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001 CREUTZFELDT-JAKOB DISEASE (CJD)
R. G. Will. CJD Surveillance Unit, Western General Hospital, Edinburgh, UK
CJD is one of the transmissible spongiform encephalopathies or prion diseases. There are a number of subtypes of human prion disease, including sporadic CJD, which occurs worldwide with an annual mortality rate of about 1 case/million population, hereditary forms associated with mutations of the human prion protein gene, and iatrogenic cases related to accidental transmission of infection from person to person; for example, through human pituitary hormones and human dura mater grafts.
This group of diseases has become the subject of widespread public concern following the identification of variant CJD as a zoonotic disease, caused by transmission of the agent of bovine spongiform encephalopathy (BSE) from cattle to humans. 151 cases of variant CJD have been identified in the UK, eight in France and single cases in Italy, Ireland, Canada, and the USA. The number of annual deaths from variant CJD in the UK appears to be in decline, but uncertainty remains about the future course of the epidemic.
Public health concerns have increased following the recent identification of a possible case of transfusion-transmitted variant CJD and a second “pre-clinical” case also linked to blood transfusion.
002 CLINICAL PATHOLOGICAL FEATURES OF MULTIPLE SCLEROSIS AND NEUROMYELITIS OPTICA IN ASIA
C. Lu1, Z. Li1, Y. Wang1, Y. Hashizume2. 1Department of Neurology, Huashan Hospital, 32 Wulumuqi Road, 200040 Shanghai, China; 2Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute-cho, Aichi-gun, 480–1195, Japan
Early clinical and epidemiological cohorts have shown the distinguished features between oriental multiple sclerosis (MS) and western MS in terms of clinical manifestation, the process of disease, the severity, and the response for therapy. To evaluate the spectrum of MS and neuromyelitis optica (NMO), including demographic data, clinical characteristics, clinical courses, and to evaluate CSF, and serologic studies, we reviewed 226 patients with MS and 32 patients with NMO evaluated at Huashan Hospital between 1994 and 2003. In the past 10 years, the number of MS patients per year tended to increase rapidly, whereas the number of NMO per year was stable. Women were more susceptible to either MS or NMO. Most patients with MS experienced the first attack at the age of 30 years and over time the patients usually entered the stage of relapsing-remitting and progression. The average onset age was 32.51±10.04 years. Parenthesis, transitory abnormal sensory feeling such as numbness or “pins and needles”, and muscle weakness were the most common initial syndrome, which often involved one extremity at the very beginning and extended to bilateral body. In our series, spinal cord and optic nerves were the most often involved. Oligoclonal bands of CSF were found in 49.2% MS patients and in 21.9% NMO patients. The clinical, laboratory, and demography features are consistent with the other reports from Asian countries, which confirmed the existence of difference between oriental and western population.
The pathological hallmark of MS is the demyelinating plaque with reactive glial scar formation and infiltration of immune cells. We observed postmortem samples obtained from 13 patients with MS or NMO. A morphometric study on the cross-sections and demyelinating plaques of the spinal cord was made. The lesions disseminated in the CNS at random. The spinal cord was the most commonly involved, followed by the involvement of brain stem, optic nerves, cerebral hemisphere, and cerebellum. We found a high incidence of spinal cord lesions with extremely heterogeneous pathology as revealed in other structures of CNS. The cervical and upper thoracic cords most frequently had demyelinating plaques in the lateral and dorsal columns and in the dorsal horn with various topographic patterns. In acute patients, coagulate necrosis and oedema were predominant in the spinal cord, often resulting in virulence. In chronic patients, the average cross-sectional area correlated negatively with disease duration, but the proportion of demyelinating lesions correlated with disease duration only in the cervical cord. Some distinct features were revealed in NMO, which mostly were located along the optic tracts and the spinal cord, and characterised by necrotic myelopathy and cavitations. The infiltrating cells contained quite a lot of neutrophils and plasma cells. In some cases the pathological process diffused in the whole spinal cord or even into the lower medulla. Our data indicate that MS and NMO present heterogeneous pathology. The variety serves to a better explanation for enigmatic clinical manifestation and may reflect different immunological mechanisms.
A. Vincent. Department of Clinical Neurology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
Neuroimmunology includes the study of neurological diseases that are thought to be caused by the immune system. The diseases can be divided into antibody-mediated conditions (eg myasthenia gravis), antibody-associated conditions (eg paraneoplastic disorders), and those due to cell-mediated dysfunction (eg multiple sclerosis). There is also increasing interest in the role of the immune system in neurodegenerative diseases such as Alzheimer’s disease. My talk will focus on the role of autoantibodies in the pathology of peripheral and central nervous system disorders, and the clinical relevance of measuring the associated antibodies. I will not discuss the peripheral neuropathies since these will be dealt with by others.
First, I will summarise the main features of myasthenia gravis (MG), and the important role of antibodies to the nicotinic muscle acetylcholine receptor (AChR) at the neuromuscular junction. The antibodies are measured by immunoprecipitation of radiolabelled AChR and reduce the numbers of AChRs by a variety of mechanisms. Very occasionally, antibodies to AChR are present in women whose babies are born with multiple joint contractures and other deformities due to paralysis in utero.
MG is being increasingly recognised in the elderly. Since MG can be misdiagnosed as stroke or motor neurone disease in the elderly, it is likely that there is considerable underdiagnosis of MG in this age group.
There are some patients with MG who do not have AChR antibodies by current testing; they are often called seronegative MG patients. A negative AChR antibody result, therefore, does not exclude a diagnosis of MG. Recently, antibodies to the muscle specific receptor tyrosine kinase, MuSK, have been identified in a variable proportion of MG patients without AChR antibodies (Hoch et al,Nat Med 2001; McConville et al,Ann Neurol 2004). The remaining patients without AChR antibodies appear to have a plasma factor that inhibits AChR function but the target for these antibodies is not yet clear (Spreadbury et al, 2005).
The Lambert Eaton myasthenic syndrome (LEMS) is a condition in which muscle weakness results from a reduction in the amount of ACh released from the motor nerve terminals. It is caused by antibodies to voltage-gated calcium channels (VGCCs) that are present on the motor nerve terminal at the neuromuscular junction. About 50% of LEMS patients have a small cell lung cancer (SCLC), and SCLC cell lines contain VGCCs. Therefore the immune response against the tumour causes the neurological syndrome, and LEMS is a paradigm for paraneoplastic disorders in general. Other paraneoplastic antibodies will be mentioned and their association with different tumours summarised.
Neuromyotonia is a disorder in which patients have hyperactivity of their muscles, often associated with muscle cramps and fasiculations and increased sweating. Neuromyotonic discharges (spontaneous and repetitive motor unit discharges detected by placing a microelectrode on the surface of the muscle in vivo) are associated in about 40% of patients with antibodies binding to voltage-gated potassium channels (VGKCs). Cramp fasciculation syndrome is probably a variant of neuromyotonia (Hart et al.Brain 2001). Interestingly, the same VGKC antibodies are increasingly detected in patients with CNS disease. In the most severe but rare CNS form, Morvan’s disease, the patients may have limbic signs and also autonomic and sleep disturbance, with florid neuromyotonia (Liguori et al,Brain 2001). Increasingly, we are identifying patients with limbic encephalitis without detectable tumours who have VGKC antibodies and respond well to treatments (Vincent et al, 2004).
These assays are not difficult to establish and some commercial kits are available. Clinically, the AChR, VGCC, and VGKC antibodies can be very helpful in the diagnosis of difficult cases, and indicate a likely response to immunosuppressive treatments. Antibodies to paraneoplastic antigens indicate the presence of a tumour that should be searched for, but unfortunately these antibodies do not necessarily cause the condition and the patient’s neurological conditions does not usually respond well to treatments.
AV’s department receives royalties from RSR Ltd who market AChR and VGCC antibody kits.
004 DETECTION OF BORNA DISEASE VIRUS p24 FRAGMENT FROM PERIPHERAL BLOOD CELLS IN PATIENTS WITH VIRAL ENCEPHALITIS
P. Xie1, P. Xu2, D. Z. Zou1. 1Department of Neurology, The First Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China; 2Department of Neurology, The First Affiliated Hospital, Zunyi Medical College, Zunyi, China
Objective: To study the relationship between Borna disease virus (BDV) and the human viral encephalitis.
Methods: The p24 fragment of BDV RNA in peripheral blood mononuclear cells (PBMCs) from 59 patients with viral encephalitis diagnosed clinically, and 112 healthy donors were examined by fluorescence quantitative nested reverse transcriptase polymerase chain reaction (FQ-nRT-PCR).
Results: There were three positive of BDV p24 fragment in 59 patients with viral encephalitis, and no positive in blood donors. The positive rate of BDV p24 in PBMCs in viral encephalitis (5.08%) was significantly higher than that in blood donors (p<0.05). Furthermore, other common viruses caused viral encephalitis (such as herpes simplex virus, herpes zoster virus, mumps virus, Coxsackie virus, and cytomegalovirus, etc) could not be detected positively by PCR in cerebrospinal fluid of these three cases presented BDV p24 fragment positive.
Conclusions: The infection of BDV presents in the patients with viral encephalitis in China and may be the cause of viral encephalitis.
005 THE NEED FOR EMERGENCY TREATMENT OF TIA AND “MINOR” ISCHAEMIC STROKE
P. M. Rothwell. Stroke Prevention Research Unit, University Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
Transient ischaemic attack (TIA) and minor stroke are often not afforded emergency status. However, we now know that the early risk of stroke is much higher than previously supposed: 8.0% (95% CI = 2.3–13.7) during the 7 days after a TIA and 11.5% (4.8–11.2) after a minor ischaemic stroke.1 The subgroup of patients who have carotid stenosis account for the highest proportion of early recurrent strokes,2 and absolute benefit from endarterectomy falls rapidly during the first few weeks after the presenting event.3 Although endarterecomy has a high operative risk in the hyper-acute phase in patients with major stroke or unstable neurological syndromes,3 this is not the case in stable patients operated within the first week after a TIA or non-disabling stroke.3,4 There is now also evidence that combination antiplatelet therapy is effective in the acute phase, and trials are ongoing of blood pressure lowering and of neuroprotective agents to “pre-treat” patients prior to any recurrent stroke.
006 INTRACRANIAL ATHEROSCLEROSIS, MICROEMBOLISM, AND HAEMODYNAMIC INFARCTS
K. S. L. Wong. Department of Medicine & Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR, China
Large artery atherosclerosis accounts for about half of the ischaemic stroke in Chinese. Intracranial internal carotid, vertebrobasilar, and cerebral arteries are the predominant sites for occlusive while extracranial stenosis is relatively less common. The location of atherosclerosis is usually diffuse and multifocal. With the use of transcranial Doppler, it is now possible to monitor microembolism real-time. Microembolism is more common in stroke patients with large artery atherosclerotic stenosis. The availability of diffusion weighted MRI also allows accurate diagnosis of acute and small infarcts. The common pattern of infarcts in patients with intracranial stenosis is multiple small infarcts in chain along the borderzone region. Recent studies have found that anticoagulation is not superior to aspirin in patients with intracranial atherosclerosis. This observation is in accord with our observations that small microemboli, which usually consist of platelet-rich clot, and impaired washout of these microemboli may be the mechanism of stroke in patients with intracranial atherosclerosis. Future directions to treat intracranial atherosclerosis should include revascularisation or reperfusion strategies.
007 THE CHARACTERISTIC TYPES OF STROKE IN CHINESE
W-JWong. National Yang-Ming University, School of Medicine, Neurological Institute, Veterans General Hospital-Taipei, Taiwan 11217
It is well known that the types of stroke in Asians and blacks are different from the Caucasians. The most common finding is that the rates of haemorrhagic stroke in Asians and blacks than in Caucasians are higher. The characteristic types of ischaemic stroke are also different between orients and western peoples. There are more intracranial arterial diseases in Asians and the extracranial carotid diseases are more prominent in western patients. However, rates of different stroke types in Chinese were changing in last 30 years. The Veterans General Hospital-Taipei is a service hospital, especially for veterans that most of them migrated from different provinces of the Mainland China since the 1940s. It was noted that the rate of haemorrhagic stroke was greatly reduced from 40% in 1970 to 20% in 2000. The types of ischaemic stroke were also changed. There were only 10% of extracranial carotid diseases in the 1970s but it was increased to 20% in the 2000s. The characteristic types of stroke in intracranial arterial lesions were also changed from a more dominant lacunar infarction to a higher rate of intracranial large artery lesions. Using sophisticated diagnostic instruments for the cerebrovascular diseases, such as computed tomogram, magnetic resonance image and cerebral angiogram, we can make more precise diagnosis for strokes, especially for the intracranial arterial lesions. According to the TOAST classification of the types of stroke in recent stroke registry of Veterans General Hospital-Taipei, 47% was atherthromboembolic brain infarction (27% intracranial and 20% extracranial), 25% was small vessel disease (lacunar infarction), 20% was cardiogenic brain infarction, and 8% was unclassified. In conclusion, although the types of ischaemic stroke have some differences by the time changing, intracranial arterial diseases are still the major characteristic types of stroke in Chinese who live in Taiwan. The clinical important key point is that the increasing rates of large artery diseases, extracranial and intracranial, especially for the tandem lesions required more carefully handled during the procedure of carotid stenting or endarterectomy.
008 MITOCHONDRIAL DISORDERS
D. Turnbull. Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK;
Defects of mitochondrial oxidation are proving to be common genetic causes of neurological disease. Mitochondria are under the genetic control of both the nuclear and mitochondrial genome. The mitochondrial genome is small (16.5 kb), present in many copies in individual cells and is maternally inherited.
Patients with mitochondrial defects may present with a variety of neurological abnormalities although there are some clearly defined clinical syndromes such as chronic progressive external ophthalmoplegia and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS). Investigation can include screening of blood or urine cells for mitochondrial DNA mutations, but in many patients the studies include a muscle biopsy. The characteristic findings on the biopsy is the presence of respiratory deficient (cytochrome c oxidase deficient) muscle fibres. Genetic studies for both mitochondrial and nuclear genetic defects are now possible and help establish the diagnosis and confirm the pattern of inheritance.
At present treatment for these patients is predominantly supportive, but there are important issues of genetic counselling, cardiac complications, metabolic, respiratory and gastrointestinal problems to be considered. Exercise therapy for patients with mitochondrial myopathies is currently being assessed as are ways to prevent the transmission of mitochondrial DNA defects.
009 MIGRAINE: AURAS AND COMPLICATIONS
R. Lane. West London Neurosciences Centre, Charing Cross Hospital, London, UK
Primary headaches are defined by their symptom characteristics, notably the frequency and duration of attacks, and the presence of trigeminal autonomic symptoms. Although a multitude of headache types is recognised, there is increasing evidence that similar neural processes, mainly in the brainstem and sometimes in the cortex, especially the posterior regions, may drive these individual headache forms. This process may be symptomless, or cause only non-descript malaise, but if the “migraine mechanism” involves eloquent structures, the patient perceives an aura.
Auras can encompass a wide variety of symptoms, in addition to the “typical” visual, somasthetic, and dysphasic forms. These include auras involving other primary sensory modalities, motor auras, and auras involving higher cortical functions, such as memory, affect, and perceptions of time and space. A classification of auras is proposed, based on a database of more than 300 cases collected over the last decade. It is likely that many of the otherwise unexplained paroxysmal neurological symptoms encountered in neurology clinics, such as recurrent vertigo, syncope, and transient amnesia, are migraine “auras”.
Functional neuroimaging involving a variety of methods has begun to provide insight into the “migraine mechanism”. It seems that the fundamental neural activation that underlies attacks does not injure the brain directly; yet migraine can cause serious disorders, including stroke and epilepsy. Possible reasons for this will be considered.
010 THE VISUAL BRAIN IN HEALTH AND DISEASE
C. Kennard. Division of Neuroscience and Mental Health, Imperial College, London, UK
Our perception of the visual world depends on the complex interactions of many cortical visual centres, but does the visual system provide a truthful representation of the visual world or does it merely generate hypotheses of reality? The study of visual illusions can offer us a useful window into the neurobiology of vision and the complex neurophysiological interactions occurring at a neuronal level.
The visual brain is however, an excellent exemplar of the concept of functional specialisation since each of these cortical visual centres has a specific role in our perception of the many different visual attributes such as colour, form, motion, and depth. The analysis of this functional specialisation depends on a synthesis of functional brain imaging studies and the visual deficits observed by patients with focal cortical lesions of their visual brain. For example, some patients can identify patterns and shapes but not colour (achromatopsia), whereas others are unaware of movement (akinetopsia), or fail to recognise familiar faces (prosopagnosia) or objects (visual object agnosia).
011 SFEMG AND INCHING TECHNIQUE IN THE STUDY ALS AND MMN
L. Y. Cui, M. S. Liu, X. F. Tang. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
Objective: To evaluate single fibre electromyography (SFEMG) and Inching technique in the diagnosis of amytrophy lateral sclerosis (ALS) and multifocal motor neuropathy (MMN) and explore the mechanism of pathophysiology.
Methods: Extensor digitorum communis muscle SFEMG and Inching technique were studied in 162 patients with ALS and 12 with MMN. Three indexes (jitter, block, and fibre density) were measured during the SFEMG test. Conduction block (CB) was measured in the Inching technique.
Results: Remarkable increased jitter (mean 108.2±30.7 μs), block (39.5%±26.9%) and increased FD (3.9±0.6) were found in ALS patients. Mild increased jitter (50.3±24.1), block (10.6±18.6), and FD (2.8±0.7) were found in MMN patients. There was a significant difference between two groups. Three patients with ALS had CB on routine nerve conduction, but there was no CB on Inching technique. Four of 12 patients with MMN was diagnosed ALS after follow up because CB disappeared.
Conclusion: Inching technique was important in the diagnosis of MMN from suspected ALS clinically. CB was rare in ALS patients. Follow up is very important in the differential diagnosis between the ALS and MMN.
012 GUILLAIN-BARRÉ SYNDROME
R. Hughes. Department of Clinical Neurosciences, Guy’s Hospital, King’s College, London, UK
Guillain-Barré syndrome has a worldwide incidence of 1–2 per 100 000. There are clinical and pathological subtypes including acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and other less common variants. The commonest antecedent infection is Campylobacter jejuni, which accounts for about 25% of cases. Cross-reactivity between carbohydrate epitopes on the bacterium is blamed for inducing an immune response directed against ganglioside GQ1b on the peri-synaptic Schwann cell at the neuromuscular junction in Miller Fisher syndrome or against ganglioside GM1 on the axolemma of motor axons in acute motor axonal neuropathy. Other infections are also implicated, especially cytomegalovirus. Acute inflammatory demyelinating polyradiculoneuropathy resembles experimental autoimmune neuritis, an experimental predominantly T helper cell mediated disease. An immune response against myelin protein antigens, such as the major nerve glycoprotein P0 is the likely culprit. About 25% of patients require artificial ventilation, 5 to 15% die, 20% are left disabled, and a high proportion have persistent fatigue. Cochrane systematic reviews have concluded that plasma exchange and intravenous immunoglobulin accelerate recovery. Oral corticosteroids delay recovery and intravenous corticosteroids are ineffective. More research is needed to identify better treatments.
013 EPILEPSY IN WOMEN
P. Crawford. Director of the Special Centre for Epilepsy, York, UK
Catamenial Epilepsy: Although this phenomenon is over reported by women, there are undoubtedly some girls in whom seizures tend to occur around the time of menstruation or more rarely at the mid cycle, which can be treated with intermittent clobazam.
Fertility: Studies have suggested that women with epilepsy have reduced fertility, mainly from social and psychological reasons. There is also a high incidence of polycystic ovary syndrome in women who have taken sodium valproate in childhood and adolescence.
Contraception: Many anti-epileptic drugs (barbiturates, phenytoin, carbamazepine, oxcarbazepine, and topiramate) interact with the combined oral contraceptive pill. A higher dose combined oral contraceptive pill (i.e. one containing at least 50 μg of oestrogen) is therefore needed. Contraceptive efficacy appears maintained with medroxyprogesterone (Depo-Provera) but there have been many cases of contraceptive failure in women with epilepsy with Norplant.
Pregnancy: The majority of women with epilepsy will have a normal pregnancy and delivery, an unchanged seizure frequency, and over a 90% chance of a normal baby but these are high risk pregnancies. Women of child bearing age need to be counselled and told to seek advice about their anticonvulsant therapy should they wish to become pregnant polytherapy and sodium valproate should be avoided. Folate supplements (5 mg) before conception and for the first 3 months of pregnancy should be given. Oral vitamin K should be given to the mother receiving enzyme inducing anti-epileptic drugs (phenytoin, carbamazepine, or phenobarbitone) in the last month of pregnancy.
Breast feeding: Virtually all the anticonvulsant drugs are excreted in breast milk in low concentrations. Feeding difficulties, irritability, and lethargy can occur. However, the benefits of breast feeding usually far outweigh any minor risks to the baby.
014 CHILDHOOD ABSENCE EPILEPSY AND T-TYPE CALCIUM CHANNEL GENE CACNA1H
X. R. Wu, Y. C. Chen, J. J. Lu, Y. H. Zhang, H. Pan, H. S. Wu, K. M. Xu, Y. Shen. Department of Pediatrics, First Hospital, Peking University, China
Childhood absence epilepsy (CAE) is idiopathic generalised nonconvulsive epilepsy with a complex genetic mode. Prevalence is 5–15% among children with any type of epilepsy. The basic underlying mechanisms of CAE appear to involve thalamocortical circuitry and the generation of abnormal oscillatory rhythms from the neuronal network. Major related factors are GABA-A, GABA-B receptors, and T-type calcium channels in this network as recent research determined. Direct sequencing of exon 3 to 35 and the exon-intron boundaries of CACNA1H gene was conducted in 118 CAE patients of Han ethnicity recruited from North China (with informed consent from their parents). 68 variations have been detected in the CACNA1H gene, and among the variations identified, 12 were missense mutations and only found in 14 of the 118 cases in a heterozygous state, but not found in any of 230 unrelated controls. Results of conservation study from different species (human, mice, and rat) showed most of the identified missense mutations occurred in the highly conserved residues of the seven T-type calcium channel gene products. Our results suggested that CACNA1H might be an important susceptibility gene involved in the pathogenesis of CAE. Functional studies of mutant CACNA1H gene are during working.
Supported by grants from Beijing nature Science Foundation 7001003, PUHDGRCF 2000-A-8, and BMCST H010210230119; collaborated with National Center of Human Genome Research of Beijing, Beijing Children’s Hospital, Capital Institute of Pediatrics.
015 DEMENTIA IN PARKINSON’S DISEASE
D. J. Burn. University of Newcastle upon Tyne, Newcastle upon Tyne, UK
The 8 year cumulative incidence of dementia in Parkinson’s disease (PD) may be as high as 78%. Increasing age is the most significant risk factor for dementia in PD (PDD), although there may be synergy with other factors, including severity of motor impairment, longer disease duration, excessive day-time somnolence, apathy, presence of depression, motor phenotype, early appearance of drug induced psychosis, and poor a motor response to levodopa. In common with dementia with Lewy bodies (DLB), apolipoprotein E4 genotype may be a risk factor.
The phenomenology of the dementia syndrome is similar to that seen in DLB. Dysexecutive and visuospatial deficits dominate in the early stages, with relative preservation of mnemonic function. Impaired attention, with slowed reaction time, is common in PDD, while attention may also fluctuate, giving a pattern on computerised choice reaction time testing indistinguishable to DLB. Visual hallucinations occur in 70% of PDD patients, compared with 10% of non-demented PD cases and 25% of AD patients.
When managing PDD, anti-parkinsonian drug treatment should be rationalised. PDD patients treated with “conventional” high D2 receptor affinity antipsychotic medication may suffer a catastrophic exacerbation of parkinsonian symptoms. Cholinesterase inhibitors (ChEIs) in PDD can improve cognition and neuropsychiatric symptoms, while extrapyramidal features are relatively unaffected. The magnitude of the response to ChEIs and the adverse effect profile in PDD is similar to that seen in DLB.
016 DEMENTIA IN CHINA: PREVALENCE IN BEIJING, CHENGDU, SHANGHAI, AND XIAN
Z-XZhang*, G. E. P. Zahner, G. C. Román, J. Liu, Z. Hong, Q-MQu, X-HLiu, X-JZhang, B. Zhou, C-BWu, M-NTang, X. Hong, H. Li. *Departments of Clinical Epidemiology, Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
Prevalence of Alzheimer’s disease (AD) and Vascular Dementia (VaD) in China reportedly differs from Western countries.
Objective: To estimate prevalence AD and VaD in four regions of China.
Design: Cross-sectional, population based prevalence survey with a stratified, multi-stage cluster sampling design.
Setting: Rural (n = 99) and urbanised (n = 71) communities of Beijing, Xian, Shanghai, and Chengdu.
Participants: A sample of 34 807 community residents (94% of eligibles) aged ⩾55 years.
Main outcome measures: Participants were screened with the Chinese Mini-Mental State Examination. Those who screened positive (n = 3 950) underwent a standardised diagnostic workup. Screening sensitivity was assessed in a 3.3% random sample (n = 1 008). AD and VaD were diagnosed according NINCDS-ADRDA, and NINDS-AIREN criteria, respectively. Final diagnoses were made after a 6 month confirmation interva.
Results: We identified 732 AD and 295 VaD cases. Prevalence in ages ⩾65 years was 5.0% (95% CI: 4.5%–5.5%) for dementia, 3.5% (95% CI: 3.0%–3.9%) for AD, and 1.1% (95% CI: 0.9%–1.1%) for VaD. After post-hoc correction for negative screening errors, prevalence increased to 4.8% for AD and remained at 1.1% for VaD. In logistic models adjusting for design and socio demographic factors, regional distribution of prevalence of dementia subtypes showed elevated in northern China for VaD, and different age trends between western and eastern China for AD. Various distributions in gender, education, occupation, marital status, and ethnicity were observed for selected dementia subtypes and population groups.
Conclusion: Prevalence of dementia subtypes in China is comparable to West countries. Prevalence distribution within China was different; incidence survey was needed to explain related factors.
017 MACHADO-JOSEPH DISEASE IN CHINESE FAMILIES
G-XWang, K. Wang, W-HGu. Department of Neurology, China-Japan Friendship Hospital, Beijing, China
Objective: 29 machado-Joseph disease (MJD) pedigrees in China were studied.
Methods: Clinical, pathological and molecular biological studies were done according to references. Linkage analyses were made.
Results: MJD covers approximately 40–44% of hereditary SCAs. Until now, there have been over 150 families reported covering 32% (54/170) of hereditary SCAs.
Pathological features include degeneration and loss of neurones in the dentate nuclei of the cerebellum, substantia nigra, medial pallidum, cranial nuclei, Clark’s column, anterior horn cells, spinocerebellar tracts, and peripheral nerves. The DA, DOPAC, and HVA levels in CSF were significantly lower in the MJD group than those in control.
We analysed the size of (CAG)n array and found that it is 14–40 in normal chromosomes, whereas it is 72–86 in affected chromosomes. The intergenerational changes of (CAG)n are unstable and that is considered the molecular basis of the clinical phenomenon of anticipation. As higher as the number of repeat goes up, the age of onset is becoming earlier. We reported the highest number (86) and the smallest number (51) of CAG repeats and the earliest age of onset. We made a linkage study of Chinese MJD pedigrees with 13 microsatellite markers on 14q and then located it in 3 cM region between D14S280 and D14S81.We found that the CAG repeat expansion was associated with 3′CGG/GGG polymorphism and implied that it was one of the causes of (CAG)n expansion instability.
018 STUDIES ON THE GENE MUTATION AND GENE DIAGNOSIS OF CHINESE PATIENTS WITH WILSON DISEASE (WD)
X. L. Liang, S. C. Ma, F. Huang, Z. Shi. Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
Objective: To investigate the genetic characteristics of Wilson disease (WD) gene mutations in Chinese patients with WD, and to establish a gene diagnostic method for WD.
Methods: (1) PCR-SSCP was used to screen exons of WD gene (ATP7B) in 45 WD patients from 39 Chinese families and 10 normal controls. DNA sequencing and restriction MspI enzyme cut were used to detect the mutant spot (1998); (2) Screening for mutation in exon 8 of ATP7B by fluorescent PCR analysis and restriction analysis was conducted in 66 Chinese patients with WD, 55 family members with normal phenotype and 30 controls, DNA sequencing was used to testify the accuracy of fluorescence PCR (2000); (3) 26 pairs of primers were employed in PCR to amplify the total 21 exons of WD gene in 39 WD patients, 11 first-degree relatives and 20 controls. Mutation analysis was carried out by use of DNA direct sequencing of all PCR products (2003).
Results: (1) 13 patients (28.8%) had mutations of Arg778Leu in exon 8 of the ATP7B gene, in which two patients were homozygous mutation while 11 heterozygous mutation; some other exons (4. 5. 12. 13. 18. 19) also had some mobility shifts, but none of them was detected mutation; (2) 26 cases (39.4%) were confirmed to have the gene mutation of Arg778Leu at exon 8, of which the homozygous mutation were five and the heterozygous mutation were 21. Out of 55 family members with normal phenotype, 12 were determined as gene carriers. The results of DNA sequencing consisted with those detected by fluorescent PCR; (3) A total of 20 mutations were found, among which Pro1273Gln, 2604DelC, 2791-2793DelCAT and IVS3+4A/G were described for the first time. A compound heterozygote patient possessing His1069Gln mutation that had never been reported in Asia was reported. Arg778Leu mutation accounted for 30.5% of the whole 39 patients.
Conclusions: Arg778Leu is the highest frequent mutation in Chinese WD patients, accompanied with a large number of rare mutation spots; His1069Gln, which is the commonest mutation spot in European, also exists in patients with Asian origin, but is very rare; MspI enzyme cut and fluorescent PCR could be effective used in diagnosing the patient with Arg778Leu mutation.
019 A STUDY OF MEMORY IMPAIRMENT IN CHRONIC HYPOXIA ENCEPHALOPATHY AT HIGH ALTITUDE
S. Wu, L. Wang, Q. Hu, X. Wang, G. Li. Department of Neurology, Qinghai provincial hospital, Xining, 810007, China
The study aimed to investigate the correlation between the impairment in memory of patients with chronic hypoxia encephalopathy and the degree of hypoxia at high altitude. Sixty patients with chronic hypoxia encephalopathy and 96 controls underwent memory tests. The clinical memory scale assessment (from the Psychology Research Institute of the Chinese Science Institute) was evaluated. Meanwhile, oxygen arterial pressure (PaO2) and oxygen saturation (SaO2) were also measured. There was a significant decrease of memory in patients with chronic hypoxia encephalopathy, especially the short-term memory. The scale measured paired-association learning, directed memory, free recall pictures, and recall of the connection between portraits. These characteristics scored lower than that of recognition of meaningless figures and the reaction time was delayed. When PaO2<7.3 kpa (55 mmHg) and SaO2<80%, the impairment in memory immediately occurred and worsened with decreasing PaO2 and SaO2. These findings indicated that high-altitude hypoxia might adversely affect memory in chronic hypoxia encephalopathy.
020 EVALUATION OF CLINICAL AND LABORATORY FINDINGS IN ACUTE BRAIN FAILURE AT HIGH ALTITUDE
S. Wu, X. Wuang, Q. Hu, A. Zhu, Z. Yang, Q. Zhang, Q. Hao, D. Zei, Z. Li. Department Of Neurology, Qinghai Provincial Hospital, Xining, 810007, China
In order to look for accurate and objective evidences for clinical diagnosis and treatment of acute brain failure at high altitude 30 cases of acute brain failure were evaluated by clinical examination and laboratory methods. EEG, BEAP, SLSEP, TCD and near-infrared spectroscope (NIRS) were used to evaluate the cases. Young grade of dynamic EEG was used to assess location and severity of disease. Six cases were diagnosed as brain death, three cases demonstrated a state of persistent vegetation, one case recovered consciousness after 3 months, and one case healed. Grade I portended a more favourable prognosis, grade III portended a poor prognosis yet still allowed for the possibility of recovery with dynamic EEG monitoring. BAEP showed that all cases had abnormalities, especially V-wave. The presence of a high sharp wave of blood flow on TCD indicated a better prognosis. However, if the concussion wave and blood flow disappeared, the prognosis was worse. NIRS monitoring showed that all cases suffered a decline in cerebral oxygen saturation. The lower the saturation, the more damage there was. An NIRS reading <40% portended a poor prognosis. The combination of clinical examination and electrophysiological index can improve the accuracy of evaluation on acute brain failure.
021 A DETAILED HISTOLOGICAL STUDY OF 565 SYMPTOMATIC CAROTID PLAQUES: PATHOLOGICAL FEATURES AND CLINICAL CORRELATES
J. K. Lovett, J. N. E. Redgrave, P. J. Gallagher, P. M. Rothwell. Stroke Prevention Research Unit, Department of Clinical Neurology, University of Oxford, UK
Aims: The pathology of unstable coronary atheroma is well described. However, the relationship between vessel stenosis and risk of acute ischaemic events is very different at the carotid bifurcation and the role of plaque instability is less clear. Previous histological studies have been too small or insufficiently detailed to reliably determine the pathology underlying carotid thromboembolism or to identify clinical and angiographic correlates. We set out to do this.
Methods: We performed the largest ever study of plaque pathology, with detailed histological assessments of plaques from 565 consecutive patients undergoing endarterectomy for symptomatic severe carotid stenosis, which we related to the nature and timing of presenting symptoms. We also determined the reproducibility of these assessments (60 plaques) and their correlation with carotid angiographic plaque surface morphology (CAPSM – 128 plaques).
Results: Cap rupture was present in 56.7%, surface thrombus in 30.1%, large lipid core in 59.6%, inflammatory infiltrate in 66.9%, haemorrhage in 63.9%, and AHA grade VI in 49.0%. These assessments were all highly reproducible (κ = 0.7–0.9) and angiographic ulceration was strongly associated with instability on histology (p = 0.001). Patients with hemispheric ischaemia had more unstable plaques than those with ocular ischaemia (p = 0.04), but this was not independent of other risk factors. Large lipid cores (p = 0.03) greater inflammation (p = 0.02), AHA grade VI (p<0.001) were all independently associated with more recent symptoms.
Conclusions: The pathological features reported in acutely symptomatic coronary plaques are present in recently symptomatic carotid plaques, suggesting similar mechanisms of the acute clinical syndromes. CAPSM is a highly sensitive marker of plaque instability and temporal changes in plaque constituents correlate with the fall in risk of ischaemic stroke with time after presenting symptoms. However, differences in plaque pathology do not fully explain the more benign prognosis of ocular vs hemispheric ischaemic events.
022 BENEFIT FROM STANDARD MANAGEMENT OF ACUTE STROKE IN THE MAINLAND OF CHINA
Y. Huang.On behave of Collaboration Group of National 10th 5-year Project for Stroke Diagnosis and Management
Objective: To establish a guideline of acute stroke diagnosis and management, then to evaluate its effect in different levels of hospitals.
Methods: It was a trial of multiple centre study. Thirty hospitals, covering county, city, or national hospitals, and the hospitals from richer or poorer regions, participated in the study. All of the physicians followed the guidelines provided from the study centre, which included the schemes of stroke units, diagnosis, management, nursing, and rehabilitation. The data before assessment of the guideline in the year 2001 were used as control, and the data after assessment of the guideline in 2002 and 2003 were defined as study group. The end points were death rate in discharge from the hospital and in 6 months after the ictus.
Results: Totally, 6967 cases were enrolled in the control group and 1115 cases as study group. Complications of acute stroke were significantly decreased in the study group (from 27.8% to 24.0%). The reduction of severe pulmonary infection is reduced more obviously. The tracheal incubation reduced in 79.1%, and tracheotomy reduced in 80%. Rehabilitation started earlier and more frequently. The improvement of management resulted in hospital fatality of acute stroke decreased. The death rate is 3.8% in the study group, while 10.7% in the control group during the hospitalisation. In follow-up for 6 months, the death rate is 0.5% in the study group and 7.1% in the control group.
Conclusions: Standardisation in the diagnosis and management of acute stroke can significantly reduce death rate in the period of hospitalisation and in 6 months of acute stroke.
023 CONFOUNDING OF HERITABILITY OF ISCHAEMIC STROKE BY HYPERTENSION AND OTHER INTERMEDIATE PHENOTYPES
E. Flossmann, P. M. Rothwell. Stroke Prevention Research Unit, University Department of Clinical Neurology, Oxford, UK
Aims: Family history of stroke (FHxstroke) is a risk factor for ischaemic stroke. However, several intermediate phenotypes (IP) also have substantial genetic components. We studied the relationship between FHx and hypertension (HTN), large vessel atherosclerosis (LVA), and diabetes mellitus (DM).
Methods: We studied FHxstroke and FHx of ischaemic heart disease (FHxIHD) in first-degree relatives (FDR) in two population-based stroke incident studies (Oxford Vascular Study; Oxfordshire Community Stroke Project) and two series of consecutive Oxford hospital-referred TIA patients. We related FHxstroke and FHxIHD to the presence of each of the IPs and compared the strength of associations with FHxstroke vs FHxIHD. We then studied actual measurements of blood pressure, glucose, and cholesterol in the subset of patients with TIA to avoid confounding by intercurrent illness.
Results: In the four Oxford cohorts, FHxstroke was associated with HTN in the proband (pooled OR = 1.68, 95% CI = 1.3–2.2, p<0.0001) but not with DM or LVA. In contrast, FHxIHD was associated with LVA (1.54, 1.2-2-0, p = 0.001) but only weakly with HTN. Isolated HTN was twice as frequent in patients with FHxstroke vs patients with FHxIHD (2.00, 1.3–3.0, p = 0.002). Moreover, mean maximum systolic and diastolic blood pressure were significantly higher in TIA-patients with FHxstroke and increased with the number of affected FDR (181/100 if nil, 186/105 if 1, 198/109 if 2+, p = 0.009). FHxIHD was associated with hypercholesterolaemia. In contrast, there was no association of FHxstroke with glucose or cholesterol levels.
Conclusions: FHxstroke is mainly associated with HTN. In contrast FHxIHD is mainly associated with LVA but less strongly with HTN. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.
024 CEREBRAL PERFUSION PARAMETERS IN ACUTE, SUBACUTE, OR CHRONIC MIDDLE CEREBRAL ARTERY TERRITORY ISCHAEMIA
R. T. F. Cheung. Department of Medicine, University of Hong Kong, Hong Kong SAR, China
Aims: We sought to measure perfusion parameters in patients with acute or subacute middle cerebral artery (MCA) ischaemic stroke, and in patients with chronic MCA territory ischaemia due to severe stenosis or occlusion of the internal carotid artery (ICA).
Materials and methods: A dynamic CT perfusion method is used to quantitatively measure cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) from the brain regions supplied by the major cerebral arteries on both sides and from the ischaemic zone in patients with acute or subacute ischaemia.
Results: CT perfusion parameters were obtained from 15 patients with acute MCA ischaemic stroke within 6 h of onset, and 11 patients with subacute stroke between 0.5 and 30 days of onset, 47 patients with unilateral severe ICA stenosis, and 39 patients with unilateral ICA occlusion. In patients with acute ischaemia, the CBF (in mL/100 g/min), CBV (in mL/100 g) and MTT (in s) over the acute ischaemic zone were 13.3±4.7 (p<0.0001), 1.37±0.47 (p<0.0005), and 8.79±3.94 (p<0.005), and those of the mirror sites of the non-ischaemic side were 59.6±12.8, 2.72±0.75 and 3.99±0.59. In patients with subacute ischaemia, the perfusion parameters of the infarct gradually “normalised” over time, representing luxury perfusion. Patients with unilateral severe stenosis or occlusion of the ICA had “chronic ischaemia” over the MCA territories with a mild (20%) reduction in CBF, a compensated CBV, and a moderate (60%) prolongation in MTT.
Conclusions: CT perfusion parameters may be useful in acute or chronic cerebral ischaemia. The perfusion abnormalities may guide the acute stroke management of acute ischaemic stroke and influence our decision on revascularisation procedures, especially in asymptomatic patients.
025 QUANTITATIVE ANALYSIS OF ARTERIOLOSCLEROSIS BETWEEN DIFFERENT ARTERIOLES AFTER CEREBRAL INFARCTION
W. Zhang, G. Zhu. Department of Neurology, Beijing Military General Hospital, Beijing 100700, China
Purpose: To find out the difference of arteriolosclerosis between different arterioles.
Method: Observe the pathological change of the arterioles in cerebral infarct case and contrast case. Analysis of the sclerotic index of the different arterioles quantitatively.
Result: The SI of arterioles whose external diameter (R) is smaller than 50 μm is much higher than other groups. The SIs of arterioles (R, 100 μm–300 μm) has no significant deviation between infarct groups and contrast groups. The SIs of arterioles (<50 μm) in white matter of infarct groups are much higher than grey matter.
Conclusions: The smaller arterioles of cerebral atherosclerotic infarct cases have higher SI, and the arterioles in white matter are easy to be suffered.
026 THE CLINICAL, MRI FEATURES AND PERIPHERAL VASCULAR CHANGES IN CHINESE CADASIL
Y. Yuan, W. Zhang, L. He, Z. Wang, Y. Huang. Department of Neurology, First Hospital of Peking University, China
Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is pathologically characterised by appearance of granular osmiophilic material (GOM) in basal lamina of vascular smooth muscle cells. Although the extracerebral biopsy is very useful for the pathological diagnosis we are not clear what pathological changes occur in extracerebral arterioles with different calibre. Moreover we need to see if the clinical and MRI features are similar to the report in Caucasian patients.
Material and methods: Among the 83 persons in the four families, 29 cases were classified as clinical suspected patients presenting with one or more of the neurological symptoms. The onset of the disease ranged mainly between the 4th and 5th decades. The main symptoms were recurrent episodic vertigo, with or without hemiplegia, and cognitive impairment. No one in our 29 patients showed migraine. Cranial MRI was performed in six patients and genetic analysis of notch 3 was performed in four probands. Sural nerve biopsies were performed in all probands. The sural biopsy of six non-CADAIL controls were examined under light and electron microscopy.
Results: Genetic analysis revealed notch 3 gene mutations in all probands. Cranial MRI revealed homogeneous and nodular lesions in deep white matter. Three of six patients showed involvement of temporal pole and corpus callosum. The vascular pathological features in sural nerve of four probands were: (1) without marked histological changes in vessel wall; (2) atrophy of medial smooth muscle fibres of arterioles with thickening of arteriole intima, capillary basal lamina, and micro-arteriole adventitia; (3) hypertrophy of medial smooth muscle fibres of arterioles with thickening of large arteriole intima and small arteriole adventitia. In all patients, GOM were noted in the basal lamina of vascular smooth muscle cells, more commonly affecting arterioles, and few affecting the capillaries and veins. Mild thickening of arteriole intima was observed in two of six controls. The media was unremarkable in all control.
Conclusions: Migraine is not frequently seen in our patients. Corpus callosum was also usually involved. The smooth muscle cells in arterioles with large calibre were affected more prominently. Therefore CADASIL should be an angiomyopathy. It should be a goal to observe arterioles in diagnostic examination in the disease. The peripheral vascular changes varied markedly among different patients. The relationship among the extra-cerebral vascular changes and the notch 3 gene mutations needs to be determined in the further.
027 DISTRIBUTION AND OUTCOMES OF ISCHAEMIC STROKE SUBTYPES BY OCSP CLASSIFICATION
M. Liu, Y. Zhang. Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China
Objectives: To analyse OCSP subtypes and to understand the relationship between OCSP classification and outcomes in a group of Chinese ischaemic stroke patients.
Methods: We registered all the stroke patients consecutively admitted in the wards of Department of Neurology, West China Hospital, Sichuan University, Chengdu from March 2002 to March 2003. We classified 321 patients with ischaemic stroke using OCSP criteria into four subtypes (total anterior circulation infarction TACI, partial anterior circulation infarction PACI, lacunar infarction LACI, and posterior circulation infarction POCI). The patients were followed up at 1, 3, and 6 months after stroke. Outcome measures included death, disability, and recurrence. Interobserver agreement was assessed by Kappa value. The relationship between OCSP subtypes and outcomes were analysed by Logistic regression models.
Results: the interobserver agreement of using OCSP classification was good (κ = 0.679, 95% CI = 0.561–0.797). Of the 321 included patients, 127(39.6%) were LACI; 121(37.7%) were PACI; 41(12.8%) were POCI; and 32 (10%) were TACI. TACI had the highest case fatality rate. At 6 months the case fatality rate of TACI was 5.4 times higher than that of PACI, and was 7.4 times higher than that of POCI. At 3 and 6 months, LACI had the lowest death or disability rate, and TACI had the highest ones. Total number of recurrence at 6 months was 15 (15/212, 7.1%). Corrected for other prognostic factors, OCSP classification was associated with the outcomes of ischaemic stroke (p<0.05).
Conclusions: The interobserver agreement of OCSP classification was good. In this study LACI was the most common subtype of ischaemic stroke and TACI was the least common. TACI had the worst outcome. OCSP classification can be used to predict outcomes of ischaemic stroke.
028 CLINICAL CHARACTERISTICS OF MOYAMOYA DISEASE SCREENING WITH TRANSCRANIAL DOPPLER
S. Gao, J. Ni, Y. N. Huang, B. Wong. Department of Neurology, Peking Union Medical College Hospital, Beijing, China
Objectives: To document the age of onset, the period of diagnosis needed, symptom of onset, symptom on diagnosis, and clinical features of Moyamoya disease screening with transcranial Doppler (TCD).
Methods: We retrospectively studied 57 patients with Moyamoya disease: 39 diagnosed with digital subtracted angiography (DSA) and 18 with magnetic resonance angiography (MRA). Among these patients, 39 (68.4%) screened with TCD first and all of these patients had ischaemic symptoms.
Results: (1) There were two onset peaks around age 10 years and 30–40 years, and also another small peak at 50 years; (2) The commonest symptom of onset was transient ischaemic attack (TIA) (56.1%) followed by headache (19.3%), cerebral haemorrhage (14%), infarct (7%), and impairment of cognition in two patients. The cerebral ischaemic symptom was the commonest onset symptom in all three different age groups. Frequency of cerebral haemorrhage in different age groups were presented as non in 1 to15 years age group, 23% in 16 to 30 years age group, and 18.5% in >30 years age group; (3) The mean period of diagnosis was 31.5±47.1 months (range from 1 to 240). The patients with TIA in posterior circulation had the longest period of diagnosis with a mean of 62.8 months and the patients with haemorrhage had the shortest period with a mean of 2.1 months; (4) Among 57 patients, 37 (64.9%) had TIA, 25 (43.9%) had headache, 22(38.6%) had infarct, 10 (17.5%) had haemorrhage, 15 (26.3%) had cognitive disturbance, 11 (19.3%) had visual impairment, and seven (12.3%) had epilepsy.
Conclusion: The recognition for Moyamoya disease was improved since the TCD applied in clinical diagnosis, that the ischaemic symptom was the commonest clinical subtype of Moyamoya disease both in the child and adult group.
029 WHAT PROPORTION OF ALL VASCULAR EVENTS IN THE UK POPULATION ARE CEREBROVASCULAR?
C. E. Lovelock, A. J. Coull, P. M. Rothwell on behalf of the Oxford Vascular Study Stroke Prevention Research Unit, Department of Clinical Neurology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
Background: The relative incidence of acute vascular events in different arterial territories varies markedly across the world. In China, mortality rates for stroke are more than double those for coronary artery disease, whereas the reverse is true in the UK. However, mortality data do not reflect the total burden of disease, and tend to underestimate the relative importance of cerebrovascular disease. The relative incidence of acute cerebrovascular events, acute coronary syndromes, and acute peripheral vascular events has never been measured reliably in any population. We set out to do this in Oxfordshire, UK.
Methods: The Oxford Vascular Study (OXVASC) is a prospective population-based study of all incident and recurrent acute vascular events in a population of 90 542. Multiple detailed and overlapping sources of ascertainment were used to identify all fatal and non-fatal acute vascular events in hospital and in the community. All surviving patients were assessed clinically as soon as possible after the event.
Results: Over 18 months there were 1012 acute vascular events: 396 cerebrovascular events (118 TIAs, 237 ischaemic strokes, 18 intracerebral haemorrhages, and 12 unknown strokes, 11 subarachnoid haemorrhages), 528 ACS (162 unstable angina, 234 non-fatal MI, and 132 fatal MI or sudden cardiac deaths), and 88 PVE (52 acute limb ischaemia, 30 acute aortic pathology, six acute bowel ischaemia). Acute cerebrovascular events accounted for 39% of all acute vascular events in the population and 41% of all incident events. Excluding sudden deaths in the community, cerebrovascular events accounted for a greater proportion of patients presenting to secondary care than does ACS.
Conclusion: Mortality data underestimate the relative burden of cerebrovascular events, which account for about 40% of all acute vascular events in the UK population, and are the most common acute vascular disorder presenting to secondary care. Funding for clinical services and research should reflect this.
030 IN VIVO MAPPING OF CORTICAL CONNECTIONS IN THE HUMAN INTERNAL CAPSULE AND ITS IMPLICATION IN FUNCTIONAL RECOVERY AFTER STROKE
M. Zarei, H. Johansen-Berg, N. Ramnani, P. M. Matthews. FMRIB Centre, John Radcliffe Hospital, University of Oxford, UK
Background: Cortical connections pass through the internal capsule in the human brain. Lesions of this tract can result in significant neurological disability particularly if they involve pyramidal tracts. However neurological disability immediately after stroke does not necessarily indicated involvement of these tracts. Here we have exploited new MRI potential (Behrens et al, 2003) for in vivo detection of cortical tracts passing through the internal capsule.
Methods and subjects: T1W and DWI-MRI scans were obtained from 11 right-handed healthy subjects (seven male, four female, ages 23–57) using EPI. Seed mask of the internal capsule was defined. Target masks were M1, S1, PMC, SMA, PPC, temporal, and occipital as well as hand, foot, and tongue region in each sensory/motor cortex. The latter were defined from overlap of anatomical and functional MRI images during cyclic movements. For each subject, probabilistic tractography was run from every voxel within the seed mask to each voxel in the target mask. Superior longitudinal fasciculus was excluded from information.
Results: Voxels connected to different cortical regions were organised topographically within the internal capsule. These voxels were organised anterior-posteriorly such that fibres from motor cortices located anteriorly in relation to fibres from sensory cortices. Voxels connecting to foot, hand, and tongue regions organised medio-laterally. Theses findings are consistent with our neuroanatomical understanding of the internal capsule. Implications of these results in prediction of recovery of function after acute stroke will be discussed.
Conclusion: DTI-MRI may be a useful tool for study of functional anatomy and determination of prognosis of after stroke.
031 ANIMAL STROKE MODELS: EVIDENCE FOR A SIGNIFICANT PUBLICATION BIAS FOR TACROLIMUS, BUT NOT FOR MELATONIN OR NICOTINAMIDE
M. R. Macleod, P. A. G. Sandercock, G. A. Donnan. Department of Clinical Neurosciences, University of Edinburgh, and National Stroke Research Institute, Australia
Aims: For candidate stroke drugs, progress to clinical trial is based on data from animal experiments. Using systematic review and meta-analysis of the animal literature we have shown substantial neuroprotective effects for three candidate stroke drugs: the fungal extract tacrolimus, the hormone melatonin, and the vitamin nicotinamide. However, publication bias might have led to a substantial over-estimation of efficacy in these meta-analyses.
Materials and methods: We have analysed, both graphically (Funnel Plot) and statistically (Egger regression), data from over 200 experiments involving over 3 000 animals, looking for evidence of publication bias. In the absence of such bias the constant (B0) of the weighted regression of effect size on precision is zero.
Results: Funnel plot asymmetry was seen for tacrolimus, but not for melatonin or nicotinamide. The regression equation constant (B0) was significantly different from 0 for tacrolimus (−1.025, 95% CI −1.813 to −0.237), but not for melatonin and nicotinamide. Taking into account this publication bias, the efficacy of tacrolimus was estimated to be 18.3% (95% CI 9.9% to 26.8%), substantially lower than the 31.5% (95% CI 28.0% to 35.0%) estimated from conventional meta-analysis.
Conclusions: There is significant publication bias in the literature for some, but not all, candidate neuroprotective drugs. Failure to account for such bias in analysis of preclinical data might lead to a substantial overestimation of potential efficacy in human stroke, and is one plausible explanation for at least some of the discrepancy between animal and human studies in this area.
032 MOTOR TRAINING AFTER STROKE
L. S. W. Li. Division of Rehabilitation and Neurology, University Department of Medicine, Tung Wah Hospital and University of Hong Kong, Hong Kong SAR, China
Aims: Neuroplasticity as shown with functional magnetic imaging studies is the key patho-physiological mechanism for motor recovery after stroke. Various techniques to enhance the neuroplasticity to facilitate motor recovery after stroke have been investigated recently. Task specific training such as partial weight-supported treadmill training for lower limb motor recovery has shown to be effective. Randomised controlled studies with more specific training modalities were done in our centre to evaluate the motor and gait recovery on the lower limbs.
Materials and methods: A randomised controlled study of 3-week treatment with functional electrical stimulation and another ongoing study with Mechanical Gait Trainer on motor and gait recovery have been performed on patients with recent stroke.
Results: After 3 weeks of FES treatment, 8 weeks post-stroke assessment showed that the FES treated group had better torque during ankle dorsiflexion than the placebo group (9.9±5.2 vs 6.8±3.8), and higher percentage to regain walking ability (84.6% vs 60.0%). The preliminary result from the Mechanical Gait Trainer has shown some significant difference in Functional Ambulatory Category and gait speed between the Gait Trainer and the controlled groups after 4 weeks of training.
Conclusions: FES and Gait Trainer are effective to enhance the motor and gait recovery after stroke. With the recent better understanding of the neuroplasticity after brain insult, more modalities in addition to the traditional physical training can be employed to facilitate the recovery from stroke.
033 THE EFFECT AND MECHANISM OF TONGXINLUO ON CEREBRAL ISCHEMIC REPERFUSION INJURY IN RATS
R. Liu, M. He. Department of Neurology, Peking University First Hospital, Beijing, China
Objectives: To investigate the effect and the potential mechanism of TongXinLuo by the dynamic changes of infarct volumes, neurological deficit scores, and the expressions of matrix metalloproteinase-9 and cleaved caspase-9 on local cerebral ischaemic-reperfusion injury in rats.
Methods: Male wistar rats were randomly divided into sham-operated control group, normal saline control group (24-hour and 5-day) and TongXinLuo treatment group (24-hour and 5-day). Animals in the latter four groups were subjected to focal ischaemia by filament occlusion of the middle cerebral artery for 90 minutes. At the different end point, infarct volumes were determined by 2, 3, 5-triphenyltetrazolium chloride (TTC) and neurological scores were investigated. The expressions of cleaved caspase-9 and matrix metalloproteinase-9 were assayed by using immunohistochemistry staining method.
Results: Compared with the control group, the size of cerebral infarction was minimised and neurological function was improved in the treatment group. The expressions of matrix metalloproteinase-9 and cleaved caspase-9 were decreased in TongXinLuo treatment group. The difference is significant (p<0.05).
Conclusions: Treatment of TongXinLuo may reduce infarct volumes and improve neurological outcome in rats with transient focal cerebral ischaemia. The protective effects of TongXinluo on cerebral ischaemia reperfusion injury may be mediated through a reduction of apoptotic processes and maintaining the integrity of blood brain barrier.
034 THE LONG TERM RESULT OF BASILAR ARTERY THROMBUSIS AFTER SELECTIVE INTRA-ARTERIAL THROMBOLYTIC THERAPY
H-XZhang1, J-QGu2. 1Department of Neurology, The Second Hospital of Baoding City, China; 2Department of Medicine, The Children’s Hospital of Baoding City, China
Objective: To study the LCFS (long term clinical follow up survey) result of basilar artery thrombosis (BAT) after selective intra-arterial thrombolytic therapy (SIATT).
Methods: 20 cases with BAT, seven in lethargy, 13 in coma, 12 in subparalysis. With digital subtractive cerebral angiography, a dose of urokinase from 300 000 to 850 000 units was injected into the obliterative site in the BAT through a micro-catheter. The patients were carefully examined on the nervous system and evaluated with Barthel index (BI). Following thrombolysis, the patients were followed up as part of the LCFS (5 years).
Results: 10 cases with BAT are complete re-unobstructed, six in partial Unobstruction and four still in obstruction after SIATT. Seven cases resulted in death in 1 to 13 weeks; 13 survived; BI was 100 in four; 45–65 in five; 0–30 in 4 within recent period. Within LCFS, BI ⩾85 in nine, (obvious functional recovery); BI 50 and 60 in two, (moderate recovery); 20 and 25 in two (poor recovery).
Conclusions: Mortality of BAT is reduced by SIATT and long-term functional recovery was much better than expected.
035 EXPERIMENTAL STUDY ON MAGNETIC RESONANCE IMAGING TRACKING OF FERUMOXIDES LABELLED NEURAL STEM CELLS MIGRATION IN VIVO
S. Wang, P. Xie, T-YLuo, F-JLu, Y-JJia, Y-LWang, S-JZhong. Department of Neurology, The First Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China
Objective: To track Ferumoxides-labelled neural stem cell (NSC) migration into rat middle cerebral artery occlusion (MCAO) in vivo by magnetic resonance imaging (MRI).
Methods: Ferumoxides is a kind of superparamagnetic iron oxides (SPIOs). Ferumoxides labelled NSCs to be magnetic labelled NSCs. With immunocytochemistry, transmission electron microscopy (TEM) and Prussian blue dye, we researched the growth, differentiation, and other biological characteristics. We migrated magnetic labelled NSCs into the lateral ventricle of rat MCAO to monitor in vivo.
Results: When NSCs incubated with Ferumoxides, we can see the iron particles are in intracellular (non-nucleus) and also existed in daughter clones. With the concentration of Ferumoxides increased (2.8 μg/ml–16.8 μg/ml). Ferumoxides had no obvious difference to the growth and differentiation of NSCs (p>0.05). Magnetic labelled NSCs were seen in low signal on MRI as magnetic labelled NSCs migrated into the occlusion area.
Conclusion: We successfully labelled NSCs with Ferumoxides to be magnetic labelled NSCs and we also tracked and observed magnetic labelled NSCs migration into rat MCAO in vivo with MRI.
036 ASSESSING THE DISEASE BURDEN DUE TO EPILEPSY IN RURAL CHINA
D. Ding, Z. Hong, W. Z. Wang, J. Z. Wu. Institute of Neurology, Fudan University, Shanghai, China; Beijng Neurosurgical Institute, Beijing, China
Objective: To demonstrate the application of Disability Adjusted Life Year (DALY) as an aid in health outcome measures to evaluate the epilepsy disease burden in rural China. To provide China data for an overall perspective to the understanding of disease burden due to epilepsy.
Methods: An epilepsy prevalence survey was conducted in 66 393 populations, which were stratified cluster sampled in six provinces in China during the WHO supported demonstration project, “epilepsy management at primary health level”. All the epilepsy cases were diagnosed by screening and examinations by neurologists. We calculated DALY directly by the aggregation of the Years Lived with Disability (YLD) and Years of Life Lost (YLL) of all the cases. In the DALY formula, the parameters such as “sex”, “age at onset”, and “treatment” were obtained from the medical reports of each case. Other necessary parameters, such as “disability weight”, “discount rate”, “age-weighting correction constant”, as well as “age-weighting function parameter” were referenced from the Global Burden of Diseases (GBD) study.
Results: The DALYs lost per 1000 population ranged from 0.71 (Shanxi) to 1.27 (Ningxia) in the six study fields in China. The trend was similar with that of active epilepsy prevalence. With the total population and epilepsy prevalence of the six areas, we estimated the overall YLLs, YLDs, and DALYs lost due to epilepsy to represent the China situation by adjusted with the China population. Epilepsy caused the 0.25/1000 of YLLs and 0.67/1000 of YLDs lost. The DALYs lost due to this disease was 0.93 per 1000 population. Larger sampled and multi-region epidemiologic studies need to be conducted in order to obtain more accurate and comparable data.
Conclusion: Compared to “prevalence”, the DALY measure, which considers the disability status of epilepsy, provides a useful tool for the epilepsy disease burden assessment. There is a consequent need to evaluate the burden of epilepsy for the society and to develop affordable and cost-effective treatment strategies.
037 DYNAMIC CHANGES OF VISUAL-SPATIAL MEMORY AND PLACE CELL FUNCTION IN RATS WITH ACUTE INDUCED SEIZURE
X-ZLiu, X-GGao. Department of Neurology, Peking University People’s Hospital, Beijing 100044, China
Objective: To explore the dynamic changes of hippocampal visual-spatial learning and memory in rats with acute induced seizure.
Methods: In order to directly address the cellular concomitants of spatial memory impairment, firstly, we recorded the activity of place cells from CA1 area of the hippocampus in freely moving normal adult Sprague-Dawley rats, and then observed the visual-spatial memory behaviour with water maze test. Thirdly, if the place cells were continuously stable for several days after water maze behavioural training was finished, the flurothyl was applied to induce acute generalised tonic-clonic seizures lasting for 1–2 minutes. At last, the place cells and water maze test were done sequentially at different time point after seizures.
Results: The rat spatial learning and memory were seriously impaired, and the firing rates of the place cells correspondingly ceased or reduced after the seizures. The restoring process of the spatial learning and memory paralleled with that of the place cell function. After 24 hours of acute seizures, both abnormal spatial learning and memory and the dysfunction of the place cells recover to normal level.
Conclusion: There was a close relationship between the abnormality of the hippocampal pyramidal cell activity and water maze performance after acute induced seizures.
038 AN EXPERIMENTAL STUDY ON MORPHOLOGICAL CHANGES OF HIPPOCAMPAL FORMATION AND MOSSY FIBRE SPROUTING IN IMMATURE EPILEPTIC RATS INDUCED BY LITHIUM-PILOCARPINE
X. Gao, X. Lu, F. Liu. Department of Neurology, Peking University People’s Hospital, Beijing 100044, China
Objective: To investigate the histopathological changes of hippocampal formation early after status epilepticus induced by lithium-pilocarpine in immature rats.
Methods: A lithium-pilocarpine induced status epilepticus model was used. Conventional histopathological method and transmission electron microscope were utilised to observe morphological changes in hippocampal formation. In addition, Timm staining technique was adopted to study mossy fibre sprouting.
Results: Status epilepticus in immature rats could cause neuronal degeneration and necrosis in hippocampal formation, especially in subfields CA1 and CA3; mossy fibre sprouting increased in CA3 subfield and supragranular region.
Conclusion: (1) Status epilepticus in young rat could lead to neuronal damage in hippocampal formation, the vulnerable regions were subfields CA1 and CA3, but damages in dentate gyrus were relatively mild; (2) Status epilepticus in immature rats could cause obvious mossy fibre sprouting.
039 QUANTITATIVE EEG EFFECTS OF TOPIRAMATE NON-LINEAR ANALYSIS
J. Li*, W. Wang, X. Wu. Department of Neurology, First Hospital of Peking University, Beijing 100034, China
Objective: To investigate the effect of topiramate (TPM) on Lyapunov exponent, fractal dimension, approximate entropy, and complexity measure of EEG by means of quantitative pharmacoelectroencephalography (QPEEG) and non-linear analysis methods.
Methods: One dose of TPM was administrated to epileptics and healthy adults. The EEG samples were obtained prior to and at regular intervals (at 0.5, 1, 2, 4, 6, 8, 12, 24 hours after the administration) within the 24 hours following the administration of TPM. The EEG activity was processed with the nonlinear analysis methods. The complexity measure, approximate entropy, Lyapunov exponent, and fractal dimension of the whole scalp areas were calculated through 60 s epochs without artefacts after each recording. The statistical difference between baseline pre-drug assessment and each post-drug control was described by analysis of variance.
Results: The Lyapunov exponents increase first, then decrease, and then increase finally. The approximate entropy and fractal dimension show the tendency of descent, the complexity measure increase in healthy adults, but decrease in patients.
Conclusion: TPM can change the complexity of EEG.
040 PAROXYSMAL DYSKINESIAS (THE CLINICAL FEATURES AND REVIEW)
F. Liu, W. Wang, J. Li, X. Li, X. Wu. Department of Neurology, Peking University First Hospital, Beijing 100034, China
Objective: To explore clinical features and therapy of paroxysmal dyskinesias.
Methods: 33 patients with paroxysmal dyskinesias.
Results: 32 patients with paroxysmal kinesigenic dyskinesia (PKD), three patients with paroxysmal non-kinesigenic dyskinesia (PNKD), six patients with paroxysmal exertion-induced dyskinesia (PED), three patients with paroxysmal hypnogenic dyskinesia (PHD). The coexistence of different types of paroxysmal dyskinesias was noted (9).The EEG were normal in most patients (32), five patients had epilepsy seizures, and 27 patients responded to antiepileptic drugs. The CT/MRI was normal in 32 patients.
Conclusions: Paroxysmal dyskinesia is one of the paroxysmal movement disorders. It may be another ion-channel disorder and associated with epilepsy. The coexistence of different types of paroxysmal dyskinesias was noted. Most cases respond to antiepileptic drugs.
041 HIGH ALTITUDE CEREBRAL OEDEMA: MECHANISMS TO EXPLAIN THE CLINICAL FEATURES
C. R. A. Clarke. Division of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, UK
Aim: To illustrate recent perspectives relating to hypoxic brain oedema.
Features: A well-recognised syndrome of intense postural headache, ataxia, papilloedema, and other signs of raised pressure occurs in some 2% of sea level natives who go to 4000 metres – potentially affecting many thousands of unacclimatised visitors annually to the western highlands of the People’s Republic of China. Many cases are transient and self-limiting. Others progress to stupor, coma, and death. Retinal haemorrhages and retinal oedema are characteristic in such cases, but are also often symptomless at altitudes over 4500 metres.
A similar brain oedema syndrome develops at extreme altitudes above 7000 metres, often suddenly, in fit, well-acclimatised mountaineers.
These conditions usually improve promptly if recognised early, with dexamethasone, oxygen and/or descent.
Autopsy in fatal cases shows severe brain oedema, microinfarction, and ring micro-haemorrhages.
Vasogenic oedema is seen on MRI, principally as a focal abnormality in the splenium of the corpus callosum.
Mechanisms: Hypobaric hypoxia leads to a sharp increase in brain blood flow and leakage through the blood-brain barrier. Postulated mechanisms involve nitric oxide, cyclic guanosine monophosphate dependent pathways and vascular endothelial growth factor.
It is also necessary to postulate a differential response of noradrenergic vascular receptors between different regions of the brain circulation. This would account for the frequency of symptomless retinal haemorrhages at altitude and the predilection of high altitude brain oedema for the posterior cerebral circulation in this serious failure of cerebral autoregulation.
042 SELECTIVE PERCUTANEOUS RADIOFREQUENCY THERMOCOAGULATION FOR THE TREATMENT OF TRIGEMINAL NEURALGIA: 1860 CASES REPORT
C-YWu, F-GMeng, H-WWang, Y-GLiu. Department of Neurosurgery, Qi-Lu hospital of Shandong University, Ji’nan, China
Objective: Selective percutaneous radiofrequency thermocoagulation was performed on 1860 cases with trigeminal neuralgia. X-ray, 3D-CT and navigation oval foramen locations were used in 22, 19, and 1 patient respectively on intractable trigeminal neuralgia.
Methods: Supraorbital foramen, infraorbital foramen, and oval foramen radiofrequency thermocoagulation were performed on 1860 cases of trigeminal neuralgia. X-ray, 3D-CT and navigation oval foramen locations were used in 42 cases intractable location so that the direction and position could be defined for trigeminal neuralgia.
Result: Pain alleviation immediately but no serious complication occurred in all of the patients. The effective rate is 96.3%.
Conclusion: Selective percutaneous radiofrequency thermocoagulation is an effective way for the treatment of trigeminal neuralgia. X-ray, 3D-CT and navigation oval foramen locations can raise the successful rate of puncture, enhance the safety and reduce the incidence rate of complication.
043 THROMBOMODULIN EXPRESSION DECREASE IN VASCULAR ENDOTHELIAL CELLS IN FABRY DISEASE
W. Zhang, Z. Wang, Y. Yuan. Department of Neurology, First Hospital of Peking University, China
Objectives: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder. Here we reported clinical features, pathological changes in sural nerves as well as thrombomodulin (TM) expression in vascular endothelial cells in probands from four Chinese AFD families. Moreover, the enzymatic and genetic influence on phenotype of the disease was discussed.
Materials and methods: Four male probands were all characterised as severe burning feet symptoms with onset of disease at the age between 5 to 8 years. Nerve suralis biopsies were performed in all probands. Routine histochemical staining, electromicroscopy examination for ultrathin sections as well as immunohistochemical study for TM were carried out. α-galA activity and GLA gene were examined.
Results: Much osmiophilic granules were accumulated in vascular endothelial cells, smooth muscle cells, and perineurium. Occlusion of arteriole was noted in some patients, in which multifocal loss of myelinated fibres appeared. In AFD patients, 13% of vessels showed a clearly positive reaction to TM, but most showed only weak or no reaction. Serum α-galA activities in AFD patients were significantly lower than in healthy controls. There was also statistical difference between male and female patients. A292P and W44C mutation in GLA gene were found in the first two families respectively.
Conclusions: Two novel mutations, A292P and W44C, were detected in Chinese AFD. Patients with mutation in exon 6 tended to show more severe clinical symptoms and poor progression, while mutation in exon 1 presented mild symptoms and better prognosis. The females showed a higher level of α-galA compared with male patients. Endothelial TM expression was decreased because of lipid deposits mainly in the vascular endothelial cells and smooth muscle cells. The decrease of TM results in arteriole thrombosis, which is the main pathogenesis of myelinated fibre loss in Fabry disease.
044 THE ROLE OF MRI BRAIN SCAN IN THE DIAGNOSIS OF HUMAN PRION DISEASE
K. L. Murray, R. S. G. Knight, D. Summers, D. A. C. Collie, R. G. Will. National Creutzfeldt-Jakob Disease Surveillance unit, Western General Hospital, Edinburgh, UK
Aims: MRI brain scan is the most useful non-invasive investigation in variant CJD. The aim of this study was to determine the utility of MRI brain scan in different subtypes of human prion disease, including iatrogenic and sporadic cases.
Methods: As part of the ongoing surveillance system for CJD in the UK, MRI images of variant CJD, sporadic CJD and iatrogenic CJD cases have been collected during a 6 year period and assessed prospectively by two neuroradiologists.
Results: In a retrospective study the “pulvinar sign” was identified on MRI brain scan in 74/82 cases of variant CJD and was present in 9% of T1 weighted, 71% of T2 weighted, 81% of PD weighted and 100% of FLAIR scans. No clear relationship between the timing of a scan and positivity for the “pulvinar sign” was identified. High signal in the caudate and putamen was seen in the majority of cases of sporadic CJD and similar changes were seen in a small number of cases of iatrogenic CJD linked to human growth hormone therapy.
Conclusions: MRI brain scan is a useful and relatively discriminatory investigation in human prion disease. The distribution of high signal changes is similar in iatrogenic CJD linked to human growth hormone therapy and sporadic CJD suggesting that the route of infection does not necessarily determine the distribution of MRI abnormalities.
045 NEW DATA ON UK IMPORTS OF MAMMALIAN MATERIAL FROM THE FAR EAST: A POTENTIAL ROUTE OF TSE TRANSMISSION
J. Ford*, N. T. H. Colchester†, A. C. F. Colchester*. *Kent Institute of Medicine and Health Sciences, University of Kent, Canterbury, UK; †College of Medicine and Veterinary Medicine, the University of Edinburgh, Edinburgh, UK
There is compelling evidence that variant Creutzeldt-Jacob disease (vCJD) was acquired from bovine spongiform encephalopathy (BSE), but the origin of BSE itself remains unclear. The most widely favoured theory is that BSE was originally transmitted from UK sheep with scrapie. However, although cattle were exposed to scrapie material via concentrated feedstuffs, no scrapie strains that resemble BSE have been identified, and experimentally it has not been possible to infect cattle with scrapie by the oral route. In addition, there has been no satisfactory explanation of why scrapie did not transmit to cattle before. Other species including exotic foreign animals have been considered as possible sources, but the circumstances of their import have remained obscure. Identifying other potential sources is crucial for directing further investigations, and will have important implications for our understanding of vCJD in humans.
We have investigated the sources of mammal-derived material used in the preparation of feedstuff and fertilisers during the period when BSE may have originated (the late 1960s until 1981). Reports indicate that poor quality material destined for fertiliser was sometimes incorporated into animal feed. Most imports were subject to little or no restriction on arrival in the UK and the mammalian origins did not have to be documented. In many of the countries from which the material originated, export regulations were equally lax. We have traced all available trade statistics, import records and other sources of information about the geographical origins of imports. Large amounts were imported into the UK. In a typical year, more than £2 million worth of animal products were imported from near and far Eastern countries, including China. These imports provided an important potential mechanism of TSE transmission.
046 A STUDY OF 22 NEW CASES OF CENTRAL NERVOUS SYSTEM INVOLVEMENT IN CAUCASIANS WITH BEHCET’S DISEASE
F. G. Joseph. (Specialist Registrar in Neurology, Derriford Hospital, Plymouth, UK). N.J. Scolding (Burden Professor of Clinical Neurosciences, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1LE, UK
The neurological features of 22 patients with Behcet’s disease and central nervous system (CNS) involvement (neuro-Behcet’s syndrome) presenting from nine major centres in the South West and South Wales over a 12-year period have been analysed. All were Caucasian with equal numbers of males and females. The mean age of occurrence of neuropsychiatric features was 30 years, with a latency of onset of 4 years from a diagnosis of Behcet’s disease. We found that non-neuropsychiatric features, oral ulceration, intraocular inflammation, and skin lesions, were virtually always present or exacerbated during neurological complications. The most frequent presentations were with headaches, cranial neuropathy and ataxia, and five initial presentations with neurological features were noted. There was a greater frequency of neurological presentations and of seizures in our northern European series compared to large published Turkish series of patients. Two patients developed movement disorders: chorea in one and Parkinsonism in the other, which have only been rarely reported in the past. CSF abnormalities were frequent, but significantly none of those tested had oligoclonal bands in the CSF. The outcome after a mean of 10 years follow up per patient was favourable; one was asymptomatic, 11 had minor disability, eight were moderately disabled and one severely disabled. The use of steroid therapy was associated with good recovery and outcome for the majority. Poor prognostic factors include male sex, early neurological presentation, two or more relapses with neurological disease, progressive course with incomplete resolution between attacks, and marked CSF leucocytosis.
047 THE EFFECT OF INTRAVENOUS IMMUNOGLUBULINS ON BRAIN ATROPHY IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS
X. Lin1,2, B. Turner2, L. D. Blumhardt2, C. S. Constantinescu2. 1Rehabilitation Research Unit, Derby City General Hospital; 2Division of Clinical Neurology, Queen’s Medical Centre, University of Nottingham, UK
Aims: Intravenous immunoglobulin (IVIG) has been reported to be effective in reducing relapse rate and disease activity on magnetic resonance imaging in relapsing-remitting multiple sclerosis (MS). The brain atrophy measure has been considered as a surrogate marker of disease progression in MS. This study was to evaluate the effect of IVIG treatment on cerebral atrophy in secondary progressive (SP) MS over 24 months.
Materials and methods: 43 patients with SP MS underwent T1-weighted 3-dimensional (3-D) magnetisation prepared rapid acquisition gradient echo images at months 0, 12, and 24. Expanded Disability Status Scale (EDSS) scores were obtained at 3-month intervals. The supratentorial, infratentorial, and lateral ventricular volumes were estimated using modern design stereology on 3-D MR images.
Results: The IVIG (n = 21) and placebo (n = 22) treated groups were well matched at baseline for age, disease duration, EDSS, and brain volumes. The placebo group had significantly greater infratentorial volume loss at month 12 (−1.8 vs +2.1%, p = 0.022) and month 24 (−3.3 vs +0.75%, p = 0.026) compared with the IVIG treated group. There was a smaller reduction of supratentorial brain volume in IVIG than placebo treated patients (−0.45 vs −2.1%) over 24 months, but this difference was not significant (p = 0.25). There was a significant enlargement of the lateral ventricles at month 24 in both IVIG and placebo treated groups, with a mean increase of 7.4% and 9.8% (p = 0.20 between groups), respectively. EDSS increased significantly in the placebo (p<0.0001), but not IVIG treated group (p = 0.07) over the study period. In the total cohort, the percentage change of lateral ventricles was correlated with the change in EDSS over 24 months (r = 0.58, p<0.0001).
Conclusions: Even though a small cohort, this study suggests that IVIG treatment does favourably reduce the rate of infratentorial brain atrophy in SP MS. The mechanism underpinning the effects is yet to be elucidated.
048 EFFECTIVENESS OF TETRACYCLINE ON THE PROTEASE-RESISTANT ACTIVITY AND THE INFECTIVITY OF SCRAPIE STRAIN 263K
Y. J. Guo1,2, J. Han2, H. L. Yao2, W. Q. Zhao1, D. X. Wang1, X. P. Dong2. 1Department of Neurology, Beijing Friendship Hospital, Capital University of Medical Sciences, China; 2National Institute for Viral Disease Control and Prevention, Beijing, China
Objective: To observe the possible effectiveness of tetracycline on the protease-resistant activity in vitro and the infectivity in vivo of a scrapie strain 263K.
Methods: Scrapie agents were incubated with different concentrated tetracycline for various periods and protease-resistant PrP signals were evaluated with proteinase K-treatment Western blots. The preparations treated with tetracycline were intracerebrally inoculated into golden hamsters and the typical TSE manifestations were noted. The presences of PrPSc in brain tissues of the illness animals were detected with PrP specific Western blot assays.
Results: Western blot assays showed that the amounts of protease-resistant PrP were significantly reduced or removed in the preparations treated with tetracycline, revealing a remarkable dose-dependant phenomenon. Compared with the control group with the mean incubation time 53.75±0.50 days, inoculations with the preparations treated with 5 mmol/L and 20 mmol/L tetracycline could prolong the incubation times of infected animals, whose mean incubation times were 61.5±1.73 and 59.5 0.58 days, respectively, showing statistic differences.
Conclusion: Treatment of scrapie agent 263K with tetracycline can reduce or remove its protease-resistant activity in vitro and prolong the incubation time of infected hamsters.
049 COMPARISON ON THE SIGNIFICANCE OF DETERMINATIONS OF CAE AND TITIN ANTIBODIES IN SERA FOR THE DIAGNOSIS OF MYASTHENIA GRAVIS WITH THYMOMA
Z-HHuang, J. Qiao, X. Zhang, Y-HGu, C-ZLu. Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China
Objective: It has been found that sera from patients with myasthenia gravis (MG) react in vitro with muscular antigens, such as CAE and Titin. In our study, we evaluated the clinical significance of determinations of CAE and Titin antibodies in sera of patients with myasthenia gravis with thymoma (MGT), and studied the correlation between these antibodies and the feature of MG.
Methods: The serum levels of CAE and Titin antibodies were determined by means of ELISA in 65 cases of MGT, 97 cases of non-thymoma myasthenia gravis (NTMG), seven cases of non-myasthenia gravis thymoma (NMGT), 35 cases of other neurological diseases (OND), and 100 individuals of normal controls (NC). We further analysed the correlation between serum levels and severity of disease in different types and histology of MG.
Results: We found that the sensitivities of CAE-ab and Titin-ab of patients with MGT were 63.1% and 61.5%, while the specificities were 75.3% and 91.8%, respectively. There was no significant difference between these two kinds of antibodies in the same pathological type of MGT. The frequency of both CAE-ab and Titin-ab was highest in MG with epithelial predominant-thymoma, 71.4% and 74.3%, respectively. The serum levels of them were correlated with the severity of MG positively.
Conclusions: We concluded that the determinations of levels of CAE and Titin antibodies may be a useful parameter in differential diagnosis of MGT prior to thymectomy, yet, the specificity of Titin antibody determination was significantly higher than CAE antibody determination. Both of them were clinically useful to estimate the severity of MG.
050 ANALYSIS OF ANTI-MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG) ANTIBODY IN PATIENTS WITH MULTIPLE SCLEROSIS (MS) AND ITS SIGNIFICANCE
F. Gao, Q. Y. Li, H-JHao, J-MYun. Department of Medicine, Division of Neurology, Peking University First Hospital, Beijing, China
Objective: To analyse anti-myelin oligodendrocyte glycoprotein (MOG) antibody in patients with multiple sclerosis (MS) and its significance.
Methods: Detect the anti- MOG antibody in serum and cerebrospinal fluid (CSF) of 56 patients with MS and 30 patients with other neurological diseases (OND) by enzyme-linked immunosorbent assay (ELISA) method.
Results: The positive rate of MS are 35.7% in serum and 42.8% in CSF, respectively. There is no significant difference between serum and CSF. The positive rate of OND are 6.7% in serum and in CSF. There is significant difference between MS and OND in both assays.
Conclusions: We can detect anti- MOG antibody in patients with MS. It is supposed to be provided evidence for the diagnosis and therapy of MS.
051 TNF-α TREATMENT AND CEREBRAL ISCHAEMIA-REPERFUSION INJURY
Y. Wu, Q. Liang, H. Lv. Department of Neurology, The Second Hospital of Harbin Medical University, Harbin, 150086, China
Objective: To study effects of TNF-α pre-treatment and after treatment on cerebral ischaemia reperfusion injury and explore possible mechanisms.
Methods: We referred to Zea Longa’s and the focal brain ischaemic model of middle cerebral artery occlusion (MCAO) was made by using inserting thread method. Several different doses of TNF-α or PBS were injected intracisternally 48 hours before ischaemia or after reperfusion. After 2 hours ischaemia and 22 hours reperfusion, the rats were killed. Then the percent of infarct volume was measured, pathological changes were observed, and GFAP and ICAM-1 expression were inspected by immunohistochemistry.
Results: Compared with PBS pre-treatment (pre), TNF-α 0.05 μg pre displayed no difference (p>0.05), TNF- 0.5 μg and TNF- 1.0 μg pre showed reduced volume of lesion (both p<0.05, the former was 70.9% and the latter was 66.5%.), less tissue damage, less GFAP and ICAM-1 expression (all p<0.05). Compared with PBS after treatment (after), TNF-α 0.05 μg after displayed no difference (p>0.05), TNF-α 0.5 μg and TNF-α 1.0 μg after showed increased volume of lesion (both p<0.05, the former was 22.3% and the latter was 46.7%.), aggravated tissue damage, more GFAP and ICAM-1 expression (all p<0.05). Between TNF-α 0.5 μg and 1.0 μg pre, there was no difference (p>0.05). Between TNF-α 0.5 μg and 1.0 μg after, there was obvious difference (p<0.05).
Conclusions: TNF-α pre-treatment was neuroprotective against cerebral ischaemia reperfusion injury. This effect did not depend on repair of astrocyte, but relied on reduced expression of ICAM-1. When TNF-α was given after cerebral ischaemia reperfusion, an exacerbation of ischaemia occurred, which was associated with elevated expression of ICAM-1. The actions of TNF-α were determined by whether TNF-α was given before or after cerebral ischaemia and were dose dependent. To study the effects of TNF-α on cerebral ischaemia reperfusion injury and to explore mechanisms that will help to develop therapeutics for ischaemic cerebral vascular diseases.
052 DETECTION OF BORNA DISEASE VIRUS p24 GENE FRAGMENTS FROM PERIPHERAL BLOOD CELLS IN PATIENTS WITH PARKINSON’S DISEASE
P. Xie1, P. Xu2, D. Z. Zou1. 1Department of Neurology, The First Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China; 2Department of Neurology, The First Affiliated Hospital, Zunyi Medical College, Zunyi, China
Objective: To study the relationship between Borna disease virus (BDV) infection and the human Parkinson’s disease.
Methods: The p24 fragment of BDV RNA in peripheral blood mononuclear cells (PBMCs) from 12 patients with Parkinson’s disease diagnosed clinically and 112 healthy blood donors were examined by nested reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence quantitative (FQ) PCR, and identified by cloning and sequencing.
Results: There was positive of BDV p24 fragment was positive in PBMCs in two of 12 cases of Parkinson’s disease, and was 96.5% homogeneous with the sequence of BDV standard strains (C6BV). There was negative in all of 112 healthy blood donors. The positive rate of BDV p24 fragment in PBMCs in Parkinson’s disease (16.67%) was higher than that in healthy blood donors (0%), the difference with statistical significance (p<0.05).
Conclusion: It is suggested that the BDV infection exists in patients with Parkinson’s disease in China. BDV infection might be one of the causes to facilitate the development of Parkinson’s disease.
053 TARGETS OF ANTIBODIES IN SERONEGATIVE MYASTHENIA GRAVIS
A. Vincent, I. Spreadbury, J. McConville. Department of Clinical Neurology, University of Oxford, UK
Aims: To determine the targets of pathogenic antibodies in the 15% of patients with generalised myasthenia gravis (MG) who do not have detectable acetylcholine receptor (AChR) antibodies by conventional radioimmunoprecipitation assays (so called “seronegative” MG, SNMG), and to define their clinical characteristics.
Materials and methods: We used a combination of in vitro cell binding, ion flux, and electrophysiological assays to characterise serum/plasma factors in SNMG patients, and tested candidate antigens for their reactivity with SNMG serum antibodies.
Results: We previously showed that some SNMG patients have a non-IgG factor that acutely inhibits AChR function in a muscle-like cell line, CN21. Here we show that the inhibitory effect of the non-IgG fraction correlates well with the desensitisation caused by 100 micromolar nicotine. Moreover, a similar effect was seen with M3C7—a monoclonal antibody that binds to the delta subunit of the human AChR. The results suggest that, rather than acting indirectly as previously proposed, the SNMG non-IgG factor, probably an IgM antibody, may bind directly to an allosteric site on the delta subunit that induces or enhances AChR desensitisation. IgG antibodies from a proportion of SNMG patients bind to the muscle specific receptor tyrosine kinase, MuSK, in ELISA and immunoprecipitation assays. MuSK antibody positive patients are usually female, and may have atypical symptoms with marked bulbar, neck, or respiratory weakness. They do not appear to benefit from thymectomy.
Conclusions: These studies demonstrate the heterogeneity of serum/plasma antibodies involved in myasthenia gravis without AChR antibodies. The non-IgG antibodies in SNMG patients do not bind to AChR in conventional assays, and new approaches for their routine detection for diagnosis are being established. MuSK antibodies can now be measured by a commercial assay and are proving useful in helping to diagnose patients with atypical myasthenic features.
054 MITOCHONDRIAL RESPIRATORY FAILURE
M. Roberts, D. DuPlessis, A. Simpson, W. Schady, P. Talbot. Centre for Clinical Neurosciences and North West Lung Centre, Manchester, UK
Introduction: The differential diagnosis of neuromuscular ventilatory failure is wide. We discuss two sibling pairs presenting with respiratory failure due to mitochondrial disease, which hitherto had been unsuspected.
Case descriptions: Patient A: a 57 year old man presented to casualty with a 1 week history of confusion and a 2 year history of breathless on lying flat. Blood gases on air compatible with type II respiratory failure (pO2 8 kPa pCO2 8 kPa), and the patient ventilated. On examination the patient had an abnormal respiratory pattern with episodes of apnoea, was cachetic and mentation was slow. Creatine kinase, acetylcholine receptor antibodies and thyroid function tests were normal, limited electromyography showed neurogenic changes and MRI scan signal change in the thalami. The patient was established on non-invasive ventilation (NIV) and later died of pneumonia. Muscle biopsy findings are discussed. Two years later the brother (patient B) presented with 2 week history of productive cough, on examination was apyrexial with a respiratory rate of 30/min and blood gases showed pO2 13.6, pCO2 4.7 kPa. His mentation was slow and his affect unusual. There was a rapid deterioration in ventilatory state with prolonged periods of apnoea, patient was not ventilated, and died 24 hours later. The results of an extensive post mortem are discussed, emphasising evidence of diffuse mitochondrial pathology. A further unrelated sibling pair (patients C and D) presenting in type II respiratory failure due to mitochondrial disease are briefly described. In both patients muscle biopsies showed extensive mitochondrial pathology, and both required NIV.
Conclusions: Mitochondrial disease needs to be considered in patients with ventilatory failure. Clinical pointers, common phenotypes, and the utility of NIV are discussed.
055 ANTIBODIES TO PERIPHERAL NERVE MYELIN PROTEINS IN CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY
D. Allen, K. Giannopoulos, N. A. Gregson, A. Makowska, J. Pritchard, R. A. C. Hughes. Department of Clinical Neurosciences, Guy’s Campus, Guy’s, King’s and St. Thomas’ School of Medicine, King’s College, London, UK
Aims: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired disorder of the peripheral nervous system with a likely autoimmune pathogenesis. We have previously shown that immunisation of rats with myelin protein zero, the major peripheral nerve glycoprotein, will induce experimental autoimmune neuritis and that antibodies to this protein will induce demyelination in rats following intraneural injection. The presence of antibodies to myelin protein zero and other proteins in CIDP is controversial. We therefore sought evidence of antibodies against peripheral nerve myelin proteins in CIDP and control subjects.
Materials and methods: We collected sera from CIDP, chronic idiopathic axonal neuropathy, and healthy control subjects. We applied the sera to electrophoretic gels of human cauda equina homogenate using the Western immunoblot technique and identified IgG, IgA, or IgM antibodies to nerve proteins.
Results: Eight of 32 CIDP sera reacted with peripheral nerve antigens, significantly more than two of 32 from normal controls (p = 0.04) and zero of 30 from chronic idiopathic axonal neuropathy patients (p = 0.005). Six CIDP sera had IgG or IgA antibodies reacting with a 28 kDa protein comparable to a band labelled with a mouse monoclonal antibody against myelin protein zero.
Conclusion: Antibodies to a peripheral nerve myelin protein with the same molecular weight as myelin protein zero, a known neurogenic antigen, are more common in the sera of patients with CIDP than those of control subjects.
056 SINGLE VERSUS REPEAT STEROID INJECTIONS IN CARPAL TUNNEL SYNDROME: A RANDOMISED CLINICAL TRIAL
A. C. F. Hui, S. M. Wong, L. Wong. Department of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, China
Aim: Steroid injections are commonly used in the treatment of carpal tunnel syndrome. This may be repeated in patients who relapse but the efficacy of a further steroid injection is unknown. We investigated the efficacy of a single steroid injection versus two injections in the treatment of idiopathic carpal tunnel syndrome (CTS).
Methods: Patients with electrophysiologically confirmed idiopathic CTS were randomised into two groups: 20 were given two injections of methylprednisolone acetate and another 20 were given one injection of methylprednisolone acetate and one of placebo. Patients were evaluated using a multiperspective approach with the Global Symptom Score (GSS) as the primary outcome measure.
Results: The GSS of the re-injection group improved from 26.7 at baseline to 12.6 at 40 weeks while the single injection group improved from 25.6 to 14.1. Although symptoms improved in both groups compared with baseline, there was no significant difference between the two sets of patients at any of the follow-up assessment points. At 40 weeks there was no difference in symptomatic relief as measured by Global Symptom Score and on secondary outcome parameters (median nerve distal motor latencies, sensory nerve action potential, and grip strength).
Conclusions: The results suggest that an additional steroid injection confers no added benefit to a single injection in patients with idiopathic CTS.
057 THE VALUE OF INCHING TECHNIQUE IN THE DIAGNOSIS OF MOTOR NERVE CONDUCTION BLOCK
L. Cui, M. Lui, X. Tang, B. Li, H. Du. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
Objective: To determine the value of inching technique in detection of conduction block (CB) and explore the natures of CB.
Methods: Three groups of subjects including 30 healthy controls, 44 patients with ALS, 38 patients with demyelinating neuropathy (14 patients with AIDP, 12 with CIDP, and 12 with MMN) were recruited in 4 years. Standard segmental motor nerve conduction studies and inching techniques were performed in median nerves and ulnar nerves simultaneously. The features of segmental motor nerve conduction studies in different groups were compared.
Results: (1) According to the criteria recommended by AAEM, four standard segments of four patients with ALS met the criteria of CB or probable CB but not confirmed by inching technique. (2) For the standard segments with a reduction in amplitude from 20% to 40%, when measured by inching technique, 21 short segments with CBs and 18 PCBs were detected in 18 nerves of patients with demyelinating neuropathy, while no CB in 19 nerves of patients with ALS. (3) In the segments with a reduction in amplitude of 20% or less, no CB was detected in all the subjects studied. (4) CBs were detected in eight nerves innervating non-weakened muscles in five patients with MMN, two patients with CIDP, and one patient with GBS. In segments with abnormal temporal dispersion, CBs were detected with inching technique across a short segment.
Conclusions: Inching technique is more sensitive in detecting CB, and could eliminate the influence of phase cancellation in some degree and extract CB from temporal dispersion. However, for segments with a reduction in amplitude of 20% or less, inching technique is not recommended.
058 DOWNREGULATED EXPRESSION OF 4-1BB AND INCREASED LEVELS OF SOLUBLE 4-1BB PROTEIN IN PERIPHERAL BLOOD OF PATIENTS WITH CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY
A. C. Gomes*1, G. Z. Liu*#1, P. Putheti2, K. Kostulas1, R. Press1, P. Hjelmström1. 1Division of Neurology, NEUROTEC Department, Huddinge University Hospital; 2Division of Neuroimmunology, NEUROTEC Department, Karolinska Institute, Stockholm, Sweden; #Current address: Department of Neurology, People Hospital of Peking University, Beijing, China; *These authors have contributed equally to this work
Objective: The tumour necrosis factor superfamily members, 4-1BB receptor (CD137) and 4-1BB ligand (4-1BBL) function as costimulatory molecules for the induction, differentiation, and survival of T cell subsets. Previous studies revealed elevated levels of activated T lymphocytes in peripheral blood of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Increased levels of soluble 4-1BB (s4-1BB) released by activated peripheral blood mononuclear cells (PBMC) and purified primary lymphocytes have been found in some autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis. In this study, we detected the expression of 4-1BB and 4-1BBL molecules at different levels in CIDP patients.
Methods: Using real-time PCR and flow cytometry, we investigated the levels of mRNA and surface protein expression of 4-1BB and 4-1BBL in PBMC of patients with CIDP, other neurological (noninflammatory) diseases (OND), and healthy controls. Moreover, s4-1BB protein was quantified by enzyme-linked immunosorbent assay (ELISA) in plasma specimens.
Results: In this study of 13 patients with CIDP, we found: (1) a significant decrease of 4-1BB mRNA levels in PBMC and an increase of s4-1BB protein level in plasma of CIDP patients in comparison with healthy controls; (2) lower protein expression of 4-1BB on CD4+CD25high T cells as well as of 4-1BBL on PBMC in CIDP patients compared to healthy controls.
Conclusion: These results indicate a potential and complex role of 4-1BB costimulation in the immune process of CIDP.
059 MITOCHONDRIAL DNA MUTATION ANALYSIS IN 57 CHINESE PATIENTS WITH MITOCHONDRIAL ENCEPHALOMYOPATHY
Z. Wang, F. Gao, Y. Yuan. Department of Neurology, First Hospital of Peking University, Beijing 100034, China
Objective: To investigate the characteristics of mitochondrial DNA mutations in 57 Chinese patients with mitochondrial encephalomyopathies.
Methods: Southern blot, PCR-RFLP, and direct sequencing of PCR products were performed to search large scale deletions and common pathological point mutations in patients’ muscle and/or blood mtDNA.
Results: Twenty-eight patients were identified harbouring mitochondrial DNA mutations, including A3243G point mutation in 11 patients (one with KSS, nine with MELAS, and one with mitochondrial entero-myopathy), A8344G point mutation in four patients (two with MERRF and two with LS), T8993G point mutation in one patient with LS, T8993C point mutation in one patient with LS, T3271C point mutation in one patient with mitochondrial entero-myopathy (MEM), and large deletions in 10 patients (seven with CPEO and three with KSS). The mutation hot spots in MEM were similar with that in MELAS. Direct sequencing of the PCR products revealed five novel large deletions. All of the mutations were heteroplasmic—i.e., mutant and wild mtDNA coexisted. The proportion of mutant mtDNA was 37.6%–97.8% in muscles (25 cases), and 10.8%–72.9% in blood cells (nine cases).
Conclusion: (1) The type and frequency of mtDNA mutations in this series of Chinese mitochondrial encephalopathies are consistent with those reported from other countries—i.e., most of the KSS/CPEO were associated with large scale of mtDNA deletion, MELAS with A3243G, MERRF with A8344G, and LS with T8993G or T8993C. (2) The five novel mtDNA deletions in KSS/CPEO and one MEM patient with T3271C point mutation are reported for the first time. (3) Heterogeneity in phenotype and genotype is a prominent feature seen in mitochondrial encephalomyopathies. With the judicious use of clinical, pathological, biochemical, and genetic data, the diagnosis for mitochondrial encephalomyopathies should be improved further.
060 A RARE MUTATION (SER105LEU) IN THE CU/ZN SUPEROXIDE DISMUTASE GENE ASSOCIATED WITH VARIABLY PROGRESSIVE FAMILIAL ALS IN CHINA
H. Zhang, D. Fan, H. Zhao, M. Lu, Y. Zhang, J. Zhang. Department of Neurology, Peking University Third Hospital, Beijing100083, China
Objective: Mutations in SOD1 gene are found in about 20% of familial ALS cases. So far, no mutations in SOD1 gene has been identified in Chinese ALS patients yet.
Methods: Three Chinese families of ALS were included in the present study. The clinical data of all of ALS patients were carefully collected; meanwhile, genetic studies were performed by using PCR and direct sequence analysis to detect SOD1 gene mutations. All of the exons of SOD1 gene were studied in the probands and the other members.
Results: A rare mutation of SOD1 gene was detected in two ALS patients and seven individuals without ALS symptoms in a five-generation ALS family from Guangxi province, southern China. This mutation that was heterozygous with C by T in exon 4 at position 1125 of the coding sequence, gave rise to a Ser to Leu substitution in amino acid 105 of SOD1. The analysis of the clinical data of ALS patients in this family showed that the clinical courses and features were relatively highly variable even with the same mutation.
Conclusions: The present study suggested that a rare mutation (Ser105Leu) found in a Chinese family was a pathogenic mutation in the heterozygous state that was associated with inheritance of variably progressive ALS.
061 SENSORY ABNORMALITIES IN UNAFFECTED RELATIVES IN FAMILIAL ADULT ONSET PRIMARY TORSION DYSTONIA: A SURROGATE PHENOTYPE MARKER?
J. P. O’Dwyer, S. O’Riordan, T. Lynch, F. Molloy, S. Bressman, R. Saunders-Pullman, M. Hutchinson. Department of Neurology, St. Vincent’s University Hospital, Dublin 4, Ireland
Aims: There is increasing evidence of a sensory abnormality in adult onset primary torsion dystonia (AOPTD). The spatial discrimination threshold (SDT) is a measure of spatial acuity and is abnormal in sporadic AOPTD. Familial AOPTD is an autosomal dominant condition, but with penetrance of 10–15%, and informative multiplex families are rare. Sensory changes in AOPTD may be a primary phenomenon and a possible surrogate marker. The aim of this study is to determine the SDT in affected family members and their relatives in multiplex families with AOPTD
Subjects and methods: The SDT was determined at the index fingertip bilaterally using standardised methods in 70 control subjects aged 20–45 years. In four multiplex families with AOPTD there were 29 consenting relatives and four affecteds (all cervical dystonia) <45 years of age. The SDT of a family member was regarded as abnormal when greater than the mean plus three standard deviations (SD) of the control group.
Results: The mean SDT for the control subjects was 1.157 mm (SD = 0.328 mm). Thus the upper limit of normal SDT for this age group was 2.141 mm (mean + 3SD). Abnormal SDTs were found in 3/4 affected, 5/11 children, 0/6 siblings and 3/12 second-degree relatives. The medians for the children and second-degree relatives were significantly greater than the control median (p<0.0001 and p = 0.0078, respectively). There was good correlation between SDT for each hand.
Conclusions: These markedly significant abnormalities of SDT found in eight out of 29 unaffected relatives may represent a surrogate marker for carriage of the gene responsible for AOPTD. The abnormal SDTs may reflect a primary structural abnormality in the sensory cortex that in a small proportion of patients may produce dystonia. SDT testing is less sensitive over the age of 45 years; however, it may aid genetic linkage studies of multiplex families.
062 SENSORY ATAXIC NEUROPATHY AS THE MAJOR FEATURE OF RECESSIVE POLG MUTATIONS
A. Al-Memar1, A. Lofgren2, M. Rantamaki3, W. Robberecht4, P. De Jonghe2, B. Udd5, C. Van Broeckhoven2, G. Van Goethem2. 1Department of Neurology, St George’s Hospital, London, UK; 2Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology; 3Department of Neurology, Seinajoki Central Hospital, Finland; 4Department of Neurology, Catholic University of Leuven, Belgium; 5Department of Neurology, Vaasa Central Hospital, Finland
POLG mutations are typically associated with progressive external ophthalmoplegia. We identified a novel POLG mutation in six patients presenting with sensory ataxic neuropathy. Ataxia was accompanied by various CNS features, including epilepsy, nystagmus, and dysarthria, and thalamic and cerebella white matter lesions on MRI. Ophthalmoparesis was mild to moderate and, in one patient, even absent. In muscle, typical findings of mitochondrial disease, such as ragged red fibres and Southern blot mtDNA abnormalities were absent. The novel mutation W748S was present in three Finnish siblings and in three isolated patients. In Finnish patients, W748S occurred in homozygous state. In isolated patients of British and Belgian origin, W748S occurred in compound heterozygous state together with the previously reported A467T. We expand the clinical spectrum of recessive POLG mutations by sensory ataxic neuropathy, combined with variable features of involvement of the CNS and other organs. POLG mutations should be considered in diagnostic work-up of juvenile or adult onset sensory ataxia, the more if ophthalmoparesis is present.
063 MSCs FUNCTIONALLY DIFFERENTIATED INTO DOPAMINE RODUCING CELLS AFTER ENGRAFTING INTO THE STRIATUM OF PARKINSON’S RAT
P. Xu, H. Yang, J. Li, Z. Liu. Department of Neurology, The first affiliated hospital of Sun Yat-sen University, Guangzhou, China
Objective: To investigate the potential of rat bone marrow mesenchymal stem cells (rMSCs) differentiating into dopamine-producing cells and restore its function in rat Parkinson model in vivo.
Methods: To better repair the 6-hydroxydopamine (6-OHDA) unilateral lesioned dysfunction in the substantia nigra of rats, rMSCs was prepared from adult Sprague-Dawley (SD) rat, firstly proliferated and differentiated in vitro into neurone-like cells in serum-free medium with a Chinese medicine, Musk’s polypeptide named Musk-1, then grafted into Parkinson rats that had unilateral Dopaminergic (DA) - depleted striatum, following its behavioural properties evaluated.
Results: Once Musk-1 added 2 hours after, cells started to differentiate into neurone-like cells, making those cell spheres nestin, NSE, NF-H positive, and GFAP-negative. After cell implantation, animals promoted significant improvement in function (apomorphine- induced rotation ameliorated in 25 grafted animals and persisted for 56 days on average) compared to the lesion-control group (p<0.001). Histology analysis confirmed a large number of rMSCs-derived cells survived well in the transplantation zoon and migrated around the host lesion as far as 5 mm, following developed DA neurone phenotype on approximately 50–55% of overall cells tested by the DA neurone marker tyrosine hydroxylase (TH).
Conclusion: These findings demonstrated that grafted rMSCs-derived cells can survive, migrate, and spontaneously develop into Dopamine-producing cells in striatum and restore behavioural properties expected of neurones from the midbrain.
064 INTRACEREBRAL TRANSPLANTION OF TH-TRANSFECTION/ENGINEERED CELL IN TREATING MONKEY WITH PARKINSON’S DISEASE
C-YWu, Y-GLiu, J. Wang, Y. Yang. Department of Neurosurgery, Qi-Lu Hospital of Shandong University, Jinan, 250012, China
Objective: Transfecting recombined plasmid with human TH gene to neuroblastoma cells to construct cell lines expressing TH gene. After being capsulated, they were transplanted into brains of monkey models. By efficient and stable expression, TH deficiency of striatum increased to a therapeutic level.
Methods: Cloned E. Coli with pcDNA3/hTH plasmid were transfected into human neuroblastomacyte line SY5Y. Positive clones were selected for transplantation into PD monkey models. Behaviour and DA concentration in CSF were observed. Transplanted cells were also examined by immunocytochemistry to determine their survival.
Results: (1) Subcloned and purified plasmid with pcDNA3/hTH gene were resolved into fragments of 1.9 Kb and 5.5 Kb by ECORI enzyme. It was in accordance with anticipated results. So recombined plasmid were testified to be right. Immunohistochemical staining of transgenetic SY5Y cells showed strong positive. (2) Symptoms of post-transplanted monkeys improved dramatically. DA concentration in CSF also increased. (3) Large numbers of transplanted TH-stained positive gliocytes were found in transplanting areas by SABC immunocytochemistry.
Conclusion: (1) Human neuroblastoma SY5Y cells constructed by gene transfection can express human TH gene in vitro following transplantation. (2) Microcapsulated transgenic cells can live and function well in monkey brain.
065 PHENOTYPE HETEROGENEITY IN PATIENTS WITH MTDNA A3243G MUTATION
Z. Wang2, Y. Zhang1, Y. Yuan2. 1Department of Central Laboratory; 2Neurology, Peking University First Hospital, Beijing 100034, China
Objectives: MitDNA A3243G mutation is usually found in mitochondrial encephalopathy with lactate acidosis and stroke like episodes (MELAS). Therefore MELAS gene is named in some reports. However the mtDNA A3243G mutation appeared also in other forms of mitochondrial disease. Here we discuss the clinical characteristics in the patients with mitochondrial DNA A3243G mutation.
Material and methods: Clinical manifestations as well as results of cranial CT and/or MRI scanning, blood level of lactic acid, and pathology of muscle biopsies of 25 mitochondrial encephalomyopathies cases with MELAS gene mutation were analysed.
Results: The diagnoses were: MELAS (19 patients), encephalopathies that could not be classified into any specific type (two patients), floppy infant (two children), KSS (one patient), and mitochondrial entero-myopathy (one patient). Elevation of blood lactic acid was notably found in all of the 25 patients. However, six non-MELAS patients showed normal CT or MRI findings. Two MELAS patients showed no ragged-red-fibres on muscle biopsies.
Conclusion: mtDNA A3243G point mutation appeared mainly in MELAS, but also in other clinical syndrome of mitochondrial disease. Because mtDNA A3243G mutation is the most frequently found in our patients, clinically diagnosed as mitochondrial disease and a few of the patients with this mutation have no RRF or cranial MRI changes, it should be as routine genetic examination in young patients with multiple organ involvement and elevated serum lactic acid.
066 POLYMORPHISMS IN THE 5′-FLANKING REGION OF CYP2E1 GENE AND GENETIC SUSCEPTIBILITY TO SPORADIC ALS
D. Fan, H. Zhang, J. Cui, M. Lu, Y. Zhang, J. Zhang. Department of Neurology, Peking University Third Hospital, Beijing, 100083, China
Objective: We first explore a hypothesis on the relation of the Pst I and Rsa I polymorphism in the 5′-flanking region of the cytochrome P450 2E1 gene (CYP2E1) gene and genetic susceptibility to sporadic ALS.
Methods: Using PCR and restriction digest analysis, the frequencies of the polymorphisms in 5′-flanking region of CYP2E1 were investigated in 104 patients with sporadic ALS and compared to those in 242 Chinese Hans controls.
Results: The frequency of the allele c2 was 19.7% in ALS patients and 17.6% in controls, and there were no significant differences between the patients and the controls. However, when each group was divided into two parts according to gender, there was a significant increase (p = 0.047) in the proportion of male patients with c1/c2 genotype compared with male controls. In ALS patients with at least two sites of motor neurone damage, a more significant difference was detected in the frequencies of c1/c2 (p = 0.019) and c1/c2 combined with c2/c2 genotype (p = 0.031) compared to the controls.
Conclusions: The results of the present study suggest that possession of a CYP2E1 c1/c2 genotype may be a risk factor for the development of sporadic ALS in male individuals.
067 CLINICAL FEATURES OF AUTOSOMAL RECESSIVE JUVENILE PARKINSONISM
J. Guo, B. Tang, Y. Zhang, X. Yang. Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
Objective: To explore the clinical features of autosomal recessive juvenile Parkinsonism (AR-JP).
Methods: The clinical materials of 28 patients from 15 families with AR-JP were analysed retrospectively.
Result: Among the 28 cases, age at onset was young. The symptoms of the Parkinsonian triad were mild, slow progression, and non-symmetric. Gait abnormality, diurnal fluctuation of symptoms, and hyperreflexia were relatively prominent. Brain CT and MRI were often normal. Response to levodopa was satisfactory.
Conclusion: The clinical features of patients with AR-JP are peculiar. AR-JP should be differentiated from other diseases to avoid misdiagnosis for its symptoms at earlier period atypical.
068 EXPERIMENTAL AND CLINICAL STUDIES ON TREATMENT OF MYSTHENIA GRAVIS WITH ZHONG JILING TABLET
Y-lWu1, Y. Zhou2, Y. Yang1, X-DWang2, J. Wang2, Z-HZhang1. 1Hebei Yiling Hospital, Hebei, Shijiazhuang 050091, China; 2Beijing University of Chinese Traditional Medicine, Beijing 100029, China
Objective: To objectively evaluate the clinical effect of treatment of Mysthenia gravis with Zhong Jiling tablet and explore functionary mechanisms, carried out through experimental and clinical studies.
Methods: A double-blind and double-controlled method was adopted in this study. IIA MG patients were randomly divided into the treatment group and treated with Zhong Jiling tablet and the control group was treated with Qiang Disong tablet. Clinical grades of curative effect, symptomatic integral of traditional medicine, repetitive nerve stimulation and anti-N2-AchRab titres in serum were observed. The effect of the Zhong Jiling tablet on the degree of clinical assessment of rats, weight, intramuscular strength, ability of movement, serum level of anti-AchR antibody, repetitive nerve stimulation, AchR content of the post-synaptic membrane, and IFN-γ, IL-4, and TGF-β were measured on base of experimental autoimmune myasthenia gravis (EAMG).
Results: Compared with control rats, clinical symptomatic integral, intramuscular strength, the percentage of decrement of the fifth wave and of experimental rats were obviously improved.
Zhong Jiling tablet also could reduce levels of anti-AchR antibody, IFN-γ, IL-4 and T lymphocyte proliferation and improve the content of TGF-β. At the same time, the disruption of AchR was reduced. The improvement in clinical symptoms in the treatment group was markedly higher than in the control group. Side effects and toxic reactions were not found in the treatment group. However, the effects of clinical grades, declining serum anti-AchRab titres and the attenuate rate of potential energy were parallel in the two groups.
Conclusions: This shows in a double blind trial that Zhong Jiling tablet can influence immune regulation, which is different from immunosuppression Western medicine.
069 THE PATHOLOGY OF SEMANTIC DEMENTIA
R. R. Davies, J. H. Xuereb, P. Waley, G. M. Halliday, J. J. Kril, J. R. Hodges. Dept. of Clinical Neurosciences & Dept. of Pathology, University of Cambridge, Cambridge, UK; Centre for Education and Research on Ageing, University of Sydney; Prince of Wales Medical Research Institute, University of New South Wales, Australia; MRC Cognition and Brain Sciences Unit, Cambridge, UK
Aims: This study examines the nature and the distribution of pathology in semantic dementia (SD). SD is a syndrome of progressive deterioration in semantic memory (knowledge of objects, people, concepts, and word meanings) with typical aphasia consisting of profound anomia, impaired comprehension, and preserved fluency of speech. SD falls within the clinical spectrum of fronto-temporal dementia (FTD) and structural scanning characteristically shows temporal lobe atrophy. The pathology of SD has been studied less systematically than its clinical and imaging features (largest published series, n = 3).
Materials and methods: 13 consecutive post mortem cases in which a diagnosis of SD had been reached in life were examined. The cases were taken from series in Cambridge, UK and Sydney, Australia. Standard histological (haematoxylin&eosin, Gallyas) and immunohistochemical stains (ubiquitin, tau, alpha-synuclein, amyloid-beta, neurofilament) were applied to 10 micron paraffin-embedded sections. In each case, six cortical and four subcortical regions were sampled. Lesion types were noted and semi-quantitative assessment of neuronal loss and lesion density was undertaken across all regions.
Results: Six cases had ubiquitin positive inclusions of the type seen in motor neurone disease (MND); four had Pick bodies; and three lacked distinctive immunostaining. Initial analysis of the data on lesion distribution suggests that anterior and inferior temporal regions bear the brunt of disease.
Conclusions: This study confirms that SD is a pathologically heterogeneous syndrome. In all cases, however, this heterogeneity was confined to recognised pathological subtypes of FTD. MND-type inclusions occurred in almost one half of the cases, emphasising the link between FTD and MND. Alzheimer pathology did not occur. Across pathological subtypes, the most severe abnormalities centred on the anterior and inferior temporal gyri, implicating this as a key region in semantic processing.
070 DIFFUSION TENSOR IMAGING ANALYSIS OF SENSORY APHASIA
Y. Zhang, Y. Wang, Y. Zhu. Department of Neurology, Tiantan Hospital of Capital Medical University, Beijing 100050, China
Purpose: We used 3.0T magnetic resonance machine diffusion tensor imaging technique, especially the fibre tracking method, to analyse the changes of cerebral nerve fibres between Broca’s area and Wernicke’s area of a sensory aphasia patient secondary to acute stroke.
Methods: We used 3.0T SIEMENS Trio 2003T and AG 2003 work station-siemens to scan and analysis diffusion tensor imaging of a diagnosed sensory aphasia patient using the Western Aphasia Battery. Diffusion tensor imaging method used seeds to track corticospinal tract fibres.
Results: Diffusion tensor imaging revealed that right fibre fasciculus were 234, mean factional anisotropy (FA) was 0.488175, left was 220, and mean FA was 0.479196. Left corticospinal tract value of FA and fibres were light reduced. The right transverse fibres of corpus callosum body were abnormal, with right frontal ascending fibres reducing. Left Broca’s area fibres tracking, fasciculus were 96, mean FA was 0.265547, the fibres related with middle and superior frontal gyrus, but there were no fibres related with Wernicke’s area. Right corresponding area’s fibres were 94, mean FA was 0.355798, and associated with superior frontal gyrus, temporal gyrusm, and occipital gyrus. Left Wernicke’s area fibres were 134, mean FA was 0.390709, fibres up to postcentral gyrus and inferior parietal lobule, no fibres ahead. Right corresponding area’s fibres were 233, mean FA was 0.323245. Fibres ascended to superior parietal lobule and ahead through arcuate fasciculus to opercula of frontal lobe.
Conclusions: Diffusion tensor imaging suggested that left corticospinal tract value of FA and fibres were light reduced, which means there were structure lost. Left Broca’s area fibre related with middle and superior frontal gyrus. There were no fibres related between Broca’s area and Wernicke’s area. Hence, there were nerve structure lost and fasciculus between language function areas reduced, which may be the pathogenesis of aphasia.
071 SELECTIVE IMMUNORESPONSIVITY TO Aβ40 AND MONOMERIC AβS, BUT IMMUNOTOLERANCE TO OLIGOMEIC Aβ42 OCCURRED NATURALLY IN PATIENTS WITH ALZHEIMER’S DISEASE AND AGE-MATCHED NORMAL CONTROLS
W. Xu1, S. Zhang1, J. Xiao1, E. Matsubara2, M. Shoji2. 1Department of Neurology, Guangzhou Red Cross Hospital, the Fourth Affiliated Hospital of Jinan University Medical College, Guangzhou 510220, China; 2Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700–8558, Japan
Objective: Recent studies suggest that a vaccine may be the most promising among the many candidate therapies for AD. In Zurich cohort of Phase II study, patients generated antibodies to amyloid plaques in plasma as determined by tissue amyloid plaque immunoreactivity (TAPIR) assay. They showed significantly slower decline rates of cognitive functions than those who did not generate antibodies to A after A vaccine injections, suggesting that antibodies against amyloid plaque may play a protective role in preventing AD progress. In this study, we hypothesised that naturally occurring antibodies to A will make similar beneficial clinical effects to these post-vaccine ones, and investigated their prevalence in AD patients and healthy elderly controls. Our aim was to clarify the possible role of vaccine treatment in preventing AD or slowing the AD process.
Methods: Plasma from 113 AD patients (AD group) and 155 age matched normal controls (aNC group) were examined by TAPIR assay, in which plasma levels of A 40 and A 42 were quantitatively measured by a sandwich ELISA. TAPIR positive plasma were immunoprecipitated with synthetic Aβ40, A 42 peptides and formic acid soluble fractions extracted from AD brain (FA), the immunoprecipitates were detected by monoclonal anti-A antibody 6E10 after electrophoresis in 4 to 12% NuPage Bis-Tris gel and sequent transfer into PVDF membranes in order to clarify immune specialities. MMS scores and illness durations were related with TAPIR findings in order to investigate their effects on clinical symptoms.
Results: High TAPIR positive rates were revealed in both AD (45.1%) and aNC group (41.2%) with no significant difference (p>0.05, t-test). TAPIR positive plasma could immunoprecipitate with more monomeric and dimeric A 40 and FA than monomeric A 42, but with no dimeric A 42. No significant difference of MMS scores (p = 0.912, ANOVA) and illness duration (p = 0.267, Kruskal-Wallis test) were observed between TAPIR positive and negative plasma. No significant correlations were revealed between plasma A levels and TAPIR findings (p>0.05, ANOVA).
Conclusion and Discussion: (1) Naturally occurring plasma antibodies to Aβ were frequently present in both AD patients and normal aged controls. This indicates that Aβ, as a normal antigen, may be positively selected into normal repertoire of immunoreactivity by the immune system; (2) Antibodies to A showed a different immunoresponsivity to A 40, A and FA. The selective immunotolerance to A 42 provides a reasonable explanation for the absence of significantly beneficial effect on AD progress; (3) Combined with previous studies, our data also suggested that naturally occurring antibodies to Aβ, like those occurring after A vaccine, could not modify plasma A variables including A 40, A 42 levels and their ratios. It should be necessary to further clarify the mechanism of selective immunotolerance to A 42. An enhanced immune response to A 42 may be helpful in producing a statistically significant beneficial effect on AD progression.
072 AGRAPHIA WITHOUT APHASIA DUE TO LEFT CEREBRAL HEMISPHERIC STROKE IN DEXTRALS
C. Haibo, C. Xiaojie, G. Tao, L. Shuhua, S. Wen, W. Xinde. Department of Neurology, Beijing Hospital, Beijing 100730, China
Objective: To investigate the occurrence, neurolinguistic features, and responsible focus for agraphia without aphasia in right handed patients.
Methods: Twenty-one non-aphasic patients with left hemispheric stroke were examined with Chinese Aphasia Examination Scale and asked to draw a human face, a clock, and a house for assessing their visuospatial ability.
Results: Six out of 21 patients showed pure agraphia, accounting for 28.6%. All six patients had no visuospatial impairment. Five patients with agraphia wrote using their left hands and one using both his hands when examined. The linguistic features of agraphia include construction disorder of characters, pictographic writing, lexical agraphia, and mirror writing. The responsible foci for agraphia were respectively located at left thalamus, parietal lobe, basal ganglion, parieto-frontal lobe, and white matter surrounding lateral ventricle.
Conclusions: (1) Pure agraphia is a rather common than rare syndrome. (2) Various sites of lesions led to agraphia is suggestive of the complexity of agraphic neuropathogenesis and neurolinguistic mechanism.
073 SUSCEPTIBILITY GENES FOR PARKINSON DISEASE
X. Zhao1, W. Zhang1, H. Xie2, S. Ding2, L. Li1. 1Department of Neurology, General Hospital of Beijing Military Commanding Region, Beijing 100700, China; 2Department of Neurology, Changhai Hospital, The Second Military medical University, Shanghai 200433, China
Objective: To investigate the association between 11 polymorphisms of eight candidate genes: dopamine beta hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxydase A and B (MAOA, MAOB), dopamine transporter 1 (DAT1), α-synuclein, Parkin, γ-synuclein with the susceptibility of Parkinson disease (PD).
Methods: Association study was performed in 154 PD patients and 210 healthy subjects. Polymorphisms of each gene were genotyped with polymerase chain reaction (PCR).
Results: (1) Polymorphisms of DBH, MAOB, and α-synuclein genes were associated with PD risk (for DBH A2/A2 genotype, OR = 2.094; for MAOB (GT)n 168 bp, 170 bp, 184 bp, 186 bp alleles total, OR = 3.976; for α-synuclein (GT)n 265 bp allele, OR = 6.183), but not COMT, MAOA, DAT1, Parkin, γ-synuclein genes polymorphisms, and α-synuclein mutations. (2) The COMT G/G genotype increased the DBH A1/A2-PD risk (OR = 5.633) and the COMT G/A genotype combined with MAOA T genotype can also confer an increased risk for PD (OR = 2.727). Individuals with DAT1-440/480-MAOA-T genotype had high risk for PD. (3) DBH A2 allele, MAOA T, and parkin A/A genotypes were more related to PD in males. MAOA T and COMT A/A genotypes might be risk factors of tremor onset PD, and γ-synuclein gene C/G genotype, rigidity onset PD. DBH A2 allele was risk factor of left side of body onset PD, and COMT A/A genotype, right side onset. DBH, MAOB, and COMT genes might modify the onset age of PD.
Conclusion: DBH, MAOB, α-synuclein genes were associated with PD risk, and polymorphisms chosen in MAOA, COMT, DAT1, Parkin, and γ-synuclein genes were mini-risk factors of PD.
074 ALZHEIMER’S DISEASE CAN BE ACCURATELY DIAGNOSED BY LONG DELAYED RECALL TEST
X. Hong, J. Wei, L. Y. Wu. Department of Neurology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing 100730, China
Objective: To compare validity on diagnosis of Alzheimer’s disease (AD) between immediate recall and long delayed recall.
Methods: 183 AD patients (118 mild, 65 moderate in degree), 1417 controls (1283 normal individuals, 134 individuals suffering from other disease) were recruited. California verbal learning test (CVLT) Chinese version, Complex figure (CF), Logistic memory (LM) Chinese version were conducted. Immediate recall was sum of immediate recall of CVLT, CF, and LM. Long delayed recall was sum of long delayed recall of CVLT, CF, and LM. Long delayed recognition was sum of long recognition of CVLT, CF, and LM. Sum of recall was the sum of immediate recall, long delayed recall, and long delayed recognition.
Results: Educational level (F = 357.22, p = 0.0001) was the most obvious factor in demographic data to influence sum of recall by a fitting of multiple regression models. There is significant different sum of recall between normal controls (76.8±0.4), other disease controls (59.8±1.5), mild AD patients (31.5±1.5), moderate AD patients (19.3±2.0), after adjusted educational level, age, sex, rural/urban status by multiple analysis covariance; p values between every two different groups were 0.0001. The cut off points to diagnose AD were taken from fifth percentage of normal controls of different kinds of recall score in different educational level, respectively. The sensitivity was 81.87%, 84.70%, 87.13%; the specificity was 94.13%, 92.61%, 93.53% for immediate recall, long-delayed recall, sum or recall, respectively.
Conclusions: Compared to using immediate recall separately, adding long delayed recall, and long delayed recognition increased sensitivity in diagnosing AD obviously. Application of long delayed recall is recommended in the diagnosis of mild to moderate AD.
075 STUDY OF PLASMA LEVELS OF Aß1-42, Aß1-40, AND P-TAU IN ALZHEIMER DISEASE
D. Peng, X. Cai, X. Xu, X. Wang. Beijing Hospital, Ministry of Health, Beijing, China
Alzheimer disease (AD) is a neurodegenerative disease that accompanies specific pathology and biochemical alterations, and is now the fourth major cause of death. After longitudinal study, some cholinesterase inhibitors have been found useful in improving the cognitive functions, but the early clinical diagnosis of AD is still difficult. Affected brains of AD patients are characterised by the presence of senile plaques (SP) and neurofibrillary tangles (NFT), senile plaques are mainly composed of ß-amyloid protein (containing 40–42 peptides), and the major protein component of NFT is a phosphorylated tau (microtubule-associated protein). This article is focused on recent advances measuring Aß1-42/1-40 and tau phosphorylated at specific epitope 181, aiming to clarify the alterations of Aß1-42/1-40 and p-tau (181p) in plasma of AD, and evaluating their significance for the diagnosis of AD.
Objective: To study the significance of plasma level of Aß1-42/1-40 and p-tau (181p) in the diagnosis of AD.
Subjects and methods: Subjects with AD (n = 58) and age-matched healthy control (HC, n = 30) were included in this study. All AD patients were diagnosed according to the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association) criteria and DSM-IVR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition revised) criteria. Twenty-three mild AD (19⩽MMSE⩽26) and 35 moderate and severe AD (MMSE<19, CDR⩾2 were included in AD group. Blood was collected from subjects into tubes containing Na-EDTA; plasma fraction was separated by centrifuge at 4°C, kept around 4°C less than 2 h, and measured using ELISA.
Results: The mean level of Aß1-42 was 105.6±8.3 pg/ml in the plasma of AD group (146.4±9.7 pg/ml in the mild, 84.4±6.6 pg/ml in the moderate-AD group), and 95.1±7.2 pg/ml in the HC group. Levels of Aß1-42 were higher in the mild AD group than that in HC, p<0.001, and levels of Aß1-42 were similar between patients with moderate-AD and HC. The plasma level of Aß1-40 was slightly higher in AD patients than that in HC, but there was no statistically significant difference between the two groups. The mean p-tau level was statistically significantly higher in the moderate-AD patients (18.3±20.3 pg/ml) than that in the HC group (5.7±4.3 pg/ml) (p<0.001). There was no significant difference of the mean p-tau level among the other three groups (14.5±18.9 pg/ml in the AD group, 8.5±14.9 pg/ml in the mild AD group, and in the HC group). A specificity level of plasma p-tau was 93%, but sensitivity was low, about 20% patients in the AD group had high plasma levels.
Conclusion: Our data suggest that plasma Aß1-42 is increased in mild AD, if improving the determining technique, it might be a potential biochemical tool for the diagnosis of AD.
076 THE SINGLE NEUCLEOTIDE POLYMORPHISMS OF LIVER X RECEPTOR BETA GENE AND ITS ASSOCIATION WITH SPORADIC ALZHEIMER’S DISEASE IN CHINESE
F. G. Zhao1, Y. H. Wang1, P. Chan2. Department of Neurology, First Hospital of Peking University, Beijing, China; Institute of Geriatrics, Department of Neurology, Xuanwu Hospital of Capital University of Medical Science, Beijing, China
Objective: Alzheimer’s disease (AD) is a complex disease caused by an interaction of multiple environmental and genetic factors. Mounting evidence suggests that cholesterol is involved in the pathogenesis through regulating α- and β-cleavage. Since liver X receptor beta (LXRβ), a member of the nuclear receptor superfamily, has been shown to play critical roles in the regulation of cholesterol balance, we hypothesised that LXRβ may be one of new genetic susceptibility genes of sporadic AD.
Methods: We scanned LXRβ gene for the presence of sequence variations by denaturing high performance liquid chromatography (DHPLC) combined with direct sequencing and analysed their distribution in our northern Han-Chinese subjects of 108 sporadic AD patients and 118 age and gender matched controls.
Results: We found 15 different polymorphisms: two low transversion frequency deletions causing an amino acid change (c.526_528deoCAG, c.1056delC); the others are either silent or in non-coding regions. None of them were significantly associated with the disease; date stratification by apolipoprotein Eε4 carrier status or the age of subjects show a trend (p<0.05) for the transversion c.519A>G in the population of non-Eε4 carrier status.
Conclusion: Our data suggest that the silent polymorphism c.519A>G in the exon 6 of LXRβ gene had a statistical trend association with sporadic AD independence of apolipoprotein Eε4 in our northern Han-Chinese sample.
077 GOAT SERUM PRODUCT RESTORES CONDUCTION IN DEMYELINATED HUMAN OPTIC NERVE FIBRES
B. Youl, S. D. T. White, M. Cadogan, A. G. Dalgleish. Department of Clinical Neurophysiology, The Royal Free Hospital, London, UK
Aims: Multiple sclerosis (MS) patients receiving Aimspro, a polyclonal antibody product derived from purified goat serum (1 ml sub-cutaneously twice weekly) have reported improvement in colour vision within as little as 10 minutes after their first injection. We sought to determine whether this anecdotal evidence could be substantiated.
Materials and methods: Six patients with stable visual dysfunction due to chronic optic neuropathy in the setting of MS were studied. Distance acuity and colour vision data were acquired and monocular visual evoked potential (VEP) studies were carried out before and after the first injection, and at follow up.
Results: Within an hour of injection, there was significant improvement in colour vision (p = 0.008) and comparison of pre-treatment and follow up data (at 4 to 7 weeks) also showed significant benefit (p = 0.003). In one patient no response could be obtained from the right eye before treatment but 30 minutes later, a markedly delayed but reproducible P100 response was seen.
Conclusion: This uncontrolled, unblinded observational series raises the possibility that fixed or slowly progressive visual dysfunction in MS may be ameliorated by administration of this well tolerated medication. The neurophysiological finding suggests that reversal of conduction block in severely demyelinated fibres may account for this effect. The fact that no improvement in P100 latency could be detected from any eye over the study period argues against there having been significant remyelination during this time.
078 NEUTRALISING ANTIBODIES TO BETA- INTERFERON INCREASE THE TREATMENT FAILURE RATE IN MULTIPLE SCLEROSIS
K. O’Rourke, M. Hutchinson. Department of Neurology, St.Vincent’s University Hospital, Dublin, Ireland
Objective: To investigate whether neutralising antibodies (NAB) have an effect on the response of patients with relapsing-remitting multiple sclerosis (RRMS) to beta-interferon (IFNB) in clinical practice.
Methods: In this observational study of a cohort of 85 RRMS patients seen from disease diagnosis and treated with IFNB, patients were followed at 6 to 12 monthly intervals for up to 5 years. Relapses were noted at each assessment and a Kurtzke expanded disability status scale (EDSS) measurement was performed at least yearly. Patients were considered to have failed IFNB therapy (1) when there was no reduction in the pre-treatment relapse rate; (2) if they sustained two disabling relapses within any twelve-month period after starting IFNB; (3) when there was a one-point increase in the pre-treatment EDSS without a relapse in the previous six months. The cytopathic effect (CPE) assay in a single laboratory was used for quantification of NAB titres.
Results: Of the 85 patients, 26 (31%) were found to have significant levels (>10 iu) of NABs. 59 patients (69%) were deemed NAB-negative. Demographics were similar in the two groups. 17 (66%) of NAB-positive patients were deemed to have failed IFNB therapy; 12 (71%) of these treatment failures were due to persistent relapses. 28 (48%) of NAB-negative patients met treatment failure criteria, and this was due to persistent relapses in 14% (50%). Kaplan-Meier analysis showed that the NAB-positive group met relapse-based treatment failure criteria significantly earlier than NAB-negative patients (p = 0.02). When disability-based failure was included there was a trend towards earlier treatment failure in the NAB-positive group (p = 0.06).
Conclusion: NAB-positive patients with RRMS meet relapse-based treatment failure criteria earlier than NAB-negative patients.
079 FRAGILE-X-ASSOCIATED TREMOR/ATAXIA SYNDROME IN A WOMAN UNMASKED BY CHEMOTHERAPY
J. P. O’Dwyer, M. Sweeney, J. Crown, D. E. Barton, M. Hutchinson. Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland
Aims: The Fragile-X Tremor-Ataxia Syndrome (FXTAS) is characterised by tremor, gait ataxia, cognitive impairment and occasionally parkinsonism, usually in male premutation carriers of the FMR1 gene. The aim is to describe FXTAS in a woman, which became clinically apparent after a single dose of chemotherapy.
Case report: A 70-year old woman developed an acute onset gait ataxia, postural tremor of the upper limbs, and titubation after starting carboplatin and docetaxel (in non-toxic doses) for metastatic breast cancer. She has two sons with Fragile-X mental retardation syndrome. Chemotherapy was stopped and she improved to her baseline of mild gait ataxia and head tremor and mild cognitive impairment. Docetaxel alone was recommenced with no deterioration. MRI brain showed atrophy of the posterior vermis and cerebella hemispheres. PCR and southern blotting identified her as a premutation carrier with 95 CGG repeats (normal<55).
Conclusion: Only five women have been reported with FXTAS, and in one of these, autopsy showed intraneuronal inclusions. In this woman, a subclinical FXTAS became symptomatic due to chemotherapy. Such patients may be more susceptible to toxic insults.
080 A COMPARISON OF THE IMMUNOLOGY AND HISTOPATHOLOGY IN POST MORTEM MULTIPLE SCLEROSIS BRAIN
E. T. Lim, K. Schmierer, D. Grant, G. Keir, E. J. Thompson, D. H. Miller, G. Giovannoni. Department of Neuroinflammation, Institute of Neurology, Queen Square, London, UK
Aims: (1) To determine whether the markers for brain specific proteins (BSP) correlate with myelin content, axonal count and gliosis as determined by quantitative histology in post-mortem multiple sclerosis (MS) brains and; (2) to evaluate for differences in BSP between normal appearing brain tissue and MS lesions.
Materials and methods: Twenty-four 5-mm slices of brain were studied. Macroscopically visible lesions (n = 96) and normal appearing (NA) grey matter (GM) and NA white matter (WM) (n = 193) were sampled, homogenised and analysed for BSP using ELISA technique. The BSP measured were ferritin, a marker of microglial activation; S100B and glial fibrillary protein (GFAP), markers of astrocytic activation and gliosis; and two neurofilament heavy chain phosphoforms (NfHSMI34 and NfHSMI35), markers of axonal damage or loss. Histologically the myelin content, extent of gliosis and axonal count in lesions and areas of NAWM were assessed by applying quantitative techniques on sections stained for Luxol Fast blue, GFAP and Bielschowsky’s silver impregnation.
Results: (1) Areas of NAWM and lesions in 11 brain slices were studied for both BSP and neuropathological markers. GFAP (ELISA) inversely correlated with axonal density (r = −0.51, p<0.01) and the number of axons (r = −0.47, p = 0.01). There was marginal evidence that S100B inversely correlates with axonal density (r = −0.36 p = 0.06). (2) A total of 289 samples of NAWM, NAGM and lesions were evaluated for BSP. Significant differences were detected between lesions and both NAWM and NAGM for ferritin, S100B, GFAP and NfHSMI34 (all p values <0.05).
Conclusions: This study using in vitro ELISA techniques suggests that axonal changes are more pronounced in the vicinity of reactive gliosis, but it is also noted that a previous study (using quantitative histology only) detected no such correlation.
081 REGIONAL METABOLITE RATIOS IN TWO SYNDROMIC VARIANTS OF FRONTO-TEMPORAL DEMENTIA USING 1H MAGNETIC RESONANCE SPECTROSCOPY
P. Garrard, D. G. MacManus, A. D. Waldman. Institute of Neurology, University College London, London, UK
Aims: Magnetic resonance spectroscopy (MRS) provides in vivo information about the biochemical composition of healthy and diseased brain. Specific metabolite profiles appear to characterize the changes of early Alzheimer’s disease (AD), in which abnormally low levels of N-Acetyl aspartate (NAA) and high levels of myoinositol (MI) have been consistently documented. Less information is available about the changes seen in other forms of dementia. We studied patients with frontotemporal dementia (FTD), a focal neurodegenerative process associated with a number of clinical variants involving either behaviour (frontal variant), or language (primary progressive aphasia (PPA)). We examined a region, which is consistently associated with typical changes in AD.
Materials and methods: Nine patients with PPA-variant FTD (five with fluent and four with nonfluent aphasic syndromes) and five age-matched cognitively normal controls participated in the study. Short echo time (TR 3,000 ms; TE 30 ms) 1H MRS was performed on a 1.5T GE Signa scanner. Spectra were acquired from single midline volumes of interest (∼3.5 ml) immediately posterior to the splenium of the corpus callosum. Metabolite concentrations were fitted to the linear combination (LC) model. Values for NAA and myoinositol MI were expressed as ratios to Creatine (Cre) and compared across subject groups.
Results: Significantly higher MI:Cre ratios were found in patients compared to controls, but NAA:Cre ratios did not differ between the two groups. No differences were found in either metabolite ratio between the fluent and nonfluent aphasic subgroups of FTD patients.
Conclusions: There is overlap between AD and FTD in terms of metabolite abnormalities in the posterior cingulate region, though this appears to be limited to MI. Further studies will attempt to determine whether this finding is focal, indicative of a nonspecific response to pathological change, or an artefact of inaccurate clinical classification.
082 SCREENING FOR GLUTAMATE TRANSPORTER MODULATORS
M. R. Douglas, J. Adu, E. Goodall, K. E. Morrison. Department of Clinical Neuroscience, Division of Neuroscience, The Medical School, University of Birmingham, Birmingham, UK
Aims: Glutamate is the primary excitatory neurotransmitter in the central nervous system, with activity dependent on excitatory amino acid transporter (EAAT) function. Transporter dysfunction is postulated to play a role in stroke, epilepsy and neurodegenerative conditions. This study evaluated potential modulators of the astroglial EAAT2 protein, responsible for 90% of all glutamate transport activity in the CNS.
Methods: EAAT2 contains two cytoplasmic domains, forming likely interaction sites for activity-regulating proteins. A carboxy-terminal cytoplasmic domain of EAAT2 was used as bait in a yeast two-hybrid screen of an adult human cDNA library. Resultant clones were isolated, sequenced and characterised.
Results: This approach led to the isolation of number of genes whose protein products interact with the EAAT2 bait. These include several cytoplasmic and transmembrane proteins with identified roles in cellular interactions including cell adhesion, and neural growth. The specificity of these interactions has been confirmed in yeast cells and are being further characterised in mammalian cells using biochemical and cellular approaches.
Conclusions: The yeast two-hybrid approach provides an efficient screening technique for potential modulators of the glutamate transporter EAAT2. Investigating the nature of these interacting proteins may provide significant insights into the pathogenesis of a range of disabling neurological conditions, potentially leading to novel therapeutic approaches to their treatment.
083 INTERNATIONAL CAROTID STENTING STUDY (ICSS): WHAT IS THE OPTIMUM TREATMENT FOR CAROTID STENOSIS?
M. M. Brown.Institute of Neurology, University College London, UK
Aims: Stenting for carotid stenosis avoids general anaesthesia, cranial nerve injury and the discomforts of carotid endarterectomy. Our systematic review of the randomised trials of carotid stenting showed no difference in the major risks of stenting compared with surgery, but the confidence intervals were wide and both methods carried a significant risk of stroke. Protection devices may improve the safety of stenting, but there is still little randomised data available about long term outcomes, except from the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). We have therefore started CAVATAS-2, known as the International Carotid Stenting Study (ICSS), to obtain more data on the risks and long term benefits of carotid stenting in comparison to surgery.
Methods: ICSS is a multicentre, randomised, controlled, open, prospective clinical trial. Centres are required to have a neurologist/stroke physician, vascular surgeon/neurosurgeon and interventionist, with audited expertise in carotid interventions and attendance at a carotid stenting training course. Centres with limited experience can join as probationary centres, but stenting must be proctored by an experienced interventionist. Patients over 40 years old with atherosclerotic carotid stenosis are randomised in equal proportions to carotid endarterectomy or stenting. Patients are followed up for 30 days after treatment, 6 months after randomisation and then annually. Doppler ultrasound is used to assess restenosis. The recruitment target is 1500 patients.
Results: By June 2004, 25 centres in 10 countries in Europe, North America and Australia, had enrolled 342 patients. Several other centres, including one in China, are currently enrolling. New centres are welcome.
Conclusions: The trial will help to establish the optimum method of treating carotid stenosis. Further details may be found on the trial website (www.cavatas.com).
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