Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

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29.Lodi R, Taylor DJ, Tabrizi SJ et al (1997) In vivo skeletal muscle mitochondrial function in Leber’s hereditary optic neuropathy assessed by 31P magnetic resonance spectroscopy. Ann Neurol 42:573–579

30.Lodi R, Carelli V, Cortelli P et al (2002) Phosphorous MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatr 72:805–807

31.Man PYW, Turnbull DM, Chinnery PF (2002) Leber hereditary optic neuropathy. J Med Genet 39:162–169

32.Man PYW, Griffiths PG, Brown DT et al (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72:333–339

33.Marchbank NJ, Craig JE, Leek JP et al (2002) Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease. J Med Genet 39:e47

34.Misaka T, Miyashita T, Kubo Y (2002) Primary structure of a dynamin-related mouse mitochondrial GTPase and its distribution in brain, subcellular localization and effect on mitochondrial morphology. J Biol Chem 277:15834–15842

35.Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746

36.Olsen NK, Hansen AW, Norby S et al (1995) Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 91:326–329

37.Payne M, Yang Z, Katz JB et al (2004) Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1. Am J Ophthalmol 138:749–755

38.Pesch AEA, Leo-Kottler B, Mayer S et al (2001) OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-domi- nant inheritance. Hum Mol Genet 10:1359–1368

39.Reynier P, Amati-Bonneau P, Verny C et al (2004) OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet 41:e110

40.Riordan-Eva P, Harding AE (1995) Leber’s hereditary optic neuropathy: the clinical relevance of different mitochondrial DNA mutations. J Med Genet 32:81–87

41.Riordan-Eva P, Sanders MD, Govan GG et al (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118:319–337

42.Satoh M, Hamamoto T, Seo N et al (2002) Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria. Biochem Biophys Res Commun 300:482–493

43.Shimizu S, Mori N, Kishi M et al (2003) A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy. Am J Ophthalmol 135:256–257

44.Simunovic M, Votruba M, Regan B et al (1998) Residual colour discrimination in low vision patients: results of a new test in dominant optic atrophy. Vision Res 38:3413–3419

45.Thiselton DL, Alexander C, Taanman J-W et al (2002) A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy (ADOA). Inv Ophthalmol Vis Sci 43:1715–1724

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Core Messages

■Optic nerve tumours are rare.

■There is a clear association with neurofibromatosis.

■Clinical monitoring of children with optic pathway gliomas may need to continue into adulthood.

■Appropriate neuroimaging is required to demonstrate these tumours. MRI is preferable to CT.

■Omission of fat suppression or gadolinium enhancement risks failure to demonstrate the tumour.

■Masquerade syndromes are usually distinguishable by combining information from the history, examination and special investigations.

■Observation is an accepted management approach if there is minimal visual dysfunction.

■Radiotherapy, when used, should be delivered by a modern technique to spare

adjacent vital structures and the opposite optic nerve.

5.1 Introduction

Isolated tumours of the optic nerve are a rare occurrence. How rare is a difficult question to answer as most of our epidemiological evidence comes from retrospective reviews of practice in single institutes where patients are referred after the diagnosis of their condition. Despite these deficiencies Dutton has provided us with the best reviews of the available literature on the two most common types of tumour: meningiomas [15] and gliomas [16]. Patients usually present with minimal signs of orbital pathology and subtle changes in visual function

in middle age (meningioma) or as children (glioma). If the tumour is present in association with neurofibromatosis type 1 (NF1) the patient may be entirely asymptomatic and the tumour discovered on routine screening.

Exact prevalence data are not available for either of these tumours. Wright et al. [65, 66] provided estimates based on the numbers attending his orbital clinic at Moorfields Eye Hospital. Given the inherent bias in this sampling technique we find that gliomas (17/1000) and meningiomas (50/3000) each comprise approximately 1.7% of all orbital tumours.

Bias and controversy are rife in the literature of these tumours and consensus has been extremely slow in arriving. The advent of current imaging modalities and the fortitude of individuals to monitor these tumours over many years has led to a better understanding of their indolent natural history. Recently, novel delivery systems for radiotherapy and new modalities including the gamma knife and proton beams have opened up new therapeutic opportunities which spare adjacent vital structures from the damaging effects of conventional external beam radiotherapy. Our understanding of the tolerance of the optic nerve to fractionated radiotherapy has also increased, allowing therapists the possibility to treat the tumours while sparing the visual apparatus. The precise timing of therapeutic intervention is still a subject of debate but guidelines for the overall management of these tumours are emerging. The rarity and natural history of these tumours ensure that true randomized controlled trials are at best unlikely.

5.1.1 Gliomas

Optic nerve gliomas are the most common tumour of the optic nerve, but still a very infrequent clinical encounter. Tumours

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restricted to the optic nerve are part of a spectrum of disease involving the visual pathway. It is more useful, therefore, to consider this tumour as a part of the spectrum of optic pathway gliomas (OPG) [34]. Although benign pilocytic astrocytomas that present primarily in the paediatric age group predominate (90% presenting within the first two decades), there is a malignant variant affecting the chiasm which presents in middle age – see Sect. 5.3.1.2. It is essential that this group is considered separately, as this tumour is invariably fatal (usually within months).

The presentation, associations, progression and management of these tumours vary depending on the portion of the anterior visual pathway affected [62]. Tow et al. [62] divided their patients into three groups for analysis: (1) tumours restricted to the optic nerve, no chiasmal involvement (optic nerve gliomas or ONG),

(2) tumours involving the chiasm (± one or both nerves) but no involvement of the hypothalamus (optic chiasm gliomas or OCG) and (3) tumours additionally involving the hypothalamus (optic chiasm and hypothalamic gliomas or OCHG). This division is largely similar to that used by Grill et al. [21] (suggested by Dodge prior to the advent of CT).

The diagnosis of OPG is often incidental. More anterior lesions are likely to be discovered either during screening (in patients with NF1) or due to the presence of signs in asymptomatic individuals. Optic nerve gliomas were discovered incidentally in 50% of patients and OCGs were incidentally discovered in 43% [62]. Optic chiasm and hypothalamic gliomas, however, are much more likely to present symptomatically with visual failure, neurological symptoms or endocrine abnormalities. Only one tumour of this type was discovered incidentally, in a patient with NF1 [62]. Although vision is often decreased even in asymptomatic individuals, patients with incidentally discovered tumours are more likely to have good vision at presentation. Combining the data from the two anterior groups, the Tow et al. [62] paper identifies patients with vision at presentation of less than 6/12 (20/40) in only 4 of 23 affected eyes (17%) in incidentally discovered tumours. In contrast, symptomatic patients

had vision of less than 6/12 in 19 of 26 affected eyes (73%). Other signs in anterior tumours include proptosis, strabismus and swollen or pale optic discs in ONG and strabismus or nystagmus in OCG. Precocious puberty appears to be restricted to the more posterior tumours.

The vast majority of the literature concerning these tumours comes from tertiary referral centres. Making things even more difficult is that the majority of these are either surgical practices or oncological institutes. Thus selection bias and the inherent bias of the treating centre make the process of extracting meaningful data applicable to an individual patient almost impossible. Patients with ONG are underrepresented in most series if Tow’s data approximate to the whole population. Most of the patients (78%) in Grill’s series had posterior (OCHG) tumours compared to 31% in Tow’s series. As these tumours are more likely to produce neurological and endocrine abnormalities it is not surprising that a greater number are referred for treatment. Unfortunately we have much less data on the patients who are either asymptomatic or never referred for treatment.

A further difficulty with this literature is again due to the rarity of the condition. In order to gather large enough numbers to make statistical analysis valid, most large series report data gathered over decades rather than years [25]. During this time imaging has developed considerably, treatment protocols have changed dramatically and associated conditions have been further characterized. Patients seen at the beginning of some of these series will have been classified quite differently from some seen towards the end of the series.

Summary for the Clinician

■Gliomas are the most common tumour of the optic nerve.

■They will often present without symptoms if anterior.

■Visual, neurologic and endocrine dysfunction maybe presenting features in posterior tumours.

5.1.1.1 NF1

There is a clear association between NF1 and OPGs. Dutton [16] quotes a very wide range of 10%–70% for the frequency of NF1 in this condition. This variation exists for a number of reasons. The literature on OPGs overlaps the recognition of two distinct forms of neurofibromatosis. As the majority of the epidemiological data comes from treatment centres there may be less emphasis placed on establishing the context in which these tumours arise compared to data from referral centres. Between 50% and 75% of patients with OPG in NF1 are asymptomatic [16, 34]. Of those children that have OPG in association with NF1, only a quarter to a third will progress to a point where treatment may be indicated [3].

Our understanding of the nature of NF1 has increased considerably in the last 15 years. The establishment of the nature of the genetic defect in NF1 has led to a better understanding of the pathogenesis of pilocytic astrocytomas in both NF1 and sporadic cases [3].

Optic pathway gliomas in patients with NF1 are more likely to be anteriorly situated [3, 29] although Liu et al. [36] have drawn our attention to a rare manifestation where these tumours are present in the optic radiations as well as the pregeniculate optic pathway. The consensus statement on OPG in NF1 [34] suggests that symptomatic presentation is rare beyond the age of 6. For this reason it was suggested that routine neuroimaging for OPG was unnecessary in asymptomatic patients with a normal ophthalmological examination after the age of 6. Although Massry et al. [39] identifies the fact that negative neuroimaging at a young age does not preclude the appearance of an OPG on imaging at a later stage, both of the patients presented with signs that would have led to imaging at the time the OPGs were detected. Of more concern is the possibility that patients with NF1 may present for the first time with an OPG at a late age. Listernick et al. [35] have recently reported eight such patients. Although these were drawn from regional NF1 centres around the world, indicating the rarity of this presentation, it clearly shows that there is no room for complacency in

the ophthalmic screening of patients with NF1. Screening may need to continue into adulthood. The author has personal experience of a patient with NF1 presenting for the first time aged 24 with a symptomatic OCG and progressive visual loss (Fig. 5.1).

Summary for the Clinician

■There is a high frequency of asymptomatic tumours in NF1.

■There is a low frequency of patients requiring treatment.

■Ophthalmic screening of patients with NF1 may need to continue into adulthood.

5.1.2 Meningiomas

Meningiomas affecting the sheath of the optic nerve may be divided into those which arise in the arachnoid cap cells within the orbit (primary) and those which secondarily involve the optic nerve or orbit, having their origin in the cranial fossa [45]. Irrespective of this distinction, when the tumour has spread beneath the dura of the optic nerve, the neural vascular supply and axonal transport are slowly compromised. This results in the most prevalent clinical symptom of visual loss (present in >90% of patients) and the signs of optic disc swelling or atrophy [15, 40, 44, 45, 60]. Other features of an optic neuropathy are also present with dyschromatopsia and field loss reported in significant numbers. As Miller [45] points out, colour vision deficits are often present in association with a minimal drop in acuity. Colour vision is often not reported upon, but when it is significant numbers of patients have dyschromatopsia. Dutton [15] found 73% and Turbin et al. [63] identified 82% of patients with a colour vision deficit. An afferent pupil defect at presentation is an almost universal finding [45, 63]. Other features are dependent on the anatomical location of the tumour [40, 44, 45].

There is a female preponderance in patients

with optic nerve sheath meningiomas (ONSM) [15, 45, 54, 63]. In the majority of large series women make up approximately three-fifths of patients (F:M = 3:2). The peak incidence is in middle age [15, 54, 63]. Most papers indicating a preponderance of children predate MR imaging and may well have classified gliomas as meningiomas in this group [40].

Patients with neurofibromatosis are represented in disproportionately large numbers in the population of patients with ONSM [15, 45]. Many of the studies that demonstrate this predate the recognition of the two distinct forms of neurofibromatosis. More recently the clear association between NF2 and ONSM [6] and in particular bilateral ONSM has been reported [12]. Although NF2 and ONSM have both been linked to defects on chromosome 22, distinct defects at differing loci seem to be responsible [40].

Summary for the Clinician

■The most common presentation is with progressive visual loss.

■Colour vision is affected early.

■There is a female preponderance.

■There is an association with NF2.

5.1.2.1 Retino-Choroidal Collaterals

Venous bypass channels connecting the circulation on the surface of the optic disc to the venous network below the retina have been described by many terms in the ophthalmic literature. Unfortunately the most commonly used term (optociliary shunt vessels) is incorrect in every part of its description. There is no optic circulation, the ciliary vessels are not involved and these vessels

do not take blood from an arterial to a venous circulation (a shunt). A more correct term for these connections describes the two circulations that are connected, retinal and choroidal, and the nature of the connection, a bypass channel or collateral circulation. As these connections occur on the venous side of the circulation some authors have added the word vein [19] to an otherwise complete descriptor: retino-choroidal collateral (RCC). Figure 5.2 shows the evolution of these channels in a patient with an ONSM over a period of 7 years.

Although these were thought to have pathognomic significance in the presence of painless loss of vision and optic atrophy [18], Miller and Solomon [46] indicated the non-specific nature of this triad 15 years ago. These collateral channels may be congenital [23] and may be differentiated from acquired collaterals by their filling pattern on angiography. As one might expect indocyanine green offers certain advantages in visualizing these vessels [48].

Using fine serial sections through the anterior optic nerve, Schatz et al. [56] demonstrated that the majority of these collaterals pass around the margin of Bruch’s membrane connecting the retinal veins on the surface of the optic disc to the choroidal vascular plexus. Interestingly, the patient also had a juxtapapillary choroidal neovascular membrane and two of the identified six RCCs passed into this membrane to join the choroidal circulation via a break in Bruch’s membrane.

These vessels will be present in up to 30% of patients with ONSM but may wax and wane, vessels in one quadrant being more visible at one visit and those in another more visible at a later date (Fig. 5.2). Although Hollenhorst et al. [22] paint a bleak picture for visual prognosis when these collaterals are present (nine eyes in nine patients lost all vision), modern management may mean that RCCs do not have the same prognostic significance today. Indeed following radiotherapy or decompression of the optic nerve there has been apparent resolution of these channels [7, 38, 59].

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Summary for the Clinician

■The retino-choroidal collaterals redirect blood from the retinal to the choroidal circulation.

■They represent bypass channels (collaterals) between two venous circulations.

■They may appear and disappear during the disease process and treatment.

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5.2 Imaging

As the presentation of these tumours may be as an acute or chronic optic neuropathy with few other signs, imaging in these patients needs to detect and differentiate between the common causes of this as well as delineate the extent and nature of any compressive or infiltrative pathology. For these reasons the best imaging technique will not only demonstrate these tumours eloquently but also differentiate them from other causes of optic neuropathy. Due to its multiplanar imaging capability, the absence of bone artefact and its excellent contrast sensitivity, magnetic resonance imaging (MRI) is superior to all other imaging modalities when we consider imaging of the anterior visual pathway as a whole [40].

Both of these tumours are best demonstrated with MRI following the injection of a paramagnetic contrast medium. However, when the tumours are confined to the orbit, the signal returned from gadolinium DTPA is almost the same as that returned by orbital fat, unless specific sequences are used to suppress the fat signal. Differentiation from other causes of optic neuropathy may require other specific sequences and often a thorough knowledge of the presenting symptoms and signs.

5.2.1 Gliomas

The imaging appearances of gliomas restricted to the optic nerve depend upon the presence of the NF1 gene. Fusiform enlargement of the nerve is more common in the absence of NF1, whereas concentric enlargement of the nerve with elon-

gation and kinking is more common in the presence of NF1 [29, 44] (Fig. 5.1a). Cystic components within the tumour are more common in the absence of NF1 and may account for a large percentage of the tumour mass [29].

5.2.1.1 Typical

MRI has supplanted CT and plain imaging as the imaging modality of choice in OPG. As these tumours occur predominantly in the paediatric age group and serial imaging is likely, MRI offers significant advantages over CT scanning due to the absence of ionizing radiation.

As gliomas have a normal or slightly prolonged T1 relaxation time, they either appear isointense or slightly hypointense to the optic pathway on T1 images. Gliomas return a hyperintense image on T2-weighted scans due to prolongation of the T2 relaxation time [16, 58]; although, oedema in the optic pathway will also lead to prolongation of the T2 time, making it difficult to correctly identify tumour, particularly in the optic tracts [29]. Mucinous degeneration or areas of necrosis will be apparent as areas of hypointensity relative to normal tissue on T1 imaging. Gadolinium will shorten the T1 relaxation time of the tumour thereby increasing its intensity. Fat suppression techniques are required to delineate the T1 signal of the nerve/tumour from the high T1 signal of orbital fat [58].

5.2.1.2 Masquerade

As the arachnoid hyperplasia associated with gliomas does not return a high signal with gadolinium (unlike that associated with meningiomas) MRI is less likely to produce the confusion described by Cooling and Wright [11] in the pre-MRI era; although, due to omission of a T2 sequence, other authors have described mistaking a glioma for a meningioma on MRI in an adult [32]. Thickening of the chiasm may be caused by a variety of pathologies and some of these may mimic the signal pattern one would expect from OPG. Both intrachiasmatic craniopharyngioma and neurosar-

coidosis were mistaken for gliomas in the MRI era [9, 50]. There were clues on the MRI scans, in both cases, to the ultimate pathology. The craniopharyngioma returned a mixed signal, when a reasonably uniform signal would be expected with a glioma. Also there was evidence of leptomeningeal enhancement in the case of neurosarcoidosis, a sign that has not been described in OPG.

5.2.2 Meningiomas

Although characteristic signs of ONSM are present on CT scans (calcification, tram tracking, pneumosinus dilatans) [40, 45], MR imaging has largely supplanted CT imaging in this condition. The ability to detect meningioma within the confines of the optic canal and early extension into the intracranial cavity has led to clinicians’ preference for this imaging modality [33].

5.2.2.1 Typical

The appearance of ONSM on imaging falls largely into one of three groups: tubular, fusiform or globular [15, 45, 54]. Irrespective of the imaging technique used, the majority of ONSM have a tubular arrangement. These tumours grow to gradually encase the optic nerve and then extend along the nerve sheath. They may be expanded at either the anterior or posterior end of the intraorbital optic nerve [15, 44, 45, 54]. Tubular tumours have a high incidence of involvement of the optic canal and intracranial extension [54]. Indeed the intracranial extension is often only seen on MRI scanning, leading some authors to caution against interpreting this finding on a patient’s first MRI scan as evidence of recent intracranial spread [33]. Indeed when CT scanning and MRI scanning were done in close temporal proximity in four patients in Saaed’s series [54], intracranial extension was visible on the MRI scans but not the CT scans. When MRI is performed, the appearance of a thin line of tumour within the optic canal and a blossom of tumour in the region of

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the anterior clinoid process (Fig. 5.3) is the rule rather than the exception [33].

Even with MRI, tumours restricted to the intracanalicular nerve can be difficult to demonstrate [24]. As meningiomas are generally isointense to brain on both T1and T2-weighted imaging, it is essential to use gadolinium to detect small tumours. This excellent review highlights the incidence of repeated imaging in the presence of a high index of clinical suspicion and details the importance of fat suppression along with gadolinium enhancement to demonstrate these difficult tumours [24].

5.2.2.2 Masquerade

The presence of a meningioma may well be overlooked and an alternate diagnosis entertained particularly if gadolinium has not been given [64]. In addition many disparate conditions have been confused for meningiomas on MR imaging [4, 26, 53, 57, 61]. In the majority of cases clues from the history or examination will have alerted the clinician to the correct diagnosis prior to an imaging report suggesting ONSM. A positive response to steroids and the presence of uveitis may aid the diagnosis of sarcoidosis [53]. But these signs may well be absent and a gradual decline in vision with an isolated optic nerve lesion in the absence of any other systemic features to suggest sarcoidosis may very rarely mimic an ONSM [26].

The very rare occurrence of a metastasis from a breast carcinoma presenting in the optic nerve of an elderly woman was reported recently by Backhouse et al. [4]. Again other features in the history (including presentation with a central retinal vein occlusion and subsequent rubeotic glaucoma) were atypical for an ONSM. Sclerosing orbital inflammation has also presented with imaging findings consistent with ONSM. As in the case of the breast metastasis there was evidence of venous stasis on fundoscopy. The omission of enhanced imaging in this case makes it more difficult to know if the diagnostic dilemma would have persisted in the presence of a complete imaging assessment [61].

Finally, orbital lymphoma has also masqueraded as ONSM on imaging [57]. Selva et

al. [57] presented two cases where the imaging was consistent with ONSM but biopsy later demonstrated lymphoma. The visual loss was minimal in one case, despite a large tumour mass and the vision deteriorated rapidly in the second. The authors advocate that this atypical behaviour should warrant review of the diagnosis and suggest the possibility of obtaining a tissue diagnosis, as lymphoma will respond to much lower doses of radiotherapy than ONSM.

Summary for the Clinician

■The imaging modality of choice is T1 and T2 MRI using fat suppression before and after gadolinium enhancement.

■Omission of gadolinium significantly increases the risk of misdiagnosis.

■CT may offer supplementary information but offers less overall in terms of diagnostic information.

5.3 Management

Consensus about the management of tumours of the optic nerve has been a long and arduous process. Timing of any intervention is still the subject of some debate as treatment-associated morbidity may take years to develop. For both of these conditions observation is now a recognized treatment option particularly in patients with stable visual function and no signs of progression on serial neuroimaging.

5.3.1 Gliomas

There are no randomized controlled trials of treatment for this condition in the literature. Almost all of the papers reporting experience with treatment for OPGs report on a single treatment modality used over decades. The patients were often imaged using CT or plain radiographs and there was not the same degree of diagnostic certainty (particularly regarding intracranial disease) as one would expect today. For those patients treated with conventional radiotherapy, wide safety mar-