogonal to mid-sagittal plane. Results: 550 of 669 stimulations were clinically eloquent in the absence of any post-discharge (237 and 313 respectively in right and left insula). Somatosensory responses (61% of evoked sensations) including pain and visceral sensations (14.9%) were the most frequent, followed by auditory sensations (8%), vestibular illusions (7.5%), speech impairment (5%), gustatory, (2.7%) and olfactory (1%) sensations. Although these responses showed some functional segregation (in particular a privileged pain representation in the postero-superior quadrant), there was a clear spatial overlap between representations of the different modalities. Discussion: Symptoms evoked by insular stimulations are multiple. None of them can be considered as absolutely specific to the insular cortex, but the occurrence in given seizure of a somatosensory symptom such as pain or of a laryngeal spasm associated to vestibular, auditory, aphasic, or olfacto-gustatory symptoms points to a discharge development in the insular cortex. Conclusion: Inular cortex is the only cortical region where stimulations demonstrate such a multi-modal representation. Keywords: Insular epilepsy, Functional anatomy, Cortical stimulations doi:10.1016/j.clinph.2017.07.054

S44 Non-invasive presurgical evaluation of insular cortex epilepsy—Dang Khoa Nguyen (Centre Hospitalier de l’Université de Montréal (CHUM), Division of Neurology, Montréal, Canada) Introduction: Considering the variability in seizure semiology, recognition of operculo-insular epilepsy (OIE) may be challenging and confirmation by non-invasive tests is warranted although few studies have assessed their value. Methods: Surface EEG (n = 9), MRI (n = 48), 1H-MRS (n = 12), ictal SPECT (n = 18), interictal PET (n = 17) and MEG (n = 14) findings of OIE cases proven by the presence of an insular epileptogenic lesion or good surgical outcome were reviewed. Results: (1) Scalp EEG: spikes were found over fronto, temporal and central leads, generally allowing adequate lateralization; ictal discharges were also generally lateralizing but more extent in distribution; auras lacked EEG changes. (2) MRI identified a neoplastic lesion in 27%, a malformation of cortical development in 21%, a vascular malformation in 19% and atrophy/gliosis from an acquired insult in 17%. (3) No significant differences in insular [NAA] or NAA/Cr ratios were found between the OIE group, the non-OIE group and healthy controls. (4) Ictal SPECT showed maximum hyperperfusion in the operculo-insular region in 65%; PET findings were localizing in 29%, lateralizing in another 18%, falsely localizing in 24% and with no hypometabolism in 29%. (5) Tight anterior and posterior operculo-insular clusters of dipoles were observed in 50% and 14%, respectively, while 29% had diffuse perisylvian dipoles. Focal resection in 6/7 patients with anterior or posterior operculo-insular clusters of dipoles resulted in seizure freedom, whereas both surgically treated patients with scattered perisylvian spike sources had an Engel II seizure outcome. Discussion: Detection of an insular lesion on MRI greatly facilitates the diagnosis. Scalp EEG findings in fronto-central and/or temporal derivations generally allow lateralization of the seizure focus. Ictal SPECT has moderate sensitivity while PET findings were less

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Abstracts / Clinical Neurophysiology 128 (2017) e178–e303

localizing. Among newer techniques, MEG was found to be highly beneficial while MRS currently has limited value. Conclusion: When OIE is clinically suspected, non-invasive tests (MRI, SPECT and especially MEG) may provide additional supporting information. Keywords: Insular epilepsy, PET, SPECT, MRI, MEG, MRS doi:10.1016/j.clinph.2017.07.055

S45 Invasive EEG investigation of insular cortex epilepsy—Pierre Bourdillon 1, Marc Guénot 1, Jean Isnard 2,3,4 (1 Hospices Civils de Lyon, Hospital for Neurology and Neurosurgery Pierre Wertheimer, Department of Neurosurgery, Lyon, France, 2 Brain and Spine Institute, INSERM U1127, CNRS 7225, Paris, France, 3 Université de Lyon, Université Claude Bernard, Lyon, France, 4 Sorbonne Universités, Université Pierre et Marie Curie, Paris, France) Introduction: The possible involvement of the insular cortex in the constitution of the epileptogenic zone can sometimes be suspected thanks to pre-surgical phase 1 non-invasive investigations. Electrophysiological abnormalities largely consist of indirect signs, and the suspected diagnosis relies on the clinical description of seizures and on metabolic imaging. This is due to the deepness of the insular cortex and this explains why invasive phase II investigations are necessary in most cases. Invasive pre-surgical investigations are based on, either Subdural Grid Electrodes (SGE), or StereoElectroEncephaloGraphy (SEEG). Methods: We systematically reviewed the literature about phase II insular investigation. Results: In addition to a significantly lower complication rate, when compared to SGE, SEEG appears to be more suitable to explore a deep structure like insula. SGE offers a good electrophysiological sampling of the superficial cortex but cannot accurately investigate, neither the deep parts of the sulci, nor the cortex of the insula itself. Conversely, SEEG allows direct and precise investigation of the insula. Trans-opercular trajectories allow to reach almost any part of the insula, while recording the operculum at the same time. Last, SEEG makes it possible to perform SEEG-guided radiofrequency thermo-coagulations. Discussion: The anatomical proximity of the sylvian vessels requires to use a robust stereotactic methodology for SEEG: namely a frame-based procedure associated with X-ray vascular investigation. Moreover, SEEG may offer a therapeutic option when resective surgery, for any reason, is not feasible. Conclusion: SEEG with trans-sylvian trajectory is the most appropriate technique for intracranial insular investigation. doi:10.1016/j.clinph.2017.07.056

Symposium IV. – Recent insights into axonal excitability and ion channel redistribution in neurological diseases S46 Recent insights into the biophysical differences between human sensory and motor axons—David Burke (Royal Prince Alfred Hospital and University of Sydney, Department of Neurology, Sydney, Australia) Axons serve only one role, to transmit an impulse from one to the other with minimal expenditure of energy. In doing so sensory and motor axons discharge at different rates and in different patterns, and the most energy-efficient solution will impose different properties on different axons. It is a theme of many of our studies that motor axons are more likely to block than sensory for the same

insult and that, in critically impaired axons, normally innocuous manoeuvres can precipitate conduction block. There are three relevant differences between sensory and motor axons. (i) The resting membrane potential of sensory axons seems to be about 4 mV more depolarised than that for motor axons. (ii) There is a greater persistent Na+ current on sensory axons than motor. This can be adequately explained by the difference in resting membrane potential, such that there is no need to postulate a greater expression of Na+ channels behaving in a persistent manner. (iii) There is greater activity of HCN channels (hyperpolarization-activated cyclic nucleotidegated channels) on sensory axons than motor, such that activity causes greater hyperpolarization for motor axons than sensory for the same discharge rate. These three differences render sensory axons more excitable than motor, with a lower threshold for activation, as all electromyographers can confirm. Being more excitable, ectopic activity is more easily triggered in them, but the differences also offer some protection against conduction block. Keywords: Axonal excitability, Threshold tracking, Sensory axons, Motor axons, Biophysical differences doi:10.1016/j.clinph.2017.07.057

S47 Changes in voltage gated channels in regenerated axons distal and proximal to a nerve lesion—Christian Krarup 1, Susana Alvarez 2, Dragos Muraru 3, Mihai Moldovan 4 (1 Rigshospitalet, Clinical Neurophysiology, Copenhagen, Denmark, 2 University of Copenhagen, Center for Neuroscience, Copenhagen, Denmark, 3 ‘‘Carol Davila” University of Medicine and Pharmacy, Plastic Surgery, Bucharest, Romania, 4 Rigshospitalet, Department of Clinical Neurophysiology, Copenhagen, Denmark) Objectives: We compare function of regenerated motor axons and changes in the parent axons of young and aged mice after a sciatic nerve lesion with focus on voltage gated sodium channels (VGSC). Methods: Excitability was measured in motor fibers up to 4 months after crushing or sectioning and suture of the sciatic nerve in 10-week and more than 20-month old healthy C57Bl mice. Recovery of multiple measures of motor axon excitability by ‘‘thresh old-tracking” was studied at the tibial nerve distally and at the sciatic notch proximally to the nerve lesion. Results: Regeneration at 4 months after section and suture was impaired in aged mice. Recovery of CMAP was nearly complete after crushing whereas excitability remained abnormal in both age groups. In contrast, only aged nerves acquired depolarizing features at the tibial and sciatic stimulation sites which were attenuated by the selective NaV1.8 blocker (Compound 31, AbbVie Inc.). Discussion: Regenerated human and mouse myelinated motor axons show similar persistent abnormalities in membrane excitability resulting from alterations in both cable and voltage-dependent properties. In regenerated nerve the increased Na+ influx was attributed to an increase in number of nodes in regenerated axons. Recently we found that motor nerve fibers in healthy aged mice show depolarizing features due to an ectopic expression of the ‘‘sensory neuron specific” NaV1.8 VGSC. Conclusions and significance: Our data suggest that regeneration aggravates the ectopic NaV1.8 VGSC expression on aged motor axons, which could impair the functional recovery of nerve fibers after a nerve lesion with advancing age. Keywords: Axonal excitability, Nerve regeneration, Sodiumchannels doi:10.1016/j.clinph.2017.07.058