4.1 Anosmia
Anosmia denotes the complete inability to detect odors on both sides of the nose, whereas decreased ability to detect odors is known as hyposmia. There are several other types of disorders related to ability to detect odors, such as dysosmia that is the distorted identification of smell. Parosmia is altered perception of smell in the presence of an odor, usually unpleasant. Phantosmia refers to the perception of smell without an odor present. Agnosiais the inability to classify or contrast odors, although in this case people are able to detect odors.
The common causes of primary olfactory deficits are aging, nasal and/or sinus disease, prior viral upper respiratory tract infections, and head trauma. These four causes comprise more than two-thirds of all patients with olfactory dysfunction.
Disturbances of olfaction can be classified as conductive (i.e., transport) defects where transmission of an odorant stimulus to the olfactory neuroepithelium is disrupted; and sensorineural defects that involve more central neural structures.
4.1.1 Conductive defects
Inflammatory processes cause a large proportion of olfactory defects.
Chronic inflammatory rhinitis (syphilis, tuberculosis, sarcoidosis, leprosy, Wegener’s granulomatosis)
Trauma—fracture causing airway obstruction
Patients with laryngectomies or tracheostomies experience hyposmia due to decreased or absent nasal airflow. Children with tracheostomies are cannulated for a long time.
Neoplasia—masses may block the nasal cavity
Benign (papilloma (most common), angiofibroma, osteoma, schwannoma)
Malignant (squamous cell carcinoma, adenocarcinoma, esthesioneuroblastoma, lymphoma, salivary carcinoma, metastasis)
Developmental anomalies may cause obstruction
4.1.2 Central/sensorineural defects
Sense of smell decreases with age. The number of fibers in the olfactory bulb decrease throughout one’s lifetime.
Head trauma, brain surgery, or subarachnoid hemorrhage may stretch, damage, or transect the delicate fila olfactoria or damage brain parenchyma resulting in anosmia.
Infectious and inflammatory processes
Viral infections (damage of neuroepithelium)
Sarcoidosis (affecting neural structures)
Chronic rhinosinusitis (irreversible loss of olfactory receptors through upregulated apoptosis)
Benign (papilloma, meningioma, craniopharyngioma, glioma)
Malignant (leukemia, esthesioneuroblastoma, metastasis)
Endocrine disturbances may affect olfactory function
Congenital syndromes—aplasia of the olfactory bulbs
Absence of neuroepithelium (agenesis/intrauterine infection)
Kallmann syndrome (hypogonadism with eunuchoid gigantism, absence of puberty, and occasional color blindness)
Toxicity of systemic or inhaled drugs
Degenerative processes of the central nervous system (CNS)
Local radiation therapy: radiotherapy of head and neck
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4.2 Oculomotor Nerve Palsy
Third cranial nerve (CN III) dysfunction can present with diplopia, ptosis, eye pain, headache, pupillary dilatation, monocular blurry near vision, or any combination thereof. The primary symptom is mixed horizontal and vertical binocular diplopia from deviation of the two visual axes. The clinical presentation is remarkably varied, as the CN III supplies seven different muscles, and almost any combination of these can be affected to varying degrees.
With the extremely rare unilateral CN III palsy, the involved eye usually is deviated down and out (infraducted, abducted), and there is ptosis which may be severe enough to cover the pupil. In addition, pupillary dilatation can cause symptomatic glare in bright light (if the ptotic lid does not cover the pupil), and paralysis of accommodation causes blurred vision for near objects. CN III is most often affected in combination with other cranial nerves, particularly II, IV, V, and VI (▶Fig. 4.1).
Fig. 4.1 Complete left oculomotor nerve palsy. (a) Complete ptosis of the left eye. (b) The examiner lifts the ptotic eyelid to reveal the mydriatic, fixed (i.e., unreactive) pupil. The eye is also mildly abducted through the predominant effect of the lateral rectus and superior oblique muscles, which are innervated by the abducens and trochlear nerves. (Reproduced from 12.3 Disturbances of Ocular and Pupillary Motility. In: Mattle H, Mumenthaler M, Taub E, ed. Fundamentals of Neurology: An Illustrated Guide. 2nd edition. Thieme; 2017.)
With a complete CN III palsy, the eye in primary position is depressed and abducted, i.e., “down and out.” It cannot elevate or adduct but has full abduction and some residual depression. Depression is accompanied by intorsion, maximally when the eye is abducted, and is due to the action of the superior oblique. This evidence of superior oblique function should be sought, as the differential diagnosis of CN III nerve palsy differs considerably from that of combined III and IV nerve palsies. Ptosis is severe, accommodation is impaired, and the pupil is large and does not constrict to light or vergence efforts.
Incomplete CN III palsies are more common than complete ones. If so, the examination should seek to determine whether the partial involvement conforms to a superior or inferior divisional palsy.
The most frequently identified causes of III nerve palsies are ischemia and aneurysms. Tumors and trauma account for another 10% each, and a cause is not found in 20%. Two clinical signs that help differentiate aneurysmal and neoplastic palsies from the more benign ischemic palsy are: pupillary involvement and oculomotor synkinesis.
The pupil is spared in 75% of ischemic III nerve palsies, but involved in over 90% of aneurysmal palsies. Furthermore, pupil-sparing in aneurysmal palsies almost never occurs with complete dysfunction of all other III nerve muscles. Hence the correct “pupil rule” is that complete pupil-sparing with otherwise complete and isolated palsy of the III nerve is never due to an aneurysm. A small degree anisocoria (< 1 mm) occurs in 30% of microvascular CN III palsies. Relative pupil-sparing in an otherwise complete III nerve palsy, and complete pupil-sparing with incomplete palsy of extraocular muscles and the levator do not reliably exclude an aneurysm or other mass lesion. Also, the presence of pain and the degree of associated external ophthalmoplegia do not distinguish microvascular from compression causes of relative pupil-sparing III nerve palsies. The presence of other cranial nerve palsies or neurologic signs should prompt investigation for a mass lesion. Caution is required to ensure that a coexistent Horner’s syndrome or aberrant regeneration of the pupil are not mimicking pupil-sparing, as these may indicate a mass.
Oculomotor synkinesis(anomalous cocontraction of muscles)
The most common sign is lid elevation on adduction. Pupillary constriction on attempted adduction or depression also occurs often with light reaction. Synkinesis between extraocular muscles causes adduction or globe retraction with attempted vertical gaze. Any of these signs in an adult implies CN III nerve compression by an aneurysm or tumor until proven otherwise, since microvascular or idiopathic lesions are rare if ever responsible. Oculomotor synkinesis also occurs after trauma, including neurosurgical procedures and migraine.
4.2.1 Topographic diagnosis of oculomotor nerve paralysis
Ischemia—paramedian/basal midbrain infarction produces:
i. Benedikt’s syndrome: Ipsilateral CN III palsy, ipsilateral hand tremor (rubral tremor), and ataxia
ii. Weber’s syndrome: Ipsilateral CN III palsy and contralateral hemiplegia or hemiparesis
iii. Millard–Gubler syndrome: Characterized by cross paralysis, contralateral limbs, ipsilateral face due to the involvement of CN VI and VII, and the corticospinal tract.
Tumor (e.g., glioma, metastasis)
Inflammation/demyelination (e.g., herpes zoster encephalitis, poliomyelitis, MS)
Hemorrhage (e.g., intracranial hematoma, subarachnoid hemorrhage)
Aneurysm: It is the most common lesion to affect the CN III in this location following a subarachnoid hemorrhage, therefore, sudden severe headache, stiff neck and loss of consciousness may be present. For example, posterior communicating, less commonly, posterior cerebral, basilar tip or superior cerebellar).
Basal infectious meningitis (e.g., bacterial, fungal/parasitic, viral)
Basal meningeal neoplastic infiltration and miscellaneous inflammatory lesions may involve the third and all the other cranial nerves with the primary symptoms of meningitis, such as headache, stiff neck, fever, and altered level of consciousness. The examples are carcinomatous/lymphomatous/leukemic infiltration, granulomatous inflammation (sarcoidosis, lymphomatoid granulomatosis, Wegener’s granulomatosis), and meningovascular syphilis.
Cavernous sinus and superior orbital fissure
Tumor—Isolated CN III palsy may result from lateral extension of pituitary adenoma or other primary intrasellar mass (e.g., sphenoid wing meningioma, pituitary adenoma, nasopharyngeal, and other metastases).
Inflammatory—Tolosa–Hunt syndrome (idiopathic or granulomatous inflammation). Inflammatory diffused lesions within the cavernous sinus typically give rise to simultaneous involvement of the CNs III, IV, VI, and first divisions of the V in various combinations that serve to define a cavernous sinus syndrome (CSS).
Pituitary apoplexy (infarction within existing pituitary adenoma)
Carotid artery–cavernous sinus fistula
Carotid dural branch–cavernous sinus fistula: Typically present with CN III palsy plus other cranial nerve involvement in the cavernous sinus and proptosis with arterialized conjunctival veins, due to a large volume of arterial blood into the anterior draining veins of the cavernous sinus. Isolated CN III palsy without the orbital congestion can occur when the primary drainage is posterior from the cavernous sinus, the so-called white eye fistulas.
Diabetic infarction of the nerve trunk—microvascular disease in vasa vasorum (pupil spared in 80% of cases; classically described as painful although it can be painless; reversible within 3 months).
Fungal infection (e.g., mucormycosis, usually found in diabetics)
Inflammatory: Nonspecific or granulomatous inflammation in the orbit is referred to as orbital inflammatory pseudotumor.
Orbital blowout fracture: Lesions in the orbit tend to produce associated proptosis, lid swelling, conjunctival injection, and chemosis. There also may be involvement of the other cranial nerves that innervate extraocular muscles (IV and VI) or involvement of the muscles themselves.
Orbital tumors (e.g., meningioma 40%, hemangioma 10%, carcinoma of the lacrimal duct, neurofibroma, lipoma, epidermoid, fibrous dysplasia, sarcoma, and melanoma 35%).
Ophthalmoplegic migraine: Presents mainly in children under the age of 10 years with recurring bouts of unilateral headache and ipsilateral CN III palsy that may last for several weeks.
Arteritis, giant-cell arteritis
Guillain–Barre syndrome (GBS) (Fisher syndrome of isolated polyradiculitis)
Sarcoidosis (Schaumann’s syndrome)
Infectious mononucleosis and other viral infections
Albers-Schonberg syndrome (marble bone disease, osteopetrosis)
Associated with aspirin poisoning
Conditions simulating oculomotor nerve lesion
Thyrotoxicosis: Weakness of the superior and lateral rectus muscles due to an inflammatory myopathic process.
Myasthenia gravis: Diplopia, ptosis, varying eye signs or fatigability of eye movements should always raise this possibility.
Internuclear ophthalmoplegia: Diplopia without weakness of any eye movement, disruption of the conjugate eye movements, e.g., MS, brainstem infarction.
Latent strabismus: Diplopia under conditions of fatigue or drowsiness.
Progressive ocular myopathy (familial ptosis variant): Rare form of muscular dystrophy affecting the extraocular muscles.
Childhood causes of oculomotor nerve palsy
4.2.2 Differential diagnosis
The diagnosis of CN III palsy includes the following conditions:
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Lazaridis C, Torabi A, Cannon S. Bilateral third nerve palsy and temporal arteritis. Arch Neurol 2005;62(11):1766–1768
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Taw LB, Taw M. Oculomotor nerve palsy—An integrative East-West approach Proceedings of UCLA Healthcare 2015; 19
4.3 Trochlear Nerve Palsy
This condition may be clinically characterized by vertical diplopia, incomitant hypertropia that increases upon head tilt toward the paralyzed site (positive Bielschowsky test), excyclotropia, and head tilt (▶Fig. 4.2). This nerve controls the superior oblique muscle, which helps the eye to look downward and assists with eye rotation when one tilts his/her head sideways. A person with trochlear nerve palsy complains of vertical double vision, where objects look stacked on top of each other. The double vision may get worse when looking to the side or trying to read a book. Trochlear nerve palsies can be subtle and hard to detect as the eyes appear normal on casual inspection. There are many causes of trochlear nerve palsy. The number of cases with undetermined cause was 60%.
Fig. 4.2 CN IV palsy. (a) Traumatic left fourth nerve palsy showing left hypertropia in primary gaze. (b) Patient with left fourth nerve palsy. Note the left eye hypertropia and the limitation of the left eye to look down and in compared with the right eye. (Reproduced from 55.6 Cranial Nerve IV. In: Sekhar L, Fessler R, ed. Atlas of Neurosurgical Techniques: Brain, Volume 2. 2nd edition. Thieme; 2015.)
4.3.1 Causes of trochlear nerve palsy
Meningitis (infectious and neoplastic)
Tumor (e.g., tentorial meningioma, germinoma, teratoma, gliomas, choriocarcinoma, trochlear schwannoma, metastases)
Cavernous sinus and superior orbital fissure
Diabetic infarction (this is the most common cause; reversible within 3 months)
Aneurysm (e.g., congenital, aneurysmal dilatation of the intracavernous portion of the internal carotid artery (ICA) usually occurring in elderly hypertensive females)
Carotico-cavernous fistula (e.g., traumatic, spontaneous)
Cavernous sinus thrombosis (serious complication from sepsis of the skin over the upper face or in the paranasal sinuses)
Tumor (e.g., pituitary adenoma, parasellar, tuberculum, or diaphragm sella meningioma, teratoma, dysgerminoma, metastases)
Conditions simulating trochlear nerve palsy
4.3.2 Differential diagnosis of trochlear nerve palsy
Fourth cranial nerve palsies must first be distinguished from other causes of vertical diplopia. These include oculomotor palsy, skew deviation, myasthenia gravis, and Grave’s ophthalmopathy. These patients typically have other clinical findings that help differentiate them from isolated CN IV palsies. Furthermore, in time, these patients often develop other findings that unmask the diagnosis. (1) The differential diagnosis of a CN IV palsy can be subdivided into congenital and acquired. Congenital CN IV palsies are identified in several ways. First, the patient will often have very high vertical fusional amplitudes. Normal vertical fusional amplitudes are in the range of 1–3 prism diopters. Patients with a congenital CN IV palsy can often fuse 10–15 prism diopters. Also, old pictures can show whether or not there has been long-standing head tilt since childhood. This would give more evidence to suggest that a CN IV palsy was congenital. When a cause can be identified, the most common etiology of an acquired CN IV palsy is trauma (30%). Another common etiology is microvascular or ischemic, often in the setting of diabetes or hypertension (8%). (2) Other etiologies include compressive lesions such as tumors (6%) or aneurysms (8%), increased intracranial pressure, intrinsic neoplasms of the CN IV, and, very rarely, giant cell arteritis.
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Gentry LR, Mehta RC, Appen RE, Weinstein JM. MR imaging of primary trochlear nerve neoplasms. AJNR Am J Neuroradiol 1991;12(4):707–713
4.4 Abducens Nerve Palsy (Sixth Cranial Nerve)
This condition is a common cause of acquired horizontal diplopia. Signs pointing toward the diagnosis are an abduction deficit and an esotropia increasing with gaze toward the side of the deficit. The most important characteristic of the condition is double vision in which a patient sees two side-by-side images of any object. The diplopia is typically worse at distance. However, children may not complain of diplopia. In case of unilateral abducens nerve palsy, the distance between the two images appears to be greatest when the gaze is directed to the affected side. Measurements are made with the uninvolved eye fixing (primary deviation), and will be larger with the involved eye fixing (secondary deviation), A small vertical defect may accompany a CN VI palsy, which may raise the question of additional pathology, such as a CN IV palsy or skew deviation. (▶Fig. 4.3)
Fig. 4.3 Partial right abducens nerve palsy. (a) On leftward gaze, the eyes are parallel; (b) on rightward gaze, the right eye fails to abduct to the full extent. (Reproduced from 12.3 Disturbances of Ocular and Pupillary Motility. In: Mattle H, Mumenthaler M, Taub E, ed. Fundamentals of Neurology: An Illustrated Guide. 2nd edition. Thieme; 2017.)
Abducens nerve palsy is the most common encountered extraocular muscle palsy and its incidence is 11.3 in 100,000 people. In 35% of the cases, the patients had hypertension and/or, less frequently, diabetes, 26% were undetermined, 5% had a neoplasm, and 2% had an aneurysm.
Bilateral abduction deficit in the setting of trauma or subarachnoid hemorrhage often indicate increased intracranial pressure causing a bilateral CN VI palsy. This sudden rise in intracranial pressure can lead to downward displacement of the brain stem which can compress CN VI in the prepontine cistern as it makes a 90° bend and exits the pontomedullary junction to ascend along the clivus toward the cavernous sinus. Other causes of acquired bilateral abduction deficits include damage to the convergence pathway, thalamic esodeviation, or breakdown of a pre-existing phoria due to loss of conscious control, diabetes mellitus type II, Kearns–Sayre syndrome, cavernous sinus thrombosis, Wildervanck syndrome, thiamine deficiency, Tolosa–Hunt syndrome, Duane’s ocular retraction syndrome, Moebius syndrome, Raymond Cestan syndrome, Gradenigo–Lannois syndrome.
4.4.1 Causes of abducens nerve palsy and differential diagnosis
Infarction: Paramedian and basal pontine infarction; e.g., Foville’s syndrome, Gasperini’s syndrome, and Millard–Gubler syndrome.
Wernicke′s encephalopathy: Serious complication of alcoholism and severe malnutrition; reversible following intravenous therapy with vitamin B1.
Moebius syndrome: Congenital absence of facial nerve nuclei and associated absence of the abducens nuclei.
Pontine glioma: Many of these tumors start in the region of the abducens nerve nucleus; any combination of CN VI and VII palsy in a young child or a patient with neurofibromatosis should be regarded with suspicion.
Demyelination (e.g., MS; internuclear ophthalmoplegia or isolated CN VI palsy is a common manifestation.)
Duane’s ocular retraction syndrome (abduction defect with palpebral fissure narrowing)
Trauma (16–17%) (e.g., severe head injury and movement of the brain stem)
Raised intracranial pressure (causing downward displacement of the brain stem and stretching of the abducens nerve over the petrous tip leading to its paresis)
Basal meningeal process (e.g., tuberculous, fungal, bacterial, and carcinomatous meningitis, meningovascular syphilis)
Subarachnoid hemorrhage (obstruction of the cerebrospinal fluid at the aqueduct level causing obstructive hydrocephalus and raised ICP)
Clival tumors (e.g., chordoma, chondroma, sarcoma, metastases, Paget’s disease)
Large cerebellopontine angle tumors (e.g., acoustic neurinoma, meningioma, epidermoid, metastases, giant aneurysm—AICA or BA aneurysm—arachnoid cyst)
Gradenigo’s syndrome (diffuse inflammation of the petrous bone and thrombosis of the petrosal sinus causing severe ear pain and a combination of CNs VI, VII, VIII, and occasionally CN V nerve lesions)
Infiltration (e.g., carcinomas of the nasopharynx or the paranasal sinuses, leukemias, CNS lymphoma)
Cavernous sinus and superior orbital fissure
Aneurysm (e.g., congenital, aneurysmal dilatation of the intracavernous portion of the ICA usually occurring in elderly hypertensive females)
Carotico-cavernous fistula (e.g., traumatic, spontaneous)
Cavernous sinus thrombosis: Serious complication from sepsis of the skin over the upper face or in the paranasal sinuses
Tumor (e.g., pituitary adenoma, parasellar, tuberculum, or diaphragm sella meningioma, metastases, nasopharyngeal carcinoma)
Nonspecific febrile illness (benign transient CN VI palsy, particularly in children
Infectious (e.g., diphtheria, botulism intoxication) and parainfectious diseases: Spontaneous recovery of the CN VI palsy is almost the rule.
Lumbar puncture: Differential pressure gradients between the supra and infratentorial compartments causes downward herniation resulting in a reversible CN VI palsy.
Conditions simulating abducens nerve palsy
Thyrotoxicosis (myopathy of the extraocular muscles)
Thyroid eye disease and orbital inflammatory disease may result in restriction of extraocular muscles, but are typically accompanied by characteristic signs and symptoms, such as proptosis, injection over the rectus, muscle insertions, lid retraction, and lid lag. Forced duction testing may be helpful to rule out a restrictive etiology for an abduction deficit.
This condition is always an etiologic consideration with the acute onset of strabismus. The ice test and rest test are useful office procedures to look for functional improvement in cases with myasthenia. Tensilon test may give a false-negative result. Single muscle fiber electromyography may be the best test for definitive diagnosis.
Spasm of the near reflex can stimulate an abduction deficit. The convergence is associated with miotic pupils, and ductions are full with one eye occluded.
Divergence paresis or divergence insufficiency with a comitant esodeviation greater at distance than near (or none at near), and with decreased divergence fusional amplitudes can also simulate a sixth nerve weakness. Divergence paresis has little localizing value.
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Durkin SR, Tennekoon S, Kleinschmidt A, Casson RJ, Selva D, Crompton JL. Bilateral sixth nerve palsy. Ophthalmology 2006;113(11):2108–2109
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