JON_Suppl_Abstract_02_06 05.05.2006 10:42 Uhr Seite 1
`
`J Neurol (2006) 253 [Suppl 2]: II/1–II/170
`DOI 10.1007/s00415-006-2001-2
`
`Sixteenth Meeting of the
`European Neurological Society
`27–31 May 2006, Lausanne, Switzerland
`Symposia and Free Communications
`
`The abstracts have been reviewed by:
`Z. Argov, O. A. Bajenaru, J. Bogousslavsky, O. Combarros, G. Comi,V. Dietz,
`M. Donaghy, C. Elger, J. M. Ferro, C. Krarup, I. Milonas, G. Moonen,
`Y. Parman,V. Planté-Bordeneuve, G. Said, E. Scarpini, R. Soffietti,
`E. Schmutzhard, A. Steck, E. Tolosa, J.Valls-Solé, M. J. D.Vidailhet
`
`Sawai (IPR2019-00789), Ex. 1007, p. 001
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`

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`JON_Suppl_Abstract_02_06 05.05.2006 10:42 Uhr Seite 2
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`II/2
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`Contents
`
`Presidential symposium
`Brain ischaemia, new patterns and treatments
`
`II/3
`
`Symposia
`Neurology of sleep II/3
`II/4
`Imaging brain diseases
`New trends in treatment of neurological disorders
`
`II/5
`
`FREE COMMUNICATIONS
`Oral Sessions
`
`II/16
`II/18
`
`II/21
`
`Session 1: Multiple sclerosis 1 II/6
`Session 2: Multiple sclerosis 2 II/8
`Session 3: Peripheral neuropathies 1 – Hereditary neuropathies
`Session 4: Peripheral neuropathies 2
`II/11
`Session 5: Extrapyramidal disorders
`II/13
`Session 6: Headache and pain II/14
`Session 7: Cerebrovascular disorders 1
`Session 8: Cerebrovascular disorders 2
`Session 9: Epilepsy
`II/19
`Session 10: Higher function disorders and dementia
`Session 11: Infection of the nervous system II/22
`Session 12: Neuro-oncology
`II/23
`Session 13: Multiple sclerosis 3
`II/25
`Session 14: Multiple sclerosis 4
`II/27
`Session 15: Neuro-ophthalmology
`II/28
`Session 16: Motor neuron disease
`II/29
`Session 17: Clinical neuroscience
`II/31
`Session 18: Clinical neurophysiology
`II/32
`Session 19: Cerebrovascular disorders 3
`II/34
`Session 20: Cerebrovascular disorders 4
`II/35
`Session 21: Genetics
`II/37
`Session 22: Muscle disorders
`Session 23: Dementia
`II/39
`
`II/38
`
`POSTER SESSIONS
`
`Poster Session 1
`Cerebrovascular disorders
`Clinical neurophysiology
`
`II/41
`II/45
`
`II/46
`
`Extrapyramidal disorders
`General neurology
`II/48
`Genetics
`II/50
`Infection II/53
`Multiple sclerosis
`Neuro-oncology
`
`II/55
`II/59
`
`Poster session 2
`II/64
`Cerebrovascular disorders
`II/68
`Clinical neurophysiology
`Dementia/Higher function disorders
`Epilepsy
`II/74
`Extrapyramidal disorders
`General neurology
`II/78
`Multiple sclerosis
`II/80
`Peripheral neuropathy
`
`II/76
`
`II/84
`
`II/9
`
`Poster session 3
`II/88
`Cerebrovascular disorders
`Dementia/Higher function disorders
`Extrapyramidal disorders
`II/93
`Infection II/95
`II/97
`Motor neuron disease
`Multiple sclerosis
`II/99
`Muscle disorders
`II/103
`Peripheral neuropathy
`II/107
`
`II/111
`
`Poster session 4
`Cerebrovascular disorders
`General neurology
`II/114
`Immunology
`II/117
`II/120
`Motor neuron disease
`Multiple sclerosis
`II/123
`Neurobiology
`II/127
`Pain and headache
`II/129
`Sleep disorders
`II/132
`
`II/70
`
`II/89
`
`II/135
`
`II/140
`
`Poster session 5
`Cerebrovascular disorders
`Child neurology
`II/139
`Extrapyramidal disorders
`Multiple sclerosis
`II/142
`Neuro-ophthalmology
`II/147
`Neurorehabilitation II/149
`Pain and headache
`II/154
`Sleep disorders
`II/156
`
`Author index II/160
`
`Sawai (IPR2019-00789), Ex. 1007, p. 002
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`JON_Suppl_Abstract_02_06 05.05.2006 10:42 Uhr Seite 3
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`II/3
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`4P
`
`enumbra is brain: targeted neuro-imaging in hyperacute stroke
`J. Bogousslavsky, P. Michel, M. Reichhart, M. Wintermark, P. Maeder, R.Meuli
`Centre Hospitalier Universitaire Vaudois (Lausanne, CH); University of
`California (San Francisco, USA)
`
`Given the millions of neurons dying every hour in acute ischemic stroke, we
`need more advanced methods to treat the appropriate patient with the ap-
`propriate method. Shortening symptom-to-treatment delays is mandatory
`for all stroke patients, but clinicians and scientists have recognized for quite
`a while that stroke is highly variable from one individual to the other. This
`applies particularly to the amount of irreversibly damaged and salvageable
`tissue (“core”and “penumbra”) and to the localisation of arterial occlusions.
`Measuring tissue perfusion with various methods (PET, SPECT, Xenon-
`Ct, PWI-DWI MRI, perfusion-CT etc.), we are recognizing that time is not
`the gold standard but a surrogate marker when it comes to predicting the
`presence of penumbra. Mounting evidence, most recently from the DEFUSE
`trial, confirms that patients without penumbra do not benefit from recanal-
`isation, and may even be harmed. On the other hand, the DIAS trial has
`shown that patients may benefit from thrombolysis well beyond the 3 hour
`limit if they have a persistent penumbra.These data strongly support the no-
`tion that “penumbra is brain” rather than “time is brain”, and that the time
`clock should be replaced by a pathophysiological clock in most patients
`when it comes to acute treatment decisions.
`The second, similarly important requirement for successful stroke treat-
`ment is rapid, complete, and persistent recanalisation. Early recanalisation,
`whether spontaneous or treatment-related, has been associated in most
`studies with better radiological and clinical outcomes. We therefore should
`use all efforts available to recanalize arteries in acute stroke.
`Thirdly, advanced neuroimaging may predict of the neurovascular com-
`plications. Examples are haemorrhagic transformation in patients with se-
`vere and large volume ischemia who recanalize rapidly, or mass effect from
`brain ischaemia. When data about perfusion and arterial imaging are com-
`bined, the best stroke outcomes occur as expected in patients with a small
`core, a large penumbra and early recanalisation. Although not proven yet, it
`is likely that neuroprotective treatments will be particularly effective in ex-
`actly the same population, because the therapeutic agents are more likely to
`reach their intended target.
`Which acute neuroimaging technique should we use to identify the treat-
`able patient? Plain CT main be a suitable screening tool for non-invasive re-
`canalisation and neuroprotection in the very early phase (< 90 min. or so),
`where it can be assumed that most patients have a significant penumbra.
`Thereafter, perfusion-imaging and arterial imaging becomes essential, ei-
`ther to decide about the indication and contraindications of different re-
`canalisation and neuroprotective strategies, or to decide about further treat-
`ment in patients who have undergone ultra-early (< 90 min) treatment
`based on a plain CT. Both perfusion-MRI our perfusion-CT reliably detect
`and distinguish reversible from irreversible ischemia. For imaging of arter-
`ial pathology, CT- and MR-angiography are similary accurate, and transcra-
`nial Doppler/Duplex may be a valuable alternative. Only few centers now
`take the risk of performing conventional angiography without first doing a
`non-invasive study in candidates for intraarterial therapy.
`Ideally, all these advanced imaging methods should be available
`24/24hours. The technique that fits the patient (contraindications, availabil-
`ity) and his doctor (experience, availability) most may be then be chosen as
`the “best” imaging in a given situation.
`
`Symposium
`
`Neurology of sleep
`
`15
`Sleep and synaptic plasticity
`G. Tononi
`Department of Psychiatry, University of Wisconsin (Madison, USA)
`
`Background: This paper will discuss a novel hypothesis – the synaptic home-
`ostasis hypothesis – which claims that sleep plays a role in the regulation of
`synaptic weight in the brain [1]. In brief, the hypothesis is as follows: 1.
`Wakefulness is associated with synaptic potentiation in several cortical cir-
`cuits; 2. Synaptic potentiation is tied to the homeostatic regulation of slow
`wave activity; 3. Slow wave activity is associated with synaptic downscaling;
`
`Presidential symposium
`
`Brain ischaemia, new patterns and treatments
`
`1W
`
`hite matter ischaemic syndromes
`M. Hennerici
`Mannheim, D
`
`Subcortical nuclear and white matter ischaemic lesions have long been
`known to present with less impressive signs and symptoms and cortical is-
`chaemia: these reange from a) often clinically asymptomatic, incidental
`findings once CT-/MRI studies are performed through b) occasionally
`oligosymptomatic, uncharacteristic patterns (in particular if overlap exists
`in diaschisis) to c) few very typical lesions if nuclear structures are heavily
`involved (brainstem, thalamus, lentiform nuclei etc). Isolated white matter
`lesions,manifest mostly once disseminated chronic ischaemia occurs as sub-
`cortical vascular encephalopathy (SVE), if remote focal strokes coinciden-
`tally happen in synergistics syndromes or due to large sensory-motor tract
`disruption in severe lacunar strokes. Etiologies are widespread and overlap
`with many other white matter diseases ranging from multiple sclerosis in the
`younger to cerebral amyloid angiopathy in the elderly often with unknowen
`mechanisms as far as neurodegeneration is concerned (Alzheimer’s disease,
`CJD,“paraneoplastic syndromes” etc). This review concentrates on probably
`the only “vascular” type dementia studied intensively during recent years
`and attempts to demonstrate potentials of insight to be achived not only for
`a better understanding of such diseases in increasingly older populations
`but also what can be tranferred to other diseases still difficult to understand
`today.
`
`3P
`
`resent and future of acute stroke therapy
`M. Fisher
`University of Massachusetts Medical School (Worcester, USA)
`
`The current status of acute stroke therapy remains limited to one approved
`drug,intravenous (i. v.) tPA initiated within 3 hours of stroke onset.This lim-
`ited therapeutic armamentarium is reflected by the small number of acute
`ischemic stroke (AIS) patients that are currently treated. Other strategies for
`the use of thrombolytic therapy in AIS, such as intraarterial delivery of the
`thrombolytic agent, combined i. v. and i. a. therapy and the use of other
`thrombolytic agents are being explored. Thrombolytic therapy is directed at
`restoring or improving blood flow to the ischemic brain, but not at amelio-
`rating the consequences of ischemia within brain tissue related to reduced
`or absent blood flow, i. e. the ischemic cascade. Recent advances regarding
`thrombolytic therapy have occurred. Intravenous Desmoteplase was shown
`to improve cerebral perfusion and tended to improve clinical outcome in two
`small trials with a 3–9 hour treatment window. A larger trial with a 9-hour
`treatment window is underway. In the DEFUSE study of i. v. t-pa given be-
`tween 3–6 hours after stroke onset, patients with a diffusion/perfusion mis-
`match benefited from treatment while those without mismatch did not. This
`observation supports the results of several observational studies that
`demonstrated apparent clinical benefit with i. v. t-pa when given 3–6 hours
`after stroke onset in patients with an MRI-confirmed mismatch. In the
`United States, the MERCI clot retrieval device has been approved for re-
`moving thrombi from intracranial vessels but not as a stroke treatment.Con-
`cerns remain about the safety of this device and further clinical trials and
`registries should provide additional information about safety and efficacy
`Drugs directed at the ischemic cascade are termed neuroprotectants and
`many different types of neuroprotective drugs have been developed targeted
`at the manifold aspects of ischemic brain injury. Many neuroprotective
`drugs were evaluated in advanced clinical trials,but until recently all of these
`trials were not positive for a variety of reasons. No neuroprotective drug is
`currently available for clinical use. In the recently reported SAINT-1 trial of
`the spin-trap agent, NXY-059 a positive effect on the primary outcome mea-
`sure was observed. The primary outcome measure was a shift of the modi-
`fied Rankin scale of at least one point across the whole range of the scale and
`not a dichotomized outcome as was used in all previous AIS trials. This out-
`come measure is targeted to look for a modest but likely clinically meaning-
`ful treatment effect as opposed to a “cure” when the goal was to assess the
`percentage of patients with little or no deficit, i. e. Rankin 0–1. In future AIS
`trials it is likely that the Rankin shift approach will be used as the primary
`outcome measure. In the SAINT-1 trial no effect was observed on the change
`from baseline to day 90 on the NIHSS scale but efficacy trends were observed
`on other relevant outcome measures.The ongoing SAINT-2 trial will provide
`vital information about the efficacy or lack thereof on NXY-059.
`
`Sawai (IPR2019-00789), Ex. 1007, p. 003
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`II/4
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`4. Synaptic downscaling is tied to the beneficial effects of sleep on neural
`function and, indirectly, on performance.
`Methods: Evidence for the hypothesis has been obtained using many ex-
`perimental paradigms, from molecular studies of sleep and wakefulness to
`neuroimaging studies in humans.
`Results: The synaptic homeostasis hypothesis can account for several as-
`pects of sleep and its regulation, and several of its specific predictions were
`confirmed experimentally.
`Conclusions: According to the hypothesis, plastic processes occurring
`during wakefulness result in a net increase in synaptic strength in many
`brain circuits. The role of sleep is to downscale synaptic strength to a base-
`line level that is energetically sustainable, makes efficient use of gray matter
`space, and is beneficial for learning and memory. Thus, sleep is the price we
`pay for plasticity, and its goal is the homeostatic regulation of the total
`synaptic weight impinging on neurons. The hypothesis accounts for a large
`number of experimental facts, makes several specific predictions, and has
`implications for sleep, neurological, and psychiatric disorders.
`Supported by NIH Director Pioneer Award
`
`16
`Sleep apnoea and cardiovascular diseases
`P. Lavie
`Technion-Israel Institute of Technology, Lloyd Rigler Sleep Apnea Research
`Laboratory (Haifa, IL)
`
`Obstructive sleep apnea characterized by intermittent and recurrent pauses
`in respiration during sleep resulting in a decreased oxygen saturation and
`sleep fragmentation is closely associated with cardiovascular morbidity and
`mortality. Sleep apnea has been shown to be causally related with hyperten-
`sion and to be associated with strokes, ischemic heart diseases and cardiac
`arrhythmias. Evidence accumulated in recent years shed a new light on the
`natural evolution of cardiovascular morbidity in obstructive sleep apnea.
`Several studies demonstrated the existence of endothelial dysfunction and
`early clinical signs of atherosclerosis in patients with sleep apnea who were
`free of any overt cardiovascular diseases. This suggests that the cardiovas-
`cular morbidity in sleep apnea is developing over several years through ac-
`cumulated damage to the vasculature.Research performed in our laboratory
`has focused on the pathophysiology of atherogenic processes in sleep apnea
`syndrome. We showed that hypoxia/reoxygenation, that is the most impor-
`tant characteristic of sleep apnea, promotes the formation of reactive oxy-
`gen species that activate critical redox-sensitive signaling pathways and
`transcription factors. This facilitates the expression of sets of genes that en-
`code proteins essential to adaptation to hypoxia, as well those that elicit in-
`flammatory pathways such as adhesion molecules and inflammatory cy-
`tokines. Consequently, inflammatory and immune responses are activated
`thus resulting in the activation of endothelial cells/leukocytes/platelets.
`These activated cells express adhesion molecules and pro-inflammatory cy-
`tokines that in turn may further exacerbate inflammatory responses and
`cause endothelial cell injury and dysfunction. This newly acquired insight
`into the pathophysiology of cardiovascular morbidity in OSA have impor-
`tant implications regarding the diagnosis and treatment of the syndrome.
`
`18
`Narcolepsy
`C. L. Bassetti
`University Hospital Zurich (Zurich, CH)
`
`Narcolepsy is a life-long, usually sporadic (rarely familial) sporadic which
`usually starts in the 2. or 3. decade of life. The prevalence of narcolepsy is
`similar to that of multiple sclerosis (about 1:2000 in the adult population).
`Excessive daytime sleepiness (EDS) is usually the first and most dis-
`abling symptom. Cataplexy – a sudden and short loss of muscle tone trig-
`gered by emotions with preserved consciousness – is the only pathogno-
`monic symptom of narcolepsy and shares features with physiological REM
`sleep atonia. Associated, non specific symptoms of narcolepsy include sleep
`paralysis, hallucinations, parasomnias, weight gain, and psychosocial dis-
`ability. Biological markers of narcolepsy are diagnostic helpful and include
`1) a specific HLA class II-subtype (DQ1*0602, 90–95 % of patients), 2) the
`appearance of REM-sleep within 15–20 minutes after sleep-onset (sleep on-
`set REM, 70–80 %), and 3) the absence/reduction of the recently discovered
`hypothalamic peptide hypocretin-1 (orexin A, 90 %) in the cerebrospinal
`fluid.
`Narcolepsy usually arises from a combination of genetic and -yet to be
`identified- environmental factors. In fact, only about one third of monozy-
`gotic twins are concordant for the disease. Less commonly, genetic factors
`(familial narcolepsy) or acquired brain disorders (symptomatic narcolepsy)
`prevail. Narcolepsy is associated with multiple neurotransmitter signalling
`
`deficiencies (hypocretin, dopamine, dynorphine, neuronal activity-regu-
`lated pentraxin, ...).Based also on studies in rodent and canine models of the
`disease,narcolepsy is thought to be due to an instability of sleep-wake mech-
`anisms with rapid transitions between wakefulness, NREM and REM sleep
`and appearance of dissociated states (in which elements of different states
`intermingle).
`Treatment of narcolepsy is successful in the majority of patients and in-
`clude information/counselling; scheduled naps; stimulants (e. g. modafinil,
`methylphenidate); and anticataplectic drugs (e. g. clomipramine, sodium
`oxybate).
`Future research will clarify the possibility of an autoimmune origine of
`narcolepsy, the exact correlation between signalling deficiencies and clinical
`manifestations, and the value of new treatment strategies (hypocretin ago-
`nists, immunomodulation).
`
`Imaging brain diseases
`
`19
`Movement disorders
`D. J. Brooks
`Imperial College (London, UK)
`
`This talk will review findings obtained in movement disorders with recent
`advances in neuroimaging technology. Application of advances in magnetic
`resonance imaging such as voxel based morphometry, transcranial sonog-
`raphy, diffusion weighted and magnetization transfer MRI, to parkinsonian
`syndromes and dystonia are highlighted. The role of postron emission to-
`mography to detect microglial activation in Parkinson’s and Huntington’s
`disease and measure changes in synaptic dopamine levels is also featured.
`Finally, some future directions in neuroimaging are presented.
`
`20
`Spinal cord disorders
`M. Forsting
`Department of Diagnostic and Interventional Radiology and Neuroradiol-
`ogy, University Hospital of Essen (Essen, D)
`
`Spinal cord disorders include a huge variety of totally different diseases
`starting from congenital malformations over non-neoplastic disorders and
`ending with tumours and tumour-like lesions of the spinal cord.
`Congenital anomalies of the spinal cord include open spinal dysraphism,
`occult spinal dysraphism and anomalies of abnormal canalisation and ret-
`rogressive differentiation of the cord.
`Non-neoplastic disorders start with infectious diseases like spondylitis,
`epidural and subdural infections and spinal cord abscesses. As in the brain
`demyelating diseases can occur within the spinal cord as well as vascular
`problems like spinal cord ischemia and different kinds of vascular malfor-
`mations.Specifically in young age patients spinal cord injuries are important
`and have to be diagnosed accurately.
`Intramedular tumours are usually not benigne and most of them are ei-
`ther astrocytomas or ependymomas.The talk will focus on vascular diseases
`of the spinal cord and tumour- and tumour-like lesions.
`The imaging modality of choice for all spinal cord lesions is nowadays
`clearly MR including MR-angiography. Specifically for vascular malforma-
`tions the classical DSA is often still mandatory and sometimes endovascu-
`lar therapy is the matter of choice in vascular malformations of the spinal
`cord.
`
`21
`Cerebrovascular disorders
`F. Fazekas
`Medical University Graz (Graz, A)
`
`Recent advances of modern imaging technology have greatly expanded our
`capabilities for the in-vivo assessment of cerebrovascular disorders. In this
`context treatment-oriented optimization of acute stroke imaging certainly
`has remained the foremost challenge. The importance of more slowly pro-
`gressing and diffuse vascular brain damage, however, is now also increas-
`ingly recognized.
`With constant improvement of CT scanners and increasing experience of
`interpreters, CT nowadays not only serves to rule out intracerebral or sub-
`arachnoid bleeding but can display changes indicative of ischaemic damage
`already within the first hours after stroke. Nevertheless, magnetic resonance
`imaging (MRI) clearly surpasses the sensitivity for acute ischaemic damage,
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`JON_Suppl_Abstract_02_06 05.05.2006 10:42 Uhr Seite 5
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`and it is especially diffusion weighted imaging (DWI) that has revolution-
`ized stroke imaging by allowing to depict morphologic brain changes as
`early as 1 hour after the acute event. Concerns that MRI may fail to depict in-
`tracerebral hemorrhage as accurately as CT have also been ruled out. DWI
`is especially helpful in depicting small acute ischaemic lesions and to sepa-
`rate them from old cerebral damage. This helps to improve clinicoradiologic
`correlations and can add important information regarding specific stroke
`mechanisms. Similar to the concepts of “ischaemic penumbra” a mismatch
`between the abnormality seen on DWI and that indicated by perfusion-
`weighted MRI can serve to identify threatened but still salvageable tissue
`and thus may help to extend the time window of successful acute thrombol-
`ysis and for guiding more complex treatment decisions.
`The sensitivity of MRI for subtle tissue changes has also served to in-
`creasingly recognize the importance of chronic vascular damage most often
`from microangiopathy which appears to threaten brain functioning in a
`more global manner.Abnormalities consist of diffuse white matter changes,
`silent lacunes and infarcts and there is evidence that vascular damage may
`even promote brain shrinkage. Specific MRI pulse sequences also allow the
`detection of remnants of minimal blood seepage through damaged intra-
`cerebral vessels which is likely to be an indicator of more pronounced mi-
`croangiopathy. All these abnormalities have been shown to progress over
`time and are associated with increasing cognitive impairment up to full-
`blown dementia as well as gait disorders and a higher probability for falls in
`the elderly. Finally, there is evidence for an association between small-vessel
`disease-related brain tissue changes and mood disorders especially depres-
`sion. Efforts to also prevent chronic vascular damage thus become more and
`more important as its frequency increases in parallel with the life ex-
`pectancy of western populations.
`
`22
`Brain imaging in dementia
`M. Filippi
`Ospedale San Raffaele, Neuroimaging Research Unit (Milan, I)
`
`The review of all possible dementing conditions and all imaging techniques
`used to investigate their structural and functional substrates is beyond the
`scope of the present abstract. As a consequence, this abstract is focussed on
`the use of magnetic resonance imaging (MRI) in the study of Alzheimer’s
`disease (AD), as a model for cortical dementia, and multiple sclerosis (MS),
`as a model for subcortical dementia.
`AD is the most common form of age-related dementia and affects ap-
`proximately 1–5 % of the population over 65 years. In AD, seminal conven-
`tional MRI (cMRI) studies have shown the presence of gray matter (GM)
`loss, mainly in the medial temporal structures. Hippocampal size reduction
`was also found in patients with mild cognitive impairment (MCI) and was
`predictive for subsequent transition to AD.The atrophy process later spreads
`to associative temporo-parietal and frontal cortical areas. However, the cor-
`relation between regional GM atrophy and global cognitive impairment is
`relatively weak, suggesting that other pathological processes are at work.
`Non-conventional MRI techniques have indeed shown that AD also causes
`marked microstructural damage to the residual GM and that the combined
`quantification of GM loss and intrinsic damage is strongly correlated to the
`severity of cognitive impairment. Normal-appearing (NA) WM regions
`linked to associative cortices are also damaged and the severity of such dam-
`age is strongly related to AD cognitive decline. In MCI, damage to the NA
`brain tissue is intermediate between those of normals and AD patients, sug-
`gesting that WM and GM microstructural abnormalities are early events in
`AD. Functional MRI (fMRI) studies with cognitive tasks suggested that
`significant functional cortical changes also occur in AD patients with the
`potential to limit the clinical outcome of the underlying tissue damage.
`Cognitive impairment affects approximately 40–70 % of patients with
`MS. In these patients, the extent of WM lesions visible on cMRI scans, and
`their location in the hemispheric WM were found to be associated moder-
`ately with the level of neuropsychological performances. Linear and volu-
`metric MRI-derived quantities reflecting brain parenchymal loss in general
`and neocortical tissue loss in particular were found to be correlated with
`neuropsychological test scores and with comprehensive cognitive impair-
`ment indexes, at a greater magnitude than the corresponding lesion vol-
`umes.More recently,the use of non-conventional MRI techniques has shown
`that subtle changes to the NAWM, overall intrinsic GM pathology and in-
`trinsic T2-visible lesion damage also contribute to MS-related cognitive im-
`pairment. In fMRI studies with cognitive tasks, MS patients contrasted to
`matched normal controls exhibit different distribution and extent of corti-
`cal activations and this is believed to have, at least partially, a compensatory
`role, which contributes in limiting the neuropsychological manifestations of
`the disease.
`All these observations suggest that the in-vivo assessment through imag-
`ing-based technology of factors contributing to the cognitive decline asso-
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`ciated to the different potentially dementing neurological conditions is a
`rather complicated business. Such an assessment would require a careful as-
`sessment of the extent of tissue loss and the status of the remaining tissue in
`the different brain compartments, as well as the role of compensatory mech-
`anisms.
`
`New trends in treatment of neurological disorders
`
`28
`Specific and aspecific immune interventions in multiple sclerosis
`G. Comi
`IRCCS San Raffaele (Milan, I)
`
`Immunomodulating and immunosuppressive treatments for multiple scle-
`rosis patients are directed against the inflammatory process and are only
`partially effective. This partial failure could be explained by mechanisms of
`axonal damage at least partially independent from acute or chronic inflam-
`mation. This suggests that there is a need for better use of available treat-
`ments and the necessity of alternative new therapeutic options to halt dis-
`ease progression and enhance recovery mechanisms. Concerning actual
`treatments, two strategies are quite interesting: early treatment and combi-
`nation therapy. The former approach is based on converging epidemiologi-
`cal, immunological and pathological studies and is proved by some recent
`clinical trials. The second one is under evaluation on ongoing clinical trials.
`Progress in understanding the mechanisms of T cell activation, inactivation
`and modulation has been translated into new therapeutic strategies aiming
`at inducing selective immunosuppression.Such an approach is now tested in
`phase II-III clinical trials.
`
`29
`Alzheimer’s amyloid immunotherapy
`J-M. Orgogozo
`Hôpital Pellegrin (Bordeaux, F)
`
`Accumulation of aggregated beta-amyloid protein in strategic areas of the
`cerebral cortex is associated to Alzheimer’s diseaise (AD) in the common
`sporadic form of the elderly as well as in the rare heredidary forms.
`Schenk et al. (1999) were able, in a milestone experiment, to prevent and
`even partly revert the amyloid burden and the associated neuropathological
`changes, in the brain of transgenic mice expressing the human amyloid pro-
`tein involved in MA, by active anti-amyloid immunization. This remarkable
`result was shortly after replicated by other groups, either by active immuni-
`sation with the human aggregated A-beta or a passive immunization with
`anti A-beta monoclonal antibodies.
`A phase 1 study in 20 healthy volunteers of single doses of the Elan ag-
`gregated amyloid antigen was first conducted in the USA, with excellent tol-
`erability except minor local reactions at the site of intra-muscular injection
`(Elan, data on file).
`Then a phase 2a randomized trial was carried on in 84 patients with AD,
`in UK, with repeated i. m. injections of the antigen or placebo. The main re-
`sult was the demonstration of a predetermined antibody response in about
`25 % of patients (Wilkinson et al. 2005). Side effects were mainly local in-
`flammatory reactions and a single occorence of neurological worsening,
`later identified at autopsy as due to a new type of inflammatory menin-
`goencephalitis (Nicoll et al. 2003).
`Lastly – so far – a phase 2b trial recruited 375 patients, to be given re-
`peated i. m. injections of either the Elan amyloid antigen (AN1792) or
`matched placebo. The injections were discontinued, after 2 injections in
`most cases, because of the occurence of several cases of subacute menin-
`goencephalitis (SAME) of presumed auto-immune origin: in total 18 (6 %)
`of patients developed a syndrome of SAME, severe in 6, followed by death in
`2 or a bedridden state in 1 (Orgogozo et al. 2003).
`Despite the truncated antigen administration the predetermined anti-
`body respose was achieved in 20 % of the exposed patients (none under
`placebo), without correlation with the occurrence of SAME. Neither the
`main clinical outcomes (ADAS-cog, MMSE, CDR ...) nor the total brain vol-
`ume at MRI showed aparent benefit, in total and in the antibody responders
`(Gilman et al. 2005; Fox et al. 2005). However a positive response was objec-
`tived with an ad hoc neuropsychological test battery, correlated with the an-
`tibody response and with changes in the A-beta/tau ratios in the CSF to-
`wards more normal values (Gilman et al. 2005).
`In the few patients from this trial who went to autopsy, with or without
`SAME, a consistent reduction of the expected amyloid deposits with some
`evidence of amyloid removal was observed (Ferrer et al. 2004).
`
`Sawai (IPR2019-00789), Ex. 1007, p. 005
`
`

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`
`All these data strongly indicate that amyloid clearance from the brain is
`achievable with immunotherapy and thar markers of clinical efficacy are
`correlated with antibody response. Whether these findings predict a future
`relevant clinical benefit in AD is currently addressed by at least four ongo-
`ing trials, two with actice ant two with active immunization.
`
`FREE COMMUNICATIONS
`Oral Sessions
`
`30
`Disease-modifying treatments for chronic inflammatory neuromuscular
`diseases
`R. A. C. Hughes
`Department of Clinical Neuroscience, King’s College London School of
`Medicine (London, UK)
`
`There are more patients with chronic inflammatory neuromuscular diseases
`participating in randomised controlled trials (RCTs) now than have cumu-
`latively been included in all the trials undertaken until now. The Cochrane
`reviews reveal limitations of the current evidence (www.kcl.ac.uk/cochra-
`nenmd/www.cochrane.org).
`The use of corticosteroids in chronic inflammatory demyelinating
`polyradiculoneuropathy (CIDP), myasthenia gravis and dermatomyositis is
`supported by observational studies but has not been the subject of adequate
`RCTs. There are RCTs of intravenous immunoglobulin (IVIg) in all three
`conditions confirming its value but the only licensed neurological indication
`remains Guillain-Barre syndrome. There are RCTs showing short term ben-
`efit from plasma exchange in CIDP and myasthenia gravis but not in der-
`matomyositis but it is so inconvenient that it is usually kept in reserve as a
`third line treatment.
`Immunosuppressive agents such as azathioprine, methotrexate, ci-
`closporin, mycophenolate and cyclophosphamide are often used in refrac-
`tory cases of all three conditions and RCTs are in progress to try to establish
`their value.Autologous periphe