Harrison Neurology in Clinical Medicine Second Edition

182 SECTION II Clinical Manifestations of Neurologic Disease FIGURE 17-12 FIGURE 17-13 Papilledema means optic disc edema from raised intracra- Optic disc drusen are calcified deposits of unknown etiol- nial pressure. This obese young woman with pseudotumor ogy within the optic disc. They are sometimes confused with cerebri was misdiagnosed as a migraineur until fundus papilledema. examination was performed, showing optic disc elevation, hemorrhages, and cotton-wool spots. shows enlarged blind spots and peripheral constriction the surface of the optic disc. However, in many patients (Fig. 17-3F). With unremitting papilledema, peripheral they are hidden beneath the surface, producing pseudo- visual field loss progresses in an insidious fashion while papilledema. It is important to recognize optic disc drusen the optic nerve develops atrophy. In this setting, reduction to avoid an unnecessary evaluation for papilledema. of optic disc swelling is an ominous sign of a dying nerve Ultrasound or CT scanning is sensitive for detection of rather than an encouraging indication of resolving buried optic disc drusen because they contain calcium. papilledema. In most patients, optic disc drusen are an incidental, innocuous finding, but they can produce visual obscura- Evaluation of papilledema requires neuroimaging tions. On perimetry they give rise to enlarged blind spots to exclude an intracranial lesion. MR angiography is and arcuate scotomas from damage to the optic disc.With appropriate in selected cases to search for a dural venous increasing age, drusen tend to become more exposed on sinus occlusion or an arteriovenous shunt. If neuroradio- the disc surface as optic atrophy develops. Hemorrhage, logic studies are negative, the subarachnoid opening choroidal neovascular membrane, and AION are more pressure should be measured by lumbar puncture. An likely to occur in patients with optic disc drusen. No treat- elevated pressure, with normal cerebrospinal fluid, points ment is available. by exclusion to the diagnosis of pseudotumor cerebri (idio- pathic intracranial hypertension).The majority of patients Vitreous Degeneration are young, female, and obese. Treatment with a carbonic anhydrase inhibitor such as acetazolamide lowers intracra- This occurs in all individuals with advancing age, lead- nial pressure by reducing the production of cerebrospinal ing to visual symptoms. Opacities develop in the vitre- fluid. Weight reduction is vital but often unsuccessful. If ous, casting annoying shadows upon the retina. As the acetazolamide and weight loss fail, and visual field loss is eye moves, these distracting “floaters” move synchro- progressive, a shunt should be performed without delay nously, with a slight lag caused by inertia of the vitreous to prevent blindness. Occasionally, emergency surgery gel.Vitreous traction upon the retina causes mechanical is required for sudden blindness caused by fulminant stimulation, resulting in perception of flashing lights. papilledema. This photopsia is brief and confined to one eye, in con- trast to the bilateral, prolonged scintillations of cortical Optic Disc Drusen migraine. Contraction of the vitreous can result in sud- den separation from the retina, heralded by an alarming These are refractile deposits within the substance of the shower of floaters and photopsia.This process, known as optic nerve head (Fig. 17-13). They are unrelated to vitreous detachment, is a frequent involutional event in the drusen of the retina, which occur in age-related macular elderly. It is not harmful unless it damages the retina. A degeneration. Optic disc drusen are most common in careful examination of the dilated fundus is important in people of northern European descent. Their diagnosis is any patient complaining of floaters or photopsia to obvious when they are visible as glittering particles upon

search for peripheral tears or holes. If such a lesion is Classic Migraine 183 found, laser application can forestall a retinal detach- ment. Occasionally a tear ruptures a retinal blood vessel, (See also Chap. 6) This usually occurs with a visual aura CHAPTER 17 Disorders of Vision causing vitreous hemorrhage and sudden loss of vision. lasting about 20 min. In a typical attack, a small central On attempted ophthalmoscopy the fundus is hidden by disturbance in the field of vision marches toward the a dark red haze of blood. Ultrasound is required to periphery, leaving a transient scotoma in its wake. The examine the interior of the eye for a retinal tear or expanding border of migraine scotoma has a scintillating, detachment. If the hemorrhage does not resolve sponta- dancing, or zig-zag edge, resembling the bastions of a neously, the vitreous can be removed surgically.Vitreous fortified city, hence the term fortification spectra. Patients’ hemorrhage also occurs from the fragile neovascular descriptions of fortification spectra vary widely and can vessels that proliferate on the surface of the retina in be confused with amaurosis fugax. Migraine patterns usu- diabetes, sickle cell anemia, and other ischemic ocular ally last longer and are perceived in both eyes, whereas diseases. amaurosis fugax is briefer and occurs in only one eye. Migraine phenomena also remain visible in the dark or Retinal Detachment with the eyes closed. Generally they are confined to either This produces symptoms of floaters, flashing lights, and a the right or left visual hemifield, but sometimes both scotoma in the peripheral visual field corresponding to fields are involved simultaneously. Patients often have a the detachment (Fig. 17-14). If the detachment long history of stereotypic attacks. After the visual symp- includes the fovea, there is an afferent pupil defect and toms recede, headache develops in most patients. the visual acuity is reduced. In most eyes, retinal detach- ment starts with a hole, flap, or tear in the peripheral Transient Ischemic Attacks retina (rhegmatogenous retinal detachment). Patients with peripheral retinal thinning (lattice degeneration) Vertebrobasilar insufficiency may result in acute are particularly vulnerable to this process. Once a break homonymous visual symptoms. Many patients mistak- has developed in the retina, liquified vitreous is free to enly describe symptoms in their left or right eye, when enter the subretinal space, separating the retina from the in fact they are occurring in the left or right hemifield pigment epithelium. The combination of vitreous trac- of both eyes. Interruption of blood supply to the visual tion upon the retinal surface and passage of fluid behind cortex causes a sudden fogging or graying of vision, the retina leads inexorably to detachment. Patients with occasionally with flashing lights or other positive phe- a history of myopia, trauma, or prior cataract extraction nomena that mimic migraine. Cortical ischemic attacks are at greatest risk for retinal detachment. The diagnosis are briefer in duration than migraine, occur in older is confirmed by ophthalmoscopic examination of the patients, and are not followed by headache.There may be dilated eye. associated signs of brainstem ischemia, such as diplopia, vertigo, numbness, weakness, or dysarthria. FIGURE 17-14 Retinal detachment appears as an elevated sheet of retinal Stroke tissue with folds. In this patient the fovea was spared, so acuity was normal, but a superior detachment produced an This occurs when interruption of blood supply from the inferior scotoma. posterior cerebral artery to the visual cortex is pro- longed. The only finding on examination is a homony- mous visual field defect that stops abruptly at the vertical meridian. Occipital lobe stroke is usually due to throm- botic occlusion of the vertebrobasilar system, embolus, or dissection. Lobar hemorrhage, tumor, abscess, and arteri- ovenous malformation are other common causes of hemi- anopic cortical visual loss. Factitious (Functional, Nonorganic) Visual Loss This is claimed by hysterics or malingerers. The latter comprise the vast majority, seeking sympathy, special treat- ment, or financial gain by feigning loss of sight.The diag- nosis is suspected when the history is atypical, physical findings are lacking or contradictory, inconsistencies emerge on testing, and a secondary motive can be identi- fied. In our litigious society, the fraudulent pursuit of rec- ompense has spawned an epidemic of factitious visual loss.

SECTION II Clinical Manifestations of Neurologic Disease184 CHRONIC VISUAL LOSS FIGURE 17-15 Glaucoma results in “cupping” as the neural rim is Cataract destroyed and the central cup becomes enlarged and exca- vated. The cup-to-disc ratio is about 0.7/1.0 in this patient. This is a clouding of the lens sufficient to reduce vision. Most cataracts develop slowly as a result of aging, leading and visual field loss have intraocular pressures that appar- to gradual impairment of vision.The formation of cataract ently never exceed the normal limit of 20 mm Hg (so- occurs more rapidly in patients with a history of ocular called low-tension glaucoma). trauma, uveitis, or diabetes mellitus. Cataracts are acquired in a variety of genetic diseases, such as myotonic dystro- In acute angle-closure glaucoma, the eye is red and phy, neurofibromatosis type 2, and galactosemia. Radiation painful due to abrupt, severe elevation of intraocular therapy and glucocorticoid treatment can induce cataract pressure. Such cases account for only a minority of glau- as a side effect. The cataracts associated with radiation or coma cases: most patients have open, anterior chamber glucocorticoids have a typical posterior subcapsular loca- angles. The cause of raised intraocular pressure in open tion. Cataract can be detected by noting an impaired red angle glaucoma is unknown, but it is associated with reflex when viewing light reflected from the fundus with gene mutations in the heritable forms. an ophthalmoscope or by examining the dilated eye using the slit lamp. Glaucoma is usually painless (except in angle-closure glaucoma). Foveal acuity is spared until end-stage dis- The only treatment for cataract is surgical extraction ease is reached. For these reasons, severe and irreversible of the opacified lens. Over a million cataract operations damage can occur before either the patient or physician are performed each year in the United States.The oper- recognizes the diagnosis. Screening of patients for glau- ation is generally done under local anesthesia on an out- coma by noting the cup-to-disc ratio on ophthal- patient basis. A plastic or silicone intraocular lens is moscopy and by measuring intraocular pressure is vital. placed within the empty lens capsule in the posterior Glaucoma is treated with topical adrenergic agonists, chamber, substituting for the natural lens and leading to cholinergic agonists, beta blockers, and prostaglandin ana- rapid recovery of sight. More than 95% of patients who logues. Occasionally, systemic absorption of beta blocker undergo cataract extraction can expect an improvement from eye drops can be sufficient to cause side effects of in vision. In some patients, the lens capsule remaining in bradycardia, hypotension, heart block, bronchospasm, or the eye after cataract extraction eventually turns cloudy, depression.Topical or oral carbonic anhydrase inhibitors causing secondary loss of vision. A small opening is are used to lower intraocular pressure by reducing made in the lens capsule with a laser to restore clarity. aqueous production. Laser treatment of the trabecular meshwork in the anterior chamber angle improves Glaucoma aqueous outflow from the eye. If medical or laser treat- ments fail to halt optic nerve damage from glaucoma, a This is a slowly progressive, insidious optic neuropathy, filter must be constructed surgically (trabeculectomy) or usually associated with chronic elevation of intraocular a valve placed to release aqueous from the eye in a con- pressure. In Americans of African descent it is the leading trolled fashion. cause of blindness. The mechanism whereby raised intraocular pressure injures the optic nerve is not under- Macular Degeneration stood. Axons entering the inferotemporal and superotem- poral aspects of the optic disc are damaged first, producing This is a major cause of gradual, painless, bilateral central typical nerve fiber bundle or arcuate scotomas on peri- visual loss in the elderly. The old term, “senile macular metric testing. As fibers are destroyed, the neural rim of the optic disc shrinks and the physiologic cup within the optic disc enlarges (Fig. 17-15).This process is referred to as pathologic “cupping.” The cup-to-disc diameter is expressed as a ratio (e.g., 0.2/1). The cup-to-disc ratio ranges widely in normal individuals, making it difficult to diagnose glaucoma reliably simply by observing an unusu- ally large or deep optic cup. Careful documentation of ser- ial examinations is helpful. In the patient with physiologic cupping, the large cup remains stable, whereas in the patient with glaucoma it expands relentlessly over the years. Detection of visual field loss by computerized perimetry also contributes to the diagnosis. Finally, most patients with glaucoma have raised intraocular pressure. However, many patients with typical glaucomatous cupping

degeneration,” misinterpreted by many patients as an in age-related macular degeneration have not improved 185 CHAPTER 17 Disorders of Vision unflattering reference, has been replaced with “age-related vision in most patients. However, outcomes have been macular degeneration.” It occurs in a nonexudative (dry) more encouraging for patients with choroidal neovascu- form and an exudative (wet) form. Inflammation may be lar membranes from ocular histoplasmosis syndrome. important in both forms of macular degeneration; recent genetic data indicates that susceptibility is associ- Major or repeated hemorrhage under the retina from ated with variants in the gene for complement factor H, neovascular membranes results in fibrosis, development an inhibitor of the alternative complement pathway.The of a round (disciform) macular scar, and permanent loss nonexudative process begins with the accumulation of of central vision. extracellular deposits, called drusen, underneath the reti- nal pigment epithelium. On ophthalmoscopy, they are Central Serous Chorioretinopathy pleomorphic but generally appear as small discrete yellow lesions clustered in the macula (Fig. 17-16). This primarily affects men between 20 and 50 years of With time they become larger, more numerous, and age. Leakage of serous fluid from the choroid causes small, confluent.The retinal pigment epithelium becomes focally localized detachment of the retinal pigment epithelium detached and atrophic, causing visual loss by interfering and the neurosensory retina. These detachments produce with photoreceptor function. Treatment with vitamins acute or chronic symptoms of metamorphopsia and C and E, beta carotene, and zinc may retard dry macular blurred vision when the macula is involved.They are dif- degeneration. ficult to visualize with a direct ophthalmoscope because the detached retina is transparent and only slightly ele- Exudative macular degeneration, which develops in vated. Diagnosis of central serous chorioretinopathy is only a minority of patients, occurs when neovascular made easily by fluorescein angiography, which shows dye vessels from the choroid grow through defects in streaming into the subretinal space. The cause of central Bruch’s membrane into the potential space beneath the serous chorioretinopathy is unknown. Symptoms may retinal pigment epithelium. Leakage from these vessels resolve spontaneously if the retina reattaches, but recur- produces elevation of the retina and pigment epithe- rent detachment is common. Laser photocoagulation has lium, with distortion (metamorphopsia) and blurring of benefited some patients with this condition. vision. Although onset of these symptoms is usually gradual, bleeding from subretinal choroidal neovascular Diabetic Retinopathy membranes sometimes causes acute visual loss.The neo- vascular membranes can be difficult to see on fundus A rare disease until 1921, when the discovery of insulin examination because they are beneath the retina. Fluo- resulted in a dramatic improvement in life expectancy rescein or indocyanine green angiography is extremely for patients with diabetes mellitus, it is now a leading useful for their detection. Neovascular membranes are cause of blindness in the United States. The retinopathy treated with either photodynamic therapy or intraocular of diabetes takes years to develop but eventually appears injection of vascular endothelial growth factor antago- in nearly all cases. Regular surveillance of the dilated nists. Surgical attempts to remove subretinal membranes fundus is crucial for any patient with diabetes. In advanced diabetic retinopathy, the proliferation of neovas- cular vessels leads to blindness from vitreous hemorrhage, retinal detachment, and glaucoma. These complications can be avoided in most patients by administration of panretinal laser photocoagulation at the appropriate point in the evolution of the disease. FIGURE 17-16 Retinitis Pigmentosa Age-related macular degeneration begins with the accu- mulation of drusen within the macula. They appear as scat- This is a general term for a disparate group of rod and tered yellow subretinal deposits. cone dystrophies characterized by progressive night blind- ness, visual field constriction with a ring scotoma, loss of acuity, and an abnormal electroretinogram (ERG). It occurs sporadically or in an autosomal recessive, domi- nant, or X-linked pattern. Irregular black deposits of clumped pigment in the peripheral retina, called bone spicules because of their vague resemblance to the spicules of cancellous bone, give the disease its name (Fig. 17-17). The name is actually a misnomer because retinitis pig- mentosa is not an inflammatory process. Most cases are

186 SECTION II Clinical Manifestations of Neurologic Disease FIGURE 17-17 FIGURE 17-18 Retinitis pigmentosa with black clumps of pigment in the Melanoma of the choroid, appearing as an elevated dark retinal periphery known as “bone spicules.” There is also mass in the inferior temporal fundus, just encroaching upon atrophy of the retinal pigment epithelium, making the vascu- the fovea. lature of the choroid easily visible. due to a mutation in the gene for rhodopsin, the rod and loss of vision. A small melanoma is often difficult to photopigment, or in the gene for peripherin, a glycopro- differentiate from a benign choroidal nevus. Serial exam- tein located in photoreceptor outer segments.Vitamin A inations are required to document a malignant pattern of (15,000 IU/day) slightly retards the deterioration of the growth.Treatment of melanoma is controversial. Options ERG in patients with retinitis pigmentosa but has no include enucleation, local resection, and irradiation. beneficial effect on visual acuity or fields. Some forms of Metastatic tumors to the eye outnumber primary tumors. retinitis pigmentosa occur in association with rare, hered- Breast and lung carcinoma have a special propensity to itary systemic diseases (olivopontocerebellar degenera- spread to the choroid or iris. Leukemia and lymphoma tion, Bassen-Kornzweig disease, Kearns-Sayre syndrome, also commonly invade ocular tissues. Sometimes their Refsum’s disease). Chronic treatment with chloroquine, only sign on eye examination is cellular debris in the vit- hydroxychloroquine, and phenothiazines (especially thior- reous, which can masquerade as a chronic posterior idazine) can produce visual loss from a toxic retinopathy uveitis. Retrobulbar tumor of the optic nerve (meningioma, that resembles retinitis pigmentosa. glioma) or chiasmal tumor (pituitary adenoma, menin- gioma) produces gradual visual loss with few objective Epiretinal Membrane findings, except for optic disc pallor. Rarely, sudden expansion of a pituitary adenoma from infarction and This is a fibrocellular tissue that grows across the inner bleeding (pituitary apoplexy) causes acute retrobulbar visual surface of the retina, causing metamorphopsia and loss, with headache, nausea, and ocular motor nerve reduced visual acuity from distortion of the macula. A palsies. In any patient with visual field loss or optic atro- crinkled, cellophane-like membrane is visible on the phy, CT or MR scanning should be considered if the retinal examination. Epiretinal membrane is most com- cause remains unknown after careful review of the his- mon in patients older than 50 years and is usually unilat- tory and thorough examination of the eye. eral. Most cases are idiopathic, but some occur as a result of hypertensive retinopathy, diabetes, retinal detachment, PROPTOSIS or trauma. When visual acuity is reduced to the level of about 6/24 (20/80), vitrectomy and surgical peeling of When the globes appear asymmetric, the clinician must the membrane to relieve macular puckering are recom- first decide which eye is abnormal. Is one eye recessed mended. Contraction of an epiretinal membrane some- within the orbit (enophthalmos) or is the other eye protu- times gives rise to a macular hole. Most macular holes, berant (exophthalmos, or proptosis)? A small globe or a however, are caused by local vitreous traction within the Horner’s syndrome can give the appearance of enoph- fovea.Vitrectomy can improve acuity in selected cases. thalmos. True enophthalmos occurs commonly after trauma, from atrophy of retrobulbar fat, or fracture of Melanoma and Other Tumors the orbital floor. The position of the eyes within the orbits is measured using a Hertel exophthalmometer, a Melanoma is the most common primary tumor of the eye hand-held instrument that records the position of the (Fig. 17-18). It causes photopsia, an enlarging scotoma,

anterior corneal surface relative to the lateral orbital rim. blindness, septic cavernous sinus thrombosis, and menin- 187CHAPTER 17 Disorders of Vision If this instrument is not available, relative eye position gitis. To avert this disaster, orbital cellulitis should be can be judged by bending the patient’s head forward and managed aggressively in the early stages, with immediate looking down upon the orbits. A proptosis of only 2 mm imaging of the orbits and antibiotic therapy that in one eye is detectable from this perspective.The devel- includes coverage of methicillin-resistant Staphylococcus opment of proptosis implies a space-occupying lesion in aureus. Prompt surgical drainage of an orbital abscess or the orbit, and usually warrants CT or MR imaging. paranasal sinusitis is indicated if optic nerve function deteriorates despite antibiotics. Graves’ Ophthalmopathy Tumors This is the leading cause of proptosis in adults.The prop- tosis is often asymmetric and can even appear to be uni- Tumors of the orbit cause painless, progressive proptosis. lateral. Orbital inflammation and engorgement of the The most common primary tumors are hemangioma, extraocular muscles, particularly the medial rectus and the lymphangioma, neurofibroma, dermoid cyst, adenoid inferior rectus, account for the protrusion of the globe. cystic carcinoma, optic nerve glioma, optic nerve menin- Corneal exposure, lid retraction, conjunctival injection, gioma, and benign mixed tumor of the lacrimal gland. restriction of gaze, diplopia, and visual loss from optic Metastatic tumor to the orbit occurs frequently in breast nerve compression are cardinal symptoms. Graves’ oph- carcinoma, lung carcinoma, and lymphoma. Diagnosis thalmopathy is treated with oral prednisone (60 mg/d) for by fine-needle aspiration followed by urgent radiation 1 month, followed by a taper over several months, topical therapy can sometimes preserve vision. lubricants, eyelid surgery, eye muscle surgery, or orbital decompression. Radiation therapy is not effective. Carotid Cavernous Fistulas Orbital Pseudotumor With anterior drainage through the orbit these produce proptosis, diplopia, glaucoma, and corkscrew, arterialized This is an idiopathic, inflammatory orbital syndrome, fre- conjunctival vessels. Direct fistulas usually result from quently confused with Graves’ ophthalmopathy. Symptoms trauma. They are easily diagnosed because of the promi- are pain, limited eye movements, proptosis, and congestion. nent signs produced by high-flow, high-pressure shunting. Evaluation for sarcoidosis, Wegener’s granulomatosis, and Indirect fistulas, or dural arteriovenous malformations, are other types of orbital vasculitis or collagen-vascular disease more likely to occur spontaneously, especially in older is negative. Imaging often shows swollen eye muscles women. The signs are more subtle and the diagnosis is (orbital myositis) with enlarged tendons. By contrast, in frequently missed. The combination of slight proptosis, Graves’ ophthalmopathy the tendons of the eye muscles are diplopia, enlarged muscles, and an injected eye is often usually spared.The Tolosa-Hunt syndrome may be regarded mistaken for thyroid ophthalmopathy. A bruit heard upon as an extension of orbital pseudotumor through the supe- auscultation of the head, or reported by the patient, is a rior orbital fissure into the cavernous sinus. The diagnosis valuable diagnostic clue. Imaging shows an enlarged supe- of orbital pseudotumor is difficult. Biopsy of the orbit fre- rior ophthalmic vein in the orbits. Carotid cavernous quently yields nonspecific evidence of fat infiltration by shunts can be eliminated by intravascular embolization. lymphocytes, plasma cells, and eosinophils. A dramatic response to a therapeutic trial of systemic glucocorticoids PTOSIS indirectly provides the best confirmation of the diagnosis. Blepharoptosis Orbital Cellulitis This is an abnormal drooping of the eyelid. Unilateral or This causes pain, lid erythema, proptosis, conjunctival bilateral ptosis can be congenital, from dysgenesis of the chemosis, restricted motility, decreased acuity, afferent levator palpebrae superioris, or from abnormal insertion pupillary defect, fever, and leukocytosis. It often arises of its aponeurosis into the eyelid. Acquired ptosis can from the paranasal sinuses, especially by contiguous develop so gradually that the patient is unaware of the spread of infection from the ethmoid sinus through the problem. Inspection of old photographs is helpful in lamina papyracea of the medial orbit. A history of recent dating the onset. A history of prior trauma, eye surgery, upper respiratory tract infection, chronic sinusitis, thick contact lens use, diplopia, systemic symptoms (e.g., dys- mucous secretions, or dental disease is significant in any phagia or peripheral muscle weakness), or a family his- patient with suspected orbital cellulitis. Blood cultures tory of ptosis should be sought. Fluctuating ptosis that should be obtained, but they are usually negative. Most worsens late in the day is typical of myasthenia gravis. patients respond to empirical therapy with broad- Examination should focus upon evidence for proptosis, spectrum IV antibiotics. Occasionally, orbital cellulitis eyelid masses or deformities, inflammation, pupil follows an overwhelming course, with massive proptosis, inequality, or limitation of motility. The width of the

SECTION II Clinical Manifestations of Neurologic Disease188 palpebral fissures is measured in primary gaze to quanti- limitation of adduction, elevation, and depression, a tate the degree of ptosis. The ptosis will be underesti- pupil-sparing oculomotor nerve palsy is likely (see next mated if the patient compensates by lifting the brow section). Rarely, a lesion affecting the small, central sub- with the frontalis muscle. nucleus of the oculomotor complex will cause bilateral ptosis with normal eye movements and pupils. Mechanical Ptosis DOUBLE VISION (DIPLOPIA) This occurs in many elderly patients from stretching and redundancy of eyelid skin and subcutaneous fat (derma- The first point to clarify is whether diplopia persists in tochalasis). The extra weight of these sagging tissues either eye after covering the opposite eye. If it does, the causes the lid to droop. Enlargement or deformation of diagnosis is monocular diplopia. The cause is usually the eyelid from infection, tumor, trauma, or inflamma- intrinsic to the eye and therefore has no dire implica- tion also results in ptosis on a purely mechanical basis. tions for the patient. Corneal aberrations (e.g., kerato- conus, pterygium), uncorrected refractive error, cataract, Aponeurotic Ptosis or foveal traction may give rise to monocular diplopia. Occasionally it is a symptom of malingering or psychi- This is an acquired dehiscence or stretching of the atric disease. Diplopia alleviated by covering one eye is aponeurotic tendon, which connects the levator muscle binocular diplopia and is caused by disruption of ocular to the tarsal plate of the eyelid. It occurs commonly in alignment. Inquiry should be made into the nature of older patients, presumably from loss of connective tissue the double vision (purely side-by-side versus partial ver- elasticity. Aponeurotic ptosis is also a frequent sequela of tical displacement of images), mode of onset, duration, eyelid swelling from infection or blunt trauma to the intermittency, diurnal variation, and associated neuro- orbit, cataract surgery, or hard contact lens usage. logic or systemic symptoms. If the patient has diplopia while being examined, motility testing should reveal a Myogenic Ptosis deficiency corresponding to the patient’s symptoms. However, subtle limitation of ocular excursions is often The causes of myogenic ptosis include myasthenia gravis difficult to detect. For example, a patient with a slight (Chap. 42) and a number of rare myopathies that mani- left abducens nerve paresis may appear to have full eye fest with ptosis. The term chronic progressive external oph- movements, despite a complaint of horizontal diplopia thalmoplegia refers to a spectrum of systemic diseases upon looking to the left. In this situation, the cover test caused by mutations of mitochondrial DNA. As the provides a more sensitive method for demonstrating the name implies, the most prominent findings are symmet- ocular misalignment. It should be conducted in primary ric, slowly progressive ptosis and limitation of eye move- gaze, and then with the head turned and tilted in each ments. In general, diplopia is a late symptom because all direction. In the above example, a cover test with the eye movements are reduced equally. In the Kearns-Sayre head turned to the right will maximize the fixation shift variant, retinal pigmentary changes and abnormalities of evoked by the cover test. cardiac conduction develop. Peripheral muscle biopsy shows characteristic “ragged-red fibers.” Oculopharyngeal Occasionally, a cover test performed in an asympto- dystrophy is a distinct autosomal dominant disease with matic patient during a routine examination will reveal onset in middle age, characterized by ptosis, limited eye an ocular deviation. If the eye movements are full and movements, and trouble swallowing. Myotonic dystrophy, the ocular misalignment is equal in all directions of gaze another autosomal dominant disorder, causes ptosis, (concomitant deviation), the diagnosis is strabismus. In ophthalmoparesis, cataract, and pigmentary retinopathy. this condition, which affects about 1% of the popula- Patients have muscle wasting, myotonia, frontal balding, tion, fusion is disrupted in infancy or early childhood. and cardiac abnormalities. To avoid diplopia, vision is suppressed from the nonfix- ating eye. In some children, this leads to impaired vision Neurogenic Ptosis (amblyopia, or “lazy” eye) in the deviated eye. This results from a lesion affecting the innervation to Binocular diplopia occurs from a wide range of either of the two muscles that open the eyelid: Müller’s processes: infectious, neoplastic, metabolic, degenerative, muscle or the levator palpebrae superioris. Examination inflammatory, and vascular. One must decide if the diplopia of the pupil helps to distinguish between these two pos- is neurogenic in origin or due to restriction of globe rota- sibilities. In Horner’s syndrome, the eye with ptosis has a tion by local disease in the orbit. Orbital pseudotumor, smaller pupil and the eye movements are full. In an ocu- myositis, infection, tumor, thyroid disease, and muscle lomotor nerve palsy, the eye with the ptosis has a larger, entrapment (e.g., from a blowout fracture) cause restrictive or a normal, pupil. If the pupil is normal but there is diplopia.The diagnosis of restriction is usually made by rec- ognizing other associated signs and symptoms of local orbital disease in conjunction with imaging.

Myasthenia Gravis to the red nucleus results in ipsilateral oculomotor palsy 189CHAPTER 17 Disorders of Vision and contralateral tremor, chorea, and athetosis. Claude’s (See Chap. 42) This is a major cause of diplopia. The syndrome incorporates features of both the aforemen- diplopia is often intermittent, variable, and not confined tioned syndromes, by injury to both the red nucleus and to any single ocular motor nerve distribution.The pupils the superior cerebellar peduncle. Finally, in Weber’s syn- are always normal. Fluctuating ptosis may be present. drome, injury to the cerebral peduncle causes ipsilateral Many patients have a purely ocular form of the disease, oculomotor palsy with contralateral hemiparesis. with no evidence of systemic muscular weakness. The diagnosis can be confirmed by an IV edrophonium In the subarachnoid space the oculomotor nerve is injection or by an assay for antiacetylcholine receptor vulnerable to aneurysm, meningitis, tumor, infarction, antibodies. Negative results from these tests do not and compression. In cerebral herniation the nerve exclude the diagnosis. Botulism from food or wound becomes trapped between the edge of the tentorium poisoning can mimic ocular myasthenia. and the uncus of the temporal lobe. Oculomotor palsy can also occur from midbrain torsion and hemorrhages After restrictive orbital disease and myasthenia gravis during herniation. In the cavernous sinus, oculomotor are excluded, a lesion of a cranial nerve supplying inner- palsy arises from carotid aneurysm, carotid cavernous fis- vation to the extraocular muscles is the most likely cause tula, cavernous sinus thrombosis, tumor (pituitary ade- of binocular diplopia. noma, meningioma, metastasis), herpes zoster infection, and the Tolosa-Hunt syndrome. Oculomotor Nerve The etiology of an isolated, pupil-sparing oculomotor The third cranial nerve innervates the medial, inferior, palsy often remains an enigma, even after neuroimaging and superior recti; inferior oblique; levator palpebrae and extensive laboratory testing. Most cases are thought superioris; and the iris sphincter. Total palsy of the ocu- to result from microvascular infarction of the nerve, lomotor nerve causes ptosis, a dilated pupil, and leaves somewhere along its course from the brainstem to the the eye “down and out” because of the unopposed orbit. Usually the patient complains of pain. Diabetes, action of the lateral rectus and superior oblique. This hypertension, and vascular disease are major risk factors. combination of findings is obvious. More challenging is Spontaneous recovery over a period of months is the the diagnosis of early or partial oculomotor nerve palsy. rule. If this fails to occur, or if new findings develop, the In this setting, any combination of ptosis, pupil dilation, diagnosis of microvascular oculomotor nerve palsy and weakness of the eye muscles supplied by the oculo- should be reconsidered. Aberrant regeneration is com- motor nerve may be encountered. Frequent serial exam- mon when the oculomotor nerve is injured by trauma or inations during the evolving phase of the palsy help compression (tumor, aneurysm). Miswiring of sprouting ensure that the diagnosis is not missed.The advent of an fibers to the levator muscle and the rectus muscles results oculomotor nerve palsy with a pupil involvement, espe- in elevation of the eyelid upon downgaze or adduction. cially when accompanied by pain, suggests a compressive The pupil also constricts upon attempted adduction, ele- lesion, such as a tumor or circle of Willis aneurysm. vation, or depression of the globe. Aberrant regeneration Neuroimaging should be obtained, along with a CT or is not seen after oculomotor palsy from microvascular MR angiogram. Occasionally, a catheter arteriogram must infarct and hence vitiates that diagnosis. be done to exclude an aneurysm. Trochlear Nerve A lesion of the oculomotor nucleus in the rostral midbrain produces signs that differ from those caused by The fourth cranial nerve originates in the midbrain, just a lesion of the nerve itself. There is bilateral ptosis caudal to the oculomotor nerve complex. Fibers exit the because the levator muscle is innervated by a single cen- brainstem dorsally and cross to innervate the contralat- tral subnucleus.There is also weakness of the contralateral eral superior oblique.The principal actions of this muscle superior rectus, because it is supplied by the oculomotor are to depress and to intort the globe. A palsy therefore nucleus on the other side. Occasionally both superior results in hypertropia and excyclotorsion. The cyclotor- recti are weak. Isolated nuclear oculomotor palsy is rare. sion is seldom noticed by patients. Instead, they complain Usually neurologic examination reveals additional signs to of vertical diplopia, especially upon reading or looking suggest brainstem damage from infarction, hemorrhage, down.The vertical diplopia is also exacerbated by tilting tumor, or infection. the head toward the side with the muscle palsy, and alle- viated by tilting it away.This “head tilt test” is a cardinal Injury to structures surrounding fascicles of the ocu- diagnostic feature. lomotor nerve descending through the midbrain has given rise to a number of classic eponymic designations. Isolated trochlear nerve palsy occurs from all the causes In Nothnagel’s syndrome, injury to the superior cerebellar listed above for the oculomotor nerve, except aneurysm. peduncle causes ipsilateral oculomotor palsy and con- The trochlear nerve is particularly apt to suffer injury tralateral cerebellar ataxia. In Benedikt’s syndrome, injury after closed head trauma.The free edge of the tentorium

SECTION II Clinical Manifestations of Neurologic Disease190 is thought to impinge upon the nerve during a concussive As mentioned above for isolated trochlear or oculomo- blow. Most isolated trochlear nerve palsies are idiopathic tor palsy, most cases are assumed to represent microvas- and hence diagnosed by exclusion as “microvascular.” cular infarcts because they often occur in the setting of Spontaneous improvement occurs over a period of diabetes or other vascular risk factors. Some cases may months in most patients. A base-down prism (conve- develop as a postinfectious mononeuritis (e.g., following niently applied to the patient’s glasses as a stick-on Fresnel a viral flu). Patching one eye or applying a temporary lens) may serve as a temporary measure to alleviate prism will provide relief of diplopia until the palsy diplopia. If the palsy does not resolve, the eyes can be resolves. If recovery is incomplete, eye muscle surgery can realigned by weakening the inferior oblique muscle. nearly always realign the eyes, at least in primary posi- tion. A patient with an abducens palsy that fails to Abducens Nerve improve should be reevaluated for an occult etiology (e.g., chordoma, carcinomatous meningitis, carotid cav- The sixth cranial nerve innervates the lateral rectus mus- ernous fistula, myasthenia gravis). cle. A palsy produces horizontal diplopia, worse on gaze to the side of the lesion. A nuclear lesion has different Multiple Ocular Motor Nerve Palsies consequences, because the abducens nucleus contains interneurons that project via the medial longitudinal fas- These should not be attributed to spontaneous ciculus to the medial rectus subnucleus of the contralat- microvascular events affecting more than one cranial eral oculomotor complex.Therefore, an abducens nuclear nerve at a time.This remarkable coincidence does occur, lesion produces a complete lateral gaze palsy, from weak- especially in diabetic patients, but the diagnosis is made ness of both the ipsilateral lateral rectus and the contralat- only in retrospect after exhausting all other diagnostic eral medial rectus. Foville’s syndrome following dorsal alternatives. Neuroimaging should focus on the cav- pontine injury includes lateral gaze palsy, ipsilateral facial ernous sinus, superior orbital fissure, and orbital apex, palsy, and contralateral hemiparesis incurred by damage to where all three ocular motor nerves are in close proxim- descending corticospinal fibers. Millard-Gubler syndrome ity. In the diabetic or compromised host, fungal infec- from ventral pontine injury is similar, except for the eye tion (Aspergillus, Mucorales, Cryptococcus) is a frequent findings. There is lateral rectus weakness only, instead of cause of multiple nerve palsies. In the patient with sys- gaze palsy, because the abducens fascicle is injured rather temic malignancy, carcinomatous meningitis is a likely than the nucleus. Infarct, tumor, hemorrhage, vascular diagnosis. Cytologic examination may be negative malformation, and multiple sclerosis are the most com- despite repeated sampling of the cerebrospinal fluid.The mon etiologies of brainstem abducens palsy. cancer-associated Lambert-Eaton myasthenic syndrome can also produce ophthalmoplegia. Giant cell (temporal) After leaving the ventral pons, the abducens nerve arteritis occasionally manifests as diplopia from ischemic runs forward along the clivus to pierce the dura at the palsies of extraocular muscles. Fisher syndrome, an ocu- petrous apex, where it enters the cavernous sinus.Along its lar variant of Guillain-Barré, produces ophthalmoplegia subarachnoid course it is susceptible to meningitis, tumor with areflexia and ataxia. Often the ataxia is mild, and (meningioma, chordoma, carcinomatous meningitis), sub- the reflexes are normal. Antiganglioside antibodies arachnoid hemorrhage, trauma, and compression by (GQ1b) can be detected in about 50% of cases. aneurysm or dolichoectatic vessels. At the petrous apex, mastoiditis can produce deafness, pain, and ipsilateral Supranuclear Disorders of Gaze abducens palsy (Gradenigo’s syndrome). In the cavernous sinus, the nerve can be affected by carotid aneurysm, These are often mistaken for multiple ocular motor carotid cavernous fistula, tumor (pituitary adenoma, nerve palsies. For example, Wernicke’s encephalopathy meningioma, nasopharyngeal carcinoma), herpes infec- can produce nystagmus and a partial deficit of horizon- tion, and Tolosa-Hunt syndrome. tal and vertical gaze that mimics a combined abducens and oculomotor nerve palsy. The disorder occurs in mal- Unilateral or bilateral abducens palsy is a classic sign nourished or alcoholic patients and can be reversed by of raised intracranial pressure.The diagnosis can be con- thiamine. Infarct, hemorrhage, tumor, multiple sclerosis, firmed if papilledema is observed on fundus examina- encephalitis, vasculitis, and Whipple’s disease are other tion. The mechanism is still debated but is probably important causes of supranuclear gaze palsy. Disorders of related to rostral-caudal displacement of the brainstem. vertical gaze, especially downwards saccades, are an early The same phenomenon accounts for abducens palsy from feature of progressive supranuclear palsy. Smooth pursuit low intracranial pressure (e.g., after lumbar puncture, is affected later in the course of the disease. Parkinson’s spinal anesthesia, or spontaneous dural cerebrospinal fluid disease, Huntington’s chorea, and olivopontocerebellar leak). degeneration can also affect vertical gaze. Treatment of abducens palsy is aimed at prompt correc- tion of the underlying cause. However, the cause remains obscure in many instances, despite diligent evaluation.

The frontal eye field of the cerebral cortex is involved 191 in generation of saccades to the contralateral side. After hemispheric stroke, the eyes usually deviate towards the CHAPTER 17 Disorders of Vision lesioned side because of the unopposed action of the frontal eye field in the normal hemisphere. With time, this deficit resolves. Seizures generally have the opposite effect: the eyes deviate conjugately away from the irrita- tive focus. Parietal lesions disrupt smooth pursuit of targets moving toward the side of the lesion. Bilateral parietal lesions produce Balint’s syndrome, characterized by impaired eye-hand coordination (optic ataxia), difficulty initiating voluntary eye movements (ocular apraxia), and visuospatial disorientation (simultanagnosia). Horizontal Gaze FIGURE 17-19 Left internuclear ophthalmoplegia (INO). A. In primary posi- Descending cortical inputs mediating horizontal gaze tion of gaze the eyes appear normal. B. Horizontal gaze to the ultimately converge at the level of the pons. Neurons in left is intact. C. On attempted horizontal gaze to the right, the the paramedian pontine reticular formation are respon- left eye fails to adduct. In mildly affected patients the eye may sible for controlling conjugate gaze toward the same adduct partially, or more slowly than normal. Nystagmus is side. They project directly to the ipsilateral abducens usually present in the abducted eye. D. T2-weighted axial MRI nucleus. A lesion of either the paramedian pontine retic- image through the pons showing a demyelinating plaque in ular formation or the abducens nucleus causes an ipsilat- the left medial longitudinal fasciculus (arrow). eral conjugate gaze palsy. Lesions at either locus produce nearly identical clinical syndromes, with the following exception: vestibular stimulation (oculocephalic maneu- ver or caloric irrigation) will succeed in driving the eyes conjugately to the side in a patient with a lesion of the paramedian pontine reticular formation, but not in a patient with a lesion of the abducens nucleus. Internuclear Ophthalmoplegia This results from damage to the medial longitudinal fas- ciculus ascending from the abducens nucleus in the pons to the oculomotor nucleus in the midbrain (hence, “internuclear”). Damage to fibers carrying the conju- gate signal from abducens interneurons to the contralat- eral medial rectus motoneurons results in a failure of adduction on attempted lateral gaze. For example, a patient with a left internuclear ophthalmoplegia will have slowed or absent adducting movements of the left eye (Fig. 17-19). A patient with bilateral injury to the medial longitudinal fasciculus will have bilateral inter- nuclear ophthalmoplegia. Multiple sclerosis is the most common cause, although tumor, stroke, trauma, or any brainstem process may be responsible. One-and-a-half syndrome is due to a combined lesion of the medial lon- gitudinal fasciculus and the abducens nucleus on the same side.The patient’s only horizontal eye movement is abduction of the eye on the other side. Vertical Gaze This is controlled at the level of the midbrain.The neu- ronal circuits affected in disorders of vertical gaze are not fully elucidated, but lesions of the rostral interstitial

SECTION II Clinical Manifestations of Neurologic Disease192 nucleus of the medial longitudinal fasciculus and the Gaze-Evoked Nystagmus interstitial nucleus of Cajal cause supranuclear paresis of This is the most common form of jerk nystagmus. upgaze, downgaze, or all vertical eye movements. Distal When the eyes are held eccentrically in the orbits, they basilar artery ischemia is the most common etiology. have a natural tendency to drift back to primary posi- Skew deviation refers to a vertical misalignment of the tion. The subject compensates by making a corrective eyes, usually constant in all positions of gaze.The finding saccade to maintain the deviated eye position. Many has poor localizing value because skew deviation has normal patients have mild gaze-evoked nystagmus. been reported after lesions in widespread regions of the Exaggerated gaze-evoked nystagmus can be induced by brainstem and cerebellum. drugs (sedatives, anticonvulsants, alcohol); muscle paresis; myasthenia gravis; demyelinating disease; and cerebello- Parinaud’s Syndrome pontine angle, brainstem, and cerebellar lesions. Also known as dorsal midbrain syndrome, this is a distinct supranuclear vertical gaze disorder from damage to the Vestibular Nystagmus posterior commissure. It is a classic sign of hydrocephalus Vestibular nystagmus results from dysfunction of the from aqueductal stenosis. Pineal region tumors, cysticer- labyrinth (Ménière’s disease), vestibular nerve, or cosis, and stroke also cause Parinaud’s syndrome. Features vestibular nucleus in the brainstem. Peripheral vestibular include loss of upgaze (and sometimes downgaze), con- nystagmus often occurs in discrete attacks, with symptoms vergence-retraction nystagmus on attempted upgaze, of nausea and vertigo. There may be associated tinnitus downwards ocular deviation (“setting sun” sign), lid retrac- and hearing loss. Sudden shifts in head position may tion (Collier’s sign), skew deviation, pseudoabducens provoke or exacerbate symptoms. palsy, and light-near dissociation of the pupils. Downbeat Nystagmus Nystagmus Downbeat nystagmus occurs from lesions near the cranio- cervical junction (Chiari malformation, basilar invagina- This is a rhythmical oscillation of the eyes, occurring tion). It has also been reported in brainstem or cerebellar physiologically from vestibular and optokinetic stimulation stroke, lithium or anticonvulsant intoxication, alcoholism, or pathologically in a wide variety of diseases (Chap. 9). and multiple sclerosis. Upbeat nystagmus is associated Abnormalities of the eyes or optic nerves, present at birth with damage to the pontine tegmentum, from stroke, or acquired in childhood, can produce a complex, demyelination, or tumor. searching nystagmus with irregular pendular (sinusoidal) and jerk features. This nystagmus is commonly referred Opsoclonus to as congenital sensory nystagmus. It is a poor term, because even in children with congenital lesions, the nystagmus This rare, dramatic disorder of eye movements consists does not appear until several months of age. Congenital of bursts of consecutive saccades (saccadomania). When motor nystagmus, which looks similar to congenital sensory the saccades are confined to the horizontal plane, the nystagmus, develops in the absence of any abnormality of term ocular flutter is preferred. It can occur from viral the sensory visual system.Visual acuity is also reduced in encephalitis, trauma, or a paraneoplastic effect of neu- congenital motor nystagmus, probably by the nystagmus roblastoma, breast carcinoma, and other malignancies. It itself, but seldom below a level of 20/200. has also been reported as a benign, transient phenomenon in otherwise healthy patients. Jerk Nystagmus This is characterized by a slow drift off the target, fol- FURTHER READINGS lowed by a fast corrective saccade. By convention, the nystagmus is named after the quick phase. Jerk nystag- ALBERT DM et al (eds): Albert and Jakobiec’s Principles and Practice of mus can be downbeat, upbeat, horizontal (left or right), Ophthalmology, 3d ed. Philadelphia, Saunders, 2007 and torsional. The pattern of nystagmus may vary with gaze position. Some patients will be oblivious to their D’AMICO DJ: Clinical practice: Primary Retinal Detachment. N Engl nystagmus. Others will complain of blurred vision, or a J Med 359:2346, 2008 subjective, to-and-fro movement of the environment (oscillopsia) corresponding to their nystagmus. Fine nys- ROSENFELD PJ et al: Ranibizumab for neovascular age-related macu- tagmus may be difficult to see upon gross examination lar degeneration. N Engl J Med 355:1419, 2006 of the eyes. Observation of nystagmoid movements of the optic disc on ophthalmoscopy is a sensitive way to RUTAR T et al: Ophthalmic manifestations of infections caused by detect subtle nystagmus. the USA300 clone of community-associated methicillin-resistant Staphylococcus aureus. Ophthalmology 113:1455, 2006 TING AY et al: Genetics of age-related macular degeneration. Curr Opin Ophthalmol 20:369, 2009

CHAPTER 18 DISORDERS OF SMELL, TASTE, AND HEARING Anil K. Lalwani ■ Smell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 ■ Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Physiology of Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Physiology of Smell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Genetic Causes of Hearing Loss . . . . . . . . . . . . . . . . . . . . . . 199 Disorders of the Sense of Smell . . . . . . . . . . . . . . . . . . . . . . 194 Disorders of the Sense of Hearing . . . . . . . . . . . . . . . . . . . . . 201 Laboratory Assessment of Hearing . . . . . . . . . . . . . . . . . . . . 204 ■ Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Physiology of Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Disorders of the Sense of Taste . . . . . . . . . . . . . . . . . . . . . . 197 SMELL to as an odorant. Each category of smell dysfunction can be further subclassified as total (applying to all odorants) The sense of smell determines the flavor and palatability or partial (dysfunction of only select odorants). of food and drink and serves, along with the trigeminal system, as a monitor of inhaled chemicals, including PHYSIOLOGY OF SMELL dangerous substances such as natural gas, smoke, and air pollutants. Olfactory dysfunction affects ~1% of individ- The olfactory epithelium is located in the superior part of uals younger than 60 years and more than one-half of the nasal cavities and is highly variable in its distribution the population beyond this age. between individuals. Over time the olfactory epithelium loses its homogeneity, as small areas undergo metaplasia DEFINITIONS producing islands of respiratory-like epithelium. This process is thought to be secondary to insults from envi- Smell is the perception of odor by the nose. Taste is the ronmental toxins, bacteria, and viruses.The primary sen- perception of salty, sweet, sour, or bitter by the tongue. sory neuron in the olfactory epithelium is the bipolar Related sensations during eating such as somatic sensa- cell.The dendritic process of the bipolar cell has a bulb- tions of coolness, warmth, and irritation are mediated shaped vesicle that projects into the mucous layer and through the trigeminal, glossopharyngeal, and vagal affer- bears six to eight cilia containing odorant receptors. On ents in the nose, oral cavity, tongue, pharynx, and larynx. average, each bipolar cell elaborates 56 cm2 (9 in.2) of Flavor is the complex interaction of taste, smell, and surface area to receive olfactory stimuli. These primary somatic sensation. Terms relating to disorders of smell sensory neurons are unique among sensory systems in include anosmia, an absence of the ability to smell; hypos- that they are short-lived, regularly replaced, and regener- mia, a decreased ability to smell; hyperosmia, an increased ate and establish new central connections after injury. sensitivity to an odorant; dysosmia, distortion in the per- Basal stem cells, located on the basal surface of the olfac- ception of an odor; phantosmia, perception of an odorant tory epithelium, are the progenitors that differentiate where none is present; and agnosia, inability to classify, into new bipolar cells (Fig. 18-1). contrast, or identify odor sensations verbally, even though Between 50 and 200 unmyelinated axons of receptor the ability to distinguish between odorants or to recog- cells form the fila of the olfactory nerve; they pass through nize them may be normal. An odor stimulus is referred the cribriform plate to terminate within spherical masses 193

194 Olfactory Olfactory bulb bulb Axons Olfactory Cribriform FIGURE 18-1 epithelium plate Olfaction. Olfactory sensory neurons (bipolar cells) are embedded in a small area of specialized SECTION II Clinical Manifestations of Neurologic Disease Olfactory epithelium in the dorsal posterior recess of the sensory nasal cavity. These neurons project axons to the neurons olfactory bulb of the brain, a small ovoid structure that rests on the cribriform plate of the ethmoid Dendrite bone. Odorants bind to specific receptors on olfac- tory cilia and initiate a cascade of action potential Mucous layer Cilia Basal events that lead to the production of action poten- cells tials in the sensory axons. of neuropil, termed glomeruli, in the olfactory bulb. acetylcholine receptors; and neurotransmitter receptors Olfactory ensheathing cells, which have features resem- for dopamine, serotonin, and substance P. In humans, bling glia of both the central and peripheral nervous sys- there are 300–1000 olfactory receptor genes belonging tems, surround the axons along their course. The to 20 different families located in clusters at >25 differ- glomeruli are the focus of a high degree of convergence ent chromosomal locations. Each olfactory neuron of information, since many more fibers enter than leave expresses only one or, at most, a few receptor genes, thus them. The main second-order neurons are mitral cells. providing the molecular basis of odor discrimination. The primary dendrite of each mitral cell extends into a Bipolar cells that express similar receptors appear to be single glomerulus. Axons of the mitral cells project along scattered across discrete spatial zones. These similar cells with the axons of adjacent tufted cells to the limbic sys- converge on a select few glomeruli in the olfactory tem, including the anterior olfactory nucleus and the bulb. The result is a potential spatial map of how we amygdala. Cognitive awareness of smell requires stimula- receive odor stimuli, much like the tonotopic organiza- tion of the prepiriform cortex or amygdaloid nuclei. tion of how we perceive sound. A secondary site of olfactory chemosensation is DISORDERS OF THE SENSE OF SMELL located in the epithelium of the vomeronasal organ, a tubular structure that opens on the ventral aspect of the These are caused by conditions that interfere with the nasal septum. In humans, this structure is rudimentary access of the odorant to the olfactory neuroepithelium and nonfunctional, without central projections. Sensory (transport loss), injure the receptor region (sensory loss), neurons located in the vomeronasal organ detect or damage central olfactory pathways (neural loss). Cur- pheromones, nonvolatile chemical signals that in lower rently no clinical tests exist to differentiate these differ- mammals trigger innate and stereotyped reproductive ent types of olfactory losses. Fortunately, the history of and social behaviors, as well as neuroendocrine changes. the disease provides important clues to the cause. The leading causes of olfactory disorders are summarized in The sensation of smell begins with introduction of an Table 18-1; the most common etiologies are head odorant to the cilia of the bipolar neuron. Most odor- trauma in children and young adults, and viral infections ants are hydrophobic; as they move from the air phase of in older adults. the nasal cavity to the aqueous phase of the olfactory mucous, they are transported toward the cilia by small Head trauma is followed by unilateral or bilateral water-soluble proteins called odorant-binding proteins and impairment of smell in up to 15% of cases; anosmia is reversibly bind to receptors on the cilia surface. Binding more common than hyposmia. Olfactory dysfunction is leads to conformational changes in the receptor protein, more common when trauma is associated with loss of activation of G protein–coupled second messengers, and consciousness, moderately severe head injury (grades generation of action potentials in the primary neurons. II–V), and skull fracture. Frontal injuries and fractures Intensity appears to be coded by the amount of firing in disrupt the cribriform plate and olfactory axons that the afferent neurons. perforate it. Sometimes there is an associated cere- brospinal fluid (CSF) rhinorrhea resulting from a tearing Olfactory receptor proteins belong to the large family of the dura overlying the cribriform plate and paranasal of G protein–coupled receptors that also includes rhodopsins; α- and β-adrenergic receptors; muscarinic

TABLE 18-1 disease, amyotrophic lateral sclerosis, and multiple sclerosis. 195 In Alzheimer’s and Parkinson’s, olfactory loss may be the CAUSES OF OLFACTORY DYSFUNCTION first clinical sign of the disease. In Parkinson’s disease, bilat- eral olfactory deficits occur more commonly than the car- Transport Losses Neural Losses dinal signs of the disorder such as tremor. In multiple scle- CHAPTER 18 Disorders of Smell, Taste, and Hearing Allergic rhinitis AIDS rosis, olfactory loss is related to lesions visible by MRI, in Bacterial rhinitis and sinusitis Alcoholism olfactory processing areas in the temporal and frontal lobes. Congenital abnormalities Alzheimer’s disease Nasal neoplasms Cigarette smoke Dysosmia, subjective distortions of olfactory percep- Nasal polyps Depression tion, may occur with intranasal diseases that partially Nasal septal deviation Diabetes mellitus impair smell or during recovery from a neurogenic Nasal surgery Drugs/toxins anosmia. Most dysosmic disorders consist of disagreeable Viral infections Huntington’s chorea odors, sometimes accompanied by distortions of taste. Hypothyroidism Dysosmia also can occur with depression. Sensory Losses Kallmann syndrome Drugs Malnutrition Approach to the Patient: Neoplasms Neoplasms DISORDERS OF THE SENSE OF SMELL Radiation therapy Neurosurgery Toxin exposure Parkinson’s disease Unilateral anosmia is rarely a complaint and is only Viral infections Trauma recognized by testing of smell in each nasal cavity sepa- Vitamin B12 deficiency rately. Bilateral anosmia, on the other hand, brings Zinc deficiency patients to medical attention. Anosmic patients usually complain of a loss of the sense of taste even though sinuses. Anosmia may also follow blows to the occiput. their taste thresholds may be within normal limits. In Once traumatic anosmia develops, it is usually perma- actuality, they are complaining of a loss of flavor detec- nent; only 10% of patients ever improve or recover. Per- tion, which is mainly an olfactory function.The physi- version of the sense of smell may occur as a transient cal examination should include a thorough inspection phase in the recovery process. of the ears, upper respiratory tract, and head and neck. A neurologic examination emphasizing the cranial Viral infections can destroy the olfactory neuroep- nerves and cerebellar and sensorimotor function is ithelium, which is then replaced by respiratory epithe- essential.Any signs of depression should be noted. lium. Parainfluenza virus type 3 appears to be especially detrimental to human olfaction. HIV infection is associ- Sensory olfactory function can be assessed by sev- ated with subjective distortion of taste and smell, which eral methods.The Odor Stix test uses a commercially may become more severe as the disease progresses. The available odor-producing magic marker–like pen held loss of taste and smell may play an important role in the ~8–15 cm (3–6 in.) from the patient’s nose. The development and progression of HIV-associated wasting. 30-cm alcohol test uses a freshly opened isopropyl Congenital anosmias are rare but important. Kallmann alcohol packet held ~30 cm (12 in.) from the patient’s syndrome is an X-linked disorder characterized by con- nose. There is a commercially available scratch-and- genital anosmia and hypogonadotropic hypogonadism sniff card containing three odors available for gross resulting from a failure of migration from the olfactory testing of olfaction. A superior test is the University placode of olfactory receptor neurons and neurons syn- of Pennsylvania Smell Identification Test (UPSIT). thesizing gonadotropin-releasing hormone. Anosmia can This consists of a 40-item, forced choice, scratch-and- also occur in albinos. The receptor cells are present but sniff paradigm. For example, one of the items reads, are hypoplastic, lack cilia, and do not project above the “This odor smells most like (a) chocolate, (b) banana, surrounding supporting cells. (c) onion, or (d) fruit punch.”The test is highly reliable, is sensitive to age and sex differences, and provides an Meningiomas of the inferior frontal region are the most accurate quantitative determination of the olfactory frequent neoplastic cause of anosmia; loss of smell may be deficit.The UPSIT, which is a forced-choice test, can the only neurologic abnormality. Rarely, anosmia can occur also be used to identify malingerers who typically with gliomas of the frontal lobe. Occasionally, pituitary ade- report fewer correct responses than would be nomas, craniopharyngiomas, suprasellar meningiomas, and expected by chance.The average score for total anos- aneurysms of the anterior part of the circle of Willis mics is slightly higher than that expected on the basis extend forward and damage olfactory structures. These of chance because of the inclusion of some odorants tumors and hamartomas may also induce seizures with that act by trigeminal stimulation. olfactory hallucinations, indicating involvement of the uncus of the temporal lobe. Olfactory dysfunction is common in a variety of neuro- logic diseases, including Alzheimer’s disease, Parkinson’s

SECTION II Clinical Manifestations of Neurologic Disease196 Olfactory threshold testing is another method of In addition, early recognition and counseling can help assessing olfactory function. Following assessment of patients to compensate for the loss of smell. The inci- sensory olfactory function, the detection threshold dence of natural gas–related accidents is disproportion- for an odorant such as methyl ethyl carbinol is estab- ately high in the elderly, perhaps due in part to the lished using graduated concentrations for each side of gradual loss of smell. Mercaptan, the pungent odor in the nose. Nasal resistance can also be measured with natural gas, is an olfactory stimulant that does not acti- anterior rhinomanometry for each side of the nose. vate taste receptors. Many elderly with olfactory dys- CT or MRI of the head is required to rule out function experience a decrease in flavor sensation and paranasal sinusitis; neoplasms of the anterior cranial find it necessary to hyperflavor food, usually by increas- fossa, nasal cavity, or paranasal sinuses; or unsuspected ing the amount of salt in their diet. fractures of the anterior cranial fossa. Bone abnormal- ities are best seen with CT. MRI is the most sensitive TASTE method to visualize olfactory bulbs, ventricles, and other soft tissue of the brain. Coronal CT is optimal Compared with disorders of smell, gustatory disorders for assessing cribriform plate, anterior cranial fossa, are uncommon. Loss of olfactory sensitivity is often and sinus anatomy. accompanied by complaints of loss of the sense of taste, Biopsy of the olfactory epithelium is possible. usually with normal detection thresholds for taste. However, given the widespread degeneration of the olfactory epithelium and intercalation of respiratory DEFINITIONS epithelium in the olfactory area of adults with no apparent olfactory dysfunction, biopsy results must be Disturbances of the sense of taste may be categorized as interpreted with caution. total ageusia, total absence of gustatory function or inability to detect the qualities of sweet, salt, bitter, or Treatment: sour; partial ageusia, ability to detect some but not all of DISORDERS OF THE SENSE OF SMELL the qualitative gustatory sensations; specific ageusia, inabil- ity to detect the taste quality of certain substances; total Therapy for patients with transport olfactory losses due hypogeusia, decreased sensitivity to all tastants; partial to allergic rhinitis, bacterial rhinitis and sinusitis, polyps, hypogeusia, decreased sensitivity to some tastants; and dys- neoplasms, and structural abnormalities of the nasal geusia or phantogeusia, distortion in the perception of a cavities can be undertaken with a high likelihood for tastant, i.e., the perception of the wrong quality when a improvement. Allergy management; antibiotic therapy; tastant is presented or the perception of a taste when topical and systemic glucocorticoid therapy; and there has been no tastant ingested. Confusion between surgery for nasal polyps, deviation of the nasal septum, sour and bitter, and less commonly between salty and and chronic hyperplastic sinusitis are frequently effec- bitter, may represent a semantic misunderstanding or tive in restoring the sense of smell. have a true pathophysiologic basis. It may be possible to differentiate between the loss of flavor recognition in There is no proven treatment for sensorineural olfac- patients with olfactory losses who complain of a loss of tory losses. Fortunately, spontaneous recovery often taste as well as smell by asking if they are able to taste occurs. Zinc and vitamin therapy (especially with vita- sweetness in sodas, saltiness in potato chips, etc. min A) are advocated by some. Profound zinc deficiency can produce loss and distortion of the sense of smell PHYSIOLOGY OF TASTE but is not a clinically important problem except in very limited geographic areas. The epithelial degeneration The taste receptor cells are located in the taste buds, associated with vitamin A deficiency can cause anos- spherical groups of cells arranged in a pattern resem- mia, but in western societies the prevalence of vitamin bling the segments of a citrus fruit (Fig. 18-2). At the A deficiency is low. Exposure to cigarette smoke and surface, the taste bud has a pore into which microvilli of other airborne toxic chemicals can cause metaplasia of the receptor cells project. Unlike the olfactory system, the olfactory epithelium, and spontaneous recovery can the receptor cell is not the primary neuron. Instead, gus- occur if the insult is removed. Counseling of patients is tatory afferent nerve fibers contact individual taste therefore helpful in such cases. receptor cells. The papillae lie along the lateral margin and dorsum of the tongue; at the junction of the dor- More than one-half of people older than 60 years suf- sum and the base of the tongue; and in the palate, fer from olfactory dysfunction. No effective treatment epiglottis, larynx, and esophagus. exists for presbyosmia, but patients are often reassured to learn that this problem is common in their age group.

Chorda tympani Tastants gain access to the receptor cells through the 197 nerve (VII) taste pore. Four classes of taste have been traditionally recognized: sweet, salt, sour, and bitter, and more Glossopharyngeal recently “umami” (monosodium glutamate, disodium nerve (IX) gluanylate, disodium inosinate). Tastants enter the taste pore in a solution and initiate transduction by either Circumvallate activating receptors coupled to G-proteins or by directly CHAPTER 18 Disorders of Smell, Taste, and Hearing activating ion channels on the microvillae within the Serous taste bud. Individual gustatory afferent fibers almost gland always respond to a number of different chemicals. As with olfaction and other sensory systems, intensity Foliate appears to be encoded by the quantity of neural activity. Taste The sense of taste is mediated through the facial, bud glossopharyngeal, and vagal nerves. The chorda tympani A B Fungiform branch of the facial nerve subserves taste from the ante- rior two-thirds of the tongue.The posterior third of the Taste pore tongue is supplied by the lingual branch of the glos- sopharyngeal nerve. Afferents from the palate travel with Epithelial cell the greater superficial petrosal nerve to the geniculate Taste cell ganglion and then via the facial nerve to the brainstem. The internal branch of the superior laryngeal nerve of Basal cell the vagus nerve contains the taste afferents from the lar- ynx, including the epiglottis and esophagus. Gustatory afferent The central connections of the nerves terminate in To sensory nerve the brainstem in the nucleus of the tractus solitarius.The central pathway from the nucleus of the tractus solitarius C ganglion projects to the ipsilateral parabrachial nuclei of the pons. Two divergent pathways project from the parabrachial FIGURE 18-2 nuclei. One ascends to the gustatory relay in the dorsal Taste. A. The taste buds of the anterior two-thirds of the thalamus, synapses, and continues to the cortex of the tongue are innervated by the gustatory fibers that travel in a insula. There is also evidence for a direct pathway from branch of the facial nerve (VII) called the chorda tympani. The the parabrachial nuclei to the cortex. (Olfaction and taste buds of the posterior third of the tongue are innervated gustation appear to be unique among sensory systems in by gustatory fibers that travel in the lingual branch of the that at least some fibers bypass the thalamus.) The other glossopharyngeal nerve (IX). [Adapted from ER Kandel et al pathway from the parabrachial nuclei goes to the ventral (eds): Principles of Neural Science, 4th ed., New York, forebrain, including the lateral hypothalamus, substantia McGraw-Hill, 2000; with permission.] B. The main types of innominata, central nucleus of the amygdala, and the taste papillae are shown in schematic cross sections. Each stria terminalis. type predominates in specific areas of the tongue, as indi- cated by the arrows from A. C. Each taste bud contains DISORDERS OF THE SENSE OF TASTE 50–150 taste cells that extend from the base of the taste bud to the taste pore, where the apical microvilli of taste cells Disorders of the sense of taste are caused by conditions have contact with tastants dissolved in saliva and taste pore that interfere with the access of the tastant to the recep- mucus. Access of tastants to the basolateral regions of these tor cells in the taste bud (transport loss), injure receptor cells is generally prevented by tight junctions between taste cells (sensory loss), or damage gustatory afferent nerves cells. Taste cells are short-lived cells that are replaced from and central gustatory pathways (neural loss) (Table 18-2). stem cells at the base of the taste bud. Three types of taste Transport gustatory losses result from xerostomia due to cells in each taste bud (light cells, dark cells, and intermedi- many causes, including Sjögren’s syndrome, radiation ate cells) may represent different stages of differentiation or therapy, heavy-metal intoxication, and bacterial coloniza- different cell lineages. Taste stimuli, detected at the apical tion of the taste pore. Sensory gustatory losses are caused by end of the taste cell, induce action potentials that cause the inflammatory and degenerative diseases in the oral cavity; release of neurotransmitter at synapses formed at the base a vast number of drugs, particularly those that interfere of the taste cell with gustatory fibers that transmit signals to with cell turnover such as antithyroid and antineoplastic the brain. agents; radiation therapy to the oral cavity and pharynx; viral infections; endocrine disorders; neoplasms; and aging. Neural gustatory losses occur with neoplasms, trauma, and

198 TABLE 18-2 Approach to the Patient: DISORDERS OF THE SENSE OF TASTE CAUSES OF GUSTATORY DYSFUNCTION Patients who complain of loss of taste should be eval- SECTION II Clinical Manifestations of Neurologic Disease Transport Gustatory Losses Neural Gustatory Losses uated for both gustatory and olfactory function. Clin- Drugs Diabetes mellitus ical assessment of taste is not as well developed or Heavy-metal intoxication Hypothyroidism standardized as that of smell. The first step is to per- Radiation therapy Oral neoplasms form suprathreshold whole-mouth taste testing for Sjögren’s syndrome Oral surgery quality, intensity, and pleasantness perception of four Xerostomia Radiation therapy taste qualities: sweet, salty, sour, and bitter. Most com- Sensory Gustatory Losses Renal disease monly used reagents for taste testing are sucrose, citric Aging Stroke and other CNS acid or hydrochloric acid, caffeine or quinine (sulfate Candidiasis or hydrochloride), and sodium chloride. The taste Drugs (antithyroid and disorders stimuli should be freshly prepared and have similar antineoplastic) Trauma viscosity. For quantification, detection thresholds are Endocrine disorders Upper respiratory tract obtained by applying graduated dilutions to the Oral neoplasms tongue quadrants or by whole-mouth sips. Electric Pemphigus infections taste testing (electrogustometry) is used clinically to Radiation therapy identify taste deficits in specific quadrants of the Viral infections (especially tongue. Regional gustatory testing may also be per- with herpes viruses) formed to assess for the possibility of loss localized to one or several receptor fields as a result of a periph- surgical procedures in which the gustatory afferents are eral or central lesion. The history of the disease and injured.Taste buds degenerate when their gustatory affer- localization studies provide important clues to the ents are transected but remain when their somatosensory causes of the taste disturbance. For example, absence afferents are severed. Patients with renal disease have of taste on the anterior two-thirds of the tongue asso- increased thresholds for sweet and sour tastes, which ciated with a facial paralysis indicates that the lesion is resolves with dialysis. proximal to the juncture of the chorda tympani branch with the facial nerve in the mastoid. A side effect of medication is the single most com- mon cause of taste dysfunction in clinical practice. Treatment: Xerostomia, regardless of the etiology, can be associated DISORDERS OF THE SENSE OF TASTE with taste dysfunction. It is associated with poor oral clearance and poor dental hygiene and can adversely Treatment of gustatory disorders is limited. No effective affect the oral mucosa, all leading to dysgeusia. However, therapies exist for the sensorineural disorders of taste. severe salivary gland failure does not necessarily lead to Altered taste due to surgical stretch injury of the chorda taste complaints. Xerostomia, the use of antibiotics or tympani nerve usually improves within 3–4 months, glucocorticoids, or immunodeficiency can lead to over- while dysfunction is usually permanent with transection growth of Candida; overgrowth alone, without thrush or of the nerve. Taste dysfunction following trauma may overt signs of infection, can be associated with bad taste resolve spontaneously without intervention and is more or hypogeusia. When taste dysfunction occurs in a likely to do so than posttraumatic smell dysfunction. patient at risk for fungal overgrowth, a trial of nystatin Idiopathic alterations of taste sensitivity usually remain or other antifungal medication is warranted. stable or worsen; zinc and vitamin therapy are of unproven value. Directed therapy to address factors that Upper respiratory infections and head trauma can affect taste perception can be of value. Xerostomia can lead to both smell and taste dysfunction; taste is more be treated with artificial saliva, providing some benefit likely to improve than smell. The mechanism of taste to patients with a disturbed salivary milieu. Oral pilo- disturbance in these situations is not well understood. carpine may be beneficial for a variety of forms of xeros- Trauma to the chorda tympani branch of the facial tomia. Appropriate treatment of bacterial and fungal nerve during middle ear surgery or third molar extrac- infections of the oral cavity can be of great help in tions is relatively common and can cause dysgeusia. improving taste function. Taste disturbance related to Bilateral chorda tympani injuries are usually associated drugs can often be resolved by changing the prescribed with hypogeusia, whereas unilateral lesions produce only medication. limited symptoms. As noted above, aging itself may be associated with reduced taste sensitivity. The taste dysfunction may be limited to a single compound and may be mild.

HEARING mechanoreceptors.The afferent innervation relates prin- 199 CHAPTER 18 Disorders of Smell, Taste, and Hearing cipally to the inner hair cells, and the efferent innerva- Hearing loss is one of the most common sensory disor- tion relates principally to outer hair cells. The motility ders in humans and can present at any age. Nearly 10% of the outer hair cells alters the micromechanics of the of the adult population has some hearing loss, and one- inner hair cells, creating a cochlear amplifier, which third of individuals >65 years have a hearing loss of suf- explains the exquisite sensitivity and frequency selectiv- ficient magnitude to require a hearing aid. ity of the cochlea. PHYSIOLOGY OF HEARING Beginning in the cochlea, the frequency specificity is maintained at each point of the central auditory pathway: (Fig. 18-3) The function of the external and middle ear dorsal and ventral cochlear nuclei, trapezoid body, superior is to amplify sound to facilitate mechanotransduction by olivary complex, lateral lemniscus, inferior colliculus, hair cells in the inner ear. Sound waves enter the exter- medial geniculate body, and auditory cortex. At low fre- nal auditory canal and set the tympanic membrane in quencies, individual auditory nerve fibers can respond motion, which in turn moves the malleus, incus, and more or less synchronously with the stimulating tone. At stapes of the middle ear. Movement of the footplate of higher frequencies, phase-locking occurs so that neurons the stapes causes pressure changes in the fluid-filled alternate in response to particular phases of the cycle of the inner ear eliciting a traveling wave in the basilar mem- sound wave. Intensity is encoded by the amount of neural brane of the cochlea. The tympanic membrane and the activity in individual neurons, the number of neurons that ossicular chain in the middle ear serve as an impedance- are active, and the specific neurons that are activated. matching mechanism, improving the efficiency of energy transfer from air to the fluid-filled inner ear. GENETIC CAUSES OF HEARING LOSS Stereocilia of the hair cells of the organ of Corti, More than half of childhood hearing impairment is which rests on the basilar membrane, are in contact with thought to be hereditary; hereditary hearing impair- the tectorial membrane and are deformed by the travel- ment (HHI) can also manifest later in life. HHI may ing wave. A point of maximal displacement of the basilar be classified as either nonsyndromic, when hearing loss is membrane is determined by the frequency of the stimu- the only clinical abnormality, or syndromic, when hearing lating tone. High-frequency tones cause maximal dis- loss is associated with anomalies in other organ systems. placement of the basilar membrane near the base of the Nearly two-thirds of HHIs are nonsyndromic, and the cochlea. As the frequency of the stimulating tone remaining one-third are syndromic. Between 70 and 80% decreases, the point of maximal displacement moves of nonsyndromic HHI is inherited in an autosomal reces- toward the apex of the cochlea. sive manner and designated DFNB; another 15–20% is autosomal dominant (DFNA). Less than 5% is X-linked or The inner and outer hair cells of the organ of maternally inherited via the mitochondria. Corti have different innervation patterns, but both are External acoustic Middle ear Semicircular Anterior Bony labyrinth meatus canals (contains perilymph) Stapes Auricle or Incus Semicircular canals Inner Posterior Membranous labyrinth pinna Malleus ear Lateral (contains endolymph) Cochlea Vestibulocochlear Ampulla of nerve semicircular canal Utricle Saccule Cochlea External Tympanic Vestibule Oval acoustic membrane B window canal Eustachian tube Round window Lobe Cochlear duct A External ear FIGURE 18-3 and inner ear demonstrated. B. High-resolution view of Ear anatomy. A. Drawing of modified coronal section through inner ear. external ear and temporal bone, with structures of the middle

200 Nearly 100 loci harboring genes for nonsyndromic factors (POU3F4, POU4F3), ion channels (KCNQ4, HHI have been mapped, with equal numbers of domi- SLC26A4), and gap junction proteins (GJB2, GJB3, GJB6). Several of these genes, including connexin 26 nant and recessive modes of inheritance; numerous genes (GJB2),TECTA, and TMC1, cause both autosomal dom- inant and recessive forms of nonsyndromic HHI. In gen- have now been cloned (Table 18-3). The hearing genes eral, the hearing loss associated with dominant genes has fall into the categories of structural proteins (MYH9, MYO7A, MYO15, TECTA, DIAPH1), transcription SECTION II Clinical Manifestations of Neurologic Disease TABLE 18-3 HEREDITARY HEARING IMPAIRMENT GENES DESIGNATION GENE FUNCTION Autosomal Dominant CRYM Thyroid hormone binding protein DIAPH1 Cytoskeletal protein DFNA1 GJB3 (Cx31) Gap junctions DFNA2 KCNQ4 Potassium channel DFNA2 GJB2 (Cx26) Gap junctions DFNA3 GJB6 (Cx30) Gap junctions DFNA3 MYH14 Class II nonmuscle myosin DFNA4 DFNA5 Unknown DFNA5 WFS Transmembrane protein DFNA6/14/38 TECTA Tectorial membrane protein DFNA8/12 COCH Unknown DFNA9 EYA4 Developmental gene DFNA10 MYO7A Cytoskeletal protein DFNA11 COL11A2 Cytoskeletal protein DFNA13 POU4F3 Transcription factor DFNA15 MYH9 Cytoskeletal protein DFNA17 ACTG1 Cytoskeletal protein DFNA20/26 MYO6 Unconventional myosin DFNA22 TFCP2L3 Transcription factor DFNA28 TMC1 Transmembrane protein DFNA36 MYO1A Unconventional myosin DFNA48 SLC26A5 (Prestin) Motor protein Autosomal Recessive GJB2 (CX26) Gap junction GJB6(CX30) Gap junction DFNB1 MYO7A Cytoskeletal protein MYO15 Cytoskeletal protein DFNB2 PDS(SLC26A4) Chloride/iodide transporter DFNB3 TMIE Transmembrane protein DFNB4 TMC1 Transmembrane protein DFNB6 OTOF Trafficking of membrane vesicles DFNB7/B11 TMPRSS3 Transmembrane serine protease DFNB9 CDH23 Intercellular adherence protein DFNB8/10 STRC Stereocilia protein DFNB12 USH1C Unknown DFNB16 TECTA Tectorial membrane protein DFNB18 OTOA Gel attachement to nonsensory cell DFNB21 PCDH15 Morphogenesis and cohesion DFNB22 TRIOBP Cytoskeletal-organizing protein DFNB23 CLDN14 Tight junctions DFNB28 MYO3A Hybrid motor-signaling myosin DFNB29 WHRN PDZ domain–containing protein DFNB30 ESPN Ca-insensitive actin-bundling protein DFNB31 MYO6 Unconventional myosin DFNB36 TMHS Unknown function; tetraspan protein DFNB37 DFNB67

its onset in adolescence or adulthood and varies in sever- syndrome (prolonged QT interval and hearing loss), 201 CHAPTER 18 Disorders of Smell, Taste, and Hearing ity, whereas the hearing loss associated with recessive neurofibromatosis type 2 (bilateral acoustic schwan- inheritance is congenital and profound. Connexin 26 is noma), and mitochondrial disorders [mitochondrial particularly important because it is associated with nearly encephalopathy, lactic acidosis, and stroke-like episodes 20% of cases of childhood deafness. Two frame-shift (MELAS); myoclonic epilepsy and ragged red fibers mutations, 35delG and 167delT, account for >50% of the (MERRF); progressive external ophthalmoplegia (PEO)] cases; however, screening for these two mutations alone is (Table 18-4). insufficient to diagnose GJB2-related recessive deafness. The 167delT mutation is highly prevalent in Ashkenazi DISORDERS OF THE SENSE OF HEARING Jews; ~1 in 1765 individuals in this population are homozygous and affected.The hearing loss can also vary Hearing loss can result from disorders of the auricle, among the members of the same family, suggesting that external auditory canal, middle ear, inner ear, or central other genes or factors influence the auditory phenotype. auditory pathways (Fig. 18-4). In general, lesions in the auricle, external auditory canal, or middle ear cause conductive The contribution of genetics to presbycusis (see hearing losses, whereas lesions in the inner ear or eighth nerve later) is also becoming better understood. In addition to cause sensorineural hearing losses. GJB2, several other nonsyndromic genes are associated with hearing loss that progresses with age. Sensitivity to Conductive Hearing Loss aminoglycoside ototoxicity can be maternally transmit- ted through a mitochondrial mutation. Susceptibility to This results from obstruction of the external auditory noise-induced hearing loss may also be genetically canal by cerumen, debris, and foreign bodies; swelling of determined. the lining of the canal; atresia or neoplasms of the canal; perforations of the tympanic membrane; disruption of There are >400 syndromic forms of hearing loss. the ossicular chain, as occurs with necrosis of the long These include Usher syndrome (retinitis pigmentosa and process of the incus in trauma or infection; otosclerosis; hearing loss),Waardenburg syndrome (pigmentary abnor- or fluid, scarring, or neoplasms in the middle ear. Rarely, mality and hearing loss), Pendred syndrome (thyroid organification defect and hearing loss), Alport syndrome (renal disease and hearing loss), Jervell and Lange-Nielsen TABLE 18-4 SYNDROMIC HEREDITARY HEARING IMPAIRMENT GENES SYNDROME GENE FUNCTION Alport syndrome BOR syndrome COL4A3-5 Cytoskeletal protein Jervell and Lange-Nielsen EYA1 Developmental gene SIX1 Developmental gene syndrome KVLQT1 Delayed rectifier K+ channel Norrie disease KCNE1 Delayed rectifier K+ channel Pendred syndrome Norrin Cell-cell interactions Treacher Collins SLC26A4 Chloride/iodide transporter Usher syndrome TCOF1 Nucleolar-cytoplasmic transport MYO7A Cytoskeletal protein WS type I, III USH1C Unknown WS type II CDH23 Intercellular adherence protein WS type IV PCDH15 Cell adhesion molecule SANS Harmonin associated protein USH2A Cell adhesion molecule VLGR1 G protein–coupled receptor USH3 Unknown PAX3 Transcription factor MITF Transcription factor SLUG Transcription factor EDNRB Endothelin-B receptor EDN3 Endothelin-B receptor ligand SOX10 Transcription factor Note: BOR, branchio-oto-renal syndrome; WS, Waardenburg syndrome.

202 Hearing Loss History Cerumen impaction abnormal normal TM perforation Otologic examination Cholesteatoma Pure tone and SOM speech audiometry AOM External auditory canal atresia/ stenosis Eustachian tube dysfunction Tympanosclerosis SECTION II Clinical Manifestations of Neurologic Disease Conductive HL Mixed HL SNHL Impedence audiometry Impedence audiometry Acute Chronic Asymmetric/symmetric normal abnormal normal abnormal Otosclerosis AOM Stapes gusher AOM CNS infection† Asymmetric Symmetric Cerumen SOM syndrome* TM perforation* Tumors† MRI/BAER TM perforation* Cholesteatoma* Inner ear impaction Eustachian tube Inner ear Temporal bone Cerebellopontine malformation* Ossicular malformation* angle dysfunction trauma* Presbycusis fixation Cerumen Otosclerosis Middle ear tumors* CNS Noise exposure Cholesteatoma* Temporal bone Stroke† Radiation therapy Temporal bone impaction glomus Trauma* Cholesteatoma* trauma* tympanicum trauma* Temporal bone glomus jugulare trauma* Ossicular normal abnormal discontinuity* Endolymphatic hydrops Labyrinthitis* Middle ear tumor* Labyrinthitis* Inner ear malformations* Perilymphatic fistula* Cerebellopontine angle tumors Radiation therapy Arachnoid cyst; facial nerve tumor; lipoma; meningioma; vestibular schwannoma Multiple sclerosis† FIGURE 18-4 membrane; SOM, serous otitis media; AOM, acute otitis An algorithm for the approach to hearing loss. HL, hear- media; *, CT scan of temporal bone; †, MRI scan. ing loss; SNHL, sensorineural hearing loss; TM, tympanic inner-ear malformations may present as conductive impairment usually presents between the late teens to hearing loss beginning in adulthood. the forties. In women, the otosclerotic process is acceler- ated during pregnancy, and the hearing loss is often first Cholesteatoma, stratified squamous epithelium in the noticeable at this time. A hearing aid or a simple outpa- middle ear or mastoid, occurs frequently in adults.This is tient surgical procedure (stapedectomy) can provide ade- a benign, slowly growing lesion that destroys bone and quate auditory rehabilitation. Extension of otosclerosis normal ear tissue. Theories of pathogenesis include trau- beyond the stapes footplate to involve the cochlea matic implantation and invasion, immigration and inva- (cochlear otosclerosis) can lead to mixed or sensorineural sion through a perforation, and metaplasia following hearing loss. Fluoride therapy to prevent hearing loss chronic infection and irritation. On examination, there is from cochlear otosclerosis is of uncertain value. often a perforation of the tympanic membrane filled with cheesy white squamous debris. A chronically draining ear Eustachian tube dysfunction is extremely common in that fails to respond to appropriate antibiotic therapy adults and may predispose to acute otitis media (AOM) should raise suspicion of a cholesteatoma. Conductive or serous otitis media (SOM). Trauma, AOM, or chronic hearing loss secondary to ossicular erosion is common. otitis media are the usual factors responsible for tympanic Surgery is required to remove this destructive process. membrane perforation. While small perforations often heal spontaneously, larger defects usually require surgical Conductive hearing loss with a normal ear canal and intervention.Tympanoplasty is highly effective (>90%) in intact tympanic membrane suggests ossicular pathology. the repair of tympanic membrane perforations. Otoscopy Fixation of the stapes from otosclerosis is a common cause is usually sufficient to diagnose AOM, SOM, chronic of low-frequency conductive hearing loss. It occurs equally otitis media, cerumen impaction, tympanic membrane in men and women and is inherited as an autosomal perforation, and eustachian tube dysfunction. dominant trait with incomplete penetrance. Hearing

Sensorineural Hearing Loss Unfortunately, there is no effective therapy for hearing 203 CHAPTER 18 Disorders of Smell, Taste, and Hearing loss, tinnitus, or aural fullness from Ménière’s disease. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs Sensorineural hearing loss may also result from any (e.g., salicylates, quinine and its synthetic analogues, neoplastic, vascular, demyelinating, infectious, or degen- aminoglycoside antibiotics, loop diuretics such as erative disease or trauma affecting the central auditory furosemide and ethacrynic acid, and cancer chemothera- pathways. HIV leads to both peripheral and central peutic agents such as cisplatin), fractures of the temporal auditory system pathology and is associated with sen- bone, meningitis, cochlear otosclerosis (see earlier), sorineural hearing impairment. Ménière’s disease, and aging. Congenital malformations of the inner ear may be the cause of hearing loss in A finding of conductive and sensory hearing loss in some adults. Genetic predisposition alone or in concert combination is termed mixed hearing loss. Mixed hearing with environmental exposures may also be responsible. losses are due to pathology of both the middle and inner ear, as can occur in otosclerosis involving the ossicles and the Presbycusis (age-associated hearing loss) is the most cochlea, head trauma, chronic otitis media, cholesteatoma, common cause of sensorineural hearing loss in adults. In middle ear tumors, and some inner ear malformations. the early stages, it is characterized by symmetric, gentle to sharply sloping high-frequency hearing loss. With Trauma resulting in temporal bone fractures may be progression, the hearing loss involves all frequencies. associated with conductive, sensorineural, or mixed More importantly, the hearing impairment is associated hearing loss. If the fracture spares the inner ear, there with significant loss in clarity.There is a loss of discrimi- may simply be conductive hearing loss due to rupture of nation for phonemes, recruitment (abnormal growth of the tympanic membrane or disruption of the ossicular loudness), and particular difficulty in understanding chain. These abnormalities can be surgically corrected. speech in noisy environments. Hearing aids may provide Profound hearing loss and severe vertigo are associated limited rehabilitation once the word recognition score with temporal bone fractures involving the inner ear. A deteriorates below 50%. Cochlear implants are the treat- perilymphatic fistula associated with leakage of inner- ment of choice when hearing aids prove inadequate, ear fluid into the middle ear can occur and may require even when hearing loss is incomplete. surgical repair. An associated facial nerve injury is not uncommon. CT is best suited to assess fracture of the Ménière’s disease is characterized by episodic vertigo, traumatized temporal bone, evaluate the ear canal, and fluctuating sensorineural hearing loss, tinnitus, and aural determine the integrity of the ossicular chain and the fullness. Tinnitus and/or deafness may be absent during involvement of the inner ear. CSF leaks that accompany the initial attacks of vertigo, but invariably appear as the temporal bone fractures are usually self-limited; the disease progresses and increase in severity during acute value of prophylactic antibiotics is uncertain. attacks. The annual incidence of Ménière’s disease is 0.5–7.5 per 1000; onset is most frequently in the fifth Tinnitus is defined as the perception of a sound when decade of life but may also occur in young adults or the there is no sound in the environment. It may have a elderly. Histologically, there is distention of the endolym- buzzing, roaring, or ringing quality and may be pulsatile phatic system (endolymphatic hydrops) leading to degen- (synchronous with the heartbeat).Tinnitus is often associ- eration of vestibular and cochlear hair cells. This may ated with either a conductive or sensorineural hearing result from endolymphatic sac dysfunction secondary to loss. The pathophysiology of tinnitus is not well under- infection, trauma, autoimmune disease, inflammatory stood.The cause of the tinnitus can usually be determined causes, or tumor; an idiopathic etiology constitutes the by finding the cause of the associated hearing loss.Tinnitus largest category and is most accurately referred to as may be the first symptom of a serious condition such as a Ménière’s disease. Although any pattern of hearing loss vestibular schwannoma. Pulsatile tinnitus requires evalua- can be observed, typically, low-frequency, unilateral sen- tion of the vascular system of the head to exclude vascular sorineural hearing impairment is present. MRI should be tumors such as glomus jugulare tumors, aneurysms, and obtained to exclude retrocochlear pathology such as a stenotic arterial lesions; it may also occur with SOM. cerebellopontine angle tumor or demyelinating disorder. Therapy is directed toward the control of vertigo. A Approach to the Patient: low-salt diet is the mainstay of treatment for control of DISORDERS OF THE SENSE OF HEARING rotatory vertigo. Diuretics, a short course of glucocorti- coids, and intratympanic gentamicin may also be useful The goal in the evaluation of a patient with auditory adjuncts in recalcitrant cases. Surgical therapy of vertigo complaints is to determine (1) the nature of the hearing is reserved for unresponsive cases and includes endolym- impairment (conductive vs. sensorineural vs. mixed), (2) phatic sac decompression, labyrinthectomy, and vestibular the severity of the impairment (mild, moderate, severe, nerve section. Both labyrinthectomy and vestibular nerve profound), (3) the anatomy of the impairment (external section abolish rotatory vertigo in >90% of patients. ear, middle ear, inner ear, or central auditory pathway),

SECTION II Clinical Manifestations of Neurologic Disease204 and (4) the etiology.The history should elicit character- then the stem is placed on the mastoid process; for istics of the hearing loss, including the duration of deaf- direct contact, it may be placed on teeth or dentures. ness, unilateral vs. bilateral involvement, nature of onset The patient is asked to indicate whether the tone is (sudden vs. insidious), and rate of progression (rapid vs. louder by air conduction or bone conduction. Nor- slow). Symptoms of tinnitus, vertigo, imbalance, aural mally, and in the presence of sensorineural hearing fullness, otorrhea, headache, facial nerve dysfunction, loss, a tone is heard louder by air conduction than by and head and neck paresthesias should be noted. Infor- bone conduction; however, with conductive hearing mation regarding head trauma, exposure to ototoxins, loss of ≥30 dB (see Audiologic Assessment, below), the occupational or recreational noise exposure, and family bone-conduction stimulus is perceived as louder than history of hearing impairment may also be important.A the air-conduction stimulus. For the Weber test, the sudden onset of unilateral hearing loss, with or without stem of a vibrating tuning fork is placed on the head tinnitus, may represent a viral infection of the inner ear in the midline and the patient asked whether the tone or a stroke. Patients with unilateral hearing loss (sensory is heard in both ears or better in one ear than in the or conductive) usually complain of reduced hearing, other. With a unilateral conductive hearing loss, the poor sound localization, and difficulty hearing clearly tone is perceived in the affected ear. With a unilateral with background noise. Gradual progression of a hear- sensorineural hearing loss, the tone is perceived in the ing deficit is common with otosclerosis, noise-induced unaffected ear. A 5-dB difference in hearing between hearing loss, vestibular schwannoma, or Ménière’s dis- the two ears is required for lateralization. ease. Small vestibular schwannomas typically present with asymmetric hearing impairment, tinnitus, and LABORATORY ASSESSMENT OF HEARING imbalance (rarely vertigo); cranial neuropathy, in partic- ular of the trigeminal or facial nerve, may accompany Audiologic Assessment larger tumors. In addition to hearing loss, Ménière’s dis- ease may be associated with episodic vertigo, tinnitus, The minimum audiologic assessment for hearing loss and aural fullness. Hearing loss with otorrhea is most should include the measurement of pure tone air- likely due to chronic otitis media or cholesteatoma. conduction and bone-conduction thresholds, speech Examination should include the auricle, external ear reception threshold, discrimination score, tympanome- canal, and tympanic membrane.The external ear canal try, acoustic reflexes, and acoustic-reflex decay. This test of the elderly is often dry and fragile; it is preferable to battery provides a screening evaluation of the entire clean cerumen with wall-mounted suction and ceru- auditory system and allows one to determine whether men loops and to avoid irrigation. In examining the further differentiation of a sensory (cochlear) from a eardrum, the topography of the tympanic membrane neural (retrocochlear) hearing loss is indicated. is more important than the presence or absence of the light reflex. In addition to the pars tensa (the lower Pure tone audiometry assesses hearing acuity for pure two-thirds of the eardrum), the pars flaccida above the tones. The test is administered by an audiologist and is short process of the malleus should also be examined performed in a sound-attenuated chamber. The pure for retraction pockets that may be evidence of chronic tone stimulus is delivered with an audiometer, an elec- eustachian tube dysfunction or cholesteatoma. Insuf- tronic device that allows the presentation of specific fre- flation of the ear canal is necessary to assess tympanic quencies (generally between 250 and 8000 Hz) at specific membrane mobility and compliance. Careful inspec- intensities. Air and bone conduction thresholds are estab- tion of the nose, nasopharynx, and upper respiratory lished for each ear. Air conduction thresholds are deter- tract is indicated. Unilateral serous effusion should mined by presenting the stimulus in air with the use of prompt a fiberoptic examination of the nasopharynx headphones. Bone conduction thresholds are determined to exclude neoplasms. Cranial nerves should be evalu- by placing the stem of a vibrating tuning fork or an ated with special attention to facial and trigeminal oscillator of an audiometer in contact with the head. nerves, which are commonly affected with tumors In the presence of a hearing loss, broad-spectrum noise involving the cerebellopontine angle. is presented to the nontest ear for masking purposes so The Rinne and Weber tuning fork tests, with a that responses are based on perception from the ear 512-Hz tuning fork, are used to screen for hearing under test. loss, differentiate conductive from sensorineural hear- ing losses, and to confirm the findings of audiologic The responses are measured in decibels.An audiogram is evaluation. Rinne’s test compares the ability to hear by a plot of intensity in decibels of hearing threshold versus air conduction with the ability to hear by bone con- frequency. A decibel (dB) is equal to 20 times the loga- duction. The tines of a vibrating tuning fork are held rithm of the ratio of the sound pressure required to near the opening of the external auditory canal, and achieve threshold in the patient to the sound pressure required to achieve threshold in a normal hearing person.

Therefore, a change of 6 dB represents doubling of sound SRT also suggests a lesion in the eighth nerve or central 205CHAPTER 18 Disorders of Smell, Taste, and Hearing pressure, and a change of 20 dB represents a tenfold auditory pathways. change in sound pressure. Loudness, which depends on the frequency, intensity, and duration of a sound, doubles Tympanometry measures the impedance of the middle with approximately each 10-dB increase in sound pres- ear to sound and is useful in diagnosis of middle-ear sure level. Pitch, on the other hand, does not directly cor- effusions. A tympanogram is the graphic representation of relate with frequency. The perception of pitch changes change in impedance or compliance as the pressure in slowly in the low and high frequencies. In the middle the ear canal is changed. Normally, the middle ear is tones, which are important for human speech, pitch varies most compliant at atmospheric pressure, and the com- more rapidly with changes in frequency. pliance decreases as the pressure is increased or decreased; this pattern is seen with normal hearing or in Pure tone audiometry establishes the presence and the presence of sensorineural hearing loss. Compliance severity of hearing impairment, unilateral vs. bilateral that does not change with change in pressure suggests involvement, and the type of hearing loss. Conductive middle-ear effusion. With a negative pressure in the hearing losses with a large mass component, as is often middle ear, as with eustachian tube obstruction, the seen in middle-ear effusions, produce elevation of point of maximal compliance occurs with negative pres- thresholds that predominate in the higher frequencies. sure in the ear canal. A tympanogram in which no point Conductive hearing losses with a large stiffness compo- of maximal compliance can be obtained is most com- nent, as in fixation of the footplate of the stapes in early monly seen with discontinuity of the ossicular chain. A otosclerosis, produce threshold elevations in the lower reduction in the maximal compliance peak can be seen frequencies. Often, the conductive hearing loss involves in otosclerosis. all frequencies, suggesting involvement of both stiffness and mass. In general, sensorineural hearing losses such as During tympanometry, an intense tone elicits con- presbycusis affect higher frequencies more than lower traction of the stapedius muscle. The change in compli- frequencies. An exception is Ménière’s disease, which is ance of the middle ear with contraction of the stapedius characteristically associated with low-frequency sen- muscle can be detected. The presence or absence of this sorineural hearing loss. Noise-induced hearing loss has acoustic reflex is important in the anatomic localization of an unusual pattern of hearing impairment in which the facial nerve paralysis as well as hearing loss. Normal or loss at 4000 Hz is greater than at higher frequencies. elevated acoustic reflex threshold in an individual with Vestibular schwannomas characteristically affect the sensorineural hearing impairment suggests a cochlear higher frequencies, but any pattern of hearing loss can hearing loss. Assessment of acoustic reflex decay helps dif- be observed. ferentiate sensory from neural hearing losses. In neural hearing loss, the reflex adapts or decays with time. Speech recognition requires greater synchronous neural firing than is necessary for appreciation of pure Otoacoustic emissions (OAE) can be measured with tones. Speech audiometry tests the clarity with which one microphones inserted into the external auditory canal. hears. The speech reception threshold (SRT) is defined as The emissions may be spontaneous or evoked with the intensity at which speech is recognized as a mean- sound stimulation. The presence of OAEs indicates that ingful symbol and is obtained by presenting two-syllable the outer hair cells of the organ of Corti are intact and words with an equal accent on each syllable. The inten- can be used to assess auditory thresholds and to distin- sity at which the patient can repeat 50% of the words guish sensory from neural hearing losses. correctly is the SRT. Once the SRT is determined, dis- crimination or word recognition ability is tested by pre- Evoked Responses senting one-syllable words at 25–40 dB above the SRT. The words are phonetically balanced in that the Electrocochleography measures the earliest evoked poten- phonemes (speech sounds) occur in the list of words at tials generated in the cochlea and the auditory nerve. the same frequency that they occur in ordinary conver- Receptor potentials recorded include the cochlear sational English. An individual with normal hearing microphonic, generated by the outer hair cells of the or conductive hearing loss can repeat 88–100% of the organ of Corti, and the summating potential, generated phonetically balanced words correctly. Patients with a by the inner hair cells in response to sound. The whole sensorineural hearing loss have variable loss of discrimi- nerve action potential representing the composite firing nation. As a general rule, neural lesions produce greater of the first-order neurons can also be recorded during deficits in discrimination than do lesions in the inner electrocochleography. Clinically, the test is useful in the ear. For example, in a patient with mild asymmetric sen- diagnosis of Ménière’s disease, where an elevation of the sorineural hearing loss, a clue to the diagnosis of ratio of summating potential to action potential is seen. vestibular schwannoma is the presence of a substantial deterioration in discrimination ability. Deterioration in Brainstem auditory evoked responses (BAERs) are useful discrimination ability at higher intensities above the in differentiating the site of sensorineural hearing loss. In response to sound, five distinct electrical potentials arising from different stations along the peripheral and

SECTION II Clinical Manifestations of Neurologic Disease206 central auditory pathway can be identified using com- Tympanostomy tubes allow the prompt return of nor- puter averaging from scalp surface electrodes. BAERs are mal hearing in individuals with middle-ear effusions. valuable in situations in which patients cannot or will Hearing aids are effective and well-tolerated in patients not give reliable voluntary thresholds. They are also used with conductive hearing losses. to assess the integrity of the auditory nerve and brain- stem in various clinical situations, including intraopera- Patients with mild, moderate, and severe sen- tive monitoring and in determination of brain death. sorineural hearing losses are regularly rehabilitated with The vestibular-evoked myogenic potential (VEMP) test hearing aids of varying configuration and strength. elicits a vestibulocollic reflex whose afferent limb arises Hearing aids have been improved to provide greater from acoustically sensitive cells in the saccule, with sig- fidelity and have been miniaturized. The current genera- nals conducted via the inferior vestibular nerve.VEMP is tion of hearing aids can be placed entirely within the a biphasic, short-latency response recorded from the ton- ear canal, thus reducing any stigma associated with ically contracted sternocleidomastoid muscle in response their use. In general, the more severe the hearing to loud auditory clicks or tones.VEMPs may be dimin- impairment, the larger the hearing aid required for audi- ished or absent in patients with early and late Ménière’s tory rehabilitation. Digital hearing aids lend themselves disease, vestibular neuritis, benign paroxysmal positional to individual programming, and multiple and direc- vertigo, and vestibular schwannoma. On the other hand, tional microphones at the ear level may be helpful in the threshold for VEMPs may be lower in cases of supe- noisy surroundings. Since all hearing aids amplify noise rior canal dehiscence and perilymphatic fistula. as well as speech, the only absolute solution to the problem of noise is to place the microphone closer to Imaging Studies the speaker than the noise source. This arrangement is not possible with a self-contained, cosmetically accept- The choice of radiologic tests is largely determined by able device. whether the goal is to evaluate the bony anatomy of the external, middle, and inner ear or to image the auditory In many situations, including lectures and the the- nerve and brain. Axial and coronal CT of the temporal ater, hearing-impaired persons benefit from assistive bone with fine 1-mm cuts is ideal for determining the devices that are based on the principle of having the caliber of the external auditory canal, integrity of the speaker closer to the microphone than any source of ossicular chain, and presence of middle-ear or mastoid noise. Assistive devices include infrared and frequency- disease; it can also detect inner-ear malformations. CT is modulated (FM) transmission as well as an electromag- also ideal for the detection of bone erosion with chronic netic loop around the room for transmission to the indi- otitis media and cholesteatoma. MRI is superior to CT vidual’s hearing aid. Hearing aids with telecoils can also for imaging of retrocochlear pathology such as vestibular be used with properly equipped telephones in the schwannoma, meningioma, other lesions of the cerebel- same way. lopontine angle, demyelinating lesions of the brainstem, and brain tumors. Both CT and MRI are equally capa- In the event that the hearing aid provides inade- ble of identifying inner-ear malformations and assessing quate rehabilitation, cochlear implants may be appro- cochlear patency for preoperative evaluation of patients priate. Criteria for implantation include severe to pro- for cochlear implantation. found hearing loss with word recognition score Յ 30% under best aided conditions. Worldwide, >20,000 deaf Treatment: individuals (including 4000 children) have received DISORDERS OF THE SENSE cochlear implants. Cochlear implants are neural pros- OF HEARING theses that convert sound energy to electrical energy and can be used to stimulate the auditory division of In general, conductive hearing losses are amenable to the eighth nerve directly. In most cases of profound surgical correction, while sensorineural hearing losses hearing impairment, the auditory hair cells are lost but are more difficult to manage. Atresia of the ear canal can the ganglionic cells of the auditory division of the be surgically repaired, often with significant improve- eighth nerve are preserved. Cochlear implants consist of ment in hearing. Tympanic membrane perforations due electrodes that are inserted into the cochlea through to chronic otitis media or trauma can be repaired with the round window, speech processors that extract an outpatient tympanoplasty. Likewise, conductive hear- acoustical elements of speech for conversion to electri- ing loss associated with otosclerosis can be treated by cal currents, and a means of transmitting the electrical stapedectomy, which is successful in 90–95% of cases. energy through the skin. Patients with implants experi- ence sound that helps with speech reading, allows open- set word recognition, and helps in modulating the person’s own voice. Usually, within 3 months after implanta- tion, adult patients can understand speech without visual cues. With the current generation of multichannel

cochlear implants, nearly 75% of patients are able to antibiotics can largely be prevented by careful monitor- 207 CHAPTER 18 Disorders of Smell, Taste, and Hearing converse on the telephone. For individuals who have ing of serum peak and trough levels. had both eighth nerves destroyed by trauma or bilateral vestibular schwannomas (e.g., neurofibromatosis type 2), Some 10 million Americans have noise-induced hear- brainstem auditory implants placed near the cochlear ing loss, and 20 million are exposed to hazardous noise in nucleus may provide auditory rehabilitation. their employment. Noise-induced hearing loss can be prevented by avoidance of exposure to loud noise or by Tinnitus often accompanies hearing loss. As for back- regular use of ear plugs or fluid-filled ear muffs to atten- ground noise, tinnitus can degrade speech comprehen- uate intense sound. High-risk activities for noise-induced sion in individuals with hearing impairment. Therapy for hearing loss include wood and metal working with elec- tinnitus is usually directed toward minimizing the trical equipment and target practice and hunting with appreciation of tinnitus. Relief of the tinnitus may be small firearms. All internal-combustion and electric obtained by masking it with background music. Hearing engines, including snow and leaf blowers, snowmobiles, aids are also helpful in tinnitus suppression, as are tinni- outboard motors, and chain saws, require protection of tus maskers, devices that present a sound to the the user with hearing protectors. Virtually all noise- affected ear that is more pleasant to listen to than the induced hearing loss is preventable through education, tinnitus. The use of a tinnitus masker is often followed which should begin before the teenage years. Programs by several hours of inhibition of the tinnitus. Antide- of industrial conservation of hearing are required when pressants have been shown to be beneficial in helping the exposure over an 8-h period averages 85 dB.Workers patients cope with tinnitus. in such noisy environments can be protected with pre- employment audiologic assessment, the mandatory use of Hard-of-hearing individuals often benefit from a hearing protectors, and annual audiologic assessments. reduction in unnecessary noise (e.g., radio or television) to enhance the signal-to-noise ratio. Speech compre- ACKNOWLEDGMENT hension is aided by lip reading; therefore the impaired listener should be seated so that the face of the speaker The author acknowledges the contributions of Dr. James B. Snow, Jr., is well-illuminated and easily seen. Although speech to this chapter. should be in a loud, clear voice, one should be aware that in sensorineural hearing losses in general and in FURTHER READINGS hard-of-hearing elderly in particular, recruitment (abnormal perception of loud sounds) may be trouble- BRESLIN PA, HUANG L: Human taste: Peripheral anatomy, taste trans- some. Above all, optimal communication cannot take duction, and coding.Adv Otorhinolaryngol 63:152, 2006 place without both parties giving it their full and undi- vided attention. DOTY RL: The olfactory system and its disorders. Semin neurol 29:74, 2009 PREVENTION DULAC C: Sparse encoding of natural scents. Neuron 50:816, 2006 Conductive hearing losses may be prevented by prompt GATES GA, MILLS JH: Presbycusis. Lancet 366:1111, 2005 antibiotic therapy of adequate duration for AOM and by HASIN-BRUMSHTEIN Y et al: Human olfaction: from genomic varia- ventilation of the middle ear with tympanostomy tubes in middle-ear effusions lasting Ն12 weeks. Loss of tion to phenotypic diversity. Trends Genet. 25:178, 2009 vestibular function and deafness due to aminoglycoside HECKMANN JG, LANG CJ: Neurological causes of taste disorders. Adv Otorhinolaryngol 63:255, 2006 KATZ DB et al: Receptors, circuits, and behaviors: new directions in chemical senses. J Neurosci 28:11802, 2008 LALWANI AK (ed): Current Diagnosis and Treatment in Otolaryngology— Head & Neck Surgery, 2d ed. New York, McGraw-Hill, 2007

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SECTION III DISEASES OF THE CENTRAL NERVOUS SYSTEM

CHAPTER 19 MECHANISMS OF NEUROLOGIC DISEASES Stephen L. Hauser I M. Flint Beal I Neurogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 I Ion Channels and Channelopathies . . . . . . . . . . . . . . . . . . . . 211 I Neurotransmitters and Neurotransmitter Receptors . . . . . . . 212 I Signaling Pathways and Gene Transcription . . . . . . . . . . . . . 213 I Myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 I Neurotrophic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 I Stem Cells and Transplantation . . . . . . . . . . . . . . . . . . . . . . . 216 I Cell Death—Excitotoxicity and Apoptosis . . . . . . . . . . . . . . . 217 I Protein Aggregation and Neurodegeneration . . . . . . . . . . . . . 219 I Systems Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 The human nervous system is the organ of conscious- monogenic causes of common phenotypes. Examples of ness, cognition, ethics, and behavior; as such, it is the the latter include mutations of the amyloid precursor most intricate structure known to exist. More than one- protein in familial Alzheimer’s disease, the microtubule- third of the 23,000 genes encoded in the human genome associated protein tau (MAPT) in frontotemporal dementia, are expressed in the nervous system. Each mature brain is and α-synuclein in Parkinson’s disease. These discoveries composed of 100 billion neurons, several million miles of have been profoundly important because the mutated axons and dendrites, and >1015 synapses. Neurons exist gene in the familial disorder often encodes a protein that within a dense parenchyma of multifunctional glial cells is also pathogenetically involved (although not mutated) that synthesize myelin, preserve homeostasis, and regulate in the typical, sporadic form. The common mechanism immune responses. Measured against this background of involves disordered processing and, ultimately, aggregation complexity, the achievements of molecular neuroscience of the protein, leading to cell death (see Protein Aggrega- have been extraordinary. This chapter reviews selected tion and Neurodegeneration, later in the chapter). themes in neuroscience that provide a context for under- standing fundamental mechanisms underlying neurologic There is great optimism that complex genetic disor- disorders. ders, caused by combinations of both genetic and envi- ronmental factors, have now become tractable problems. NEUROGENETICS The development of new genetic approaches, such as haplotype mapping for the efficient screening of variants The landscape of neurology has been transformed by genome-wide along with advances in high-throughput modern molecular genetics. More than 350 different sequencing, are beginning to delineate incompletely disease-causing genes have now been identified, and penetrant genetic variants that influence susceptibility >1000 neurologic disorders have been genetically mapped to, or modify the expression of, complex diseases includ- to various chromosomal locations. The vast majority of ing age-related macular degeneration, type 2 diabetes these represent highly penetrant mutations that cause rare mellitus, and Alzheimer’s disease. neurologic disorders; alternatively, they represent rare Not all genetic diseases of the nervous system are caused by simple changes in the linear nucleotide sequence of 210

genes. As the complex architecture of the human genome Imprinting refers to an epigenetic feature, present for a 211CHAPTER 19 Mechanisms of Neurologic Diseases becomes better defined, many disorders that result subset of genes, in which the predominant expression of from alterations in copy numbers of genes (“gene-dosage” one allele is determined by its parent-of-origin.The distinc- effects) resulting from unequal crossing-over are likely to be tive neurodevelopmental disorders Prader-Willi syndrome identified.The first copy-number disorders to be recognized (mild mental retardation and endocrine abnormalities) were Charcot-Marie-Tooth disease type 1A (CMT1A), and Angelman syndrome (cortical atrophy, cerebellar caused by a duplication in the gene encoding the myelin dysmyelination, Purkinje cell loss) are classic examples of protein PMP22, and the reciprocal deletion of the gene imprinting disorders whose distinctive features are causing hereditary liability to pressure palsies (HNPP) determined by whether the paternal or maternal copy (Chap. 40). Gene-dosage effects are causative in some cases of chromosome of the critical genetic region 15q11-13 of Parkinson’s disease (α-synuclein), Alzheimer’s disease was responsible. Preferential allelic expression, whether (amyloid precursor protein), spinal muscular atrophy (sur- due to imprinting, resistance to X-inactivation, or other vival motor neuron 2), the dysmyelinating disorder mechanisms, is likely to play a major role in determining Pelizaeus-Merzbacher syndrome (proteolipid protein 1), complex behaviors and susceptibility to many neuro- late-onset leukodystrophy (lamin B1), and a variety of logic and psychiatric disorders. developmental neurologic disorders. It is now evident that copy-number variations contribute substantially to normal ION CHANNELS AND CHANNELOPATHIES human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regula- The resting potential of neurons and the action poten- tion of metabolism. It is also likely that gene-dosage effects tials responsible for impulse conduction are generated by will influence many behavioral phenotypes, learning disor- ion currents and ion channels. Most ion channels are ders, and autism spectrum disorders. gated, meaning that they can transition between confor- mations that are open or closed to ion conductance. The role of splicing variation as a contributor to neuro- Individual ion channels are distinguished by the specific logic disease is another area of active investigation. Alterna- ions they conduct; by their kinetics; and by whether tive splicing refers to the inclusion of different combinations they directly sense voltage, are linked to receptors for of exons in mature mRNA, resulting in the potential for neurotransmitters or other ligands such as neurotrophins, many different protein products encoded by a single gene. or are activated by second messengers.The diverse char- Alternative splicing represents a powerful mechanism for acteristics of different ion channels provide a means by generation of complexity and variation, and this mecha- which neuronal excitability can be exquisitely modu- nism appears to be highly prevalent in the nervous system, lated at both the cellular and the subcellular levels. Dis- affecting key processes such as neurotransmitter receptors orders of ion channels—channelopathies—are responsi- and ion channels. Numerous diseases are already known to ble for a growing list of human neurologic diseases result from abnormalities in alternative splicing. Increased (Table 19-1). Most are caused by mutations in ion inclusion of exon 10-containing transcripts of MAPT can channel genes or by autoantibodies against ion channel cause frontotemporal dementia. Aberrant splicing also proteins. One example is epilepsy, a syndrome of diverse contributes to the pathogenesis of Duchenne, myotonic, causes characterized by repetitive, synchronous firing of and fascioscapulohumeral muscular dystrophies; ataxia neuronal action potentials. Action potentials are nor- telangiectasia; neurofibromatosis; some inherited ataxias; mally generated by the opening of sodium channels and and fragile X syndrome; among other disorders. It is also the inward movement of sodium ions down the intra- likely that subtle variations of splicing will influence many cellular concentration gradient. Depolarization of genetically complex disorders. Recently a splicing variant the neuronal membrane opens potassium channels, of the interleukin 7 receptor α chain, resulting in produc- resulting in outward movement of potassium ions, tion of more soluble and less membrane-bound receptor, repolarization, closure of the sodium channel, and was found to be associated with susceptibility to multiple hyperpolarization. Sodium or potassium channel sub- sclerosis (MS) in multiple different populations. unit genes have long been considered candidate dis- ease genes in inherited epilepsy syndromes, and recently Epigenetics refers to the mechanisms by which levels such mutations have been identified. These mutations of gene expression can be exquisitely modulated, not by appear to alter the normal gating function of these variations in the primary genetic sequence of DNA but channels, increasing the inherent excitability of neuronal rather by postgenomic alterations in DNA and chro- membranes in regions where the abnormal channels matin structure, which influence how, when, and where are expressed. genes are expressed. DNA methylation, as well as methylation and acetylation of histone proteins that Whereas the specific clinical manifestations of chan- interact with nuclear DNA to form chromatin, are key nelopathies are quite variable, one common feature is mediators of these events. Epigenetic processes appear to be dynamically active even in postmitotic neurons.

212 TABLE 19-1 EXAMPLES OF NEUROLOGIC CHANNELOPATHIES CATEGORY DISORDER CHANNEL TYPE MUTATED GENE CHAP. REF. SECTION III Diseases of the Central Nervous System Genetic Episodic ataxia-1 K KCNA1 26 Ataxias Episodic ataxia-2 Ca CACNL1A Spinocerebellar ataxia-6 Ca CACNL1A 6 Migraine Familial hemiplegic migraine 1 Ca CACNL1A Epilepsy Familial hemiplegic migraine 2 Na SCN1A 20 Benign neonatal familial convulsions 43 Periodic paralysis Generalized epilepsy with febrile K KCNQ2, KCNQ3 43 Myotonia Na SCN1B 18 Deafness convulsions plus Na SCN4A Hyperkalemic periodic paralysis Ca CACNL1A3 39 Autoimmune Hypokalemic periodic paralysis Cl CLCN1 39 Paraneoplastic Myotonia congenita Na SCN4A 39 Paramyotonia congenita K KCNQ1, KCNE1 39 Jorvell and Lange-Nielsen syndrome (deafness, prolonged QT interval, K KCNQ4 and arrythmia) Autosomal dominant progressive deafness Kv1 — Kv1 — Limbic encephalitis Ca (P/Q type) — Acquired neuromyotonia Ca (P/Q type) — Cerebellar ataxia Lambert-Eaton syndrome that manifestations tend to be intermittent or paroxys- the synaptic cleft, where they bind to receptors on the mal, such as occurs in epilepsy, migraine, ataxia, myoto- postsynaptic cell. Secreted neurotransmitters are elimi- nia, or periodic paralysis. Exceptions are clinically nated by reuptake into the presynaptic neuron (or glia), progressive channel disorders such as autosomal domi- by diffusion away from the synaptic cleft, and/or by spe- nant hearing impairment. The genetic channelopathies cific inactivation. In addition to the classic neurotransmit- identified to date are all uncommon disorders caused by ters, many neuropeptides have been identified as definite obvious mutations in channel genes. As the full reper- or probable neurotransmitters; these include substance P, toire of human ion channels and related proteins is neurotensin, enkephalins, β-endorphin, histamine, vasoac- identified, it is likely that additional channelopathies will tive intestinal polypeptide, cholecystokinin, neuropeptide be discovered. In addition to rare disorders that result Y, and somatostatin. Peptide neurotransmitters are synthe- from obvious mutations, it is also likely that less pene- sized in the cell body rather than the nerve terminal and trant allelic variations in channel genes or in their pat- may colocalize with classic neurotransmitters in single tern of expression might underlie susceptibility to some neurons. Nitric oxide and carbon monoxide are gases that common forms of epilepsy, migraine, or other disorders. appear also to function as neurotransmitters, in part by For example, mutations in the T-type Ca channel gene signaling in a retrograde fashion from the postsynaptic to CACNA1H, as well as a K channel (KCND2) and vari- the presynaptic cell. ous GABA receptor genes, have been associated with an increased risk for epilepsy. Neurotransmitters modulate the function of postsy- naptic cells by binding to specific neurotransmitter recep- NEUROTRANSMITTERS AND tors, of which there are two major types. Ionotropic receptors NEUROTRANSMITTER RECEPTORS are direct ion channels that open after engagement by the neurotransmitter. Metabotropic receptors interact with G Synaptic neurotransmission is the predominant means by proteins, stimulating production of second messengers which neurons communicate with each other. Classic and activating protein kinases, which modulate a variety neurotransmitters are synthesized in the presynaptic region of cellular events. Ionotropic receptors are multiple sub- of the nerve terminal; stored in vesicles; and released into unit structures, whereas metabotropic receptors are com- posed of single subunits only. One important difference between ionotropic and metabotropic receptors is that

the kinetics of ionotropic receptor effects are fast (gener- the X-linked form of CMT disease (Chap. 40). Muta- 213 CHAPTER 19 Mechanisms of Neurologic Diseases ally <1 ms) because neurotransmitter binding directly tions in either of two gap junction proteins expressed in alters the electrical properties of the postsynaptic cell, the inner ear—connexin 26 and connexin 31—result in whereas metabotropic receptors function over longer autosomal dominant progressive hearing loss (Chap. 18). time periods. These different properties contribute to the Glial calcium waves mediated through gap junctions also potential for selective and finely modulated signaling by appear to explain the phenomenon of spreading depres- neurotransmitters. sion associated with migraine auras and the march of epileptic discharges. Spreading depression is a neural Neurotransmitter systems are perturbed in a large response that follows a variety of different stimuli and is number of clinical disorders, examples of which are high- characterized by a circumferentially expanding negative lighted in Table19-2. One example is the involvement potential that propagates at a characteristic speed of of dopaminergic neurons originating in the substantia 20 m/s and is associated with an increase in extracellular nigra of the midbrain and projecting to the striatum potassium. (nigrostriatal pathway) in Parkinson’s disease and in heroin addicts after the ingestion of the toxin MPTP (1- SIGNALING PATHWAYS AND GENE methyl-4-phenyl-1,2,5,6-tetrahydropyridine). TRANSCRIPTION A second important dopaminergic system arising in The fundamental issue of how memory, learning, and the midbrain is the mediocorticolimbic pathway, which thinking are encoded in the nervous system is likely to be is implicated in the pathogenesis of addictive behaviors clarified by identifying the signaling pathways involved in including drug reward. Its key components include the neuronal differentiation, axon guidance, and synapse for- midbrain ventral tegmental area (VTA), median fore- mation, and by understanding how these pathways are brain bundle, and nucleus accumbens (Fig. 48-2). The modulated by experience. Many families of transcription cholinergic pathway originating in the nucleus basalis of factors, each comprising multiple individual components, Meynert plays a role in memory function in Alzheimer’s are expressed in the nervous system. Elucidation of these disease. signaling pathways has already begun to provide insights into the cause of a variety of neurologic disorders, includ- Addictive drugs share the property of increasing dopamine ing inherited disorders of cognition such as X-linked release in the nucleus accumbens. Amphetamine increases mental retardation. This problem affects ~1 in 500 males, intracellular release of dopamine from vesicles and and linkage studies in different families suggest that as reverses transport of dopamine through the dopamine many as 60 different X-chromosome encoded genes may transporters. Patients prone to addiction show increased be responsible. Rett syndrome, a common cause of (domi- activation of the nucleus accumbens following adminis- nant) X-linked progressive mental retardation in females, is tration of amphetamine. Cocaine binds to dopamine trans- due to a mutation in a gene (MECP2) encoding a DNA- porters and inhibits dopamine reuptake. Ethanol inhibits binding protein involved in transcriptional repression. As inhibitory neurons in the VTA, leading to increased the X chromosome comprises only ~3% of germline dopamine release in the nucleus accumbens. Opioids DNA, then by extrapolation the number of genes that also disinhibit these dopaminergic neurons by binding potentially contribute to clinical disorders affecting intelli- to μ receptors expressed by GABA-containing interneu- gence in humans must be potentially very large. As dis- rons in the VTA. Nicotine increases dopamine release by cussed below, there is increasing evidence that abnormal activating nicotinic acetylcholine receptors on cell bod- gene transcription may play a role in neurodegenerative ies and nerve terminals of dopaminergic VTA neurons. diseases, such as Huntington’s disease, in which proteins Tetrahydrocannabinol, the active ingredient of cannabis, with polyglutamine expansions bind to and sequester tran- also increases dopamine levels in the nucleus accum- scription factors.A critical transcription factor for neuronal bens. Blockade of dopamine in the nucleus accumbens survival is CREB (cyclic adenosine monophosphate can terminate the rewarding effects of addictive drugs. responsive element-binding) protein, which also plays an important role in memory in the hippocampus. Not all cell-to-cell communication in the nervous system occurs via neurotransmission. Gap junctions pro- MYELIN vide for direct neuron-neuron electrical conduction and also create openings for the diffusion of ions and Myelin is the multilayered insulating substance that sur- metabolites between cells. In addition to neurons, gap rounds axons and speeds impulse conduction by permit- junctions are also widespread in glia, creating a syn- ting action potentials to jump between naked regions of cytium that protects neurons by removing glutamate and axons (nodes of Ranvier) and across myelinated segments. potassium from the extracellular environment. Gap junc- tions consist of membrane-spanning proteins, termed connexins, that pair across adjacent cells. Mechanisms that involve gap junctions have been related to a variety of neu- rologic disorders. Mutations in connexin 32, a gap junction protein expressed by Schwann cells, are responsible for

214 TABLE 19-2 PRINCIPAL CLASSIC NEUROTRANSMITTERS NEUROTRANSMITTER ANATOMY CLINICAL ASPECTS Acetylcholine (ACh) Motor neurons in spinal cord → Acetylcholinesterases (nerve gases) O Myasthenia gravis (antibodies to ACh neuromuscular junction receptor) Congenital myasthenic syndromes CH3—C—O—CH2—N—(CH3)3 (mutations in ACh receptor subunits) Lambert-Eaton syndrome (antibodies to Basal forebrain →widespread cortex Ca channels impair ACh release) Botulism (toxin disrupts ACh release by Interneurons in striatum exocytosis) Autonomic nervous system Alzheimer’s disease (selective cell death) Autosomal dominant frontal lobe epilepsy (preganglionic and postganglionic (mutations in CNS ACh receptor) parasympathetic; preganglionic Parkinson’s disease (tremor) sympathetic) SECTION III Diseases of the Central Nervous System Dopamine CH2—CH2—NH3 Substantia nigra → striatum Parkinson’s disease (selective cell death) HO MPTP parkinsonism (toxin transported into (nigrostriatal pathway) neurons) HO Addiction, behavioral disorders Substantia nigra → limbic system Inhibits prolactin secretion and widespread cortex Arcuate nucleus of hypothalamus → anterior pituitary (via portal veins) Norepinephrine (NE) Locus coeruleus (pons) → limbic Mood disorders (MAOA inhibitors and HO tricyclics increase NE and improve system, hypothalamus, cortex depression) HO CH—CH2—NH2 OH Medulla → locus coeruleus, Anxiety Orthostatic tachycardia syndrome spinal cord (mutations in NE transporter) Postganglionic neurons of Mood disorders (SSRIs improve sympathetic nervous system depression) Serotonin CH2—CH2—NH2 Pontine raphe nuclei → Migraine pain pathway Pain pathway HO widespread projections Stiff person syndrome (antibodies to N Medulla/pons → dorsal horn of glutamic acid decarboxylase, the H biosynthetic enzyme for GABA) spinal cord Epilepsy (gabapentin and valproic acid γ-Aminobutyric acid (GABA) increase GABA) Major inhibitory neurotransmitter in H2N—CH2—CH2—CH2—COOH brain; widespread cortical interneurons and long projection pathways Glycine Major inhibitory neurotransmitter Spasticity H2N—CH2 —COOH in spinal cord Hyperekplexia (myoclonic startle syndrome) due to mutations in glycine receptor Glutamate Major excitatory neurotransmitter; Seizures due to ingestion of domoic acid H2N—CH—CH2—CH2—COOH located throughout CNS, including (a glutamate analogue) cortical pyramidal cells Rasmussen’s encephalitis (antibody against COOH glutamate receptor 3) Excitotoxic cell death Note: CNS, central nervous system; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MAOA, monoamine oxidase A; SSRI, selective sero- tonin reuptake inhibitor.

MOG PMP22 215 PLP P0 Myelin basic protein Myelin basic protein P0 PLP MAG GQ1b Cx32 GM1 FIGURE 19-1 PMP22 are responsible for another inherited neuropathy CHAPTER 19 Mechanisms of Neurologic Diseases The molecular architecture of the myelin sheath illustrating termed hereditary liability to pressure palsies (Chap. 40). the most important disease-related proteins. The illustration represents a composite of CNS and PNS myelin. Proteins In multiple sclerosis (MS), myelin basic protein (MBP) and restricted to CNS myelin are shown in green, proteins of PNS the quantitatively minor CNS protein, myelin oligodendrocyte myelin are lavender, and proteins present in both CNS and glycoprotein (MOG), are likely T cell and B cell antigens, PNS are red. In the CNS, the X-linked allelic disorders, respectively. The location of MOG at the outermost lamella of Pelizaeus-Merzbacher disease and one variant of familial the CNS myelin membrane may facilitate its targeting by spastic paraplegia, are caused by mutations in the gene for autoantibodies. In the PNS, autoantibodies against myelin proteolipid protein (PLP) that normally promotes extracellular gangliosides are implicated in a variety of disorders, includ- compaction between adjacent myelin lamellae. The homo- ing GQ1b in the Fisher variant of Guillain-Barré syndrome, logue of PLP in the PNS is the P0 protein, mutations in which GM1 in multifocal motor neuropathy, and sulfatide con- cause the neuropathy Charcot-Marie-Tooth disease (CMT) stituents of myelin-associated glycoprotein (MAG) in periph- type 1B. The most common form of CMT is the 1A subtype eral neuropathies associated with monoclonal gammopathies caused by a duplication of the PMP22 gene; deletions in (Chap. 41). Molecular interactions between the myelin membrane and survival; some have additional functions, including and axon are required to maintain the stability, function, roles in neurotransmission and in the synaptic reorgani- and normal lifespan of both structures. A single oligo- zation involved in learning and memory. The neu- dendrocyte usually ensheaths multiple axons in the cen- rotrophin (NT) family contains nerve growth factor tral nervous system (CNS), whereas in the peripheral (NGF), brain-derived neurotrophic factor (BDNF), nervous system (PNS) each Schwann cell typically NT3, and NT4/5. The neurotrophins act at TrK and myelinates a single axon. Myelin is a lipid-rich material p75 receptors to promote survival of neurons. Because formed by a spiraling process of the membrane of the of their survival-promoting and antiapoptotic effects, myelinating cell around the axon, creating multiple mem- neurotrophic factors are in theory outstanding candi- brane bilayers that are tightly apposed (compact myelin) by dates for therapy of disorders characterized by prema- charged protein interactions. Several inhibitors of axon ture death of neurons such as occurs in amyotrophic growth are expressed on the innermost (periaxonal) lateral sclerosis (ALS) and other degenerative motor lamellae of the myelin membrane (see Stem Cells and neuron disorders. Knockout mice lacking receptors for Transplantation, below). A number of clinically impor- ciliary neurotrophic factor (CNTF) or BDNF show loss tant neurologic disorders are caused by inherited muta- of motor neurons, and experimental motor neuron tions in myelin proteins of the CNS or PNS (Fig. 19-1). death can be rescued by treatment with various neu- Constituents of myelin also have a propensity to be tar- rotrophic factors including CNTF, BDNF, and vascular geted as autoantigens in autoimmune demyelinating dis- endothelial growth factor (VEGF). However, in phase 3 orders (Fig. 19-2). clinical trials, growth factors were ineffective in human ALS. The growth factor glial-derived neurotrophic fac- NEUROTROPHIC FACTORS tor (GDNF) is important for survival of dopaminergic neurons. It has shown promising neurorestorative effects Neurotrophic factors (Table 19-3) are secreted proteins in experimental models of Parkinson’s disease and is that modulate neuronal growth, differentiation, repair, being tested using gene therapy in early-stage human clinical trials.

216 Mg2+ Mg2+ Glutamate NMDA receptor Glutamate NMDA receptor Glycine-(D-series) Glycine-(D-series) Impaired Preserved ATP generation ATP generation [Ca2+] [Ca2+] NOS Mitochondrial swelling, rupture of outer membrane PTP activation NOS NO + O2 ONOO– NO + O2 Oxidative stress [Ca2+] O2 [Ca2+] O2 AIF Caspase 9 Cytc SOD Catalase SECTION III Diseases of the Central Nervous System O2 H2O2 H2O ONOO– Hydrogen peroxide Peroxynitrite OH AIF Apaf1 + dATP Hydrogen ion Nucleus Protein oxidation Nucleus Activation of Lipid peroxidation caspase cascade DNA/RNA oxidation PARS activation ATP depletion Cell death by apoptosis NAD depletion Cell death by necrosis A B FIGURE 19-2 insult can occur due either to an abnormality in an excitotoxi- Involvement of mitochondria in cell death. A severe excito- city amino acid receptor, allowing more Ca2+ flux, or to toxic insult (A) results in cell death by necrosis, whereas a impaired functioning of other ionic channels or of energy pro- mild excitotoxic insult (B) results in apoptosis. After a severe duction, which may allow the voltage-dependent NMDA insult (such as ischemia), there is a large increase in gluta- receptor to be activated by ambient concentrations of gluta- mate activation of NMDA receptors, an increase in intracellu- mate. This event can then lead to increased mitochondrial lar Ca2+ concentrations, activation of nitric oxide synthase Ca2+ and free radical production, yet relatively preserved ATP (NOS), and increased mitochondrial Ca2+ and superoxide generation. The mitochondria may then release cytochrome c generation followed by the formation of ONOO–. This sequence (Cytc), caspase 9, apoptosis-inducing factor (AIF), and per- results in damage to cellular macromolecules including DNA, haps other mediators that lead to apoptosis. The precise role leading to activation of poly-ADP-ribose polymerase (PARS). of the PTP in this mode of cell death is still being clarified, Both mitochondrial accumulation of Ca2+ and oxidative dam- but there does appear to be involvement of the adenine age lead to activation of the permeability transition pore (PTP) nucleotide transporter that is a key component of the PTP. that is linked to excitotoxic cell death. A mild excitotoxic STEM CELLS AND TRANSPLANTATION growth, survival, differentiation, and migration of these cells exists in the mature nervous system. In rodents, The nervous system is traditionally considered to be a neural stem cells, defined as progenitor cells capable of nonmitotic organ, in particular with respect to neurons. differentiating into mature cells of neural or glial lineage, These concepts have been challenged by the finding that have been experimentally propagated from fetal CNS neural progenitor or stem cells exist in the adult CNS and neuroectodermal tissues and also from adult germi- that are capable of differentiation, migration over long nal matrix and ependyma regions. Human fetal CNS distances, and extensive axonal arborization and synapse tissue is also capable of differentiation into cells with neu- formation with appropriate targets.These capabilities also ronal, astrocyte, and oligodendrocyte morphology when indicate that the repertoire of factors required for cultured in the presence of growth factors. Impressively,

TABLE 19-3 development. Human ES cells can be differentiated into 217 dopaminergic neurons, which reverse symptoms of NEUROTROPHIC FACTORS Parkinson’s disease in experimental animal models. Studies of transplantation for patients with Huntington’s disease Neurotrophin family Transforming growth factor have also reported encouraging, although very prelimi- Nerve growth factor β family nary, results. Oligodendrocyte precursor cells transplanted Brain-derived into mice with a dysmyelinating disorder effectively neurotrophic factor Glial-derived neurotrophic migrated in the new environment, interacted with axons, Neurotrophin-3 family and mediated myelination; such experiments raise hope Neurotrophin-4 Neurturin that similar transplantation strategies may be feasible in Neurotrophin-6 Persephin human disorders of myelin such as MS. The promise of Fibroblast growth factor stem cells for treatment of both neurodegenerative dis- Cytokine family family eases and neural injury is great, but development has Ciliary neurotrophic factor Hepatocyte growth factor been slowed by unresolved concerns over safety (includ- Leukemia inhibitory factor Insulin-like growth factor ing the theoretical risk of malignant transformation of Interleukin-6 (IGF) family transplanted cells), ethics (particularly with respect to use Cardiotrophin-1 IGF-1 of fetal tissue), and efficacy. IGF-2 In developing brain, the extracellular matrix provides such cells could be stably engrafted into mouse CNS tis- stimulatory and inhibitory signals that promote neuronal CHAPTER 19 Mechanisms of Neurologic Diseases sue, creating neural chimeras. Another approach is to use migration, neurite outgrowth, and axonal extension. somatic cell nuclear transfer, in which cell nuclei are placed After neuronal damage, reexpression of inhibitory mole- inside an enucleated oocyte and then differentiated into cules such as chondroitin sulfate proteoglycans may pre- stem cells with an identical genetic background to the vent tissue regeneration. Chondroitinase degraded these donor. This technique has been utilized successfully in inhibitory molecules and enhanced axonal regeneration animal models of Parkinson’s disease. Once the repertoire and motor recovery in a rat model of spinal cord injury. of signals required for cell type specification is better Several myelin proteins, specifically Nogo, oligodendro- understood, differentiation into specific neural or glial cyte myelin glycoprotein (OMGP), and myelin-associated subpopulations can be directed in vitro; such cells could glycoprotein (MAG), may also interfere with axon also be engineered to express therapeutic molecules. regeneration. Sialidase, which cleaves one class of recep- Another promising approach is to utilize growth factors, tors for MAG, enhances axonal outgrowth. Antibodies such as BDNF, to stimulate endogenous stem cells to against Nogo promote regeneration after experimental proliferate and migrate to areas of neuronal damage. focal ischemia or spinal cord injury. Nogo, OMGP, and Administration of epidermal growth factor with fibrob- MAG all bind to the same neural receptor, the Nogo last growth factor replenished up to 50% of hippocampal receptor, which mediates its inhibitory function via the CA1 neurons a month after global ischemia in rats. The p75 neurotrophin receptor signaling. new neurons made connections and improved perfor- mance in a memory task. CELL DEATH—EXCITOTOXICITY AND APOPTOSIS Although stem cells hold tremendous promise for the treatment of debilitating neurologic diseases, such as Excitotoxicity refers to neuronal cell death caused by acti- Parkinson’s disease and spinal cord injury, it should be vation of excitatory amino acid receptors (Fig. 19-3). emphasized that medical application is in its infancy. Compelling evidence for a role of excitotoxicity, espe- Major obstacles are the generation of position- and cially in ischemic neuronal injury, is derived from exper- neurotransmitter-defined subtypes of neurons and their iments in animal models. Experimental models of stroke isolation as pure populations of the desired cells. This is are associated with increased extracellular concentrations crucial to avoid persistence of undifferentiated embry- of the excitatory amino acid neurotransmitter glutamate, onic stem (ES) cells, which can generate tumors. The and neuronal damage is attenuated by denervation of establishment of appropriate neural connections and glutamate-containing neurons or the administration of afferent control is also critical. For instance, human ES glutamate receptor antagonists. The distribution of cells motor neurons will need to be introduced at multiple sensitive to ischemia corresponds closely with that of segments in the neuraxis, and then their axons will need N-methyl-D-aspartate (NMDA) receptors (except for cere- to regenerate from the spinal cord to distal musculature. bellar Purkinje cells, which are vulnerable to hypoxia- ischemia but lack NMDA receptors); and competitive Experimental transplantation of human fetal dopamin- and noncompetitive NMDA antagonists are effective in ergic neurons in patients with Parkinson’s disease has preventing focal ischemia. In global cerebral ischemia, shown that these transplanted cells can survive within the host striatum; however, some patients developed disabling dyskinesias and this approach is no longer in clinical

218 Rolling Triggering Strong adhesion Extravasation Flow B cell Activated Gelatinases lymphocyte α4 Integrin VCAM CD 31 LFA-1 ICAM Blood-brain Chemokines Basal lamina barrier and cytokines Microglia/macrophages endothelium Astrocytes SECTION III Diseases of the Central Nervous System Activated Heat shock T cell Microglia/ proteins activation macrophages IFN-γ IL-2 Fc receptor Chemokines Antibody Brain tissue IL-1, IL-12 complement TNF, IFN, free radicals, vasoactive amines, complement, proteases, cytokines, eicosanoids Myelin damage recruitment of a secondary inflammatory wave; and immune- mediated myelin destruction. ICAM, intercellular adhesion FIGURE 19-3 molecule; LFA-1, leukocyte function-associated antigen-1; A model for experimental allergic encephalomyelitis (EAE). VCAM, vascular cell adhesion molecule; IFN, interferon; IL, Crucial steps for disease initiation and progression include interleukin; TNF, tumor necrosis factor. peripheral activation of preexisting autoreactive T cells; hom- ing to the CNS and extravasation across the blood-brain bar- rier; reactivation of T cells by exposed autoantigens; secre- tion of cytokines; activation of microglia and astrocytes and non-NMDA receptors (kainic acid and AMPA) are acti- polymerase, or those that overexpress superoxide dismu- vated, and antagonists to these receptors are protective. tase, are resistant to focal ischemia. Experimental brain damage induced by hypoglycemia is also attenuated by NMDA antagonists. Although excitotoxicity is clearly implicated in the pathogenesis of cell death in stroke, to date treatment Excitotoxicity is not a single event but rather a cascade with NMDA antagonists has not proven to be clinically of cell injury. Excitotoxicity causes influx of calcium into useful. Transient receptor potentials (TRP) are calcium cells, and much of the calcium is sequestered in mito- channels that are activated by oxidative stress in parallel chondria rather than in the cytoplasm. Increased cytoplas- with excitotoxic signal pathways. In addition, glutamate- mic calcium causes metabolic dysfunction and free radical independent pathways of calcium influx via acid-sensing generation; activates protein kinases, phospholipases, nitric ion channels have been identified.These channels trans- oxide synthase, proteases, and endonucleases; and inhibits port calcium in the setting of acidosis and substrate protein synthesis. Activation of nitric oxide synthase gen- depletion, and pharmacologic blockade of these chan- erates nitric oxide (NO•), which can react with superox- nels markedly attenuates stroke injury. These channels ide (O•2) to generate peroxynitrite (ONOO–), which offer a potential new therapeutic target for stroke. may play a direct role in neuronal injury. Another critical pathway is activation of poly-ADP-ribose polymerase, Apoptosis, or programmed cell death, plays an impor- which occurs in response to free radical–mediated DNA tant role in both physiologic and pathologic conditions. damage. Experimentally, mice with knockout mutations During embryogenesis, apoptotic pathways operate to of neuronal nitric oxide synthase or poly-ADP-ribose destroy neurons that fail to differentiate appropriately or reach their intended targets. There is mounting evidence

for an increased rate of apoptotic cell death in a variety of ubiquitin carboxy-terminal hydrolase. Parkin, which causes 219CHAPTER 19 Mechanisms of Neurologic Diseases acute and chronic neurologic diseases. Apoptosis is char- autosomal recessive early-onset Parkinson’s disease, is a acterized by neuronal shrinkage, chromatin condensation, ubiquitin ligase. The characteristic histopathologic feature and DNA fragmentation, whereas necrotic cell death is of Parkinson’s disease is the Lewy body, an eosinophilic associated with cytoplasmic and mitochondrial swelling cytoplasmic inclusion that contains both neurofilaments followed by dissolution of the cell membrane. Apoptotic and α-synuclein. Huntington’s disease and cerebellar and necrotic cell death can coexist or be sequential degenerations are associated with expansions of polyglut- events, depending on the severity of the initiating insult. amine repeats in proteins, which aggregate to produce Cellular energy reserves appear to have an important role neuronal intranuclear inclusions. Familial ALS is associ- in these two forms of cell death, with apoptosis favored ated with superoxide dismutase mutations and cytoplas- under conditions in which ATP levels are preserved. Evi- mic inclusions containing superoxide dismutase. In dence of DNA fragmentation has been found in a num- autosomal dominant neurohypophyseal diabetes insipidus, ber of degenerative neurologic disorders, including mutations in vasopressin result in abnormal protein pro- Alzheimer’s disease, Huntington’s disease, and ALS. The cessing, accumulation in the endoplasmic reticulum, and best characterized genetic neurologic disorder related to cell death. apoptosis is infantile spinal muscular atrophy (Werdnig- Hoffmann disease), in which two genes thought to be The current major scientific question is whether pro- involved in the apoptosis pathways are causative. tein aggregates contribute to neuronal death or whether they are merely secondary bystanders. A major focus in all Mitochondria are essential in controlling specific the neurodegenerative diseases is now on small protein apoptosis pathways. The redistribution of cytochrome c, aggregates termed oligomers.These may be the toxic species as well as apoptosis-inducing factor (AIF), from mito- of β-amyloid, α-synuclein, and proteins with expanded chondria during apoptosis leads to the activation of a polyglutamines such as are associated with Huntington’s cascade of intracellular proteases known as caspases. disease. Protein aggregates are usually ubiquinated, which Caspase-independent apoptosis occurs after DNA dam- targets them for degradation by the 26S component of the age, activation of poly-ADP-ribose polymerase, and proteosome. An inability to degrade protein aggregates translocation of AIF into the nucleus. Redistribution of could lead to cellular dysfunction, impaired axonal trans- cytochrome c is prevented by overproduction of the apop- port, and cell death by apoptotic mechanisms. totic protein BCL2 and is promoted by the proapoptotic protein BAX. These pathways may be triggered by acti- In experimental models of Huntington’s disease and vation of a large pore in the mitochondrial inner mem- cerebellar degeneration, protein aggregates are not well brane known as the permeability transition pore, although correlated with neuronal death and may be protective. in other circumstances they occur independently. A substantial body of evidence suggests that the mutant Recent studies suggest that blocking the mitochondrial proteins with polyglutamine expansions in these diseases pore reduces both hypoglycemic and ischemic cell bind to transcription factors and that this contributes to death. Mice deficient in cyclophilin D, a key protein disease pathogenesis. In Huntington’s disease there is involved in opening the permeability transition pore, are dysfunction of the transcriptional co-regulator, PGC- resistant to necrosis produced by focal cerebral ischemia. 1α, a key regulator of mitochondrial biogenesis. Agents that upregulate gene transcription are neuroprotective in PROTEIN AGGREGATION AND animal models of these diseases. A number of com- NEURODEGENERATION pounds have been developed to block β-amyloid pro- duction and/or aggregation, and these agents are being The possibility that protein aggregation plays a role in studied in early clinical trials in humans. the pathogenesis of neurodegenerative diseases is a major focus of current research. Protein aggregation is a major SYSTEMS NEUROSCIENCE histopathologic hallmark of neurodegenerative diseases. Deposition of β-amyloid is strongly implicated in the Systems neuroscience refers to study of the functions of pathogenesis of Alzheimer’s disease. Genetic mutations in neurocircuits and how they relate to brain function, familial Alzheimer’s disease cause increased production of behavior, motor activity, and cognition. Brain imaging β-amyloid with 42 amino acids, which has an increased techniques, primarily functional MRI (fMRI) and posi- propensity to aggregate, as compared to β-amyloid with tion emission tomography (PET), have made it possible 40 amino acids. Mutations in genes encoding the MAPT to investigate cognitive processes such as perception, lead to altered splicing of tau and the production of neu- making judgments, paying attention, and thinking. This rofibrillary tangles in frontotemporal dementia and pro- has allowed insights into how networks of neurons gressive supranuclear palsy. Familial Parkinson’s disease is operate to produce behavior. Many of these studies at associated with mutations in α-synuclein, parkin, and the present are based on determining the connectivity of neural circuits and how they operate, and how this can

SECTION III Diseases of the Central Nervous System220 be then modeled to produce improved understanding of with declarative memory consolidation, but it also physiologic processes. fMRI uses contrast mechanisms involves activation in the ventral medial prefrontal cor- related to physiologic changes in tissue, and brain perfu- tex. Consolidation of memory over time results in sion can be studied by observing the time-course of decreased activity of the hippocampus and progressively changes in brain water signal as a bolus of injected stronger activation in the ventral medial prefrontal paramagnetic gadolinium contrast moves through the region associated with retrieval of consolidated memo- brain. More recently, to study intrinsic contrast-related ries. An elegant study used MRI to identify the brain local changes in blood oxygenation with brain activity, protein KIBRA as being significantly associated with blood-oxygen-level-dependent (BOLD) contrast has human memory performance. This locus was initially been used to provide a rapid noninvasive approach for identified in a genome-wide screen of three indepen- functional assessment. These techniques have been reli- dent populations, which were studied in relation to the ably utilized in the field of both behavior and cognitive inability to perform verbal memory tasks. Several sciences. One example is the use of fMRI to demon- KIBRA alleles were associated with improved free recall strate mirror neuron systems, imitative pathways acti- performance. The authors then utilized fMRI to detect vated when observing actions of others (Fig. 19-4). KIBRA allele–dependent differences in hippocampal Mirror neurons are thought to be important for social activation during memory retrieval. These experiments conditioning and for many forms of learning, and provided strong evidence that KIBRA plays a direct role abnormalities in mirror neurons may underlie some in human memory function. fMRI has also been uti- autism disorders. Data also suggest that enhancement of lized to identify sequences of brain activation involved mirror neuron pathways might have potential for reha- in normal movements and alterations in their activation bilitation after stroke. Other examples of the use of associated with both injury and recovery, and to plan fMRI include the study of memory. Recent studies have neurosurgical operations. Diffusion tensor imaging is a shown that not only is hippocampal activity correlated recently developed MRI technique that can measure A BC FIGURE 19-4 presented to the right visual field (in red, left visual cortex) Mirror neuron systems are bilaterally activated during and to the left visual field (in blue, right visual cortex). C. Lat- imitation. A. Bilateral activations (circled in yellow) in inferior eralized primary motor activation for hand actions imitated frontal mirror neuron areas during imitation, as measured by with the right hand (in red, left motor cortex) and with the left BOLD fMRI signal changes. In red, activation during right hand (in blue, right motor cortex). (From L. Aziz-Zadeh et al: hand imitation. In blue, activation during left hand imitation. J Neurosci 26:2964, 2006.) B. In contrast, there is lateralized (contralateral) primary visual activation of the primary visual cortex for imitated actions

macroscopic axonal organization in nervous system tis- disease onset delay and survival extension in transgenic ALS 221 sues; it appears to be useful in assessing myelin and axonal injuries as well as brain development. mice. Gene Ther. 12:2134, 2009 KRIEGSTEIN A, ALVAREZ-BUYLLA A: The glial nature of embryonic FURTHER READINGS and adult neural stem cells.Annu Rev Neurosci. 32:149, 2009 BATES TC et al: Association of KIBRA and memory. Neurosci Lett LIN MT, BEAL MF: Mitochondrial dysfunction and oxidative stress in 458:140, 2009 neurodegenerative diseases. Nature 443:787, 2006 BURATTI E, BARALLE FE:The molecular links between TDP-43 dys- LUKONG KE et al: RNA-binding proteins in human genetic disease. function and neurodegenration.Adv Genet 66:1, 2009 Trends Genet. 24:416, 2008 CATTENEO L, RIZZOLATTI G:The mirror neuron system.Arch Neurol. MEHLER MF: Epigenetics and the nervous system. Ann Neurol 66:557, 2009 64:602, 2008 DOYLE KP et al: Mechanisms of ischemic brain damage. Neurophar- ROY NS et al: Functional engraftment of human ES cell–derived macology 55:310, 2008 dopaminergic neurons enriched by coculture with telomerase- HWANG DH et al: Intrathecal transplantation of human neural stem immortalized midbrain astrocytes. Nat Med 12:1259, 2006 cells overexpressing VEGF provide behavioral improvement, TAKASHIMA A et al: Declarative memory consolidation in humans: A prospective functional magnetic resonance imaging study. Proc Natl Acad Sci USA 103:756, 2006 YANG LJS et al: Sialidase enhances spinal axon outgrowth in vivo. Proc Natl Acad Sci USA 103:11057, 2006 CHAPTER 19 Mechanisms of Neurologic Diseases

CHAPTER 20 SEIZURES AND EPILEPSY Daniel H. Lowenstein I Classification of Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 Electrophysiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Partial Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Brain Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Generalized Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 I Differential Diagnosis of Seizures . . . . . . . . . . . . . . . . . . . . . . 234 Unclassified Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Psychogenic Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 I Epilepsy Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Status Epilepticus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Juvenile Myoclonic Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . 226 I Beyond Seizures: Other Management Issues . . . . . . . . . . . . 243 Lennox-Gastaut Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Interictal Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Mesial Temporal Lobe Epilepsy Syndrome . . . . . . . . . . . . . . 226 Mortality of Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 Psychosocial Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 I The Causes of Seizures and Epilepsy . . . . . . . . . . . . . . . . . . 226 Employment, Driving, and Other Activities . . . . . . . . . . . . . . . 244 Causes According to Age . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 I Special Issues Related to Women and Epilepsy . . . . . . . . . . 244 Catamenial Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 I Basic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 Mechanisms of Seizure Initiation and Propagation . . . . . . . . . 230 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Mechanisms of Epileptogenesis . . . . . . . . . . . . . . . . . . . . . . 231 Breast-Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Genetic Causes of Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . 231 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Mechanisms of Action of Antiepileptic Drugs . . . . . . . . . . . . 232 History and Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 A seizure (from the Latin sacire, “to take possession of ”) among the many causes of epilepsy there are various is a paroxysmal event due to abnormal, excessive, hyper- epilepsy syndromes in which the clinical and pathologic synchronous discharges from an aggregate of central characteristics are distinctive and suggest a specific under- nervous system (CNS) neurons. Depending on the dis- lying etiology. tribution of discharges, this abnormal CNS activity can Using the definition of epilepsy as two or more unpro- have various manifestations, ranging from dramatic con- voked seizures, the incidence of epilepsy is ~0.3–0.5% in vulsive activity to experiential phenomena not readily different populations throughout the world, and the discernible by an observer. Although a variety of factors prevalence of epilepsy has been estimated at 5–10 persons influence the incidence and prevalence of seizures, per 1000. ~5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood. CLASSIFICATION OF SEIZURES The meaning of the term seizure needs to be carefully distinguished from that of epilepsy. Epilepsy describes a Determining the type of seizure that has occurred is condition in which a person has recurrent seizures due to essential for focusing the diagnostic approach on partic- a chronic, underlying process. This definition implies ular etiologies, selecting the appropriate therapy, and that a person with a single seizure, or recurrent seizures providing potentially vital information regarding prog- due to correctable or avoidable circumstances, does not nosis. In 1981, the International League against Epilepsy necessarily have epilepsy. Epilepsy refers to a clinical (ILAE) published a modified version of the Interna- phenomenon rather than a single disease entity, since tional Classification of Epileptic Seizures that has con- there are many forms and causes of epilepsy. However, tinued to be a useful classification system (Table 20-1). 222

TABLE 20-1 involuntary movements of the contralateral, left hand. 223 CHAPTER 20 Seizures and Epilepsy These movements are typically clonic (i.e., repetitive, flexion/ CLASSIFICATION OF SEIZURES extension movements) at a frequency of ~2–3 Hz; pure tonic posturing may be seen as well. Since the cortical 1. Partial seizures region controlling hand movement is immediately adja- a. Simple partial seizures (with motor, sensory, cent to the region for facial expression, the seizure may autonomic, or psychic signs) also cause abnormal movements of the face synchronous b. Complex partial seizures with the movements of the hand. The electroencephalo- c. Partial seizures with secondary generalization gram (EEG) recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal discharges 2. Primarily generalized seizures in a very limited region over the appropriate area of cere- a. Absence (petit mal) bral cortex if the seizure focus involves the cerebral con- b. Tonic-clonic (grand mal) vexity. Seizure activity occurring within deeper brain c. Tonic structures is often not recorded by the standard EEG, d. Atonic however, and may require intracranial electrodes for its e. Myoclonic detection. 3. Unclassified seizures Three additional features of partial motor seizures are a. Neonatal seizures worth noting. First, in some patients the abnormal b. Infantile spasms motor movements may begin in a very restricted region such as the fingers and gradually progress (over seconds This system is based on the clinical features of seizures to minutes) to include a larger portion of the extremity. and associated electroencephalographic findings. Other This phenomenon, described by Hughlings Jackson and potentially distinctive features such as etiology or cellular known as a “Jacksonian march,” represents the spread of substrate are not considered in this classification system, seizure activity over a progressively larger region of although this will undoubtedly change in the future as motor cortex. Second, patients may experience a local- more is learned about the pathophysiologic mechanisms ized paresis (Todd’s paralysis) for minutes to many hours that underlie specific seizure types. in the involved region following the seizure. Third, in rare instances the seizure may continue for hours or A fundamental principle is that seizures may be either days. This condition, termed epilepsia partialis continua, is partial (synonymous with focal) or generalized. Partial often refractory to medical therapy. seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. Generalized seizures Simple partial seizures may also manifest as changes in involve diffuse regions of the brain simultaneously. Partial somatic sensation (e.g., paresthesias), vision (flashing lights seizures are usually associated with structural abnormali- or formed hallucinations), equilibrium (sensation of falling ties of the brain. In contrast, generalized seizures may or vertigo), or autonomic function (flushing, sweating, result from cellular, biochemical, or structural abnormali- piloerection). Simple partial seizures arising from the tem- ties that have a more widespread distribution. poral or frontal cortex may also cause alterations in hearing, olfaction, or higher cortical function (psychic symptoms). PARTIAL SEIZURES This includes the sensation of unusual, intense odors (e.g., burning rubber or kerosene) or sounds (crude or highly Partial seizures occur within discrete regions of the complex sounds), or an epigastric sensation that rises from brain. If consciousness is fully preserved during the the stomach or chest to the head. Some patients describe seizure, the clinical manifestations are considered rela- odd, internal feelings such as fear, a sense of impending tively simple and the seizure is termed a simple partial change, detachment, depersonalization, déjà vu, or illusions seizure. If consciousness is impaired, the symptomatology that objects are growing smaller (micropsia) or larger is more complex and the seizure is termed a complex par- (macropsia). When such symptoms precede a complex tial seizure. An important additional subgroup comprises partial or secondarily generalized seizure, these simple par- those seizures that begin as partial seizures and then spread tial seizures serve as a warning, or aura. diffusely throughout the cortex, i.e., partial seizures with secondary generalization. Complex Partial Seizures Simple Partial Seizures Complex partial seizures are characterized by focal seizure activity accompanied by a transient impairment Simple partial seizures cause motor, sensory, autonomic, or of the patient’s ability to maintain normal contact with psychic symptoms without an obvious alteration in con- the environment. The patient is unable to respond sciousness. For example, a patient having a partial motor appropriately to visual or verbal commands during the seizure arising from the right primary motor cortex in the seizure and has impaired recollection or awareness of the vicinity controlling hand movement will note the onset of

SECTION III Diseases of the Central Nervous System224 ictal phase. The seizures frequently begin with an aura GENERALIZED SEIZURES (i.e., a simple partial seizure) that is stereotypic for the patient. The start of the ictal phase is often a sudden By definition, generalized seizures arise from both cere- behavioral arrest or motionless stare, which marks the bral hemispheres simultaneously. However, it is currently onset of the period of amnesia. The behavioral arrest is impossible to exclude entirely the existence of a focal usually accompanied by automatisms, which are involun- region of abnormal activity that initiates the seizure tary, automatic behaviors that have a wide range of man- prior to rapid secondary generalization. For this reason, ifestations.Automatisms may consist of very basic behav- generalized seizures may be practically defined as bilat- iors such as chewing, lip smacking, swallowing, or eral clinical and electrographic events without any “picking” movements of the hands, or more elaborate detectable focal onset. Fortunately, several types of gen- behaviors such as a display of emotion or running. The eralized seizures have distinctive features that facilitate patient is typically confused following the seizure, and clinical diagnosis. the transition to full recovery of consciousness may range from seconds up to an hour. Examination imme- Absence Seizures (Petit Mal) diately following the seizure may show an anterograde amnesia or, in cases involving the dominant hemisphere, Absence seizures are characterized by sudden, brief a postictal aphasia. lapses of consciousness without loss of postural control. The routine interictal (i.e., between seizures) EEG in The seizure typically lasts for only seconds, conscious- patients with complex partial seizures is often normal or ness returns as suddenly as it was lost, and there is no may show brief discharges termed epileptiform spikes, or postictal confusion. Although the brief loss of conscious- sharp waves. Since complex partial seizures can arise from ness may be clinically inapparent or the sole manifesta- the medial temporal lobe or inferior frontal lobe, i.e., tion of the seizure discharge, absence seizures are usually regions distant from the scalp, the EEG recorded during accompanied by subtle, bilateral motor signs such as the seizure may be nonlocalizing. However, the seizure rapid blinking of the eyelids, chewing movements, or focus is often detected using sphenoidal or surgically small-amplitude, clonic movements of the hands. placed intracranial electrodes. The range of potential clinical behaviors linked to Absence seizures usually begin in childhood (4–8 complex partial seizures is so broad that extreme caution years) or early adolescence and are the main seizure type is advised before concluding that stereotypic episodes of in 15–20% of children with epilepsy. The seizures can bizarre or atypical behavior are not due to seizure activ- occur hundreds of times per day, but the child may be ity. In such cases additional, detailed EEG studies may be unaware of or unable to convey their existence. Since helpful. the clinical signs of the seizures are subtle, especially to new parents, it is not surprising that the first clue to Partial Seizures with Secondary Generalization absence epilepsy is often unexplained “daydreaming” and a decline in school performance recognized by a Partial seizures can spread to involve both cerebral teacher. hemispheres and produce a generalized seizure, usually of the tonic-clonic variety (discussed later). Secondary The electrophysiologic hallmark of typical absence generalization is observed frequently following simple seizures is a generalized, symmetric, 3-Hz spike-and-wave partial seizures, especially those with a focus in the discharge that begins and ends suddenly, superimposed on a frontal lobe, but may also be associated with partial normal EEG background. Periods of spike-and-wave dis- seizures occurring elsewhere in the brain. A partial charges lasting more than a few seconds usually correlate seizure with secondary generalization is often difficult to with clinical signs, but the EEG often shows many more distinguish from a primary generalized tonic-clonic brief bursts of abnormal cortical activity than were sus- seizure, since bystanders tend to emphasize the more pected clinically. Hyperventilation tends to provoke these dramatic, generalized convulsive phase of the seizure and electrographic discharges and even the seizures themselves overlook the more subtle, focal symptoms present at and is routinely used when recording the EEG. onset. In some cases, the focal onset of the seizure becomes apparent only when a careful history identifies Typical absence seizures are often associated with a preceding aura (i.e., simple partial seizure). Often, generalized, tonic-clonic seizures, but patients usually however, the focal onset is not clinically evident and have no other neurologic problems and respond well to may be established only through careful EEG analysis. treatment with specific anticonvulsants. Although esti- Nonetheless, distinguishing between these two entities is mates vary, ~60–70% of such patients will have a sponta- extremely important, as there may be substantial differ- neous remission during adolescence. ences in the evaluation and treatment of partial versus generalized seizure disorders. Atypical Absence Seizures Atypical absence seizures have features that deviate both clinically and electrophysiologically from typical absence

seizures. For example, the lapse of consciousness is usu- polyspike discharges. In the clonic phase, the high- 225 CHAPTER 20 Seizures and Epilepsy ally of longer duration and less abrupt in onset and ces- amplitude activity is typically interrupted by slow waves sation, and the seizure is accompanied by more obvious to create a spike-and-wave pattern. The postictal EEG motor signs that may include focal or lateralizing fea- shows diffuse slowing that gradually recovers as the patient tures. The EEG shows a generalized, slow spike-and- awakens. wave pattern with a frequency of Յ2.5/s, as well as other abnormal activity. Atypical absence seizures are usually There are many variants of the generalized tonic-clonic associated with diffuse or multifocal structural abnor- seizure, including pure tonic and pure clonic seizures. malities of the brain and therefore may accompany Brief tonic seizures lasting only a few seconds are espe- other signs of neurologic dysfunction such as mental cially noteworthy since they are usually associated with retardation. Furthermore, the seizures are less responsive specific epileptic syndromes having mixed seizure phe- to anticonvulsants compared to typical absence seizures. notypes, such as the Lennox-Gastaut syndrome (discussed later). Generalized, Tonic-Clonic Seizures (Grand Mal) Atonic Seizures Primary generalized, tonic-clonic seizures are the main Atonic seizures are characterized by sudden loss of pos- seizure type in ~10% of all persons with epilepsy. They tural muscle tone lasting 1–2 s. Consciousness is briefly are also the most common seizure type resulting from impaired, but there is usually no postictal confusion. A metabolic derangements and are therefore frequently very brief seizure may cause only a quick head drop or encountered in many different clinical settings. The nodding movement, while a longer seizure will cause seizure usually begins abruptly without warning, the patient to collapse.This can be extremely dangerous, although some patients describe vague premonitory since there is a substantial risk of direct head injury with symptoms in the hours leading up to the seizure. This the fall. The EEG shows brief, generalized spike-and- prodrome is distinct from the stereotypic auras associated wave discharges followed immediately by diffuse slow with focal seizures that secondarily generalize.The initial waves that correlate with the loss of muscle tone. Similar phase of the seizure is usually tonic contraction of mus- to pure tonic seizures, atonic seizures are usually seen in cles throughout the body, accounting for a number of association with known epileptic syndromes. the classic features of the event. Tonic contraction of the muscles of expiration and the larynx at the onset will Myoclonic Seizures produce a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis Myoclonus is a sudden and brief muscle contraction that develops. Contraction of the jaw muscles may cause bit- may involve one part of the body or the entire body. A ing of the tongue. A marked enhancement of sympa- normal, common physiologic form of myoclonus is the thetic tone leads to increases in heart rate, blood pressure, sudden jerking movement observed while falling asleep. and pupillary size. After 10–20 s, the tonic phase of the Pathologic myoclonus is most commonly seen in associ- seizure typically evolves into the clonic phase, produced ation with metabolic disorders, degenerative CNS dis- by the superimposition of periods of muscle relaxation eases, or anoxic brain injury (Chap. 22). Although the on the tonic muscle contraction. The periods of relax- distinction from other forms of myoclonus is imprecise, ation progressively increase until the end of the ictal phase, myoclonic seizures are considered to be true epileptic which usually lasts no more than 1 min. The postictal events since they are caused by cortical (versus subcorti- phase is characterized by unresponsiveness, muscular flac- cal or spinal) dysfunction.The EEG may show bilaterally cidity, and excessive salivation that can cause stridorous synchronous spike-and-wave discharges synchronized breathing and partial airway obstruction. Bladder or bowel with the myoclonus, although these can be obscured by incontinence may occur at this point. Patients gradually movement artifact. Myoclonic seizures usually coexist regain consciousness over minutes to hours, and during with other forms of generalized seizure disorders but are this transition there is typically a period of postictal con- the predominant feature of juvenile myoclonic epilepsy fusion. Patients subsequently complain of headache, (discussed below). fatigue, and muscle ache that can last for many hours. The duration of impaired consciousness in the postictal UNCLASSIFIED SEIZURES phase can be extremely long, i.e., many hours, in patients with prolonged seizures or underlying CNS diseases such Not all seizure types can be classified as partial or gener- as alcoholic cerebral atrophy. alized. This appears to be especially true of seizures that occur in neonates and infants. The distinctive pheno- The EEG during the tonic phase of the seizure types of seizures at these early ages likely result, in part, shows a progressive increase in generalized low-voltage from differences in neuronal function and connectivity fast activity, followed by generalized high-amplitude, in the immature versus mature CNS.

SECTION III Diseases of the Central Nervous System226 EPILEPSY SYNDROMES appears to be essential in the pathophysiology of MTLE for many patients (Fig. 20-1). Recognition of this syn- Epilepsy syndromes are disorders in which epilepsy is a drome is especially important because it tends to be predominant feature, and there is sufficient evidence refractory to treatment with anticonvulsants but responds (e.g., through clinical, EEG, radiologic, or genetic obser- extremely well to surgical intervention. Advances in the vations) to suggest a common underlying mechanism. understanding of basic mechanisms of epilepsy have Three important epilepsy syndromes are listed below; come through studies of experimental models of additional examples with a known genetic basis are MTLE, discussed later. given in Table 20-2. THE CAUSES OF SEIZURES JUVENILE MYOCLONIC EPILEPSY AND EPILEPSY Juvenile myoclonic epilepsy (JME) is a generalized seizure Seizures are a result of a shift in the normal balance of disorder of unknown cause that appears in early adoles- excitation and inhibition within the CNS. Given the cence and is usually characterized by bilateral myoclonic numerous properties that control neuronal excitability, it jerks that may be single or repetitive. The myoclonic is not surprising that there are many different ways to seizures are most frequent in the morning after awaken- perturb this normal balance, and therefore many differ- ing and can be provoked by sleep deprivation. Con- ent causes of both seizures and epilepsy. Three clinical sciousness is preserved unless the myoclonus is especially observations emphasize how a variety of factors deter- severe. Many patients also experience generalized tonic- mine why certain conditions may cause seizures or clonic seizures, and up to one-third have absence seizures. epilepsy in a given patient. The condition is otherwise benign, and although com- plete remission is uncommon, the seizures respond well 1. The normal brain is capable of having a seizure under the to appropriate anticonvulsant medication. There is often appropriate circumstances, and there are differences between a family history of epilepsy, and genetic linkage studies individuals in the susceptibility or threshold for seizures. suggest a polygenic cause. For example, seizures may be induced by high fevers in children who are otherwise normal and who LENNOX-GASTAUT SYNDROME never develop other neurologic problems, including epilepsy. However, febrile seizures occur only in a Lennox-Gastaut syndrome occurs in children and is relatively small proportion of children. This implies defined by the following triad: (1) multiple seizure types there are various underlying endogenous factors that (usually including generalized tonic-clonic, atonic, and influence the threshold for having a seizure. Some atypical absence seizures); (2) an EEG showing slow (<3 of these factors are clearly genetic, as it has been Hz) spike-and-wave discharges and a variety of other shown that a family history of epilepsy will influ- abnormalities; and (3) impaired cognitive function in ence the likelihood of seizures occurring in other- most but not all cases. Lennox-Gastaut syndrome is asso- wise normal individuals. Normal development also ciated with CNS disease or dysfunction from a variety plays an important role, since the brain appears to of causes, including developmental abnormalities, peri- have different seizure thresholds at different matura- natal hypoxia/ischemia, trauma, infection, and other tional stages. acquired lesions. The multifactorial nature of this syn- drome suggests that it is a nonspecific response of the 2. There are a variety of conditions that have an extremely brain to diffuse neural injury. Unfortunately, many high likelihood of resulting in a chronic seizure disorder. patients have a poor prognosis due to the underlying One of the best examples of this is severe, penetrat- CNS disease and the physical and psychosocial conse- ing head trauma, which is associated with up to a quences of severe, poorly controlled epilepsy. 50% risk of subsequent epilepsy. The high propen- sity for severe traumatic brain injury to lead to MESIAL TEMPORAL LOBE EPILEPSY epilepsy suggests that the injury results in a long- SYNDROME lasting pathologic change in the CNS that trans- forms a presumably normal neural network into Mesial temporal lobe epilepsy (MTLE) is the most com- one that is abnormally hyperexcitable. This process mon syndrome associated with complex partial seizures is known as epileptogenesis, and the specific changes and is an example of a symptomatic, partial epilepsy that result in a lowered seizure threshold can be with distinctive clinical, electroencephalographic, and considered epileptogenic factors. Other processes asso- pathologic features (Table 20-3). High-resolution MRI ciated with epileptogenesis include stroke, infections, can detect the characteristic hippocampal sclerosis that and abnormalities of CNS development. Likewise, the genetic abnormalities associated with epilepsy likely

TABLE 20-2 227 EXAMPLES OF GENES ASSOCIATED WITH EPILEPSY SYNDROMESa GENE (LOCUS) FUNCTION OF GENE CLINICAL SYNDROME COMMENTS CHRNA4 Nicotinic acetylcholine Autosomal dominant nocturnal Rare; first identified in a large CHAPTER 20 Seizures and Epilepsy (20q13.2) receptor subunit; mutations frontal lobe epilepsy (ADNFLE); Australian family; other families cause alterations in Ca2+ childhood onset; brief, nighttime found to have mutations in KCNQ2 flux through the receptor; seizures with prominent motor CHRNA2 or CHRNB2, and some (20q13.3) this may reduce amount movements; often misdiagnosed families appear to have mutations of GABA release in as primary sleep disorder at other loci SCN1B presynaptic terminals (19q12.1) Benign familial neonatal Rare; other families found to have Voltage-gated potassium convulsions (BFNC); autosomal mutations in KCNQ3; sequence and LGI1 (10q24) channel subunits; mutation dominant inheritance; onset in functional homology to KCNQ1, in pore regions may cause 1st week of life in infants who mutations of which cause long QT CSTB a 20–40% reduction of are otherwise normal; remission syndrome and a cardiac-auditory potassium currents, which usually within weeks to months; syndrome EPM2A (6q24) will lead to impaired long-term epilepsy in 10–15% repolarization Incidence uncertain; GEFS+ identified Doublecortin Generalized epilepsy with febrile in other families with mutations in (Xq21-24) β subunit of a voltage-gated seizures plus (GEFS+); autosomal other sodium channel subunits sodium channel; mutation dominant inheritance; presents (SCN1A and SCN2A) and GABAA disrupts disulfide bridge that with febrile seizures at median receptor subunit (GABRG2 and is crucial for structure of 1 year, which may persist GABRA1); significant phenotypic extracellular domain; mutated >6 years, then variable seizure heterogeneity within same family, β subunit leads to slower types not associated with fever including members with febrile sodium channel inactivation seizures only Autosomal dominant partial Leucine-rich glioma-inactivated epilepsy with auditory features Mutations found in approximately 1 gene; previous evidence for (ADPEAF); a form of idiopathic 50% of families containing two or role in glial tumor progression; lateral temporal lobe epilepsy more subjects with idiopathic protein homology suggests with auditory symptoms or localization-related epilepsy with a possible role in nervous aphasia as a major simple partial ictal auditory symptoms, suggesting system development seizure manifestation; age of that at least one other gene may onset usually between 10 and underlie this syndrome. LGI1 is the Cystatin B, a noncaspase 25 years only gene identified so far in cysteine protease inhibitor; temporal lobe epilepsy normal protein may block Progressive myoclonus epilepsy neuronal apoptosis by (PME) (Unverricht-Lundborg Overall rare, but relatively common in inhibiting caspases directly disease); autosomal recessive Finland and Western Mediterranean or indirectly (via cathepsins), inheritance; age of onset between (>1 in 20,000); precise role of or controlling proteolysis 6 and 15 years, myoclonic cystatin B in human disease seizures, ataxia, and progressive unknown, although mice with null Laforin, a protein tyrosine cognitive decline; brain shows mutations of cystatin B have similar phosphatase (PTP); may neuronal degeneration syndrome influence glycogen Progressive myoclonus epilepsy metabolism, which is known (Lafora’s disease); autosomal Most common PME in Southern to be regulated by recessive inheritance; onset age Europe, Middle East, Northern phosphatases 6–19 years, death within 10 years; Africa, and Indian subcontinent; brain degeneration associated genetic heterogeneity; unknown Doublecortin, expressed with polyglucosan intracellular whether seizure phenotype due to primarily in frontal lobes; inclusion bodies in numerous degeneration or direct effects of function unknown; potentially organs abnormal laforin expression. an intracellular signaling Classic lissencephaly associated molecule with severe mental retardation Relatively rare but of uncertain and seizures in men; subcortical incidence, recent increased band heterotopia with more subtle ascertainment due to improved findings in women (presumably imaging techniques; relationship due to random X-inactivation); between migration defect and X-linked dominant seizure phenotype unknown aThe first four syndromes listed in the table (ADNFLE, BFNC, GEFS+, and ADPEAF) are examples of idiopathic epilepsies associated with identified gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype. Note: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy.

228 TABLE 20-3 CHARACTERISTICS OF THE MESIAL TEMPORAL LOBE EPILEPSY SYNDROME History History of febrile seizures Rare secondarily generalized seizures Family history of epilepsy Seizures may remit and reappear Early onset Seizures often intractable Clinical observations Aura common Postictal disorientation, memory loss, Behavioral arrest/stare dysphasia (with focus in dominant Complex automatisms hemisphere) Unilateral posturing Laboratory studies Unilateral or bilateral anterior temporal spikes on EEG Hypometabolism on interictal PET Hypoperfusion on interictal SPECT Material-specific memory deficits on intracranial amobarbital (Wada) test MRI findings Small hippocampus with increased signal on T2-weighted sequences SECTION III Diseases of the Central Nervous System Small temporal lobe Enlarged temporal horn Pathologic findings Highly selective loss of specific cell populations within hippocampus in most cases Note: EEG, electroencephalogram; PET, positron emission tomography; SPECT, single photon emission computed tomography. involve processes that trigger the appearance of spe- even years between seizures. This implies there are cific sets of epileptogenic factors. important provocative or precipitating factors that induce 3. Seizures are episodic. Patients with epilepsy have seizures seizures in patients with epilepsy. Similarly, precipitating intermittently and, depending on the underlying cause, factors are responsible for causing the single seizure in many patients are completely normal for months or someone without epilepsy. Precipitants include those due to intrinsic physiologic processes, such as psycho- FIGURE 20-1 logical or physical stress, sleep deprivation, or hormonal Mesial temporal lobe epilepsy. The EEG suggested a right changes associated with the menstrual cycle.They also temporal lobe focus. Coronal high-resolution T2-weighted include exogenous factors such as exposure to toxic fast spin echo magnetic resonance image obtained through substances and certain medications. the body of the hippocampus demonstrates abnormal high- signal intensity in the right hippocampus (white arrows; com- These observations emphasize the concept that the pare with the normal hippocampus on the left, black arrows) many causes of seizures and epilepsy result from a consistent with mesial temporal sclerosis. dynamic interplay between endogenous factors, epilepto- genic factors, and precipitating factors. The potential role of each needs to be carefully considered when determin- ing the appropriate management of a patient with seizures. For example, the identification of predisposing factors (e.g., family history of epilepsy) in a patient with febrile seizures may increase the necessity for closer follow-up and a more aggressive diagnostic evaluation. Finding an epileptogenic lesion may help in the estimation of seizure recurrence and duration of therapy. Finally, removal or modification of a precipitating factor may be an effective and safer method for preventing further seizures than the prophylactic use of anticonvulsant drugs. CAUSES ACCORDING TO AGE In practice, it is useful to consider the etiologies of seizures based on the age of the patient, as age is one of the most

important factors determining both the incidence and replacement.The idiopathic or inherited forms of benign 229 the likely causes of seizures or epilepsy (Table 20-4). neonatal convulsions are also seen during this time period. During the neonatal period and early infancy, potential causes include hypoxic-ischemic encephalopathy, trauma, The most common seizures arising in late infancy and CNS infection, congenital CNS abnormalities, and meta- early childhood are febrile seizures, which are seizures bolic disorders. Babies born to mothers using neurotoxic associated with fevers but without evidence of CNS drugs such as cocaine, heroin, or ethanol are susceptible to infection or other defined causes.The overall prevalence drug-withdrawal seizures in the first few days after is 3–5% and even higher in some parts of the world, delivery. Hypoglycemia and hypocalcemia, which can such as Asia. Patients often have a family history of occur as secondary complications of perinatal injury, are febrile seizures or epilepsy. Febrile seizures usually occur also causes of seizures early after delivery. Seizures due to between 3 months and 5 years of age and have a peak inborn errors of metabolism usually present once regular incidence between 18 and 24 months. The typical sce- feeding begins, typically 2–3 days after birth. Pyridoxine nario is a child who has a generalized, tonic-clonic (vitamin B6) deficiency, an important cause of neonatal seizure during a febrile illness in the setting of a com- seizures, can be effectively treated with pyridoxine mon childhood infection such as otitis media, respira- tory infection, or gastroenteritis. The seizure is likely to TABLE 20-4 occur during the rising phase of the temperature curve CHAPTER 20 Seizures and Epilepsy CAUSES OF SEIZURES (i.e., during the first day) rather than well into the course of the illness. A simple febrile seizure is a single, isolated Neonates Perinatal hypoxia and ischemia event, brief, and symmetric in appearance. Complex (<1 month) Intracranial hemorrhage and trauma febrile seizures are characterized by repeated seizure Acute CNS infection activity, duration >15 min, or by focal features. Approxi- Infants and Metabolic disturbances mately one-third of patients with febrile seizures will children (hypoglycemia, hypocalcemia, have a recurrence, but <10% have three or more episodes. (>1 mo and hypomagnesemia, pyridoxine Recurrences are much more likely when the febrile <12 years) deficiency) seizure occurs in the first year of life. Simple febrile Drug withdrawal seizures are not associated with an increase in the risk of Adolescents Developmental disorders developing epilepsy, while complex febrile seizures have (12–18 years) Genetic disorders a risk of 2–5%; other risk factors include the presence of Febrile seizures preexisting neurologic deficits and a family history of Young adults Genetic disorders (metabolic, nonfebrile seizures. (18–35 years) degenerative, primary epilepsy Childhood marks the age at which many of the well- Older adults syndromes) defined epilepsy syndromes present. Some children who (>35 years) CNS infection are otherwise normal develop idiopathic, generalized Developmental disorders tonic-clonic seizures without other features that fit into Trauma specific syndromes. Temporal lobe epilepsy usually pre- Idiopathic sents in childhood and may be related to mesial tempo- Trauma ral lobe sclerosis (as part of the MTLE syndrome) or Genetic disorders other focal abnormalities such as cortical dysgenesis. Infection Other types of partial seizures, including those with sec- Brain tumor ondary generalization, may be the relatively late mani- Illicit drug use festation of a developmental disorder, an acquired lesion Idiopathic such as head trauma, CNS infection (especially viral Trauma encephalitis), or very rarely a CNS tumor. Alcohol withdrawal Illicit drug use The period of adolescence and early adulthood is one of Brain tumor transition during which the idiopathic or genetically Idiopathic based epilepsy syndromes, including JME and juvenile Cerebrovascular disease absence epilepsy, become less common, while epilepsies Brain tumor secondary to acquired CNS lesions begin to predomi- Alcohol withdrawal nate. Seizures that begin in patients in this age range Metabolic disorders (uremia, hepatic may be associated with head trauma, CNS infections failure, electrolyte abnormalities, (including parasitic infections such as cysticercosis), brain hypoglycemia) tumors, congenital CNS abnormalities, illicit drug use, Alzheimer’s disease and other or alcohol withdrawal. degenerative CNS diseases Idiopathic Head trauma is a common cause of epilepsy in ado- lescents and adults. The head injury can be caused by a Note: CNS, central nervous system. variety of mechanisms, and the likelihood of developing

SECTION III Diseases of the Central Nervous System230 epilepsy is strongly correlated with the severity of the TABLE 20-5 injury.A patient with a penetrating head wound, depressed skull fracture, intracranial hemorrhage, or prolonged DRUGS AND OTHER SUBSTANCES THAT CAN CAUSE posttraumatic coma or amnesia has a 40–50% risk of SEIZURES developing epilepsy, while a patient with a closed head injury and cerebral contusion has a 5–25% risk. Recur- Alkylating agents (e.g., busulfan, chlorambucil) rent seizures usually develop within 1 year after head Antimalarials (chloroquine, mefloquine) trauma, although intervals of Ն10 years are well known. Antimicrobials/antivirals In controlled studies, mild head injury, defined as a con- cussion with amnesia or loss of consciousness of <30 min, β-lactam and related compounds was found to be associated with only a slightly increased Quinolones likelihood of epilepsy. Nonetheless, most epileptologists Acyclovir know of patients who have partial seizures within hours Isoniazid or days of a mild head injury and subsequently develop Ganciclovir chronic seizures of the same type; such cases may repre- Anesthetics and analgesics sent rare examples of chronic epilepsy resulting from Meperidine mild head injury. Tramadol The causes of seizures in older adults include cerebrovas- Local anesthetics cular disease, trauma (including subdural hematoma), CNS Dietary supplements tumors, and degenerative diseases. Cerebrovascular disease Ephedra (ma huang) may account for ~50% of new cases of epilepsy in patients Gingko older than 65 years. Acute seizures (i.e., occurring at the Immunomodulatory drugs time of the stroke) are seen more often with embolic Cyclosporine rather than hemorrhagic or thrombotic stroke. Chronic OKT3 (monoclonal antibodies to T cells) seizures typically appear months to years after the initial Tacrolimus event and are associated with all forms of stroke. Interferons Metabolic disturbances such as electrolyte imbalance, Psychotropics hypo- or hyperglycemia, renal failure, and hepatic fail- Antidepressants ure may cause seizures at any age. Similarly, endocrine Antipsychotics disorders, hematologic disorders, vasculitides, and many Lithium other systemic diseases may cause seizures over a broad Radiographic contrast agents age range. A wide variety of medications and abused Theophylline substances are known to precipitate seizures as well Sedative-hypnotic drug withdrawal (Table 20-5). Alcohol Barbiturates (short-acting) BASIC MECHANISMS Benzodiazepines (short-acting) Drugs of abuse MECHANISMS OF SEIZURE INITIATION AND Amphetamine PROPAGATION Cocaine Phencyclidine Partial seizure activity can begin in a very discrete Methylphenidate region of cortex and then spread to neighboring Flumazenila regions, i.e., there is a seizure initiation phase and a seizure propagation phase.The initiation phase is characterized by aIn benzodiazepine-dependent patients. two concurrent events in an aggregate of neurons: (1) high-frequency bursts of action potentials and (2) from a sufficient number of neurons result in a so-called hypersynchronization. The bursting activity is caused by spike discharge on the EEG. a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), Normally, the spread of bursting activity is prevented which leads to the opening of voltage-dependent by intact hyperpolarization and a region of surrounding sodium (Na+) channels, influx of Na+, and generation of inhibition created by inhibitory neurons. With suffi- repetitive action potentials. This is followed by a hyper- cient activation there is a recruitment of surrounding polarizing afterpotential mediated by γ-aminobutyric neurons via a number of mechanisms. Repetitive dis- acid (GABA) receptors or potassium (K+) channels, charges lead to the following: (1) an increase in extracel- depending on the cell type. The synchronized bursts lular K+, which blunts hyperpolarization and depolarizes neighboring neurons; (2) accumulation of Ca2+ in presy- naptic terminals, leading to enhanced neurotransmitter release; and (3) depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excita- tory amino acid receptor, which causes Ca2+ influx and

neuronal activation. The recruitment of a sufficient MECHANISMS OF EPILEPTOGENESIS 231 number of neurons leads to a loss of the surrounding inhibition and propagation of seizure activity into con- Epileptogenesis refers to the transformation of a normal CHAPTER 20 Seizures and Epilepsy tiguous areas via local cortical connections, and to more neuronal network into one that is chronically hyperex- distant areas via long commissural pathways such as the citable.There is often a delay of months to years between corpus callosum. an initial CNS injury such as trauma, stroke, or infection and the first seizure. The injury appears to initiate a Many factors control neuronal excitability, and thus process that gradually lowers the seizure threshold in the there are many potential mechanisms for altering a neu- affected region until a spontaneous seizure occurs. In ron’s propensity to have bursting activity. Mechanisms many genetic and idiopathic forms of epilepsy, epilepto- intrinsic to the neuron include changes in the conduc- genesis is presumably determined by developmentally tance of ion channels, response characteristics of mem- regulated events. brane receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene Pathologic studies of the hippocampus from patients transcription, translation, and posttranslational modifica- with temporal lobe epilepsy have led to the suggestion that tion. Mechanisms extrinsic to the neuron include changes some forms of epileptogenesis are related to structural in the amount or type of neurotransmitters present at the changes in neuronal networks. For example, many patients synapse, modulation of receptors by extracellular ions with MTLE have a highly selective loss of neurons that and other molecules, and temporal and spatial properties may contribute to inhibition of the main excitatory neu- of synaptic and nonsynaptic input. Nonneural cells, such rons within the dentate gyrus. There is also evidence that, as astrocytes and oligodendrocytes, have an important in response to the loss of neurons, there is reorganization or role in many of these mechanisms as well. “sprouting” of surviving neurons in a way that affects the excitability of the network. Some of these changes can be Certain recognized causes of seizures are explained seen in experimental models of prolonged electrical by these mechanisms. For example, accidental ingestion seizures or traumatic brain injury. Thus, an initial injury of domoic acid, which is an analogue of glutamate (the such as head injury may lead to a very focal, confined principal excitatory neurotransmitter in the brain), region of structural change that causes local hyperexcitabil- causes profound seizures via direct activation of excita- ity. The local hyperexcitability leads to further structural tory amino acid receptors throughout the CNS. changes that evolve over time until the focal lesion pro- Penicillin, which can lower the seizure threshold in duces clinically evident seizures. Similar models have also humans and is a potent convulsant in experimental provided strong evidence for long-term alterations in intrin- models, reduces inhibition by antagonizing the effects sic, biochemical properties of cells within the network, such as of GABA at its receptor.The basic mechanisms of other chronic changes in glutamate or GABA receptor function. precipitating factors of seizures, such as sleep depriva- tion, fever, alcohol withdrawal, hypoxia, and infection, GENETIC CAUSES OF EPILEPSY are not as well understood but presumably involve analogous perturbations in neuronal excitability. Simi- The most important recent progress in epilepsy larly, the endogenous factors that determine an indi- research has been the identification of genetic muta- vidual’s seizure threshold may relate to these properties tions associated with a variety of epilepsy syndromes as well. (Table 20-2). Although all of the mutations identified to date cause rare forms of epilepsy, their discovery has led to Knowledge of the mechanisms responsible for initia- extremely important conceptual advances. For example, it tion and propagation of most generalized seizures appears that many of the inherited, idiopathic epilepsies (including tonic-clonic, myoclonic, and atonic types) (i.e., the relatively “pure” forms of epilepsy in which remains rudimentary and reflects the limited understand- seizures are the phenotypic abnormality and brain struc- ing of the connectivity of the brain at a systems level. ture and function are otherwise normal) are due to muta- Much more is understood about the origin of general- tions affecting ion channel function. These syndromes are ized spike-and-wave discharges in absence seizures.These therefore part of the larger group of channelopathies caus- appear to be related to oscillatory rhythms normally gen- ing paroxysmal disorders such as cardiac arrhythmias, erated during sleep by circuits connecting the thalamus episodic ataxia, periodic weakness, and familial hemiplegic and cortex. This oscillatory behavior involves an interac- migraine. In contrast, gene mutations observed in sympto- tion between GABAB receptors, T-type Ca2+ channels, matic epilepsies (i.e., disorders in which other neurologic and K+ channels located within the thalamus. Pharmaco- abnormalities, such as cognitive impairment, coexist with logic studies indicate that modulation of these receptors seizures) are proving to be associated with pathways influ- and channels can induce absence seizures, and there is encing CNS development or neuronal homeostasis. speculation that the genetic forms of absence epilepsy A current challenge is to identify the multiple susceptibility may be associated with mutations of components of this system.