Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

Fig. 20.13 The micrograph shows neurons and corresponding nerve fibers in the paramedian pontine part of the reticular formation of monkey

distant premotor structures include the vestibular nuclei, cerebellum, frontal eye field, the pretectal nuclei, and the superior colliculus. The PPRF is therefore the immediate premotor structure responsible for executing conjugate horizontal saccades, and contains neurons that fire immediately before and during ipsilateral saccades. The same neurons are found to be inactive during smooth pursuit eye movements and when the eyes are fixating. Excitatory burst neurons are believed to activate the required number of motor units in the medial rectus subnuclei and contra lateral abducens nucleus. Corresponding inhibitory neurons inhibit the antagonistic muscles during the duration of the saccade.

The paramedian reticular formation, which occupies only a part of the whole reticular formation, consists of neurons with large intercellular distances in comparison to other premotor and cortical regions (Fig. 20.13). This indicates that that when one neuron dies, there will be a limited number of neighboring neurons to replace it. Clinical observations of patients with lesions in the PPRF seem to confirm this notion. These patients present large deficits in horizontal eye movements, even in cases where the estimated cellular damage is limited. However, it seems that progressive age-related changes in the PPRF do not cause the same deficits as sudden lesions do—suggesting a certain ability to adapt to the process of senescence.

Superior Colliculus (SC)

On the dorsal aspect of the mesencephalon, there are four elevations referred to as the superior and inferior colliculi (corpora quadrigemina). The superior colliculus receives fibers from the optic nerve, visual cortex, and other cortical regions, including the somatosensory cortex. This sensory input enables SC to initiate reflex

movements in response to various stimuli. Several neurons in the mesencephalon have descending fibers to the spinal cord, and many of these originate from the superior colliculus. This pathway—the tectospinal pathway—provides contraction of somatic muscles in the head and neck. The SC also influences the motor neurons in the oculorotatory cranial nuclei through reticular formation. Together, these pathways provide reflex-based direction of the eyes towards the object of interest.

The SC is also likely to participate in auditory reflexes through interneurons from the inferior colliculus, which is responsible for conveying auditory information, to higher levels of the central nervous system. Adaptation of the latter reflex is essential because the auditory input varies over a large scale. The adaptive process is influenced by the facial and trigeminal nuclei, which innervate muscles in the middle ear such as the stapedius muscle and the tensor tympani. These muscles reduce the effect of the auditory signal and protect the system against loud sounds. Facial palsies can hence create oversensitivity to sound because this protective mechanism is then lost. A similar affect can be caused by age-related changes in the neuromuscular arrangement. The muscle fibers in the muscles referred to above have histological features that correspond to the slow contracting multiply innervated muscle fibers found in the extraocular muscles. Previous studies have shown that these fibers are subjected to a variety of age-related changes (described in “Age-related Changes in the Muscle Fiber Population”). Decline in the auditory functions with age may therefore include an inability to adapt to sound, in addition to reduced sensitivity to various frequencies. Declining auditory functions in oculomotor control can also be caused through atrophy of interneurons connecting the superior and inferior colliculus.

The SC also participates in the accommodation reflex to a larger extent than previously assumed. Axons from the visual cortex are believed to terminate on the SC in addition to the pretectal nucleus, with further projections to the PPRF. From there, axons travel to the parasympathetic motor neurons in the superior aspect of the III nerve nuclear complex. Stimulation of these neurons will, in turn, initiate contraction of the ciliary muscle through postganglionic parasympathetic nerve fibers.

Age-Related Changes in the Subnuclear System

of the Oculomotor System

The final common pathway from the motor neurons in the III, IV, and VI cranial nerves, down to their termination on the extraocular muscle fibers, constitutes the subnuclear level of the oculomotor system.

This pathway has a generous complement of efferent nerves in comparison to the rather modest number of muscle fibers they supply (i.e., a small motor unit). It also contains a large number of afferent nerve fibers conveying information from a unique complement of sensory receptors not compatible with their somatic counterparts. The extraocular muscles are therefore a diverse muscle mass with a structural and functional organization that differs from skeletal muscle in numerous

Fig. 20.15 Histogram illustrating the mean value of all nerve fiber diameter spectrums. The trimodal distribution was apparent in all specimens

Kjellevold Haugen I-B, Bruenech JR. (2005) Histological analysis of the efferent innervation of human extraocular muscles. In: De Faber, J-T. (ed.) 29th European Strabismological Association Meeting Transactions, Izmir, Turkey, June 1–4, 2004, ISBN: 0415372119, Publisher Taylor & Francis

of these multiply innervated muscle fibers were found to be profoundly more generous than previously assumed, with a motor unit ranging from 1:1 to 1:3. The ratio for the Fibrillenstruktur fibers was 1:7 to 1:10, depending on the morphology of the associated muscle fiber. The low motor units, which have seemingly been missed in previous studies using lower resolution techniques, have functional implications and suggest that EOMs have the ability to recruit one muscle fiber at a time. Adjusting muscle contraction by adding the force of one single muscle fiber is the most precise motor control theoretically possible.

There is an apparent change in the size of the motor unit with age. This is caused by a decrease in muscle fibers with age (addressed next). Because the nerve fibers do not seem to suffer the same extent of degeneration, there are many redundant nerve fibers in adult human extraocular muscles attempting to seek new targets.46 Alterations in the size of the motor unit will have functional implications, not only in terms of a reduction in muscle force, but also in terms of interfering with the correlation between the efferent signal traveling in the final common pathway and the corresponding rotation of the eye. Unless the information from the sensory receptors within the muscle can be tuned to fit the new situation, there will be a neural disagreement between proprioception, efferent innervation, and the general visual information.

The existence of two morphologically distinct fiber types in extraocular muscles has led to the notion that they may serve different functions in oculomotor control. The nature of the slow fiber system, comprised of the Felderstruktur fibers, has been subject to the most speculation. The existence of such a system must clearly have some functional implications, and the supply of strong tonic activity in eye fixation has been suggested as one plausible function.56 Accepting this view implies that subjects with a low concentration of Felderstruktur fibers in their extraocular muscles would be more subjected to fixation instability and fatigue during prolonged close work.

Previous estimates have found that the Felderstruktur fiber constitutes approximately 20 percent of the fiber population in human extraocular muscles.57,58 However, recent studies have found that even though the majority of subjects fall within the range of 18 and 23 percent, significant variations between healthy individuals do occur.52 The potential implications of a low complement of Felderstruktur fibers has been investigated in a recent study where there seems to be a correlation between the number of Felderstruktur fibers and congenital oculomotor abnormalities.50

Age-related Changes in the Muscle Fiber Population

Age-related changes in extraocular muscle fibers are well-documented in the ophthalmic literature and there is a consistency in the observations of the senescence process in these muscles.57,59,60 The most commonly observed features were described in a recent paper, and new information regarding the pattern of innervation was added.39 The study in question confirmed many of the morphological features previously described by others. Fragmentation and loss of myofilaments (Fig. 20-19a), along with the presence of lipofuscin (Fig. 20.19b), were regularly occurring features in muscles from subjects over 70 years of age. Muscle fibers with concentric striated annulets of myofibrils, resembling the previously described Ringbinden fibers (Fig. 20.19c), was a regular feature in all mature muscles and increase in number with age.39

Fig. 20.19 Micrographs showing fragmentation of myofilaments (A), accumulations of lipofuscin

(B), and a muscle fiber displaying concentric striated annulets of myofibrils (C)

Kjellevold Haugen I-B, Bruenech JR. (2006) Age-related neuromuscular changes in human extraocular muscles. In: R. Gomez de Liano (ed.) 30th European Strabismological Association Meeting Transactions, Killarney, Co Kerry, Ireland, June 8–11, 2005, Publisher Taylor & Francis. (reprinted with permission)

Fig. 20.20 An electron micrograph of a Fibrillenstruktur fiber with modest amounts of mitochondria (A) and a light micrograph of Fibrillenstruktur fibers (B) and corresponding nerves embedded in connective tissue

Kjellevold Haugen I-B, Bruenech JR. (2006) Age-related neuromuscular changes in human extraocular muscles. In: R. Gomez de Liano (ed.) 30th European Strabismological Association Meeting Transactions, Killarney, Co Kerry, Ireland, June 8–11, 2005, Publisher Taylor & Francis. (reprinted with permission)

Through electron microscopy, the size and number of mitochondria was found to decline with age (Fig. 20.20a), which also is in agreement with previous reports.61 The nerve fibers were frequently found to share their connective tissue sheet with associated muscle fibers, making their point of termination predictable (Fig. 20.20b). The perineural sheathing of muscle fibers was not observed in tissues from young subjects—an observation consistent with previous reports.62

A counting of fibers revealed a reduction in muscle fiber population with age. The oldest subjects were found to have a decline in muscle fiber content of more than 50 percent in comparison to the youngest subjects. In contrast, the numbers of nerve fibers were sustained.

On most Fibrillenstruktur fibers, the nerve fiber terminated in a single, conventional motor endplate (MEP), displaying prominent boutons, postsynaptic folds, and soleplate nuclei. In selected specimens from the oldest subjects, muscle fibers were found to have more than one MEP.39

In a number of these samples, the MEPs were found to be interconnected by single myelinated axons with a neural arrangement best described as multiple innervation (Fig. 20.21), yet with clear structural differences from the innervation of Felderstruktur fibers. In other samples, however, there were no neural connections between the two MEPs, nor was any common origin revealed between the motor nerves when traced backwards to their point of entry into the muscle. These muscle fibers seemed to be served by more than one motor neuron with a seemingly polyneural innervation (Fig. 20.22).

Muscle fibers holding more than one MEP suggest that the neuromuscular arrangement in ageing EOM is labile. The polyneural innervation and the observed reduction of muscle fiber content indicate that redundant nerve fibers may seek new targets—subsequently forming more than one MEP.

This progressive neural reorganization, along with other age-related changes such as the loss of myofilaments and a reduction in mitochondrial content, will

Fig. 20.21 Micrographs of two motor endplates associated with the same Fibrillenstruktur fiber. The MEPs were found to be interconnected by a myelinated axon, as described in the middle illustration. The conventional innervation of Felderstruktur fibers is illustrated at the top of the middle figure

Fig. 20.22 Micrographs of two motor endplates associated with the same Fibrillenstruktur fiber. In contrast to micrographs in Fig. 20.21, the two MEPs were not interconnected (middle illustration) and had seemingly no common neural origin. The conventional innervation of Felderstruktur fibers is illustrated at the top of the middle figure

arguably change the length-tension relationship of the muscle, making the correlation between the degree of contraction and development of muscle force less predictable. Furthermore, age-related changes in the neuromuscular arrangement of human extraocular muscles might have other implications than those related to muscle contraction and the length tension curve.

Recent observations promote the view that a significant portion of muscle fibers depart from the main bulk of the muscle and terminate on connective tissue related to Tenon’s capsule.63,64 Any potential function these fibers may have on the distal insertion, or the so-called sleeve/pulley system, would therefore suffer accordingly. The reduction in ocular motility observed in elderly patients may be caused by some of the age-related changes described above, either directly through a reduced oculorotatory capacity or indirectly through a reduced ability to manipulate the insertion-angle of the distal tendon during eye-rotation. The latter concept is worthy of some further consideration and is described next.

Age-related Changes in the Distal Insertions and Associated Structures

Collagen consists of long-chain macromolecules produced by fibroblasts. During production of new macromolecules, the new fibers become enmeshed with old fibers and form crosslinks. This process forms the basis for the crosslink theory of aging, which promotes the view that the crosslink process increases the density of the collagen molecules that, in turn, decreases the capacity to transport nutrients into the cells.3 Removal of waste products from the cells is believed to decrease for the same reason. This theory has potential implications for collagen-rich tissues, such as the extraocular muscles that have large amounts of epimysium, perimysium, and endomysium compared with their somatic counterparts. The crosslink theory of aging has been subjected to criticism over the years, and the metabolic consequences of crosslinkage of the macromolecules are still debated. However, regardless of the validity of this theory, it is legitimate to argue that any age-related changes affecting the structural organization of collagen would have great implications for the proposed role of the distal insertion of human extraocular muscles.

Histological examination of rectus muscles and magnetic resonance imaging of healthy volunteers has revealed evidence that not all muscle fibers insert onto the globe. A substantial number of fibers insert in the orbital side of the fibroelastic Tenon’s capsule, forming a connective tissue pulley or muscle sleeve.63,64,65

According to the pulley hypothesis, the distal ends of the muscles slide through the sleeves/pulleys, which act, in principal, as the muscle origin. By altering the position of the sleeves through separate adjustment of the orbital fibers, the axis of rotation can be changed.66,67 This theory is attractive in the sense that it explains how pulleys can be manipulated so that the eye can comply with Listings law (any orientation of the eye is attainable by rotating around axes lying in Listing’s plane), and many of the mechanical and neural aspects of the pulley hypothesis have been demonstrated through sophisticated and elaborate mathematical models.68

Over the years, a steadily increasing number of observations have confirmed that the orbital fibers of rectus muscles separate from the global fibers and insert in the muscle sheath.63 The double insertion suggests that orbital fibers are unlikely to contribute significantly to ocular rotation (Fig. 20.23). The functional implications of this observation are still being debated, and the degree of differential contraction between the orbital and global fibers, as well as the muscle fibers’ ability to slide through the sleeve/pulley, remains unresolved. Histological examination of both monkey and human material has only demonstrated a modest separation between the orbital and global layers, and the connective tissue between them seems to be continuous with the collagen of the surrounding pulley/muscle sleeve.63 Although such observations offer little indication of that sliding could occur, they do not preclude the notion that the pulley may fulfill its proposed role. New models (coordinated pulleys, weak differential pulleys, and strong differential pulleys) have been promoted to investigate how different degrees of freedom between the various layers would affect ocular rotation.66

Detailed information regarding the principals of these various models is beyond the scope of this chapter, but if we accept the notion that the pulleys/muscle sleeves