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International audience; Recombinant interferon alpha is used to treat several immunological, oncological, and infectious diseases,1 and various serious side-effects have been associated with its therapeutic use. We want to bring attention to the development of neuromyelitis optica spectrum disorder (NMOSD) [...]

40-year-old man was admitted for right sided weakness of his arm and leg. He walked with a limp. Following discussion with the patient and his family, onset of symptoms seemed subacute and progressive. Symptoms started “weeks ago” but he was “getting worse”. The patient had smoked 30–40 cigarettes every day for more than two decades. He denied any head or neck injury. On objective examination there was hyperreflexia with positive plantars bilaterally. His right sided weakness (hemiparesis) was relatively severe (3/5) and it seemed to be upper motor neurone in origin. His right calf (m. gastrocnemius) appeared wasted and atrophic. There were no sensory or bladder symptoms. Cranial nerves (including facial nerves) and cerebellar functions were normal.

30-year-old very active, hardworking woman attended our clinic with sharp pain in the left arm and hand. Her left leg “probably felt a bit different too”. On further questioning she mentioned some discomfort in the abdomen on the left as well. Pain was present for 11 months; started as paresthesias (pins and needles) and was gradually progressive. She denied other symptoms including sphincters. She did not respond to neuropathic pain treatments. On objective testing we found monofilament sensation reduced and proprioception and vibration sense was impaired as well in left upper extremity. There was no convincing objective sensory deficit in lower extremities (only subjective as above). Sensory deficit/light touch hypoesthesia was seen in the abdomen and chest with no convincing sensory level. Reflexes were present and symmetrical and there was no paresis. From sensory point of view face was spared and cranial nerves and cerebellar functions were normal.

27-year-old man was admitted with a severe occipital headache, acute in onset. He also complained of very severe bilateral leg and arm pain. Reflexes were increased and plantars negative. Cranial nerves and cerebellar functions were normal. Sphincters were normal. Rest of neurological examination was influenced by serious pain in all four extremities (showed on diagram), therefore patient was very difficult to examine. He had a dry cough. CRP was marginally increased (25). Hi temperature was increased (37.4 °C). During admission his pain became more prominent in arms and forearms, suggestive of radiculopathic pain.

63-year-old man was referred to the Neurology outpatient clinic for left sided headaches. He also complained about hearing problems on the left described as “muffled hearing”. Symptoms started 3 months ago with a pain around his left ear which then spread to the jaw. There was some facial numbness around his eye on the left side. There was also a pain behind the left ear. Effusion behind tympanic membrane was found so his headaches were originally assumed to be linked to a middle ear infection and an initial diagnosis of chronic otitis media was made. He underwent myringotomy and insertion of grommet. Patient felt instant relief and significantly better for a week but then his headache and the pain around the left ear reappeared. No cultures grew from effusion sent to microbiology. Ten days before neurology review he developed left facial nerve palsy, and a week later he developed diplopia especially when looking to the left. On objective examination left abducens, facial nerve palsy (lower motor neurone) and trigeminal/V nerve symptoms were found – hypoasthesia (light touch) and allodynia (pin-prick), mainly V1 and V2 were involved (ophthalmic and maxillary). There was asymmetry of reflexes in legs, with increased reflexes on the right (ankle). There was no weakness of limbs and sphincter functions were normal. Cerebellar functions were normal. Pupils were symmetrical and reactive to light.

66-year-old gentleman was admitted to the hospital following a fall. He was a gentleman with a history of atrial fibrillation (AF) on warfarin, hypertension and diabetes. So far AF has responded well to “rate control” treatment (previously on beta blocker, currently on calcium channels blocker). He complained about intermittent dizzy spells and was seen by Cardiology. However the history surrounding the fall (and how he had actually arrived to hospital) was a bit vague. On the day of admission he was walking to his GP surgery to have his INR checked as it had been raised the previous day (4.2). He suddenly felt very dizzy and fell over. He did not lose consciousness. He eventually managed to get to surgery and had an ECG which showed AF with fast heart rate of about 150 bpm. It transpired that he had been unsteady on his feet “for months” and used a stick for walking now. There was also urinary urgency with intermittent urinary incontinence. His wife admitted that he was generally “slower”.

46-year-old lady had a long history of migraines for many years. Headaches were usually linked to menstrual cycle and usually well controlled by sumatriptan, diclofenac and propanolol (as preventative agent it reduced the frequency of headaches). She required diamorphine very rarely. She presented with a headache which she felt was “different” in nature. The previous night she was woken from sleep by the pain at around 3 am (this never occurred with her migraines) and took sumatriptan with minimal benefit or response. She described “feeling certain she was going to die” as her headache was very severe. She came to AE sluggish but responding to light. She was hypertensive (156/106). Treating physician referred her for a non contrast CT brain which did not show any obvious pathology (no intracranial bleed). She eventually responded to opiates and her diagnosis was concluded as hemicrania/migraine. In following 48 hours her pain transformed into painful hypoesthesia of the scalp on the left (numb pain reported by patient). Asymmetry of pupils persisted. Patient was reviewed by neurologist 3 days later.

59-year-old gentleman on warfarin for paroxysmal atrial fibrillation, COPD and hypertension presented 2 days after a fall; he was walking his dog, animal pulled the lead and he fell forward. He was brought to the hospital by wife and daughter with forehead bruising and pyrexia (38 °C). Neurological examination at Accident and Emergency was concluded as normal and the same was valid for his cognitive performance. Clinical picture changed during admission.

75-year-old man with ankylosing spondylitis (Bechterew’s disease) was admitted with walking difficulties. Symptoms had gradually progressed over the period of 2–3 years. There was bilateral leg weakness, with left leg being described as “less reliable” than the right. Patient had suffered from ankylosing spondylitis for decades and for last 2 years he had been off all treatments. In the past whole spine “irradiation” was used (no further information had been available, historical notes also not available). On objective examination we found paraparesis/weakness with prevalence on the left (4/5 vs. 4+/5 on the right). There was hyperreflexia in legs with clonus in left ankle. Patient had obvious sphincter problems (having catheter for more than 3 years for retention- so likely pre-dating walking issues). There was light touch hypoesthesia in lower extremities and loss of vibration sense, there was not any sensory level on trunk. Plantars were positive/extensor. Findings in upper extremities were normal. Cranial nerves and cerebellar functions were unremarkable as well.

75-year-old woman was referred to us by general practitioner for two episodes of “memory lapses” (3 and 1 month ago respectively). On the first occasion she was sitting at the bingo waiting for numbers to be drawn for the last time that evening. The next thing she remembers is that everyone else was leaving the room as the game was over. She lost approx. 3–5 minutes. She was not communicating with others during that time but her friends assumed that she was focusing on the game. Second episode led to an accident when she drove her mobility scooter into a fence, not knowing why and not having any recollection about it. She did not have any incontinence, bitten tongue or obvious seizure activity. Objective findings were generally normal, with no obvious paresis, sensory or cerebellar signs. Ankle reflexes were absent. She walked unsupported but for longer distances (shopping) she used a mobility scooter.

67-year-old gentleman was referred to Neurology outpatient department for a 6 month history of gait difficulties, incontinence and occasional swallowing issues. He also reported a numb right side of his face (“like having local anaesthesia at the dentist”) and that his symptoms were gradually progressing. He was referred by his Haematologist as he had a history of Chronic Lymphocytic leukaemia (CLL) with lymphadenopathy, splenomegalia and leukocytosis. This diagnosis was known for more than 5 years (verified by bone marrow biopsy) and clinically he seemed stable from a haematology point of view.

48-year-old female was admitted with a 3 days history of “being unwell”, tired and having headaches. Eventually she developed confusion and became progressively sleepy (oscillating level of consciousness (GCS between 14 and 11). According to family she had been incontinent over that period. On admission patient was drowsy, confused and pyrexic (38.1 °C). Her responses were incoherent (usually responded by single words or provided yes/no answers). On objective examination left sided hemiparesis was found, with increased reflexes on the left. There was bilateral ataxia visible especially when walking (gait ataxia) and during finger/nose test (dysmetria). There was also dysdiadochokinesia. There was around 350 ml of residuum in her bladder. There were positive plantars bilaterally. Blood tests revealed CRP of 35 with only borderline leukocytosis.

70-year-old man came to Neurology outpatient clinic with symptoms he had had for approximately 12 months. Symptoms were fluctuating. He reported “weird feeling” in both his legs. He described them as being numb as he “could not feel them properly and they were occasionally weaker”. He also had constipation and significantly delayed start of urination. There was previous history of sciatica 20 years ago. On objective examination reflexes were quite brisk in upper extremities. In lower extremities patellar reflex was increased on the left, normal on the right. Ankle reflexes were absent bilaterally. His right leg was weaker (4+/5) with normal strength (5/5) on the left. There was thermoception deficit on the right with normal pain and light touch perception. Proprioception was reduced on the right. On the left there was reduced pain, light touch and thermoception but proprioception seemed normal. Sensory functions in upper extremities and torso looked normal. Plantars were neutral/negative. There was urinary retention. Cranial nerves and cerebellar functions were normal.

73-year-old gentleman was referred to Neurology outpatient clinic by his General Practitioner for gait and balance issues. Patient reported a 3 year history of difficulty mobilising due to leg weakness, as well as his problems with balance. He also mentioned memory problems, which was corroborated by his wife. His symptoms had progressively worsened over the years. He also complained of proximal limb weakness, worse on the left, long standing urinary problems (urgency with occasional “incidents”), intermittent faecal incontinence and lower back pain, not-radiating to his legs. He also reported significant weight loss despite a good appetite. His swallowing had become of some concern recently as well due to occasionally choking. His symptoms seemed to worsen as the day progressed (aggravated by fatigue/exertion). On examination he had a broad based gait, decreased power in legs, with a grade of 4/5 on the right and 3/5 on the left. There was some loss of dexterity in his hands when picking up small things (coins, pencil etc.) but muscle strength seemed normal. There were increased reflexes in lower extremities and normal reflexes in upper extremities. He had bilateral nystagmus with diplopia in lateral position. There was also finger/nose and finger/finger ataxia with dysmetria and intention tremor. He struggled to drink (choked on examination) but soft palate and tongue moved well. His speech seemed slurred/dysarthric, but according to his family it had not progressed recently. His jaw jerk was increased. There was no facial asymmetry (no ptosis or facial drooping).

19-year-old man was admitted to hospital with left arm weakness and altered sensation as the main complaint lasting for 24 hours and a 5 day history of altered sensation in both feet and weakness in his legs. The day before admission he realised that he could not lift his left arm above his head. He also had pins and needles in his fingertips bilaterally. He denied any head injury or other trauma. He had no recent illness including diarrhoea and vomiting. He had felt fatigued and exhausted for last 4 weeks. On examination there was bilateral ankle weakness (4+/5) with foot drop, more prominent on the right (4/5). He was not able to lift his left arm over his head (2/5 proximally). He also had some difficulties lifting his right arm over his head (especially against resistance – 3/5). There was some ataxia and dysmetria (during finger/nose testing) but likely due to weakness. Reflexes were absent in all four extremities. Cranial nerves were normal. He was not breathless during physical activity. Bulbar functions were normal. There was rather distal light touch hypoasthesia but rest of the sensory functions were normal (vibration sense, pain). His complexion was slightly pale and yellowish. He had a temperature of 37.6 °C.

55-year-old lady came to clinic complaining about several months history of paresthesias (tingling) affecting left side of her face and tongue. Symptoms came on gradually. She also noticed a reduction in her sense of taste. There was no facial asymmetry. She suffered from migraines in the past, which have become more frequent lately (occurring on a weekly basis). During a migraine the pain was generally situated behind the right eye (contralateral side to paresthesias/tingling). Patient was very philosophical about her symptoms, explaining them as complicated migraine and “definitely linked to her migraines”. On objective examination reduced pinprick and light touch sensation within the first, second and third left trigeminal nerve division was found. There was hypoacusis (Rinne and Weber tests were both reduced) on the left. Rest of cranial nerves looked normal. Cerebellar functions were normal. She possibly felt less inner cheek (mucosa) on the left and left side of her tongue when touched by spatula. Muscles of mastication and facial muscles were normal. Taste was not tested in the clinic. Reflexes were brisk, but otherwise there was no other focal symptomatology.

20-year-old man was referred to neurology clinic for pins and needles in both hands. Symptoms started 6 months ago. Symptoms were provoked by physical activity and became much worse after busy day; he worked hard as a joiner. He was referred as a suspected diagnosis of multiple sclerosis (MS). He did not have any other symptoms. On objective examination reflexes were present and not increased; apart from absent ankle jerks bilaterally. Plantars were negative. Muscle strength was normal. There were no sphincter symptoms. He did not have any symptoms on examination but paresthesias in his hands did not seem to respect any particular dermatome. Vibration sense was reduced in legs (ankle level) but light touch and pin prick were normal. Cranial nerves were normal and there was no ataxia.

67-year-old gentleman was referred to the neurology outpatient clinic by General Practitioner for weakness in his arms, especially shoulders. He also had difficulties holding his arms elevated or raising them above horizontal line. In his past medical history there was since youth bilateral longstanding hypoacusis. However it became more prominent on the right, alongside tinnitus, over last 2 years (progressing). Rest of medical history was unremarkable. On objective examination reflexes in arms were absent. There was bilateral rather proximal (girdle) weakness (3/5) with some weakness distally (4/5) in upper extremities. Plantar responses were positive. Reflexes in legs were present (not increased). There were fasciculations in deltoids and obvious atrophy of trapezius and biceps bilaterally. Patient reported occasional bladder issues (retention/delayed start). Weber and Rinne tests responses were both reduced significantly, almost absent. Cerebellar functions were normal. Rest of cranial nerves and sensory functions were normal. Patient also complained about bilateral tinnitus.

44-year-old man with history of opiate addiction (last 12 month on methadone 40–70 mg/daily) and alcohol problems in the past (admitting up to 15 units a day) was admitted via A&E. At A&E he complained about speech difficulties and right sided headache. He reported his symptoms lasting for last 2 weeks. During that period he drank alcohol extensively. He could not rule out neck or head injury as there was significant amnesia linked to alcohol. For the same reason he also could not rule out any loss of consciousness during that period. He was not certain about use of other illicit drugs (e.g. cocaine, heroin, amphetamine). On admission there was obvious dysarthria/slurred speech and dysphagia. There were no obvious traumatic changes on his neck or head. On objective examination bilateral complete hypoglossal nerve palsy was found. Other cranial nerves were normal. There were no other signs of motor or sensory deficit. Pupils were symmetrical and responsive with no signs of Horner’s syndrome. Masseter jerk was absent. Patient was significantly hypertensive on admission (systolic pressure 143–192, diastolic 103–128.). Speech and language team reviewed patient and swallowing was assessed. Nasogastric tube was not needed.

32-year-old woman was referred by general practitioner for 3 weeks of gradually progressing left sided facial pain. Pain was present in her forehead, cheek and jaw and probably crossing the facial midline. She had a history of paranoia (schizoaffective disorder mentioned in historical notes) and dependent personality disorder. Patient records also revealed recurrent admissions for minor injuries occurring under influence of alcohol. During examination patient was agitated and it proved to be difficult to examine her properly. She was also very hesitant to let doctors examine her face because of facial pain. However there was allodynia/painful reaction in the left trigeminal territory.

72-year-old gentleman, previously relatively fit, former soldier was admitted for 1 week history of poor balance, instability and gait difficulties. He also mentioned intermittent pins and needles in his legs. There was a past history of chronic lumbar spine issues (including surgery/laminectomy L4, L5 in the past) and longstanding foot drop on the left. He said that “his legs can not bear him” now. He was seen 6 weeks before current admission by psychiatrist with conclusion of mild cognitive decline, possibly related to early Alzheimer’s dementia and he was started on Donepezil. Psychiatrist requested CT scan of his brain which was reported normal (6 weeks before current admission).

22-year-old young lady came to Neurology outpatient clinic with her mum and both were very distressed. She was referred by her General Practitioner with a 5 week history of sudden onset right hand weakness (she woke up with symptoms). Her grip strength was reduced and she had difficulties moving her wrist. She had pins and needles in the right forearm, right thumb and dorsum of her hand. She did not report any other symptoms. Initial clinical discussion was dominated by overwhelming fear that she was suffering from multiple sclerosis. Level of panic was aggravated by the fact that close relatives (mother’s sister) was diagnosed with multiple sclerosis some years ago. On objective examination obvious wrist drop was found and on the right side there was reduced contraction and muscle bulk of brachioradilais muscle during elbow flexion examination. Wrist flexion, triceps and biceps strength were normal. There were no intrinsic muscles wasted.

With the rapid development of information and communication technologies and the increasing dependence of modern civilization on them, the number and significance of threats to the functioning of the whole of society (not only smart society) are constantly increasing. Prevention, security, and protection against cyber threats pose a challenge that will have to be faced in the future. This article presents systems thinking and system dynamics approaches to solving complex problems and shows their potential use in cybersecurity, with a particular focus on the current state of cybersecurity in the Czech Republic.

Hana Tomaskova,1 Jitka Kuhnova,2 Richard Cimler,1,3 Ondrej Dolezal,1 Kamil Kuca3 1Faculty of Informatics and Management, 2Faculty of Science, 3Center for Basic and Applied Research (CZAV), University of Hradec Králové, Hradec Králové, Czech Republic Introduction: Alzheimer’s disease (AD) is a slowly progressing neurodegenerative brain disease with irreversible brain effects; it is the most common cause of dementia. With increasing age, the probability of suffering from AD increases. In this research, population growth of the European Union (EU) until the year 2080 and the number of patients with AD are modeled.Aim: The aim of this research is to predict the spread of AD in the EU population until year 2080 using a computer simulation.Methods: For the simulation of the EU population and the occurrence of AD in this population, a system dynamics modeling approach has been used. System dynamics is a useful and effective method for the investigation of complex social systems. Over the past decades, its applicability has been demonstrated in a wide variety of applications. In this research, this method has been used to investigate the growth of the EU population and predict the number of patients with AD. The model has been calibrated on the population prediction data created by Eurostat.Results: Based on data from Eurostat, the EU population until year 2080 has been modeled. In 2013, the population of the EU was 508 million and the number of patients with AD was 7.5 million. Based on the prediction, in 2040, the population of the EU will be 524 million and the number of patients with AD will be 13.1 million. By the year 2080, the EU population will be 520 million and the number of patients with AD will be 13.7 million.Conclusion: System dynamics modeling approach has been used for the prediction of the number of patients with AD in the EU population till the year 2080. These results can be used to determine the economic burden of the treatment of these patients. With different input data, the simulation can be used also for the different regions as well as for different noncontagious disease predictions. Keywords: Alzheimer’s disease, population modeling, system dynamics, prediction model

BACKGROUND AND PURPOSE: Recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS. Our aim was to investigate the difference in the extent of SDGM and cortical atrophy in a large sample of patients with CIS and early RRMS and to explore the relationship between SDGM and cortical atrophy and other MR imaging and clinical outcomes. MATERIALS AND METHODS: Two hundred twelve patients with CIS recruited at the first clinical event (mean age, 29.3 years; median EDSS, 1.5; median disease duration, 3 months) and 177 patients with early RRMS (mean age, 30.7 years; median EDSS, 2.0; median disease duration, 47 months) were imaged on a 1.5T scanner by using a high-resolution 3D T1 spoiled gradient-recalled sequence. Volumetric data for SDGM structures were obtained by using FSL FIRST, while whole-brain, GM, white matter, cortical, and lateral ventricle volumes were estimated by using SIENAX software. Comparisons between the groups were adjusted for age and sex. RESULTS: Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P < .0001), total SDGM (P = .0001), and globus pallidus (P = .01). Patients with CIS with a median T2 lesion volume >4.49 mL showed lower total SDGM, caudate, thalamus (P < .001), globus pallidus (P = .007), hippocampus (P = .004), and putamen (P = .01) volumes and higher lateral ventricle volume (P = .001) than those with a median T2 lesion volume

We assessed the relationship between gray matter (GM) and white matter (WM) atrophy and clinical status in early relapsing-remitting multiple sclerosis (MS) patients over 5 years. A group of 181 patients who participated in the ASA (Avonex-Steroid-Azathioprine) study and had complete clinical and MRI assessments over 2 and 5 years was investigated. One hundred seventy (170) patients completed the 12-month follow-up, 147 the 24-month, 98 the 36-month, 65 the 48-month and 47 the 60-month. Changes in GM (GMV), WM (WMV) and peripheral GM (PGV) volumes, whole brain volume (percentage brain volume change PBVC), lateral ventricle volume (LVV), third ventricle width (3VW) and T2-lesion volume (T2-LV) were measured. Patients were assigned according to their clinical status to one of two groups: the Stable group, and the Reached Confirmed Sustained Progression (RCSP) group (24-week interval). At 0-6 months PBVC and GMV, at 0-12 months PBVC, GMV and T2-LV, at 0-24 months PBVC and GMV, at 0-36 months PBVC, GMV and T2-LV, and at 0-48 PBVC predicted the differences between the RCSP and Stable groups. PBVC and LVV showed the strongest ability to differentiate patients who presented 0 or >or=3 relapses in the Stable group. Decline in PBVC and GMV were predictive markers of disability deterioration. Correlation of T2-LV with clinical status was weaker and decreased over time. Higher number of relapses was associated with faster decline in whole brain volume.

Background Studies evaluating interferon beta (IFNβ) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNβ does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNβ with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. Objective The Avonex–Steroids–Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNβ-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. Methods A total of 181 patients with relapsing–remitting MS (RRMS) were randomized to receive IFNβ-1a 30 μg intramuscularly (IM) once weekly, IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily, or IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. Results At 2 years, adjusted ARR was 1.05 for IFNβ-1a, 0.91 for IFNβ-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNβ-1a, 20.7% for IFNβ-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNβ-1a alone (+30.3%, P Conclusion In IFNβ-naïve patients with early active RRMS, combination treatment did not show superiority over IFNβ-1a monotherapy.

Objective: To investigate whether neurorehabilitation is able to influence clinical parameters and brain function measured radiologically. Design: A group of healthy probands was compared with two groups of multiple sclerosis (MS) patients, one of which received rehabilitative therapy. Setting: Outpatient in a university hospital. Subjects: Twenty-eight patients with multiple sclerosis (MS), 17 of whom received rehabilitative therapy, and 13 healthy controls. Interventions: Two months of rehabilitative eclectic therapy based on principles of sensorimotor learning and adaptation. Main measures: Multiple Sclerosis Functional Composite, Modified Fatigue Impact Scale, Beck Depression Inventory Score, Barthel Index, Environment Status Scale and Multiple Sclerosis Quality of Life-54, and functional magnetic resonance imaging (fMRI). Results: Patients who underwent neurorehabilitation showed a greater drop in fatigue, depression, impairment, disability and handicap and more improvement in quality of life than those who did not receive therapy. Correlation of brain activity between the right and the left hemisphere is greater in healthy individuals than in MS patients. Neurorehabilitation resulted in a trend for increased correlation between the left and the right hemisphere in patients (approaching the standard). In comparison with control groups, signal amplitudes in anatomical areas did not show any significant changes. Conclusion: Clinical changes seen with neurorehabilitation were not associated with any detectable changes in fMRI observations.

Objectives The aim of this study was to explore the evolution of MRI related gender differences in patients with relapsing–remitting (RR) multiple sclerosis (MS) who participated in a clinical trial over the 5 years. Methods 181 patients (39 males and 142 females) were assessed for clinical and neuroradiological disease activity over a period of 5 years. Clinical and MRI examination were performed at the baseline, 6, 12, 24, 36, 48 and 60 months. Longitudinal percentage volume changes in whole brain (PBVC), gray matter (PGMVC) white matter (PWMVC) cortex (PCVC), and lateral ventricles (PLVVC) were calculated by using direct methods (SIENA and SIENAX-multitimepoint). Absolute tissue volume changes of subcortical deep GM structures including caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala and nucleus accumbens were estimated using FIRST, a model based segmentation/registration tool. T2 lesion volume (T2-LV) and lesion activity analyses were performed, using a contouring-threshold and subtraction techniques. All clinical and MRI variables were analyzed between males and females. Results Global (PBVC) and tissue specific (PGMVC, PWMVC, PCVC, PLVVC) brain volume changes showed no significant gender differences over the 5-year follow-up period. Although total subcortical deep GM, caudate, putamen, globus palidus, thalamus and nucleus accumbens normalized volumes were significantly larger in male subjects at baseline, the follow-up analysis showed no differences over the 5 years. There were no gender differences in lesion activity or T2-LV changes over the 5 years. Conclusion No MRI lesion, global, tissue specific or regional brain volume gender change differences were found over the 5-year follow-up.

We investigated the evolution of cortical atrophy in patients with early relapsing-remitting (RR) multiple sclerosis (MS) and its association with lesion volume (LV) accumulation and disability progression. 136 of 181 RRMS patients who participated in the Avonex-Steroids-Azathioprine study were assessed bimonthly for clinical and MRI outcomes over 2 years. MS patients with disease duration (DD) at baseline of ≤24 months were classified in the early group (DD of 1.2 years,n=37), while patients with DD > 24 months were classified in the late group (DD of 7.1 years,n=99). Mixed effect model analysis was used to investigate the associations. Significant changes in whole brain volume (WBV) (P<0.001), cortical volume (CV) (P<0.001), and in T2-LV (P<0.001) were detected. No significant MRI percent change differences were detected between early and late DD groups over 2 years, except for increased T2-LV accumulation between baseline and year 2 in the early DD group (P<0.01). No significant associations were found between changes in T2-LV and CV over the followup. Change in CV was related to the disability progression over the 2 years, after adjusting for DD (P=0.01). Significant cortical atrophy, independent of T2-LV accumulation, occurs in early RRMS over 2 years, and it is associated with the disability progression.

Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect.

Objective To identify early clinical and MRI predictors of non-response to interferon (IFN) treatment in multiple sclerosis (MS). Methods In 172 patients with relapsing-remitting MS treated with IFNβ, we evaluated prediction of future treatment non-response. Candidate predictors comprised disability and its sustained progression, relapse score (combining frequency and severity of relapses), brain volume change, brain parenchymal fraction, number of new T2 lesions, and T2 and T1 lesion volume within the initial year of treatment. Treatment non-response was evaluated as confirmed disability progression or overall average annual relapse score exceeding 1 over the following 5 years. Logistic regression model was adjusted for patient age, gender, disease duration and changes in treatment. Results Ninety patients (52%) reached the status of IFN non-responders in years 2–6. Patients with ≥1 new T2 lesion and relapse score ≥2 (odds ratio ≥5.7) or those with ≥3 new T2 lesions regardless of the relapse score (odds ratio = 3) were in a significantly higher risk of future treatment non-response. Conclusions In patients with MS treated with IFNβ for 1 year, number of new T2 lesions and annualized relapse score predict individual risk of treatment non-response over the following 5 years.

Objective To evaluate long-term effects of 2-year treatment with interferon beta combined with low-dose azathioprine and prednisone in multiple sclerosis. Methods In the original 2-year ASA study, 181 patients with early relapsing–remitting multiple sclerosis were randomised into 3 treatment arms: those treated with interferon beta ( n =60), with interferon beta and low-dose azathioprine ( n =58), and interferon beta, azathioprine and low-dose prednisone ( n =63). Of these, 172 were included in this 4-year non-study extension. Three monthly clinical controls and annual MRI scans were carried out. The primary endpoint was annual relapse activity. The secondary endpoints were disability and quantitative MRI parameters. Results Nine patients were lost to follow-up and 172 were included in the analyses. None of relapse activity, disability accumulation or MRI parameters differed significantly between the groups over 6 years. Only 5.5% and 0.6% of patients were free from disease activity at year 2 and year 6 of the treatment initiation. Conclusion The tested combined therapeutic regimen does not improve long-term outcomes in patients with multiple sclerosis. Furthermore, interferon is not able to completely abolish disease activity.

We assessed the relationship between gray matter (GM) and white matter (WM) atrophy and clinical status in early relapsing-remitting multiple sclerosis (MS) patients over 5 years. A group of 181 patients who participated in the ASA (Avonex-Steroid-Azathioprine) study and had complete clinical and MRI assessments over 2 and 5 years was investigated. One hundred seventy (170) patients completed the 12-month follow-up, 147 the 24-month, 98 the 36-month, 65 the 48-month and 47 the 60-month. Changes in GM (GMV), WM (WMV) and peripheral GM (PGV) volumes, whole brain volume (percentage brain volume change PBVC), lateral ventricle volume (LVV), third ventricle width (3VW) and T2-lesion volume (T2-LV) were measured. Patients were assigned according to their clinical status to one of two groups: the Stable group, and the Reached Confirmed Sustained Progression (RCSP) group (24-week interval). At 0-6 months PBVC and GMV, at 0-12 months PBVC, GMV and T2-LV, at 0-24 months PBVC and GMV, at 0-36 months PBVC, GMV and T2-LV, and at 0-48 PBVC predicted the differences between the RCSP and Stable groups. PBVC and LVV showed the strongest ability to differentiate patients who presented 0 oror=3 relapses in the Stable group. Decline in PBVC and GMV were predictive markers of disability deterioration. Correlation of T2-LV with clinical status was weaker and decreased over time. Higher number of relapses was associated with faster decline in whole brain volume.

Aims: The objective was to correlate the change in the lesion load (LL) and brain atrophy in patients with multiple sclerosis (MS) with progression of clinical disability, represented by the Expanded Disability Status Scale (EDSS), and to test if stratification of patients according to magnetic resonance imaging (MRI) criteria can increase the predictive ability of MRI for MS clinical development. Methods: 181 patients with clinically definite relapsing-remitting MS underwent MRI for a period of up to 5 years. Grouping of patients according to the LL value at the study entry revealed a substantial increase in the Spearman rank correlation coefficient R. Results: For the low LL cohort of patients, we found a statistically significant correlation (R up to –0.71 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with increased brain atrophy in the first 2 years. For the high LL group, we found a statistically significant correlation (R up to 0.72 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with an increase in the LL value in the first year. Conclusions: We conclude that stratification of patients according to the MRI criterion (LL) can increase the predictive ability of MRI.

There is growing evidence for the concept of multiple sclerosis (MS) as an inflammatory neurodegenerative disease, with a different pattern of atrophy evolution in grey matter (GM) and white matter (WM) tissue compartments.We aimed to investigate the evolution of different MRI measures in early relapsing-remitting patients with MS and in normal controls (NCs) over 2 years. We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years.Included in this study were 147 patients who participated in the combination ASA (Avonex Steroids Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months. A subgroup of 66 patients was followed for 36 months, 51 patients for 48 months and 43 patients for 60 months. Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualised relapse rate before study entry was 1.7. MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years. In addition to the MS group, 27 NCs were examined at months 0, 12 and 24 using the same MRI protocol. Percentage brain volume change (PBVC), GM volume (GMV), WM volume (WMV) and peripheral grey volume (PGV) were measured annually using SIENA/X software. T2-hyperintense lesion volume (LV), lateral ventricle volume (LVV) and third ventricle width (3VW) were also assessed annually.Over the period of 0-24 months, patients with MS lost significantly more GMV (-2.6% vs -0.72%, p0.001), PGV (-2.4% vs -1.03%, p0.001) and PBVC (-1.2% vs -0.22%, p0.001), and increased in LVV (+16.6% vs +0.55%, p0.003) and 3VW (+9.3% vs 0%, p = 0.003), when compared with NCs. Within-person change in MRI measures for patients with MS over 5 years was -4.2% for PBVC, -6.2% for GMV, -5.8% for PGV, -0.5% for WMV (all p0.001), +68.7 for LVV (p0.001), +4% for 3VW (p0.001) and +42% for T2-LV (p0.001).Our study confirmed a different pattern of GM, WM and central atrophy progression over 2 years between patients with MS and NCs. The study showed a different evolution of tissue compartment atrophy measures in patients with MS, with faster decline in cortical and deep GM regions, as well as periventricular WM regions, over a 5-year period.

Understanding the importance of cortical lesions in MS pathogenesis has changed. Histopathologic studies using new immunohistochemical methods show that cortical lesions can be detected more frequently than previously reported. Newer MRI sequences also detect cortical lesions more accurately. The aim of this study was to evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). We aimed also to investigate the relationship of cortical lesions with clinical status or other MRI variables. Forty-one patients with relapsing-remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) underwent scans of Two-dimensional (2D)-fluid-attenuated inversion recovery (FLAIR) and 3D-T1-WI at 1.5-, 3-, and 5-mm slice thicknesses on 1.5-T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. 2D-FLAIR and 3D-T1-WI were coregistered and the matrix of the neocortical volume (NCV) segmentation mask (SIENAX-generated) was used to classify the location of the cortical-subcortical lesions. Cortical lesions fell into three classes: (1) class 1 were defined as lesions located in the NCV, (2) class 2 were juxtacortical lesions in contact with the NCV mask, and (3) class 3 were cortical-juxtacortical lesions situated in both regions. We measured NCV and normalized gray matter (GM) volume as well. We used partial correlation and multiple regressions to investigate the relationship between cortical lesions and other clinical and MRI variables. Of the total T2-lesion volume (T2-LV) measured on 1.5-mm th scans (mean 16108 mm(3)), cortical lesions represented 2.4% (276 mm(3)), juxtacortical lesions 6.1% (760 mm(3)), and cortical-juxtacortical 3.7% (491 mm(3)). Compared to 1.5-mm th scan, cortical LV was reduced by -28.3%, p0.001 on 3-mm th and by -40.78%, p0.001 on 5-mm th scans. Results for juxtacortical LV were for 3-mm th scans (-17.9%, p0.01) and for 5-mm th scans (-30.3%, p0.01). The figures for cortical-juxtacortical LV were also for 3-mm th scans (-16.2%, p0.01) and for 5-mm th scans (-26.7%, p0.01). We observed a significant correlation between T2-LV and GM atrophy in all slice thickness (r = -0.4 to -0.48, p = 0.001-0.003) and a modest relationship between cortical and cortical-juxtacortical LVs and disability, especially at 1.5-mm slice thickness (r = 0.35, p = 0.025). Use of thinner slices (1.5 mm) on 2D-FLAIR images can significantly increase the sensitivity and precision of detecting cortical and juxtracotical lesions in patients with MS. Cortical and juxtacortical lesions contribute more to disability development than total T2-LV alone.

Understanding the importance of cortical lesions in MS pathogenesis has changed. Histopathologic studies using new immunohistochemical methods show that cortical lesions can be detected more frequently than previously reported. Newer MRI sequences also detect cortical lesions more accurately. The aim of this study was to evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). We aimed also to investigate the relationship of cortical lesions with clinical status or other MRI variables. Forty‐one patients with relapsing‐remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) underwent scans of Two‐dimensional (2D)‐fluid‐attenuated inversion recovery (FLAIR) and 3D‐T1‐WI at 1.5‐, 3‐, and 5‐mm slice thicknesses on 1.5‐T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. 2D‐FLAIR and 3D‐T1‐WI were coregistered and the matrix of the neocortical volume (NCV) segmentation mask (SIENAX‐generated) was used to classify the location of the cortical–subcortical lesions. Cortical lesions fell into three classes: (1) class 1 were defined as lesions located in the NCV, (2) class 2 were juxtacortical lesions in contact with the NCV mask, and (3) class 3 were cortical–juxtacortical lesions situated in both regions. We measured NCV and normalized gray matter (GM) volume as well. We used partial correlation and multiple regressions to investigate the relationship between cortical lesions and other clinical and MRI variables. Of the total T2‐lesion volume (T2‐LV) measured on 1.5‐mm th scans (mean 16108 mm 3 ), cortical lesions represented 2.4% (276 mm 3 ), juxtacortical lesions 6.1% (760 mm 3 ), and cortical–juxtacortical 3.7% (491 mm 3 ). Compared to 1.5‐mm th scan, cortical LV was reduced by −28.3%, p p p p p p r = −0.4 to −0.48, p = 0.001–0.003) and a modest relationship between cortical and cortical–juxtacortical LVs and disability, especially at 1.5‐mm slice thickness ( r = 0.35, p = 0.025). Use of thinner slices (1.5 mm) on 2D‐FLAIR images can significantly increase the sensitivity and precision of detecting cortical and juxtracotical lesions in patients with MS. Cortical and juxtacortical lesions contribute more to disability development than total T2‐LV alone.

Objective: Investigate the association between long-term subcortical deep gray matter (SDGM) and cortical volume changes and disability progression in early relapsing-remitting multiple sclerosis (RRMS). Background Pathological changes in gray matter are thought to have an important role in MS disease progression. However, no long-term clinical studies of SDGM and cortical changes have been reported in early RRMS. Design/Methods: One hundred eighty RRMS patients who participated in the Avonex-Steroid-Azathioprine study were assessed yearly for clinical and magnetic resonance imaging outcomes over 5 years. Healthy controls (n=48) were also assessed yearly over 2 years. MS patients were divided into those with and without sustained disability progression (SDP), defined as a ≥1.0-point increase in Expanded Disability Status Scale score lasting for ≥12 weeks at any time over the 5-year study period. Results: Of the 180 patients, 90 patients experienced SDP and 90 had stable disease after 5 years. At baseline, SDP patients were older and had longer disease duration, greater T2 lesion volume, and smaller SDGM and cortical volumes ( P ≤0.014). At 2 years, significant differences were seen in T2 and lateral ventricle volumes as well as whole brain, total SDGM, putamen, thalamus, nucleus accumbens, and amygdala volumes across the 2 RRMS groups and healthy controls; SDP patients had larger percentage changes in these same measures except for nucleus accumbens and amygdala when compared with stable MS patients at 2 years. At 5 years, SDP patients had greater percentage change decreases in volumes of whole brain, total SDGM, putamen, and thalamus and a greater increase in lateral ventricle volume than patients with stable disease ( P ≤0.02). No differences in cortical, white matter, or T2 lesion volumes were observed between patients with and without SDP at 5 years. Conclusions: SDP in early RRMS is associated with SDGM atrophy progression, especially in the putamen and thalamus, but not with cortical atrophy. Supported by: Biogen Idec Inc. and Czech Ministry of Education, Research Program MSM 0021620849. Disclosure: Dr. Zivadinov has received personal compensation for activities with Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals as a speaker and/or consultant. Dr. Zivadinov has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corporation, Bracco, Questcor Pharmaceuticals and EMD Serono. Dr. Bergsland has nothing to disclose. Dr. Dolezal has received personal compensation for activities with Merck Serono, Biogen Idec, and Novartis as a consultant. Dr. Hussein has nothing to disclose. Dr. Seidl has received research support from Biogen Idec. Dr. Dwyer has nothing to disclose. Dr. Vaneckova has nothing to disclose. Dr. Krasensky has received research support from Biogen Idec. Dr. Potts has received personal compensation for activities with Biogen Idec. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Horakova has received personal compensation for activities with Biogen Idec as a speaker.Dr. Horakova has received research support from Biogen Idec.