Phenytoin

Myriam Weyl Ben-Arush, MD

Pediatric Hematology Oncology Department
Meyer Children? Hospital
Rambam Medical Center, Technion
The Bruce Rappaport Faculty of Medicine
Haifa, Israel

Sensory neuronopathy is a loss of cell bodies in the posterior root ganglion that results in a sensory loss involving both distal and proximal portions of an extremity and may include most or all sensory modalities symptoms lactose intolerance purchase cheap phenytoin line. Motor neuronopathy is seen in a loss of anterior horn motor neurons with resultant flaccid weakness treatment 2 degree burns purchase phenytoin overnight, muscle fasciculations medicine 752 order generic phenytoin, and eventual muscle atrophy medications safe while breastfeeding buy phenytoin 100 mg overnight delivery. Some descending fibers modulate the transmission of nociceptive information in the posterior horn; others influence the activity of motor neurons treatment urticaria purchase phenytoin without prescription. Ascending and descending propriospinal fibers form the basis for a wide variety of intraspinal reflexes. Many tracts or fibers in the nervous system are named according to the location of their cell body of origin and the area where their axons terminate. For example, the corticospinal fibers originate in the cerebral cortex (cortico-) and end in the spinal cord (-spinal). These are descending fibers because the cortex is a more rostral part of the neuraxis than is the spinal cord. Fibers in the gracile fasciculus originate from sacral, lumbar, and lower thoracic (below T6) levels; those in the cuneate fasciculus originate from upper thoracic (above T6) and cervical levels. Injury to the posterior columns on one side results in a loss of proprioception, discriminative touch, and vibratory sense below the level of the lesion on the same side. However, there is clinical evidence that pain signals may also be transmitted via the posterior columns, especially the gracile fasciculus, from the pelvic viscera to the thalamus. This information is most likely processed through the postsynaptic posterior column system. The information conveyed on spinocerebellar fibers, through synaptic relays in the cerebellum, thalamus, and motor cortex, influences the efficiency of motor activity. This system encompasses those regions of the white matter that were classically divided into anterior and lateral spinothalamic tracts. Damage to these fibers as they cross in the anterior white commissure results in bilateral loss of pain and thermal perception, beginning at about one level below the lesion, with sparing of these modalities ascending from lower levels. Nociceptive input and some discriminative touch are also carried by postsynaptic posterior column fibers and by the spinocervicothalamic tract. The existence of these minor fiber populations in humans may explain the recurrence of pain perception in some patients who have had an anterolateral cordotomy for intractable pain. Other, more diffusely arranged ascending fibers include spinoolivary, spinovestibular, and spinoreticular fibers. Corticospinal fibers arise from the cerebral cortex and descend through the brainstem. One important function of this tract is to influence spinal motor neurons, especially those controlling fine movements of the distal musculature. Consequently, lesions of lateral corticospinal fibers on one side of the cervical cord result in ipsilateral paralysis of the upper and lower extremities (hemiplegia). In general, rubrospinal fibers excite flexor motor neurons and inhibit extensor motor neurons. Reticulospinal fibers in this area originate from the medullary reticular formation, and fastigiospinal fibers originate from the fastigial nucleus of the cerebellum. At spinal levels, the reticulospinal fibers are uncrossed and the fastigiospinal fibers are crossed. Because their function is to help maintain posture, these fibers tend to excite extensor motor neurons and inhibit flexor motor neurons. Raphespinal fibers originate mainly from the nucleus raphe magnus of the brainstem, descend bilaterally in posterior areas of the lateral funiculus, and function to modulate the transmission of nociceptive information at spinal levels. Lesions in the brainstem or cervical spinal cord that interrupt these fibers result in ipsilateral ptosis, miosis, anhidrosis, and enophthalmos (Horner syndrome). Reticulospinal fibers in this area arise in the pontine reticular formation of the Spinal Cord 151 the brainstem, whereas vestibulospinal fibers originate from the vestibular nuclei. Lateral vestibulospinal fibers arise from the lateral vestibular nucleus, and medial vestibulospinal fibers originate primarily from the medial vestibular nucleus. Reticulospinal and vestibulospinal fibers of the anterior funiculus function in postural mechanisms through their general excitation of extensor motor neurons and inhibition of flexor motor neurons. Fibers of the anterior corticospinal tract are uncrossed, but most of these fibers cross in the ventral white commissure before terminating on medial motor neurons that innervate axial muscles. Tectospinal and vestibulospinal fibers are found only at cervical levels; the other fibers extend to lower cord levels. The comparatively simple structure of the spinal cord significantly misrepresents its functional importance. Although the cord is smaller in diameter than the little finger, descending motor control of the body below the neck and all sensory input from the same areas must traverse it. Consequently, small lesions in the spinal cord that would be considered of little consequence in larger parts of the brain may cause global deficits or death. As the cord merges into the brainstem, the organization and function of the central nervous system become progressively more complex. Syringomyelia is commonly seen in patients with Chiari malformations in the posterior fossa but may also be a consequence of trauma to the spinal cord, tumors, and infections, the symptoms are highly variable but most frequently include loss of pain and temperature sensations, extremity weakness, and unsteady gait. These lesions are frequently called functional hemisections in recognition of the fact that the cord is not perfectly cut halfway across but may be injured or deformed by, for example, pieces of a damaged vertebra. It is appropriate at this point to touch on some general features that correlate primarily with the structure of the spinal cord. Consequently, a lesion of this structure will damage fibers coursing in both directions, resulting in a bilateral loss of pain and thermal sensations that correlate with the damaged levels of the spinal cord. For example, if the lesion is in mid to low cervical levels, the pain and thermal sensory deficits will fall over the shoulders and arm in a "cape distribution. Because these lesions are usually in the cervical levels, extension of the syrinx into one anterior horn results in an ipsilateral weakness of the upper extremity; if both anterior horns are involved, the weakness is bilateral. In syringomyelia, the cavity that develops in central areas of the spinal cord does not have a lining of ependymal cells and therefore is not an enlargement of the central canal. This is sometimes called a noncommunicating syringomyelia to differentiate it from a cystic structure that may connect with the central canal (communicating syringomyelia). On the other hand, a cavitation of the central canal is called a Injury to high cervical levels of the spinal cord is, in general, a catastrophic event. In addition to the potential for a total loss of sensation for the body below the lesion and of voluntary motor control below the lesion, there is another important complicating factor. The phrenic nucleus is located in the central regions of the anterior horn at levels C3 to C6. This cell group innervates the diaphragm and in high cervical lesions is disconnected from the centers of the medulla that control breathing. Consequently, in patients with high cervical lesions, preservation of the ability to breathe becomes a major factor in care. Acute Central Cervical Spinal Cord Syndrome Syringomyelia the acute central cervical spinal cord syndrome, commonly called the central cord syndrome, is an incomplete spinal cord injury. This may result from hyperextension of the neck (sometimes in a patient with bone spurs on the vertebrae) that momentarily occludes blood supply to the cord via the anterior spinal artery. Consequently, the deficits reflect the territory served by the branches of this vessel. The results are bilateral weakness of the extremities (more so of the upper than of the lower), varying degrees and patterns of pain and thermal sensation loss, and bladder dysfunction. In general, function of the lower extremities returns first, bladder function next, and function of the upper extremities last. Pain and thermal sensations may return at any time, and posterior column sensations are not affected in these patients. For example, a spinal cord hemisection at T8 would affect the body below that level but would spare the upper trunk and upper extremity. A lesion involving the posterior columns bilaterally would result in proprioceptive and discriminative touch losses below the level of the lesion but would spare pain and thermal sensations. In our study of systems neurobiology, we shall explore these and other examples of dysfunction resulting from spinal cord lesions. Organization in the Spinal Cord: the Anatomy and Physiology of Identified Neurons. Spinothalamic and spinohypothalamic tract neurons in the cervical enlargement of rats: I. Spinal cord: cytoarchitectural, dendroarchitectural, and myeloarchitectural organization. The pain system, the neural basis of nociceptive transmission in the mammalian nervous system. Spinomesencephalic tract: projections from the lumbosacral spinal cord of the rat, cat, and monkey. For example, the central regions of the medulla contain the cranial nerve nuclei affiliated with the medulla. This medullary area is rostrally continuous with the pontine tegmentum, which contains the cranial nerve nuclei associated with the pons. The basilar pons is bulbous and quite characteristic of the anterior aspect of the pons. The pontine tegmentum contains portions of the trigeminal nuclei and the vestibular nuclei and, just rostral to the pons-medulla junction, the facial motor nucleus, superior salivatory nucleus, and abducens nucleus. These are the inferior cerebellar peduncle, the middle cerebellar peduncle (or brachium pontis), and the superior cerebellar peduncle (or brachium conjunctivum), connecting the cerebellum to the medulla oblongata, basilar pons, and midbrain, respectively. Pons the term brainstem (sometimes written brain stem) can mean either the portion of the brain that consists of the medulla oblongata, pons, and midbrain or the portion that consists of these structures plus the diencephalon. For our purposes, therefore, the brainstem consists of the rhombencephalon, comprising the myelencephalon and metencephalon (but excluding the cerebellum), and the mesencephalon. These regions of the brainstem share a basic organization, which is the topic of this chapter. The nuclei of the hypoglossal, vagal, and glossopharyngeal nerves as well as portions of the nuclei of the trigeminal nerve are located in the medulla. The exit of the trochlear nerve is regarded as the pontomesencephalic junction on the posterior aspect of the brainstem; along with its decussating fibers, it composes the isthmus rhombencephali (the transitional zone from pons to midbrain). In C, the cerebellum is removed to expose the posterior surface of the brainstem and the fourth ventricle. The posterior aspect of the midbrain is characterized by the superior and inferior colliculi, and their respective nuclei, and the anterior aspect by the crus cerebri and interpeduncular fossa. The tegmental and basilar areas and contiguous areas of the medulla are shown in light and dark gray, respectively. Medulla Cisterna magna Tegmental and Basilar Areas the central core of the midbrain and the pons is called the tegmentum, and their anterior (ventral) parts are the basilar areas. Basilar structures of the brainstem include the descending fibers of the crus cerebri (midbrain), basilar pons, and pyramid (medulla) and specific populations of neurons in the midbrain and pons that originate from the alar plate of the embryonic brain. The cerebral aqueduct is a narrow channel, 1 to 3 mm in diameter, that connects the third ventricle (the cavity of the diencephalon) with the fourth ventricle (the rhombencephalic cavity). The cerebral aqueduct contains no choroid plexus; its walls are formed by a continuous mantle of cells collectively called the periaqueductal gray. The fourth ventricle is continuous rostrally with the cerebral aqueduct, caudally with the central canal of the caudal medulla and cervical spinal cord, and laterally with the subarachnoid space via the midline foramen of Magendie and the two lateral foramina of Luschka. The medial portions on 154 Regional Neurobiology this cistern at the interface of the medulla, pons, and cerebellum comprise the cerebellopontine angle. The tela arises from the inferior surface of the cerebellum and sweeps caudally to attach to the V-shaped edges of the medullary portion of the ventricular space. There are two slight depressions along the course of the sulcus limitans, somewhat like deep spots within this sulcus. In some surgical procedures involving the fourth ventricle or medulla, the sulcus limitans and the superior and inferior foveae represent important landmarks. The rostral edge of these fibers is generally regarded as the pons-medulla junction in the floor of the fourth ventricle. Medial to the sulcus limitans, the hypoglossal and vagal trigones represent the underlying hypoglossal and dorsal motor vagal nuclei. In the caudal pontine region, the facial colliculus, located medial to the sulcus limitans, marks the location of the underlying abducens motor nucleus and the internal genu of the facial nerve. Lateral to the sulcus limitans in the medulla and caudal pons is a flattened region called the vestibular area, which marks the location of the vestibular nuclei. The cerebellum is removed to expose the posterior aspect of the medulla and midbrain and the rhomboid fossa. The trigeminal motor nucleus, located medial to the principal sensory nucleus, is not labeled. Cranial nerves, like spinal nerves, contain sensory or motor fibers or a combination of these fiber types. These various fibers are classified on the basis of their embryologic origin or common structural and functional characteristics. Primary sensory fibers, somatic motor neurons, and preganglionic and postganglionic visceromotor neurons that exhibit "like anatomical and physiological characters so that they. For example, fibers conveying sharp pain, a specific type of input, from widely separated body parts (the foot, hand, and face) have the same functional component. An Overview of the Brainstem 155 introduced in relation to spinal nerves (see Chapter 9), is also directly applicable to cranial nerves. Early in development, the rostrocaudally oriented cell columns forming the alar and basal plates of the spinal cord essentially extend throughout the brainstem. As development progresses, maturing neurons in alar and basal plates (these may also be called alar and basal cell columns) begin to migrate to form their adult structures, and the caudocephalic continuity of the cell columns may be disrupted. Motor nuclei of cranial nerves arise from basal plate neurons, whereas the nuclei that receive primary sensory input via cranial nerves originate from the alar plate.

The anterior nucleus forms a prominent wedge on the rostral aspect of the dorsal thalamus just caudolateral to the interventricular foramen; this wedge is the anterior thalamic tubercle medicine 2 order generic phenytoin on line. Rostrally symptoms you have diabetes discount phenytoin 100mg, the internal medullary lamina divides to partially encapsulate the anterior nucleus symptoms 6 dpo order generic phenytoin pills. The cells of this nucleus receive dense limbic-related projections from (1) the mammillary nuclei via the mammillothalamic tract and (2) the medial temporal lobe (hippocampus) via the fornix medical treatment purchase 100 mg phenytoin visa. The anterior nucleus is an important synaptic station in the Papez circuit medications causing hyponatremia purchase phenytoin on line, which is related to emotion and memory acquisition. Cells of the paralaminar subdivision receive input from the frontal lobe and substantia nigra and may play a role in the control of eye movement. D Lateral Thalamic Nuclei this large collection of thalamic neurons is grouped into dorsal and ventral tiers. The large pulvinar nucleus consists of anterior, medial, lateral, and inferior subdivisions. The inferior division receives input from the superior colliculus and projects to the visual association cortex. Although many structures are clearly seen, emphasis in the labeling is placed on diencephalic structures. The former receives input from the medial segment of the globus pallidus, and the latter receives afferents from the reticular portion of substantia nigra. The largest of these, the pars oralis, receives a dense projection from the internal segment of the ipsilateral globus pallidus; some of these afferents enter the caudal subdivision. Consequently, pallidal and cerebellar projections are largely segregated within this nucleus. These cells process vestibular input and project to lateral areas of the postcentral gyrus that are located in the depths of the central sulcus. Each thalamic nucleus is pattern coded or color coded to match its target area in the cerebral cortex. Located in the posterior thalamus at about the level of the pulvinar and geniculate nuclei is a cluster of cell groups collectively called the posterior nuclear complex. This complex consists of the suprageniculate nucleus, the nucleus limitans, and the posterior nucleus. These nuclei are positioned superior to the medial geniculate and medial to the rostral pulvinar. The posterior nuclear complex receives and sends to the cortex nociceptive cutaneous input that is transmitted over somatosensory pathways. Midline Nuclei the midline nuclei are the least understood components of the thalamus. The largest is the paratenial nucleus, which is located just ventral to the rostral portion of the stria medullaris thalami; other cells are associated with the interthalamic adhesion (massa intermedia). Although inputs are poorly defined, efferent fibers reach the amygdaloid complex and the anterior cingulate cortex, suggesting a role in the limbic system. Axons of these cells project medially into the nuclei of the dorsal thalamus or to other parts of the reticular nucleus, but not into the cerebral cortex. Afferents are received from the cortex and from nuclei of the dorsal thalamus via collaterals of thalamocortical and corticothalamic axons. It appears that thalamic reticular neurons modulate, or gate, the responses of thalamic neurons to incoming cerebral cortical input. Intralaminar Nuclei Summary of Thalamic Organization Embedded within the internal medullary lamina are the discontinuous groups of neurons that form the intralaminar nuclei. These cells are characterized by their projections to the neostriatum and to other thalamic nuclei, along with diffuse projections to the cerebral cortex. The centromedian nucleus projects to the neostriatum and to motor areas of the cerebral cortex, whereas the parafascicular nucleus projects to rostral and lateral areas of the frontal lobe. Other intralaminar nuclei receive input from ascending pain pathways and project to the somatosensory and parietal cortex. Each thalamic nucleus (with a few exceptions) gives rise to efferent projections (thalamocortical fibers) that target some portion of the cerebral cortex. That region of cortex then typically provides a reciprocal projection (corticothalamic fibers) that returns to the original thalamic nucleus. Some thalamic nuclei are primarily associated with a particular function and in turn with a specific gyrus (and functional area) of the cerebral cortex. The anterior nucleus projects primarily to the cingulate gyrus and functions in the broad area of behavior. The nuclei of the thalamus have been classified according to their connections as either relay nuclei or association nuclei. A relay nucleus is one that receives input predominantly from a single source, such as a sensory pathway or a cerebellar nucleus, or from the basal nuclei. The incoming neural information is processed and then sent to a localized region of sensory, motor, or limbic cortex. These nuclei do not merely relay neural signals; in fact, considerable neural processing also takes place in these nuclei. However, their position in a modalityspecific pathway linking one particular source to one particular destination makes the word "relay" a useful designation. In contrast, an association nucleus receives input from a number of different structures or cortical regions and usually sends its output to more than one of the association areas of the cerebral cortex. Association nuclei include dorsomedial, lateral dorsal, lateral posterior, and the nuclei of the pulvinar complex. A thalamic nucleus can also be designated specific or nonspecific on the basis of thalamocortical signals generated in response to electrical stimulation delivered to a localized site in that thalamic nucleus. Focal electrical stimulation of a specific nucleus produces a rapidly conducted, sharply localized evoked response in the ipsilateral cerebral cortex. Focal electrical stimulation of a nonspecific nucleus produces widespread activity in the cortex of both hemispheres, at a significantly longer time delay than with stimulation of a specific nucleus. It is thought that nonspecific nuclei play a role in modulating the excitability of large regions of cortex. The genu is located immediately lateral to the anterior thalamic nucleus, at about the same level as the interventricular foramen. The anterior limb extends rostrolateral from the genu and is insinuated between the caudate and lenticular nuclei. The posterior limb extends caudolateral from the genu and separates the thalamus from the globus pallidus. As its name implies, the retrolenticular limb is the white matter located immediately caudal to the lenticular nucleus (Latin retro-, for "behind"). A sublenticular limb (see Chapter 16) passes inferior to the lenticular nucleus but is not typically seen in axial sections. Even though this structure consists mostly of axons that reciprocally link the thalamus and cerebral cortex, it also contains cortical efferent fibers that project to the brainstem (corticorubral, corticoreticular, corticonuclear-corticobulbar) or spinal cord (corticospinal). Although the internal capsule is described in detail in Chapter 16, it is summarized here because of its important relationship to the thalamus. The hypothalamus and related limbic structures receive sensory input regarding the internal environment and in turn regulate the motor systems that modify the internal environment through four mechanisms. First, the hypothalamus is a principal modulator of autonomic nervous system function. Second, it is a viscerosensory transducer, containing neurons with specialized receptors capable of responding to changes in the temperature or osmolality of blood as well as to specific hormonal levels in the general circulation. Third, the hypothalamus regulates the activity of the anterior pituitary through the production of releasing factors (hormone-releasing hormones). Fourth, it performs an endocrine function by producing and releasing oxytocin and vasopressin into the general circulation within the posterior pituitary. The periventricular zone includes the neurons that border the ependymal surfaces of the third ventricle. The latter, which form the medial forebrain bundle, are diffusely organized in the human brain. No discrete named nuclei are present in this lateral area, although the supraoptic nucleus is considered by some authorities to be part of it. Cells of the lateral hypothalamic area are involved in cardiovascular function and in the regulation of food and water intake. The medial hypothalamic zone contains discrete groups of neurons whose function and connections are established. Nuclei in the chiasmatic region are generally involved in regulating hormone release (preoptic, supraoptic, periventricular), cardiovascular function (anterior), circadian rhythms (suprachiasmatic), and body temperature and heat loss mechanisms (preoptic). Bilateral lesions of this hypothalamic region produce hyperphagia, a greatly increased food intake with resultant obesity. Cells of the arcuate nucleus deliver peptides to the portal vessels and, through these channels, to the anterior pituitary. Some of these peptides are releasing factors, which cause an increase in the secretion of specific hormones by the anterior pituitary, and some are inhibiting factors, which inhibit the secretion of specific hormones by the anterior pituitary. In humans, the mammillary nuclei consist of a large medial nucleus and a small lateral nucleus. Although both of these nuclei receive input via the fornix, only the medial nucleus projects to the anterior thalamic nucleus through the mammillothalamic tract. The stria medullaris thalami has disappeared at this level because its fibers have dispersed to end in the habenular nuclei. The neurons of the posterior nucleus are involved in activities that include elevation of blood pressure, pupillary dilation, and shivering or body heat conservation. The mammillary nuclei are involved in the control of various reflexes associated with feeding as well as in mechanisms relating to memory formation. Afferent Fiber Systems Although many axonal systems extend into the hypothalamus, only four inputs are mentioned here (see Chapter 30). As mentioned earlier, the medial forebrain bundle passes bidirectionally through the lateral hypothalamic region. This composite fiber bundle consists of ascending axons that originate in areas throughout the neuraxis and terminate in the hypothalamus and other axons that exit the hypothalamus to reach forebrain and brainstem targets. Patients with this involuntary movement disorder exhibit rapid and forceful flailing movements, which usually involve the contralateral upper extremity. These movements can be very debilitating because the patient has no control over their initiation or duration. The zona incerta contains output neurons that project to a variety of locations, including the cerebral cortex, the superior colliculus, the pretectal region, and the basilar pons. Afferent projections arise from the motor cortex and as collaterals from the medial lemniscus. Several nuclei give rise to descending fibers that contribute to the dorsal longitudinal fasciculus and the medial forebrain bundle and to diffuse projections that pass into the tegmentum. These fiber systems project directly to numerous brainstem nuclei as well as to preganglionic sympathetic and parasympathetic neurons in the spinal cord. Other projections reach the thalamus and frontal cortex, and still others extend to the posterior pituitary or to the tuberohypophysial portal system for delivery of substances to the anterior pituitary. As the term ventral thalamus (or subthalamus) implies, these cell groups are located ventral (anterior) to the large expanse of the dorsal thalamus. The cells of the subthalamic nucleus receive input from motor areas of the cerebral cortex, project to the substantia nigra, and are reciprocally connected with the globus pallidus. The pineal gland consists of richly vascularized connective tissue containing glial cells and pinealocytes but no true neurons. Mammalian pinealocytes are related to the photoreceptor elements found in this gland in lower forms, such as amphibians. In humans, however, they remain only indirectly light sensitive and receive information concerning photic stimuli through a multisynaptic neural circuit. Pinealocytes have club-like processes that are apposed to blood vessels but do not have direct synaptic contacts with central nervous system neurons. These cells synthesize melatonin from serotonin via enzymes that are sensitive to diurnal fluctuations in light. Levels of serotonin N-acetyltransferase increase during the night (in the absence of photic stimulation), and the synthesis of melatonin is enhanced. Exposure to light turns off the enzymatic activity, and melatonin production is diminished. Thus the production of melatonin by pinealocytes is rhythmic and calibrated to the 24-hour cycle of photic input to the retina. Retinal ganglion cells project to the suprachiasmatic nucleus of the hypothalamus, which in turn influences neurons of the intermediolateral cell column in the spinal cord through descending connections. These preganglionic sympathetic neurons project to the superior cervical ganglion, which in turn innervates the pineal gland via postganglionic fibers that travel on branches of the internal carotid artery. A view in the axial plane (B) through the hemisphere shows the internal territories served. The distribution of the main striate arteries, especially to the internal capsule, is also shown. Pinealocytes also produce serotonin, norepinephrine, and neuroactive peptides, such as thyrotropin-releasing hormone, which are normally associated with the hypothalamus. These secretory products are released into the general circulation or the cerebrospinal fluid. Pinealomas (tumors with large numbers of pinealocytes) are accompanied by depression of gonadal function and delayed puberty, whereas lesions that lead to the loss of pineal cells are associated with precocious puberty. This indicates that pineal secretory products exert an inhibitory influence on gonadal formation. Both nuclei contribute axons to the habenulointerpeduncular tract (fasciculus retroflexus), which terminates in the midbrain interpeduncular nucleus. The stria medullaris thalami, which arches over the medial aspect of the dorsal thalamus near the midline, conveys input to both habenular nuclei. The habenular commissure, a small bundle of fibers riding on the upper edge of the posterior commissure, connects the habenular regions of the two sides.

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The main vessels serving the limbic system are the anterior and posterior cerebral arteries medicine etodolac cheap phenytoin american express, the anterior choroidal artery symptoms 9 days past iui buy phenytoin paypal, and branches arising from the circle of Willis treatment jiggers discount phenytoin uk. Most of the cingulate gyrus and its isthmus receive blood supply via the pericallosal artery symptoms zika virus purchase genuine phenytoin online, a branch of the anterior cerebral artery medicine world nashua nh order phenytoin 100 mg mastercard. Temporal branches of the posterior cerebral artery (P3 segment) supply the parahippocampal gyrus. The anterior choroidal artery usually originates from the internal carotid artery and follows the general trajectory of the optic tract. It sends branches into the choroidal fissure of the temporal horn of the lateral ventricle. This vessel serves the choroid plexus of the temporal horn, the hippocampal formation, parts of the amygdaloid complex, and adjacent structures, such as the tail of the caudate nucleus, the stria terminalis, and the sublenticular and retrolenticular limbs of the internal capsule. Vessels serving hypothalamic nuclei that are functionally associated with the limbic system originate from the circle of Willis. The anterior nucleus of the thalamus, an important synaptic station in the limbic system, is supplied by thalamoperforating arteries that arise from the P1 segment of the posterior cerebral artery. The subiculum is laterally continuous with the cortex of the parahippocampal gyrus and an area of the periallocortex. Medially, the edge of the hippocampal formation is formed by the dentate gyrus and the fimbria of the hippocampus. Developmentally, the hippocampal formation originates dorsally and migrates into its ventral and medial positions in the temporal lobe. These structures are small in the human brain and extend rostrally along the dorsal aspect of the corpus callosum into the subcallosal area. The cell types of the dentate gyrus, hippocampus, and subiculum are shown diagrammatically. The general locations of fields C1 to C4 are shown on the lower left; a Golgi stain of double pyramidal cells is shown at the lower right. This transitional zone, although small, can be divided into a prosubiculum, subiculum proper, presubiculum, and parasubiculum. These areas are essential for the flow of information into the hippocampal formation. The external layer is called the molecular layer and contains afferent axons and dendrites of cells intrinsic to each structure. These layers are named according to the shape of the cell body of the principal type of neuron found therein. The inner layer, called the polymorphic layer (also called the stratum oriens in the hippocampus), contains the axons of pyramidal and granule cells, a few intrinsic neurons, and many glial elements. In addition, the polymorphic layer of the hippocampus contains the elaborate basal dendrites of some larger pyramidal somata that are located in the pyramidal layer. The innermost part of the hippocampus borders on the wall of the lateral ventricle and is a layer of myelinated axons arising from cell bodies located in the subiculum and hippocampus. In both cases, axons of these neurons enter the alveus, coalesce to form the fimbria of the hippocampus, and then continue as the fornix. These glutaminergic fibers traverse the entire extent of the fornix, although some cross the midline in the hippocampal decussation just anterior (ventral) to the splenium of the corpus callosum. The precommissural fornix is composed of fibers arising primarily in the hippocampus. Most fibers of the perforant pathway terminate in the molecular layer of the dentate gyrus, although a few terminate in the subiculum and hippocampus. In addition, the subiculum also receives a modest projection from the amygdaloid complex. Although the fornix is mainly an efferent path from the hippocampus, it also conveys cholinergic septohippocampal projections to the hippocampal formation and entorhinal cortex. As noted previously, the initial segment of the Papez circuit is a projection primarily from the subiculum (a part of the hippocampal formation) to the medial mammillary nucleus via the postcommissural fornix. Other areas of the cerebral cortex are recruited into the various functions associated with the Papez circuit largely through connections of the cingulate gyrus. For example, the cingulate cortex receives input from premotor and prefrontal areas and from visual, auditory, and somatosensory association cortices. The cingulate gyrus thus is not only an integral part of the Papez circuit but also an important conduit through which a wide range of information can reach the limbic system. Immediate (or sensory) memory and short-term memory refer to types of memory that persist for seconds and minutes, respectively (Table 31. Normally, these memories can be incorporated into longterm memory, which can be recalled days, months, or years later. However, in persons with hippocampal lesions, this conversion is not accomplished. Although patients may be able to recall events or concepts for seconds or minutes, they are unable to incorporate the short-term memory into long-term memory. The redundancy and feedback in the hippocampus are ideal for this imprinting of memory (Table 31. Affected patients retain short-term memory but have difficulty learning new concepts because the new information is not retained (remembered) long enough to become a long-term memory. The subiculum and entorhinal cortices are among the first sites in which these abnormalities appear. As a result, the relay of information through the hippocampal formation is impeded. Procedural or implicit memory, the motor skills for performing tasks, is relatively spared because this type of memory is encoded by the basal ganglia and cerebellum. Typically, the mammillary bodies are involved, with some incursion into the dorsomedial nucleus of the thalamus and the columns of the fornix. In B, a T1-weighted axial magnetic resonance image, note the atrophy of both hippocampi with enlarged temporal horns (arrows) and atrophy of the orbitofrontal cortex in a patient with Alzheimer dementia. These patients with Korsakoff psychosis (alcoholic dementia) show a defect in short-term memory and consequently also in long-term memory for events occurring since the onset of the disease. They may appear demented, and they are prone to confabulation; that is, they tend to string together fragments of memory from several different events to form a synthetic "memory" of an event that never occurred (Table 31. Thiamine deficiency may also be manifested more acutely as a triad of eye movement abnormalities, ataxia, and confusion known as Wernicke encephalopathy, which is reversible with thiamine replacement. In severe cases, patients may present with the Wernicke triad accompanied by profound memory loss; this condition is called Wernicke-Korsakoff syndrome. When several synapses are present on a single cell, the input from these synapses the Limbic System 463 current synaptic activity increases the probability that future synaptic activity will take place. This mechanism causes stimuli and responses to be paired in the process we call memory. It is immediately rostral to the hippocampal formation and the anterior end of the temporal horn of the lateral ventricle. For our purposes, these nuclei can be grouped into a larger basolateral group and a smaller corticomedial group (including the central nucleus). The corticomedial group is more closely related to olfaction, whereas the basolateral group has extensive interconnections with cortical structures. These fibers supply a wide range of somatosensory, visual, and visceral information to the amygdaloid complex. In addition, this cell group, particularly its central nucleus, receives ascending input from nuclei in the brainstem known to be involved in visceral functions. Among others, these include the parabrachial nuclei, the solitary nucleus, and portions of the periaqueductal gray. The stria terminalis is a small fiber bundle that arises primarily from cells of the corticomedial group. Through most of its course, this bundle lies in the groove between the caudate nucleus and the dorsal thalamus, where it is accompanied by the superior thalamostriate (terminal) vein. It is associated along its length with discontinuous aggregations of cells, which collectively are called the bed nucleus of the stria terminalis. The ventral amygdalofugal pathway is the major efferent fiber bundle of the amygdaloid complex. Axons primarily from the basolateral cells pass medially through the substantia innominata (in which some of these fibers terminate) to eventually synapse in the hypothalamus and septal nuclei. The substantia innominata gives rise to a diffuse cholinergic projection to the cerebral cortex. It is probable that these fibers play a role in the activation of the cerebral cortex in response to behaviorally significant stimuli. In long-term potentiation, one synapse fires in a particular temporal pattern (such as bursts or trains of action potentials). This synaptic activity increases the likelihood that the target cells will be activated by that synapse and other synapses. This increased likelihood may be due to an increased probability that transmitter will be released from the presynaptic cell or an increased response in the postsynaptic cell to the same amount of neurotransmitter, or both. The gaseous neuromodulator nitric oxide is released and diffuses back to the presynaptic terminal. It acts on the presynaptic terminal to permanently increase the release of glutamate. As noted previously, most of those brainstem areas that receive input from the amygdala project back to this structure. Another route by which hippocampal and amygdaloid efferents influence the brainstem is through the stria medullaris thalami. The latter cell groups, in turn, give rise to the habenulointerpeduncular tract, which projects to the interpeduncular nucleus and other midbrain sites, including the ventral tegmental area and periaqueductal gray. Rage behavior has been seen in a small group of patients with midline infarcts in this area. Fibers also originate from the preoptic, anterior, and paraventricular hypothalamic nuclei and from the lateral hypothalamic area. Many of the fibers in the stria terminalis and fornix also send branches into the nucleus accumbens. The preoptic, anterior, and ventromedial nuclei and the lateral hypothalamic areas also receive input from the septal nuclei. This bundle is complex in that it conveys ascending inputs into the hypothalamus and through this area into the septal region. The dopamine-containing fibers in this area are thought to be related to perceptions of pleasure or drive reduction. The ventral tegmental area also gives rise to ascending fibers that enter the nucleus accumbens via the medial forebrain bundle. In addition, amygdalofugal fibers traversing the stria terminalis also enter the nucleus accumbens. Cells within the nucleus accumbens have receptors for a variety of neurotransmitters, including endogenous opiates. The nucleus accumbens may play an important role in behaviors related to addiction and chronic pain. Recent observations in addicted humans likewise reinforce the concept that the nucleus accumbens is a gratification site. Nucleus accumbens fibers to the last target represent an important route through which the limbic system may access the motor system. These sites, which are often interspersed in a given region of the brain, are frequently called either aversion centers or gratification centers. For example, some reports have linked activation of the amygdala during rapid eye movement sleep with nightmares and posttraumatic stress disorder. Functional interconnections between aversion and gratification centers probably contribute to emotional stability (Table 31. Although most limbic structures contain both gratification and aversion centers, one or the other type of center seems to predominate in some structures (Table 31. For example, the hippocampus and amygdala have an abundance of aversion centers, whereas the nucleus accumbens contains an abundance of gratification centers. Consequently, stimulation of the amygdala may elicit fear, whereas stimulation of the nucleus accumbens results in feelings of joy and pleasure. The emotion-related deficits resulting from small lesions in the limbic system are difficult to predict. They typically result in the flattening of emotions, as reflected by the fact that emotional extremes (joy and anxiety) are reduced. This phenomenon, presumably due to the loss of both aversion and gratification centers, commonly results from large lesions in the amygdala, hippocampus, fornix, or cingulate or prefrontal cortex. Bilateral lesions of the anterior part of the cingulate gyrus greatly diminish the emotional responses of the patient and may result in akinetic mutism. This is a state in which the patient is immobile, mute, and unresponsive but not in a coma. Other patients with cingulate damage may be alert but have no idea of who they are. In addition to these predictable deficits, these patients may also experience tactile agnosia (inability to recognize objects by touch despite intact proprioception and cutaneous sensation), auditory agnosia (inability to recognize or differentiate sounds despite intact hearing), amnesia, dementia, or aphasia, depending on the extent of the lesion of the temporal lobe. These deficits were initially described in a series of animal experiments, but they have also been seen in patients as a result of either trauma to the temporal lobe or temporal lobe surgery for epilepsy. Damage to the amygdaloid complex frequently involves portions of adjacent structures and of the surrounding white matter, and these incursions into other structures may contribute to the clinical picture. Damage to the amygdala and the hippocampus results in a greater memory deficit than the deficit noted with damage to either one alone. This type of seizure starts in a specific area of the brain, resulting in a wide range of physical and emotional behaviors with alteration of consciousness. For example, seizures that start in the area of the uncus may be associated with olfactory or gustatory hallucinations referred to as uncinate fits. These sensations are explainable given the functions of the amygdala and the destinations of the olfactory-gustatory fiber systems.

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Some proprioceptive receptors are innervated by trigeminal ganglion cells medications and mothers milk 2014 order phenytoin 100 mg amex, such as those with receptors 254 Systems Neurobiology in the temporomandibular joint medicine you can overdose on phenytoin 100mg mastercard, the extraocular muscles medications osteoarthritis pain buy generic phenytoin 100mg online, and some periodontal ligaments medications lexapro order cheapest phenytoin. Because most trigeminal ganglion axons bifurcate when they enter the brainstem symptoms night sweats order phenytoin toronto, both the principal sensory and the spinal trigeminal nucleus receive proprioceptive input. Proprioceptive input to the spinal trigeminal nucleus is relayed to the cerebellum, the spinal cord, and the thalamus. However, the principal sensory nucleus receives a disproportionate share of large-diameter, heavily myelinated fibers and may be considered the trigeminal homologue of the posterior column nuclei. These pathways provide the substrate for cortical processing that permits the full hedonic appreciation of foods with different textural properties (oral stereognosis). One cortical area, located in the depth of the central sulcus, corresponds to area 3b. The other cortical locus of increased activity identified in these studies is posterior and lateral and corresponds to area 1. Each column contains neurons responsive to one submodality, and the cells in a column all have similar peripheral receptive field loci. Axons of the stellate cells distribute information vertically to the pyramidal cells within individual columns. The receptive field properties of cortical neurons are more complex than those at subcortical levels. Cortical neurons respond to a specific stimulus orientation (edges) and to specific textures. They are also capable of coding the velocity, speed, and direction of moving stimuli. The first consists of simple neurons that receive input from a single joint or muscle group. The second group consists of postural neurons that signal the final position of a joint once the movement is completed. The third is made of neurons that receive inputs from several joints and muscle groups (multijoint) and signal complex joint-muscle interactions. The functional properties of cortical neurons reflect the processing and integration of sensory information as it ascends from the posterior column and ventral posterior nuclei to the final processing station in the cortical columns. This sensory signal processing can include (1) convergence of afferent input, which increases receptive field size while decreasing resolution; (2) divergence of output signal, which allows relay cells to amplify the sensory signal and supply it to multiple targets; (3) facilitation; and (4) inhibition. These processes act in concert to enhance the signal-to-noise ratio in terms of both space and time. In general, larger receptive fields and more complex inhibitory surrounds are displayed by cortical neurons than by their subcortical inputs. For example, a tactile stimulus in the center of a receptive field results in amplification of the sensory signal and increased activity in a restricted population of cortical cells. Conversely, stimulation at the edge of the receptive field suppresses the activity in these neurons. These techniques have elegantly demonstrated the functional organization of somatosensory areas activated by application of various tactile stimuli. However, on closer examination, some individuals appear to "recover" lost functions, whereas others remain relatively unchanged. To understand possible mechanisms for this apparent recovery, we must first look at brain development. Many of these connections will be retained through usage and experience, whereas others will be "pruned" by programmed cell death (apoptosis) and other cellular mechanisms. These processes will continue for a finite time (a critical period), thus giving many brain regions the potential to function in a variety of ways. Children with brain trauma due to a birth injury may appear to be normal with respect to sensory, motor, and cognitive abilities. The developing brain possesses the ability to reassign brain functions to other brain regions. In contrast to that in children, the nervous system in the adult has passed beyond the critical periods of brain development and has become relatively nonmalleable. It has been a commonly held view that most neural connections in the adult are stable and have lost much of their capacity to form new synapses. The existence of neurogenesis in the adult nervous system, together with the formation of new neural connections. Evidence suggests, however, that the somatosensory cortex can undergo reorganization. An example of this phenomenon is the changes in the cortical map after limb or digit amputation. When digits are amputated, there is a loss of input to the corresponding areas of the somatosensory cortex from the missing digits. The cortical neurons or areas representing the missing body part now respond when skin regions adjacent to the amputated body part are stimulated. Although many of these cortical changes are subtle, one study suggests that the time course of this reorganization can be rapid, beginning within 10 days after amputation. Thus it appears that the adult brain can exhibit plastic changes and undergo reorganization in response to specific peripheral perturbations. Similar phenomena have been described by molecular biologic methods within hours after experimental induction by appropriate stimuli. In contrast to young patients, who may experience a complete (or almost complete) recovery, older patients may experience less than full recovery. These sensory signals include information about limb position, joint angles, and muscle tension and length. Input to the cerebellum plays an integral role in guiding cerebellar control of body muscle tone, movement, and posture. Spinocerebellar tract axons terminate in the cerebellar nuclei and, as mossy fibers, in the vermis and paravermal region of the cerebellum. Degeneration of the major spinocerebellar tracts occurs in diseases such as Friedreich ataxia. The result is cerebellar ataxia-lack of coordination during walking and other movements that occurs because the cerebellum is not receiving the sensory feedback necessary to regulate movement. Primary afferent fibers from the spinal cord levels caudal to L2 ascend in the posterior funiculus to reach this nucleus. Group I muscle spindle and Golgi tendon organ afferents monosynaptically activate cells in the Clarke nucleus (thoracic nucleus). The discharge rate of these posterior spinocerebellar tract cells shows a linear relationship to muscle length; therefore their firing rate can encode muscle length as a frequency code. Axons from cells in the Clarke nucleus traverse the ipsilateral lateral funiculus and collect on the surface of the spinal cord lateral to the corticospinal tract. Posterior root fibers in spinal segments C2 to T4 carry muscle spindle and exteroceptive information in the ipsilateral cuneate fasciculus to the cuneate nucleus. In the lower medulla, proprioceptive primary afferent fibers terminate somatotopically in the lateral cuneate nucleus. Cells of the lateral cuneate nucleus project as cuneocerebellar fibers to the cerebellum via the restiform body. Exteroceptive input arising from the rostral end of the cuneate nucleus also ascends to the cerebellar cortex to terminate in the folia of the anterior lobe in lobule V. Anterior Spinocerebellar Tract this pathway relays information from group I afferents arising in the lower limb. In the pons, these fibers turn posterolateral to enter the cerebellum via the superior cerebellar peduncle. Most fibers recross to terminate in the cerebellum ipsilateral to their side of origin. The efferent projections from these neurons ascend uncrossed in the lateral funiculus of the spinal cord. Although most of these axons enter the cerebellum via the restiform body, some travel in the superior cerebellar peduncle. Trigeminocerebellar Connections the oral motor system requires continual feedback during mastication. As food is chewed, its texture and consistency are altered, changing the demands on jaw muscles. For example, there are modifications in jaw motility patterns during the transition from suckling to chewing in the newborn and from natural dentition to the use of dentures. It is probable that proprioceptive information reaching the cerebellum from jaw muscle spindles, periodontal afferents, and the temporomandibular joint is involved in these processes. Additional proprioceptive signals from the spinal trigeminal nucleus pars interpolaris and pars caudalis enter the cerebellum by way of the restiform body. They contribute a head representation to the two somatotopic maps in the cerebellar cortex. Attention to touch modulates activity in both primary and secondary somatosensory areas. Cortical and subcortical contributions to activity-dependent plasticity in primate somatosensory cortex. Tactile sensory nerve potentials elicited by air-puff stimulation: a microneurographic study. Single-unit analysis of human ventral thalamic nuclear group: somatosensory responses. Neurotransmitters and synaptic components in the Merkel cell-neurite complex, a gentle-touch receptor. Functional localization of the sensory hand area with respect to the motor central gyrus knob. Microstimulation of single tactile afferents from the human hand: sensory attributes related to unit type and properties of receptive fields. These signals are then relayed to lateral and medial thalamic nuclei and from there to the trunk and extremity representations in the primary and secondary somatosensory cortex and limbic cortex. These are relayed through brainstem and thalamic nuclei to face areas of the sensory cortex. Hit your thumb with a hammer and, if you are lucky, only high-threshold mechanoreceptors that signal excess skin deformation will be activated. After the hammer has done its damage, tissues release chemicals that activate another type of pain receptor, chemonociceptors. These receptors may contribute to the mechanism underlying long-term pain and tenderness (hyperalgesia). If a burn is produced, the tissue damage is signaled by high-frequency firing of thermonociceptors. This older view of separate tracts conveying separate modalities of sensory information is not used in this chapter. The direct pathway is the neospinothalamic pathway (spinal cord lateral thalamus somatosensory cortices), and the indirect pathway is the polysynaptic paleospinothalamic pathway (spinal cord reticular formation medial thalamus cingulate, frontal + limbic cortices). Although spinoreticular fibers project to the reticular formation of the medulla, pons, and midbrain, collaterals may ascend as reticulothalamic fibers to other targets, such as the intralaminar and dorsomedial nuclei of the thalamus. Thus ascending axons originating in the spinal cord can have multiple collaterals terminating in different locations throughout the brainstem. Spinohypothalamic fibers terminate in hypothalamic areas and nuclei, including some that give rise to hypothalamospinal axons. Projections of less relevance to the somatosensory system, such as spinoolivary fibers, are grouped under the category of spinobulbar fibers. The basis for their submodality specificity likely depends upon a unique array of membrane receptor complexes. Nonetheless, these submodalities are transduced by activation of peripheral branches of either thinly myelinated A (A-delta) fibers or unmyelinated C fibers. Regardless of size or location, however, each field is exquisitely sensitive to thermal, chemical, or mechanical stimuli. Nondiscriminative touch results from the stimulation of free nerve endings that act as nonnoxious high-threshold mechanoreceptors (Table 18. With repeated stimulation, these receptors become sensitized and have a decreased activation threshold and a larger response to the application of a stimulus. The cutaneous receptive field of an A nociceptor consists of a number of small sensitive spots (2 to 30) scattered over an area of skin. A mechanical nociceptors respond to mechanical injury accompanied by tissue damage. The cutaneous receptive field of a C-polymodal nociceptor usually consists of one or two sensitive spots, with each spot covering an area of skin 1 to 2 mm2. For a comparable region of skin, the C fiber spots are larger but fewer in number than the A spots, which are smaller but more numerous. Although the mechanisms responsible for receptor sensitization are not completely known, irritating chemicals (capsaicin), inflammatory mediators (bradykinin, prostaglandins), and neurotransmitters (serotonin, histamine, norepinephrine) released from damaged skin or by-products from plasma, or both, are thought to contribute to this phenomenon. As a result of this heightened sensitivity, the affected area is exquisitely sensitive to painful stimuli, and patients experience a sensory disturbance called hyperalgesia (exaggerated response to a painful stimulus). This condition can be differentiated into primary hyperalgesia and secondary hyperalgesia. Primary hyperalgesia occurs in the region of damaged skin and is probably the result of receptor sensitization. Secondary hyperalgesia occurs in the skin immediately bordering the damaged tissue. Although receptor sensitization may contribute to secondary hyperalgesia, there is likely to be a central. Thermoreceptors show a graded response to increases in temperature (B, left), whereas burns produced by prolonged thermal stimulation evoke high-frequency response in thermonociceptors (B, right).

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The Buehler Guinea Pig Sensitization assay (with exposure to simulated light) is preferred over the Guinea Pig Maximization Assay symptoms magnesium deficiency buy 100 mg phenytoin visa, which although considered more sensitive than the Buehler assay medications prescribed for adhd buy phenytoin 100 mg overnight delivery, is associated with subcutaneous reactions attributed to the use of adjuvant in this assay symptoms prostate cancer order phenytoin with amex. Although photogenotoxicity testing was included in previous regulatory guidance recommendations symptoms cervical cancer purchase genuine phenytoin, it is now generally accepted by regulatory agencies that photogenotoxicity testing not be conducted since there are too many false positives treatment 3 antifungal purchase phenytoin now, even with compounds that are not photoreactive. Photocarcinogenicity testing may be required for topical compounds that are used chronically, are phototoxic, and are topically applied or if there is indication for concern based on the class of compound. However, photocarcinogenicity testing may not be needed for compounds that are photoirritants if a warning is provided in patient information. Photococarcinogenic potential must also be taken into consideration for chemicals that may not be photoreactive but may influence carcinogenicity through immunosuppressive effects. Despite the limited range of response, there is still a great deal that can be ascertained from the different morphologic, physiologic, and molecular alterations that arise in response to injury. This barrier disruption manifests in the form of both morphologic and physiologic alterations that will vary depending on the degree of barrier damage, and to some extent on the specific irritant, although most pathophysiologic responses are generalized and independent of the specific initiating factor(s). These chemokines and cytokines recruit and activate leukocytes and convert the initial innate immune response to an adaptive immune response. Even the immune-mediated/autoimmune disease, psoriasis, is now believed to be at least partially caused by inappropriate or poorly regulated activation of epidermal keratinocytes, which in turn leads to inflammation and the hallmark morphologic changes associated with this condition. A third set of cells implicated in the initiation of the cutaneous immune response are skin-resident T lymphocytes, found both within the epidermis as well as in the dermis. Thus, Th17 cells and their cytokines link the adaptive immune response to the innate immune response of keratinocytes in order to optimize the host immune response to cutaneous pathogens. Skin-resident T cells are believed to play a major role in skin immune homeostasis and surveillance, and have also been implicated in the pathogenesis of psoriasis and atopic dermatitis. Specific Cutaneous Morphologic Lesions and Patterns of Injury the histopathologic interpretation of lesions in the integument, is based on the basic morphologic reaction patterns in the integument as much and perhaps more so than in other organ systems. Pattern recognition for the diagnosis of inflammatory conditions in the skin was pioneered by A. Bernard Ackerman in his seminal book Histologic Diagnosis of Inflammatory Skin Diseases: A Method Based on Pattern Analysis, and has been extensively used for the recognition and diagnosis of dermatitides in both human and veterinary pathology since. These basic morphologic reaction patterns serve as a very useful device for the recognition of specific cutaneous morphologic responses to injury. Its aim is to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions across organ systems in laboratory rodents. Substances that decrease normal keratinocyte proliferation and metabolic activity, such as topical corticosteroids, are a common cause of epidermal atrophy. Skin-resident immune cells are key sentinels for restoring homeostasis but can also be effector cells during cutaneous injury. T cell-derived pro-inflammatory cytokines and chemokines in turn can further stimulate epithelial and mesenchymal cells, including keratinocytes and fibroblasts, thus forming an amplifying feedback loop for the inflammatory reaction. Moreover, skin-resident T cells can migrate into the epidermis, engaging in cross-talk between immune cells and keratinocytes. Erosions are always due to superficial epidermal trauma, and are most commonly associated with trauma from scratching. Ulceration is also often caused by superficial epidermal trauma, but may also be the result of toxicity or a necrotizing dermatitis. Epidermal necrosis can be classified as either single cell or full-thickness necrosis. Single cell necrosis of keratinocytes may be further subdivided into apoptosis, or programmed cell death, and dyskeratosis, which is the occurrence of terminal keratinization of individual keratinocytes that has not occurred as part of the orderly process of epidermal keratinization; apoptosis cannot be differentiated from dyskeratosis on H&E stained sections. If vesicular change is severe, keratinocytes may rupture and form intraepidermal vesicles. In contrast to vesicular changes, spongiosis refers to intercellular edema between epidermal keratinocytes and is characterized by widened intercellular spaces with accentuation of desmosomes. Severe epidermal spongiosis may lead to rupture of intercellular desmosomes and the formation of intraepidermal vesicles. A vesicle is an intra- or subepidermal cavity or cleft filled with fluid and is also referred to as a bulla. It occurs following loss of cohesion between epidermal keratinocytes or between epidermis and dermis, resulting in the formation of a fluid-filled cavity. A pustule, also referred to as a microabscess, is a focal intraepidermal accumulation of leukocytes, and is commonly found as a feature of generalized skin inflammation. In contrast, leukocytes which are diffusely, rather than focally infiltrating throughout the epidermis are referred to as exocytosis. Pustules that are filled with isolated rounded keratinocytes with a normal nucleus are referred to as acantholytic pustules. Hyperkeratosis frequently accompanies epidermal hyperplasia and is often associated with chronic epidermal irritation. Squamous cell cysts can spontaneously occur in mice, particularly in the B6C3F1 strain. Nonproliferative Lesions of the Cutaneous Adnexa Many of the lesions found in cutaneous adnexa have been previously described under the epidermis, such that only features unique to the adnexal condition will be covered in this section. Adnexal atrophy is defined by a marked reduction in follicular and sebaceous gland size and cell number well beyond that found physiologically during the normal telogen stage of the hair cycle. It is characterized by small remnants of follicles and sebaceous glands appearing as strands of keratinocytes surrounded by a thickened connective tissue sheath. Most follicles lose their hair shaft, and dermal atrophy or scarring may be present. Hair follicles lose cells when they undergo regression in the catagen stage of the hair cycle. Therefore, hair follicle atrophy must be distinguished from catagen and telogen stages of the hair cycle. Hair follicle atrophy can be caused by a number of different compound classes such as antiproliferatives and steroid hormones. Follicular dysplasia is an abnormality in the shape of the hair follicle and/or the hair shaft with no evident reduction in size. While for the epidermis dysplasia usually denotes a preneoplastic proliferative change, in cutaneous adnexa it is primarily describing a malformation of the adnexal structure. In addition, rete ridge formation is often present, but the epidermal basement membrane remains intact. Cellular atypia is not present, and the epidermal basement membrane still remains intact. Proliferative Nonneoplastic Lesions of the Adnexa Sebaceous cell hyperplasia is characterized by enlargement of sebaceous glands with maintenance of the normal glandular architecture. Enlarged sebaceous gland acini contain increased cells that are primarily mature, sebum-containing cells. Sebaceous cell hyperplasia frequently accompanies squamous cell hyperplasia, and both are commonly seen with chronic inflammation. Proliferative Nonneoplastic Lesions of the Dermis Pigment cell hyperplasia is an accumulation of pigmented melanocytes within the dermis between hair follicles and sebaceous glands. It can also occur during chronic dermal inflammation, where it needs to be distinguished from the dermal accumulation of pigment-laden macrophages, or melanomacrophages, that have engulfed melanin pigment. Follicular necrosis is similar to epidermal necrosis, and is characterized by degeneration of follicular keratinocytes, either as single cells (single cell type) or as multiple cells (diffuse type). Chemotherapeutic agents such as paclitaxel and doxorubicin induce follicular necrosis of the single cell type, thereby inducing alopecia. Hair follicle dystrophy can be classified as a form of necrosis, as follicular keratinocytes undergo uncoordinated vacuolar degeneration or apoptosis. Adnexal, and particularly follicular inflammation, is classified according to its pattern or location (perifollicular, intrafollicular, luminal, mural), similarly to inflammation affecting the dermis. Inflammation can also be subcategorized according to its character (lymphocytic, plasmacytic, neutrophilic, eosinophilic, and granulomatous). Interface folliculitis refers to perifollicular and mural inflammation that is generally associated with distinct necrosis of follicular keratinocytes. Follicular inflammation that has penetrated through the follicular wall leading to follicular rupture and marked inflammation in the surrounding dermis and connective tissue due to a foreign body inflammatory response to the hair shaft and follicular keratins is termed furunculosis. Neoplastic Lesions and Carcinogenesis Models Carcinogenesis Models the multistage model of mouse skin carcinogenesis is a very well-established model that has greatly aided in the identification of the underlying cellular, biochemical, and molecular mechanisms associated with the various stages of epithelial carcinogenesis. In this model, tumor development occurs via three distinct stages: initiation, promotion, and progression. Following initiation, tumor promotion occurs by increased expression of growth regulatory genes and sustained stimulation of epidermal keratinocyte proliferation and hyperplasia. These changes are believed to result from epigenetic mechanisms such as activation of the cellular receptor, protein kinase C. There are three mouse models that have been commonly used for cutaneous carcinogenesis evaluation, although none are currently approved for stand-alone cutaneous carcinogenicity assessment by regulatory agencies: the Tg. Hemizygous rasH2 mice respond with greater sensitivity to carcinogens than nontransgenic mice and are similarly recommended for genotoxic and nongenotoxic carcinogen identification. These mice respond rapidly and sensitively with skin tumors following topical application of a single low dose of an initiating agent, typically a mutagenic carcinogen, followed by multiple applications of a tumor promoting agent. When evaluated for sensitivity and predictability of mouse skin models for carcinogenic hazard identification, all of the three mouse models respond similarly, with mild inflammation and epidermal squamous cell proliferation and hyperplasia, to several weeks of treatment with topical carcinogens. All of the three mouse models are also similar in their development of the reporter phenotype: the development of squamous cell papillomas following extended carcinogen treatment. Cutaneous tumors, particularly those derived from the epidermis and cutaneous adnexa, are not uncommon spontaneous findings in rodents, so attention must be paid to the potential occurrence of spontaneous tumors in the commonly used mouse models of skin carcinogenesis. In these mouse models, the typical carcinogen-induced tumors are squamous cell papilloma with malignant progression to squamous cell carcinoma, such that it is essential to differentiate these carcinogen-induced epidermal keratinocyte-derived epithelial tumors from other spontaneously occurring tumors derived from epidermal keratinocytes as well as spontaneously occurring tumors derived from cutaneous adnexal epithelia. Neoplastic Proliferative Lesions of the Epidermis Squamous cell neoplasms are the typical tumors that occur in all mouse skin tumor models, and arise first as squamous cell hyperplasia (described earlier) followed by the development of squamous papillomas, described here, and finally malignant squamous cell carcinomas. Squamous cell papillomas are benign neoplasms that are derived from epidermal keratinocytes, and are the earliest neoplastic lesion induced by carcinogens in the mouse models of skin carcinogenesis. They can be further characterized into four types: exophytic, endophytic, dysplastic, and nonkeratinizing. The exophytic type has a stalk at its base, and is also often referred to as a pedunculated papilloma. The dysplastic type contains atypical squamous cells with large hyperchromatic nuclei that are found primarily in the basal and suprabasal layer of the epidermis. Regardless of type, all papillomas are wellcircumscribed papilliform exophytic or endophytic masses with no compression of the surrounding tissue and no capsule. They are composed of keratinizing squamous cells overlying a well-vascularized stroma. Individual suprabasal cells may show premature keratinization or dyskeratosis, and there is a variable degree of parakeratotic hyperkeratosis. Squamous cell carcinomas, also referred to as epidermoid carcinoma, are malignant neoplasms derived from epidermal keratinocytes. Neoplastic cells demonstrate variable evidence of squamous differentiation and keratinization. The tumor is composed of islands or cords of cells that penetrate the basal lamina and invade the dermis, with the neoplastic cells sometimes invading the underlying subcutis or subcutaneous muscle. Centrally located, concentric layers of keratin that are often termed keratin pearls, cancer pearls or horn pearls are also frequently present. Some neoplastic cords may show a central lumen containing individualized (acantholytic) keratinocytes that are surrounded by several layers of neoplastic epithelial cells (pseudo-glandular pattern). Abnormal keratinization (dyskeratosis) of single cells occurs sporadically and intercellular bridges are generally present except in very poorly differentiated tumors. Benign basal cell tumors are derived from stem cells within hair follicles and/or the interfollicular epidermis and are classified into three distinct types: basosquamous type, trichoblastoma type, and granular type. All basal cell tumors are fairly well circumscribed and multilobulated with some association to the epidermis. The neoplasm is composed of uniform lobules, islands, or cords of closely packed cells that are supported by a variable degree of fibrovascular stroma. Neoplastic basal cells also may be arranged in cords or fine ribbons that may become cystic. There is no invasion of the basement membrane and no compression or desmoplasia of the surrounding dermal mesenchyme. Tumor cells generally resemble normal epidermal basal cells without intercellular bridges, and palisade at the periphery of lobules. Foci of squamous cell differentiation may occur and sebaceous cells may also be present. In the trichoblastoma type, small foci of sebaceous cells and/or follicular differentiation are present. Malignant basal cell tumor is also referred to as basal cell carcinoma or basosquamous carcinoma, and is a malignant tumor derived from stem cells within hair follicles and/or the interfollicular epidermis. Malignant basal cell tumors are poorly circumscribed dermal tumors with some association to the epidermis or adnexa and extensive local invasion. They are composed of lobules and cords of closely packed cells that are supported by a variable degree of fibrovascular stroma. Central necrosis in tumor lobules may be present; these necrotic areas are referred to as pseudocysts. In pigmented strains, melanin pigmentation is commonly found, desmoplasia in the surrounding mesenchyme is common, and extensive local invasion may be present. Benign and malignant basal cell tumor development has been very convincingly linked to upregulated hedgehog (Hh) signaling via several lines of evidence, including genetic mutation analyses, mouse models of basal cell tumors, and the successful treatment of malignant basal cell tumors in the clinic using Hh signaling inhibitors. In addition, many if not all basal cell tumors are believed to derive from hair follicle stem cells. This early benign basal cell tumor is a very well-circumscribed lobule that is connected to the overlying epidermis and demonstrates no invasion of the basement membrane and no compression or desmoplasia of the surrounding dermal mesenchyme.

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