- Email: [email protected]
DS4.3 Inflammatory myopathies
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Disease Specific Symposia / Clinical Neurophysiology 117 (2006) S18–S24
there is strong evidence of increased incidence of more minor cognitive dysfunction. Aims: To assess pathological factors associated with HAD and minor cognitive deficits in HIV-infected individuals. Methods: Examination of postmortem tissue correlating results with clinical data acquired in life. Results: HAD in the pre-HAART era shows a partial association with a variety of pathological factors including: microglial activation, presence of HIVE, blood–brain barrier damage, and neuronal damage. In the post-HAART era many subjects display an accelerated deposition of hyperphosphorylated Tau. The abuse of IV drugs also enhances these measures of brain damage. Discussion: There is no single key pathological factor in the development of HAD, but there are several linked factors many of which are exacerbated by the combination of IV drug abuse with HIV. Since the introduction of HAART minor cognitive deficits have increased. We have found evidence of early deposition of hyperphosphorylated Tau in HAART-treated subjects. This neurodegenerative protein is associated with ageing and Alzheimer’s disease and its presence raises concerns for the long-term health of individuals maintained on HAART. doi:10.1016/j.clinph.2006.07.057
DS4.1 Muscular dystrophies A. Amato Brigham and Women’s Hospital, Department of Neurology, USA The muscular dystrophies are a clinically and genetically heterogeneous group of myopathies typically associated with progressive weakness. Weakness may be noted at birth or develop in late adult life. Some patients manifest with myalgias, rhabdomyolysis, or only elevated serum creatine kinase levels without any symptoms or signs of weakness. The muscular dystrophies can be inherited in an X-linked, autosomal recessive, or autosomal-dominant fashion and can result from mutations affecting structural proteins localizable to the sarcolemma proteins, nuclear membrane, basement membrane, sarcomere, or non-structural enzymatic proteins. Electrophysiological and routine histological examination of muscle biopsies is usually not helpful in distinguishing the different types of muscular dystrophy. Therefore, it is important for the clinician to understand the phenotypic differences that may be seen in the various types of dystrophies and tests available to make accurate diagnoses, provide genetic counseling and treatment for patients with dystrophies. doi:10.1016/j.clinph.2006.07.058
DS4.2 Non-dystrophic myotonias and periodic paralyses R.J. Barohn University of Kansas Medical Center, Neurology, USA The non-dystrophic myotonias (NDM) and periodic paralyses (PP) are inherited disorders of muscle resulting from molecular defects in Na+, Cl , and Ca2+ channels. PP include hyperkalemic (HyperPP), Hpokalemic (HypoPP), and Andersen’s syndrome (AS) and are typified by episodic attacks of weakness associated with extracellular changes in K+. NDM include myotonia congenita (MC), paramyotonia congenita (PMC), and potassium aggravated myotonia (PAM) and are typified by stiffness, pain, and myotonic potentials on EMG. In classic myotonia symptoms improve with repeated effort (warm-up), while in PMC symptoms get worse (paradoxical). There is overlap between NDM and PP, with HyperPP having myotonia and PMC having weakness. The channelopathies are grouped together by location of the molecular defect. The sodium channelopathies are caused by mutations in SCN4A and include PMC, HyperPP, and PAM. Alterations in the fast inactivation gate lead to a depolarizing current that, depending on the degree of depolarization, causes myotonia, paralysis, or both. The chloride channelopathies include autosomal-dominant (Thompson’s) and autosomal-recessive (Becker’s) forms of MC and are caused by mutations in the CLC-1 channel. A decrease in muscle Cl conductance causes depolarization of the membrane and myotonia. HypoPP is caused by mutations in the CACNA1 channel that links the t-tubule to Ca2+ release. In the setting of K+ influx the membrane becomes depolarized and inexcitable. AS is caused by mutations in a K+ channel and is a multisystem disorder characterized by episodes of weakness, dysmorphic features, and cardiac arrhythmias. Both NDM and PP show characteristic changes in CMAP amplitude following short and long periods of exercise. These tests may be useful in differentiating NDM and PP subtypes. Common to all these disorders is depolarization of the muscle membrane. How this causes myotonia or paralysis will be elucidated as more is learned about the specific channel mutations. doi:10.1016/j.clinph.2006.07.059
DS4.3 Inflammatory myopathies S. Greenberg Brigham and Women’s Hospital, Neurology, USA Background: The inflammatory myopathies are diseases characterized by varying skeletal muscle weakness and the presence of immune system cells within muscle tissue. The principal inflammatory myopathies are dermatomyositis, inclusion body myositis, and polymyositis.
Disease Specific Symposia / Clinical Neurophysiology 117 (2006) S18–S24
Aim/objective: We discuss recent findings that clarify the nature of the immune system cells present in muscle. Methods: Combined microarray, immunohistochemical studies, and analysis of immune system cell antigen specific receptors have been used to define newly discovered immune system cells present in muscle in the inflammatory myopathies. Results: Microarray studies identified transcripts unique to specific populations of immune system cells not previously recognized as present in muscle in the inflammatory myopathies and these findings were confirmed by immunohistochemistry. For dermatomyositis, plasmacytoid dendritic cells are present in muscle and are major secretors of interferon-a and -b. For inclusion body myositis, myeloid dendritic cells and differentiated B cells, in the form of plasma cells, are present in muscle. Analysis of immunoglobulin sequences in muscle from dermatomyositis, inclusion body myositis, and polymyositis indicates an antigen-driven B cell response is present. Conclusions: Several previously unrecognized immune system cell populations are present in muscle in the inflammatory myopathies. Defining these populations and their role in the disease pathogenesis provides significant insight into the mechanism of tissue injury present in these diseases. doi:10.1016/j.clinph.2006.07.060
DS5.2 The role of EEG in diagnosis of idiopathic generalised epilepsies M. Koutroumanidis Guy’s and St. Thomas’ NHS Trust, Clinical Neurophysiology and Epilepsies, UK Background: Clinical criteria alone may not always be sufficient or indeed infallible for the diagnosis of epilepsy and the characterisation of its type. The EEG can contribute to this diagnostic refinement, but EEG phenomena may not comply with the dichotomy ‘‘focal-generalised’’ of syndrome classification: generalised spike-wave (GSW) discharges do not necessarily indicate IGE, and not all focal SW reflect symptomatic foci. Aims: (i) To present the morphological spectrum and behavioural characteristics of the interictal and ictal EEG markers of IGE that may guide recording strategies to augment diagnostic yield; (ii) to delineate features that may be relevant to different IGE sub-syndromes; (iii) to explore the boundaries (and their vagueness) between IGE and other epilepsies and non-epileptic paroxysmal electroclinical phenomena, with due emphasis on focal abnormalities. Patients and methods: Video EEG analysis of more than 300 patients with different IGE syndromes from our epilepsy clinic/review of literature. Results and conclusions: A regular 3 Hz GSW discharge is the archetypal IGE feature but diagnosis should rely on
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the whole electroclinical picture and not on isolated EEG features that may conflict. What we accept as IGE depends on our experience and ability to recognise distinct electroclinical patterns and presentations and associate them with other information in a meaningful way. Attention should perhaps shift from elaborating on the morphology of a bilateral and diffuse SW discharge to deducing its possible aetiology by identifying markers that would predict stable (symptomatic) or unstable (idiopathic) regional hyperexcitability, and this is why focal discharges are also important. doi:10.1016/j.clinph.2006.07.061
DS5.3 Generalised management H. Cock
epilepsies:
Treatment
issues
and
St. Georges, University of London and Atkinson Morley Regional Neuroscience Centre, Epilepsy Group, UK Idiopathic generalized epilepsies (IGEs) constitute nearly 1/3 of all epilepsies, usually arising in childhood/ early adulthood. Good management as for all epilepsies includes provision of accurate information on diagnosis, risks (of seizures and treatment), prognosis, and relevant lifestyle advice. Where possible, a correct syndromic classification is important as the basis for advice on prognosis and decisions about treatment in particular, though will not be covered in detail. Most IGE syndromes respond well to appropriate antiepileptic drugs (AEDs), but treatment can be demanding because: (a) some AEDs of benefit in focal epilepsies can be deleterious in IGEs, and (b) efficacy of AEDs can differ across seizure types, including on an individual level. In addition, treatment is often lifelong, meaning potential long-term side effects such as bone health must be considered. Furthermore, as one of the most efficacious drugs (valproate) carries higher risks than others of foetal malformations, and possible other effects during pregnancy, decisions about treatment for women of potential childbearing age with IGE are particularly difficult. There are relatively few clinical trials in IGEs compared to focal epilepsies, but available data will be reviewed. It has been estimated that up to 50% of patients with IGE are currently taking ill-advised AED medication. Together with misdiagnosis, this contributes to avoidable morbidity, and sometimes mortality in IGE which needs to be addressed internationally. doi:10.1016/j.clinph.2006.07.062
DS6.1 Unique electrophysiology of anti-MAG polyneuropathy A. Sumner Louisiana State University Health Sciences Center, Neurology, USA
Disease Specific Symposia / Clinical Neurophysiology 117 (2006) S18–S24
there is strong evidence of increased incidence of more minor cognitive dysfunction. Aims: To assess pathological factors associated with HAD and minor cognitive deficits in HIV-infected individuals. Methods: Examination of postmortem tissue correlating results with clinical data acquired in life. Results: HAD in the pre-HAART era shows a partial association with a variety of pathological factors including: microglial activation, presence of HIVE, blood–brain barrier damage, and neuronal damage. In the post-HAART era many subjects display an accelerated deposition of hyperphosphorylated Tau. The abuse of IV drugs also enhances these measures of brain damage. Discussion: There is no single key pathological factor in the development of HAD, but there are several linked factors many of which are exacerbated by the combination of IV drug abuse with HIV. Since the introduction of HAART minor cognitive deficits have increased. We have found evidence of early deposition of hyperphosphorylated Tau in HAART-treated subjects. This neurodegenerative protein is associated with ageing and Alzheimer’s disease and its presence raises concerns for the long-term health of individuals maintained on HAART. doi:10.1016/j.clinph.2006.07.057
DS4.1 Muscular dystrophies A. Amato Brigham and Women’s Hospital, Department of Neurology, USA The muscular dystrophies are a clinically and genetically heterogeneous group of myopathies typically associated with progressive weakness. Weakness may be noted at birth or develop in late adult life. Some patients manifest with myalgias, rhabdomyolysis, or only elevated serum creatine kinase levels without any symptoms or signs of weakness. The muscular dystrophies can be inherited in an X-linked, autosomal recessive, or autosomal-dominant fashion and can result from mutations affecting structural proteins localizable to the sarcolemma proteins, nuclear membrane, basement membrane, sarcomere, or non-structural enzymatic proteins. Electrophysiological and routine histological examination of muscle biopsies is usually not helpful in distinguishing the different types of muscular dystrophy. Therefore, it is important for the clinician to understand the phenotypic differences that may be seen in the various types of dystrophies and tests available to make accurate diagnoses, provide genetic counseling and treatment for patients with dystrophies. doi:10.1016/j.clinph.2006.07.058
DS4.2 Non-dystrophic myotonias and periodic paralyses R.J. Barohn University of Kansas Medical Center, Neurology, USA The non-dystrophic myotonias (NDM) and periodic paralyses (PP) are inherited disorders of muscle resulting from molecular defects in Na+, Cl , and Ca2+ channels. PP include hyperkalemic (HyperPP), Hpokalemic (HypoPP), and Andersen’s syndrome (AS) and are typified by episodic attacks of weakness associated with extracellular changes in K+. NDM include myotonia congenita (MC), paramyotonia congenita (PMC), and potassium aggravated myotonia (PAM) and are typified by stiffness, pain, and myotonic potentials on EMG. In classic myotonia symptoms improve with repeated effort (warm-up), while in PMC symptoms get worse (paradoxical). There is overlap between NDM and PP, with HyperPP having myotonia and PMC having weakness. The channelopathies are grouped together by location of the molecular defect. The sodium channelopathies are caused by mutations in SCN4A and include PMC, HyperPP, and PAM. Alterations in the fast inactivation gate lead to a depolarizing current that, depending on the degree of depolarization, causes myotonia, paralysis, or both. The chloride channelopathies include autosomal-dominant (Thompson’s) and autosomal-recessive (Becker’s) forms of MC and are caused by mutations in the CLC-1 channel. A decrease in muscle Cl conductance causes depolarization of the membrane and myotonia. HypoPP is caused by mutations in the CACNA1 channel that links the t-tubule to Ca2+ release. In the setting of K+ influx the membrane becomes depolarized and inexcitable. AS is caused by mutations in a K+ channel and is a multisystem disorder characterized by episodes of weakness, dysmorphic features, and cardiac arrhythmias. Both NDM and PP show characteristic changes in CMAP amplitude following short and long periods of exercise. These tests may be useful in differentiating NDM and PP subtypes. Common to all these disorders is depolarization of the muscle membrane. How this causes myotonia or paralysis will be elucidated as more is learned about the specific channel mutations. doi:10.1016/j.clinph.2006.07.059
DS4.3 Inflammatory myopathies S. Greenberg Brigham and Women’s Hospital, Neurology, USA Background: The inflammatory myopathies are diseases characterized by varying skeletal muscle weakness and the presence of immune system cells within muscle tissue. The principal inflammatory myopathies are dermatomyositis, inclusion body myositis, and polymyositis.
Disease Specific Symposia / Clinical Neurophysiology 117 (2006) S18–S24
Aim/objective: We discuss recent findings that clarify the nature of the immune system cells present in muscle. Methods: Combined microarray, immunohistochemical studies, and analysis of immune system cell antigen specific receptors have been used to define newly discovered immune system cells present in muscle in the inflammatory myopathies. Results: Microarray studies identified transcripts unique to specific populations of immune system cells not previously recognized as present in muscle in the inflammatory myopathies and these findings were confirmed by immunohistochemistry. For dermatomyositis, plasmacytoid dendritic cells are present in muscle and are major secretors of interferon-a and -b. For inclusion body myositis, myeloid dendritic cells and differentiated B cells, in the form of plasma cells, are present in muscle. Analysis of immunoglobulin sequences in muscle from dermatomyositis, inclusion body myositis, and polymyositis indicates an antigen-driven B cell response is present. Conclusions: Several previously unrecognized immune system cell populations are present in muscle in the inflammatory myopathies. Defining these populations and their role in the disease pathogenesis provides significant insight into the mechanism of tissue injury present in these diseases. doi:10.1016/j.clinph.2006.07.060
DS5.2 The role of EEG in diagnosis of idiopathic generalised epilepsies M. Koutroumanidis Guy’s and St. Thomas’ NHS Trust, Clinical Neurophysiology and Epilepsies, UK Background: Clinical criteria alone may not always be sufficient or indeed infallible for the diagnosis of epilepsy and the characterisation of its type. The EEG can contribute to this diagnostic refinement, but EEG phenomena may not comply with the dichotomy ‘‘focal-generalised’’ of syndrome classification: generalised spike-wave (GSW) discharges do not necessarily indicate IGE, and not all focal SW reflect symptomatic foci. Aims: (i) To present the morphological spectrum and behavioural characteristics of the interictal and ictal EEG markers of IGE that may guide recording strategies to augment diagnostic yield; (ii) to delineate features that may be relevant to different IGE sub-syndromes; (iii) to explore the boundaries (and their vagueness) between IGE and other epilepsies and non-epileptic paroxysmal electroclinical phenomena, with due emphasis on focal abnormalities. Patients and methods: Video EEG analysis of more than 300 patients with different IGE syndromes from our epilepsy clinic/review of literature. Results and conclusions: A regular 3 Hz GSW discharge is the archetypal IGE feature but diagnosis should rely on
S23
the whole electroclinical picture and not on isolated EEG features that may conflict. What we accept as IGE depends on our experience and ability to recognise distinct electroclinical patterns and presentations and associate them with other information in a meaningful way. Attention should perhaps shift from elaborating on the morphology of a bilateral and diffuse SW discharge to deducing its possible aetiology by identifying markers that would predict stable (symptomatic) or unstable (idiopathic) regional hyperexcitability, and this is why focal discharges are also important. doi:10.1016/j.clinph.2006.07.061
DS5.3 Generalised management H. Cock
epilepsies:
Treatment
issues
and
St. Georges, University of London and Atkinson Morley Regional Neuroscience Centre, Epilepsy Group, UK Idiopathic generalized epilepsies (IGEs) constitute nearly 1/3 of all epilepsies, usually arising in childhood/ early adulthood. Good management as for all epilepsies includes provision of accurate information on diagnosis, risks (of seizures and treatment), prognosis, and relevant lifestyle advice. Where possible, a correct syndromic classification is important as the basis for advice on prognosis and decisions about treatment in particular, though will not be covered in detail. Most IGE syndromes respond well to appropriate antiepileptic drugs (AEDs), but treatment can be demanding because: (a) some AEDs of benefit in focal epilepsies can be deleterious in IGEs, and (b) efficacy of AEDs can differ across seizure types, including on an individual level. In addition, treatment is often lifelong, meaning potential long-term side effects such as bone health must be considered. Furthermore, as one of the most efficacious drugs (valproate) carries higher risks than others of foetal malformations, and possible other effects during pregnancy, decisions about treatment for women of potential childbearing age with IGE are particularly difficult. There are relatively few clinical trials in IGEs compared to focal epilepsies, but available data will be reviewed. It has been estimated that up to 50% of patients with IGE are currently taking ill-advised AED medication. Together with misdiagnosis, this contributes to avoidable morbidity, and sometimes mortality in IGE which needs to be addressed internationally. doi:10.1016/j.clinph.2006.07.062
DS6.1 Unique electrophysiology of anti-MAG polyneuropathy A. Sumner Louisiana State University Health Sciences Center, Neurology, USA