# 26 - 35 Disorders of Smell and Taste

### 35 Disorders of Smell and Taste

Exaggerated gaze-evoked nystagmus can be induced by drugs (seda­
tives, anticonvulsants, alcohol); muscle paresis; myasthenia gravis; 
demyelinating disease; and cerebellopontine angle, brainstem, and 
cerebellar lesions.
VESTIBULAR NYSTAGMUS  Vestibular nystagmus results from dysfunc­
tion of the labyrinth (Ménière’s disease, benign paroxysmal positional 
vertigo), vestibular nerve, or vestibular nucleus in the brainstem. 
Peripheral vestibular nystagmus often occurs in discrete attacks, with 
symptoms of nausea and vertigo. There may be associated tinnitus and 
hearing loss. Sudden shifts in head position may provoke or exacerbate 
symptoms.
DOWNBEAT NYSTAGMUS  Downbeat nystagmus results from lesions 
near the craniocervical junction (Chiari malformation, basilar invagi­
nation). It also has been reported in brainstem or cerebellar stroke, lith­
ium or anticonvulsant intoxication, alcoholism, and multiple sclerosis. 
Upbeat nystagmus is associated with damage to the pontine tegmentum 
from stroke, demyelination, or tumor.
Opsoclonus 
This rare, dramatic disorder of eye movements con­
sists of bursts of consecutive saccades (saccadomania). When the 
saccades are confined to the horizontal plane, the term ocular flutter is 
preferred. It can result from viral encephalitis, trauma, or a paraneo­
plastic effect of neuroblastoma, breast carcinoma, and other malignan­
cies. It has also been reported as a benign, transient phenomenon in 
otherwise healthy patients.
■
■FURTHER READING
Albert DM et al: Albert and Jakobiec’s Principles and Practice of 
Ophthalmology, 4th ed. New York, Springer Link, 2022.
Apte RS: Age-related macular degeneration. N Engl J Med 385:540, 
2021.
Chen X et al: Shape perception via a high-channel-count neuroprosthesis 
in monkey visual cortex. Science 370:1191, 2020.
Durand ML et al: Infectious keratitis. JAMA 326:1319, 2021.
Heier JS et al: Pegcetacoplan for the treatment of geographic atrophy 
secondary to age-related macular degeneration (OAKS and DERBY): 
Two multicentre, randomised, double-masked, sham-controlled, 
phase 3 trials. Lancet 402:1434, 2023.
Jhaveri CD: Aflibercept monotherapy or bevacizumab first for diabetic 
macular edema. N Engl J Med 387:692, 2022.
Sahel JA: Partial recovery of visual function in a blind patient after 
optogenetic therapy. Nature Med 27:1223, 2021.
Toth CA: Optical coherence tomography and eye care. N Engl J Med 
389:1526, 2023.
Yanoff M, Duker J: Ophthalmology, 6th ed. Singapore, Elsevier, 2023.
Richard L. Doty, Steven M. Bromley

Disorders of Smell 

and Taste
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 longitudinal study of 1162 nondemented elderly 
persons found, even after controlling for confounders, that those with 
the lowest baseline olfactory test scores had a 45% mortality rate over 

a 4-year period, compared to an 18% mortality rate for those with the 
highest olfactory test scores. 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 chemo­
sensory dysfunction. Among the more important recent developments 
in neurology is the discovery that decreased smell function is among 
the first signs of such neurodegenerative diseases as Parkinson’s disease 
(PD) and Alzheimer’s disease (AD), signifying their “presymptomatic” 
phase.
■
■ANATOMY AND PHYSIOLOGY
Disorders of Smell and Taste 
CHAPTER 35
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. 35-1). Nearly 400 types of G-protein-coupled odor receptors 
(GPCRs) are expressed on the cilia of the receptor cells, with only one 
type of GPCR being expressed on a given cell. Other receptors, includ­
ing trace amine-associated receptors and members of the non-GPCR 
membrane-spanning 4-domain family, subfamily A (MS4A) protein 
family, are also present on some receptor cells. Such a plethora of recep­
tor cell types does not exist in any other sensory system. Importantly, 
when damaged, the receptor cells can be replaced by stem cells near the 
basement membrane, although such replacement is often incomplete.
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. 35-2). These spherical structures, 
which make up a distinct layer of the olfactory bulb, are a site of con­
vergence 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 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.
The axons of the mitral and tufted cells synapse within secondary 
olfactory structures, which largely compose the primary olfactory 
cortex (POC) (Fig. 35-3). The POC is defined as those cortical struc­
tures that receive direct projections from the olfactory bulb, most nota­
bly 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 POC and the orbitofrontal cortex 
(OFC), where odor identification largely occurs. The close anatomic 
ties between the olfactory system and the 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.
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. 35-4). Lin­
gual taste buds are embedded in well-defined protuberances, termed

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 35-1  Anatomy of the nose, 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.)
fungiform, 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 
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 GPCRs, 
Olfactory
bulb
Granule cell
Mitral/tufted cell
Periglomerular cell
Glomerulus
Cribriform plate
Olfactory neurons
Olfactory receptor cells
Supporting cell 
Olfactory cilia
FIGURE 35-2  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. (Adapted from https://medicine.yale.edu/.)

namely T1R1, T1R2, and T1R3, mediate sweet and umami taste sensa­
tions. 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.
It is now well established that both bitter and sweet taste-related 
receptors are also present elsewhere in the body, most notably in the 
alimentary and respiratory tracts. This important discovery general­
izes 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 specifi­
cally 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 
Olfactory bulb
Olfactory tract
Medial olfactory
stria
Lateral olfactory
stria
Amygdala
Pyriform
area
Entorhinal
area
Vagus
nerve
Spinal cord
Cerebellar
vermis
Cerebellum
FIGURE 35-3  Anatomy of the base of the brain showing the primary olfactory cortex.

FIGURE 35-4  Schematic of the taste bud and its opening (pore), as well as the location of buds on the three major types of papillae: fungiform (anterior), foliate (lateral), and 
circumvallate (posterior). TRC, taste receptor cell.
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 entero­
endocrine 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 enteroendo­
crine 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 respond 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 aerugi­
nosa and other gram-negative bacteria. Differences in T2R38 function­
ality, as related to TAS2R38 genotype, correlate with susceptibility to 
upper respiratory infections in humans.
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. 35-5). 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 proxi­
mal 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, 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 exit­
ing 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.

Taste pore
Taste
bud
Circumvallate
Disorders of Smell and Taste 
CHAPTER 35
Taste
bud
TRC
Foliate
Taste
bud
Fungiform
The axons of the projection cells, which synapse with taste buds, 
enter the rostral portion of the nucleus of the solitary tract (NTS) 
within the medulla of the brainstem (Fig. 35-5). From the NTS, neu­
rons 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). Pro­
jections 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.”
FIGURE 35-5  Schematic of the cranial nerves (CNs) that mediate taste function, 
including the chorda tympani nerve (CN VII), the glossopharyngeal nerve (CN 
IX), and the vagus nerve (CN X). (Copyright David Klemm, Faculty and Curriculum 
Support [FACS], Georgetown University Medical Center.)

■
■DISORDERS OF OLFACTION
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.

Estimates of the prevalence of olfactory dysfunction in the general 
population vary; a cross-sectional analysis from the National Health 
and Nutrition Examination Survey (NHANES 2013–2014) found an 
overall prevalence of 13.5%. However, it is apparent that significant 
decrements in the ability to smell are present in >50% of the popula­
tion between 65 and 80 years of age and in 75% of those aged ≥80 
years (Fig. 35-6). Such presbyosmia helps to explain why many elderly 
patients report that food has little flavor, a problem that can result in 
nutritional disturbances. This also helps to explain why a dispropor­
tionate number of elderly people die in accidental gas poisonings. A 
relatively complete listing of conditions and disorders that have been 
associated with olfactory dysfunction is presented in Table 35-1.
PART 2
Cardinal Manifestations and Presentation of Diseases
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 
MALE NORMS: PERCENTILE VALUES
Age of Examinee
5–9
10–14 15–19 20–24 25–29
30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84
≥85

NORMOSMIA
NORMOSMIA
MILD MICROSMIA
MILD MICROSMIA
MODERATE MICROSMIA
MODERATE MICROSMIA
SEVERE MICROSMIA
SEVERE MICROSMIA
Test Score
PROBABLE MALINGERING
PROBABLE MALINGERING

N =
FIGURE 35-6  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. Women identify odorants better than men at all ages. (Reproduced with permission from RL Doty. Measurement of chemosensory function. WJOHNS  4:11-28, 
2018.)

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 posttrau­
matic 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. Respiratory infections, such as those associated 
with the common cold, influenza, pneumonia, HIV, and COVID-19, can 
directly and permanently damage the olfactory epithelium, decreas­
ing 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 
related to disease severity, with most loss occurring in cases where 
rhinosinusitis and polyposis are both present. Smell loss is among 
the first signs of the severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection, which is responsible for COVID-19. In most 
cases, this loss is independent of nasal inflammation. Many of those 
afflicted are unaware of their deficit until objectively tested. Failure to 
regain normal olfactory function occurs in up to 30% even a year after 
ANOSMIA
ANOSMIA

TABLE 35-1  Disorders and Conditions Associated with Compromised Olfactory Function, as Measured by Olfactory Testing
Endocrine and Metabolic Conditions
Adrenal cortical insufficiency (Addison’s disease)
Chromatin-negative gonadal dysgenesis (Turner’s 
syndrome)
Cushing’s syndrome
Diabetes
Hypertension
Hypothyroidism
Idiopathic hypogonadotropic hypogonadism
Kallmann’s syndrome
Liver disease
Renal disease/kidney failure
Pregnancy
Pseudohypoparathyroidism
Wilson’s disease
Nasosinus Disorders
Adenoid hypertrophy
Bacterial and viral upper respiratory infections
Laryngopharyngeal reflux disease
Rhinosinusitis/polyposis
Neurologic Diseases/Disorders
Alzheimer’s disease
Amyotrophic lateral sclerosis (ALS)
Bell’s palsy
Degenerative ataxias
Down’s syndrome
Epilepsy
Facial paralysis
Fibromyalgia
Frontotemporal lobe degeneration
Guamanian ALS/Parkinson’s disease/dementia 
syndrome
Head trauma
Huntington’s disease
Idiopathic inflammatory myopathies
Korsakoff psychosis
Lubag disease
Migraine
Multi-infarct dementia
Narcolepsy with cataplexy
Neoplasms, cranial/nasal
Orthostatic tremor
Parkinson’s disease
Pick’s disease
Rapid eye movement behavioral sleep disorder
Stroke
Immune-Related Diseases
Acute disseminated encephalomyelitis
Allergic rhinitis
Asthma
Autoimmune pancreatitis
Behçet’s disease
Churg-Strauss syndrome
Cystic fibrosis
Fibromyalgia
Giant cell arteritis
Hereditary angioedema
Idiopathic inflammatory myopathies
Inflammatory bowel diseases
Lupus
Mikulicz’s disease
Multiple sclerosis
Myasthenia gravis
Neuromyelitis optica
Pemphigus vulgaris
Psoriasis vulgaris
Rheumatoid arthritis
Sjögren’s syndrome
Systemic sclerosis (scleroderma)
Wegener’s granulomatosis
Psychiatric-Related Diseases/Disorders
Anorexia nervosa
Asperger’s syndrome
Attention deficit/hyperactivity disorder
Depression
Obsessive compulsive disorder
Panic disorder
Posttraumatic stress disorder
Psychopathy
Schizophrenia
Seasonal affective disorder
22q11 deletion syndrome
Note: These disease/disorder classifications are not necessarily mutually exclusive.
diagnosis, with 5–10% experiencing total loss. Although in rhinosi­
nusitis cases systemic glucocorticoid therapy can usually induce shortterm 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.
A number of neurodegenerative diseases are accompanied by olfactory 
impairment, including PD, AD, Huntington’s disease, parkinsonism-

dementia complex of Guam, dementia with Lewy bodies (DLB), 
multiple system atrophy, corticobasal degeneration, frontotemporal 
dementia, and Down’s syndrome; smell loss can also occur in idio­
pathic rapid eye movement (REM) behavioral sleep disorder (iRBD), as 
well as in multiple sclerosis (MS) related to lesions within olfaction-related 
structures. Olfactory impairment in PD often predates the clinical 
diagnosis by a number of years. In staged cases, studies of the sequence 
of formation of abnormal α-synuclein aggregates and Lewy bodies 

Viral, Bacterial, and Fungal Infections
Candidiasis
COVID-19
Hepatitis C
Herpetic meningoencephalitis
Human immunodeficiency virus
Legionnaires’ disease
Leprosy (Hansen’s disease)
Lyme disease
Poliomyelitis
Rhinosinusitis
Upper respiratory infections
Disorders of Smell and Taste 
CHAPTER 35
Other Disorders or Factors
Alcoholism
Bardet-Biedl syndrome
Chemical exposure
Congenital
Iatrogenesis, including chemotherapy and radiation
Nutritional deficiencies
Obesity
Tobacco smoking
Toxic chemical exposures
Vitamin B12 deficiency
suggest that the olfactory bulbs may be, along with the dorsomotor 
nucleus of the vagus, the first site of neural damage in PD. In postmor­
tem 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 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. The relative contributions of disease-specific pathology 
or differential damage to forebrain neuromodulator/neurotransmitter 
systems in explaining different degrees of olfactory dysfunction among 
the various neurodegenerative diseases are presently unknown.
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 fre­
quently develop PD and hyposmia. REM behavior disorder is not only 
seen in its idiopathic form but can also be associated with narcolepsy 
(Chap. 33). A study of narcoleptic patients with and without REM 
behavior disorder demonstrated that narcolepsy, independent of REM

behavior disorder, was associated with impairments in olfactory func­
tion. Loss of hypothalamic neurons expressing orexin (also known as 
hypocretin) neuropeptides is believed to be responsible for narcolepsy 
and cataplexy. Orexin-containing neurons project throughout the 
entire olfactory system (from the olfactory epithelium to the olfac­
tory cortex), and damage to these projections may be one underlying 
mechanism for impaired olfactory performance in narcoleptic patients. 
Administration of intranasal orexin A (hypocretin-1) improved olfac­
tory function, supporting the notion that mild olfactory impairment 
is not only a primary feature of narcolepsy with cataplexy, but that 
orexin deficiency may be directly responsible for the loss of smell in 
this condition.

PART 2
Cardinal Manifestations and Presentation of Diseases
■
■DISORDERS OF TASTE
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 impair­
ment 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 CN pathways. Taste function can 
be influenced by age, diet, smoking behavior, use of medications, and 
other subject-related factors including (1) the release of foul-tasting 
materials from the oral cavity from oral medical conditions (e.g., 
gingivitis, purulent sialadenitis) or appliances; (2) transport problems 
of tastants to the taste buds (e.g., drying, infections, or inflammatory 
conditions of the orolingual mucosa), (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 infec­
tions), (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, laryn­
goscopy, endotracheal intubation, and radiation therapy can result in 
selective injury. CN VII damage commonly results from mastoidec­
tomy, tympanoplasty, and stapedectomy, in some cases inducing per­
sistent metallic sensations. Bell’s palsy (Chap. 452) is one of the most 
common causes of CN VII injury that results in taste disturbance. On 
rare occasions, migraine (Chap. 441) is 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 (also termed glossodynia or glossalgia), as does dry mouth 
and thirst. Burning mouth syndrome is likely associated with dysfunc­
tion 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 thrust­
ing, teeth grinding, jaw clenching), (6) tongue ischemia as a result of 
temporal arteritis, (7) periodontal disease, (8) reflux esophagitis, and 
(9) geographic tongue.
Although both taste and smell can be adversely influenced by drugs, 
taste alterations are more common. Indeed, >250 medications have 
been reported to alter the ability to taste. Major offenders include 
antineoplastic agents, antirheumatic drugs, antibiotics, and blood pres­
sure 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) for 
insomnia experienced a bitter dysgeusia that was stronger in women, 
systematically related to the time since drug administration, and posi­
tively correlated with both blood and saliva levels of the drug. Intra­
nasal 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 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 to 76% depending on the type of cancer treatment. 
Attempts to prevent taste problems from such drugs using prophylac­
tic 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.
As with olfaction, a number of systemic disorders can affect taste. 
These include, but are not limited to, chronic renal failure, end-stage 
liver disease, vitamin and mineral deficiencies, diabetes mellitus, and 
hypothyroidism. 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 associ­
ated with chemosensory alterations (e.g., depression, schizophrenia, 
bulimia). A recent review of tactile, gustatory, and olfactory hallucina­
tions demonstrated that no one type of hallucinatory experience is 
pathognomonic to any given diagnosis.
Pregnancy is 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 rela­
tive 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.
■
■CLINICAL EVALUATION
In most cases, a careful clinical history will establish the probable etiol­
ogy 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, although gradual loss can also follow head trauma. 
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 alco­
holism), exposures to pesticides and other toxic agents, and medical 
interventions is also informative. A determination of all the medica­
tions that the patient was taking before and at the time of symptom 
onset is important because many can cause chemosensory distur­
bances. Comorbid medical conditions associated with smell impair­
ment, 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, par­
kinsonian symptoms, and seizure activity (e.g., automatisms, blackouts, 
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 CN function, with particular attention to possible skull 
base and intracranial lesions. Visual acuity, field, and optic disc exami­
nations aid in detection of intracranial mass lesions that produce raised 
intracranial pressure (papilledema) and optic atrophy. Foster Kennedy 
syndrome refers to raised intracranial pressure plus a compressive optic 
neuropathy; typical causes are olfactory groove meningiomas or other 
frontal lobe tumors. 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, 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 some patients 
who complain of chemosensory dysfunction have normal function 
for their age and gender. Quantitative smell and taste testing provides 
objective information for worker’s compensation and other legal claims, 
as well as a way to accurately assess the effects of treatment interven­
tions. A number of standardized olfactory and taste tests are com­
mercially available. The most widely used olfactory test, the 40-item 
University of Pennsylvania Smell Identification Test (UPSIT), uses 
norms based on over 10,000 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 avail­
able 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 excep­
tion of electrogustometers, commercially available taste tests have only 
recently become available. Most use filter paper strips or similar materi­
als impregnated with tastants, so no stimulus preparation is required.
■
■TREATMENT AND MANAGEMENT
Given the various mechanisms by which olfactory and gustatory distur­
bance 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. Chlorhexi­
dine 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 arti­
ficial 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 dis­
continued and replaced with other types of medications or modes of 
therapy. As mentioned earlier, pharmacologic agents result in taste dis­
turbances much more frequently than smell disturbances. It is impor­
tant to note, however, that many drug-related effects are long lasting and 
not reversed by short-term drug discontinuance.
A study of endoscopic sinus surgery in patients with chronic rhi­
nosinusitis 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 pred­
nisone. Topical intranasal administration of glucocorticoids 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 adminis­
tered 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.
Treatments are limited for patients with chemosensory loss or pri­
mary 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 dys­
function at the time of presentation, not etiology, was the best predictor 
of prognosis. Other predictors were age and the duration of dysfunc­
tion prior to initial testing.

Several studies have reported that patients with hyposmia may 
benefit from repeated smelling of odors over the course of weeks or 
months, although it remains to be determined how much improve­
ment, if any, occurs over that known to occur spontaneously. The usual 
paradigm is to smell odors such as eucalyptol, citronella, eugenol, and 
phenyl ethyl alcohol before going to bed and immediately upon awak­
ening each day. 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. There is also limited 
evidence that α-lipoic acid (400 mg/d), an essential cofactor for many 
enzyme complexes with possible antioxidant effects, may be beneficial 
in mitigating smell loss following viral infection of the upper respira­
tory tract. However, double-blind studies are needed to confirm this 
observation. α-Lipoic acid has also been suggested to be useful in some 
cases of hypogeusia and burning mouth syndrome.
Disorders of Smell and Taste 
CHAPTER 35
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 occa­
sionally 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 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.
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 per­
centage of responders was about the same (~50%) as that noted by others 
to show spontaneous improvement over a similar time period. Anti­
epileptics 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 medica­
tions that can ultimately distort smell and taste function, possibly from 
its anticholinergic effects. One study suggested that the centrally acting 
acetylcholinesterase inhibitor donepezil in AD resulted in improve­
ments on smell identification measures that correlated with overall 
clinician-based impressions of change in dementia severity scores.
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.
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