Cranial Nerve and Neuro-Ophthalmologic Disorders

Anatomy

The olfactory nerves are concerned with the special sense of smell. The nerve fibers are the central processes of bipolar nerve cells located in the olfactory epithelium, which covers most of the superior-posterior nasal septum and the lateral wall of the nasal cavity. The unmyelinated peripheral olfactory fibers aggregate into approximately 20 slender olfactory bundles that make up the olfactory nerve. The nerve traverses the ethmoidal cribriform plate surrounded by finger-like extensions from the dura mater and arachnoid to end in the “glomeruli” of the homolateral olfactory bulb. Within the bulb, these fibers synapse with second-order neurons called mitral and tufted cells whose axons constitute the olfactory tract that courses along the frontal lobe base. It then divides into the medial and lateral olfactory striae on either side of the anterior perforated substance and projects directly into the primary olfactory cortex within the temporal lobe. This direct pathway without a central sensory relay site (such as in the thalamic nuclei) is unique among the cranial nerves. Although most of the olfactory tract fibers have ipsilateral central connections, some fibers decussate in the anterior commissure, making the cortical representation of smell bilateral. The human primary olfactory cortex includes the uncus, hippocampal gyrus, amygdaloid complex, and entorhinal cortex.

Olfactory Nerve Disorders

Anosmia is not always apparent to the patient, and due to the close association of flavor perception and olfaction, may be reported as altered taste rather than loss of smell. Bilateral anosmia is more common and usually of benign nature, whereas unilateral anosmia should raise suspicion for a more serious disorder, such as an olfactory groove meningioma or frontal basal tumor. The most common cause of anosmia is nasal and paranasal sinus infection with inflammation and is referred to as transport or conductive olfactory disorders. Post-traumatic olfactory dysfunction is the cause for 20% of patients with anosmia and is the result of olfactory nerve shearing as it passes through the cribriform plate. In more substantial damage, the olfactory nerve is torn by fractures involving the cribriform plate, with cerebrospinal fluid rhinorrhea and possible meningeal infection. Post-traumatic anosmia or hyposmia may be either unilateral or bilateral. Tumors of the olfactory groove affect the olfactory bulb and tract. The most common are olfactory groove meningiomas, which are usually histologically benign tumors causing mostly unilateral, and occasionally bilateral, gradual olfactory dysfunction. Other tumors include sphenoid and frontal osteomas, pituitary tumors, and nasopharyngeal carcinomas. Unless specifically tested, a presentation of anosmia is unusual because of generally unilateral involvement and slow tumor growth with slow decline in olfactory function. Once such tumors are large enough (>4 cm in diameter), they cause pressure on the frontal lobes and the optic tracts, with symptoms of headaches, visual disturbances, personality changes, and memory impairment. Very large olfactory groove tumors on rare occasion cause ipsilateral optic atrophy by exerting direct pressure on the optic nerve with contralateral papilledema from increased intracranial pressure. The finding of ipsilateral optic atrophy, contralateral papilledema, and ipsilateral anosmia is known as the Foster-Kennedy syndrome. Esthesioneuroblastomas arise from the upper nasal cavity and manifest with nasal obstruction and epistaxis. Rarely, they involve the orbit and cause diplopia, visual loss, proptosis, and periorbital swelling. Anosmia is an early sign of neurodegenerative processes, particularly Parkinson disease, Alzheimer disease, and Lewy body dementia. It frequently precedes other neurologic signs, such as motor findings or cognitive changes. Olfactory discrimination is affected by many medications thought to disrupt the physiologic turnover of receptor cell and includes opiates, anticonvulsants, and various immunosuppressive agents. Congenital or hereditary anosmia is rare. Kallmann syndrome consists of congenital hypoplasia or absence of the olfactory bulbs and hypogonatropic hypogonadism.

Olfactory Receptors

Receptors responsible for the sense of smell are found in the patch of olfactory epithelium that is located on the superior-posterior nasal septum and the lateral wall of the nasal cavity. In addition to the receptor cells, this epithelium contains olfactory (Bowman's) glands and sustentacular cells, both contribute to the mucous secretion that coats the epithelial surface and makes odorants soluble. The sustentacular cells also act as supporting cells for the slender olfactory receptors.

Olfactory receptor cells may be considered specialized, primitive-type, bipolar neurons. Their nuclei are located at the base of the epithelial layer. Basal stem cells located along the basement membrane differentiate into olfactory receptors or supporting cells, replenishing the olfactory epithelium about every 2 weeks. From the nuclear region of the olfactory receptor cell, a thin dendritic process extends toward the surface of the epithelium. At its apical end, this process widens into an olfactory rod, or vesicle, from which 10 to 15 motile cilia project into the mucous layer covering the epithelium. Desmosomes at the base of the olfactory vesicle provide a tight seal between the membranes of olfactory and sustentacular cells, thus preventing external substances from entering the intercellular spaces. At its base, the olfactory receptor cell narrows and gives rise to a fine (0.2 to 0.3 µm) unmyelinated axon. Large numbers of these axons converge to run together within a single Schwann cell sheath. The fibers then penetrate the cribriform plate to collectively form the olfactory nerve. In humans, this nerve contains on the order of 100 million axons.

Odorant Transduction . The cell membranes of the olfactory receptor cells are able to convert chemical odorants into an electrical signal by activation of a G-protein–coupled protein receptor cascade that activates the enzyme adenylate cyclase, which produces cyclic adenosine monophosphate (cAMP) as a second messenger. cAMP then changes the structure of the cell membrane channel proteins to an open state. The channel is permeable to cations that flow from the nasal mucosa into the cell. The negative resting membrane potential (−70 mV) is shifted to a more positive value. Once a certain threshold is reached, the analog sensor potential is converted to a digital action potential, which is conducted via the axon of the olfactory cell to the brain.

Sense of Smell . As with taste fibers, which may respond to a variety of taste stimuli, individual olfactory nerve fibers respond to a number of different odors. Humans differentiate the odors of thousands of chemicals; nevertheless, it has not been possible to identify a set of primary odor qualities analogous to the four primary tastes.

Olfactory Pathway

Olfactory Bulb . About 100 million olfactory afferent fibers enter the olfactory bulb, a flattened, oval mass lying near the lateral margin of the cribriform plate of the ethmoid bone. The incoming olfactory fibers coalesce in the outermost layer of the olfactory bulb to form presynaptic nests, or glomeruli. Each glomerulus is composed of about 25,000 receptor cell axon terminals. The terminals synapse and excite the dendrites of mitral and tufted cells, which are the second-order neurons in the olfactory bulb. Each mitral cell sends its dendrite to only a single glomerulus, while each tufted cell sends dendrites to several glomeruli. Olfactory afferents within the glomeruli also activate periglomerular cells, which then inhibit mitral and tufted cells. Further inhibition arises at the dendrodendritic contacts between mitral and tufted cells and the processes of granule cells, which lie deeper still within the olfactory bulb. These contacts are an example of two-way synaptic feedback connections: the granule cells are excited by mitral and tufted cells and, in turn, inhibit them. Integration of olfactory information occurs when excitation is spread throughout the multiple-branched granule cell processes, and also when granule cells are excited by the centrifugal efferent fibers that reach the olfactory bulb from higher centers. Another factor in this highly complex integrative process is the recurrent collaterals of mitral cells that appear to excite mitral, tufted, and granule cells.

There is a dramatic transformation in the response to odors between the glomeruli and the mitral cells. The glomeruli respond to different substances based on their physiochemical properties, whereas mitral cells respond to groups of substances that evoke subjective sensations.

Olfactory Tract and Central Connections . The axons of mitral and tufted cells form the olfactory tract, through which they project to the olfactory trigone and into the lateral and medial olfactory striae, establishing a complex pattern of central connections. Some mitral and tufted cell axons terminate in the anterior olfactory nucleus (a continuation of the granule cell layer throughout the olfactory tract) and olfactory tubercle, the sites of origin of the efferent fibers projecting to both the ipsilateral and contralateral olfactory bulbs. Other axons from the lateral stria reach the piriform lobe of the temporal cortex and terminate in the amygdala (amygdaloid body), the septal nuclei, and the hypothalamus.

Human Eye

The human eye is a highly developed sense organ containing numerous accessory structures that modify visual stimuli before they reach the photoreceptors. The extraocular muscles move the eyeball, thus causing the image of the object viewed to fall on the fovea , the retinal area of highest visual acuity. The shape of the eyeball, its surfaces, and the refractive properties of the tear film, cornea, lens, and aqueous and vitreous humors assist in focusing the image on the retina. To allow viewing of near and far objects, this focus can be adjusted by the action of the ciliary muscle , which changes the shape of the lens. The intensity of the light reaching the retina is controlled by the muscles of the iris , which vary the size of the pupillary aperture . Incident light must traverse most of the retinal layers before it reaches the photoreceptor cells lying in the outer part of the retina. Beyond the photoreceptors is a layer of pigment cells , which eliminates back reflections by absorbing any light passing through the photoreceptor layer.

Retina

The retina has several distinct layers. Rods and cones form synaptic connections with bipolar and horizontal cells. Bipolar cells are relay neurons that transmit visual signals from the inner to the outer plexiform layer of the retina; horizontal cells are interneurons activated by rods and cones and send their axons laterally to act on neighboring bipolar cells. As a result of the actions of horizontal cells, bipolar cells have concentric receptive fields; that is, their membrane potentials are shifted in one direction by light reaching the center of their receptive field, and in the opposite direction by light reaching the surrounding area. Neither bipolar nor horizontal cells generate action potentials; all information is transferred by changes in membrane potential, which spread passively through the cell bodies and axons.

The processes of bipolar cells that reach the outer plexiform layer form synapses with ganglion cells and amacrine cells. Ganglion cells are output neurons whose axons comprise the optic nerves and optic tracts; amacrine cells are interneurons. Unlike other retinal neurons, both amacrine and ganglion cells generate action potentials.

The photoreceptor cells are called rods and cones because of the shapes of their outer segments. Rods function as receptors in a highly sensitive, monochromatic visual system, whereas cones serve as receptors in the color vision system, which is less sensitive but more acute. Both receptors, however, are activated in a similar manner—they are hyperpolarized by photons of light falling directly upon them. For example, the detection of light in the rod begins with the absorption of photons by the visual pigment, rhodopsin . Rhodopsin is a combination of the protein, opsin and the cis isomer of retinine, a compound derived from vitamin A. It is located within the membranous lamellae of the rod's outer segment, a highly modified cilium associated with a typical basal body. Upon the absorption of a photon, rhodopsin is converted to lumirhodopsin , which is unstable and changes spontaneously to metarhodopsin , which is then degraded by a chemical reaction known as bleaching. Rhodopsin lost by this bleaching process is restored to its active form by enzymatic reactions that require metabolic energy and vitamin A. After a brief time lag, the absorption of a photon leads to changes in the ionic permeability of the membrane of the outer segment. The change in the receptor membrane triggered in the rod by light absorption is not the typical increase in ion permeability most sensory receptors undergo when activated; rather, there is a decrease in the permeability of the outer segment membrane to sodium ions (Na ⁺ ). In the absence of light, this permeability is relatively high, and there is a steady inward flow of Na ⁺ (the current flow resulting from this ionic movement, known as the “dark current,” keeps the entire rod in a depolarized state). When light absorption provokes a decrease in Na ⁺ permeability, the dark current is cut off and the rod becomes more hyper-polarized. This hyperpolarization influences the synaptic action of the rod on horizontal and bipolar cells. Polarization changes in one rod may also spread to neighboring receptors via electrical synapses. Any photon that is successfully absorbed by photopigment produces the same electrochemical result, regardless of the wavelength of that photon. However, the probability that a photon will be absorbed by photopigment varies considerably with the wavelength of the incident light, and rhodopsin has a maximal absorbency for light with a wavelength of 500 nm. Cones may contain one of three different photopigments, with a maximum absorbency at 445 nm (blue), 535 nm (green), and 570 nm (red). Cone pigments all contain cis retinine but have different forms of opsin, which modify the light absorption pattern. By analyzing the relative activity produced by the three types of cones, the central nervous system (CNS) is able to determine the wavelength of the incident light, and a sensation of color vision results.

Retinogeniculostriate Visual Pathway

In mammals, most retinal ganglion cells send excitatory or inhibitory impulses via the optic nerves and tracts to the dorsal lateral geniculate nucleus of the lateral geniculate body of the thalamus, from where retinal information is relayed to the primary visual cortex via the geniculostriate projection , or optic radiations . In man, this cortical area covers both walls of the posterior calcarine fissure and adjacent parts of the occipital pole (Brodmann's area 17). The transmission of information from retina to visual cortex is topographically organized . Stimuli in the right half of the visual field activate neurons in the left half of each retina. Ganglion cells from these areas project to the left lateral geniculate body, which then projects to the left visual cortex. Input from both eyes is relayed by neurons in different layers of the lateral geniculate body. Similarly, stimuli in the left half of the visual field are relayed to the right visual cortex.

The upper and lower visual fields are also topographically mapped onto the lateral geniculate body and visual cortex. The upper field is represented in the lateral parts of the lateral geniculate nuclei and the inferior portions of the visual cortex, and the lower visual field is represented in the corresponding medial and superior regions. The macula (central visual field) is represented in the central parts of the lateral geniculate nuclei and the posterior visual cortex, and in the peripheral retina , in the peripheral parts of the lateral geniculate nuclei, and the anterior visual cortex. The fovea, the central spot of the macula, is represented by a proportionally larger cortical area than the periphery of the retina.

Neurologic Deficits of the Retina and Optic Nerve

Neurologic deficits in the visual system can be localized by determining the type and extent of the resultant visual field deficit. Retinal and optic nerve damage produces vision loss in the affected eye. Most retinal lesions will be visible on ophthalmoscopy of the ocular fundus. Optic nerve lesions will produce central scotomas and visual field defects that might respect the horizontal meridian. If the optic nerve is affected in its anterior portion (i.e., where it is visualized on ocular funduscopy), one may see swelling of the optic nerve head during the acute phase of injury. If the retrobulbar portion of the optic nerve is the site of injury, then the optic nerve head (so-called “optic disc”) will look normal acutely. After several weeks, injury to the optic nerve anywhere along its course will manifest as relative pallor of the optic nerve head. Unilateral or asymmetric bilateral optic nerve damage will cause a relative afferent pupillary defect (less transmission of light along the more damaged optic nerve to the brain centers controlling pupillary constriction).

Chiasmal and Postchiasmal Neurologic Deficits

Lesions at the optic chiasm will result in bitemporal hemianopsia, caused by damage to the fibers from the nasal segment of both retinas. Interruption of the optic tract (that portion of the visual pathways between the chiasm and lateral geniculate body) results in a contralateral homonymous hemianopsia. Similarly, lesions of the optic radiations or striate cortex will cause partial or complete contralateral homonymous hemianopic defects.

Visual System: Retinal Projections

The main retinal projection is to the dorsal lateral geniculate nucleus , which then projects to the visual cortex. The retinogeniculostriate system thus formed is the basis for essentially the entire visual consciousness in man.

Other optic nerve fibers terminate within the superior colliculus . This multilayered structure plays an important role in orienting the reactions that shift the head and eyes in order to bring an object of interest into the center of the visual field. In addition to direct optic nerve input, the superior colliculus receives indirect visual input via the visual cortex. As is the case throughout the visual system, this input is topographically organized so that each point within the colliculus corresponds to a particular region within the visual field. Collicular neurons tend to respond best to interesting or moving stimuli, and the discharge of neurons in the deeper layers of the colliculus is closely related to the orienting movements of the eyes evoked by such stimuli.

The deeper collicular layers are the source of several efferent projections. One group of fibers crosses the midline and runs caudally, sending terminals to the brainstem reticular formation and then continuing on to cervical and thoracic levels as the tectospinal tract ; these fibers are probably involved in the orienting movements of the head and body. A second group of fibers projects to the posterior thalamus (pulvinar), which then projects to the cortical association areas. Fiber projections responsible for eye movements relay in the mesencephalic reticular formation below the superior colliculus (vertical eye movements), and in the paramedian pontine reticular formation (horizontal eye movements).

Pupillary Light Reflex and the Accommodation Reflex

The pretectum , like the superior colliculus, receives visual information from optic nerve fibers not destined to synapse in the lateral geniculate bodies. This area is involved in the pupillary light reflex (which regulates the size of the pupil) and the accommodation reflex (which controls the degree of curvature of the lens). The former is a subcortical reflex and relays in the accessory oculomotor (Edinger-Westphal) nucleus, whereas the latter involves pathways through the cerebral cortex. In the pupillary light reflex, afferent pupillary fibers leave the optic tract before the lateral geniculate bodies, travel in the brachium of the superior colliculus, and synapse in the pretectal nuclei (explaining why lesions of the geniculate bodies, the optic radiations, or the visual cortex do not affect the pupillary reactivity, and why lesions of the brachium of the superior colliculus can cause a relative afferent pupillary defect without causing a visual field defect). Both pretectal nuclei receive input from both eyes, and each sends axons to both Edinger-Westphal nuclei. Parasympathetic fibers for pupillary constriction leave the Edinger-Westphal nucleus and travel along the ipsilateral third cranial nerve to the ipsilateral ciliary ganglion within the orbit. The postganglionic parasympathetic fibers innervate the pupillary constrictor muscle and the ciliary muscle for accommodation.

Oculomotor Nerve

The oculomotor nerve carries somatic motor fibers to the levator palpebrae superioris muscle and to the medial, superior, and inferior rectae muscles, and to the inferior oblique muscle. It also conveys important parasympathetic fibers to intraocular structures, such as the sphincter pupillae and ciliary muscles, and is joined by sympathetic fibers from the internal carotid plexus, which are distributed with its branches. Some oculomotor proprioceptive fibers may reach the midbrain through the oculomotor nerve; most of them join the ophthalmic branch of the trigeminal nerve via its communications with the oculomotor nerve.

Oculomotor Nuclei . The somatic and parasympathetic efferent fibers in the oculomotor nerve are the axons of cells located in the complex oculomotor nuclei situated anterolateral to the upper end of the cerebral aqueduct. The nuclei are composed of groups of large and small multipolar cells. The main groups of large cells are arranged in two columns of posterolateral, intermediate, and anteromedial nuclei , one on each side of the midline, which control the rectus and oblique extraocular muscles. A single median nucleus , composed of similar cells and partly overlying the caudal and posterior aspects of the bilateral columns, controls the levator muscles of the upper eyelids. Cranial to the median nucleus, and also partially overlying the posterior aspects of the main bilateral columns, are two narrow, wing-shaped nuclei, which are interconnected across the midline at their cranial ends—the accessory (autonomic) nuclei (Edinger-Westphal). They are the source of parasympathetic preganglionic fibers for the ciliary ganglion. The multiple subnuclei of the oculomotor nucleus each project ipsilaterally via the oculomotor nerve to the individual muscles that they innervate, with the exception of the superior rectus subnucleus, which projects contralaterally via the contralateral oculomotor nerve to the contralateral superior rectus muscle.

Oculomotor Nerve . The axons from the bilateral oculomotor nuclear cells form minute bundles, which run through the mesencephalic tegmentum, traversing the red nuclei to emerge from the mesencephalic oculomotor sulcus as the oculomotor nerve rootlets.

Each oculomotor nerve runs forward between the posterior cerebral and superior cerebellar arteries and lateral to the posterior communicating artery in the interpeduncular subarachnoid cistern. It pierces the arachnoid and dura mater in the angle between the free and attached margins of the tentorium cerebelli to enter first the roof of the cavernous sinus and then its lateral wall. Continuing forward above the trochlear nerve, the oculomotor nerve divides into superior and inferior rami as it enters the orbit through the superior orbital fissure.

The smaller superior division supplies the superior rectus muscle and the main superficial (voluntary, or striated, muscular) lamina of the levator palpebrae superioris. The deep lamina is a tenuous layer of involuntary, or unstriated, fibers—the superior tarsal muscle; a similar but even more tenuous inferior tarsal muscle is present in the lower eyelid, and both these tarsal muscles are innervated by sympathetic fibers. The larger inferior division supplies the medial and inferior recti and the inferior oblique muscles.

Ciliary Ganglion

The ciliary ganglion is tiny and lies in the posterior part of the orbit between the optic nerve and the lateral rectus muscle. Only the first of its three roots is constant because the sensory and/or sympathetic roots may bypass the ganglion.

Motor Root . The ciliary ganglion is the relay station for preganglionic parasympathetic fibers , which originate in the accessory (autonomic) oculomotor nucleus and reach the ganglion through a short offshoot from the oculomotor branch to the inferior oblique muscle. The postganglionic fibers form the 12 to 20 delicate short ciliary nerves that penetrate the sclera around the optic nerve and continue forward in the perichoroidal space to supply the ciliaris and sphincter pupillae muscles and the intraocular vessels.

The sensory and sympathetic roots of the ciliary ganglion are derived from the nasociliary nerve and the internal carotid vascular nerve plexus, but they do not always join the ganglion. Instead, their fibers may reach the eye by joining the ciliary nerves directly, while the sympathetic fibers (already postganglionic after relaying in the superior cervical trunk ganglia) may follow the ophthalmic artery and its branches to their destinations. The sensory fibers convey impulses from the cornea, iris, and choroid and the intraocular muscles.

Trochlear Nerve

The trochlear nerve is slender, and its nucleus of origin is located in the midbrain just caudal to the oculomotor nuclei. The trochlear fibers curve posterolaterally and slightly caudally around the cerebral aqueduct to reach the upper part of the superior medullary velum; here the nerve fibers from opposite sides decussate before emerging on either side of the frenulum veli, below the inferior colliculi. No other cranial nerves emerge from the dorsal aspect of the brainstem.

Each trochlear nerve winds forward around the midbrain below the free edge of the tentorium cerebelli, passes between the superior cerebellar and posterior cerebral arteries and above the trigeminal nerve, and pierces the inferior surface of the tentorium near its attachment to the posterior clinoid process to run forward in the lateral wall of the cavernous sinus between the oculomotor and ophthalmic nerves. The nerve enters the orbit through its superior fissure, immediately lateral to the common annular tendon, and passes medially between the orbital roof and the levator palpebrae superioris to supply the superior oblique muscle. Proprioceptive fibers are transferred through a communication with the ophthalmic nerve to the trigeminal nerve. The trochlear nerve usually receives sympathetic filaments from the internal carotid nerve plexus.

Abducens Nerve

The abducens nerve arises from the abducens nucleus, which is located in the pons, subjacent to the facial colliculus in the upper half of the floor of the fourth ventricle. The nucleus is encircled by fibers of the homolateral facial nerve. The abducens nerve fibers pass forward to emerge near the midline through the groove between the pons and the pyramid of the medulla oblongata. Each abducens nerve then inclines upward in front of the pons, usually behind the inferior cerebellar artery. Near the apex of the petrous part of the temporal bone, the nerve bends sharply forward above the superior petrosal sinus to enter the cavernous sinus, where it lies adjacent to the internal carotid artery. There the abducens may transfer proprioceptive fibers to the ophthalmic branch of the trigeminal nerve and receive sympathetic filaments from the internal carotid nerve plexus. The abducens nerve enters the orbit through the superior orbital fissure, within the common annular tendon, and ends by supplying the lateral rectus muscle.

The abducens has a relatively long intracranial route in the posterior cranial fossa and cavernous sinus. Consequently, it is vulnerable to increases in intracranial pressure and to pathologic or traumatic lesions affecting nearby parts of the brain, skull, or sinus.