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Seizures and Epilepsy

STEM CELLS AND TRANSPLANTATION

The nervous system is traditionally considered to be a nonmitotic organ, in particular withrespect to neurons. These concepts have been challenged by the finding that neuralprogenitor or stem cells exist in the adult CNS that are capable of differentiation, migrationover long distances, and extensive axonal arborization and synapse formation with

appropriate targets. These capabilities also indicate that the repertoire of factors required forgrowth, survival, differentiation, and migration of these cells exists in the mature nervoussystem. In rodents, neural stem cells, defined as progenitor cells capable of differentiatinginto mature cells of neural or glial lineage, have been experimentally propagated from fetalCNS and neuroectodermal tissues and also from adult germinal matrix and ependymaregions. 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.

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 cellscould also be engineered to express therapeutic molecules. Another promising approach is touse growth factors, such as BDNF, to stimulate endogenous stem cells to proliferate andmigrate to areas of neuronal damage.

A major advance has been the development of induced pluripotent stem cells. Using thistechnique, adult somatic cells such as skin fibroblasts are treated with four pluripotencyfactors (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 cellsderived from human embryos. The development of these cells has tremendous promise forboth studying disease mechanisms and testing therapeutics. As yet there is no consensus onthe best way to generate and differentiate the iPSCs; however, techniques to avoid using viralvectors and use of Cre-lox systems to remove reprogramming factors result in a better matchof gene expression profiles with those of embryonic stem cells. Over the years, the field ofdirected differentiation has used three main strategies to specify neural lineages from humanpluripotent stem cells. These strategies are embryoid body formation, coculture on neural-inducing feeders, and direct neural induction. Thus far, iPSCs have been made from patientswith all of the major human neurodegenerative diseases, and studies using them are underway.

Although stem cells hold tremendous promise for the treatment of debilitating neurologicdiseases, such as Parkinsons disease and spinal cord injury, it should be emphasized thatmedical application is in its infancy. Major obstacles are the generation of position- andneurotransmitter-defined subtypes of neurons and their isolation as pure populations of thedesired cells. This is crucial to avoid persistence of undifferentiated embryonic stem (ES)cells, which can generate tumors. The establishment of appropriate neural connections andafferent control is also critical. For instance, human ES motor neurons will need to beintroduced at multiple segments in the neuraxis, and then their axons will need to regeneratefrom the spinal cord to distal musculature.

Experimental transplantation of human fetal dopaminergic neurons in patients withParkinsons disease has shown that these transplanted cells can survive within the hoststriatum; however, some patients developed disabling dyskinesias, and this approach is nolonger in clinical development. The possibility that iPSCs will be used in Parkinsons disease

was strengthened by studies showing that they can be differentiated into dopaminergicneurons. The dopaminergic neurons were then shown to rescue the parkinsonian phenotypein a MPTP-induced primate model with excellent dopaminergic neuron survival function andlack of neural overgrowth. The correction of tau mutations in iPSC-derived neurons has beenshown to reverse the toxic phenotype in dendrite retraction and cell death.

Another new use for iPSCs is to screen drugs as potential treatments for neurodegenerativeand other diseases. The feasibility of this has been shown using iPSC-induced macrophagesfrom patients with Gauchers disease, and verifying the efficacy of protein chaperones inthese cells as a means of stabilizing the mutant glucocerebrosidase and increasing its activityand the duration of its effects. Other approaches are to attempt to reduce expression ofproteins, such as amyloid, tau, and -synuclein, implicated in the pathogenesis ofneurodegenerative diseases. One difficulty has been that reprogramming cells to iPSCs

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resets their identity back to an embryonic age, which is a hurdle in modeling of late-onsetdiseases. One approach to this has been to express a fragment of the mutated gene, such asa portion of lamin A, which causes premature aging in progeria. This approach showed thatdendrite degeneration and progressive loss of tyrosine hydroxylase expression, as well asenlarged mitochondria and Lewy body precursor inclusions, were induced in iPSC-deriveddopaminergic neurons with progerin-induced aging.

Studies of transplantation for patients with Huntingtons disease have also reportedencouraging, although very preliminary, results. OPCs transplanted into mice with adysmyelinating disorder effectively migrated in the new environment, interacted with axons,and mediated myelination; such experiments raise hope that similar transplantation strategiesmay be feasible in human disorders of myelin such as MS. The promise of stem cells fortreatment of both neurodegenerative diseases and neural injury is great, but developmenthas been slowed by unresolved concerns over safety (including the theoretical risk ofmalignant transformation of transplanted cells), ethics (particularly with respect to use of fetaltissue), and efficacy.

In developing brain, the extracellular matrix provides stimulatory and inhibitory signals thatpromote neuronal migration, neurite outgrowth, and axonal extension. After neuronaldamage, reexpression of inhibitory molecules such as chondroitin sulfate proteoglycans mayprevent tissue regeneration. Chondroitinase degraded these inhibitory molecules andenhanced axonal regeneration and motor recovery in a rat model of spinal cord injury. Severalmyelin proteins, specifically Nogo, oligodendrocyte myelin glycoprotein (OMGP), and myelin-associated glycoprotein (MAG), may also interfere with axon regeneration. Sialidase, whichcleaves 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 itsinhibitory function via the p75 neurotrophin receptor signaling.

CELL DEATH: EXCITOTOXICITY AND APOPTOSIS

Excitotoxicityrefers to neuronal cell death caused by activation of excitatory amino acid

receptors (Fig. 444e-4). Compelling evidence for a role of excitotoxicity, especially in ischemicneuronal injury, is derived from experiments in animal models. Experimental models of strokeare associated with increased extracellular concentrations of the excitatory amino acidneurotransmitter 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-methyl-D-aspartate (NMDA)receptors (except for cerebellar Purkinje cells, which are vulnerable to hypoxia-ischemia butlack NMDA receptors); and competitive and noncompetitive NMDA antagonists are effective inpreventing focal ischemia. In global cerebral ischemia, non-NMDA receptors (kainic acid and-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate [AMPA]) are activated, and antagonists tothese receptors are protective. Experimental brain damage induced by hypoglycemia is alsoattenuated by NMDA antagonists.



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nitric oxide synthase or poly-ADP-ribose polymerase, or those that overexpress superoxidedismutase, are resistant to focal ischemia.

Another aspect of excitotoxicity is that it has been demonstrated that stimulation ofextrasynaptic NMDA receptors mediates cell death, where as stimulation of synaptic receptorsis protective. This has been shown to play a role in excitotoxicity in transgenic mouse modelsof Huntingtons disease, in which using low-dose memantine to selectively block theextrasynaptic receptors is beneficial.

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

Apoptosis, or programmed cell death, plays an important role in both physiologic andpathologic conditions. During embryogenesis, apoptotic pathways operate to destroy neuronsthat fail to differentiate appropriately or reach their intended targets. There is mountingevidence for an increased rate of apoptotic cell death in a variety of acute and chronic

neurologic diseases. Apoptosis is characterized by neuronal shrinkage, chromatincondensation, and DNA fragmentation, whereas necrotic cell death is associated withcytoplasmic and mitochondrial swelling followed by dissolution of the cell membrane.Apoptotic and necrotic cell death can coexist or be sequential events, depending on theseverity of the initiating insult. Cellular energy reserves appear to have an important role inthese two forms of cell death, with apoptosis favored under conditions in which ATP levels arepreserved. Evidence of DNA fragmentation has been found in a number of degenerativeneurologic disorders, including AD, Huntingtons disease, and ALS. The best characterizedgenetic 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 arecausative.

Mitochondria are essential in controlling specific apoptosis pathways. The redistribution ofcytochrome 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 byoverproduction of the apoptotic protein BCL2 and is promoted by the proapoptotic proteinBAX. These pathways may be triggered by activation of a large pore in the mitochondrialinner membrane known as the permeability transition pore, although in other circumstances,they occur independently. The permeability transition pore is made up of dimers of ATPsynthase and is activated by cyclophilin D, leading to large calcium fluxes across the innermitochondrial membrane. Certain forms of congenital muscular dystrophies are caused bymutations in collagen VI, which leads to increased activation of the permeability transitionpore. Recent studies suggest that blocking the mitochondrial pore reduces bothhypoglycemic and ischemic cell death. Mice deficient in cyclophilin D, a key protein involvedin opening the permeability transition pore, are resistant to necrosis produced by focalcerebral ischemia.

PROTEIN AGGREGATION AND NEURODEGENERATION

The possibility that protein aggregation plays a role in the pathogenesis of neurodegenerativediseases is a major focus of current research. Protein aggregation is a major histopathologichallmark of neurodegenerative diseases. Deposition of -amyloid is strongly implicated in thepathogenesis of AD. Genetic mutations in familial AD cause increased production of-amyloid with 42 amino acids, which has an increased propensity to aggregate, as comparedto -amyloid with 40 amino acids. Furthermore, mutations in the amyloid precursor protein(APP), which reduce the production of -amyloid, protect against the development of AD andare associated with preserved cognition in the elderly. Mutations in genes encoding the MAPTlead to altered splicing of tau and the production of neurofibrillary tangles in frontotemporaldementia and progressive supranuclear palsy. Familial Parkinsons disease is associated withHarrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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mutations in leucine-rich repeat kinase 2 (LRRK2), -synuclein, parkin, PINK1,and DJ-1.PINK1 is a mitochondrial kinase (see below), and DJ-1 is a protein involved in protection fromoxidative stress. Parkin, which causes autosomal recessive early-onset Parkinsons disease, isa ubiquitin ligase. The characteristic histopathologic feature of Parkinsons disease is theLewy body, an eosinophilic cytoplasmic inclusion that contains both neurofilaments and-synuclein. Huntingtons disease and cerebellar degenerations are associated withexpansions of polyglutamine repeats in proteins, which aggregate to produce neuronalintranuclear inclusions. Familial ALS is associated with superoxide dismutase mutations andcytoplasmic inclusions containing superoxide dismutase. An important finding was thediscovery 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), werefound in familial ALS. Both of these proteins are involved in transcription regulation as well asRNA metabolism. In autosomal dominant neurohypophyseal diabetes insipidus, mutations invasopressin result in abnormal protein processing, accumulation in the endoplasmicreticulum, and cell death.

Another key mechanism linked to cell death is mitochondrial dynamics, which refers to theprocesses involved in movement of mitochondria, as well as in mitochondrial fission andfusion, which play a critical role mitochondrial turnover and in replenishment of damagedmitochondria. Mitochondrial dysfunction is strongly linked to the pathogenesis of a number ofneurodegenerative diseases such as Friedreichs ataxia, which is caused by mutations in aniron-binding protein that plays an important role in transferring iron to iron-sulfur clusters inaconitase and complex I and II of the electron transport chain. Mitochondrial fission isdependent on the dynamin-related proteins (Drp1), which bind to its receptor Fis, whereasmitofuscins 1 and 2 (MF 1/2) and optic atrophy protein 1 (OPA1) are responsible for fusion ofthe outer and inner mitochondrial membrane, respectively. Mutations in MFN2 cause Charcot-Marie-Tooth neuropathy type 2A, and mutations in OPA1 cause autosomal dominant opticatrophy. Both -amyloid and mutant huntingtin protein induce mitochondrial fragmentationand neuronal cell death associated with increased activity of Drp1. In addition, mutations ingenes causing autosomal recessive Parkinsons disease, parkinand PINK1, cause abnormalmitochondrial morphology and result in impairment of the ability of the cell to removedamaged mitochondria by autophagy.

One major scientific question is whether protein aggregates directly contribute to neuronaldeath or whether they are merely secondary bystanders. A current focus in all the

neurodegenerative diseases is on small protein aggregates termed oligomers. These may bethe toxic species of -amyloid, -synuclein, and proteins with expanded polyglutamines suchas are associated with Huntingtons disease. Protein aggregates are usually ubiquinated,

which targets them for degradation by the 26S component of the proteasome. An inability todegrade protein aggregates could lead to cellular dysfunction, impaired axonal transport, andcell death by apoptotic mechanisms.

Autophagy is the degradation of cystolic components in lysosomes. There is increasingevidence that autophagy plays an important role in degradation of protein aggregates in theneurodegenerative diseases, and it is impaired in AD, Parkinsons disease, and Huntingtonsdisease. Autophagy is particularly important to the health of neurons, and failure ofautophagy contributes to cell death. In Huntingtons disease, a failure of cargo recognitionoccurs, contributing to protein aggregates and cell death. Rapamycin, which inducesautophagy, exerts beneficial therapeutic effects in transgenic mouse models of AD,Parkinsons disease, and Huntingtons disease.

There is other evidence for lysosomal dysfunction and impaired autophagy in Parkinsons

disease. Mutations in glucocerebrosidase are associated with 5% of all Parkinsons diseasecases as well as 89% of patients with dementia with Lewy bodies. Therefore, this is the mostimportant genetic cause of both disorders thus far identified. There appear to be reciprocalinteractions between glucocerebrosidase and -synuclein. It has been shown thatglucocerebrosidase concentrations and enzymatic activity are reduced in the substantia nigraof sporadic Parkinsons disease patients. Furthermore, -synuclein is degraded bychaperone-mediated and macro autophagy. The degradation of -synuclein has been shownto be impaired in transgenic mice deficient in glucocerebrosidase as well as in mice in whichthe enzyme has been inhibited. Furthermore, it is known that -synuclein inhibits the activityof glucocerebrosidase. Therefore, there is bidirectional feedback between -synuclein andglucocerebrosidase. An attractive therapeutic intervention could be to use protein chaperonesto increase the activity and duration of action of glucocerebrosidase. This would also reduce-synuclein levels and block the degeneration of dopaminergic neurons.Harrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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The retromer complex is a conserved membrane-associated protein complex that functions inthe endosome-to-Golgi complex. The retromer complex contains a cargo selective complexconsisting 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 Parkinsonsdisease. The retromer also traffics APP away from endosomes, where it is cleaved to generate-amyloid. Deficiencies of VPS35 and VPS26 were also identified in hippocampal brain tissuefrom AD. A new therapeutic approach to these diseases might therefore be to usechaperones to stabilize the retromer and reduce the generation of -amyloid and -synuclein.

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

Interestingly, in experimental models of Huntingtons disease and cerebellar degeneration,protein aggregates are not well correlated with neuronal death and may be protective. Asubstantial body of evidence suggests that the mutant proteins with polyglutamineexpansions in these diseases bind to transcription factors and that this contributes to diseasepathogenesis. In Huntingtons disease, there is dysfunction of the transcriptional co-regulator,PGC-1, a key regulator of mitochondrial biogenesis. There is evidence that impaired functionof PGC-1is also important in both Parkinsons disease and AD, making it an attractive targetfor treatments. Agents that upregulate gene transcription are neuroprotective in animalmodels of these diseases. A number of compounds have been developed to block -amyloidproduction 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-amyloid, tau, or -synuclein. These studies have shown efficacy in preventing the spread ofamyloid, tau, and -synuclein in animal studies, raising hopes that this could lead to effectivetherapies by blocking neuron-to-neuron propagation. Two large clinical trials of -amyloidimmunotherapy, however, did not show efficacy, although this therapeutic strategy is stillbeing studied.

PRIONS AND NEURODEGENERATIVE DISEASES

As we have learned more about the etiology and pathogenesis of the neurodegenerativediseases, it has become clear that the histologic abnormalities that were once curiosities, infact, are likely to reflect the etiologies. For example, the amyloid plaques in kuru and

Creutzfeldt-Jakob disease (CJD) are filled with the PrPScprions that have assembled intofibrils. 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-actingviruses, but a large body of experimental evidence argues that the infectious pathogenscausing 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 -sheet and can assemble into amyloid fibrils.

Similar to the plaques in kuru and CJD that are composed of PrP prions, the amyloid plaquesin AD are filled with Aprions that have polymerized into fibrils. This relationship between theneuropathologic findings and the etiologic prion was strengthened by the genetic linkagebetween familial CJD and mutations in the PrP gene, as well as (as noted above) betweenfamilial AD and mutations in the APPgene. Moreover, a mutation in the APPgene thatprevents Apeptide formation was correlated with a decreased incidence of AD in Iceland.

The heritable neurodegenerative diseases offer an important insight into the pathogenesis ofthe more common, sporadic ones. Although the mutant proteins that cause these disordersare expressed in the brains of people early in life, the diseases do not occur for manydecades. Many explanations for the late onset of familial neurodegenerative diseases havebeen offered, but none are supported by substantial experimental evidence. The late onsetmight 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 alsoconsistent with data showing that the protein quality-control mechanisms diminish inefficiency with age. Thus, the prion forms of both wild-type and mutant proteins are likely tobe efficiently degraded in younger people but are less well handled in older individuals. Thisexplanation is consistent with the view that neurodegenerative diseases are disorders of theaging nervous system.



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FIGURE 444e-5 Video game training can enhance cognitive performance. A.An olderparticipant engaging in NeuroRacer training (driving while responding to target signs), with(B) a screen shot of the experimental training session. C.NeuroRacer multitasking costs fortarget discrimination increased (i.e., a larger percentage decrease from single taskperformance when multitasking) in (i) a linear fashion across the lifespan and with ( ii) costsbefore training 1 month after training and 6 months after training, showing a differentialbenefit of multitasking training compared to a no-contact control group and a single-tasktraining group. D.Midline frontal theta activity obtained with electroencephalogram showedsignificantly enhanced activity only following multitasking training, mimicking the pattern ofchange in the behavioral data as well as performance improvements on untrained tests ofworking memory and sustained attention (not presented). For details, see JA Anguera et al:Nature 501:97, 2013.

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 accumulatedimplicating prions in each of these illnesses. In addition to kuru and CJD, Gerstmann-

Strussler-Scheinker disease (GSS) and fatal insomnia in humans are caused by PrPSc

prions. In animals, PrPScprions cause scrapie of sheep and goats, bovine spongiformencephalopathy (BSE), chronic wasting disease (CWD) of deer and elk, feline spongiformencephalopathy, and transmissible mink encephalopathy (TME). Similar to PrP, A, tau,-synuclein, superoxide dismutase 1 (SOD1), and possibly huntingtin all adopt alternativeconformations that become self-propagating, and thus, each protein can become a prion andbe transferred to synaptically connected neurons. Moreover, each of these prions causes adistinct constellation of neurodegenerative diseases.Harrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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TABLE

444e-4

A PRION-BASED CLASSIFICATION OF NEURODEGENERATIVE

DISEASES

Evidence for a prion etiology of AD comes from a series of transmission experiments initiallyperformed in marmosets and more recently in transgenic (Tg) mice inoculated with asynthetic Apeptide folded into a prion. Studies with the tau protein have shown that it notonly features in the pathogenesis of AD, but also causes such illnesses as the frontotemporaldementias including chronic traumatic encephalopathy, which has been reported in bothcontact 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 canbecome a prion and multiply in the brain. In contrast to the Aand tau prions, a strain of-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 -synuclein prionsformed spontaneously in Tg mouse brains killed recipient mice in ~200 days.

For many years, the most frequently cited argument against prions was the existence ofstrains that produced distinct clinical presentations and different patterns of neuropathologiclesions. Some investigators argued that the biologic information carried in different prionstrains could only be encoded within a nucleic acid. Subsequently, many studies

demonstrated that strain-specified variation is enciphered in the conformation of PrPSc, butthe molecular mechanisms responsible for the storage of biologic information remainsenigmatic. The neuroanatomical patterns of prion deposition have been shown to bedependent on the particular strain of prion. Convincing evidence in support of this proposition

has been accumulated for PrP, A, tau, and -synuclein prions.

Although the number of prions identified in mammals and in fungi continues to expand, theexistence of prions in other phylogeny remains undetermined. Some mammalian prionsperform vital functions and do not cause disease; such nonpathogenic prions include thecytoplasmic polyadenylation element binding (CPEB) protein, the mitochondrial antiviral-signaling (MAVS) protein, and T cellrestricted intracellular antigen 1 (TIA-1).

All mammalian prion proteins adopt a -sheet-rich conformation and appear to readilyoligomerize as this process becomes self-propagating. Control of the self-propagating state ofbenign 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 themechanisms by which they cause disease are poorly defined. We do not know if prionsHarrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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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 prionsare thought to be the toxic forms, and assembly into larger polymers, such as amyloid fibrils,seems to be a mechanism for minimizing toxicity.

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 proteinsinto prions or to enhance the degradation of prions focuses on the initial step in prionaccumulation. Although several drugs that cross the blood-brain barrier have been identifiedthat prolong the lives of mice infected with scrapie prions, none have been identified that

extend the lives of Tg mice that replicate human CJD prions. Despite doubling the length ofincubation times in mice inoculated with scrapie prions, all of the mice eventually succumb toillness. Because all of the treated mice develop neurologic dysfunction at the same time, themutation rate as judged by drug resistance is likely to approach 100%, which is much higherthan mutation rates recorded for bacteria and viruses. Mutations in prions seem likely torepresent conformational variants that are selected for in mammals where survival becomeslimited by the fastest-replicating prions. The results of these studies make it likely thatcocktails of drugs that attack a variety of prion conformers will be required for thedevelopment of effective therapeutics.

SYSTEMS NEUROSCIENCE

Systems neurosciencerefers to study of the functions of neural circuits and how they relate tobrain function, behavior, motor activity, and cognition. Brain imaging techniques, primarily

functional magnetic resonance imaging (fMRI) and position emission tomography (PET), havemade it possible to investigate, noninvasively and in awake individuals, cognitive processessuch as perception, making judgments, paying attention, and thinking. This has allowedinsights into how networks of neurons operate to produce behavior. Many of these studies atpresent 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 physiologicprocesses. fMRI uses contrast mechanisms related to physiologic changes in tissue, andbrain perfusion can be studied by observing the time course of changes in brain water signalas a bolus of injected paramagnetic gadolinium contrast moves through the brain. Morerecently, to study intrinsic contrast-related local changes in blood oxygenation with brainactivity, blood-oxygen-level-dependent (BOLD) contrast has been used to provide a rapidnoninvasive approach for functional assessment. These techniques have been reliably usedin the field of both behavior and cognitive sciences. One example is the use of fMRI todemonstrate mirror neuron systems, imitative pathways activated when observing actions of

others. Mirror neurons are thought to be important for social conditioning and for many formsof learning, and abnormalities in mirror neurons may underlie some autism disorders.

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

Other examples of the use of fMRI include the study of memory, revealing that not only ishippocampal activity correlated with declarative memory consolidation, but it also involvesactivation in the ventral medial prefrontal cortex. Consolidation of memory over time results indecreased activity of the hippocampus and progressively stronger activation in the ventral

medial prefrontal region associated with retrieval of consolidated memories. fMRI has alsobeen used to identify sequences of brain activation involved in normal movements andalterations in their activation associated with both injury and recovery, to plan neurosurgicaloperations, and remarkably, to reconstruct actual visual images from the occipital cortex.Noninvasive brain-computer interfaces have extraordinary potential to advance thedevelopment of robotics and exoskeleton devices guided by brain activity for patients with avariety of nervous system afflictions. Diffusion tensor imaging is a recently developed MRItechnique that can measure macroscopic axonal organization in nervous system tissues; itappears 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 todemonstrate that humans have online voluntary control of human temporal lobe neurons.

Multitasking capabilities, including attention to tasks when faced with distractions, decline asHarrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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we age due to a decline in medial prefrontal cognitive control system. When faced with amultitasking challenge, video game training can improve cognitive control capabilities byaugmenting prefrontal suppression of the default network and, as measured byelectroencephalography 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 whilepreserving most protein and structural elements and providing opportunities to identify brainstructures and neural networks with unprecedented detail.

A therapeutic technology that has long-reaching implications for the development of novelinterventions for neurologic, including behavioral, conditions has been the development ofdeep-brain stimulation as a highly effective therapeutic intervention for treating excessivelyfiring neurons in the subthalamic nucleus of patients with Parkinsons disease and theprecingulate cortex in patients with depression.

BRAIN RESEARCH THROUGH ADVANCING INNOVATIVENEUROTECHNOLOGIES (BRAIN) INITIATIVE

The BRAIN initiative, grand in scope, was launched in 2013 to speed development ofadvances to understand, treat, repair, and prevent common neurologic disorders that, inaggregate, affect more than 1 billion people worldwide. The initial goal of BRAIN is to bringtogether experts in neurobiology (including optogenetics), engineering, information

technology, and other fields to develop novel visualization and electrophysiologic methods tobetter define and understand neural circuits and all the connections among individualneurons. The announcement of the BRAIN initiative followed just weeks after a similarlyambitious 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 brainusing computer technologies. Its architects also envision layering clinical and biomarker datafrom large health care databases to identify biosignatures associated with humanphenotypes, possibly leading to a fundamental reclassification of disease, a concept alsoproposed by others, including in a 2011 report of the National Academy of Sciences (TowardPrecision Medicine: Building a Knowledge Network for Biomedical Research and a NewTaxonomy of Disease). These two ambitious projects are expected to be complementary andover time will hopefully become increasingly integrated. Emerging discoveries are also certainto stimulate a range of ethical questions, many of which are not unique to the neurosciencesbut do come into sharpest focus in this area. These include possible risks to the privacy ofpersonal information about our health, cognitive capabilities, or behavioral attributes; thesanctity of our private thoughts; as well as concerns regarding neuroenhancementtechnologies, including their potential military use. Both the BRAIN and HBP initiatives haveput into place strong ethical components to ensure that these programs are carried out, fromthe outset and to the fullest extent possible, consistent with guiding ethical principles thatinclude respect for individuals, public beneficence, justice and fairness, democraticdeliberation, and transparency.



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SECTION

2

DISEASES OF THE CENTRAL NERVOUS

SYSTEM



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445 Seizures and Epilepsy

Daniel H. Lowenstein

A seizure(from the Latin sacire, to take possession of) is a paroxysmal event due toabnormal excessive or synchronous neuronal activity in the brain. Depending on thedistribution of discharges, this abnormal brain activity can have various manifestations,ranging from dramatic convulsive activity to experiential phenomena not readily discernible byan observer. Although a variety of factors influence the incidence and prevalence of seizures,~510% of the population will have at least one seizure, with the highest incidence occurringin early childhood and late adulthood.

The meaning of the term seizureneeds to be carefully distinguished from that of epilepsy.Epilepsydescribes a condition in which a person has recurrentseizures due to a chronic,underlying process. This definition implies that a person with a single seizure, or recurrentseizures due to correctable or avoidable circumstances, does not necessarily have epilepsy.Epilepsy refers to a clinical phenomenon rather than a single disease entity, because thereare many forms and causes of epilepsy. However, among the many causes of epilepsy there

are various epilepsy syndromesin which the clinical and pathologic characteristics aredistinctive and suggest a specific underlying etiology.

Using the definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsyis ~0.30.5% in different populations throughout the world, and the prevalence of epilepsyhas been estimated at 530 persons per 1000.

CLASSIFICATION OF SEIZURES

Determining the type of seizure that has occurred is essential for focusing the diagnosticapproach on particular etiologies, selecting the appropriate therapy, and providing potentiallyvital information regarding prognosis. The International League against Epilepsy (ILAE)Commission on Classification and Terminology, 20052009 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 potentiallydistinctive features such as etiology or cellular substrate are not considered in thisclassification system, although this will undoubtedly change in the future as more is learnedabout the pathophysiologic mechanisms that underlie specific seizure types.

TABLE

445-1

CLASSIFICATION OF SEIZURES

1. Focal seizures

(Can be further described as having motor, sensory, autonomic, cognitive, or otherfeatures)

2. Generalized seizures

a. Absence

Typical

Atypical

b. Tonic clonic

c. Clonic

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e. Atonic

f. Myoclonic

3. May be focal, generalized, or unclear

Epileptic spasms

A fundamental principle is that seizures may be either focal or generalized. Focal seizuresoriginate within networks limited to one cerebral hemisphere (note that the term partial

seizuresis no longer used). Generalized seizuresarise within and rapidly engage networksdistributed across both cerebral hemispheres. Focal seizures are usually associated withstructural abnormalities of the brain. In contrast, generalized seizures may result fromcellular, biochemical, or structural abnormalities that have a more widespread distribution.There are clear exceptions in both cases, however.

FOCAL SEIZURES

Focal seizures arise from a neuronal network either discretely localized within one cerebralhemisphere or more broadly distributed but still within the hemisphere. With the newclassification system, the subcategories of simple focal seizures and complex focalseizures 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 typeof generalized seizures that evolve from the focal seizure.

The routine interictal (i.e., between seizures) electroencephalogram (EEG) in patients withfocal 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 inferiorfrontal lobe (i.e., regions distant from the scalp), the EEG recorded during the seizure may benonlocalizing. However, the seizure focus is often detected using sphenoidal or surgicallyplaced intracranial electrodes.

Focal Seizures Without Dyscognitive Features Focal seizures can cause motor, sensory,autonomic, or psychic symptoms without impairment of cognition. For example, a patienthaving a focal motor seizure arising from the right primary motor cortex near the areacontrolling 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 ~23 Hz; pure tonic posturing may be seen as well. Since the cortical regioncontrolling hand movement is immediately adjacent to the region for facial expression, theseizure may also cause abnormal movements of the face synchronous with the movements ofthe hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) mayshow abnormal discharges in a very limited region over the appropriate area of cerebral cortexif the seizure focus involves the cerebral convexity. Seizure activity occurring within deeperbrain structures is sometimes not detected by the standard EEG, however, and may requireintracranial electrodes for its detection.

Three additional features of focal motor seizures are worth noting. First, in some patients, theabnormal motor movements may begin in a very restricted region such as the fingers andgradually progress (over seconds to minutes) to include a larger portion of the extremity. Thisphenomenon, 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 (Todds paralysis) for minutes to manyhours in the involved region following the seizure. Third, in rare instances, the seizure maycontinue for hours or days. This condition, termed epilepsia partialis continua, is oftenrefractory to medical therapy.

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), orautonomic function (flushing, sweating, piloerection). Focal seizures arising from the temporalor 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., burningrubber or kerosene) or sounds (crude or highly complex sounds), or an epigastric sensationthat rises from the stomach or chest to the head. Some patients describe odd, internalfeelings such as fear, a sense of impending change, detachment, depersonalization, dj vu,



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or illusions that objects are growing smaller (micropsia) or larger (macropsia). Thesesubjective, internal events that are not directly observable by someone else are referred toas auras.

Focal Seizures with Dyscognitive Features Focal seizures may also be accompanied bya transient impairment of the patients ability to maintain normal contact with the environment.The patient is unable to respond appropriately to visual or verbal commands during theseizure and has impaired recollection or awareness of the ictal phase. The seizuresfrequently begin with an aura (i.e., a focal seizure without cognitive disturbance) that isstereotypic 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 behavioralarrest is usually accompanied by automatisms, which are involuntary, automatic behaviorsthat have a wide range of manifestations. Automatisms may consist of very basic behaviorssuch as chewing, lip smacking, swallowing, or picking movements of the hands, or moreelaborate behaviors such as a display of emotion or running. The patient is typically confusedfollowing the seizure, and the transition to full recovery of consciousness may range fromseconds up to an hour. Examination immediately following the seizure may show ananterograde amnesia or, in cases involving the dominant hemisphere, a postictal aphasia.

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

EVOLUTION OF FOCAL SEIZURES TO GENERALIZED SEIZURES

Focal seizures can spread to involve both cerebral hemispheres and produce a generalizedseizure, usually of the tonic-clonic variety (discussed below). This evolution is observedfrequently following focal seizures arising from a focus in the frontal lobe, but may also beassociated with focal seizures occurring elsewhere in the brain. A focal seizure that evolvesinto a generalized seizure is often difficult to distinguish from a primary generalized-onsettonic-clonic seizure, because bystanders tend to emphasize the more dramatic, generalizedconvulsive phase of the seizure and overlook the more subtle, focal symptoms present atonset. In some cases, the focal onset of the seizure becomes apparent only when a carefulhistory identifies a preceding aura. Often, however, the focal onset is not clinically evident andmay be established only through careful EEG analysis. Nonetheless, distinguishing betweenthese two entities is extremely important, because there may be substantial differences in theevaluation and treatment of epilepsies associated with focal versus generalized seizures.

GENERALIZED SEIZURESGeneralized seizures are thought to arise at some point in the brain but immediately andrapidly engage neuronal networks in both cerebral hemispheres. Several types of generalizedseizures have features that place them in distinctive categories and facilitate clinicaldiagnosis.

Typical Absence Seizures Typical absence seizures are characterized by sudden, brieflapses of consciousness without loss of postural control. The seizure typically lasts for onlyseconds, consciousness returns as suddenly as it was lost, and there is no postictalconfusion. Although the brief loss of consciousness may be clinically inapparent or the solemanifestation 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.

Typical absence seizures are associated with a group of genetically determined epilepsieswith onset usually in childhood (ages 48 years) or early adolescence and are the mainseizure type in 1520% of children with epilepsy. The seizures can occur hundreds of timesper day, but the child may be unaware of or unable to convey their existence. Because theclinical signs of the seizures are subtle, especially to parents who may not have had previousexperience with seizures, it is not surprising that the first clue to absence epilepsy is oftenunexplained daydreaming and a decline in school performance recognized by a teacher.

The electrophysiologic hallmark of typical absence seizures is a generalized, symmetric, 3-Hzspike-and-wave discharge that begins and ends suddenly, superimposed on a normal EEGbackground. Periods of spike-and-wave discharges lasting more than a few seconds usuallycorrelate with clinical signs, but the EEG often shows many more brief bursts of abnormalcortical activity than were suspected clinically. Hyperventilation tends to provoke theseHarrison's Principles of Internal Medicine 19_E (Vol.1 & Vol.2)_nodrm


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electrographic discharges and even the seizures themselves and is routinely used whenrecording the EEG.

Atypical Absence Seizures Atypical absence seizures have features that deviate bothclinically and electrophysiologically from typical absence seizures. For example, the lapse ofconsciousness is usually of longer duration and less abrupt in onset and cessation, and theseizure is accompanied by more obvious motor signs that may include focal or lateralizingfeatures. The EEG shows a generalized, slow spike-and-wave pattern with a frequency of2.5 per second, as well as other abnormal activity. Atypical absence seizures are usuallyassociated 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.

Generalized, Tonic-Clonic Seizures Generalized-onset tonic-clonic seizures are the mainseizure type in ~10% of all persons with epilepsy. They are also the most common seizuretype resulting from metabolic derangements and are therefore frequently encountered inmany different clinical settings. The seizure usually begins abruptly without warning,although some patients describe vague premonitory symptoms in the hours leading up to theseizure. This prodrome is distinct from the stereotypic auras associated with focal seizuresthat generalize. The initial phase of the seizure is usually tonic contraction of musclesthroughout the body, accounting for a number of the classic features of the event. Toniccontraction of the muscles of expiration and the larynx at the onset will produce a loud moanor ictal cry. Respirations are impaired, secretions pool in the oropharynx, and cyanosisdevelops. Contraction of the jaw muscles may cause biting of the tongue. A markedenhancement of sympathetic tone leads to increases in heart rate, blood pressure, andpupillary size. After 1020 s, the tonic phase of the seizure typically evolves into the clonicphase, produced by the superimposition of periods of muscle relaxation on the tonic musclecontraction. 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 byunresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorousbreathing and partial airway obstruction. Bladder or bowel incontinence may occur at thispoint. Patients gradually regain consciousness over minutes to hours, and during thistransition, there is typically a period of postictal confusion. Patients subsequently complain ofheadache, fatigue, and muscle ache that can last for many hours. The duration of impairedconsciousness in the postictal phase can be extremely long (i.e., many hours) in patients withprolonged seizures or underlying central nervous system (CNS) diseases such as alcoholiccerebral atrophy.



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