Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008
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ized and lack control groups. It is therefore difficult to compare the studies, even qualitatively, due to the relatively isolated information provided by each study on the spontaneous visual recovery that appears with a relatively high frequency after TON. Indeed, Yu Wai Man and Griffiths [45] reviewed the effects and safety of surgical interventions in the management of TON by searching the Cochrane Central Register of Controlled Trials (CENTRAL) between 1966 and August 2005, and found no evidence that surgical decompression of the optic nerve is beneficial. Moreover, surgery is associated with a risk of defined complications such as leakage of cerebrospinal fluid and meningitis. They suggested that it is necessary to perform a controlled and randomized trial of surgical interventions in TON.
The largest group of patients was included in the International Optic Nerve Trauma Study (IONTS), which was designed as a comparative and nonrandomized interventional study with concurrent treatment groups involving a total of 133 TON cases [19] whose visual function was assessed within 3 days of injury. On the basis of treatment received within 7 days of trauma, the authors concluded that there was no indication that either the dosage or the timing of corticosteroid treatment, or the timing of surgery was associated with an increased probability of visual improvement. The study found that visual acuity recovered in 57% of the untreated group, 32% of the surgery group, and 52% of the steroid group, and found no clear benefit for either steroid therapy or decompression surgery [19]. The authors recommended that it is clinically reasonable to decide upon treatment on an individual-case basis.
In a recently published epidemiologic study in adolescence, Goldenberg-Cohen et al. [11] presented 40 patients younger than 19 years, with blunt trauma being the reason for loss of vision in 78% of the cases. After treatment with steroids (n=18), decompression of the optic canal (n=3), or optic sheath fenestration (n=1), the vision was better than 20/80 in only four patients, with the rate or degree of improvement not differing between treated and untreated patients.
The studies of Yang et al. [43] (n=42) and Ra-
jiniganth et al. [28] (n=44) combined high-dosage intravenous steroids with optic canal decompression. Although both studies found that combination treatment results in a better visual outcome, in neither study were the investigators blinded or the subjects randomized. However, the results do suggest that the outcome is better when decisions are made on an individual patient basis.
A further retrospective case series presented by Jiang et al. (n=17) [15] included patients with TON who presented after failure of initial medical treatment. The authors performed endoscopic optic nerve decompression (EOND), and observed an improvement of vision in nine cases with a follow-up of more than 6 months. A similar study with a larger number of patients (n=72) with TON resistant to high-dose steroids was performed by Li et al. [20]. The authors reported that EOND improved visual recovery in 46 eyes followed-up for more than 3 months. The visual acuity improved in 31 out of 55 cases with no preoperative light perception, with even delayed EOND resulting in a pronounced visual improvement.
The efficacy of delayed optic nerve decompression in TON was addressed in a prospective study involving 35 cases with a median injury-to-sur- gery interval of 56 days [36]. That study included only cases with poor vision after treatment with steroid (1 mg/kg prednisolone). Delayed surgery was found to be useful only in patients who were not completely blind (20 of 26 cases improved). A prognostic factor for whether surgical treatment results in a positive outcome is whether the eyes are completely blind [36]. Other studies include that of Hsieh et al. [13], which involved 45 cases of TON complicated with periorbital facial bone fractures. The authors found that there was no significant difference between treatment with megadose steroids and no treatment. Slightly different conclusions were drawn by Acarturk et al. [1], who reported on 11 patients with orbital fissure and orbital apex syndromes. In their cases the neuropathy caused by edema, contusion, and compression was reversible with very high doses of corticosteroids.
A meta-analysis of the literature on TON published up to 1996 revealed that the recovery of vision was significantly better in patients who
received any treatment than in those who were not treated [6]. Recovery was also related to the severity of the initial lesion, e.g., better initial visual acuity was associated with better recovery, but did not differ significantly between corticosteroid and surgical treatments [6].
Similar findings were obtained in 113 eyes with indirect TON in which the initial posttraumatic vision was better than light perception [10]. The authors concluded that conservative treatment must first be given, with surgery being indicated when the vision does not improve to 0.5 or better within 3 weeks. The authors recommended the earliest possible surgical intervention when complete visual loss is evident after injury [10].
Endoscopic decompression of the optic canal combined with steroids appeared to be a successful approach in cases of total blindness due to TON, as revealed by the visual acuity returning to preinjury levels in four blind patients (i.e., no light perception) [16]. On the other hand, Wohlrab et al. [42] reported also on visual improvement in 8 out of 20 eyes, 5 of which had no light perception preoperatively. The primary treatment was transsphenoid decompression.
Based on a retrospective analysis of 65 primarily decompressed optic nerves of conscious (n=52) and comatose (n=13) patients, Lubben et al. [21] reported a success rate (improvement in visual acuity of at least three lines on an eye chart) of about 60%, and confirmed the efficacy of early decompression in both groups. Notably, 5 of the 13 comatose patients improved completely, 3 improved partially, whereas 3 remained amaurotic [21].
Mine et al. [23] reported that neither the age nor the occurrence of optic canal fracture influenced the visual improvement in 34 patients with indirect TON. When comparing the efficacy of surgery (n=12) with nonsurgery (n=24), a significant improvement was found in eyes that had an initial visual acuity better than hand movements.
The above studies together provide no compelling evidence that either type of treatment provides statistically significant advantages over the other or over nontreatment [2, 4, 19, 33, 41]. Also, one of the difficulties in managing patients
6.3 Histopathology of TON |
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with TON is to determine the exact mechanism of optic nerve injury.
Summary for the Clinician
■According to the International Optic Nerve Trauma Study (IONTS) no treatment procedure has statistically improved the visual outcome of TON.
■Treatment of TON should be done on individual basis.
6.3 Histopathology of TON
The onset of cellular changes following various types of injury to the optic nerve may be influenced by both the severity of the lesion and its distance from the ganglion cell bodies. It has been suggested that the responses are more rapid for transection of the optic nerve at the globe than for those at a more posterior location involving the intracranial optic tract or the chiasm. Radius and Anderson [27] found that disc pallor developed as early as 2 weeks after a proximal photo- coagulation-induced injury in the monkey. However, the ganglion cells and the intraretinal axon segments survived for longer. By 3 weeks there were perceptible changes in the ganglion cells and the nerve fiber layer, leading to a decrease in ganglion cell population, with this becoming significant after 4 weeks. The time of onset and the progression of the ganglion cell atrophy were similar after optic nerve transection in the posterior orbit in owl monkeys [26]. Both of these studies showed that the timing of the atrophy of the ganglion cell bodies is independent of the location of injury along the optic nerve.
Apoptosis of ganglion cells and atrophy occur as early as 2 weeks after injury, whereas adjacent cells such as astroglial and microglial cells respond earlier. Very early changes were demonstrated in an eye enucleated 30 h following optic nerve transaction, 24 mm behind the globe (Fig. 6.2). Immunohistologic changes culminated in responses of astrocytes, macrophages and microglial cells. However, no apoptotic profiles or
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Fig. 6.2 Transection of the retrobulbar optic nerve. This eye was enucleated 30 h after TON and transection at the optic canal level. Immunohistochemistry results are detailed in Table 6.1
Table 6.1. Early cellular changes associated with optic nerve cut (30 h)
1. Activation of microglial cells and macrophages (NDPase, OX-42, ED-1 immunostaining
2. Onset of astrocyte activation (GFAP staining)
3. Stainable ganglion cell axons (neurofilament, GAP-43 staining) 4. Stainable microvessels and capillaries (endothelin staining)
5. Necrotic zone and myelin disarrangement at the site of necrosis 6. Normal cytoarchitecture of retina
7. No apoptosis within the retina (TUNEL)
disruption of the retinal layers occurred (Table 6.1). As expected, a necrotic zone was present in the vicinity of the optic nerve transection, with accumulation of macrophages and axonal debris, and disruption of myelin (Table 6.1).
The optic atrophy of the later stages of
TON |
is characterized |
by loss of axons in |
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both |
directions |
from |
the site of injury, and |
by gradual loss |
of oligodendrocytes includ- |
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ing their myelin sheaths. The typical organization of glial columns between the parallel nerve fascicles is disrupted, and the astrocytes begin to proliferate (gliosis) together with a profound thickening of interseptal pial membranes. In spite of gliotic proliferation and meningeal thickening, the optic nerve diameter decreases and the subarachnoid space is widened. The ramified resident microglial cells phagocytose
degenerating neuronal debris as well as myelin, thereby transforming into lipid-loaded amebashaped macrophages.
6.4Mechanisms of TON-Induced Ganglion Cell Death
Retrograde degeneration of the retinal ganglion cells is the final common outcome underlying TON, wherever the initial site or mechanism of injury. The axon injury (either compressed or sectioned) initiates ganglion cell disease and death. The molecular responses at the site of axon injury involve interruption of axonal transport, local excitotoxicity from physiologic or pathologic levels of glutamate, the formation of free radicals, a decrease in the flow of neurotrophic factors from targets to the ganglion cells, leakage of potentially toxic constituents at the axonal stump, activation of microglial cells, proliferation of astrocytes, accumulation of retrogradely transportable molecules, and local breakdown of the blood–brain barrier. It is certain that multiple mechanisms account for the axonal response, and an influence of different factors can also be assumed.
Further, the presence and posttraumatic expression of receptors to neurite inhibitors such as Nogos (NogoR) [40], which are myelin-as- sociated glycoproteins, may be seen as an additional mechanism leading to the death of ganglion cells. These inhibitors prevent the successful formation of axonal growth cones at the tips of cut axons, and thereby convert a primarily anabolic response (e.g., chromatolysis [7]) into a suicide response. This may occur in conjunction with deprivation of neurotrophic factors, which are blocked by the injury, and by additional factors that are normally retrogradely transported to the ganglion cell body.
Apoptosis of the ganglion cell body seems to be the final fate. While proteases are activated in typical cascades to allow clearance of cytoplasmic proteins, DNases are activated within the nucleus to prevent further translation and transcription. At the same time calcium homeostasis is disturbed both intracellularly and extracellularly [12]. Neighboring
6.5 Diagnosis of TON |
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microglial cells are activated to become phagocytic, ingesting disintegrating ganglion cells [37]. There is actually no possible replacement of dying ganglion cells, despite the recent hopes that intraretinal or other intraocular stem cells may be used to substitute the ganglion cell layer.
Summary for the Clinician
■TON results in ganglion cell death, which is irreversible.
■No replacement of ganglion cells is yet possible.
6.5 Diagnosis of TON
Advanced TON is visible ophthalmoscopically at the optic nerve head, which shows a differential pattern of pallor depending on the location and severity of the injury. Although loss of vision may occur immediately after injury, pallor of the optic nerve head occurs with a delay of weeks (Fig. 6.3). Ophthalmoscopy is therefore not the diagnostic tool of first choice, although
Fig. 6.3. Fundus photography of a left eye showing complete atrophy of the optic nerve head 3 months after TON
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Fig. 6.4. Fundus photography showing bilateral severe optic nerve atrophy. Despite a history of unilateral injury, bilateral total blindness was present
it is recommendable for examining the status immediately after injury. Assessments of the visual acuity, visual field (in conscious and cooperative patients), and pupillary reflexes are essential for determining further management. Examination of both eyes with comparative evaluations of visual acuity, visual field, and fundoscopic status are necessary to exclude the bilateral TON (Fig. 6.4) that results from injury to both optic nerves at the optic canal level.
Intraorbital injuries close to the optic nerve head result in a descending atrophy of the ganglion cells within 2–4 weeks and ascending atrophy within 4–6 weeks. Ophthalmoscopically visible atrophy of the nerve head becomes apparent at a few weeks after injury proximal to the optic canal, and is clearly visible 3 months later even in the case of a partial lesion (Fig. 6.1). Examination of experimentally induced TON in monkeys showed a similar chronologic sequence of cellular responses, with the ganglion cells degenerating by 4–5 weeks after optic nerve section and the intraretinal glial cells proliferating over the same period [3]. Optic nerve myelin degenerates more slowly, some remnants of myelin being still detectable 6 months after injury [17]. Although these changes may also occur in the human TON, diagnosis of TON should be based on various grounds, including the trauma history, assessment of visual function, ultraso-
nography, magnetic resonance imaging (MRI), and computed tomography (CT).
High-resolution MRI is the preferred imaging technique for evaluating soft-tissue lesions, in particular those within the orbital apex and intracranially. CT is necessary to search for bone fractures around the orbit [18, 38], in the optic canal, at the orbital apex [44], and intracranially, to plan surgical intervention, or when MRI is contraindicated. Ultrasonography can assess anterior orbital fractures including rim and zygoma injuries, in particular when combined with ocular trauma.
A complete ophthalmic examination is essential, including slit-lamp microscopy, fundoscopy, and the pupillary reflexes to light, the latter being especially useful in assessing an unconscious patient. Measuring visually evoked potentials is recommended for functionality assessments in conscious and motile patients, in particular if remnant potentials can be detected. Recently introduced methods of scanning laser polarimetry may be helpful in assessing the optic nerve fiber layer after TON. Miyahara et al. [24] described a case in which the retinal nerve fiber thickened immediately after a trauma that resulted in acute visual loss, and then progressively thinned until disappearing altogether after 3 months Whenever possible, measurement of the nerve fiber layer is a reliable and specific
parameter for detecting intraretinal changes after TON.
6.6 Therapeutic Concepts of TON
6.6.1 Steroids
Steroids have often been cited as effective in treating central nervous system (CNS) trauma including spinal cord injuries, head trauma, and TON, by inhibiting lipid peroxidation induced by oxygen free radicals. Papers published in the 1990s and thereafter often cite the National Acute Spinal Cord Injury Study (NASCIS) 2 and 3 trials as evidence that high-dose methylprednisolone is an effective therapy in acute spinal cord injury. However, these trials are questionable from various points of view [25], and the evidence from them is now insufficient to support the use of prednisolone in the standard treatment of acute spinal cord injury [31]. Steroids continue to be given to individuals suffering of acute spinal cord injury, and some adverse effects have been reported [14]. Steroids are given to TON patients, even though a critical review of their effects by the IONTS [19] found no significant visual acuity improvement compared to either spontaneous recovery or surgical treatment. Further, Steinsapir et al. [34] found that high-dose methylprednisolone exacerbated axonal loss following optic nerve trauma in animals. The concept of using high-dose steroids must then be reconsidered until a prospective, controlled, and randomized trial delivers decisive evidence.
6.6.2 Neuroprotection
Neuroprotectants form a heterogeneous group of substances derived from a wealth of studies involving experimental models on ganglion cell death under different circumstances, including glaucoma, ischemia, and crush and transection of the optic nerve. Neurotrophic factors have been used to enhance survival of axotomized retinal ganglion cells in rats [22]. However, none of these agents has successfully entered the
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clinical phase of testing, although some are still considered to have positive effects in glaucoma. In our opinion, the potential of neurotrophic therapy is limited to its use as a complementary therapy.
6.6.3 Surgical Decompression
Surgical decompression at the optic canal has been recommended as having beneficial effects on visual acuity and is considered by some authors to be the therapy of choice after initial, unsuccessful use of steroids either alone or in combination with decompression. However, a critical evaluation of retrospective case series revealed that most of the studies were nonrandomized and lacked reliable control groups, such as an untreated group. Such inclusions are mandatory, since there is a high incidence of spontaneous recovery of visual acuity in untreated TON. New approaches may be developed as new surgical techniques evolve and research into the pathophysiology of TON progresses. Endoscopic optic nerve decompression has been considered a minimally invasive procedure with no adverse cosmetic effects, but this remains to be verified given that nonrandomized studies have been used to demonstrate its efficacy [28]. Specifically, any new therapy has to be assessed in prospective and randomized clinical trials in order to avoid ill-founded recommendations with a potential risk of deleterious effects.
6.6.4 The Role of Ophthalmologists
Both conservative and surgical treatments of TON remain controversial despite numerous reports in favor of either approach, and hence a prospective, randomized, and multicentric study appears mandatory for drawing definite conclusions. Prompt and accurate ophthalmic diagnosis is essential. Results of initial ophthalmic examination (visual acuity, ophthalmoscopy, and visual field defects) might influence the choice of therapy and are necessary for inclusion/exclusion of the patient in a prospective and randomized study. The necessity for
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further research into the pathophysiology of |
Section of the optic nerve in rats and simul- |
both ganglion cell death and TON, as well as |
taneous injury to the intraocular lens stimulates |
the development of low-risk surgical techniques |
ganglion cell axons to grow within their own dis- |
and neuroprotection are obvious in the current |
tal optic nerve and reach central targets, thus elic- |
state of controversies. |
iting positive visual evoked potential responses |
|
[8]. It has also been shown that both inflam- |
|
matory responses involving macrophages and |
Summary for the Clinician |
direct lentogenic factors facilitate axonal regen- |
eration [35]. These experiments showed that the |
■There is no sufficient evidence that ste- intrinsic ganglion cell’s ability to regrow an axon roids improve the outcome of either spi- can be supported by external substitution of neu-
nal cord or optic nerve injuries.
■Decompression surgery of TON has also not been proven to result in a better outcome than steroids or no treatment.
6.7Outlook on Regeneration of the Optic Nerve
One of the most accurate descriptions on how the optic nerve responds to injuries was given by Ramón y Cajal [29], who examined various regions of the peripheral and central nervous system including the injured optic nerve: “It is to be assumed that the retina and optic nerve will react to violence not like peripheral nerves but like the brain on spinal cord … that is with small frustrated acts of growth … because of the absence of cells of Schwann which emit powerful neurotrophic agents…” Retinal ganglion cells exhibit only a limited and transient sprouting reaction after transection, and they fail to regrow axons through the interior of the optic nerve [29]. This failure of regeneration has been attributed to inhibitory factors associated with optic nerve myelin (Nogos) and/or glial scar, which also produces growth-in- hospitable extracellular matrix proteins [5].
There are, however, several experimental conditions that permit regrowth of ganglion cell axons. Complete replacement of the sectioned optic nerve with an autologous sciatic nerve segment reconnecting the retina with central targets has been successfully established. This model has been applied to the rat, hamster, mouse and cat optic nerve and shows the intrinsic ability of ganglion cells to regenerate axons and rebuild synaptic contacts with functional significance [39].
rotrophic agents.
Further, in vitro models of retinal regeneration have also been developed [35]. They allow for exploration of the mechanisms of axonal growth on various substrates, for testing of neurotrophins and for examining the effects of lens injury, as revealed by co-culture experiments [35]. Moreover, primate tissue could be examined in vitro as well, and recent experiments have indeed revealed that monkey retinal ganglion cells also have a reasonable potential to regrow their axons. Although the rate of axonal regeneration declines physiologically with increasing age, axonal regeneration is still possible, even in adulthood [30]. Consequently, axonal regeneration of retinal ganglion cells may require multiple approaches, such as
(1) inactivation of growth-inhibiting signals; (2) activation of the intrinsic growth state of neurons; and (3) adjusting the microenvironment to permit the formation of growth cones at the site of optic nerve transection.
Although the aspect of optic nerve regeneration has been addressed only in experimental models, valuable lines of evidence have been collected to encourage further research on the mechanisms initiating and maintaining axonal growth after TON. To this end, the challenge is to transfer such studies into a preclinical or clinical application, for instance by using autologous peripheral nerve grafts in very severe cases of optic nerve transections as shown in Fig. 6.2. Apposition of such a peripheral nerve graft at the site of injury may result in ingrowth of the sectioned optic nerve axons and retrograde stabilization of the ganglion cell bodies, which otherwise are inevitably lost. Stabilized and regenerating ganglion cells may then be surgically reconnected with the lateral geniculate body to rebuild synaptic contacts.
References 93
Summary for the Clinician
■All efforts to protect ganglion cells from death or force them to regenerate are experimental studies with no clinical application as yet.
6.8Current Clinical Practice and Recommendations
The following recommendations can be made based on the above review of the literature:
•Examine the patient as accurately as possible (visual acuity, visual field, pupil, and fundus) before making any decision regarding treat-
ment.
• Consult additional diagnostic procedures as necessary (MRI, CT, radiography, ultrasonography, otorhinolaryngologic, and neurologic status).
•Determine whether (rare) transection or compression of the optic nerve has occurred.
•Be aware that neither steroid treatment nor surgical decompression has shown better visual acuity recovery compared with no treatment in TON.
•Considering the lack of recommendable procedures, any choice of treatment must be performed on an individual basis.
•Neuroprotective strategies are not yet available for TON.
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