Disorders of olfaction

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olfactory disorders anosmia

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olfactory pathway anatomy diagram olfactory bulb cribriform plate

This composite educational graphic illustrates the anatomy and histology of the human olfactory system. Figure (a) is a sagittal anatomical specimen showing the olfactory cleft in the cranial nasal cavity. Figure (b) provides an endonasal endoscopic view of the olfactory cleft and the axilla of the middle turbinate (MT Axilla). Figure (c) displays a surgical or dissection view highlighting the relationship between the olfactory epithelium and the underlying bone, with a black arrow indicating the olfactory fibers. Figure (d) features a multi-level schematic: a sagittal head diagram showing the olfactory bulb's position, a zoomed histological view of the olfactory epithelium (OE), and a neural pathway diagram. The OE schematic identifies key cellular components: Olfactory Sensory Neurons (OSNs) with distal cilia, sustentacular cells, and basal cells, as well as Bowman’s glands and the cribriform plate. The neural diagram depicts OSN axons synapsing with mitral, tufted, and glomeruli cells in the olfactory bulb. This resource is designed for teaching the physiological structure and microanatomy of the human olfactory network.

This medical illustration depicts the human olfactory pathway through dual neuroanatomical perspectives: a ventral view (top) and a composite sagittal view (bottom). The ventral image highlights key structures using a color-coded schema: the olfactory bulbs and tracts (red/pink), anterior perforated substance and septal area (orange-yellow), anterior commissure (orange bar), pre-piriform cortex (green), entorhinal cortex (pale blue), and amygdala (purple). Yellow mammillary bodies and pale red medial forebrain bundles are also shown centrally. The sagittal view illustrates the pathway starting from the olfactory epithelium (red bar) through the cribriform plate to the olfactory bulb (OB). It maps secondary and tertiary projections (coded in green, dark blue, and purple) to various regions including the thalamus (Th), hypothalamus (Hy), hippocampus (Hi), and cingulate gyrus (CG). Major landmarks such as the corpus callosum (CC), ventricles (II, III, IV), and brainstem (Pons, Medulla Oblongata) provide anatomical context. This diagram is designed for neuroanatomical education, specifically illustrating the limbic connections of the olfactory system and its relative spatial distribution within the brain.

This medical illustration depicts hypothesized transneural neuroinvasion pathways within the human central nervous system (CNS). The diagram highlights two primary anatomical routes: the olfactory route and the spinal cord route. The olfactory route begins at the olfactory neurons in the nasal cavity, passing through the cribriform plate to the olfactory bulb. A dashed pink line indicates subsequent 'rostro-caudal' spread from the anterior to the posterior brain regions. The spinal route illustrates 'caudo-rostral' neuroinvasion, originating from peripheral somatic nerves that enter the spinal cord. A dashed blue line traces the ascending pathway from the spinal cord through the brain stem and into the deep cortical structures. The illustration serves as an educational tool for understanding how neurotropic pathogens, such as arboviruses or rabies, utilize existing neural architecture to bypass the blood-brain barrier and disseminate throughout the CNS.

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Disorders of Olfaction

Anatomy of the Olfactory System (Overview)

The ~6 million olfactory receptor cells form a pseudostratified columnar neuroepithelium lining the cribriform plate and sectors of the superior septum, superior, and middle turbinates. This epithelium contains:

Bipolar receptor cells - project 3-30 receptor-bearing cilia into the olfactory mucus; act as both receptor and first-order neuron; can regenerate from basal cells
Sustentacular cells - support cells
Microvillar cells
Basal cells - precursors for regeneration
Bowman's glands - major source of olfactory mucus (in lamina propria)

Each receptor cell expresses only 1 of nearly 400 functional receptor protein types. Olfactory subgenomic DNA spans ~1-2% of total genomic DNA.

Axons bundle into fila, pass through cribriform plate foramina, and synapse in glomeruli of the olfactory bulb. Mitral and tufted cells (primary output neurons) then project via the lateral olfactory tract to:

Anterior olfactory nucleus
Piriform cortex (encodes odor quality and identity)
Anterior cortical nucleus of the amygdala
Periamygdaloid complex
Rostral entorhinal cortex

Olfactory pathway anatomy - olfactory bulb, cribriform plate, and central projections

Olfactory pathway - central limbic projections including piriform cortex, amygdala, hippocampus, thalamus

Terminology and Classification of Olfactory Disorders

Term	Definition
Anosmia	Total loss of smell
Hyposmia / Microsmia	Partial (less than total) smell loss
Hyperosmia	Increased sensitivity to odorants (many such patients are actually experiencing dysosmia with decrements on testing)
Dysosmia / Parosmia	Distorted smell when an odorant or warm air is present; often described as "chemical-like or garbage-like"
Phantosmia	Smell perception in the absence of any stimulus
Cacosmia	Parosmia with fecal/putrid character
Olfactory agnosia	Inability to recognize odors despite an intact olfactory system; due to some brain lesions

Dysosmia and phantosmia are usually due to peripheral causes (altered firing of receptor cells during degeneration/regeneration), although central lesions such as epilepsy can be involved. Bacterial infections within the nose, sinuses, or oral cavity can occasionally be the source of foul smells.

Bradley and Daroff's Neurology in Clinical Practice, p. 329-333

Epidemiology

Overall prevalence of olfactory dysfunction: ~13.5% (NHANES 2013-2014)
>50% of people aged 65-80 have significant smell decrements
75% of those aged ≥80 are affected (presbyosmia)
Women outperform men on olfactory tests and retain function to a later age
Presbyosmia causes elderly patients to report food as flavorless, risking nutritional deficiency, and is responsible for a disproportionate number of accidental gas poisonings in the elderly
Harrison's Principles of Internal Medicine 22E, p. 284

Causes of Olfactory Dysfunction

Three Most Common Causes of Long-Lasting or Permanent Smell Loss (in order of frequency)

Severe upper respiratory infections (URIs)
Head trauma
Chronic rhinosinusitis

Congenital, iatrogenic, and toxic chemical exposures are the next most common causes.

1. Upper Respiratory Infections

Viruses (common cold, influenza, pneumonia, HIV, COVID-19) can:

Directly damage the olfactory epithelium
Decrease receptor cell number
Damage cilia on remaining receptor cells
Induce replacement of sensory epithelium with respiratory epithelium

COVID-19 (SARS-CoV-2) smell loss is independent of nasal inflammation in most cases. Many affected patients are unaware of their deficit until objectively tested. Failure to recover normal olfactory function occurs in up to 30% at one year post-infection. Many "idiopathic" cases likely reflect unrecognized viral infections.

Neurotropic viruses (HSV-1 and -2, poliovirus, rabies, vesicular stomatitis virus, Borna disease, etc.) can enter the brain via olfactory receptor cells, potentially initiating neurodegeneration.

2. Head Trauma

Mechanism: shearing and subsequent scarring of the olfactory fila as they pass through cribriform plate foramina (the cribriform plate does not have to be fractured)
Severity correlates with poor Glasgow Coma Scale score and length of posttraumatic amnesia
<10% of posttraumatic anosmic patients recover age-related normal function over time (rises to ~25% for those with partial rather than total loss)

3. Chronic Rhinosinusitis

Smell loss correlates with disease severity
Most loss occurs when rhinosinusitis + polyposis coexist (5-10% experience total loss)
Systemic glucocorticoids can induce short-term improvement but do not return scores to normal on average, implying chronic permanent neural loss

Systemic and Metabolic Causes

A large number of systemic conditions are associated with olfactory impairment, including:

Diabetes, hypertension, hypothyroidism, kidney disease, liver disease
Most immune-mediated diseases: allergic rhinitis, asthma, autoimmune pancreatitis, Behcet disease, Churg-Strauss syndrome, Crohn disease, fibromyalgia, giant cell arteritis, lupus, MS, myasthenia gravis, rheumatoid arthritis, Sjogren syndrome, scleroderma, psoriasis

Olfactory Dysfunction in Neurological Disease

This is clinically significant because olfactory loss often predates motor symptoms and can be a biomarker for early neurodegeneration.

Relative Severity of Smell Loss by Disease (Bradley's scale):

Severity (relative)	Disease
++++ (Most severe)	Idiopathic Parkinson disease (PD), Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Guam PD-dementia complex, Idiopathic REM sleep behavior disorder (iRBD)
+++	Huntington disease, Down syndrome, PARK8 PD
++	Multiple system atrophy (type-P), PARK1 PD, schizophrenia, narcolepsy
+ (Mild)	Motor neuron disease, SCA2 PD, Friedreich ataxia, PARK3, corticobasal degeneration, frontotemporal dementia
0 (Normal)	Essential tremor, vascular parkinsonism, MPTP-induced parkinsonism, progressive supranuclear palsy, PARK2

Key clinical points:

Parkinson disease: Olfactory impairment often predates clinical diagnosis by years. Olfactory bulbs may be - along with the dorsomotor nucleus of the vagus - the first site of neural damage (based on alpha-synuclein/Lewy body staging)
Alzheimer disease: Poor smell correlates with higher AD-related pathology even in presymptomatic stages
DLB: Smell loss is more marked in early DLB than in mild AD
Progressive supranuclear palsy & MPTP-parkinsonism: Minimal or no smell loss - useful differentiating feature
iRBD: Same magnitude of smell loss as PD; iRBD patients frequently go on to develop PD and hyposmia
Narcolepsy with cataplexy: Olfactory impairment linked to loss of orexin (hypocretin) neurons; intranasal orexin-A improves olfactory function
Multiple sclerosis: Smell loss related to demyelinating lesions within olfaction-related structures
Idiopathic intracranial hypertension (IIH): Associated with impaired olfactory sensitivity
Migraine: Osmophobia during attacks; episodic migraineurs may show microsmia/hyposmia during acute attacks

Broad List of Associated Conditions (Table 35-1, Harrison's)

Including (not exhaustive): AIDS/HIV, adenoid hypertrophy, adrenal cortical insufficiency, aging, alcoholism, allergies, ALS, anorexia nervosa, asthma, ataxias, Bardet-Biedl syndrome, chemical exposure, COPD, congenital causes, CJD, Cushing syndrome, cystic fibrosis, diabetes, Down syndrome, epilepsy, frontotemporal dementia, head trauma, herpes simplex encephalitis, hypothyroidism, hyperthyroidism, Huntington disease, kidney disease, liver disease, medications, migraine, MS, multiple system atrophy, neoplasms (cranial/nasal), nutritional deficiencies, obesity, OCD, panic disorder, PD, pregnancy, pseudohypoparathyroidism, radiation, REM behavior disorder, Refsum disease, renal failure, rhinosinusitis/polyposis, schizophrenia, stroke, and vitamin B12 deficiency.

Clinical Assessment

Objective Olfactory Testing

University of Pennsylvania Smell Identification Test (UPSIT) - most widely used; a scratch-and-sniff test with forced-choice odor identification
Scores interpreted relative to age- and sex-matched normative data
Results are classified as: normosmia, mild microsmia, moderate microsmia, severe microsmia, anosmia
The UPSIT figure in Harrison's shows that women consistently identify odorants better than men at all ages, and performance declines progressively with age

The clinical approach includes:

History: onset, duration, quality (lost vs. distorted), triggering events (trauma, URI, surgery)
Nasal endoscopy and imaging (CT/MRI for sinonasal disease, intracranial lesions)
Neurological examination: especially in the context of neurodegenerative disease suspicion
Laboratory tests: thyroid function, renal/hepatic function, zinc levels

Management

Cause	Approach
Rhinosinusitis / polyposis	Systemic glucocorticoids (short-term improvement); topical corticosteroids; surgery (functional endoscopic sinus surgery)
Post-URI smell loss	Olfactory training (smell retraining); alpha-lipoic acid (some evidence); spontaneous recovery possible
Head trauma	Mainly expectant; spontaneous partial recovery in ~25% with partial loss
COVID-19 anosmia	Olfactory training; intranasal corticosteroids (limited evidence); most recover within months; 30% may have persistent loss
Medications	Discontinue offending drug where possible
Neurodegenerative disease	No effective treatment for smell loss itself; treat underlying disease

Olfactory training (systematic daily exposure to four standard odorants - rose, eucalyptus, lemon, clove) is the best-supported non-pharmacological intervention for post-infectious and post-traumatic smell loss.

Recent Evidence

A 2026 systematic review (PMID 41905561) published in Neuroscience & Biobehavioral Reviews examined the neural correlates of olfactory dysfunction, and a 2025 systematic review (PMID 40305821) in Rhinology specifically addressed olfactory disorder after COVID-19 vaccination.

Sources:

Harrison's Principles of Internal Medicine 22E (2025), Chapter 35 - Disorders of Smell, Taste, and Hearing
Bradley and Daroff's Neurology in Clinical Practice, Chapter 19 - Olfaction and Gustation
Cummings Otolaryngology Head and Neck Surgery - Olfaction Rehabilitation

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