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InternalMed_Harrison. Direct ophthalmoscopes are simple hand-held devices that include a small light source for illumination, a viewing aperture through which the examiner looks at the retina, and a lens dial used for correction of the examiner’s and the patient’s refractive errors. A more recent design, the PanOptic ophthalmoscope, provides a wider field of view. How to Use a Direct Ophthalmoscope Good alignment is the key. The goal is to align the examiner’s eye with the viewing aperture of the ophthalmoscope, the patient’s pupil, and the area of interest on the retina. Both the patient and the examiner should be in a comfortable position (sitting or lying for the patient, sitting or standing for the examiner). Dilating the pupil and dimming the room lights make the examination easier. Steps for performing direct ophthalmoscopy are summarized in Table 40e-1.


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InternalMed_Harrison. The PanOptic ophthalmoscope is a type of direct ophthalmoscope that is designed to provide a wider view of the fundus and has slightly more magnification than the standard direct ophthalmoscope. Steps for using the PanOptic Ophthalmoscope are summarized in Table 40e-2. • Instruct the patient to remove glasses, keep the head straight, and to look steadily at a distant target straight in front. You may keep or remove your own glasses. Position your head at the same level as the patient’s head. • Use your right eye and right hand to examine the patient’s right eye, and use your left eye and left hand to examine the patient’s left eye. the ophthalmoscope light as a pen light, briefly examine the external features of the eye, including lashes, lid margins, conjunctiva, sclera, iris, and pupil shape, size, and reactivity. the ophthalmoscope light into the patient’s pupil at arm’s length and observe the red reflex. Note abnormalities of the red reflex such as an opacity of the media.


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InternalMed_Harrison. the ophthalmoscope light into the patient’s pupil at arm’s length and observe the red reflex. Note abnormalities of the red reflex such as an opacity of the media. up a +10 D lens in the lens wheel, while examining the eye from 10 cm, allows magnified viewing of the anterior segment of the eye. the power of the lens in the wheel to zero, and move closer to the patient. Identify the optic disc by pointing the ophthalmoscope about 15° nasally or by following a blood vessel toward the apex of any branching. If the retina is out of focus, turn the lens dial either way, without moving your head. If the disc becomes clearer, keep turning until best focus is achieved; if it becomes more blurred, turn the dial the other way. • Once you visualize the optic nerve, note its shape, size, color, margins, and the cup. Also note the presence of any venous pulsation or surrounding pigment, such as a choroidal or scleral crescent.


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InternalMed_Harrison. • Next, examine the macula. The macula is the area between the superior and inferior temporal vascular arcades, and its center is the fovea. You can examine the macula by pointing your ophthalmoscope about 15° temporal to the optic disc. Alternatively, ask the patient to look into the center of the light. Note the foveal reflex and the presence of any hemorrhage, exudate, abnormal blood vessels, scars, deposits, or other abnormalities. • Examine the retinal blood vessels by re-identifying the optic disc and following each of the four main branches away from the disc. The veins are dark red and relatively large. The arteries are narrower and bright red. • Ask the patient to look in the eight cardinal directions to allow you to view the peripheral fundus. In a patient with a well-dilated pupil, it is possible to visualize as far as the equator.


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InternalMed_Harrison. • Ask the patient to look in the eight cardinal directions to allow you to view the peripheral fundus. In a patient with a well-dilated pupil, it is possible to visualize as far as the equator. PART 2 Cardinal Manifestations and Presentation of Diseases the ophthalmoscope: Look through the scope at an object that is at least 10 to 15 feet away. Sharpen the image of the object by using the focusing wheel. Set the aperture dial to “small” or home position. the scope on, and adjust the light intensity to “Maximum.” the patient to look straight ahead. Move the ophthalmoscope close to the patient until the eyecup touches the patient’s brow. The eye-cup should be compressed about half its length to optimize the view. the optic disc. the fundus as described in Table 40e-1. Common age-related changes include diminished foveal light reflex, drusen (small yellow subretinal deposits), mild RPE atrophy, and pigment clumping.


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InternalMed_Harrison. Retinal hemorrhages may take various shapes and sizes depending on their location within the retina (Figs. 40e-3 and 40e-4). Flame-shaped hemorrhages are located at the level of the superficial nerve fiber layer and represent bleeding from the inner capillary network of the retina. A white-centered hemorrhage is a superficial flame-shaped hemorrhage with an area of central whitening, often representing edema, focal necrosis, or cellular infiltration. Causes of white-centered hemorrhage include bacterial endocarditis and septicemia (Roth spots), lymphoproliferative disorders, diabetes mellitus, hypertension, anemia, and collagen vascular disorders. Dot hemorrhages are small, round, superficial hemorrhages that also originate from the superficial capillary network of the retina. They resemble microaneurysms. Blot hemorrhages are slightly larger in size, dark, and intraretinal. They represent bleeding from the deep capillary network of the retina. Subhyaloid hemorrhages are variable in


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InternalMed_Harrison. microaneurysms. Blot hemorrhages are slightly larger in size, dark, and intraretinal. They represent bleeding from the deep capillary network of the retina. Subhyaloid hemorrhages are variable in shape and size and tend to be larger than other types of hemorrhages. They often have a fluid level (“boat-shaped” hemorrhage) and are located within the space between the vitreous and the retina. Subretinal hemorrhages are located deep (external) to the retina. The retinal vessels can be seen crossing over (internal to) such hemorrhages. Subretinal hemorrhages are variable in size and most commonly are caused by choroidal neovascularization (e.g., wet macular degeneration).


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InternalMed_Harrison. FIgURE 40e-3 Superficial flame-shaped hemorrhages, dot hem-orrhages, and microaneurysms in a patient with nonproliferative diabetic retinopathy. patientwithchronicleukemia. Conditions associated with retinal hemorrhages include diseases causing retinal microvasculopathy (Table 40e-3), retinitis, retinal macroaneurysm, papilledema, subarachnoid hemorrhage (Terson’s syndrome), Valsalva retinopathy, trauma (ocular injury, head injury, compression injuries of chest and abdomen, shaken baby syndrome, strangulation), macular degeneration, and posterior vitreous detachment. Hyperviscosity states may produce dot and blot hemorrhages, dilated veins (“string of sausages” appearance), optic disc edema, and exudates; similar changes can occur with adaptation to high altitude in mountain climbers.


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InternalMed_Harrison. Microaneurysms are outpouchings of the retinal capillaries, appearing as red dots (similar to dot hemorrhages) and measuring 15–50 μm. Microaneurysms have increased permeability and may bleed or leak, resulting in localized retinal hemorrhage or edema. A micro-aneurysm ultimately thromboses and disappears within 3–6 months. Microaneurysms may occur in any condition that causes retinal microvasculopathy (Table 40e-3). microemboli, e.g., talc retinopathy secondary to intravenous drug abuse, septicemia, endocarditis, Purtscher’s retinopathy artery disease, carotid-cavernous fistula, aortic arch syndrome retinopathy, head/neck irradiation


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InternalMed_Harrison. Hard exudates are well-circumscribed, shiny, yellow deposits located within the retina. They arise at the margins of areas of retinal edema and indicate increased capillary permeability. Hard exudates contain lipoproteins and lipid-laden macrophages. They may clear spontaneously or following laser photocoagulation, often within 6 months. Hard exudates may occur in isolation or may be scattered throughout the fundus. They may occur in a circular (circinate) pattern centered around an area of leaking microaneurysms. A macular star consists of a radiating, star-shaped pattern of hard exudates that is characteristically seen in severe systemic hypertension and in neuroretinitis associated with cat-scratch disease. Conditions associated with hard exudates include those causing retinal microvasculopathy (Table 40e– 3), papilledema, neuroretinitis such as cat-scratch disease and Lyme disease, retinal vascular lesions (macroaneurysm, retinal capillary hemangioma, Coats’ disease), intraocular


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InternalMed_Harrison. (Table 40e– 3), papilledema, neuroretinitis such as cat-scratch disease and Lyme disease, retinal vascular lesions (macroaneurysm, retinal capillary hemangioma, Coats’ disease), intraocular tumors, and wet age-related macular degeneration. Drusen may be mistaken for hard exudates on ophthalmoscopy. Unlike hard exudates, drusen are nonrefractile subretinal deposits with blurred margins. They are usually seen in association with age-related macular degeneration.


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InternalMed_Harrison. Cotton-wool spots are yellow/white superficial retinal lesions with indistinct feathery borders measuring 0.25–1 DD in size (Fig. 40e-5). They represent areas of edema within the retinal nerve fiber layer due to focal ischemia. Cotton-wool spots usually resolve spontaneously within 3 months. If the underlying ischemic condition persists, new lesions can develop in different locations. Cotton-wool spots often occur in conjunction with retinal hemorrhages and microaneurysms and represent retinal microvasculopathy caused by a number of systemic conditions (Table 40e-3). They may occur in isolation in HIV retinopathy, systemic lupus erythematosus, anemia, bodily trauma, other systemic conditions (Purtscher’s/Purtscher’s-like retinopathy), and interferon therapy.


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InternalMed_Harrison. Retinal neovascular complexes are irregular meshworks of fine blood vessels that grow in response to severe retinal ischemia or chronic inflammation (Fig. 40e-6). They may occur on or adjacent to the optic disc or elsewhere in the retina. Neovascular complexes are very CHAPTER 40e Use of the Hand-Held Ophthalmoscope FIgURE 40e-5 Cotton-wool spots, yellow-white superficial lesions with characteristic feathery borders, in a patient with hypertensive retinopathy. (From H Tabandeh, MF Goldberg: Retina in Systemic Disease: A Color Manual of Ophthalmoscopy. New York, Thieme, 2009.) PART 2 Cardinal Manifestations and Presentation of Diseases FIgURE 40e-6 Optic disc neovascularization in a patient with severeproliferativediabeticretinopathy.Multiplehardexudatesare also present.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases FIgURE 40e-6 Optic disc neovascularization in a patient with severeproliferativediabeticretinopathy.Multiplehardexudatesare also present. fragile and have a high risk for hemorrhaging, often causing visual loss. Diseases associated with retinal neovascularization include conditions that cause severe retinal microvasculopathy, especially diabetic and sickle cell retinopathies (Table 40e-3), intraocular tumors, intra-ocular inflammation (sarcoidosis, chronic uveitis), and chronic retinal detachment. Common sources of retinal emboli include carotid artery atheromatous plaque, cardiac valve and septal abnormalities, cardiac arrhythmias, atrial myxoma, bacterial endocarditis, septicemia, fungemia, and intravenous drug abuse.


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InternalMed_Harrison. Platelet emboli are yellowish in appearance and conform to the shape of the blood vessel. They usually originate from an atheromatous plaque within the carotid artery and can cause transient loss of vision (amaurosis fugax). Cholesterol emboli, otherwise termed Hollenhorst plaques, are yellow crystalline deposits that are commonly found at the bifurcations of the retinal arteries and may be associated with amaurosis fugax. Calcific emboli have a pearly white appearance, are larger than the platelet and cholesterol emboli, and tend to lodge in the larger retinal arteries in or around the optic disc. Calcific emboli often result in retinal arteriolar occlusion. Septic emboli can cause white-centered retinal hemorrhages (Roth spots), retinal microabscesses, and endogenous endophthalmitis. Fat embolism and amniotic fluid embolism are characterized by multiple small vessel occlusions, typically causing cotton-wool spots and few hemorrhages (Purtscher’s-like retinopathy). Talc embolism


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InternalMed_Harrison. Fat embolism and amniotic fluid embolism are characterized by multiple small vessel occlusions, typically causing cotton-wool spots and few hemorrhages (Purtscher’s-like retinopathy). Talc embolism occurs with intravenous drug abuse and is characterized by multiple refractile deposits within the small retinal vessels. Any severe form of retinal artery embolism may result in retinal ischemia and its sequelae, including retinal neovascularization.


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InternalMed_Harrison. Cherry red spot at the macula is the term used to describe the dark red appearance of the central foveal area in comparison to the surrounding macular region (Fig. 40e-7). This appearance is most commonly due to a relative loss of transparency of the parafoveal retina resulting from ischemic cloudy swelling or storage of macromolecules within the ganglion cell layer. Diseases associated with a cherry red spot at the macula include central retinal artery occlusion, sphingolipidoses, and mucolipidoses. FIgURE 40e-7 Cherry red spot at the macula and cloudy swelling of the macula in a patient with central retinal artery occlusion due to embolus originating from a carotid artery atheromatous plaque.


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InternalMed_Harrison. FIgURE 40e-7 Cherry red spot at the macula and cloudy swelling of the macula in a patient with central retinal artery occlusion due to embolus originating from a carotid artery atheromatous plaque. Retinal crystals appear as fine, refractile, yellow-white deposits. Associated conditions include infantile cystinosis, primary hyperoxaluria, secondary oxalosis, Sjögren-Larson syndrome, intravenous drug abuse (talc retinopathy), and drugs such as tamoxifen, canthaxanthin, nitrofurantoin, methoxyflurane, and ethylene glycol. Crystals may also be seen in primary retinal diseases such as juxtafoveal telangiectasia, gyrate atrophy, and Bietti’s crystalline degeneration. Old microemboli may mimic retinal crystals.


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InternalMed_Harrison. Vascular sheathing appears as a yellow-white cuff surrounding a retinal artery or vein (Fig. 40e-8). Diseases associated with retinal vascular sheathing include sarcoidosis, tuberculosis, toxoplasmosis, syphilis, HIV, retinitis (cytomegalovirus, herpes zoster, and herpes simplex), Lyme disease, cat-scratch disease, multiple sclerosis, chronic leukemia, amyloidosis, Behçet’s disease, retinal vasculitis, retinal vascular occlusion, and chronic uveitis. FIgURE 40e-8 Vascular sheathing over the optic disc in a patient with neurosarcoidosis. Retinal detachment is the separation of the retina from the underlying RPE. There are three main types: (1) serous/exudative, (2) tractional, and (3) rhegmatogenous retinal detachment.


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InternalMed_Harrison. Retinal detachment is the separation of the retina from the underlying RPE. There are three main types: (1) serous/exudative, (2) tractional, and (3) rhegmatogenous retinal detachment. In serous retinal detachment, the location of the subretinal fluid is position-dependent, characteristically gravitating to the lowermost part of the fundus (shifting fluid sign), and retinal breaks are absent. Diseases associated with serous/exudative retinal detachment include severe systemic hypertension, dural arteriovenous shunt, retinal vascular anomalies, hyperviscosity syndromes, papilledema, posterior uveitis, scleritis, orbital inflammation, and intraocular neoplasms such as choroidal melanoma, choroidal metastasis, lymphoma, and multiple myeloma.


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InternalMed_Harrison. Tractional retinal detachment is caused by internal traction on the retina in the absence of a retinal break. The retina in the area of detachment is immobile and concaved internally. Fibrovascular proliferation is a frequent associated finding. Conditions associated with tractional retinal detachment include vascular proliferative retinopathies such as severe proliferative diabetic retinopathy, branch retinal vein occlusion, sickle cell retinopathy, and retinopathy of prematurity. Ocular trauma, proliferative vitreoretinopathy, and intraocular inflammation are other causes of a tractional retinal detachment.


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InternalMed_Harrison. Rhegmatogenous retinal detachment is caused by the presence of a retinal break, allowing fluid from the vitreous cavity to gain access to the subretinal space. The surface of the retina is usually convex forward. Rhegmatogenous retinal detachment has a corrugated appearance, and undulates with eye movement. Causes of retinal breaks include posterior vitreous detachment, severe vitreoretinal traction, trauma, intraocular surgery, retinitis, and atrophic holes.


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InternalMed_Harrison. Optic disc swelling is abnormal elevation of the optic disc with blurring of its margins (Fig. 40e-9). The term “papilledema” is used to describe swelling of the optic disc secondary to elevation of intra-cranial pressure. In papilledema, the normal venous pulsation at the disc is characteristically absent. The differential diagnosis of optic disc swelling includes papilledema, anterior optic neuritis (papillitis), central retinal vein occlusion, anterior ischemic optic neuropathy, toxic optic neuropathy, hereditary optic neuropathy, neuroretinitis, diabetic papillopathy, hypertension (Fig. 40e-10), respiratory failure, carotid-cavernous fistula, optic disc nerve infiltration (glioma, lymphoma, leukemia, sarcoidosis, and granulomatous infections), ocular hypotony, chronic intraocular inflammation, optic disc drusen (pseudopapilledema), and high hypermetropia (pseudopapilledema). FIgURE 40e-10 Optic disc edema and retinal hemorrhages in a patient with malignant hypertension.


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InternalMed_Harrison. FIgURE 40e-10 Optic disc edema and retinal hemorrhages in a patient with malignant hypertension. Choroidal mass lesions appear thickened and may or may not be associated with increased pigmentation. Pigmented mass lesions include choroidal nevus (usually flat), choroidal malignant melanoma (Fig. 40e-11), and melanocytoma. Nonpigmented lesions include amelanotic choroidal melanoma, choroidal metastasis, retinoblastoma, capillary hemangioma, granuloma (e.g., Toxocara canis), choroidal detachment, choroidal hemorrhage, and wet age-related macular degeneration. Other rare tumors that may be visible on ophthalmoscopy include CHAPTER 40e Use of the Hand-Held Ophthalmoscope FIgURE 40e-9 Optic disc swelling in a patient with papilledema due to idiopathic intracranial hypertension. The optic disc is hyper- emic,withindistinctmargins.Superficialhemorrhagesarepresent.


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InternalMed_Harrison. FIgURE 40e-9 Optic disc swelling in a patient with papilledema due to idiopathic intracranial hypertension. The optic disc is hyper- emic,withindistinctmargins.Superficialhemorrhagesarepresent. FIgURE 40e-11 Choroidal malignant melanoma. The lesion is highly elevated and pigmented, and has subretinal orange pigment deposits characteristic for malignant melanoma. 40e-6 osteoma, astrocytoma (e.g., tuberous sclerosis), neurilemmoma, and leiomyoma. The differential diagnosis of flat pigmented lesions of the fundus is summarized in Table 40e-4. The appearance of chorioretinal scarring from old Toxoplasma chorioretinitis is shown in Fig. 40e-12. FIgURE 40e-12 Chorioretinal scarring due to old Toxoplasma cho-rioretinitis. The lesion is flat and pigmented. Areas of hypopigmenta-tion are also present.


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InternalMed_Harrison. FIgURE 40e-12 Chorioretinal scarring due to old Toxoplasma cho-rioretinitis. The lesion is flat and pigmented. Areas of hypopigmenta-tion are also present. PART 2 Cardinal Manifestations and Presentation of Diseases retinopathy in systemic diseases: Usher’s syndrome, abetalipoproteinemia, Refsum’s disease, Kearns-Sayre syndrome, Alström’s syndrome, Cockayne’s syndrome, Friedreich’s ataxia, mucopolysaccharidoses, paraneoplastic syndrome • Infections: congenital rubella (salt and pepper retinopathy), congenital • Infections: Toxoplasma gondii, Toxocara canis, syphilis, cytomegalovirus, herpes zoster and herpes simplex viruses, west Nile virus, histoplasmosis, parasitic infection • Choroiditis: sarcoidosis, sympathetic ophthalmia, Vogt-Koyanagi-Harada infarct: severe hypertension, sickle cell hemoglobinopathies • Trauma, cryotherapy, laser photocoagulation scars • Drugs: chloroquine/hydroxychloroquine, thioridazine, chlorpromazine, hypertrophy of the retinal pigment epithelium


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InternalMed_Harrison. Video Library of Neuro-Ophthalmology Shirley H. Wray The proper control of eye movements requires the coordinated activity of many different anatomic structures in the peripheral and central nervous system, and in turn, manifestations of a diverse array 41e of neurologic and medical disorders are revealed as disorders of eye movement. In this remarkable video collection, an introduction to distinctive eye movement disorders encountered in the context of neuromuscular, paraneoplastic, demyelinating, neurovascular, and neurodegenerative disorders is presented. Cases with Multiple Sclerosis Video 41e-1 Fisher’s One-and-a-Half Syndrome (ID164-2) Video 41e-2 A Case of Ocular Flutter (ID166-2) Video 41e-3 Downbeat Nystagmus and Periodic Alternating Nystagmus (ID168-6) Video 41e-4 Bilateral Internuclear Ophthalmoplegia (ID933-1)


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InternalMed_Harrison. Cases with Myasthenia Gravis or Mitochondrial Myopathy Video 41e-5 Unilateral Ptosis: Myasthenia Gravis (Thymic Tumor) (ID163-1) Video 41e-6 Progressive External Ophthalmoplegia (Progressive External Ophthalmoplegia: Mitochondrial Cytopathy) (ID906-2) Cases with Paraneoplastic disease Video 41e-7 Paraneoplastic Upbeat Nystagmus, Cancer of the Pancreas, Positive Anti-Hu Antibody (ID212-3) Video 41e-8 Paraneoplastic Ocular Flutter, Small-Cell Adenocarcinoma of the Lung, Negative Marker (ID936-7) Video 41e-9 Opsoclonus/Flutter, Bilateral Sixth Nerve Palsy, Adenocarcinoma of the Breast, Negative Marker (ID939-8) Cases with Fisher’s Syndrome 41e-1 Video 41e-10 Bilateral Ptosis: Facial Diplegia, Total External Ophthalmoplegia, Positive Anti-GQ1b Antibody (ID944-1) Cases with Vascular disease Video 41e-11 Retinal Emboli (Film or Fundus) (ID16-1) Video 41e-12 Third Nerve Palsy (Microinfarct) (ID939-2)


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InternalMed_Harrison. Cases with Vascular disease Video 41e-11 Retinal Emboli (Film or Fundus) (ID16-1) Video 41e-12 Third Nerve Palsy (Microinfarct) (ID939-2) Case with Neurodegenerative disease Video 41e-13 Apraxia of Eyelid Opening (Progressive Supranuclear Palsy) (ID932-3) Case of Thyroid-Associated ophthalmopathy Video 41e-14 Restrictive Orbitopathy of Graves’ Disease, Bilateral Exophthalmos (ID925-4) Case with Wernicke’s encephalopathy Video 41e-15 Bilateral Sixth Nerve Palsies (ID 163-3) Case with the Locked-in-Syndrome Video 41e-16 Ocular Dipping (ID 4-1) The Video Library of Neuro-Ophthalmology shows a number of cases with eye movement disorders. All the clips are taken from Dr. Shirley Wray’s collection on the NOVEL website. To access go to: http://NOVEL.utah.edu/Wray http://Respitory.Countway.Harvard.edu/Wray and/or to her book Shirley H. Wray, MD, PhD, Oxford University Press, 2014. CHAPTER 41e Video Library of Neuro-Ophthalmology Disorders of Smell and Taste


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InternalMed_Harrison. Shirley H. Wray, MD, PhD, Oxford University Press, 2014. CHAPTER 41e Video Library of Neuro-Ophthalmology Disorders of Smell and Taste Richard L. Doty, Steven M. Bromley


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InternalMed_Harrison. All environmental chemicals necessary for life enter the body by the nose and mouth. The senses of smell (olfaction) and taste (gustation) monitor such chemicals, determine the flavor and palatability of foods and beverages, and warn of dangerous environmental conditions, including fire, air pollution, leaking natural gas, and bacteria-laden foodstuffs. These senses contribute significantly to quality of life and, when dysfunctional, can have untoward physical and psychological consequences. A basic understanding of these senses in health and disease is critical for the physician, because thousands of patients present to doctors’ offices each year with complaints of chemosensory dysfunction. Among the more important recent developments in neurology is the discovery that decreased smell function is among the first signs, if not the first sign, of such neurodegenerative diseases as Parkinson’s disease (PD) and Alzheimer’s disease (AD), signifying their “presymptomatic” phase.


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InternalMed_Harrison. ANATOMY AND PHYSIOLOgY Olfactory System Odorous chemicals enter the front of nose during inhalation and active sniffing, as well as the back of the nose (nasopharynx) during deglutition. After reaching the highest recesses of the nasal cavity, they dissolve in the olfactory mucus and diffuse or are actively transported by specialized proteins to receptors located on the cilia of olfactory receptor cells. The cilia, dendrites, cell bodies, and proximal axonal segments of these bipolar cells are located within a unique neuroepithelium covering the cribriform plate, the superior nasal septum, superior turbinate, and sectors of the middle turbinate (Fig. 42-1). Each of the ∼6 million bipolar receptor cells expresses only one of ∼450 receptor protein types, most of which respond to more than a single chemical. When damaged, the receptor cells can be replaced by stem cells near the basement membrane. Unfortunately, such replacement is often incomplete.


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InternalMed_Harrison. After coalescing into bundles surrounded by glia-like ensheathing cells (termed fila), the receptor cell axons pass through the cribriform plate to the olfactory bulbs, where they synapse with dendrites of other cell types within the glomeruli (Fig. 42-2). These spherical structures, which make up a distinct layer of the olfactory bulb, are a site of convergence of information, because many more fibers enter than leave them. Receptor cells that express the same type of receptor project to the same glomeruli, effectively making each glomerulus a functional unit. The major projection neurons of the olfactory system—the mitral and tufted cells—send primary dendrites into the glomeruli, connecting not only with the incoming receptor cell axons, but with dendrites of periglomerular cells. The activity of the mitral/tufted cells is modulated by the periglomerular cells, secondary dendrites from other mitral/tufted cells, and granule cells, the most numerous cells of the bulb. The latter


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InternalMed_Harrison. activity of the mitral/tufted cells is modulated by the periglomerular cells, secondary dendrites from other mitral/tufted cells, and granule cells, the most numerous cells of the bulb. The latter cells, which are largely GABAergic, receive inputs from central brain structures and modulate the output of the mitral/tufted cells. Interestingly, like the olfactory receptor cells, some cells within the bulb undergo replacement. Thus, neuroblasts formed within the anterior subventricular zone of the brain migrate along the rostral migratory stream, ultimately becoming granule and periglomerular cells.


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InternalMed_Harrison. The axons of the mitral and tufted cells synapse within the primary olfactory cortex (POC) (Fig. 42-3). The POC is defined as those cortical structures that receive direct projections from the olfactory bulb, most notably the piriform and entorhinal cortices. Although olfaction is unique in that its initial afferent projections bypass the thalamus, persons with damage to the thalamus can exhibit olfactory deficits, particularly ones of odor identification. Such deficits likely reflect the involvement of thalamic connections between the primary olfactory cortex and the orbitofrontal cortex (OFC), where odor identification occurs. The close anatomic ties between the olfactory system and the CHAPTER 42 Disorders of Smell and Taste FIguRE 42-3 Anatomy of the base of the brain showing the primary olfactory cortex. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. CHAPTER 42 Disorders of Smell and Taste FIguRE 42-3 Anatomy of the base of the brain showing the primary olfactory cortex. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 42-1 Anatomy of the olfactory neural pathways, showing the distribution of olfactory receptors in the roof of the nasal cavity. (Copyright David Klemm, Faculty and Curriculum Support [FACS], Georgetown University Medical Center; used with permission.) amygdala, hippocampus, and hypothalamus help to explain the intimate associations between odor perception and cognitive functions such as memory, motivation, arousal, autonomic activity, digestion, and sex.


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InternalMed_Harrison. Taste System Tastants are sensed by specialized receptor cells present within taste buds—small grapefruit-like segmented structures located on the lateral margins and dorsum of the tongue, roof of the mouth, pharynx, larynx, and superior esophagus (Fig. 42-4). Lingual taste buds are imbedded in well-defined protuberances, termed fungi-form, foliate, and circumvallate papillae. After dissolving in a liquid, tastants enter the opening of the taste bud—the taste pore—and bind to receptors on microvilli, small extensions of receptor cells within each taste bud. Such binding changes the electrical potential across the taste cell, resulting in neurotransmitter release onto the first-order taste neurons. Although humans have ∼7500 taste buds, not all harbor


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InternalMed_Harrison. FIguRE 42-2 Schematic of the layers and wiring of the olfactory bulb. Each receptor type (red, green, blue) projects to a common glomerulus. The neural activity within each glomerulus is modulated by periglomerular cells. The activity of the primary projection cells, the mitral and tufted cells, is modulated by granule cells, periglomerular cells, and secondary dendrites from adjacent mitral and tufted cells.


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InternalMed_Harrison. (From www.med.yale.edu/neurosurg/treloar/index.html.) taste-sensitive cells; some contain only one class of receptor (e.g., cells responsive only to sugars), whereas others contain cells sensitive to more than one class. The number of taste receptor cells per taste bud ranges from zero to well over 100. A small family of three G-proteincoupled receptors (GPCRs), namely T1R1, T1R2, and T1R3, mediate sweet and umami taste sensations. Bitter sensations, on the other hand, depend on T2R receptors, a family of ∼30 GPCRs expressed on cells different from those that express the sweet and umami receptors. T2Rs sense a wide range of bitter substances but do not distinguish among them. Sour tastants are sensed by the PKD2L1 receptor, a member of the transient receptor potential protein (TRP) family. Perception of salty sensations, such as induced by sodium chloride, arises from the entry of Na+ ions into the cells via specialized membrane channels, such as the amiloride-sensitive Na+ channel.


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InternalMed_Harrison. Recent studies have found that both bitter and sweet taste-related receptors are also present elsewhere in the body, most notably in the Circumvallate Foliate Fungiform Taste bud Taste pore TRC Taste bud Taste bud FIguRE 42-4 Schematic of the taste bud and its opening (pore), as well as the location of buds on the three major types of papillae: fungi-form (anterior), foliate (lateral), and circumvallate (posterior).


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InternalMed_Harrison. alimentary and respiratory tracts. This important discovery generalizes the concept of taste-related chemoreception to areas of the body beyond the mouth and throat, with α-gustducin, the taste-specific G-protein α-subunit, expressed in so-called brush cells found specifically within the human trachea, lung, pancreas, and gallbladder. These brush cells are rich in nitric oxide (NO) synthase, known to defend against xenobiotic organisms, protect the mucosa from acid-induced lesions, and, in the case of the gastrointestinal tract, stimulate vagal and splanchnic afferent neurons. NO further acts on nearby cells, including enteroendocrine cells, absorptive or secretory epithelial cells, mucosal blood vessels, and cells of the immune system. Members of the T2R family of bitter receptors and the sweet receptors of the T1R family have been identified within the gastrointestinal tract and in enteroendocrine cell lines. In some cases, these receptors are important for metabolism, with the T1R3


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InternalMed_Harrison. sweet receptors of the T1R family have been identified within the gastrointestinal tract and in enteroendocrine cell lines. In some cases, these receptors are important for metabolism, with the T1R3 receptors and gustducin playing decisive roles in the sensing and transport of dietary sugars from the intestinal lumen into absorptive enterocytes via a sodium-dependent glucose transporter and in regulation of hormone release from gut enteroendocrine cells. In other cases, these receptors may be important for airway protection, with a number of T2R bitter receptors in the motile cilia of the human airway that responded to bitter compounds by increasing their beat frequency. One specific T2R38 taste receptor is expressed in human upper respiratory epithelia and responds to acyl-monoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Differences in T2R38 functionality, as related to TAS2R38 genotype, correlate with susceptibility to


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InternalMed_Harrison. quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Differences in T2R38 functionality, as related to TAS2R38 genotype, correlate with susceptibility to upper respiratory infections in humans.


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InternalMed_Harrison. Taste information is sent to the brain via three cranial nerves (CNs): CN VII (the facial nerve, which involves the intermediate nerve with its branches, the greater petrosal and chorda tympani nerves), CN IX (the glossopharyngeal nerve), and CN X (the vagus nerve) (Fig. 42-5). CN VII innervates the anterior tongue and all of the soft palate, CN IX innervates the posterior tongue, and CN X innervates the laryngeal surface of the epiglottis, larynx, and proximal portion of the esophagus. The mandibular branch of CN V (V3) conveys somatosensory information (e.g., touch, burning, cooling, irritation) to the brain. Although not technically a gustatory nerve, CN V shares primary nerve routes with many of the gustatory nerve fibers and adds temperature, texture,


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InternalMed_Harrison. CHAPTER 42 Disorders of Smell and Taste pungency, and spiciness to the taste experience. The chorda tympani nerve is famous for taking a recurrent course through the facial canal in the petrosal portion of the temporal bone, passing through the middle ear, and then exiting the skull via the petrotympanic fissure, where it joins the lingual nerve (a division of CN V) near the tongue. This nerve also carries parasympathetic fibers to the submandibular and sublingual glands, whereas the greater petrosal nerve supplies the palatine glands, thereby influencing saliva production. The axons of the projection cells, which synapse with taste buds, enter the rostral portion of the nucleus of the solitary tract (NTS) FIguRE 42-5 Schematic of the cranial nerves (CNs) that mediate taste function, including the chorda tympani nerve (CN VII), the glos-sopharyngeal nerve (CN IX), and the vagus nerve (CN X).


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InternalMed_Harrison. FIguRE 42-5 Schematic of the cranial nerves (CNs) that mediate taste function, including the chorda tympani nerve (CN VII), the glos-sopharyngeal nerve (CN IX), and the vagus nerve (CN X). 214 within the medulla of the brainstem (Fig. 42-5). From the NTS, neurons then project to a division of the ventroposteromedial thalamic nucleus (VPM) via the medial lemniscus. From here, projections are made to the rostral part of the frontal operculum and adjoining insula, a brain region considered the primary taste cortex (PTC). Projections from the PTC then go to the secondary taste cortex, namely the caudolateral OFC. This brain region is involved in the conscious recognition of taste qualities. Moreover, because it contains cells that are activated by several sensory modalities, it is likely a center for establishing “flavor.”


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InternalMed_Harrison. The ability to smell is influenced, in everyday life, by such factors as age, gender, general health, nutrition, smoking, and reproductive state. Women typically outperform men on tests of olfactory function and retain normal smell function to a later age than do men. Significant decrements in the ability to smell are present in over 50% of the population between 65 and 80 years of age and in 75% of those 80 years of age and older (Fig. 42-6). Such presbyosmia helps to explain why many elderly report that food has little flavor, a problem that can result in nutritional disturbances. This also helps to explain why a disproportionate number of elderly die in accidental gas poisonings. A relatively complete listing of conditions and disorders that have been associated with olfactory dysfunction is presented in Table 42-1.


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InternalMed_Harrison. Aside from aging, the three most common identifiable causes of long-lasting or permanent smell loss seen in the clinic are, in order of frequency, severe upper respiratory infections, head trauma, and chronic rhinosinusitis. The physiologic basis for most head trauma– related losses is the shearing and subsequent scarring of the olfactory fila as they pass from the nasal cavity into the brain cavity. The cribriform plate does not have to be fractured or show pathology for smell loss to be present. Severity of trauma, as indexed by a poor Glasgow Coma Scale score on presentation and the length of posttraumatic amnesia, is associated with higher risk of olfactory impairment. Less than 10% of posttraumatic anosmic patients will recover age-related normal function over time. This increases to nearly 25% of those with less-than-total loss. Upper respiratory infections, such as those associated with the common cold, influenza, pneumonia, or HIV, can directly and permanently harm the


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InternalMed_Harrison. to nearly 25% of those with less-than-total loss. Upper respiratory infections, such as those associated with the common cold, influenza, pneumonia, or HIV, can directly and permanently harm the olfactory epithelium by decreasing receptor cell number, damaging cilia on remaining receptor cells, and inducing the replacement of sensory epithelium with respiratory epithelium. The smell loss associated with chronic rhinosinusitis is


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 42-6 Scores on the University of Pennsylvania Smell Identification Test (UPSIT) as a function of subject age and sex. Numbers by each data point indicate sample sizes. Note that women identify odorants better than men at all ages. (From RL Doty et al: Science 226:1421, 1984. Copyright © 1984 American Association for the Advancement of Science.)


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InternalMed_Harrison. DiSoRDERS AnD ConDiTionS ASSoCiATED wiTH CoMPRoMiSED oLfACToRy funCTion, AS MEASuRED By oLfACToRy TESTing 22q11 deletion syndrome Liver disease AIDS/HIV infection Lubag disease Adenoid hypertrophy Medications Adrenal cortical insufficiency Migraine Age Multiple sclerosis Alcoholism Multi-infarct dementia Allergies Myasthenia gravis Alzheimer’s disease Narcolepsy with cataplexy Amyotrophic lateral sclerosis (ALS) Neoplasms, cranial/nasal Anorexia nervosa Nutritional deficiencies Asperger’s syndrome Obstructive pulmonary disease Ataxias Obesity Attention deficit/hyperactivity Obsessive compulsive disorder disease Pregnancy Congenital Pseudohypoparathyroidism Cushing’s syndrome Psychopathy Cystic fibrosis Radiation (therapeutic, cranial) Degenerative ataxias REM behavior disorder related to disease severity, with most loss occurring in cases where rhinosinusitis and polyposis are both present. Although systemic glucocorticoid therapy can usually induce short-term functional improvement,


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InternalMed_Harrison. disease severity, with most loss occurring in cases where rhinosinusitis and polyposis are both present. Although systemic glucocorticoid therapy can usually induce short-term functional improvement, it does not, on average, return smell test scores to normal, implying that chronic permanent neural loss is present and/ or that short-term administration of systemic glucocorticoids does not completely mitigate the inflammation. It is well established that microinflammation in an otherwise seemingly normal epithelium can influence smell function.


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InternalMed_Harrison. A number of neurodegenerative diseases are accompanied by olfactory impairment, including PD, AD, Huntington’s disease, Down’s syndrome, parkinsonism-dementia complex of Guam, dementia with Lewy bodies (DLB), multiple system atrophy, corticobasal degeneration, and frontotemporal dementia; smell loss can also occur in multiple sclerosis (MS) and idiopathic rapid eye movement (REM) behavioral sleep disorder (iRBD). Olfactory impairment in PD often predates the clinical diagnosis by at least 4 years. In staged cases, studies of the sequence of formation of abnormal α-synuclein aggregates and Lewy bodies suggest that the olfactory bulbs may be, along with the dorsomotor nucleus of the vagus, the first site of neural damage in PD. In postmortem studies of patients with very mild “presymptomatic” signs of AD, poorer smell function has been associated with higher levels of AD-related pathology. Smell loss is more marked in patients with early clinical manifestations of DLB than in those with


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InternalMed_Harrison. signs of AD, poorer smell function has been associated with higher levels of AD-related pathology. Smell loss is more marked in patients with early clinical manifestations of DLB than in those with mild AD. Interestingly, smell loss is minimal or nonexistent in progressive supranuclear palsy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. In MS, the olfactory disturbance varies as a function of the plaque activity within the frontal and temporal lobes.


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InternalMed_Harrison. The smell loss seen in iRBD is of the same magnitude as that found in PD. This is of particular interest because patients with iRBD frequently develop PD and hyposmia. There is some evidence that iRBD may actually represent an early associated condition of PD. REM behavior disorder is not only seen in its idiopathic form, but can also be associated with narcolepsy. This led to a recent study of narcoleptic patients with and without REM behavior disorder, which demonstrated that narcolepsy, independent of REM behavior disorder, was associated with impairments in olfactory function. Orexin A, also known as hypocretin-1, is dramatically diminished or undetectable in the cerebrospinal fluid of patients with narcolepsy and cataplexy (Chap. 38). The orexin-containing neurons in the hypothalamus project throughout the entire olfactory system (from the olfactory epithelium to the olfactory cortex), and damage to these orexin-containing projections may be one underlying mechanism for impaired


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InternalMed_Harrison. project throughout the entire olfactory system (from the olfactory epithelium to the olfactory cortex), and damage to these orexin-containing projections may be one underlying mechanism for impaired olfactory performance in narcoleptic patients. The administration of intranasal orexin A (hypocretin-1) appears to result in improved olfactory function, supporting the notion that mild olfactory impairment is not only a primary feature of narcolepsy with cataplexy, but that central nervous system orexin deficiency may be a fundamental part of the mechanism for this loss.


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InternalMed_Harrison. The majority of patients who present with taste dysfunction exhibit olfactory, not taste, loss. This is because most flavors attributed to taste actually depend on retronasal stimulation of the olfactory receptors during deglutition. As noted earlier, taste buds only mediate basic tastes such as sweet, sour, bitter, salty, and umami. Significant impairment of whole-mouth gustatory function is rare outside of generalized metabolic disturbances or systemic use of some medications, because taste bud regeneration occurs and peripheral damage alone would require the involvement of multiple cranial nerve pathways. Nonetheless, taste can be influenced by (1) the release of foul-tasting materials from the oral cavity from oral medical conditions or appliances (e.g., gingivitis, purulent sialadenitis), (2) transport problems of tastants to the taste buds (e.g., drying of the orolingual mucosa, infections, inflammatory conditions), (3) damage to the taste buds themselves (e.g., local trauma,


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InternalMed_Harrison. (2) transport problems of tastants to the taste buds (e.g., drying of the orolingual mucosa, infections, inflammatory conditions), (3) damage to the taste buds themselves (e.g., local trauma, invasive carcinomas), (4) damage to the neural pathways innervating the taste buds (e.g., middle ear infections), (5) damage to central structures (e.g., multiple sclerosis, tumor, epilepsy, stroke), and (6) systemic disturbances of metabolism (e.g., diabetes, thyroid disease, medications). Unlike CN VII, CN IX is relatively protected along its path, although iatrogenic interventions such as tonsillectomy, bronchoscopy, laryngoscopy, endotracheal intubation, and radiation therapy can result in selective injury. CN VII damage commonly results from mastoidectomy, tympanoplasty, and stapedectomy, in some cases inducing persistent metallic sensations. Bell’s palsy (Chap. 455) is one of the most common causes of CN VII injury that results in taste disturbance. On rare occasions, migraines (Chap. 447)


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InternalMed_Harrison. cases inducing persistent metallic sensations. Bell’s palsy (Chap. 455) is one of the most common causes of CN VII injury that results in taste disturbance. On rare occasions, migraines (Chap. 447) are associated with a gustatory prodrome or aura, and in some cases, tastants can trigger a migraine attack. Interestingly, dysgeusia occurs in some cases of burning mouth syndrome (BMS; also termed glossodynia or glossalgia), as do dry mouth and thirst. BMS is likely associated with dysfunction of the trigeminal nerve (CN V). Some of the etiologies suggested for this poorly understood syndrome are amenable to treatment, including (1) nutritional deficiencies (e.g., iron, folic acid, B vitamins, zinc), (2) diabetes mellitus (possibly predisposing to oral candidiasis), (3) denture allergy, (4) mechanical irritation from dentures or oral devices, (5) repetitive movements of the mouth (e.g., tongue thrusting, teeth grinding, jaw clenching), (6) tongue ischemia as a result of temporal


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InternalMed_Harrison. (4) mechanical irritation from dentures or oral devices, (5) repetitive movements of the mouth (e.g., tongue thrusting, teeth grinding, jaw clenching), (6) tongue ischemia as a result of temporal arteritis, (7) periodontal 215 disease, (8) reflux esophagitis, and (9) geographic tongue.


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InternalMed_Harrison. Although both taste and smell can be adversely influenced by pharmacologic agents, drug-related taste alterations are more common. Indeed, over 250 medications have been reported to alter the ability to taste. Major offenders include antineoplastic agents, antirheumatic drugs, antibiotics, and blood pressure medications. Terbinafine, a commonly used antifungal, has been linked to taste disturbance lasting up to 3 years. In a recent controlled trial, nearly two-thirds of individuals taking eszopiclone (Lunesta) experienced a bitter dysgeusia that was stronger in women, systematically related to the time since drug administration, and positively correlated with both blood and saliva levels of the drug. Intranasal use of nasal gels and sprays containing zinc, which are common over-the-counter prophylactics for upper respiratory viral infections, has been implicated in loss of smell function. Whether their efficacy in preventing such infections, which are the most common cause of anosmia


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InternalMed_Harrison. prophylactics for upper respiratory viral infections, has been implicated in loss of smell function. Whether their efficacy in preventing such infections, which are the most common cause of anosmia and hyposmia, outweighs their potential detriment to smell function requires study. Dysgeusia occurs commonly in the context of drugs used to treat or minimize symptoms of cancer, with a weighted prevalence from 56–76% depending on the type of cancer treatment. Attempts to prevent taste problems from such drugs using prophylactic zinc sulfate or amifostine have proven to be minimally beneficial. Although antiepileptic medications are occasionally used to treat smell or taste disturbances, the use of topiramate has been reported to result in a reversible loss of an ability to detect and recognize tastes and odors during treatment.


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InternalMed_Harrison. As with olfaction, a number of systemic disorders can affect taste. These include chronic renal failure, end-stage liver disease, vitamin and mineral deficiencies, diabetes mellitus, and hypothyroidism (to name a few). In diabetes, there appears to be a progressive loss of taste beginning with glucose and then extending to other sweeteners, salty stimuli, and then all stimuli. Psychiatric conditions can be associated with chemosensory alterations (e.g., depression, schizophrenia, bulimia). A recent review of tactile, gustatory, and olfactory hallucinations demonstrated that no one type of hallucinatory experience is pathognomonic to any given diagnosis.


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InternalMed_Harrison. Pregnancy proves to be a unique condition with regard to taste function. There appears to be an increase in dislike and intensity of bitter tastes during the first trimester that may help to ensure that pregnant women avoid poisons during a critical phase of fetal development. Similarly, a relative increase in the preference for salt and bitter in the second and third trimesters may support the ingestion of much needed electrolytes to expand fluid volume and support a varied diet.


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InternalMed_Harrison. In most cases, a careful clinical history will establish the probable etiology of a chemosensory problem, including questions about its nature, onset, duration, and pattern of fluctuations. Sudden loss suggests the possibility of head trauma, ischemia, infection, or a psychiatric condition. Gradual loss can reflect the development of a progressive obstructive lesion. Intermittent loss suggests the likelihood of an inflammatory process. The patient should be asked about potential precipitating events, such as cold or flu infections prior to symptom onset, because these often go underappreciated. Information regarding head trauma, smoking habits, drug and alcohol abuse (e.g., intranasal cocaine, chronic alcoholism in the context of Wernicke’s and Korsakoff’s syndromes), exposures to pesticides and other toxic agents, and medical interventions is also informative. A determination of all the medications that the patient was taking before and at the time of symptom onset is important,


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InternalMed_Harrison. and other toxic agents, and medical interventions is also informative. A determination of all the medications that the patient was taking before and at the time of symptom onset is important, because many can cause chemosensory disturbances. Comorbid medical conditions associated with smell impairment, such as renal failure, liver disease, hypothyroidism, diabetes, or dementia, should be assessed. Delayed puberty in association with anosmia (with or without midline craniofacial abnormalities, deafness, and renal anomalies) suggests the possibility of Kallmann’s syndrome. Recollection of epistaxis, discharge (clear, purulent, or bloody), nasal obstruction, allergies, and somatic symptoms, including headache or irritation, may have localizing value. Questions related to memory, parkinsonian signs, and seizure activity (e.g., automatisms, blackouts,


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InternalMed_Harrison. CHAPTER 42 Disorders of Smell and Taste 216 auras, déjà vu) should be posed. Pending litigation and the possibility of malingering should be considered. Modern forced-choice olfactory tests can detect malingering from improbable responses. Neurologic and otorhinolaryngologic (ORL) examinations, along with appropriate brain and nasosinus imaging, aid in the evaluation of patients with olfactory or gustatory complaints. The neural evaluation should focus on cranial nerve function, with particular attention to possible skull base and intracranial lesions. Visual acuity, field, and optic disc examinations aid in the detection of intracranial mass lesions that induce intracranial pressure (papilledema) and optic atrophy, especially when considering Foster Kennedy syndrome. The ORL examination should thoroughly assess the intranasal architecture and mucosal surfaces. Polyps, masses, and adhesions of the turbinates to the septum may compromise the flow of air to the olfactory receptors,


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InternalMed_Harrison. should thoroughly assess the intranasal architecture and mucosal surfaces. Polyps, masses, and adhesions of the turbinates to the septum may compromise the flow of air to the olfactory receptors, because less than a fifth of the inspired air traverses the olfactory cleft in the unobstructed state. Blood tests may be helpful to identify such conditions as diabetes, infection, heavy metal exposure, nutritional deficiency (e.g., vitamin B6 or B12), allergy, and thyroid, liver, and kidney disease. As with other sensory disorders, quantitative sensory testing is advised. Self-reports of patients can be misleading, and a number of patients who complain of chemosensory dysfunction have normal function for their age and gender. Quantitative smell and taste testing provides valid information for worker’s compensation and other legal claims, as well as a way to accurately assess treatment interventions. A number of standardized olfactory and taste tests are commercially available. Most evaluate


InternalMed_Harrison

InternalMed_Harrison. compensation and other legal claims, as well as a way to accurately assess treatment interventions. A number of standardized olfactory and taste tests are commercially available. Most evaluate the ability of patients to detect and identify odors or tastes. For example, the most widely used of these tests, the 40-item University of Pennsylvania Smell Identification Test (UPSIT), uses norms based on nearly 4000 normal subjects. A determination is made of both absolute dysfunction (i.e., mild loss, moderate loss, severe loss, total loss, probable malingering) and relative dysfunction (percentile rank for age and gender). Although electrophysiologic testing is available at some smell and taste centers (e.g., odor event-related potentials), they require complex stimulus presentation and recording equipment and rarely provide additional diagnostic information. With the exception of electrogustometers, commercially available taste tests have only recently become available. Most use filter


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InternalMed_Harrison. equipment and rarely provide additional diagnostic information. With the exception of electrogustometers, commercially available taste tests have only recently become available. Most use filter paper strips impregnated with tastants, so no stimulus preparation is required.


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InternalMed_Harrison. Given the various mechanisms by which olfactory and gustatory disturbance can occur, management of patients tends to be condition specific. For example, patients with hypothyroidism, diabetes, or infections often benefit from specific treatments to correct the underlying disease process that is adversely influencing chemoreception. For most patients who present primarily with obstructive/transport loss affecting the nasal and paranasal regions (e.g., allergic rhinitis, polyposis, intranasal neoplasms, nasal deviations), medical and/or surgical intervention is often beneficial. Antifungal and antibiotic treatments may reverse taste problems secondary to candidiasis or other oral infections. Chlorhexidine mouthwash mitigates some salty or bitter dysgeusias, conceivably as a result of its strong positive charge. Excessive dryness of the oral mucosa is a problem with many medications and conditions, and artificial saliva (e.g., Xerolube) or oral pilocarpine treatments may prove


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InternalMed_Harrison. of its strong positive charge. Excessive dryness of the oral mucosa is a problem with many medications and conditions, and artificial saliva (e.g., Xerolube) or oral pilocarpine treatments may prove beneficial. Other methods to improve salivary flow include the use of mints, lozenges, or sugarless gum. Flavor enhancers may make food more palatable (e.g., monosodium glutamate), but caution is advised to avoid overusing ingredients containing sodium or sugar, particularly in circumstances when a patient also has underlying hypertension or diabetes. Medications that induce distortions of taste can often be discontinued and replaced with other types of medications or modes of therapy. As mentioned earlier, pharmacologic agents result in taste disturbances much more frequently than smell disturbances, and over 250 medications have been reported to alter the sense of taste. It is important to note, however, that many drug-related effects are long lasting and not reversed by short-term drug


InternalMed_Harrison

InternalMed_Harrison. and over 250 medications have been reported to alter the sense of taste. It is important to note, however, that many drug-related effects are long lasting and not reversed by short-term drug discontinuance.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. A recent study of endoscopic sinus surgery in patients with chronic rhinosinusitis and hyposmia revealed that patients with severe olfactory dysfunction prior to the surgery had a more dramatic and sustained improvement over time compared to patients with more mild olfactory dysfunction prior to intervention. In the case of intranasal and sinus-related inflammatory conditions, such as seen with allergy, viruses, and traumas, the use of intranasal or systemic glucocorticoids may also be helpful. One common approach is to use a tapering course of oral prednisone. The utility of restoring olfaction with either topical or systemic glucocorticoids has been studied. Topical intranasal administration was found to be less effective in general than systemic administration; however, the effects of different nasal administration techniques were not analyzed; for example, intranasal glucocorticoids are more effective if administered in the Moffett’s position (head in the inverted position such as


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InternalMed_Harrison. nasal administration techniques were not analyzed; for example, intranasal glucocorticoids are more effective if administered in the Moffett’s position (head in the inverted position such as over the edge of the bed with the bridge of the nose perpendicular to the floor). After head trauma, an initial trial of glucocorticoids may help to reduce local edema and the potential deleterious deposition of scar tissue around olfactory fila at the level of the cribriform plate.


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InternalMed_Harrison. Treatments are limited for patients with chemosensory loss or primary injury to neural pathways. Nonetheless, spontaneous recovery can occur. In a follow-up study of 542 patients presenting to our center with smell loss from a variety of causes, modest improvement occurred over an average time period of 4 years in about half of the participants. However, only 11% of the anosmic and 23% of the hyposmic patients regained normal age-related function. Interestingly, the amount of dysfunction present at the time of presentation, not etiology, was the best predictor of prognosis. Other predictors were age and the duration of dysfunction prior to initial testing.


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InternalMed_Harrison. A nonblinded study has reported that patients with hyposmia may benefit from smelling strong odors (e.g., eucalyptol, citronella, eugenol, and phyenyl ethyl alcohol) before going to bed and immediately upon awakening each day over the course of several months. The rationale for such an approach comes from animal studies demonstrating that prolonged exposure to odorants can induce increased neural activity within the olfactory bulb. In an uncontrolled study, α-lipoic acid (400 mg/d), an essential cofactor for many enzyme complexes with possible antioxidant effects, was reported to be beneficial in mitigating smell loss following viral infection of the upper respiratory tract; controlled studies are needed to confirm this observation. This agent has also been suggested to be useful in some cases of hypogeusia and BMS.


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InternalMed_Harrison. The use of zinc and vitamin A in treating olfactory disturbances is controversial, and there does not appear to be much benefit beyond replenishing established deficiencies. However, zinc has been shown to improve taste function secondary to hepatic deficiencies, and retinoids (bioactive vitamin A derivatives) are known to play an essential role in the survival of olfactory neurons. One protocol in which zinc was infused with chemotherapy treatments suggested a possible protective effect against developing taste impairment. Diseases of the alimentary tract can not only influence chemoreceptive function, but also occasionally influence vitamin B12 absorption. This can result in a relative deficiency of vitamin B12, theoretically contributing to olfactory nerve disturbance. Vitamin B2 (riboflavin) and magnesium supplements are reported in the alternative literature to aid in the management of migraine that, in turn, may be associated with smell dysfunction. Because vitamin D deficiency


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InternalMed_Harrison. and magnesium supplements are reported in the alternative literature to aid in the management of migraine that, in turn, may be associated with smell dysfunction. Because vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia, adding vitamin D3, 1000–2000 units per day, may benefit some patients with smell and taste complaints during or following chemotherapy.


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InternalMed_Harrison. A number of medications have reportedly been used with success in ameliorating olfactory symptoms, although strong scientific evidence for efficacy is generally lacking. A report that theophylline improved smell function was uncontrolled and failed to account for the fact that some meaningful improvement occurs without treatment; indeed, the percentage of responders was about the same (∼50%) as that noted by others to show spontaneous improvement over a similar time period. Antiepileptics and some antidepressants (e.g., amitriptyline) have been used to treat dysosmias and smell distortions, particularly following head trauma. Ironically, amitriptyline is also frequently on the list of medications that can ultimately distort smell and taste function, possibly from its anticholinergic effects. A recent study suggests that the use of the centrally acting acetylcholinesterase inhibitor donepezil in AD resulted in improvements on smell identification measures that correlated with overall


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InternalMed_Harrison. A recent study suggests that the use of the centrally acting acetylcholinesterase inhibitor donepezil in AD resulted in improvements on smell identification measures that correlated with overall clinician-based impressions of change in dementia severity scores.


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InternalMed_Harrison. Alternative therapies, such as acupuncture, meditation, cognitive-behavioral therapy, and yoga, can help patients manage uncomfortable experiences associated with chemosensory disturbance and oral pain syndromes and to cope with the psychosocial stressors surrounding the impairment. Additionally, modification of diet and eating habits is also important. By accentuating the other sensory experiences of a meal, such as food texture, aroma, temperature, and color, one can optimize the overall eating experience for a patient. In some cases, a flavor enhancer like monosodium glutamate (MSG) can be added to foods to increase palatability and encourage intake.


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InternalMed_Harrison. Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory disturbance. Patients should be warned not to overcompensate for their taste loss by adding excessive amounts of sugar or salt. Smoking cessation and the discontinuance of oral tobacco use are essential in the management of any patient with smell and/or taste disturbance and should be repeatedly emphasized.


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InternalMed_Harrison. A major and often overlooked element of therapy comes from chemosensory testing itself. Confirmation or lack of conformation of loss is beneficial to patients who come to believe, in light of unsupportive family members and medical providers, that they may be “crazy.” In cases where the loss is minor, patients can be informed of the likelihood of a more positive prognosis. Importantly, quantitative testing places the patient’s problem into overall perspective. Thus, it is often therapeutic for an older person to know that, while his or her smell function is not what it used to be, it still falls above the average of his or her peer group. Without testing, many such patients are simply told they are getting old and nothing can be done for them, leading in some cases to depression and decreased self-esteem. Disorders of Hearing Anil K. Lalwani


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InternalMed_Harrison. Disorders of Hearing Anil K. Lalwani Hearing loss is one of the most common sensory disorders in humans and can present at any age. Nearly 10% of the adult population has some hearing loss, and one-third of individuals age >65 years have a hearing loss of sufficient magnitude to require a hearing aid.


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InternalMed_Harrison. The function of the external and middle ear is to amplify sound to facilitate conversion of the mechanical energy of the sound wave into an electrical signal by the inner ear hair cells, a process called mechanotransduction (Fig. 43-1). Sound waves enter the external auditory canal and set the tympanic membrane (eardrum) in motion, which in turn moves the malleus, incus, and stapes of the middle ear. Movement of the footplate of the stapes causes pressure changes in the fluid-filled inner ear, eliciting a traveling wave in the basilar membrane of the cochlea. The tympanic membrane and the ossicular chain in the middle ear serve as an impedance-matching mechanism, improving the efficiency of energy transfer from air to the fluid-filled inner ear.


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InternalMed_Harrison. Stereocilia of the hair cells of the organ of Corti, which rests on the basilar membrane, are in contact with the tectorial membrane and are deformed by the traveling wave. A point of maximal displacement of the basilar membrane is determined by the frequency of the stimulating tone. High-frequency tones cause maximal displacement of the basilar membrane near the base of the cochlea, whereas for low-frequency sounds, the point of maximal displacement is toward 217 the apex of the cochlea. The inner and outer hair cells of the organ of Corti have different innervation patterns, but both are mechanoreceptors. The afferent innervation relates principally to the inner hair cells, and the efferent innervation relates principally to outer hair cells. The motility of the outer hair cells alters the micromechanics of the inner hair cells, creating a cochlear amplifier, which explains the exquisite sensitivity and frequency selectivity of the cochlea.


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InternalMed_Harrison. Beginning in the cochlea, the frequency specificity is maintained at each point of the central auditory pathway: dorsal and ventral cochlear nuclei, trapezoid body, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex. At low frequencies, individual auditory nerve fibers can respond more or less synchronously with the stimulating tone. At higher frequencies, phase-locking occurs so that neurons alternate in response to particular phases of the cycle of the sound wave. Intensity is encoded by the amount of neural activity in individual neurons, the number of neurons that are active, and the specific neurons that are activated.


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InternalMed_Harrison. There is evidence that the right and left ears as well as the central nervous system may process speech asymmetrically. Generally, a sound is processed symmetrically from the peripheral to the central auditory system. However, a “right ear advantage” exists for dichotic listening tasks, in which subjects are asked to report on competing sounds presented to each ear. In most individuals, a perceptual right ear advantage for consonant-vowel syllables, stop consonants, and words also exists. Similarly, whereas central auditory processing for sounds is symmetric with minimal lateral specialization for the most part, speech processing is lateralized. There is specialization of the left auditory cortex for speech recognition and production, and of the right hemisphere for emotional and tonal aspects of speech. Left hemisphere dominance for speech is found in 95–98% of right-handed persons and 70–80% of left-handed persons.


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InternalMed_Harrison. Hearing loss can result from disorders of the auricle, external auditory canal, middle ear, inner ear, or central auditory pathways (Fig. 43-2). In general, lesions in the auricle, external auditory canal, or middle ear that impede the transmission of sound from the external environment to the inner ear cause conductive hearing loss, whereas lesions that impair mechanotransduction in the inner ear or transmission of the electrical signal along the eighth nerve to the brain cause sensorineural hearing loss.


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InternalMed_Harrison. Conductive Hearing Loss The external ear, the external auditory canal, and the middle ear apparatus is designed to collect and amplify sound and efficiently transfer the mechanical energy of the sound wave to the fluid-filled cochlea. Factors that obstruct the transmission of sound or serve to dampen the acoustical energy result in conductive hearing loss. Conductive hearing loss can occur from obstruction of the external auditory canal by cerumen, debris, and foreign bodies; swelling of the lining of the canal; atresia or neoplasms of the canal; perforations of the tympanic membrane; disruption of the ossicular chain, as occurs with necrosis of the long process of the incus in trauma or infection; otosclerosis; or fluid, scarring, or neoplasms in the middle ear. Rarely, inner ear malformations or pathologies, such as superior semicircular canal dehiscence, lateral semicircular canal dysplasia, incomplete partition of the inner ear, and large vestibular aqueduct, may also be


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InternalMed_Harrison. malformations or pathologies, such as superior semicircular canal dehiscence, lateral semicircular canal dysplasia, incomplete partition of the inner ear, and large vestibular aqueduct, may also be associated with conductive hearing loss.


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InternalMed_Harrison. Eustachian tube dysfunction is extremely common in adults and may predispose to acute otitis media (AOM) or serous otitis media (SOM). Trauma, AOM, and chronic otitis media are the usual factors responsible for tympanic membrane perforation. While small perforations often heal spontaneously, larger defects usually require surgical intervention. Tympanoplasty is highly effective (>90%) in the repair of tympanic membrane perforations. Otoscopy is usually sufficient to diagnose AOM, SOM, chronic otitis media, cerumen impaction, tympanic membrane perforation, and eustachian tube dysfunction; tympanometry can be useful to confirm the clinical suspicion of these conditions. CHAPTER 43 Disorders of Hearing PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. CHAPTER 43 Disorders of Hearing PART 2 Cardinal Manifestations and Presentation of Diseases Cholesteatoma, a benign tumor composed of stratified squamous epithelium in the middle ear or mastoid, occurs frequently in adults. This is a slowly growing lesion that destroys bone and normal ear tissue. Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket, implantation of squamous epithelia in the middle ear through a perforation or surgery, and metaplasia following chronic infection and irritation. Auricle or pinna External ear ABExternal acoustic canal Tympanic membrane Semicircular canals Vestibulocochlear nerve Cochlea Stapes Incus Malleus Lobe Middle ear Eustachian tube FIguRE 43-1 Ear anatomy. A. Drawing of modified coronal section through external ear and temporal bone, with structures of the middle and inner ear demonstrated. B. High-resolution view of inner ear.


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InternalMed_Harrison. On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is highly suggestive of an underlying cholesteatoma. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a cholesteatoma. Conductive hearing loss secondary to ossicular erosion is common. Surgery is required to remove this destructive process.


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InternalMed_Harrison. Hearing Loss History Otologic examination Cerumen impaction TM perforation Cholesteatoma SOM AOM External auditory canal atresia/ stenosis Eustachian tube dysfunction Tympanosclerosis Pure tone and speech audiometry Conductive HL Impedance audiometry Mixed HL SNHL abnormal Impedance audiometry Acute Asymmetric/symmetric Chronic normal Otosclerosis Cerumen impaction Ossicular fixation Cholesteatoma* Temporal bone trauma* Inner ear dehiscence or “third window” AOM SOM TM perforation* Eustachian tube dysfunction Cerumen impaction Cholesteatoma* Temporal bone trauma* Ossicular discontinuity* Middle ear tumor* abnormal normal AOM TM perforation* Cholesteatoma* Temporal bone trauma* Middle ear tumors* glomus tympanicum glomus jugulare Stapes gusher syndrome* Inner ear malformation* Otosclerosis Temporal bone trauma* Inner ear dehiscence or “third window” CNS infection† Tumors† Cerebellopontine angle CNS Stroke† Trauma* Symmetric Asymmetric Inner ear malformation*


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InternalMed_Harrison. malformation* Otosclerosis Temporal bone trauma* Inner ear dehiscence or “third window” CNS infection† Tumors† Cerebellopontine angle CNS Stroke† Trauma* Symmetric Asymmetric Inner ear malformation* Presbycusis Noise exposure Radiation therapy MRI/BAER abnormal normal Endolymphatic hydrops Labyrinthitis* Perilymphatic fistula* Radiation therapy Labyrinthitis* Inner ear malformations* Cerebellopontine angle tumors Arachnoid cyst; facial nerve tumor; lipoma; meningioma; vestibular schwannoma Multiple sclerosis† abnormal normal FIguRE 43-2 An algorithm for the approach to hearing loss. AOM, acute otitis media; BAER, brainstem auditory evoked response; CNS, cen-tral nervous system; HL, hearing loss; SNHL, sensorineural hearing loss; SOM, serous otitis media; TM, tympanic membrane. *Computed tomog-raphy scan of temporal bone. †Magnetic resonance imaging (MRI) scan.


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InternalMed_Harrison. Conductive hearing loss with a normal ear canal and intact tympanic membrane suggests either ossicular pathology or the presence of “third window” in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. Hearing impairment usually presents between the late teens and the forties. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. A hearing aid or a simple outpatient surgical procedure (stapedectomy) can provide adequate auditory rehabilitation. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis


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InternalMed_Harrison. beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value.


InternalMed_Harrison

InternalMed_Harrison. Disorders that lead to the formation of a pathologic “third window” in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the “inner ear conductive hearing loss.” The superior semicircular canal dehiscence syndrome resulting from erosion of the otic bone over the superior circular canal can present with conductive hearing loss that mimics otosclerosis. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this


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InternalMed_Harrison. by Valsalva maneuvers that change middle ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a “third window” by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome.


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InternalMed_Harrison. Sensorineural Hearing Loss Sensorineural hearing loss results from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, auditory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs (e.g., salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, loop diuretics such as furosemide and ethacrynic acid, and cancer chemotherapeutic agents such as cisplatin), fractures of the temporal bone, meningitis, cochlear otosclerosis (see above), Ménière’s disease, and aging. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in concert with environmental exposures may also be responsible (see below).


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InternalMed_Harrison. Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. In the early stages, it is characterized by symmetric, gentle to sharply sloping high-frequency hearing loss (Fig. 43-3). With progression, the hearing loss involves all frequencies. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove


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InternalMed_Harrison. amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below).


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InternalMed_Harrison. Ménière’s disease is characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Tinnitus and/ or deafness may be absent during the initial attacks of vertigo, but it Right 50 dB 64% 55 dBSRT Left 70%Disc. CHAPTER 43 Disorders of Hearing FIguRE 43-3 Presbyacusis or age-related hearing loss. The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbyacusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. HL, hearing threshold level; SRT, speech reception threshold.


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InternalMed_Harrison. invariably appears as the disease progresses and increases in severity during acute attacks. The annual incidence of Ménière’s disease is 0.5– 7.5 per 1000; onset is most frequently in the fifth decade of life but may also occur in young adults or the elderly. Histologically, there is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. This may result from endolymphatic sac dysfunction secondary to infection, trauma, autoimmune disease, inflammatory causes, or tumor; an idiopathic etiology constitutes the largest category and is most accurately referred to as Ménière’s disease. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is present. Magnetic resonance imaging (MRI) should be obtained to exclude retrocochlear pathology such as a cerebellopontine angle tumor or demyelinating disorder. Therapy is directed toward the control of vertigo.


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InternalMed_Harrison. resonance imaging (MRI) should be obtained to exclude retrocochlear pathology such as a cerebellopontine angle tumor or demyelinating disorder. Therapy is directed toward the control of vertigo. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of glucocorticoids, and intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Unfortunately, there is no effective therapy for hearing loss, tinnitus, or aural fullness from Ménière’s disease.


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InternalMed_Harrison. Sensorineural hearing loss may also result from any neoplastic, vascular, demyelinating, infectious, or degenerative disease or trauma affecting the central auditory pathways. HIV leads to both peripheral and central auditory system pathology and is associated with sensorineural hearing impairment.


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InternalMed_Harrison. Primary diseases of the central nervous system can also present with hearing impairment. Characteristically, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone. Auditory testing is consistent with an auditory neuropathy; normal otoacoustic emissions (OAE) and an abnormal auditory brainstem response (ABR) is typical (see below). Hearing loss can accompany hereditary sensorimotor neuropathies and inherited disorders of myelin. Tumors of the cerebellopontine angle such as vestibular schwannoma and meningioma usually present with asymmetric sensorineural hearing loss with greater deterioration of speech understanding than pure tone hearing. Multiple sclerosis may present with acute unilateral or bilateral hearing loss; typically, pure tone testing remains relatively stable while speech understanding 220 fluctuates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular


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InternalMed_Harrison. pure tone testing remains relatively stable while speech understanding 220 fluctuates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular accident involving the posterior circulation, usually the anterior inferior cerebellar artery; it may also be the heralding sign of impending catastrophic basilar artery infarction (Chap. 446). A finding of conductive and sensory hearing loss in combination is termed mixed hearing loss. Mixed hearing losses are due to pathology of both the middle and inner ear, as can occur in otosclerosis involving the ossicles and the cochlea, head trauma, chronic otitis media, cholesteatoma, middle ear tumors, and some inner ear malformations. Trauma resulting in temporal bone fractures may be associated with conductive, sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rupture of the tympanic membrane or disruption of the ossicular


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InternalMed_Harrison. sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rupture of the tympanic membrane or disruption of the ossicular chain. These abnormalities can be surgically corrected. Profound hearing loss and severe vertigo are associated with temporal bone fractures involving the inner ear. A perilymphatic fistula associated with leakage of inner ear fluid into the middle ear can occur and may require surgical repair. An associated facial nerve injury is not uncommon. Computed tomography (CT) is best suited to assess fracture of the traumatized temporal bone, evaluate the ear canal, and determine the integrity of the ossicular chain and the involvement of the inner ear. Cerebrospinal fluid leaks that accompany temporal bone fractures are usually self-limited; the value of prophylactic antibiotics is uncertain. Tinnitus is defined as the perception of a sound when there is no sound in the environment. It may have a


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InternalMed_Harrison. bone fractures are usually self-limited; the value of prophylactic antibiotics is uncertain. Tinnitus is defined as the perception of a sound when there is no sound in the environment. It may have a buzzing, roaring, or ringing quality and may be pulsatile (synchronous with the heartbeat). Tinnitus is often associated with either a conductive or sensorineural hearing loss. The pathophysiology of tinnitus is not well understood. The cause of the tinnitus can usually be determined by finding the cause of the associated hearing loss. Tinnitus may be the first symptom of a serious condition such as a vestibular schwannoma. Pulsatile tinnitus requires evaluation of the vascular system of the head to exclude vascular tumors such as glomus jugulare tumors, aneurysms, dural arteriovenous fistulas, and stenotic arterial lesions; it may also occur with SOM. It is most commonly associated with some abnormality of the jugular bulb such as a large jugular bulb or jugular bulb diverticulum.


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InternalMed_Harrison. More than half of childhood hearing impairment is thought to be hereditary; hereditary hearing impairment (HHI) can also manifest later in life. HHI may be classified as either nonsyndromic, when hearing loss is the only clinical abnormality, or syndromic, when hearing loss is associated with anomalies in other organ systems. Nearly two-thirds of HHIs are nonsyndromic, and the remaining one-third are syndromic. Between 70 and 80% of nonsyndromic HHI is inherited in an autosomal recessive manner and designated DFNB; another 15–20% is autosomal dominant (DFNA). Less than 5% is X-linked (DFNX) or maternally inherited via the mitochondria.


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InternalMed_Harrison. More than 150 loci harboring genes for nonsyndromic HHI have been mapped, with recessive loci outnumbering dominant; numerous genes have now been identified (Table 43-1). The hearing genes fall into the categories of structural proteins (MYH9, MYO7A, MYO15, TECTA, DIAPH1), transcription factors (POU3F4, POU4F3), ion channels (KCNQ4, SLC26A4), and gap junction proteins (GJB2, GJB3, GJB6). Several of these genes, including GJB2, TECTA, and TMC1, cause both autosomal dominant and recessive forms of nonsyndromic HHI. In general, the hearing loss associated with dominant genes has its onset in adolescence or adulthood, varies in severity, and progresses with age, whereas the hearing loss associated with recessive inheritance is congenital and profound. Connexin 26, product of the GJB2 gene, is particularly important because it is responsible for nearly 20% of all cases of childhood deafness; half of genetic deafness in children is GJB2-related. Two frameshift mutations, 35delG and 167delT,


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InternalMed_Harrison. particularly important because it is responsible for nearly 20% of all cases of childhood deafness; half of genetic deafness in children is GJB2-related. Two frameshift mutations, 35delG and 167delT, account for >50% of the cases; however, screening for these two mutations alone is insufficient, and sequencing of the entire gene is required to diagnose GJB2-related recessive deafness. The 167delT mutation is highly prevalent in Ashkenazi Jews; ~1 in 1765 individuals in this


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases population are homozygous and affected. The hearing loss can also vary among the members of the same family, suggesting that other genes or factors influence the auditory phenotype. In addition to GJB2, several other nonsyndromic genes are associated with hearing loss that progresses with age. The contribution of genetics to presbycusis is also becoming better understood. Sensitivity to aminoglycoside ototoxicity can be maternally transmitted through a mitochondrial mutation. Susceptibility to noise-induced hearing loss may also be genetically determined.


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InternalMed_Harrison. There are >400 syndromic forms of hearing loss. These include Usher’s syndrome (retinitis pigmentosa and hearing loss), Waardenburg’s syndrome (pigmentary abnormality and hearing loss), Pendred’s syndrome (thyroid organification defect and hearing loss), Alport’s syndrome (renal disease and hearing loss), Jervell and Lange-Nielsen syndrome (prolonged QT interval and hearing loss), neurofibromatosis type 2 (bilateral acoustic schwannoma), and mitochondrial disorders (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]; myoclonic epilepsy and ragged red fibers [MERRF]; progressive external ophthalmoplegia [PEO]) (Table 43-2). APPROACH TO THE PATIENT: Disorders of the Sense of Hearing


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InternalMed_Harrison. The goal in the evaluation of a patient with auditory complaints is to determine (1) the nature of the hearing impairment (conductive vs sensorineural vs mixed), (2) the severity of the impairment (mild, moderate, severe, or profound), (3) the anatomy of the impairment (external ear, middle ear, inner ear, or central auditory pathway), and (4) the etiology. The history should elicit characteristics of the hearing loss, including the duration of deafness, unilateral versus bilateral involvement, nature of onset (sudden vs insidious), and rate of progression (rapid vs slow). Symptoms of tinnitus, vertigo, imbalance, aural fullness, otorrhea, headache, facial nerve dysfunction, and head and neck paresthesias should be noted. Information regarding head trauma, exposure to ototoxins, occupational or recreational noise exposure, and family history of hearing impairment may also be important. A sudden onset of unilateral hearing loss, with or without tinnitus, may represent a viral infection


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InternalMed_Harrison. or recreational noise exposure, and family history of hearing impairment may also be important. A sudden onset of unilateral hearing loss, with or without tinnitus, may represent a viral infection of the inner ear, vestibular schwannoma, or a stroke. Patients with unilateral hearing loss (sensory or conductive) usually complain of reduced hearing, poor sound localization, and difficulty hearing clearly with background noise. Gradual progression of a hearing deficit is common with otosclerosis, noise-induced hearing loss, vestibular schwannoma, or Ménière’s disease. Small vestibular schwannomas typically present with asymmetric hearing impairment, tinnitus, and imbalance (rarely vertigo); cranial neuropathy, in particular of the trigeminal or facial nerve, may accompany larger tumors. In addition to hearing loss, Ménière’s disease may be associated with episodic vertigo, tinnitus, and aural fullness. Hearing loss with otorrhea is most likely due to chronic otitis media or


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InternalMed_Harrison. tumors. In addition to hearing loss, Ménière’s disease may be associated with episodic vertigo, tinnitus, and aural fullness. Hearing loss with otorrhea is most likely due to chronic otitis media or cholesteatoma.


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InternalMed_Harrison. Examination should include the auricle, external ear canal, and tympanic membrane. The external ear canal of the elderly is often dry and fragile; it is preferable to clean cerumen with wall-mounted suction or cerumen loops and to avoid irrigation. In examining the eardrum, the topography of the tympanic membrane is more important than the presence or absence of the light reflex. In addition to the pars tensa (the lower two-thirds of the tympanic membrane), the pars flaccida (upper one-third of the tympanic membrane) above the short process of the malleus should also be examined for retraction pockets that may be evidence of chronic eustachian tube dysfunction or cholesteatoma. Insufflation of the ear canal is necessary to assess tympanic membrane mobility and compliance. Careful inspection of the nose, nasopharynx, and upper respiratory tract is indicated. Unilateral serous effusion should prompt a fiberoptic examination of the nasopharynx to exclude neoplasms. Cranial nerves should


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InternalMed_Harrison. of the nose, nasopharynx, and upper respiratory tract is indicated. Unilateral serous effusion should prompt a fiberoptic examination of the nasopharynx to exclude neoplasms. Cranial nerves should be evaluated with special attention to facial and trigeminal nerves, which are commonly affected with tumors involving the cerebellopontine angle.


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InternalMed_Harrison. Thyroid hormone–binding protein Cytoskeletal protein Potassium channel Gap junction Gap junction Gap junction Class II nonmuscle myosin Cell adhesion molecule Unknown Transmembrane protein Tectorial membrane protein Unknown Developmental gene Cytoskeletal protein Cytoskeletal protein Transcription factor Cytoskeletal protein Cytoskeletal protein Unconventional myosin Developmental gene Vesicular glutamate transporter Transcription factor Transmembrane protein Purinergic receptor Effector of epidermal growth factor– Gap junction Gap junction Cytoskeletal protein Cytoskeletal protein Chloride/iodide transporter Transmembrane protein Transmembrane protein Trafficking of membrane vesicles Transmembrane serine protease


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InternalMed_Harrison. The Rinne and Weber tuning fork tests, with a 512-Hz tuning fork, are used to screen for hearing loss, differentiate conductive from sensorineural hearing losses, and confirm the findings of audiologic evaluation. The Rinne test compares the ability to hear by air conduction with the ability to hear by bone conduction. The tines of a vibrating tuning fork are held near the opening of the external auditory canal, and then the stem is placed on the mastoid process; for direct contact, it may be placed on teeth or dentures. The patient is asked to indicate whether the tone is louder by air conduction or bone conduction. Normally, and in the presence of sensorineural hearing loss, a tone is heard louder by air conduction than by bone conduction; however, with conductive hearing loss of ≥30 dB (see “Audiologic Assessment,” below), the bone-conduction stimulus is perceived as louder than the air-conduction stimulus. For the Weber test, the stem of a vibrating tuning fork is placed on