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InternalMed_Harrison. Peptide neurotransmitters are synthesized in the cell body rather than the nerve terminal and may colocalize with classic neurotransmitters in single neurons. A number of neuropeptides are important in pain modulation including substance P and calcitonin gene-related peptide (CGRP), which causes migraine-like headaches in patients. As a consequence, CGRP receptor antagonists have been developed and shown to be effective in treating migraine headaches. Nitric oxide and carbon monoxide are gases that appear also to function as neurotransmitters, in part by signaling in a retrograde fashion from the postsynaptic to the presynaptic cell.


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InternalMed_Harrison. Neurotransmitters modulate the function of postsynaptic cells by binding to specific neurotransmitter receptors, of which there are two major types. Ionotropic receptors are direct ion channels that open after engagement by the neurotransmitter. Metabotropic receptors interact with G proteins, stimulating production of second messengers and activating protein kinases, which modulate a variety of cellular events. Ionotropic receptors are multiple subunit structures, whereas metabotropic receptors are composed of single subunits only. One important difference between ionotropic and metabotropic receptors is that the kinetics of ionotropic receptor effects are fast (generally <1 ms) because 444e-3 neurotransmitter binding directly alters the electrical properties of the postsynaptic cell, whereas metabotropic receptors function over longer time periods. These different properties contribute to the potential for selective and finely modulated signaling by neurotransmitters.


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InternalMed_Harrison. Neurotransmitter systems are perturbed in a large number of clinical disorders, several of which are highlighted in Table 444e-2. One example is the involvement of dopaminergic neurons originating in the substantia nigra of the midbrain and projecting to the striatum (nigrostriatal pathway) in Parkinson’s disease and in heroin addicts after the ingestion of the toxin MPTP (1-methyl-4-phenyl-1,2,5,6tetrahydropyridine). A second important dopaminergic system arising in the midbrain is the mediocorticolimbic pathway, which is implicated in the pathogenesis of addictive behaviors including drug reward. Its key components include the midbrain ventral tegmental area (VTA), median forebrain bundle, and nucleus accumbens (see Fig. 465e-2). The cholinergic pathway originating in the nucleus basalis of Meynert plays a role in memory function in Alzheimer’s disease. Chapter 444e Biology of Neurologic Diseases Arcuate nucleus of hypothalamus → anterior pituitary (via portal veins)


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InternalMed_Harrison. Chapter 444e Biology of Neurologic Diseases Arcuate nucleus of hypothalamus → anterior pituitary (via portal veins) Locus coeruleus (pons) → limbic system, hypothalamus, cortex Medulla → locus coeruleus, spinal cord Postganglionic neurons of sympathetic nervous system Medulla/pons → dorsal horn of spinal cord Major excitatory neurotransmitter; located throughout CNS, including cortical pyramidal cells Acetylcholinesterases (nerve gases) Myasthenia gravis (antibodies to ACh receptor) Congenital myasthenic syndromes (mutations in ACh Lambert-Eaton syndrome (antibodies to Ca channels impair ACh release) Botulism (toxin disrupts ACh release by exocytosis) Alzheimer disease (selective cell death) Autosomal dominant frontal lobe epilepsy (mutations in CNS Parkinson’s disease (selective cell death) MPTP parkinsonism (toxin transported into neurons) Addiction, behavioral disorders Inhibits prolactin secretion


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InternalMed_Harrison. Parkinson’s disease (selective cell death) MPTP parkinsonism (toxin transported into neurons) Addiction, behavioral disorders Inhibits prolactin secretion Stiff person syndrome (antibodies to glutamic acid decarboxylase, the biosynthetic enzyme for GABA) Epilepsy (gabapentin and valproic acid increase GABA) Spasticity Hyperekplexia (myoclonic startle syndrome) due to mutations in glycine receptor Seizures due to ingestion of domoic acid (a glutamate Abbreviations: CNS, central nervous system; MAOA, monoamine oxidase A; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SSRI, selective serotonin reuptake inhibitor.


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InternalMed_Harrison. Addictive drugs share the property of increasing dopamine release in the nucleus accumbens (Chap. 465e). Amphetamine increases intracellular release of dopamine from vesicles and reverses transport of dopamine through the dopamine transporters. Patients prone to addiction show increased activation of the nucleus accumbens following administration of amphetamine. Cocaine binds to dopamine transporters and inhibits dopamine reuptake. Ethanol inhibits inhibitory neurons in the VTA, leading to increased dopamine release in the nucleus accumbens. Opioids also disinhibit these dopaminergic neurons by binding to μ receptors expressed by γ-aminobutyric acid (GABA)–containing interneurons in the VTA. Nicotine increases dopamine release by activating nicotinic acetylcholine receptors on cell bodies and nerve terminals of dopaminergic VTA neurons. Tetrahydrocannabinol, the active ingredient of cannabis, also increases dopamine levels in the nucleus accumbens. Blockade of dopamine in the nucleus


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InternalMed_Harrison. and nerve terminals of dopaminergic VTA neurons. Tetrahydrocannabinol, the active ingredient of cannabis, also increases dopamine levels in the nucleus accumbens. Blockade of dopamine in the nucleus accumbens can terminate the rewarding effects of addictive drugs.


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InternalMed_Harrison. Not all cell-to-cell communication in the nervous system occurs via neurotransmission. Gap junctions provide for direct neuron-neuron electrical conduction and also create openings for the diffusion of ions and metabolites between cells. In addition to neurons, gap junctions are also widespread in glia, creating a syncytium that protects neurons by removing glutamate and potassium from the extracellular environment. Gap junctions consist of membrane-spanning proteins, termed connexins, that pair across adjacent cells. Mechanisms that involve gap junctions have been related to a variety of neurologic disorders. Mutations in connexin 32, a gap junction protein expressed by Schwann cells, are responsible for the X-linked form of Charcot-Marie-Tooth (CMT) disease (Chap. 459). Mutations in either of two gap junction proteins expressed in the inner ear—connexin 26 and connexin 31—result in autosomal dominant progressive hearing loss (Chap. 43). Glial calcium waves mediated through gap


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InternalMed_Harrison. either of two gap junction proteins expressed in the inner ear—connexin 26 and connexin 31—result in autosomal dominant progressive hearing loss (Chap. 43). Glial calcium waves mediated through gap junctions also appear to explain the phenomenon of spreading depression associated with migraine auras and the march of epileptic discharges. Spreading depression is a neural response that follows a variety of different stimuli and is characterized by a circumferentially expanding negative potential that propagates at a characteristic speed of 20 m/s and is associated with an increase in extracellular potassium.


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InternalMed_Harrison. The fundamental issue of how memory, learning, and thinking are encoded in the nervous system is likely to be clarified by identifying the signaling pathways involved in neuronal differentiation, axon guidance, and synapse formation, and by understanding how these pathways are modulated by experience. Many families of transcription factors, each comprising multiple individual components, are expressed in the nervous system. Elucidation of these signaling pathways has already begun to provide insights into the cause of a variety of neurologic disorders, including inherited disorders of cognition such as X-linked mental retardation. This problem affects ~1 in 500 males, and linkage studies in different families suggest that as many as 60 different X-chromosome-encoded genes may be responsible. The formation of RNA-DNA duplexes that block transcription has also been observed with the CGG repeat expansions that occur in fragile X gene-associated mental retardation. Rett’s syndrome, a


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InternalMed_Harrison. The formation of RNA-DNA duplexes that block transcription has also been observed with the CGG repeat expansions that occur in fragile X gene-associated mental retardation. Rett’s syndrome, a common cause of (dominant) X-linked progressive mental retardation in females, is due to a mutation in a gene (MECP2) encoding a DNA-binding protein involved in transcriptional repression. Because the X chromosome comprises only ~3% of germline DNA, then by extrapolation, the number of genes that potentially contribute to clinical disorders affecting intelligence in humans must be potentially very large. As discussed below, there is increasing evidence that abnormal gene transcription may play a role in neurodegenerative diseases, such as Huntington’s disease, in which proteins with polyglutamine expansions bind to and sequester transcription factors. A critical transcription factor for neuronal survival is CREB (cyclic adenosine monophosphate responsive element-binding) protein, which also plays


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InternalMed_Harrison. bind to and sequester transcription factors. A critical transcription factor for neuronal survival is CREB (cyclic adenosine monophosphate responsive element-binding) protein, which also plays an important role in memory in the hippocampus. The regulatory gene repressor element 1-silencing transcription factor (REST) coordinates the expression of neuroprotective stress genes during normal aging. It turns off genes involved in cell death and pathology and boosts protective factors. High levels of REST are associated with normal cognition even in the presence of both amyloid plaques and neurofibrillary tangles. Although REST increases with normal aging, it fails to increase in the nucleus in patients with Alzheimer’s disease and is found clumped with amyloid in autophagosomes.


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InternalMed_Harrison. Myelin is the multilayered insulating substance that surrounds axons and speeds impulse conduction by permitting action potentials to jump between naked regions of axons (nodes of Ranvier) and across myelinated segments. Molecular interactions between the myelin membrane and axon are required to maintain the stability, function, and normal life span of both structures. A single oligodendrocyte usually ensheaths multiple axons in the central nervous system (CNS), whereas in the peripheral nervous system (PNS), each Schwann cell typically myelinates a single axon. Myelin is a lipid-rich material formed by a spiraling process of the membrane of the myelinating cell around the axon, creating multiple membrane bilayers that are tightly apposed (compact myelin) by charged protein interactions. Several inhibitors of axon growth are expressed on the innermost (periaxonal) lamellae of the myelin membrane (see “Stem Cells and Transplantation,” below). A number of clinically important neurologic


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InternalMed_Harrison. inhibitors of axon growth are expressed on the innermost (periaxonal) lamellae of the myelin membrane (see “Stem Cells and Transplantation,” below). A number of clinically important neurologic disorders are caused by inherited mutations in myelin proteins of the CNS or PNS (Fig. 444e-1). Constituents of myelin also have a


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InternalMed_Harrison. FIGURE 444e-1 The molecular architecture of the myelin sheath illustrating the most important disease-related proteins. The illustration represents a composite of central nervous system (CNS) and peripheral nervous system (PNS) myelin. Proteins restricted to CNS myelin are shown in green, proteins of PNS myelin are lavender, and proteins present in both CNS and PNS are red. In the CNS, the X-linked allelic disorders, Pelizaeus-Merzbacher disease and one variant of familial spastic paraplegia, are caused by mutations in the gene for proteolipid protein (PLP) that normally promotes extracellular compaction between adjacent myelin lamellae. The homologue of PLP in the PNS is the P0 protein, mutations in which cause the neuropathy Charcot-Marie-Tooth disease (CMT) type 1B. The most common form of CMT is the 1A subtype caused by a duplication of the PMP22 gene; deletions in PMP22 are responsible for another inherited neuropathy termed hereditary liability to pressure palsies (Chap. 459).


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InternalMed_Harrison. In multiple sclerosis (MS), myelin basic protein (MBP) and the quantitatively minor CNS protein, myelin oligodendrocyte glycoprotein (MOG), are likely T cell and B cell antigens, respectively (Chap. 458). The location of MOG at the outermost lamella of the CNS myelin membrane may facilitate its targeting by autoantibodies. In the PNS, autoantibodies against myelin gangliosides are implicated in a variety of disorders, including GQ1b in the Fisher variant of Guillain-Barré syndrome, GM1 in multifocal motor neuropathy, and sulfatide constituents of myelin-associated glycoprotein (MAG) in peripheral neuropathies associated with monoclonal gammopathies (Chap. 460). Chapter 444e Biology of Neurologic Diseases Mitochondrial swelling, rupture of outer membrane NOS Activation of caspase cascadeDNA/RNA oxidation


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InternalMed_Harrison. FIGURE 444e-2 Involvement of mitochondria in cell death. A severe excitotoxic insult (A) results in cell death by necrosis, whereas a mild excitotoxic insult (B) results in apoptosis. After a severe insult (such as ischemia), there is a large increase in glutamate activation of N-methyl-D-aspartate (NMDA) receptors, an increase in intracellular Ca2+ concentrations, activation of nitric oxide synthase (NOS), and increased mitochondrial Ca2+ and superoxide generation followed by the formation of ONOO–. This sequence results in damage to cellular macromolecules including DNA, leading to activation of poly-ADP-ribose polymerase (PARS). Both mitochondrial accumulation of Ca2+ and oxidative damage lead to activation of the permeability transition pore (PTP) that is linked to excitotoxic cell death. A mild excitotoxic insult can occur due either to an abnormality in an excitotoxicity amino acid receptor, allowing more Ca2+ flux, or to impaired functioning of other ionic channels or of energy


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InternalMed_Harrison. A mild excitotoxic insult can occur due either to an abnormality in an excitotoxicity amino acid receptor, allowing more Ca2+ flux, or to impaired functioning of other ionic channels or of energy production, which may allow the voltage-dependent NMDA receptor to be activated by ambient concentrations of glutamate. This event can then lead to increased mitochondrial Ca2+ and free radical production, yet relatively preserved ATP generation. The mitochondria may then release cytochrome c (Cytc), caspase 9, apoptosis-inducing factor (Aif), and perhaps other mediators that lead to apoptosis. The precise role of the PTP in this mode of cell death is still being clarified, but there does appear to be involvement of the adenine nucleotide transporter that is a key component of the PTP.


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InternalMed_Harrison. propensity to be targeted as autoantigens in autoimmune demyelinating disorders (Fig. 444e-2).


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InternalMed_Harrison. Specification to oligodendrocyte precursor cells (OPCs) is transcriptionally regulated by the Olig 2 and Yin Yang 1 genes, whereas myelination mediated by postmitotic oligodendrocytes depends on a different transcription factor, myelin gene regulatory factor (MRF). It is noteworthy that in the normal adult brain, large numbers of OPCs (expressing PDGFR-α and NG2) are widely distributed but do not myelinate axons, even in demyelinating environments such as in lesions of MS. Several families of molecules have now been identified that regulate oligodendrocyte differentiation and myelination, including LINGO-1, PSA-NCAM, hyaluronan, Nogo-A, the Wnt pathway, notch signaling (and its receptor Jagged), and the retinoic acid receptor RXRγ; all are inhibitory, with the exception of RXRγ, which is excitatory. All are also potential targets for myelin repair therapies, and a monoclonal antibody against LINGO-1 is in clinical testing for remyelination in MS. Very recently, a series of


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InternalMed_Harrison. which is excitatory. All are also potential targets for myelin repair therapies, and a monoclonal antibody against LINGO-1 is in clinical testing for remyelination in MS. Very recently, a series of observations has called into question the traditional concept that axon-derived cues are always required for myelination to occur. Fixed (i.e., dead) axons could be efficiently myelinated by oligodendrocytes in vitro, as could artificial polystyrene nanowires of a similar diameter. This led to development of new high-throughput screening assays based on myelination of polystyrene nanowires to identify compounds that could promote myelination.


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InternalMed_Harrison. Macrophages and microglia represent the major cell types in the nervous system responsible for antigen presentation and innate immunity. Brain macrophages are derived from either hematopoietic stem cell–derived bone marrow monocytes or from brain microglia that migrate from the yolk sac early in embryogenesis before the blood-brain barrier is formed. In a murine model of autoimmune demyelination, experimental allergic encephalomyelitis (EAE) (Fig. 444e-3), macrophages derived from bone marrow monocytes, but not microglia, were found to represent the critical population that initiated inflammatory demyelination at paraxonal regions near nodes of Ranvier. An additional, unexpected role for brain microglia was also identified in the regulation of neural circuits through pruning of excitatory synapses and control of dendritic spine densities; mice depleted of microglia during development exhibited a variety of cognitive learning and behavioral deficits, including abnormal social


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InternalMed_Harrison. synapses and control of dendritic spine densities; mice depleted of microglia during development exhibited a variety of cognitive learning and behavioral deficits, including abnormal social behaviors. Remarkably, depletion of microglia in adult mice by administration of a selective inhibitor of colony-stimulating factor receptor 1 (CSFR1) was followed by their rapid repopulation, suggesting that a pool of resident microglial precursor cells may exist throughout the CNS.


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InternalMed_Harrison. proteins? activation macrophages Chemokines IL-1, IL-12 Brain tissue TNF, IFN, free radicals, vasoactive amines, complement, proteases, cytokines, eicosanoids FIGURE 444e-3 A model for experimental allergic encephalomyelitis (EAE). Crucial steps for disease initiation and progression include peripheral activation of preexisting autoreactive T cells; homing to the central nervous system (CNS) and extravasation across the blood-brain barrier; reactivation of T cells by exposed autoantigens; secretion of cytokines; activation of microglia and astrocytes and recruitment of a secondary inflammatory wave; and immune-mediated myelin destruction. ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; LFA-1, leukocyte function-associated antigen-1; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.


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InternalMed_Harrison. The human microbiome (Chap. 86e) represents the collective set of genes from the 1014 organisms living in our gut, skin, mucosa, and other sites. Different microbial communities are associated with different ethnicities, diets, and environments. In any individual, the predominant gut microbiota can be remarkably stable over decades, but also can be altered by exposure to certain microbial species, for example by ingestion of probiotics.


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InternalMed_Harrison. There is compelling evidence that gut microbes can shape immune responses through the interaction of their metabolism with that of humans. These gut-brain interactions are likely to be important in understanding the pathogenesis of many autoimmune neurologic diseases. For example, mice treated with broad-spectrum antibiotics are resistant to EAE, an effect associated with decreases in production of proinflammatory cytokines, and conversely more production of the immunosuppressive cytokines interleukin (IL) 10 and IL-13 and an increase in regulatory T and B lymphocytes. Oral administration of polysaccharide A (PSA) from Bacillus fragilis also protects mice from EAE, via increases in IL-10.


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InternalMed_Harrison. In addition to nonspecific effects on immune homeostasis mediated by cytokines and regulatory cells, some microbial proteins can trigger, in susceptible individuals, a cross-reactive immune response against a homologous protein in the nervous system, a mechanism termed molecular mimicry. Examples include cross-reactivity between the astrocyte water channel aquaporin-4 and an ABC transporter permease from Clostridia perfringens in neuromyelitis optica (Chap. 458); the neural ganglioside Gm1 and similar sialic acid–containing structures from Campylobacter jejuni in Guillain-Barré syndrome (Chap. 460); and the sleep-promoting protein hypocretin and hemagglutinin from H1N1 influenza virus in narcolepsy (Chap. 38), among others.


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InternalMed_Harrison. Recently, a number of tantalizing observations have incriminated the microbial environment in the pathogenesis of a much wider spectrum of neurologic conditions and behaviors, extending well beyond the traditional boundaries of immune-mediated pathologies. This is perhaps not surprising, as it has long been known in neurology that gut bacteria can influence brain function, based mostly on classic studies demonstrating that products of gut microbes can worsen hepatic encephalopathy, forming the basis of treatment with antibiotics for this condition.


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InternalMed_Harrison. Mice that developed in a completely germ-free environment displayed less anxiety, lower responses to stressful situations, more exploratory locomotive behaviors, and impaired memory formation compared with non-germ-free counterparts. These behaviors were related to changes in gene expression in pathways related to neural signaling, synaptic function, and modulation of neurotransmitters. Moreover, this behavior could be reversed when the germ-free mice were co-housed with non-germ-free mice.


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InternalMed_Harrison. The enteric autonomic nervous system in humans provides a bidirectional neural connection between the brain and gut. The vagus nerve, which innervates the upper gut and proximal colon, has been implicated in anxietyand depression-like behaviors in mice. Ingestion of Lactobacillus rhamnosus induced changes in expression of the inhibitory neurotransmitter GABA1b in neurons of the limbic cortex, hippocampus, and amygdala, associated with reduced levels of corticosteroids and reduced anxietyand depression-like behaviors. Remarkably, these changes could be blocked by vagotomy.


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InternalMed_Harrison. Another area of emerging interest is in a possible contribution of the gut microbiome to autism and related disorders. Children with autistic spectrum disorders have long been known to have gastrointestinal disturbances, and it has been claimed that the severity of dysbiosis correlates with the severity of autism. A murine model of autism was recently induced in offspring after injecting the pregnant mother with the viral RNA mimic polyinosinic:polycytidylic acid (poly I:C). Remarkably, oral treatment of offspring with B. fragilis corrected a range of autistic behaviors in these mice and also improved gut permeability.


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InternalMed_Harrison. Neurotrophic factors (Table 444e-3) are secreted proteins that modulate neuronal growth, differentiation, repair, and survival; some have additional functions, including roles in neurotransmission and in the synaptic reorganization involved in learning and memory. The neurotrophin (NT) family contains nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, and NT4/5. The neurotrophins act at TrK and p75 receptors to promote survival of neurons. BDNF is linked to synaptogenesis. Certain polymorphisms are linked to increased risk for Alzheimer’s disease (AD), and BDNF is depleted in Huntington’s disease. Because of their survival-promoting and antiapoptotic effects, neurotrophic factors are in theory outstanding candidates for therapy of disorders characterized by premature death of neurons such as occurs in ALS and other degenerative motor neuron disorders. Knockout mice lacking receptors for ciliary neurotrophic factor (CNTF) or BDNF show loss of motor neurons, and


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InternalMed_Harrison. death of neurons such as occurs in ALS and other degenerative motor neuron disorders. Knockout mice lacking receptors for ciliary neurotrophic factor (CNTF) or BDNF show loss of motor neurons, and experimental motor neuron death can be rescued by treatment with various neurotrophic factors including CNTF, BDNF, and vascular endothelial growth factor (VEGF). However, in phase 3 clinical trials, growth factors were ineffective in human ALS. The growth factor glial-derived neurotrophic factor (GDNF) is important for survival of dopaminergic neurons. Direct infusions of GDNF showed initial promise in Parkinson’s disease, but the benefits were not replicated in a larger clinical trial.


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InternalMed_Harrison. The nervous system is traditionally considered to be a nonmitotic organ, in particular with respect to neurons. These concepts have been challenged by the finding that neural progenitor or stem cells exist in the adult CNS that are capable of differentiation, migration over long distances, and extensive axonal arborization and synapse formation with appropriate targets. These capabilities also indicate that the repertoire of factors required for growth, survival, differentiation, and migration of these cells exists in the mature nervous system. In rodents, neural stem cells, defined as progenitor cells capable of differentiating into mature cells of neural or glial lineage, have been experimentally propagated from fetal CNS and neuroectodermal tissues and also from adult germinal matrix and ependyma regions. Human fetal CNS tissue is also capable of differentiation into cells with neuronal, astrocyte, and oligodendrocyte morphology when cultured in the presence of growth factors.


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InternalMed_Harrison. Once the repertoire of signals required for cell type specification is better understood, differentiation into specific neural or glial subpopulations can be directed in vitro; such cells could also be engineered to express therapeutic molecules. Another promising approach is to use growth factors, such as BDNF, to stimulate endogenous stem cells to 444e-7 proliferate and migrate to areas of neuronal damage.


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InternalMed_Harrison. A major advance has been the development of induced pluripotent stem cells. Using this technique, adult somatic cells such as skin fibroblasts are treated with four pluripotency factors (SOX2, KLF4, cMYC, and Oct4), and this generates induced pluripotent stem cells (iPSCs). These adult-derived stem cells sidestep the ethical issues of using stem cells derived from human embryos. The development of these cells has tremendous promise for both studying disease mechanisms and testing therapeutics. As yet there is no consensus on the best way to generate and differentiate the iPSCs; however, techniques to avoid using viral vectors and use of Cre-lox systems to remove reprogramming factors result in a better match of gene expression profiles with those of embryonic stem cells. Over the years, the field of directed differentiation has used three main strategies to specify neural lineages from human pluripotent stem cells. These strategies are embryoid body formation, coculture on


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InternalMed_Harrison. years, the field of directed differentiation has used three main strategies to specify neural lineages from human pluripotent stem cells. These strategies are embryoid body formation, coculture on neural-inducing feeders, and direct neural induction. Thus far, iPSCs have been made from patients with all of the major human neurodegenerative diseases, and studies using them are under way.


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InternalMed_Harrison. Although stem cells hold tremendous promise for the treatment of debilitating neurologic diseases, such as Parkinson’s disease and spinal cord injury, it should be emphasized that medical application is in its infancy. Major obstacles are the generation of positionand neurotransmitter-defined subtypes of neurons and their isolation as pure populations of the desired cells. This is crucial to avoid persistence of undifferentiated embryonic stem (ES) cells, which can generate tumors. The establishment of appropriate neural connections and afferent control is also critical. For instance, human ES motor neurons will need to be introduced at multiple segments in the neuraxis, and then their axons will need to regenerate from the spinal cord to distal musculature.


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InternalMed_Harrison. Experimental transplantation of human fetal dopaminergic neurons in patients with Parkinson’s disease has shown that these transplanted cells can survive within the host striatum; however, some patients developed disabling dyskinesias, and this approach is no longer in clinical development. The possibility that iPSCs will be used in Parkinson’s disease was strengthened by studies showing that they can be differentiated into dopaminergic neurons. The dopaminergic neurons were then shown to rescue the parkinsonian phenotype in a MPTP-induced primate model with excellent dopaminergic neuron survival function and lack of neural overgrowth. The correction of tau mutations in iPSC-derived neurons has been shown to reverse the toxic phenotype in dendrite retraction and cell death.


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InternalMed_Harrison. Another new use for iPSCs is to screen drugs as potential treatments for neurodegenerative and other diseases. The feasibility of this has been shown using iPSC-induced macrophages from patients with Gaucher’s disease, and verifying the efficacy of protein chaperones in these cells as a means of stabilizing the mutant glucocerebrosidase and increasing its activity and the duration of its effects. Other approaches are to attempt to reduce expression of proteins, such as amyloid, tau, and α-synuclein, implicated in the pathogenesis of neurodegenerative diseases. One difficulty has been that reprogramming cells to iPSCs resets their identity back to an embryonic age, which is a hurdle in modeling of late-onset diseases. One approach to this has been to express a fragment of the mutated gene, such as a portion of lamin A, which causes premature aging in progeria. This approach showed that dendrite degeneration and progressive loss of tyrosine hydroxylase expression, as well as enlarged


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InternalMed_Harrison. such as a portion of lamin A, which causes premature aging in progeria. This approach showed that dendrite degeneration and progressive loss of tyrosine hydroxylase expression, as well as enlarged mitochondria and Lewy body precursor inclusions, were induced in iPSC-derived dopaminergic neurons with progerin-induced aging.


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InternalMed_Harrison. Studies of transplantation for patients with Huntington’s disease have also reported encouraging, although very preliminary, results. OPCs transplanted into mice with a dysmyelinating disorder effectively migrated in the new environment, interacted with axons, and mediated myelination; such experiments raise hope that similar transplantation strategies may be feasible in human disorders of myelin such as MS. The promise of stem cells for treatment of both neurodegenerative diseases and neural injury is great, but development has Chapter 444e Biology of Neurologic Diseases been slowed by unresolved concerns over safety (including the theoretical risk of malignant transformation of transplanted cells), ethics (particularly with respect to use of fetal tissue), and efficacy.


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InternalMed_Harrison. In developing brain, the extracellular matrix provides stimulatory and inhibitory signals that promote neuronal migration, neurite outgrowth, and axonal extension. After neuronal damage, reexpression of inhibitory molecules such as chondroitin sulfate proteoglycans may prevent tissue regeneration. Chondroitinase degraded these inhibitory molecules and enhanced axonal regeneration and motor recovery in a rat model of spinal cord injury. Several myelin proteins, specifically Nogo, oligodendrocyte myelin glycoprotein (OMGP), and myelin-associated glycoprotein (MAG), may also interfere with axon regeneration. Sialidase, which cleaves one class of receptors for MAG, enhances axonal outgrowth. Antibodies against Nogo promote regeneration after experimental focal ischemia or spinal cord injury. Nogo, OMGP, and MAG all bind to the same neural receptor, the Nogo receptor, which mediates its inhibitory function via the p75 neurotrophin receptor signaling.


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InternalMed_Harrison. CELL DEATH: EXCITOTOXICITY AND APOPTOSIS


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InternalMed_Harrison. Excitotoxicity refers to neuronal cell death caused by activation of excitatory amino acid receptors (Fig. 444e-4). Compelling evidence for a role of excitotoxicity, especially in ischemic neuronal injury, is derived from experiments in animal models. Experimental models of stroke are associated with increased extracellular concentrations of the excitatory amino acid neurotransmitter glutamate, and neuronal damage is attenuated by denervation of glutamate-containing neurons or the administration of glutamate receptor antagonists. The distribution of cells sensitive to ischemia corresponds closely with that of N-methyld-aspartate (NMDA) receptors (except for cerebellar Purkinje cells, which are vulnerable to hypoxia-ischemia but lack NMDA receptors); and competitive and noncompetitive NMDA antagonists are effective in preventing focal ischemia. In global cerebral ischemia, non-NMDA receptors (kainic acid and α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate [AMPA]) are activated, and


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InternalMed_Harrison. antagonists are effective in preventing focal ischemia. In global cerebral ischemia, non-NMDA receptors (kainic acid and α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate [AMPA]) are activated, and antagonists to these receptors are protective. Experimental brain damage induced by hypoglycemia is also attenuated by NMDA antagonists.


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InternalMed_Harrison. Excitotoxicity is not a single event but rather a cascade of cell injury. Excitotoxicity causes influx of calcium into cells, and much of the calcium is sequestered in mitochondria rather than in the cytoplasm. Increased cytoplasmic calcium causes metabolic dysfunction and free radical generation; activates protein kinases, phospholipases, nitric oxide synthase, proteases, and endonucleases; and inhibits protein synthesis. Activation of nitric oxide synthase generates nitric oxide (NO•), which can react with superoxide (O•2) to generate peroxynitrite (ONOO−), which may play a direct role in neuronal injury. Another critical pathway is activation of poly-ADP-ribose polymerase, which occurs in response to free radical–mediated DNA damage. Experimentally, mice with knockout mutations of neuronal nitric oxide synthase or poly-ADP-ribose polymerase, or those that overexpress superoxide dismutase, are resistant to focal ischemia.


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InternalMed_Harrison. Another aspect of excitotoxicity is that it has been demonstrated that stimulation of extrasynaptic NMDA receptors mediates cell death, where as stimulation of synaptic receptors is protective. This has been shown to play a role in excitotoxicity in transgenic mouse models of


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InternalMed_Harrison. FIGURE 444e-4 Neurodegeneration caused by prions. A. In sporadic neurodegenerative diseases (NDs), wild-type (Wt) prions multiply through self-propagating cycles of posttranslational modification, during which the precursor protein (green circle) is converted into the prion form (red square), which generally is high in β-sheet content. Pathogenic prions are most toxic as oligomers and less toxic after polymerization into amyloid fibrils. The small polygons (blue) represent proteolytic cleavage products of the prion. Depending on the protein, the fibrils coalesce into Aβ amyloid plaques in Alzheimer’s disease (AD), neurofibrillary tangles in AD and Pick’s disease, or Lewy bodies in Parkinson’s disease and Lewy body dementia. Drug targets for the development of therapeutics include: (1) lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. B. Late-onset heritable neurodegeneration argues for two discrete events: The (i) first event is the


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InternalMed_Harrison. lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. B. Late-onset heritable neurodegeneration argues for two discrete events: The (i) first event is the synthesis of mutant precursor protein (green circle), and the (ii) second event is the age-dependent formation of mutant prions (red square). The highlighted yellow bar in the DNA structure represents mutation of a base pair within an exon, and the small yellow circles signify the corresponding mutant amino acid substitution. Green arrows represent a normal process; red arrows, a pathogenic process; and blue arrows, a process that is known to occur but unknown whether it is normal or pathogenic. (Micrographs prepared by Stephen J. DeArmond. Reprinted with permission from SB Prusiner: Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 47:601, 2013.)


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InternalMed_Harrison. Huntington’s disease, in which using low-dose memantine to selectively block the extrasynaptic receptors is beneficial.


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InternalMed_Harrison. Although excitotoxicity is clearly implicated in the pathogenesis of cell death in stroke, to date treatment with NMDA antagonists has not proven to be clinically useful. One approach has been to use an inhibitor of the postsynaptic density-95 protein that uncouples NMDA receptors from neurotoxic pathways, including the generation of nitric oxide. This approach was effective in a primate stroke model and in a phase 2 clinical trial of stroke associated with endovascular repair of cerebral aneurysms. Transient receptor potentials (TRPs) are calcium channels that are activated by oxidative stress in parallel with excitotoxic signal pathways. In addition, glutamate-independent pathways of calcium influx via acid-sensing ion channels have been identified. These channels transport calcium in the setting of acidosis and substrate depletion, and pharmacologic blockade of these channels markedly attenuates stroke injury. These channels offer a potential new therapeutic target for stroke.


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InternalMed_Harrison. Apoptosis, or programmed cell death, plays an important role in both physiologic and pathologic conditions. During embryogenesis, apoptotic pathways operate to destroy neurons that fail to differentiate appropriately or reach their intended targets. There is mounting evidence for an increased rate of apoptotic cell death in a variety of acute and chronic neurologic diseases. Apoptosis is characterized by neuronal shrinkage, chromatin condensation, and DNA fragmentation, whereas necrotic cell death is associated with cytoplasmic and mitochondrial swelling followed by dissolution of the cell membrane. Apoptotic and necrotic cell death can coexist or be sequential events, depending on the severity of the initiating insult. Cellular energy reserves appear to have an important role in these two forms of cell death, with apoptosis favored under conditions in which ATP levels are preserved. Evidence of DNA fragmentation has been found in a number of degenerative neurologic disorders,


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InternalMed_Harrison. two forms of cell death, with apoptosis favored under conditions in which ATP levels are preserved. Evidence of DNA fragmentation has been found in a number of degenerative neurologic disorders, including AD, Huntington’s disease, and ALS. The best characterized genetic neurologic disorder related to apoptosis is infantile spinal muscular atrophy (Werdnig-Hoffmann disease), in which two genes thought to be involved in the apoptosis pathways are causative.


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InternalMed_Harrison. Mitochondria are essential in controlling specific apoptosis pathways. The redistribution of cytochrome c, as well as apoptosis-inducing factor (AIF), from mitochondria during apoptosis leads to the activation of a cascade of intracellular proteases known as caspases. Caspase-independent apoptosis occurs after DNA damage, activation of poly-ADP-ribose polymerase, and translocation of AIF into the nucleus. Redistribution of cytochrome c is prevented by overproduction of the apoptotic protein BCL2 and is promoted by the proapoptotic protein BAX. These pathways may be triggered by activation of a large pore in the mitochondrial inner membrane known as the permeability transition pore, although in other circumstances, they occur independently. The permeability transition pore is made up of dimers of ATP synthase and is activated by cyclophilin D, leading to large calcium fluxes across the inner mitochondrial membrane. Certain forms of congenital muscular dystrophies are caused by


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InternalMed_Harrison. up of dimers of ATP synthase and is activated by cyclophilin D, leading to large calcium fluxes across the inner mitochondrial membrane. Certain forms of congenital muscular dystrophies are caused by mutations in collagen VI, which leads to increased activation of the permeability transition pore. Recent studies suggest that blocking the mitochondrial pore reduces both hypoglycemic and ischemic cell death. Mice deficient in cyclophilin D, a key protein involved in opening the permeability transition pore, are resistant to necrosis produced by focal cerebral ischemia.


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InternalMed_Harrison. The possibility that protein aggregation plays a role in the pathogenesis of neurodegenerative diseases is a major focus of current research. Protein aggregation is a major histopathologic hallmark of neurodegenerative diseases. Deposition of β-amyloid is strongly implicated in the pathogenesis of AD. Genetic mutations in familial AD cause increased production of β-amyloid with 42 amino acids, which has an increased propensity to aggregate, as compared to β-amyloid with 40 amino acids. Furthermore, mutations in the amyloid precursor protein (APP), which reduce the production of β-amyloid, protect against the development of AD and are associated with preserved cognition in the elderly. Mutations in genes encoding the MAPT lead 444e-9 to altered splicing of tau and the production of neurofibrillary tangles in frontotemporal dementia and progressive supranuclear palsy. Familial Parkinson’s disease is associated with mutations in leucinerich repeat kinase 2 (LRRK2), α-synuclein, parkin,


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InternalMed_Harrison. tangles in frontotemporal dementia and progressive supranuclear palsy. Familial Parkinson’s disease is associated with mutations in leucinerich repeat kinase 2 (LRRK2), α-synuclein, parkin, PINK1, and DJ-1. PINK1 is a mitochondrial kinase (see below), and DJ-1 is a protein involved in protection from oxidative stress. Parkin, which causes autosomal recessive early-onset Parkinson’s disease, is a ubiquitin ligase. The characteristic histopathologic feature of Parkinson’s disease is the Lewy body, an eosinophilic cytoplasmic inclusion that contains both neurofilaments and α-synuclein. Huntington’s disease and cerebellar degenerations are associated with expansions of polyglutamine repeats in proteins, which aggregate to produce neuronal intranuclear inclusions. Familial ALS is associated with superoxide dismutase mutations and cytoplasmic inclusions containing superoxide dismutase. An important finding was the discovery that ubiquinated inclusions observed in most cases of ALS and the


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InternalMed_Harrison. superoxide dismutase mutations and cytoplasmic inclusions containing superoxide dismutase. An important finding was the discovery that ubiquinated inclusions observed in most cases of ALS and the most common form of frontotemporal dementia are composed of TAR DNA binding protein 43 (TDP-43). Subsequently, mutations in the TDP-43 gene, and in the fused in sarcoma gene (FUS), were found in familial ALS. Both of these proteins are involved in transcription regulation as well as RNA metabolism. In autosomal dominant neurohypophyseal diabetes insipidus, mutations in vasopressin result in abnormal protein processing, accumulation in the endoplasmic reticulum, and cell death.


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InternalMed_Harrison. Another key mechanism linked to cell death is mitochondrial dynamics, which refers to the processes involved in movement of mitochondria, as well as in mitochondrial fission and fusion, which play a critical role mitochondrial turnover and in replenishment of damaged mitochondria. Mitochondrial dysfunction is strongly linked to the pathogenesis of a number of neurodegenerative diseases such as Friedreich’s ataxia, which is caused by mutations in an iron-binding protein that plays an important role in transferring iron to iron-sulfur clusters in aconitase and complex I and II of the electron transport chain. Mitochondrial fission is dependent on the dynamin-related proteins (Drp1), which bind to its receptor Fis, whereas mitofuscins 1 and 2 (MF 1/2) and optic atrophy protein 1 (OPA1) are responsible for fusion of the outer and inner mitochondrial membrane, respectively. Mutations in MFN2 cause Charcot-Marie-Tooth neuropathy type 2A, and mutations in OPA1 cause autosomal dominant optic


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InternalMed_Harrison. for fusion of the outer and inner mitochondrial membrane, respectively. Mutations in MFN2 cause Charcot-Marie-Tooth neuropathy type 2A, and mutations in OPA1 cause autosomal dominant optic atrophy. Both β-amyloid and mutant huntingtin protein induce mitochondrial fragmentation and neuronal cell death associated with increased activity of Drp1. In addition, mutations in genes causing autosomal recessive Parkinson’s disease, parkin and PINK1, cause abnormal mitochondrial morphology and result in impairment of the ability of the cell to remove damaged mitochondria by autophagy.


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InternalMed_Harrison. One major scientific question is whether protein aggregates directly contribute to neuronal death or whether they are merely secondary bystanders. A current focus in all the neurodegenerative diseases is on small protein aggregates termed oligomers. These may be the toxic species of β-amyloid, α-synuclein, and proteins with expanded polyglutamines such as are associated with Huntington’s disease. Protein aggregates are usually ubiquinated, which targets them for degradation by the 26S component of the proteasome. An inability to degrade protein aggregates could lead to cellular dysfunction, impaired axonal transport, and cell death by apoptotic mechanisms.


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InternalMed_Harrison. Autophagy is the degradation of cystolic components in lysosomes. There is increasing evidence that autophagy plays an important role in degradation of protein aggregates in the neurodegenerative diseases, and it is impaired in AD, Parkinson’s disease, and Huntington’s disease. Autophagy is particularly important to the health of neurons, and failure of autophagy contributes to cell death. In Huntington’s disease, a failure of cargo recognition occurs, contributing to protein aggregates and cell death. Rapamycin, which induces autophagy, exerts beneficial therapeutic effects in transgenic mouse models of AD, Parkinson’s disease, and Huntington’s disease. There is other evidence for lysosomal dysfunction and impaired autophagy in Parkinson’s disease. Mutations in glucocerebrosidase are associated with 5% of all Parkinson’s disease cases as well as 8–9% of patients with dementia with Lewy bodies. Therefore, this is the most


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InternalMed_Harrison. Chapter 444e Biology of Neurologic Diseases important genetic cause of both disorders thus far identified. There appear to be reciprocal interactions between glucocerebrosidase and α-synuclein. It has been shown that glucocerebrosidase concentrations and enzymatic activity are reduced in the substantia nigra of sporadic Parkinson’s disease patients. Furthermore, α-synuclein is degraded by chaperone-mediated and macro autophagy. The degradation of α-synuclein has been shown to be impaired in transgenic mice deficient in glucocerebrosidase as well as in mice in which the enzyme has been inhibited. Furthermore, it is known that α-synuclein inhibits the activity of glucocerebrosidase. Therefore, there is bidirectional feedback between α-synuclein and glucocerebrosidase. An attractive therapeutic intervention could be to use protein chaperones to increase the activity and duration of action of glucocerebrosidase. This would also reduce α-synuclein levels and block the degeneration of


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InternalMed_Harrison. intervention could be to use protein chaperones to increase the activity and duration of action of glucocerebrosidase. This would also reduce α-synuclein levels and block the degeneration of dopaminergic neurons.


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InternalMed_Harrison. The retromer complex is a conserved membrane-associated protein complex that functions in the endosome-to-Golgi complex. The retromer complex contains a cargo selective complex consisting of VPS35, VPS26, and VPS29, along with a sorting nexin dimer. Recently, mutations in VPS35 were shown to be a cause of late-onset autosomal dominant Parkinson’s disease. The retromer also traffics APP away from endosomes, where it is cleaved to generate β-amyloid. Deficiencies of VPS35 and VPS26 were also identified in hippocampal brain tissue from AD. A new therapeutic approach to these diseases might therefore be to use chaperones to stabilize the retromer and reduce the generation of β-amyloid and α-synuclein.


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InternalMed_Harrison. The LRRK2 mutations were shown to have effects on clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. LRRK2 mutations also are linked to elevated protein synthesis mediated by ribosomal protein s15 phosphorylation. Blocking this phosphorylation reduces LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons.


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InternalMed_Harrison. Interestingly, in experimental models of Huntington’s disease and cerebellar degeneration, protein aggregates are not well correlated with neuronal death and may be protective. A substantial body of evidence suggests that the mutant proteins with polyglutamine expansions in these diseases bind to transcription factors and that this contributes to disease pathogenesis. In Huntington’s disease, there is dysfunction of the transcriptional co-regulator, PGC-1α, a key regulator of mitochondrial biogenesis. There is evidence that impaired function of PGC-1α is also important in both Parkinson’s disease and AD, making it an attractive target for treatments. Agents that upregulate gene transcription are neuroprotective in animal models of these diseases. A number of compounds have been developed to block β-amyloid production and/or aggregation, and these agents are being studied in early clinical trials in humans. Another approach under investigation is immunotherapy with antibodies that bind


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InternalMed_Harrison. block β-amyloid production and/or aggregation, and these agents are being studied in early clinical trials in humans. Another approach under investigation is immunotherapy with antibodies that bind β-amyloid, tau, or α-synuclein. These studies have shown efficacy in preventing the spread of amyloid, tau, and α-synuclein in animal studies, raising hopes that this could lead to effective therapies by blocking neuron-to-neuron propagation. Two large clinical trials of β-amyloid immunotherapy, however, did not show efficacy, although this therapeutic strategy is still being studied.


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InternalMed_Harrison. As we have learned more about the etiology and pathogenesis of the neurodegenerative diseases, it has become clear that the histologic abnormalities that were once curiosities, in fact, are likely to reflect the etiologies. For example, the amyloid plaques in kuru and Creutzfeldt-Jakob disease (CJD) are filled with the PrPSc prions that have assembled into fibrils. The past three decades have witnessed an explosion of new knowledge about prions. For many years, kuru, CJD, and scrapie of sheep were thought to be caused by slow-acting viruses, but a large body of experimental evidence argues that the infectious pathogens causing these diseases are devoid of nucleic acid. Such pathogens are called prions, which are composed of host-encoded proteins that adopt alternative conformations (Chap. 453e). Prions are self-propagating by imposing their conformations on the normal, precursor protein; most prions are enriched for β-sheet and can assemble into amyloid fibrils.


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InternalMed_Harrison. Similar to the plaques in kuru and CJD that are composed of PrP prions, the amyloid plaques in AD are filled with Aβ prions that have polymerized into fibrils. This relationship between the neuropathologic findings and the etiologic prion was strengthened by the genetic linkage between familial CJD and mutations in the PrP gene, as well as (as noted above) between familial AD and mutations in the APP gene. Moreover, a mutation in the APP gene that prevents Aβ peptide formation was correlated with a decreased incidence of AD in Iceland.


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InternalMed_Harrison. The heritable neurodegenerative diseases offer an important insight into the pathogenesis of the more common, sporadic ones. Although the mutant proteins that cause these disorders are expressed in the brains of people early in life, the diseases do not occur for many decades. Many explanations for the late onset of familial neurodegenerative diseases have been offered, but none are supported by substantial experimental evidence. The late onset might be due to a second event in which a mutant protein, after its conversion into a prion, begins to accumulate at some rather advanced age (Fig. 444e-5). Such a formulation is also consistent with data showing that the protein quality-control mechanisms diminish in efficiency with age. Thus, the prion forms of both wild-type and mutant proteins are likely to be efficiently degraded in younger people but are less well handled in older individuals. This explanation is consistent with the view that neurodegenerative diseases are disorders of


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InternalMed_Harrison. are likely to be efficiently degraded in younger people but are less well handled in older individuals. This explanation is consistent with the view that neurodegenerative diseases are disorders of the aging nervous system.


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InternalMed_Harrison. A new classification for neurodegenerative diseases can be proposed based on not only the traditional phenotypic presentation and neuropathology, but also the prion etiology (Table 444e-4). Over the past decade, an expanding body of experimental data has accumulated implicating prions in each of these illnesses. In addition to kuru and CJD, Gerstmann-Sträussler-Scheinker disease (GSS) and fatal insomnia in humans are caused by PrPSc prions. In animals, PrPSc prions cause scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) of deer and elk, feline spongiform encephalopathy, and transmissible mink encephalopathy (TME). Similar to PrP, Aβ, tau, α-synuclein, superoxide dismutase 1 (SOD1), and possibly huntingtin all adopt alternative conformations that become self-propagating, and thus, each protein can become a prion and be transferred to synaptically connected neurons. Moreover, each of these prions causes a distinct constellation of


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InternalMed_Harrison. that become self-propagating, and thus, each protein can become a prion and be transferred to synaptically connected neurons. Moreover, each of these prions causes a distinct constellation of neurodegenerative diseases.


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InternalMed_Harrison. Evidence for a prion etiology of AD comes from a series of transmission experiments initially performed in marmosets and more recently in transgenic (Tg) mice inoculated with a synthetic Aβ peptide folded into a prion. Studies with the tau protein have shown that it not only features in the pathogenesis of AD, but also causes such illnesses as the frontotemporal dementias including chronic traumatic encephalopathy, which has been reported in both contact sport athletes and military personnel who have suffered traumatic brain injuries. A series of incisive studies using cultured cells and Tg mice has demonstrated that tau can become a prion and multiply in the brain. In contrast to the Aβ and tau prions, a strain of α-synuclein prions found in the brains of patients who died of multiple system atrophy (MSA) killed the Tg mouse host ~90 days after intracerebral inoculation, whereas α-synuclein prions formed spontaneously in Tg mouse brains killed recipient mice in ~200 days.


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InternalMed_Harrison. For many years, the most frequently cited argument against prions was the existence of strains that produced distinct clinical presentations and different patterns of neuropathologic lesions. Some investigators argued that the biologic information carried in different prion strains could only be encoded within a nucleic acid. Subsequently, many studies demonstrated that strain-specified variation is enciphered in the conformation of PrPSc, but the molecular mechanisms responsible for the storage of biologic information remains enigmatic. The neuroanatomical patterns of prion deposition have been shown to be dependent on the particular strain of prion. Convincing evidence in support of this proposition has been accumulated for PrP, Aβ, tau, and α-synuclein prions.


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InternalMed_Harrison. i) Experiment 1: Lifespan ii) Experiment 2: Training * Midline Frontal Theta Power (dB) Initial older adults Single-task training Multitask training No contact control Older adult post-training * = p < .05 –1.50 –1.10 –0.80 –0.45 –0.10 0.25 0.60 0.95 1.30 1.65 2.00 2.35 2.70 3.05 3.40


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InternalMed_Harrison. FIGURE 444e-5 Video game training can enhance cognitive performance. A. An older participant engaging in NeuroRacer training (driving while responding to target signs), with (B) a screen shot of the experimental training session. C. NeuroRacer multitasking costs for target discrimination increased (i.e., a larger percentage decrease from single task performance when multitasking) in (i) a linear fashion across the lifespan and with (ii) costs before training 1 month after training and 6 months after training, showing a differential benefit of multitasking training compared to a no-contact control group and a single-task training group. D. Midline frontal theta activity obtained with electroencephalogram showed significantly enhanced activity only following multitasking training, mimicking the pattern of change in the behavioral data as well as performance improvements on untrained tests of working memory and sustained attention (not presented). For details, see JA Anguera et al:


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InternalMed_Harrison. Nature 501:97, 2013. Although the number of prions identified in mammals and in fungi continues to expand, the existence of prions in other phylogeny remains undetermined. Some mammalian prions perform vital functions and do not cause disease; such nonpathogenic prions include the cytoplasmic polyadenylation element binding (CPEB) protein, the mitochondrial antiviral-signaling (MAVS) protein, and T cell– restricted intracellular antigen 1 (TIA-1).


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InternalMed_Harrison. All mammalian prion proteins adopt a β-sheet-rich conformation and appear to readily oligomerize as this process becomes self-propagating. Control of the self-propagating state of benign mammalian prions is not well understood but is critical for the well-being of the host. In contrast, pathogenic mammalian prions appear to multiply exponentially, but the mechanisms by which they cause disease are poorly defined. We do not know if prions multiply as monomers or as oligomers; notably, the ionizing radiation target size of PrPSc prions seems to suggest it is a trimer. The oligomeric states of pathogenic mammalian prions are thought to be the toxic forms, and assembly into larger polymers, such as amyloid fibrils, seems to be a mechanism for minimizing toxicity.


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InternalMed_Harrison. To date, there is no medication that halts or even slows a human neurodegenerative disease. The development of drugs designed to inhibit the conversion of the normal precursor proteins into prions or to enhance the degradation of prions focuses on the initial step in prion accumulation. Although several drugs that cross the blood-brain barrier have been identified that prolong the lives of mice infected with scrapie prions, none have been identified that extend the lives (BSE) Scrapie Chronic wasting disease (CWD) Feline spongiform encephalopathy Transmissible mink encephalopathy Alzheimer’s disease (AD) Aβ → tau Parkinson’s disease α-Synuclein Frontotemporal dementias (FTDs) Tau, TDP43, FUS (C9orf72,


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InternalMed_Harrison. Posttraumatic FTD, called chronic traumatic encephalopathy Amyotrophic lateral sclerosis SOD1, TDP43, FUS (C9orf72) Huntington’s disease Huntingtin of Tg mice that replicate human CJD prions. Despite doubling the length of incubation times in mice inoculated with scrapie prions, all of the mice eventually succumb to illness. Because all of the treated mice develop neurologic dysfunction at the same time, the mutation rate as judged by drug resistance is likely to approach 100%, which is much higher than mutation rates recorded for bacteria and viruses. Mutations in prions seem likely to represent conformational variants that are selected for in mammals where survival becomes limited by the fastest-replicating prions. The results of these studies make it likely that cocktails of drugs that attack a variety of prion conformers will be required for the development of effective therapeutics.


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InternalMed_Harrison. Systems neuroscience refers to study of the functions of neural circuits and how they relate to brain function, behavior, motor activity, and cognition. Brain imaging techniques, primarily functional magnetic resonance imaging (fMRI) and position emission tomography (PET), have made it possible to investigate, noninvasively and in awake individuals, cognitive processes such as perception, making judgments, paying attention, and thinking. This has allowed insights into how networks of neurons operate to produce behavior. Many of these studies at present are based on determining the connectivity of neural circuits and how they operate, and how this can be then modeled to produce improved understanding of physiologic processes. fMRI uses contrast mechanisms related to physiologic changes in tissue, and brain perfusion can be studied by observing the time course of changes in brain water signal as a bolus of injected paramagnetic gadolinium contrast moves through the brain. More recently,


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InternalMed_Harrison. and brain perfusion can be studied by observing the time course of changes in brain water signal as a bolus of injected paramagnetic gadolinium contrast moves through the brain. More recently, to study intrinsic contrast-related local changes in blood oxygenation with brain activity, blood-oxygen-level-dependent (BOLD) contrast has been used to provide a rapid noninvasive approach for functional assessment. These techniques have been reliably used in the field of both behavior and cognitive sciences. One example is the use of fMRI to demonstrate mirror neuron systems, imitative pathways activated when observing actions of others. Mirror neurons are thought to be important for social conditioning and for many forms of learning, and abnormalities in mirror neurons may underlie some autism disorders.


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InternalMed_Harrison. Both structural and functional connectivity methods show large-scale network dysfunction in AD and frontotemporal dementia. The networks targeted have been defined as the default network in AD and the salience network in frontotemporal dementia. The default network is characterized by an area of reduced glucose metabolism in the temporoparietal cortex, which precedes the onset of dementia and which is an area preferentially affected by amyloid deposition. These networks are now thought to be pathways accounting for the spread of abnormally templated proteins (prions; see above), including β-amyloid, tau, and α-synuclein.


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InternalMed_Harrison. Other examples of the use of fMRI include the study of memory, revealing that not only is hippocampal activity correlated with declarative memory consolidation, but it also involves activation in the ventral medial prefrontal cortex. Consolidation of memory over time results in decreased activity of the hippocampus and progressively stronger activation in the ventral medial prefrontal region associated with retrieval of consolidated memories. fMRI has also been used to identify sequences of brain activation involved in normal movements and alterations in their activation associated with both injury and recovery, to plan neurosurgical operations, and remarkably, to reconstruct actual visual images from the occipital cortex. Noninvasive brain-computer interfaces have extraordinary potential to advance the development of robotics and exoskeleton devices guided by brain activity for patients with a variety of nervous system afflictions. Diffusion tensor imaging is a recently developed MRI


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InternalMed_Harrison. to advance the development of robotics and exoskeleton devices guided by brain activity for patients with a variety of nervous system afflictions. Diffusion tensor imaging is a recently developed MRI technique that can measure macroscopic axonal organization in nervous system tissues; it appears to be useful in assessing myelin and axonal injuries as well as brain development. Advances in understanding neural processing have led to the development of the ability to demonstrate that humans have online voluntary control of human temporal lobe neurons.


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InternalMed_Harrison. Multitasking capabilities, including attention to tasks when faced with distractions, decline as we age due to a decline in medial prefrontal cognitive control system. When faced with a multitasking challenge, video game training can improve cognitive control capabilities by augmenting prefrontal suppression of the default network and, as measured by electroencephalography and fMRI, result in improved performance that is sustained and, importantly, transfers to other cognitive tasks not associated with the training paradigm. A significant recent advance in neuropathology has discovered that sodium dodecyl sulfate (SDS) detergent treatment can render the brain transparent (CLARITY), removing lipids while preserving most protein and structural elements and providing opportunities to identify brain structures and neural networks with unprecedented detail.


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InternalMed_Harrison. A therapeutic technology that has long-reaching implications for the development of novel interventions for neurologic, including behavioral, conditions has been the development of deep-brain stimulation as a highly effective therapeutic intervention for treating excessively firing neurons in the subthalamic nucleus of patients with Parkinson’s disease and the precingulate cortex in patients with depression.


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InternalMed_Harrison. The BRAIN initiative, grand in scope, was launched in 2013 to speed development of advances to understand, treat, repair, and prevent common neurologic disorders that, in aggregate, affect more than 1 billion people worldwide. The initial goal of BRAIN is to bring together experts in neurobiology (including optogenetics), engineering, information technology, and other fields to develop novel visualization and electrophysiologic methods to better define and understand neural circuits and all the connections among individual neurons. The announcement of the BRAIN initiative followed just weeks after a similarly ambitious program, the Human Brain Project (HBP), was unveiled by the European Union. The HBP seeks to model individual neurons, neural circuits, and ultimately the entire brain using computer technologies. Its architects also envision layering clinical and biomarker data from large health care databases to identify biosignatures associated with human phenotypes, possibly leading


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InternalMed_Harrison. computer technologies. Its architects also envision layering clinical and biomarker data from large health care databases to identify biosignatures associated with human phenotypes, possibly leading to a fundamental reclassification of disease, a concept also proposed by others, including in a 2011 report of the National Academy of Sciences (Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease). These two ambitious projects are expected to be complementary and over time will hopefully become increasingly integrated. Emerging discoveries are also certain to stimulate a range of their potential military use. Both the BRAIN and HBP initiatives have 444e-13 ethical questions, many of which are not unique to the neurosciences put into place strong ethical components to ensure that these programs but do come into sharpest focus in this area. These include possible risks are carried out, from the outset and to the fullest extent


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InternalMed_Harrison. place strong ethical components to ensure that these programs but do come into sharpest focus in this area. These include possible risks are carried out, from the outset and to the fullest extent possible, consisto the privacy of personal information about our health, cognitive capa-tent with guiding ethical principles that include respect for individuals, bilities, or behavioral attributes; the sanctity of our private thoughts; as public beneficence, justice and fairness, democratic deliberation, and well as concerns regarding neuroenhancement technologies, including transparency.


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InternalMed_Harrison. Chapter 444e Biology of Neurologic Diseases Daniel H. Lowenstein A seizure (from the Latin sacire, “to take possession of”) is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain. Depending on the distribution of discharges, this abnormal brain activity can have various manifestations, ranging from dramatic convulsive activity to experiential phenomena not readily discernible by an observer. Although a variety of factors influence the incidence and prevalence of seizures, ~5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood.


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InternalMed_Harrison. The meaning of the term seizure needs to be carefully distinguished from that of epilepsy. Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy. Epilepsy refers to a clinical phenomenon rather than a single disease entity, because there are many forms and causes of epilepsy. However, among the many causes of epilepsy there are various epilepsy syndromes in which the clinical and pathologic characteristics are distinctive and suggest a specific underlying etiology. Using the definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is ~0.3–0.5% in different populations throughout the world, and the prevalence of epilepsy has been estimated at 5–30 persons per 1000.


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InternalMed_Harrison. Determining the type of seizure that has occurred is essential for focusing the diagnostic approach on particular etiologies, selecting the appropriate therapy, and providing potentially vital information regarding prognosis. The International League against Epilepsy (ILAE) Commission on Classification and Terminology, 2005–2009 has provided an updated approach to classification of seizures (Table 445-1). This system is based on the clinical features of seizures and associated electroencephalographic findings. Other potentially distinctive features such as etiology or cellular substrate are not considered in this classification system, although this will undoubtedly change in the future as more is learned about the pathophysiologic mechanisms that underlie specific seizure types. A fundamental principle is that seizures may be either focal or generalized. Focal seizures originate within networks limited to one


InternalMed_Harrison

InternalMed_Harrison. A fundamental principle is that seizures may be either focal or generalized. Focal seizures originate within networks limited to one CLassifiCatioN of seiZures 1. Focal seizures (Can be further described as having motor, sensory, autonomic, cognitive, or other features) 2. Generalized seizures a. b. c. d. e. f. 3. May be focal, generalized, or unclear cerebral hemisphere (note that the term partial seizures is no longer used). Generalized seizures arise within and rapidly engage networks distributed across both cerebral hemispheres. Focal seizures are usually associated with structural abnormalities of the brain. In contrast, generalized seizures may result from cellular, biochemical, or structural abnormalities that have a more widespread distribution. There are clear exceptions in both cases, however.


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InternalMed_Harrison. Focal seizures arise from a neuronal network either discretely localized within one cerebral hemisphere or more broadly distributed but still within the hemisphere. With the new classification system, the subcategories of “simple focal seizures” and “complex focal seizures” have been eliminated. Instead, depending on the presence of cognitive impairment, they can be described as focal seizures with or without dyscognitive features. Focal seizures can also evolve into generalized seizures. In the past this was referred to as focal seizures with secondary generalization, but the new system relies on specific descriptions of the type of generalized seizures that evolve from the focal seizure.


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InternalMed_Harrison. The routine interictal (i.e., between seizures) electroencephalogram (EEG) in patients with focal seizures is often normal or may show brief discharges termed epileptiform spikes, or sharp waves. Because focal seizures can arise from the medial temporal lobe or inferior frontal lobe (i.e., regions distant from the scalp), the EEG recorded during the seizure may be nonlocalizing. However, the seizure focus is often detected using sphenoidal or surgically placed intracranial electrodes.


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InternalMed_Harrison. Focal Seizures Without Dyscognitive Features Focal seizures can cause motor, sensory, autonomic, or psychic symptoms without impairment of cognition. For example, a patient having a focal motor seizure arising from the right primary motor cortex near the area controlling hand movement will note the onset of involuntary movements of the contralateral, left hand. These movements are typically clonic (i.e., repetitive, flexion/extension movements) at a frequency of ~2–3 Hz; pure tonic posturing may be seen as well. Since the cortical region controlling hand movement is immediately adjacent to the region for facial expression, the seizure may also cause abnormal movements of the face synchronous with the movements of the hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal discharges in a very limited region over the appropriate area of cerebral cortex if the seizure focus involves the cerebral convexity. Seizure activity occurring within


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InternalMed_Harrison. ictal EEG) may show abnormal discharges in a very limited region over the appropriate area of cerebral cortex if the seizure focus involves the cerebral convexity. Seizure activity occurring within deeper brain structures is sometimes not detected by the standard EEG, however, and may require intracranial electrodes for its detection.


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InternalMed_Harrison. Three additional features of focal motor seizures are worth noting. First, in some patients, the abnormal motor movements may begin in a very restricted region such as the fingers and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This phenomenon, described by Hughlings Jackson and known as a “Jacksonian march,” represents the spread of seizure activity over a progressively larger region of motor cortex. Second, patients may experience a localized paresis (Todd’s paralysis) for minutes to many hours in the involved region following the seizure. Third, in rare instances, the seizure may continue for hours or days. This condition, termed epilepsia partialis continua, is often refractory to medical therapy.


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InternalMed_Harrison. Focal seizures may also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function (flushing, sweating, piloerection). Focal seizures arising from the temporal or frontal cortex may also cause alterations in hearing, olfaction, or higher cortical function (psychic symptoms). This includes the sensation of unusual, intense odors (e.g., burning rubber or kerosene) or sounds (crude or highly complex sounds), or an epigastric sensation that rises from the stomach or chest to the head. Some patients describe odd, internal feelings such as fear, a sense of impending change, detachment, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, “internal” events that are not directly observable by someone else are referred to as auras.


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InternalMed_Harrison. Focal Seizures with Dyscognitive Features Focal seizures may also be accompanied by a transient impairment of the patient’s ability to maintain normal contact with the environment. The patient is unable to respond appropriately to visual or verbal commands during the seizure and has impaired recollection or awareness of the ictal phase. The seizures frequently begin with an aura (i.e., a focal seizure without cognitive disturbance) that is stereotypic for the patient. The start of the ictal phase is often a sudden behavioral arrest or motionless stare, which marks the onset of the period of impaired awareness. The behavioral arrest is usually accompanied by automatisms, which are involuntary, automatic behaviors that have a wide range of manifestations. Automatisms may consist of very basic behaviors such as chewing, lip smacking, swallowing, or “picking” movements of the hands, or more elaborate behaviors such as a display of emotion or running. The patient is typically confused


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InternalMed_Harrison. basic behaviors such as chewing, lip smacking, swallowing, or “picking” movements of the hands, or more elaborate behaviors such as a display of emotion or running. The patient is typically confused following the seizure, and the transition to full recovery of consciousness may range from seconds up to an hour. Examination immediately following the seizure may show an anterograde amnesia or, in cases involving the dominant hemisphere, a postictal aphasia.


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InternalMed_Harrison. The range of potential clinical behaviors linked to focal seizures is so broad that extreme caution is advised before concluding that stereotypic episodes of bizarre or atypical behavior are not due to seizure activity. In such cases additional, detailed EEG studies may be helpful.


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InternalMed_Harrison. Focal seizures can spread to involve both cerebral hemispheres and produce a generalized seizure, usually of the tonic-clonic variety (discussed below). This evolution is observed frequently following focal seizures arising from a focus in the frontal lobe, but may also be associated with focal seizures occurring elsewhere in the brain. A focal seizure that evolves into a generalized seizure is often difficult to distinguish from a primary generalized-onset tonic-clonic seizure, because bystanders tend to emphasize the more dramatic, generalized convulsive phase of the seizure and overlook the more subtle, focal symptoms present at onset. In some cases, the focal onset of the seizure becomes apparent only when a careful history identifies a preceding aura. Often, however, the focal onset is not clinically evident and may be established only through careful EEG analysis. Nonetheless, distinguishing between these two entities is extremely important, because there may be substantial


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InternalMed_Harrison. is not clinically evident and may be established only through careful EEG analysis. Nonetheless, distinguishing between these two entities is extremely important, because there may be substantial differences in the evaluation and treatment of epilepsies associated with focal versus generalized seizures.


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InternalMed_Harrison. Generalized seizures are thought to arise at some point in the brain but immediately and rapidly engage neuronal networks in both cerebral hemispheres. Several types of generalized seizures have features that place them in distinctive categories and facilitate clinical diagnosis. Typical Absence Seizures Typical absence seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. The seizure typically lasts for only seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion. Although the brief loss of consciousness may be clinically inapparent or the sole manifestation of the seizure discharge, absence seizures are usually accompanied by subtle, bilateral motor signs such as rapid blinking of the eyelids, chewing movements, or small-amplitude, clonic movements of the hands.


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InternalMed_Harrison. Typical absence seizures are associated with a group of genetically determined epilepsies with onset usually in childhood (ages 4–8 years) or early adolescence and are the main seizure type in 15–20% of children with epilepsy. The seizures can occur hundreds of times per day, but the child may be unaware of or unable to convey their existence. Because the clinical signs of the seizures are subtle, especially to parents who may not have had previous experience with seizures, it is not sur-2543 prising that the first clue to absence epilepsy is often unexplained “daydreaming” and a decline in school performance recognized by a teacher.


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InternalMed_Harrison. The electrophysiologic hallmark of typical absence seizures is a generalized, symmetric, 3-Hz spike-and-wave discharge that begins and ends suddenly, superimposed on a normal EEG background. Periods of spike-and-wave discharges lasting more than a few seconds usually correlate with clinical signs, but the EEG often shows many more brief bursts of abnormal cortical activity than were suspected clinically. Hyperventilation tends to provoke these electrographic discharges and even the seizures themselves and is routinely used when recording the EEG.


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InternalMed_Harrison. Atypical Absence Seizures Atypical absence seizures have features that deviate both clinically and electrophysiologically from typical absence seizures. For example, the lapse of consciousness is usually of longer duration and less abrupt in onset and cessation, and the seizure is accompanied by more obvious motor signs that may include focal or lateralizing features. The EEG shows a generalized, slow spike-andwave pattern with a frequency of ≤2.5 per second, as well as other abnormal activity. Atypical absence seizures are usually associated with diffuse or multifocal structural abnormalities of the brain and therefore may accompany other signs of neurologic dysfunction such as mental retardation. Furthermore, the seizures are less responsive to anticonvulsants compared to typical absence seizures.


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InternalMed_Harrison. Generalized, Tonic-Clonic Seizures Generalized-onset tonic-clonic seizures are the main seizure type in ~10% of all persons with epilepsy. They are also the most common seizure type resulting from metabolic derangements and are therefore frequently encountered in many different clinical settings. The seizure usually begins abruptly without warning, although some patients describe vague premonitory symptoms in the hours leading up to the seizure. This prodrome is distinct from the stereotypic auras associated with focal seizures that generalize. The initial phase of the seizure is usually tonic contraction of muscles throughout the body, accounting for a number of the classic features of the event. Tonic contraction of the muscles of expiration and the larynx at the onset will produce a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops. Contraction of the jaw muscles may cause biting of the tongue. A marked enhancement of


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InternalMed_Harrison. a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops. Contraction of the jaw muscles may cause biting of the tongue. A marked enhancement of sympathetic tone leads to increases in heart rate, blood pressure, and pupillary size. After 10–20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min. The postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. Bladder or bowel incontinence may occur at this point. Patients gradually regain consciousness over minutes to hours, and during this transition, there is typically a period of postictal confusion. Patients subsequently complain of


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InternalMed_Harrison. occur at this point. Patients gradually regain consciousness over minutes to hours, and during this transition, there is typically a period of postictal confusion. Patients subsequently complain of headache, fatigue, and muscle ache that can last for many hours. The duration of impaired consciousness in the postictal phase can be extremely long (i.e., many hours) in patients with prolonged seizures or underlying central nervous system (CNS) diseases such as alcoholic cerebral atrophy.


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InternalMed_Harrison. The EEG during the tonic phase of the seizure shows a progressive increase in generalized low-voltage fast activity, followed by generalized high-amplitude, polyspike discharges. In the clonic phase, the high-amplitude activity is typically interrupted by slow waves to create a spike-and-wave pattern. The postictal EEG shows diffuse slowing that gradually recovers as the patient awakens. There are a number of variants of the generalized tonic-clonic seizure, including pure tonic and pure clonic seizures. Brief tonic seizures lasting only a few seconds are especially noteworthy since they are usually associated with specific epileptic syndromes having mixed seizure phenotypes, such as the Lennox-Gastaut syndrome (discussed below).


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InternalMed_Harrison. Atonic Seizures Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1–2 s. Consciousness is briefly impaired, 2544 but there is usually no postictal confusion. A very brief seizure may cause only a quick head drop or nodding movement, whereas a longer seizure will cause the patient to collapse. This can be extremely dangerous, because there is a substantial risk of direct head injury with the fall. The EEG shows brief, generalized spike-and-wave discharges followed immediately by diffuse slow waves that correlate with the loss of muscle tone. Similar to pure tonic seizures, atonic seizures are usually seen in association with known epilepsy syndromes.


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InternalMed_Harrison. Myoclonic Seizures Myoclonus is a sudden and brief muscle contraction that may involve one part of the body or the entire body. A normal, common physiologic form of myoclonus is the sudden jerking movement observed while falling asleep. Pathologic myoclonus is most commonly seen in association with metabolic disorders, degenerative CNS diseases, or anoxic brain injury (Chap. 330). Although the distinction from other forms of myoclonus is imprecise, myoclonic seizures are considered to be true epileptic events because they are caused by cortical (versus subcortical or spinal) dysfunction. The EEG may show bilaterally synchronous spike-and-wave discharges synchronized with the myoclonus, although these can be obscured by movement artifact. Myoclonic seizures usually coexist with other forms of generalized seizures but are the predominant feature of juvenile myoclonic epilepsy (discussed below).


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InternalMed_Harrison. Not all seizure types can be designated as focal or generalized, and they should therefore be labeled as “unclassifiable” until additional evidence allows a valid classification. Epileptic spasms are such an example. These are characterized by a briefly sustained flexion or extension of predominantly proximal muscles, including truncal muscles. The EEG in these patients usually shows hypsarrhythmias, which consist of diffuse, giant slow waves with a chaotic background of irregular, multifocal spikes and sharp waves. During the clinical spasm, there is a marked suppression of the EEG background (the “electrodecremental response”). The electromyogram (EMG) also reveals a characteristic rhomboid pattern that may help distinguish spasms from brief tonic and myoclonic seizures. Epileptic spasms occur predominantly in infants and likely result from differences in neuronal function and connectivity in the immature versus mature CNS.


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InternalMed_Harrison. Epilepsy syndromes are disorders in which epilepsy is a predominant feature, and there is sufficient evidence (e.g., through clinical, EEG, radiologic, or genetic observations) to suggest a common underlying mechanism. Three important epilepsy syndromes are listed below; additional examples with a known genetic basis are shown in Table 445-2.


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InternalMed_Harrison. Juvenile myoclonic epilepsy (JME) is a generalized seizure disorder of unknown cause that appears in early adolescence and is usually characterized by bilateral myoclonic jerks that may be single or repetitive. The myoclonic seizures are most frequent in the morning after awakening and can be provoked by sleep deprivation. Consciousness is preserved unless the myoclonus is especially severe. Many patients also experience generalized tonic-clonic seizures, and up to one-third have absence seizures. Although complete remission is relatively uncommon, the seizures usually respond well to appropriate anticonvulsant medication. There is often a family history of epilepsy, and genetic linkage studies suggest a polygenic cause.


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InternalMed_Harrison. Lennox-Gastaut syndrome occurs in children and is defined by the following triad: (1) multiple seizure types (usually including generalized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG showing slow (<3 Hz) spike-and-wave discharges and a variety of other abnormalities; and (3) impaired cognitive function in most but not all cases. Lennox-Gastaut syndrome is associated with CNS disease or dysfunction from a variety of causes, including de novo mutations, developmental abnormalities, perinatal hypoxia/ischemia, trauma, infection, and other acquired lesions. The multifactorial nature of this syndrome suggests that it is a nonspecific response of the brain to diffuse neural injury. Unfortunately, many patients have a poor prognosis due to the underlying CNS disease and the physical and psychosocial consequences of severe, poorly controlled epilepsy.


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InternalMed_Harrison. Mesial temporal lobe epilepsy (MTLE) is the most common syndrome associated with focal seizures with dyscognitive features and is an example of an epilepsy syndrome with distinctive clinical, electroencephalographic, and pathologic features (Table 445-3). High-resolution magnetic resonance imaging (MRI) can detect the characteristic hippocampal sclerosis that appears to be essential in the pathophysiology of MTLE for many patients (Fig. 445-1). Recognition of this syndrome is especially important because it tends to be refractory to treatment with anticonvulsants but responds well to surgical intervention. Advances in the understanding of basic mechanisms of epilepsy have come through studies of experimental models of MTLE, discussed below.


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InternalMed_Harrison. Seizures are a result of a shift in the normal balance of excitation and inhibition within the CNS. Given the numerous properties that control neuronal excitability, it is not surprising that there are many different ways to perturb this normal balance, and therefore many different causes of both seizures and epilepsy. Three clinical observations emphasize how a variety of factors determine why certain conditions may cause seizures or epilepsy in a given patient. 1.


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InternalMed_Harrison. 1. The normal brain is capable of having a seizure under the appropriate circumstances, and there are differences between individuals in the susceptibility or threshold for seizures. For example, seizures may be induced by high fevers in children who are otherwise normal and who never develop other neurologic problems, including epilepsy. However, febrile seizures occur only in a relatively small proportion of children. This implies there are various underlying endogenous factors that influence the threshold for having a seizure. Some of these factors are genetic, as a family history of epilepsy has a clear influence on the likelihood of seizures occurring in otherwise normal individuals. Normal development also plays an important role, because the brain appears to have different seizure thresholds at different maturational stages. 2.


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InternalMed_Harrison. 2. There are a variety of conditions that have an extremely high likelihood of resulting in a chronic seizure disorder. One of the best examples of this is severe, penetrating head trauma, which is associated with up to a 45% risk of subsequent epilepsy. The high propensity for severe traumatic brain injury to lead to epilepsy suggests that the injury results in a long-lasting pathologic change in the CNS that transforms a presumably normal neural network into one that is abnormally hyperexcitable. This process is known as epileptogenesis, and the specific changes that result in a lowered seizure threshold can be considered epileptogenic factors. Other processes associated with epileptogenesis include stroke, infections, and abnormalities of CNS development. Likewise, the genetic abnormalities associated with epilepsy likely involve processes that trigger the appearance of specific sets of epileptogenic factors. 3.


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InternalMed_Harrison. 3. Seizures are episodic. Patients with epilepsy have seizures intermittently and, depending on the underlying cause, many patients are completely normal for months or even years between seizures. This implies there are important provocative or precipitating factors that induce seizures in patients with epilepsy. Similarly, precipitating factors are responsible for causing the single seizure in someone without epilepsy. Precipitants include those due to intrinsic physiologic processes such as psychological or physical stress, sleep deprivation, or hormonal changes associated with the menstrual cycle. They also include exogenous factors such as exposure to toxic substances and certain medications. Gene (Locus) Function of Gene Clinical Syndrome Comments CHRNA4 (20q13.2) Nicotinic acetylcholine receptor subunit; mutations cause alterations in Ca2+ flux through the receptor; this may reduce amount of GABA release in presynaptic terminals


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InternalMed_Harrison. CHRNA4 (20q13.2) Nicotinic acetylcholine receptor subunit; mutations cause alterations in Ca2+ flux through the receptor; this may reduce amount of GABA release in presynaptic terminals KCNQ2 (20q13.3) Voltage-gated potassium channel subunits; mutation in pore regions may cause a 20–40% reduction of potassium currents, which will lead to impaired repolarization SCN1A (2q24.3) α-Subunit of a voltage-gated sodium channel; numerous mutations affecting sodium currents that cause either gain or loss of function; network effects appear related to expression in excitatory or inhibitory cells LGI1 (10q24) Leucine-rich glioma-inactivated 1 gene; previous evidence for role in glial tumor progression; recent studies suggest an influence in the postnatal development of glutamatergic circuits in the hippocampus