Autoimmune/Inflammatory Optic Neuropathies

Kenneth Shindler, MD, PhD Scheie Eye Institute University of Pennsylvania Philadelphia, PA

Learning Objectives with an optic neuropathy. While the presenting signs and 1. To recognize features of neuromyelitis optica; symptoms often are distinct from typical inflammatory similarities and differences from typical demyelinating demyelinating optic neuritis, patients can present with very optic neuritis. similar findings that may make diagnosis difficult. Here, the distinct features and etiologies of other automimmune/ 2. To understand manifestations of optic neuropathy inflammatory optic neuropathies (the zebras) are discussed, in systemic lupus erythematosus and other systemic including neuromyelitis optic, systemic autoimmune diseases autoimmune diseases. such as systemic lupus erythematosus, idiopathic orbital inflammatory syndrome with optic perineuritis, and sarcoid 3. To consider overlapping presentations of optic neuropathy. Potential overlapping features, as well as granulomatous inflammatory optic neuropathies that underlying etiologies, are examined. mimic optic neuritis. 4. To examine potential underlying mechanisms of inflammatory optic neuropathies. Neuromyelitis Optica Neuromyelitis optica (NMO; also referred to as Devic disease), like multiple sclerosis and idiopathic optic neuritis, CME Questions is characterized by inflammation and demyelination (Wingerchuk et al, 1999; Galetta and Bennett, 2007; Merle 1. How does vision loss present in neuromyelitis optica et al, 2007), along with loss of retinal ganglion cell axons (de and how does it compare to typical demyelinating optic Seze et al, 2008). Classically, NMO has been c haracterized as neuritis? a severe demyelinating disease affecting the spinal cord and 2. What are three types of optic neuropathy that have optic nerves, but sparing the brain. However, more recent been associated with systemic lupus erythematosus? descriptions and attempts to develop diagnostic guidelines for this disorder have suggested that some brain lesions can 3. What are three types of optic nerve involvement seen also be present in NMO (Wingerchuk et al, 2006). in sarcoidosis? NMO frequently presents with bilateral and severe optic nerve dysfunction (Merle et al, 2007), unlike the unilateral, Keywords variable severity commonly found in typical demyelinating 1. Autoimmune Optic Neuropathy optic neuritis (Arnold, 2005). The pain on eye movements that is almost always present in typical demyelinating optic 2. Neuromyelitis Optica neuritis is less common in NMO, although other features may 3. Inflammatory Optic Neuropathy overlap, including the presence or absence of disc swelling. Visual function does not always recover as well in NMO, but can occur, and recurrent episodes of optic nerve inflammation Introduction can be frequent. Many patients exhibit signs and symptoms Inflammatory, demyelinating optic neuritis is one of of spinal cord dysfunction within several weeks of, before or the most common optic neuropathies in young adults. after, the onset of visual loss (Merle et al, 2007). Like multiple It occurs idiopathically, or in association with multiple sclerosis, NMO most commonly affects young adults, but also sclerosis, and follows a typical course of progressing visual presents in childhood (Wingerchuk et al, 1999). dysfunction often with pain for one – two weeks, followed by significant resolution over the next few weeks. Due While NMO and multiple sclerosis share many common to the characteristic presentation and frequency of this characteristics, some histopathologic differences have been presumably autoimmune process, optic neuritis is often noted, and it remains debated whether NMO represents a high on the differential diagnosis for patients presenting subtype of multiple sclerosis, or is a distinct disorder (Galetta with optic neuropathy. However, it is important to recognize and Bennett, 2007). The identification of an autoantibody that a number of other autoimmune disorders and systemic that recognizes the aquaporin-4 channel that plays a role in or localized inflammatory processes can also present fluid regulation across the blood-brain barrier (Lennon et

2012 Annual Meeting Syllabus | 59 al, 2004; Lennon et al, 2005) suggests a potential antibody- the identification of the NMO antibody as a potential disease mediated pathogenesis in NMO, which may differ from the marker (Weinshenker and Wingerchuk, 2008), although complex immune responses involved in multiple sclerosis most reports continue to represent single case reports or (Noseworthy et al, 2000). Histopathological studies have small series, and it remains unclear if patients have one demonstrated both demyelinating multiple sclerosis-like underlying autoimmune disorder with overlapping features plaque lesions as well as distinct necrotic lesions in NMO of both, or two distinct processes in a patient susceptible to patients (Lefkowitz and Angelo, 1984; Mandler et al, 1993), autoimmune diseases (Jarius et al, 2011). with evidence of gliotic changes in the optic nerve. MRI can also be used to identify overlapping and distinguishing Even for patients that present with what appears to be features of NMO. As stated above, brain lesions are now typical demyelinating optic neuritis, the visual prognosis is believed to occur in some NMO patients, with about 10% worse if they already carry a diagnosis of SLE or are later of patients having lesions similar to typical demyelinating found to have SLE (Lin et al, 2009). multiple sclerosis, and more than half of patients may have more non-specific white matter lesions in the brain (Filippi et Optic neuropathies have also been observed in patients al, 2004; Pittock et al, 2006). Typically, however, lesions are with other systemic autoimmune disorders such as focused in the optic nerves and spinal cord, with extensive Sjogren’s syndrome (Bejot et al, 2008), and similar to SLE, spinal cord lesions stretching longitudinally across three antibody testing has identified optic neuropathy patients vertebral segments often present that can be used as one with markers of both Sjogren’s and NMO (Jarius et al, criterion for establishing the diagnosis (Filippi et al, 2004; 2011). Some patients present signs of optic neuropathy Wingerchuk et al, 2006). NMO antibody testing can be useful that mimic optic neuritis, but a follow a course more to establish the diagnosis, although the relative sensitivity consistent with SLE associated optic neuropathy with less has varied in different populations (Lennon et al, 2004; than expected spontaneous visual recovery, even though Wingerchuk et al, 2006; Matsuoka et al, 2007; Bizzoco et al, a specific underlying autoimmune diagnosis is not always 2009; Siritho S et al, 2011). found (Dutton et al, 1982; Kupersmith et al, 1988). These patients may respond to corticosteroids, and often have Classic presentations of NMO vision loss, with bilateral optic recurrences, suggestive of a potential autoimmune etiology. nerve involvement and severe dysfunction, are not likely The underlying etiology of the optic neuropathy is likely to be confused with typical demyelinating optic neuritis, variable, with autoimmune antibodies directly recognizing but cases that present with some of the overlapping optic nerve antigens in only some case. Other cases may feature described here may be difficult to diagnose at represent ischemia secondary to a hypercoaguable, as first. Distinguishing NMO from typical demyelinating optic can be seen in the antiphospholipid antibody syndrome neuritis or other optic neuropathies is important, however, in SLE, or from vasculitis, as suggested by the presence of for considering treatment options and discussing prognosis. perivascular infiltrates and immune complex deposition in High dose intravenous corticosteroids may attenuate the skin biopsies (Kupersmith et al, 1988; Riedel et al, 1998). severity of an episode and hasten recovery, but recovery is Search for an underlying autoimmune disorder should be not common as seen in typical demyelinating optic neuritis. considered in optic neuropathies that fail to improve after Addition of azathioprine (Mandler et al, 1998; Constazi et al, steroid therapy, and in suspected cases, antibody testing for 2011), or treatment with rituximab (Cree et al, 2005; Jacob ANA and NMO antibodies should be considered, and skin et al, 2008; Bedi et al, 2011; Pellkofer et al, 2011), may have biopsy for signs of vasculitis may be useful. some benefit, and for refractory cases, plasmaphoresis and IVIg can be considered (Magana et al, 2011). Optic Neuropathies in Granulomatous Inflammatory Disease Systemic Lupus Erythematosus and Other Autoimmune Optic Neuropathies Sarcoidosis Systemic lupus erythematosus (SLE) is a complex immune Sarcoidosis is a systemic disorder characterized by disorder involving all major components of the immune noncaseating epitheliod cell granulomas (Iannuzzi et al, system (Rahman and Isenberg, 2008). Although optic 2007). Granulomatous lesions can occur in just about neuropathy affects only a small percentage of SLE patients, every organ, with pulmonary involvement, in about 90% it’s occurrence in this disorder has been recognized for of patients, being the most common manifestation. over 30 years (Lessell, 1979; Jabs et al, 1986). The type Inflammation affects the eyes in about 25% of sarcoid of optic neuropathy that occurs in SLE varies, including patients (Jabs and Johns, 1986), most commonly with inflammatory optic neuritis with presentation similar to anterior uveitis, but also conjunctival granulomas also idiopathic demyelinating optic neuritis, papillitis, or an occur, and posterior inflammation can be found in the form ischemic optic neuropathy (Jabs et al, 1986; Lin et al, 2009). of vitritis, retinal vasculitis, or choroidal lesions. SLE patients have also been known to experience more severe optic nerve and spinal cord involvement as seen in Sarcoidosis only affects the central nervous system in about NMO (April and Vansonnenberg, 1976), and dual incidence 5% of cases (Stern et al, 1985). Optic nerve involvement of these two entities has been increasingly reported since occurs infrequently, but can take several forms (Ing et

60 | North American Neuro-Ophthalmology Society al, 1997; Frohman et al, 2003; Yu-Wai-Man et al, 2007; IOIS. As perineuritis is often bilateral and can spare central Koczman et al, 2008; Pollock et al, 2008; Phillips and vision, it can sometimes be difficult to distinguish from Eggenberger, 2010): papilledema, and lumbar puncture may be necessary to rule out increased intracranial pressure. CSF may demonstrate 1. Mimicking typical demyelinating optic neuritis with or a mild pleocytosis. Treatment for optic perineuritis, as for without mild disc swelling other forms of IOIS, is high dose corticosteroids. Patients 2. Optic perineuritis typically respond rapidly, but a slow taper is recommended 3. Granulomas of the optic nerve head to reduce the risk of recurrence. 4. Disc swelling or atrophy from granulomatous thickening of the optic nerve sheath mimicking a compressive optic Understanding Mechanisms of neuropathy from meningioma or glioma Inflammatory Optic Neuropathies As described above, there are many shared, as well as Some presentations, such as visible granulomas of the optic distinct, features observed between typical inflammatory nerve head, immediately raise suspicion for sarcoidosis, but demyelinating optic neuritis and inflammatory optic frequently diagnosis may be delayed until a patient fails to neuropathies associated with other disorders. Identifying follow an expected course for optic neuritis or when MR the underlying mechanisms mediating these optic imaging shows an unexpected appearance such as marked neuropathies, including the type of inflammation present, thickening with mass features similar to meningioma or the site of injury, and molecular signalling pathways glioma. In rare cases, sarcoid optic neuropathy can remit that mediate pathologic changes, may help the clinician spontaneously (Galetta et al, 1989), similar to idiopathic understand why different clinical phenotypes are observed, demyelinating optic neuritis, making this entity even harder and will likely help lead to the development of disease- to distinguish. Evaluation for granulomas elsewhere in the specific therapies as well as treatments that are effective in body, particularly the chest, can be useful for establishing multiple conditions. Both human studies, and studies using the diagnosis, and serum levels of angiotensin converting animal models, help increase our understanding of optic enzyme are often elevated. Ideally, biopsy of tissue with an nerve and CNS inflammatory diseases. identifiable lesion is the best way to confirm the diagnosis. Bronchoscopy is frequently performed, but biopsy of Multiple sclerosis, including demyelinating optic neuritis conjunctival or lacrimal gland lesions can also be useful. that occurs in multiple sclerosis patients, consists of a complex immune response involving most cell types of the Sarcoid inflammation often responds rapidly to immune system (Noseworthy et al, 2000). A particularly corticosteroid therapy, although continued treatment for important role has been implicated for autoreactive T several months may be needed for full treatment and cells in mediating multiple sclerosis, with two subsets of to reduce the risk of recurrence. Some patients require T helper cells (Th1 and Th17) identified that can play a chronic treatment, and steroid-sparing agents should be pathogenic role in the development of multiple sclerosis, or considered (Katz et al, 2003: Maust et al, 2003), while other its most common animal model experimental autoimmune patients may be refractory to steroid therapy. encephalomyelitis (EAE) (Axtell et al, 2011).

Idiopathic Orbital Inflammatory Syndrome Examining the relative role of Th cell subsets in the Idiopathic orbital inflammatory syndrome (IOIS) can present context of treatment for various types of inflammatory with either focal or diffuse orbital inflammation consisting diseases that present with optic neuropathy provides an of a mixed nonspecific chronic inflammation that is often important example of how therapies may be guided by granulomatous (Jacobs and Galetta, 2002; Gordon, 2006). our understanding of disease mechanisms. Interferon-beta Presenting signs and symptoms, including pain, proptosis, is commonly used to treat relapsing-remitting multiple redness, periorbital edema, diplopia, or decreased sclerosis; however, a significant number of patients fail to vision, vary depending on which orbital structures are respond to interferon-beta (Rio et al, 2006). A recent study involved. Myositis, posterior scleritis, dacryocystitis, optic demonstrated that interferon-beta suppresses disease perineuritis, or diffuse orbital inflammation can all be seen. in a Th1 mediated EAE model, but actually exacerbates disease in a Th17 driven EAE model (Axtell et al, 2010). Optic perineuritis typically presents bilaterally with pain, Correspondingly, the authors also show that high levels of IL- mild disc swelling, and decreased vision that may spare 17F, a cytokine produced by Th17 cells, is present in multiple central fixation (Margo et al, 1989; Purvin et al, 2001). MRI sclerosis patients that failed to respond to interferon- shows specific enhancement of the optic nerve sheath beta. Interestingly, Th17 cells play an important role in with relatively little or no enhancement of the nerve itself. mediating other autoimmune disorders associated with optic Optic perineuritis can occur in the setting of a systemic neuropathy that do not respond to interferon-beta therapy, inflammatory disease, such as sarcoidosis, and can occur including NMO (Ishizu et al, 2005) and SLE (Shah et al, 2010). simultaneously with other areas of the orbit affected by This may explain why interferon-beta has been known to IOIS such as myositis or posterior scleritis. Isolated optic exacerbate NMO (Shimizu et al, 2010; Palace et al, 2010), and perineuritis also occurs, and may represent a localized form highlights a need for understanding specific inflammatory

2012 Annual Meeting Syllabus | 61 mechanisms before choosing an immunomodulatory overlapping and distinct immune mechanisms are involved therapy. While exact protocols need to be examined, this in human inflammatory optic neuropathies, for both the type of evaluation raises the possibility of identifying which common demyelinating optic neuritis patients, as well as multiple sclerosis and high risk optic neuritis patients are the uncommon zebras. This may explain why some patients most likely to respond to interferon-beta. harbouring uncommon autoimmune or inflammatory optic neuropathies present with clinical features that are Unlike multiple sclerosis which is dependent on T cell indistinguishable from demyelinating optic neuritis while autoimmunity, recent studies have demonstrated that others follow distinct courses. Ongoing studies hold the the NMO antibodies that recognize aquaporin-4 are not promise of leading to new diagnostic and prognostic testing merely markers of NMO, but rather play a pathogenic role that may help distinguish different inflammatory optic in development of the disease (Bennett et al, 2009; Bradl neuropathies and guide development of novel therapies. et al, 2009; Kinoshita et al, 2009; Saadoun et al 2010). Monoclonal recombinant aquaporin-4-specific antibodies generated from immunoglobulins isolated from the CME Answers cerebral spinal fluid of an NMO patient administered to rats 1. Classically, NMO patients can present with bilateral with EAE are capable of converting the EAE into a disease vision loss that is often severe, whereas typical with histopathologic features more consistent with NMO demyelinating optic neuritis is usually unilateral and (Bennett et al, 2009). Similar conversion of EAE to an NMO can range in severity. phenotype occurs with injection of aquaporin-4-specific antibodies isolated from the sera of NMO patients (Bradl 2. Presentations include: unilateral inflammatory optic et al, 2009; Kinoshita et al, 2009). Furthermore, injection neuropathy similar to demyelinating optic neuritis, of aquaporin-4 antibodies in conjunction with human severe bilateral optic neuropathy as seen in NMO, an complement induces an NMO-like disease in mice even isolated papillitis, and ischemic optic neuropathy. without a prior underlying inflammatory disease (Saadoun 3. Presentations include: unilateral inflammatory optic et al, 2010). These animal studies confirm a pathogenic role neuropathy similar to demyelinating optic neuritis, optic of the NMO antibodies, and suggest that future therapies perineuritis, granulomas of the optic nerve head, and may be guided toward regulating aquaporin-4. disc swelling or atrophy from granulomatous thickening of the optic nerve sheath mimicking a compressive optic Specific studies examining animal models of optic neuritis neuropathy from meningioma or glioma. provide further insight into the variability of inflammatory diseases that can present with similar histopathologic features. A high incidence of optic nerve inflammation occurs References in both relapsing-remitting (Shindler et al, 2006) and chronic progressive (Shao et al, 2004; Quinn et al, 2011) mouse 1. April RS, Vansonnenberg E (1976) A case of neuromyelitis optic (Devic’s syndrome) in systemic lupus erythematosus: clinicopathologic report EAE. 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64 | North American Neuro-Ophthalmology Society Hereditary mitochondrial optic neuropathies

Valerio Carelli, MD, PhD Department of Neurological Sciences University of Bologna, Italy

Learning Objectives Introduction 1. The attendee will be able to recognize clinically and Leber’s hereditary optic neuropathy (LHON) and direct the molecular diagnosis of Leber’s hereditary dominant optic atrophy (DOA) are the two most frequent mitochondrial hereditary optic neuropathies optic neuropathy (LHON) and dominant optic [1,2] neuropathy (DOA). with monosymptomatic expression . LHON and DOA are limited to a single cellular target, i.e. the RGCs that 2. The attendee will have state of the art information on originate the optic nerve. Both LHON and DOA share the some of the unexplained features of LHON and DOA. hallmark of early and preferential involvement of the small axons that form the papillomacular bundle, the anatomical 3. The attendee will have updated information on substrate for central and colour vision. therapeutic options for LHON and DOA.

LHON clinical features CME Questions Theodor Leber first described LHON as a hereditary optic 1. The major clinical difference between LHON and DOA is atrophy affecting mostly young males [3]. It is now well (choose one): established that LHON is maternally inherited, being due to the three frequent pathogenic mtDNA point mutations a) Age of onset and timing of disease evolution at positions 11778/ND4, 3460/ND1, and 14484/ND6, b) Visual field defect affecting different complex I subunits [1,2]. Epidemiological c) Dyschromatopsia studies demonstrated that LHON is among the most d) Retinal cell type affected frequent mitochondrial disease [4]. LHON patients 2. The incomplete penetrance in LHON is possibly related to: present with rapid and painless loss of central vision in one or both eyes accompanied by the fading of colours a) Environmental factors such as tobacco smoking (dyschromatopsia). The second eye is usually involved and alcohol consumption within weeks. The loss of visual acuity is profound and b) Genetic polymorphisms elatedr to the mtDNA levels off below 20/200 within a few months; the visual background (haplogroups) field defects show large centro-coecal absolute scotomata. c) Nuclear modifying genes At fundus examination, the characteristic signs include d) All the above. circumpapillary telangiectatic microangiopathy, swelling 3. The therapeutic options currently available for LHON of the retinal nerve fiber layer (RNFL) around the disc include: (pseudoedema), and lack of leakage on fluorescein angiography (in contrast to true disc edema) [5,6]. The optic a) Gene therapy disc appears hyperemic initially, though the axonal loss in b) Use of antioxidants such as idebennone or EPI-743 the papillomacular bundle leads to severe temporal pallor c) Antiapoptotic drugs of the optic disc. In time, the optic disc turns completely d) Drugs activating mitochondrial biogenesis atrophic. Microangiopathy and fundus changes such as RNFL swelling may be present in asymptomatic maternal family members [7]. The endpoint of LHON is usually Keywords optic atrophy associated with permanent loss of central 1. Optic Nerve Atrophy vision and very poor general visual function although there is relative sparing of pupillary light responses [1,2]. 2. Mitochondria Spontaneous recovery of visual acuity may infrequently occur even years after onset, and the most favourable 3. Retinal Ganglion Cells prognostic factors are young age of onset and the 14484/ 4. Papillomacular Bundle ND6 mutation [1,2]. Recently, the use of optical coherence tomography (OCT) measurements re-described the essential features of LHON in acute and chronic cases [8,9], defining a specific pattern of sequential involvement

2012 Annual Meeting Syllabus | 65 during the acute phase that goes from the temporal- characterized by a remarkably synchronous wave of RGCs inferior, to superior and only lastly to the nasal quadrants, degeneration, most likely involving apoptotic cell death. the latter being the most spared sector in the chronic At this stage, the commitment to cell death might be phase of the disease [10]. already irreversible, as suggested by the recent failure of therapeutic trials designed to save the second eye by drug LHON genetics and pathophysiology administration in the small window of time separating the Incomplete penetrance in homoplasmic LHON maternal optic neuropathy in the first from the second eye [24,25]. lineages and male prevalence among the affected individuals are two features of LHON that remain a mystery DOA clinical features and are currently matters of intense investigation. In this DOA, also known as Kjer’s optic neuropathy [26], is regard the genetic basis of LHON is very complex. There are characterized by slowly progressive, roughly bilaterally three frequent pathogenic point mutations (11778/ND4, symmetrical visual loss in childhood, accompanied by 3460/ND1, and 14484/ND6), and a handful of other rarer temporal pallor of the optic discs [1,2]. Examination also but truly pathogenic mtDNA point mutations, all affecting demonstrates centrocaecal scotomas and impairments subunits of complex I [1,2]. Recently, the importance of of color vision (tritanopia). The disease is frequently mtDNA variation in LHON has been fully recognized. There recognized during routine vision testing (school or driving is now solid evidence that two sublineages of haplogroup license eye screenings). Disease progression may be quite J (J1c and J2b) are relevant to increase penetrance of the variable within the same family, ranging from mild cases 11778/ND4 and 14484/ND6 mutations [11,12]. with visual acuity that stabilizes in adolescence, to slowly but relentlessly progressing cases, to cases with sudden, The mtDNA pathogenic mutations and modifying background step-like decreases of visual acuity. This variability of clinical are a necessary but still not sufficient condition to expression is reflected by the different extent of optic determine the phenotypic expression. The role of nuclear atrophy shown by different patients [27]. modifying genes has been postulated and debated [13]. The X-chromosome has been under enquiry for a long time as a Despite the remarkably different clinical course, the good candidate for modifying genes, which would also explain endpoint of the pathological process in DOA is clinically the male prevalence. This two-locus model was formally indistinguishable from that in LHON [1,2]. A frequent feature of compatible with segregation studies in LHON pedigrees [14] DOA’s end-stage fundus is optic disc excavation, which is also and recent linkage analysis documented two loci on X reported in LHON [1,2]. Recent studies using OCT documented chromosome [15,16]. However, to date no significant genetic a smaller optic nerve head in OPA1 patients, suggesting a variants associated with LHON were reported by the direct reduced total number of RGCs and axons at birth [28]. sequencing of candidate genes in the X-linked loci, as well as studies on the X-inactivation pattern in affected females failed Overall, despite a remarkably different natural history, to observe the predicted excess of skewed inactivation [17]. LHON and DOA share a similar endpoint with predominant Recently, we provided a different view on the male prevalence involvement of the papillomacular bundle. Both diseases in LHON, documenting the protective role played by estrogens also share a remarkable variability in penetrance. in cultured cells carrying the LHON mutations [18]. DOA genetics and pathophysiology Environmental factors such as tobacco smoking and alcohol About 60% of DOA cases are now linked to mutations in consumption are now confirmed risk factors that may the OPA1 gene identified in 2000 [29,30]. Three further loci trigger LHON, in analogy with toxic and nutritional optic have been reported (OPA4, OPA5, and OPA8), but the genes neuropathies [19]. Exposures to less common toxic agents such involved have not yet been identified [31-33]. The screening of as solvent vapors [20], as well as head trauma, uncontrolled numerous cohorts of DOA families of different ethnic origin diabetes, or pharmaceutical agents that interfere with led to the identification of a large number (over 100) of mitochondrial metabolism, such as ethambutol and different mutations in the OPA1 gene, including missense, antiretroviral drugs have also been reported [1,2]. nonsense, deletion/insertion, and splicing mutations, mostly clustered in the GTPase domain and the 3’ end of the coding The biochemical effects of LHON mutations and region [34, see http://lbbma.univ-angers.fr]. The large majority of OPA1 the possible pathogenic mechanisms remain areas mutations are predicted to produce a premature truncated of continuous investigation. Every model of LHON protein and haploinsufficiency is the mechanism assumed to pathophysiology assumes a defective complex I function. underlay DOA in these cases, whereas missense mutations, Loss of energetic efficiency, increased oxidative stress, and mostly affecting the GTPase domain, are predicted to propensity to apoptotic cell death have all been variably exert a dominant negative effect. In general, the genotype- documented in patient’s tissues and cell models of the phenotype correlation is weak, with great variability in both disease [1,21-23]. As a consequence, altered axonal transport penetrance and clinical severity. As is the case for LHON, of organelles and axoplasmic stasis with swelling of axons other as yet unknown genetic or epigenetic/environmental has been proposed as key features leading to the threshold factors may play a role in the phenotypic expression of DOA. for the acute phase of the disease [1,21-23]. The latter is

66 | North American Neuro-Ophthalmology Society The OPA1 gene encodes a 960 amino acid residue inhibit the MPTP opening, thus forestalling mitochondrially- protein targeted to mitochondria by a leader sequence, induced apoptosis. The study was halted early, due to and belonging to a family of highly conserved GTPases insufficient enrollment and because none of the patients related to Dynamin [35,36]. OPA1 has eight mRNA isoforms achieved the target of mitigating vision loss. resulting from alternative splicing. These are expressed in a variety of tissues, with the highest levels found in retina, Antioxidant agents brain, testis, heart, and muscle. OPA1 is anchored to the Coenzyme Q-10 is a mitochondrial cofactor that shuttles mitochondrial inner membrane facing the inter-membrane electrons from complexes I and II to complex III. Coenzyme space and has an important role in the mitochondrial fusion Q-10 (or ubiquinone) is available as a nutritional supplement. process and also in protection from apoptosis by dealing A few case reports of treatment with coenzyme Q-10 have with cytochrome c storage and release. Down-regulation been published, but the lack of any successful case series gives of OPA1 using specific small interference RNA leads to rise to skepticism for this treatment. One likely limitation of fragmentation of the mitochondrial network concomitantly treatment with exogenous coenzyme Q-10 relates to its poor to dissipation of the mitochondrial membrane potential delivery crossing lipid membranes to mitochondria. and to a drastic disorganization of the cristae. Recent studies provide mounting evidence that OPA1 is also Idebenone, a coenzyme Q-10 derivative, is reported to have involved in OXPHOS efficiency [37,38]. In particular OPA1 higher delivery to mitochondria as well as a higher efficiency mutations inducing haploinsufficiency were shown to impair for crossing the blood-brain barrier. Successful treatment ATP synthesis in patient-derived fibroblasts when oxidative with idebenone has been described in a few case reports and phosphorylation was driven by complex I substrates, retrospective case series [25,43]. One such study evaluated the thus converging DOA to a final biochemical pathway with treatment of Japanese patients with LHON carrying all three LHON. A similar convergence was shown by another study mutations with a combination of idebenone, riboflavin (B- demonstrating that LHON and DOA cells suffer a similar 2) and ascorbic acid (vitamin C) [44]. The visual recovery was coupling defect in respiration [38]. An unexpected scenario and significantly earlier for treated patients carrying the 11778/ a new role for OPA1 were prompted by the discovery that a ND4 mutation and limited to small openings that appeared in subset of missense mutations, mostly affecting the GTPase the paracentral visual field (fenestrations). domain of OPA1, are linked to multisystemic mitochondrial encephalomyopathy including early onset optic atrophy Two recent studies, one prospective double-blind placebo- and deafness, followed later by mitochondrial myopathy controlled trial [45] and one very large retrospective series with progressive external ophthalmoplegia, cerebellar investigating a large cohort of idebenone treated patients involvement, white matter abnormalities, peripheral in Italy [25], validated some effectiveness of idebenone as neuropathy and spastic paraplegia [39-41]. These patients treatment for LHON, suggesting greater recovery of visual were shown to accumulate ragged red fibers and mtDNA acuity than that seen to spontaneously occur in LHON [1,2]. multiple deletions in the skeletal muscle, thus involving OPA1 However, very early idebenone treatment in patients with in mtDNA maintenance. A very recent study went further asynchronous eye involvement (and the second eye still suggesting the involvement of specific OPA1 isoforms in unaffected), failed to spare the second eye from undergoing mtDNA replication and mtDNA nucleoid organization [42]. the visual loss associated with the pathological process [25]. Thus, caution should be used in managing expectations for Treatment options idebenone therapy in patients [46]. Studies are underway for Until recently, only anecdotal data have been available about a third generation quinone and further strategies of gene therapeutic attempts in mitochondrial optic neuropathies, therapy are being studied for LHON, but these are not yet at in particular LHON, and in most cases these proved to be the stage for clinical trials in humans [47,48]. ineffective [1,2,43]. They include the following list.

Vitamins CME Answers Anecdotal reports on the therapeutic use of vitamins 1. a (especially folic acid, B-2 and B-12) and nutritional supplements (including vitamins C and E) did not 2. d prove their efficacy in LHON. Although vitamin B-12 3. b administration has not been a successful treatment for LHON, it may be helpful in the setting of a B-12 deficiency that precipitated the visual loss in LHON. References 1. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a Brimonidine cause of optic neuropathies. Prog Retin Eye Res 2004;23:53-89. Topical brimonidine, an alpha-2 agonist, also failed in a 2. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic small clinical trial as a prophylactic agent aimed to avoid neuropathies -disease mechanisms and therapeutic strategies. Prog the involvement of the fellow eye in LHON [24]. It had been Retin Eye Res 2011;30:81-114. hoped that brimonidine, by upregulating BCL-2, could

2012 Annual Meeting Syllabus | 67 3. Leber T. Uber hereditare und congenital-angelegte Sehnervenleiden. 22. Carelli V, La Morgia C, Iommarini L, et al. Mitochondrial optic Arch. Ophthalmol. 1871;17:249–291. neuropathies: how two genomes may kill the same cell type? Biosci Rep 2007;27:173-184. 4. Man PY, Griffiths PG, Brown DT, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum 23. Carelli V, La Morgia C, Valentino ML, et al. Retinal ganglion cell Genet. 2003;72:333-339. neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta. 2009;1787:518-528. 5. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy. II. The fundus findings in 24. Newman NJ, Biousse V, David R, et al. Prophylaxis for second eye affected family members. Arch. Ophthalmol. 1983;101:1059-1068. involvement in Leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J 6. Nikoskelainen E, Hoyt WF, Nummelin K, Schatz H. Fundus findings Ophthalmol 2005;140:407-415. in Leber’s hereditary optic neuropathy. III. Fluorescein angiographic studies. Arch Ophthalmol 1984;102:981-989. 25. Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. 2011 Aug 2. [Epub ahead 7. Nikoskelainen E, Hoyt WF. Nummelin K. Ophthalmoscopic findings in of print] Leber’s hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. Arch Ophthalmol 1982;100:1597-1602. 26. Kjer P, Jensen OA, and Klinken L. Histopathology of eye, optic nerve and brain in a case of dominant optic atrophy. Acta Ophthalmol. 8. Barboni P, Savini G, Valentino ML, et al., Retinal nerve fiber layer (Copenh) 1983;61:300-312. evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy. Ophthalmology 2005;112:120-26. 27. Cohn AC, Toomes C, Potter C, et al. Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 9. Savini G, Barboni P, Valentino ML, et al. Retinal nerve fiber layer mutations. Am J Ophthalmol 2007;143:656-62. evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations. Ophthalmology 28. Barboni P, Carbonelli M, Savini G, et al. OPA1 mutations associated 2005;112:127-131. with dominant optic atrophy influence optic nerve head size. Ophthalmology 2010;117:1547-1553. 10. Barboni P, Carbonelli M, Savini G, et al., Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal 29. Alexander C, Votruba M, Pesch UEA, et al. OPA1, encoding a nerve fiber layer by optical coherence tomography. Ophthalmology dynamin-related GTPase, is mutated in autosomal dominant optic 2010;117:623-27. atrophy linked to choromosome 3q28. Nat Genet 2000;26:211-15. 11. Carelli V, Achilli A, Valentino ML, et al. Haplogroup effects and 30. Delettre C, Lenaers G, Griffoin J-M, Gigarel, et al. Nuclear gene OPA1, recombination of mitochondrial DNA: novel clues from the analysis encoding a mitochondrial dynamin-related protein, is mutated in of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet dominant optic atrophy. Nat Genet 2000;26:207-10. 2006;78:564-574. 31. Kerrison JB, Arnould VJ, Ferraz Sallum JM, et al. Genetic 12. 5. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber heterogeneity of dominant optic atrophy, Kjer type: Identification hereditary optic neuropathy is affected by the mitochondrial DNA- of a second locus on chromosome 18q12.2-12.3. Arch Ophthalmol haplogroup background. Am J Hum Genet 2007;81:228-233. 1999;117:805-810. 13. Carelli V, Giordano C, d’Amati G. Pathogenic expression of 32. Barbet F, Hakiki S, Orssaud C, et al. A third locus for dominant optic homoplasmic mtDNA mutations needs a complex nuclear- atrophy on chromosome 22q. J. Med. Genet., 2005;42:e1. mitochondrial interaction. Trends Genet 2003;19:257-262. 33. Carelli V, Schimpf S, Fuhrmann N, et al. A clinically complex form of 14. Bu XD, Rotter JI. X chromosome-linked and mitochondrial gene dominant optic atrophy (OPA8) maps on chromosome 16. Hum Mol control of Leber hereditary optic neuropathy: evidence from Genet 2011;20:1893-905. segregation analysis for dependence on X chromosome inactivation. 34. Ferre M, Bonneau D, Milea D, et al. (2009) Molecular screening of Proc Natl Acad Sci USA 1991; 88: 8198-8202. 980 cases of suspected hereditary optic neuropathy with a report on 15. Hudson G, Keers S, Yu Wai Man P, et al. Identification of an 77 novel OPA1 mutations. Hum Mutat 30;E692-705. X-chromosomal locus and haplotype modulating the phenotype of a 35. Delettre C, Lenaers G, Pelloquin L, et al. OPA1 (Kjer type) dominant mitochondrial DNA disorder. Am J Hum Genet 2005;77:1086-1091. optic atrophy: a novel mitochondrial disease. Mol Genet Metab 16. Shankar SP, Fingert JH, Carelli V, et al. () Evidence for a novel X-linked 2002;75:97-107. modifier locus for Leber hereditary optic neuropathy. Ophthalmic 36. Olichon A, Guillou E, Delettre C, et al. Mitochondrial dynamics and Genet 2008;29:17-24. disease, OPA1. Biochim Biophys Acta 2006;1763:500-509. 17. Hudson G, Carelli V, Horvath R, et al. X-Inactivation patterns in 37. Chevrollier A, Guillet V, Loiseau D, et al. Hereditary optic females harboring mtDNA mutations that cause Leber hereditary neuropathies share a common mitochondrial coupling defect. Ann optic neuropathy. Mol Vis 2007;13:2339-23343. Neurol 2008;63:794-798. 18. Giordano C, Montopoli M, Perli E, et al. Oestrogens ameliorate 38. Zanna C, Ghelli A, Porcelli AM, et al. OPA1 mutations associated mitochondrial dysfunction in Leber’s hereditary optic neuropathy. with dominant optic atrophy impair oxidative phosphorylation and Brain 2011;134:220-234. mitochondrial fusion. Brain 2008;131:352-367. 19. Kirkman MA, Yu-Wai-Man P, Korsten A, et al. Gene-environment 39. Amati-Bonneau ,P Valentino ML, Reynier P, et al. OPA1 mutations interactions in Leber hereditary optic neuropathy Brain 2009; 132: induce mitochondrial DNA instability and optic atrophy ‘plus’ 2317-2326. phenotypes. Brain 2008;131:338-351. 20. Ghelli A, Porcelli AM, Zanna C, et al. The background of 40. Hudson G, Amati-Bonneau ,P Blakely EL, et al. Mutation of OPA1 mitochondrial DNA haplogroup J increases the sensitivity of Leber’s causes dominant optic atrophy with external ophthalmoplegia, hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS ataxia, deafness and multiple mitochondrial DNA deletions: a novel One. 2009;4:e7922. disorder of mtDNA maintenance. Brain 2008;131:329-337. 21. Carelli V, Rugolo M, Sgarbi G, et al. Bioenergetics shapes cellular 41. Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system death pathways in Leber’s hereditary optic neuropathy: a model neurological disease is common in patients with OPA1 mutations. of mitochondrial neurodegeneration. Biochim Biophys Acta Brain 2010;133:771-786. 2004;1658:172-179.

68 | North American Neuro-Ophthalmology Society 42. Elachouri G, Vidoni S, Zanna C, et al. OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 2011;21:12-20. 43. Sadun AA, La Morgia C, Carelli V. Leber’s Hereditary Optic Neuropathy. Curr Treat Options Neurol 2011;13:109-117. 44. Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000;20:166-170. 45. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 2011 Jul 25. [Epub ahead of print] 46. Newman NJ. Treatment of Leber hereditary optic neuropathy. Brain 2011 Aug 22. [Epub ahead of print] 47. Ellouze S, Augustin S, Bouaita A, et al. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 2008;83:373-387. 48. Koilkonda RD, Chou TH, Porciatti V, et al. Induction of rapid and highly efficient expression of the human ND4 complex I subunit in the mouse visual system by self-complementary adeno-associated virus. Arch Ophthalmol 2010;128:876-883.

2012 Annual Meeting Syllabus | 69 70 | North American Neuro-Ophthalmology Society Mitochondrial Optic Neuropathies: Toxic/metabolic

Alfredo A. Sadun, MD, PhD Doheny Eye Institute Los Angeles, CA

Learning Objectives Introduction 1. To recognize the features of mitochondrial optic Ophthalmologists have known for centuries that certain neuropathy. toxins or nutritional deficiencies can cause permanent bilateral blindness. Beginning with the description of 2. To understand the particular susceptibility of the Tobacco or Tobacco-Alcohol Amblyopia by Mackenzie1 papillo-macular bundle to mitochondrial dysfunction. in 1830, this phrase and concept have probably done a great deal to obfuscate the issue. That is, under this term 3. To consider various nutritional deficiencies and of tobacco-alcohol amblyopia, there are probably several toxic insults as they impact mitochondrial oxidative- toxic and metabolic forms of optic neuropathy, such as phosphorylation. cyanide (from tobacco), B-12 and folate deficiencies. In the 4. To know the most common list of antibiotics and common last few decades there has been a better understanding of medications that disturb mitochondrial function. the specific elements of mixed toxic and metabolic optic neuropathy (MON) and also the nature of the general class of injury as mitochondrial in nature.2-4 CME Questions In 1988, Wallace and coworkers first identified, in a 1. Toxic/metabolic optic neuropathies most likely cause RGC subset of LHON families, a pathogenic mtDNA missense injury through events related to which of the following: point mutation at position 11778 in the ND4 gene of a) NMDA receptors (excito-toxicity) complex I.5 This was followed by the identification of b) Calcium channel effects other point mutations, all affecting Complex I of the c) Electron transfer chain electron transport chain. This gave great insight into the d) Pro-inflammatory response pathophysiology of acquired as well as genetic causes of mitochondrial optic neuropathy. Subsequently, some 2. A good screening test for toxic/metabolic investigators went back and reviewed their series of mitochondrial optic neuropathy would include all the patients previously diagnosed with Tobacco-Alcohol below except: Amblyopia and found that about 20% did in fact harbor 6 a) The fundus examination LHON genetic mutations. This indicates that there b) Testing of color vision can be either masquerading of LHON that presents as c) Testing of visual acuity a toxic/metabolic optic neuropathy, or that toxic and d) Testing of the central visual fields nutritional status may be important environmental triggers that provoke mitochondrial optic neuropathy 3. Which of the following is true for mitochondrial optic (MON) in genetically predisposed individuals. neuropathies: The effect of toxins for in producing MON can therefore a) Optic trophya occurs early be considered in two general cases. There are agents to be b) There is a central scotoma identified and kept in mind as to be specifically avoided in c) Color vision is spared individuals identified genetically to be at risk (LHON and d) RPE changes are likely TAA or Ethambutol). There are also agents so dangerous or so widespread in general usage as to require special consideration. For examples, it has been estimated that one Keywords hundred thousand people, worldwide, go blind every year 1. Mitochondrial Optic Neuropathy from the use of Ethambutol.7

2. Retinal Ganglion Cells (RGCs) In thinking about toxic optic neuropathies, it is also 3. Papillo-Macular Bundle (PMB) important to understand that they represent one class of injury under the broader rubric of MON. Most generally 4. Toxic/Metabolic we can consider MON to be either congenital or acquired. Congenital MON can be simple hereditary (LHON and DOA),

2012 Annual Meeting Syllabus | 71 or syndromic. Acquired can be nutritional deficiencies or picture may extend to signs and symptoms of methanol toxic optic neuropathies. Finally, there are mixed syndromes ingestion and formate acidosis - nausea, vomiting, and such as the Cuban Epidemic of Optic Neuropathy (CEON). disturbances of consciousness leading to coma with severe acidosis requiring intensive care treatment.

In these acquired metabolic optic neuropathies, fundus examination often demonstrates a completely normal optic disc leading to the incorrect diagnosis of retrobulbar optic neuritis.11 The optic disc may be slightly hyperemic with small splinter hemorrhages on or just around the disc. Optic atrophy may early on be non-existent and only later become mild. In later stages the optic atrophy is severe and this indicates less opportunity for recovery. In ethambutol toxicity, for example, the fundus examination is normal initially, thereby rendering early diagnosis challenging. Optic disc atrophy only ensues later if the drug is not discontinued.

Some metabolic optic neuropathies may present in the early stages without the development of the full clinical picture. For example, the central scotomas may be small and not absolute in tobacco- alcohol amblyopia, whereas in Figure 1. Types of mitochondrial optic neuropathies and most cases of LHON, the scotomas are large and dense.12 their relationships Toxic optic neuropathies

Common presentation Antibiotic-related optic neuropathies As in most cases of MON, toxic/metabolic cases present Ethambutol is an anti-mycobacterial medication commonly with painless bilateral loss of visual acuity. Examination at used in the treatment of tuberculosis. The primary toxicity this time is usually unrevealing for anterior or posterior associated with ethambutol is a mitochondrial optic biomicroscopy. However, careful testing will reveal neuropathy. This complication is a dose and duration dyschromatopsia and at least relative if not absolute central dependent phenomenon. The incidence of ethambutol- or cecocentral scotomas. These tend to be very symmetrical. induced optic neuropathy has been reported to range from All of these clinical features reflect the underlying common 1.0% to 22%13, depending on the dosages employed. It is pathophysiology that affects initially affects the papillo- estimated that as many as 100,000 people, worldwide, macular bundle (PMB). This may reflect the small caliber lose vision from taking Ethambutol each year.7 WHO of the retinal ganglion cells in this area (52 that make them recommends a daily ethambutol dose of 15-20mg/kg metabolically most vulnerable. Early involvement of the daily or in some cases three times a week. WHO also PMB also may make it difficult to demonstrate on Optical suggests discontinuing ethambutol once TB cultures have Coherence Tomography (OCT) and especially on GDx demonstrated sensitivity to another antibiotic.14 Since the (scanning laser polarimetry) as these techniques are least toxicity of ethambutol is dose-dependent, age and renal sensitive in the area just temporal to the optic disc. function of the patient are important determinants.7,14

Toxic/Metabolic optic neuropathies clinically often follow Kidney function decreases with age and with diseases the common theme of all mitochondrial optic neuropathies. affecting the kidney. Overdose toxicity can also be avoided by However, there are two key features that can help in taking into consideration the patient’s weight.15 Toxicity does distinguishing inherited from acquired optic neuropathies: not usually develop until after two months of treatment. absence of family history and simultaneous involvement The reported mean interval from onset of therapy to toxic of both eyes. A history of exposure to toxins or antibiotics effects usually occurs between 3 and 6 months, but optic or lack of proper diet will of course be very helpful for the neuropathy can begin as late as 12 months after treatment is correct diagnosis. A thorough systemic examination in such initiated.16-18 Thus, it remains important to in optimize dosage a scenario must be emphasized. For instance, skin lesions for age, weight and renal function of the patient.7,19 may be observed with dietary or vitamin deficiencies.8 As in other toxic mitochondrial optic neuropathies, the The visual loss can vary from mild to severe.9 Visual loss is symptoms of ethambutol-induced optic neuropathy can progressive and painless and may therefore lead to a late occur before there is fundus evidence of optic neuropathy realization of the problem by the patient. One exception on ophthalmologic examination. Visual acuity, color vision is that the visual loss in cases of methanol intoxication can and central visual field testing is much more sensitive be extremely rapid and severe.10 In such a case, the clinical to early ethambutol-induced changes. The toxic optic

72 | North American Neuro-Ophthalmology Society neuropathy is largely reversible if ethambutol treatment Other toxins is withdrawn before severe optic atrophy develops.20,21 Toxins such as arsacetin, carbon monoxide, clioquinol, However, there are reports of some patients who develop cyanide, hexachlorophene, lead, methanol, plasmocid and severe, irreversible vision loss despite frequent monitoring triethyl tin also interfere with oxidative phosphorylation and appropriate ethambutol doses.16,17,22 Some patients and thus cause mitochondrial optic neuropathy.3 Other may have a susceptibility to optic neuropathy while on less common toxins known to cause optic neuropathy are ethambutol and this includes LHON carriers.23 carbon disulfide, pheniprazine, quinine, thallium, carbon tetrachloride, cassava, dapsone and Suramin.3 It has been hypothesized that ethambutol leads to optic neuropathy by chelating copper ions in cytochrome c oxidase Nutritional optic neuropathies (COX, complex IV) and sulphur-iron clusters in complex I, Isolated nutritional optic neuropathies are rare. They thus damaging the mitochondrial respiratory chain.2,24 Some are usually encountered mixed with each other or in studies have demonstrated that zinc may contribute to the combination with a toxic component2,4,39 Vitamin B12 pathogenesis of toxicity by formation of vacuoles, which are (cobalamin),40,41 Vitamin B1 (thiamine)2,42,43 and folic acid39,44,45 25 enlarged lysosomes and /or late endosomes. are the best described deficiency related mitochondrial optic neuropathies. Malabsorption, such as from gastric bypass Not surprisingly, given the similarities between mitochondrial surgeries, as well as poor nutrition may result in deficits of DNA, transcription/translation and that of the bacteria that sulfur amino acids and these vitamins which in combination are targeted, other antibiotics have also been noted to can cause mitochondrial optic neuropathy.46 There are a cause a mitochondrial optic neuropathy. Linezolid, a drug few case reports documenting optic neuropathy in patients used for methicillin-resistant Staphylococcus aureus (MRSA) carrying a primary LHON mtDNA mutation precipitated by and vancomycin resistant enterococcus (VRE), can cause a vitamin B12 deficiency, thus suggesting a synergism between mitochondrial optic neuropathy. Previous reports have shown genetic and acquired mitochondrial optic neuropathies.47,48 linezolid-induced optic and peripheral neuropathies to occur 26-32 beyond the 28 day safety window suggested but there Mixed toxic/metabolic and nutritional have been a few recent case reports of linezolid-induced optic mitochondrial optic neuropathy neuropathy after very short term (16day) use.33,34 Retinal nerve fiber layer swelling in linezolid-induced optic neuropathy has Tobacco-alcohol amblyopia (TAA) been demonstrated by OCT, and this is consistent with the As mentioned in the introduction, tobacco-alcohol amblyopia proposed mitochondrial mechanism for this disorder.35 (TAA) is an old and poor term for several combined elements that can lead to a mitochondrial optic neuropathy. TAA Linezolid inhibits protein synthesis by binding to the 23S rRNA characteristically affects men with a history of heavy alcohol of the 50S ribosomal subunit and thus inhibiting the formation and tobacco consumption. There is evidence that tobacco- of an initiation complex for protein synthesis36 Mammalian derived compounds including reactive oxygen species, and ribosomes lack the 50S component, however, mitochondria in mammalian cells are susceptible to this blockage. This cyanide add to a nutritional mitochondrial impairment. It has mitochondrial specific impairment can lead to similar been hypothesized that TAA is due to the cumulative cyanide respiratory chain dysfunction producing a mitochondrial toxicity from tobacco smoke and/or isolated deficiency of optic neuropathy. There is marked decrease in the activity of thiamine, riboflavin, pyridoxine, and vitamin B12. As noted, complexes I and IV found in muscle, kidney and liver samples there is overlap between LHON and TAA and such patients from a patient with linezolid induced optic neuropathy.37 should be checked for their mtDNA. It has been reported that patients previously diagnosed with TAA were actually 6 Chloramphenicol is another antibiotic associated misdiagnosed cases of LHON. Treatment of TAA with with mitochondrial optic neuropathy as it too can adequate diet, supplemental vitamins and intramuscular inhibit mitochondrial protein synthesis.38 For similar injections of hydroxycobalamin is often successful. reasons, streptomycin has also been reported to cause mitochondrial optic neuropathy. CEON (Cuban epidemic of optic neuropathy An epidemic of optic neuropathy involving nearly 50,000 (49) As previously noted, ethambutol and other antibiotic-associated people occurred in Cuba in 1992-1993 . Patients were toxicity may act in combination with inherited genetic factors affected with optic neuropathy, sensory and autonomic (figure 1) predisposing to this type of blindness. In particular, peripheral neuropathy, neural deafness, and in a few cases, 50,51 mtDNA haplogroups or specific mtDNA polymophisms may be myelopathy. The most common pattern of symptoms associated with antibiotic-induced optic neuropathy. Soon, it consisted of severe weight loss, fatigue and a subacute may be possible to identify these haplotypes to help predict loss of vision. An objective sign, a wedge defect of the which patients are susceptible to such toxicities. temporal optic disc and the loss of the corresponding PMB.49 Most of the patients reported high consumption of alcohol particularly homemade rum and smoking cigarettes.52 This was associated with severe deficiencies of protein and vitamin intake, in particular of vitamin B12

2012 Annual Meeting Syllabus | 73 and folate. This picture of vitamin deficiencies was further of mitochondrial inner membrane potential, and calcium complicated by small amounts of methanol present in fluxes all converge causing an opening of the mitochondrial homemade rum. It was thought that the Cuban epidemic permeability transition pore (MPTP). Through the MPTP, may have been caused by the chronic accumulation of the pro-apoptotic cytochrome c is released into the formate from methanol metabolism in a population with cytoplasm to initiate the apoptotic cycle.60,61 See figure 2. severe folic acid depletion and the accumulation of cyanide from cigarette smoke.49 This conclusion was supported Acquired, as well as genetic, alterations of mitochondrial by evidence of improvement in visual acuity on prompt function result in vision loss due to optic neuropathy. The optic and daily administration of cyanocobalamin (3mg) and nerve is thus the canary in the coal mine for this type of injury. folate (250 mg) along with dietary supplementation.49,52,53 Clinical similarities of CEON with LHON, TAA and methanol It is unfortunate that patients with toxic or nutritional poisoning have been established.49 However, CEON was not mitochondrial optic neuropathy are at risk for profound associated with mtDNA mutations found in LHON.54 bilateral and irreversible visual loss. It is incumbent for the clinician to be astute to these diseases and especially Thiamine deficiency was not demonstrated in CEON patients in regards to acquired causes, to promptly diagnose and when compared with local controls though this deficiency manage and mitigate the problem. was more prevalent in the geographical regions where the disease had a higher incidence, suggesting it was a surrogate for poor nutrition or part of the underlying mechanism.55

Common pathophysiology: Mitochondrial optic neuropathies, whether inherited or acquired, share impairments in the mitochondrial respiratory chain (OXPHOS) leading to both ATP depletion and increased reactive oxygen species and eventual retinal ganglion cell (RGC) loss (figure 2).56 Why should this mitochondrial insufficiency be so selective for RGCs and their axons that form the optic nerve? Immunohistochemical staining for cytochrome c oxidase and ultrastructural studies have shown a preferential localization of mitochondria to various areas of the optic nerve.4 This is especially the case in the pre-laminar unmyelinated portion of the optic disc as well as under the nodes of Ranvier in the post-laminar portion of the myelinated optic nerve.4,57,58 The non-homogeneous Figure 2. Adapted from JNO: Sadun & Wang, J distribution of mitochondria along the RGC axons parallels Neuroophthalmol, 28(4), 265-268 (2008). the specific energy requirement of these segments; the myelinated posterior portion of these axons have few mitochondria as they are energy efficient from saltatory CME Answers conduction.59 Conversely, the intraocular stretches of the optic nerve are bioenergetically inefficient because they are 1. c unmyelinated and thus remain transparent to light. Because 2. a mitochondrial transport from the soma to the optic nerve terminal is itself a very energy dependent process, energy 3. b depletion will also led to defective mitochondrial transport compounding the metabolic crisis.4 References The mitochondrial respiratory chain is also a major source 1. Mackenzie WA. Practical treatise on diseases of the eye. P835. of reactive oxygen species that chronically increase as London, Longman Reese, et al. 1830. a consequence of genetic or acquired impairments of 2. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol, 17(1), oxidative phosphorylation. Oxidative stress is also harmful 29-32 (2002). to the mtDNA causing the accumulation of multiple 3. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and deletions. Furthermore, lipid peroxidation due to ROS may mitochondrial dysfunction: genetic and acquired optic neuropathies. lead to mitochondrial membrane damage. Neurochem Int, 40(6), 573-584 (2002). 4. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a Ultimately, RGCs may undergo apoptosis. Cytochrome c, the cause of optic neuropathies. Prog Retin Eye Res, 23(1), 53-89 (2004). A phenomenal review of mitochondrial optic neuropathies electron shuttle between complex III and IV, when released from mitochondria is at the center of the apoptotic 5. Wallace DC, Singh G, Lott MT et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science, cascade. Respiratory dysfunction, oxidative stress, loss

74 | North American Neuro-Ophthalmology Society 242(4884), 1427-1430 (1988). 28. Frippiat F, Bergiers C, Michel C, Dujardin JP, Derue G. Severe bilateral optic neuritis associated with prolonged linezolid therapy. J 6. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber’s Antimicrob Chemother, 53(6), 1114-1115 (2004). hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol, 111(11), 1482-1485 (1993). 29. McKinley SH, Foroozan R. Optic neuropathy associated with linezolid treatment. J Neuroophthalmol, 25(1), 18-21 (2005). 7. Sadun AA, Wang MY. Ethambutol optic neuropathy: how we can prevent 100,000 new cases of blindness each year. J 30. Saijo T, Hayashi K, Yamada H, Wakakura M. Linezolid-induced optic Neuroophthalmol, 28(4), 265-268 (2008). neuropathy. Am J Ophthalmol, 139(6), 1114-1116 (2005). 8. Lessell S. Nutritional amblyopia. J Neuroophthalmol, 18(2), 106-111 31. Kulkarni K, Del Priore LV. Linezolid induced toxic optic neuropathy. Br (1998). J Ophthalmol, 89(12), 1664-1665 (2005). 9. Milea D. [Nutritional, oxict and drug-induced optic neuropathies]. 32. Rucker JC, Hamilton SR, Bardenstein D, Isada CM, Lee MS. Linezolid- Rev Prat, 51(20), 2215-2219 (2001). associated toxic optic neuropathy. Neurology, 66(4), 595-598 (2006). 10. Krivosic V, Vignal-Clermont C, Blain P, Gaudric A. Bilateral optic 33. Joshi L, Taylor SR, Large O, Yacoub S, Lightman S. A case of optic neuropathy in acute methanol intoxication. A case report. J Fr neuropathy after short-term linezolid use in a patient with acute Ophtalmol, 24(5), 522-526 (2001). lymphocytic leukemia. Clin Infect Dis, 48(7), e73-74 (2009). 11. Woon C, Tang RA, Pardo G. Nutrition and optic nerve disease. Semin 34. Azamfirei L, Copotoiu SM, Branzaniuc K, Szederjesi J, Copotoiu R, Ophthalmol, 10(3), 195-202 (1995). Berteanu C. Complete blindness after optic neuropathy induced by short-term linezolid treatment in a patient suffering from muscle 12. Sadun AA. Mitochondrial optic neuropathies. J Neurol Neurosurg dystrophy. Pharmacoepidemiol Drug Saf, 16(4), 402-404 (2007). Psychiatry, 72(4), 423-425 (2002). 35. Javaheri M, Khurana RN, O’Hearn T M, Lai MM, Sadun AA. 13. Lee EJ, Kim SJ, Choung HK, Kim JH, Yu YS. Incidence and clinical Linezolid-induced optic neuropathy: a mitochondrial disorder? Br J features of ethambutol-induced optic neuropathy in Korea. J Ophthalmol, 91(1), 111-115 (2007). Neuroophthalmol, 28(4), 269-277 (2008). 36. Perry CM, Jarvis B. Linezolid: a review of its use in the management 14. Talbert Estlin KA, Sadun AA. Risk factors for ethambutol optic toxicity. of serious gram-positive infections. Drugs, 61(4), 525-551 (2001). Int Ophthalmol, (2009). 37. De Vriese AS, Coster RV, Smet J et al. Linezolid-induced inhibition of 15. Hasenbosch RE, Alffenaar JW, Koopmans SA, Kosterink JG, van der mitochondrial protein synthesis. Clin Infect Dis, 42(8), 1111-1117 (2006). Werf TS, van Altena R. Ethambutol-induced optical neuropathy: risk of overdosing in obese subjects. Int J Tuberc Lung Dis, 12(8), 967- 38. Venegas-Francke P, Fruns-Quintana M, Oporto-Caroca M. [Bilateral 971 (2008). optic neuritis caused by chloramphenicol]. Rev Neurol, 31(7), 699- 700 (2000). 16. Kumar A, Sandramouli S, Verma L, Tewari HK, Khosla PK. Ocular ethambutol toxicity: is it reversible? J Clin Neuroophthalmol, 13(1), 39. Hsu CT, Miller NR, Wray ML. Optic neuropathy from folic acid deficiency 15-17 (1993). without alcohol abuse. Ophthalmologica, 216(1), 65-67 (2002). 17. Tsai RK, Lee YH. Reversibility of ethambutol optic neuropathy. J Ocul 40. Chavala SH, Kosmorsky GS, Lee MK, Lee MS. Optic neuropathy in Pharmacol Ther, 13(5), 473-477 (1997). vitamin B12 deficiency. Eur J Intern Med, 16(6), 447-448 (2005). 18. Citron KM. Ethambutol: a review with special reference to ocular 41. Larner AJ. Visual failure caused by vitamin B12 deficiency optic toxicity. Tubercle, 50, Suppl:32-36 (1969). neuropathy. 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Lopez-Hernandez N, Garcia-Escriva A, Pampliega-Perez A, Alvarez- induced optic neuropathy. Br J Ophthalmol, 91(6), 839-840 (2007). Sauco M, Martin-Estefania C, Asensio-Asensio M. [Peripheral and 22. Melamud A, Kosmorsky GS, Lee MS. Ocular ethambutol toxicity. optical myeloneuropathy in a folic acid deficient alcoholic patient]. Mayo Clin Proc, 78(11), 1409-1411 (2003). Rev Neurol, 37(8), 726-729 (2003). 23. Ikeda A, Ikeda T, Ikeda N, Kawakami Y, Mimura O. Leber’s hereditary 46. KoffmanBM, Greenfield LJ, Ali, II, Pirzada NA. Neurologic complications optic neuropathy precipitated by ethambutol. Jpn J Ophthalmol, after surgery for obesity. Muscle Nerve, 33(2), 166-176 (2006). 50(3), 280-283 (2006). 47. Pott JW, Wong KH. Leber’s hereditary optic neuropathy and vitamin 24. Kozak SF, Inderlied CB, Hsu HY, Heller KB, Sadun AA. The role of B12 deficiency. Graefes Arch Clin Exp Ophthalmol, 244(10), 1357- copper on ethambutol’s antimicrobial action and implications for 1359 (2006). ethambutol-induced optic neuropathy. Diagn Microbiol Infect Dis, 48. Rizzo JF, 3rd. Adenosine triphosphate deficiency: a genre of optic 30(2), 83-87 (1998). neuropathy. Neurology, 45(1), 11-16 (1995). 25. Chung H, Yoon YH, Hwang JJ, Cho KS, Koh JY, Kim JG. Ethambutol- 49. Sadun A. Acquired mitochondrial impairment as a cause of optic induced toxicity is mediated by zinc and lysosomal membrane nerve disease. Trans Am Ophthalmol Soc, 96, 881-923 (1998). permeabilization in cultured retinal cells. Toxicol Appl Pharmacol, 235(2), 163-170 (2009). 50. *Roman GC. An epidemic in Cuba of optic neuropathy, sensorineural deafness, peripheral sensory neuropathy and dorsolateral 26. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust, myeloneuropathy. J Neurol Sci, 127(1), 11-28 (1994). 177(6), 332 (2002). 51. 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2012 Annual Meeting Syllabus | 75 52. Sadun AA, Martone JF. Cuba: response of medical science to a crisis of 57. Andrews RM, Griffiths PG, Johnson MA, Turnbull DM. Histochemical optic and peripheral neuropathy. Int Ophthalmol, 18(6), 373-378 (1994). localisation of mitochondrial enzyme activity in human optic nerve and retina. Br J Ophthalmol, 83(2), 231-235 (1999). 53. Sadun AA, Martone JF, Muci-Mendoza R et al. Epidemic optic neuropathy in Cuba. Eye findings. Arch Ophthalmol, 112(5), 691-699 (1994). 58. Bristow EA, Griffiths PG, Andrews RM, Johnson MA, Turnbull DM. The distribution of mitochondrial activity in relation to optic nerve 54. Newman NJ, Torroni A, Brown MD, Lott MT, Fernandez MM, structure. Arch Ophthalmol, 120(6), 791-796 (2002). Wallace DC. Epidemic neuropathy in Cuba not associated with mitochondrial DNA mutations found in Leber’s hereditary optic 59. Waxman SG. Prerequisites for conduction in demyelinated fibers. neuropathy patients. Cuba Neuropathy Field Investigation Team. Am Neurology, 28(9 Pt 2), 27-33 (1978). J Ophthalmol, 118(2), 158-168 (1994). 60. Zoratti M, Szabo I. The mitochondrial permeability transition. 55. Macias-Matos C, Rodriguez-Ojea A, Chi N, Jimenez S, Zulueta D, Bates Biochim Biophys Acta, 1241(2), 139-176 (1995). CJ. Biochemical evidence of thiamine depletion during the Cuban 61. Green DR, Reed JC. Mitochondria and apoptosis. Science, 281(5381), neuropathy epidemic, 1992-1993. Am J Clin Nutr, 64(3), 347-353 (1996). 1309-1312 (1998). 56. Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. Retinal ganglion cells neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta, (2009).

76 | North American Neuro-Ophthalmology Society Syndromic Mitochondrial Optic Neuropathies

Nancy J. Newman, MD Emory University School of Medicine Atlanta, GA

Learning Objectives Syndromic optic neuropathies with optic neuropathy as a defining characteristic 1. Know which syndromic neurodegenerative disorders manifest optic neuropathy. Autosomal dominant optic atrophy and 2. Appreciate the role of mitochondrial dysfunction in sensorineural hearing loss many of the syndromic disorders which manifest optic Several pedigrees with autosomal dominant optic atrophy neuropathy. and hearing loss have been described. In many of these pedigrees, there are no other systemic or neurologic 3. Know some of the gene defects, both in the nuclear abnormalities. Some, but not all of these pedigrees have and mitochondrial DNA, which are associated with now been shown to harbor OPA1 mutations that in other syndromic mitochondrial optic neuropathies. pedigrees cause only optic neuropathy (1-4). In one Italian family, a new locus on chromosome 16 (16q21-q22) was designated OPA8, and preliminary studies suggest its CME Questions pathogenesis may also be via mitochondrial dysfunction (5). 1. True or False? Syndromic mitochondrial optic neuropathies are all caused by defects in mitochondrial In a Dutch pedigree with DOA and deafness, OPA1 mutations DNA. were excluded, but a novel missense mutation was found in the WFS1 gene on chromosome 4 (4p16.1), a common 2. True or False? All cases of Wolfram syndrome are locus for mutations typically causing the autosomal related to a single gene defect in the WFS1 gene on recessive DIDMOAD or Wolfram syndrome, a syndromic chromosome 4. optic neuropathy with diabetes mellitus, diabetes insipidus 3. True or False? Optic atrophy is uncommon in and hearing loss (see below) (6). Similarly, in another DOA Friedreich’s ataxia. pedigree with hearing impairment and impaired glucose regulation, mutation analysis excluded mutations within the OPA1, OPA3, OPA4 and OPA5 genes, but identified a novel Keywords missense mutation in the WFS1 (Wolfram) gene (7). 1. Optic Neuropathy In other pedigrees with DOA and deafness, there may be 2. Mitochondrial Disease associated ataxia, limb weakness or polyneuropathy. The hearing loss in these pedigrees may be severe at birth 3. Wolfram Syndrome with poor speech development, or may be only moderate 4. Friedreich Ataxia and slowly progressive. The acronym CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural 5. Charcot-Marie-Tooth deafness) has been suggested, but is as yet genetically undefined (1,4). “DOA Plus” with OPA1 mutations (8) may ultimately account for many of these more complicated Introduction syndromic pedigrees, but clearly the syndromic combination In some of the hereditary optic neuropathies, optic of DOA and hearing loss is genetically heterogeneous. nerve dysfunction is typically isolated. In others, various neurologic and systemic abnormalities are regularly Autosomal dominant optic atrophy with observed. Additionally, inherited diseases with primarily premature cataracts neurologic or systemic manifestations, such as the multisystem Two independent French families manifest optic atrophy degenerations, can include optic atrophy. Whether inherited and premature cataract in an autosomal-dominant mode in Mendelian fashion or as a result of mitochondrial DNA point mutations with maternal transmission, many of these of inheritance. Mutations in the OPA1 gene were excluded disorders have been linked to a final common pathway and pathogenic mutations were found in the OPA3 gene on of mitochondrial dysfunction, suggesting that optic nerve chromosome 19 (19q13.2-q13.3), a locus for mutations which function is particularly susceptible to perturbations of typically cause Costeff syndrome, an autosomal recessively- mitochondrial physiology (1-4). inherited syndromic optic neuropathy (see below). Screening

2012 Annual Meeting Syllabus | 77 for OPA3 mutations as a cause of monosymptomatic DOA Linkage analysis in several families has shown localization of a cases in multiple other pedigrees has failed to identify any Wolfram gene to chromosome 4 (4p16.1). The gene responsible pathogenic OPA3 variants, suggesting that OPA3 mutations as at this locus has been designated WFS1, in which multiple a cause of DOA are likely very rare (9). point mutations and deletions have been identified. The gene product, wolframin, is an endoplasmic reticulum protein Autosomal recessive optic atrophy with which plays a role in the regulation of intracellular calcium progressive neurodegeneration and Type (11). A second causative Wolfram gene on the other arm of III 3-methylglutaconic aciduria (Costeff chromosome 4 (4q22-24) has been identified and designated syndrome) CISD2 in consanguineous Jordanian families (12). These patients In this autosomal recessive syndrome most commonly seen show additional symptoms of bleeding tendency and peptic in Iraqi Jewish pedigrees, severe optic atrophy is associated ulcer disease. Interestingly, knockout of the CISD2 gene in with extrapyramidal signs, cognitive impairment, increased mice results in a Wolfram type syndrome associated with urinary levels of 3-methylglutaconic acid, and elevated mitochondrially-mediated premature aging. Indeed, many of plasma levels of 3-methylglutaric acid. The causative gene the associated abnormalities reported in Wolfram syndrome is located on chromosome 19 (19q13.2-q13.3), and has are commonly encountered in patients with presumed been designated OPA3 (2,3). The OPA3 gene product localizes mitochondrial diseases, especially those patients with the to the mitochondrial membrane and has an important role chronic progressive external ophthalmoplegia syndromes. This in mitochondrial fission (2). has led to speculation that the Wolfram phenotype may be nonspecific and reflect a wide variety of underlying genetic Autosomal recessive optic atrophy defects in either the nuclear or mitochondrial genomes, with with juvenile diabetes mellitus, diabetes a final common pathway of mitochondrial dysfunction (2-4). insipidus, and hearing loss (Wolfram Indeed, most cases of Wolfram have been classified as sporadic syndrome, DIDMOAD) or recessively inherited, the latter usually concluded from sibling The hallmark of this syndrome is the association of juvenile expression (which is now known to also be consistent with diabetes mellitus and progressive visual loss with optic maternal transmission). atrophy, almost always associated with diabetes insipidus, neurosensory hearing loss, or both (hence, the eponym Spastic paraplegia, optic atrophy, and DIDMOAD for diabetes insipidus, diabetes mellitus, optic neuropathy (SPOAN syndrome) atrophy, and deafness) (3,4,10). Diabetes mellitus usually develops In a large inbred Brazilian family, an autosomal recessive within the first or second decade of life and usually precedes neurodegenerative disorder was clinically defined by the development of optic atrophy. In several cases, however, nonprogressive congenital optic atrophy; infantile-onset visual loss with optic atrophy is thefi rst sign of the syndrome. spastic paraplegia; childhood-onset of progressive motor In the early stages, visual acuity may be normal despite mild and sensory axonal neuropathy; dysarthria starting in the third decade of life; exaggerated acoustic startle response; dyschromatopsia and optic atrophy. In later stages, visual loss and progressive joint contractures and spine deformities (13). becomes severe. Visual fields have shown both generalized Linkage is to chromosome 11q13, but the responsible gene constriction and central scotomas. Optic atrophy is uniformly has not yet been detected. severe, and there may be mild to moderate cupping of the disc. Both hearing loss and diabetes insipidus begin in the first Congenital cerebellar ataxia, mental or second decade of life and may be quite severe. Atonia of retardation, optic atrophy, and skin the efferent urinary tract is present in half of patients and is abnormalities (CAMOS) associated with recurrent urinary tract infections, neurogenic In a large inbred Lebaneze Druze family, non-progressive incontinence, and even fatal complications. Other systemic autosomal recessive congenital ataxia associated with and neurologic abnormalities include ataxia, axial rigidity, optic atrophy, severe mental retardation, and structural seizures, startle myoclonus, tremor, gastrointestinal dysmotility, skin abnormalities was linked to a locus on chromosome vestibular malfunction, central apnea, neurogenic upper airway 15 (15q24-q26), but the responsible gene has not yet been collapse, ptosis, cataracts, pigmentary retinopathy, iritis, lacrimal detected (14). hyposecretion, Adie’s pupil, ophthalmoplegia, convergence insufficiency, vertical gaze palsy, nystagmus, mental retardation, Deafness, dystonia, and optic neuropathy psychiatric abnormalities, short stature, primary gonadal (DDON, Mohr-Tranebjaerg syndrome) atrophy, other endocrine abnormalities, anosmia, megaloblastic In this X-linked disorder, sensorineural deafness, dystonia and sideroblastic anemia, abnormal electroretinography, and atxia present in late childhood, followed by optic and elevated CSF protein. Neuroimaging and pathology atrophy by age 20, and cognitive decline and psychiatric in some patients reveal widespread atrophic changes and manifestations before age 50 (2). The visual prognosis malformations of cortical development, and suggest a diffuse is poor with most patients legally blind by age 40. The neurodegenerative disorder, with particular involvement of the disorder is caused by mutations in the TIMM8A gene on midbrain and pons. When the syndrome is accompanied by the X chromosome (Xq22) whose gene product localizes anemia, treatment with thiamine may ameliorate the anemia to the mitochondrial intermembrane space. Mitochondrial and decrease the insulin requirement. biochemical dysfunction has been demonstrated. 78 | North American Neuro-Ophthalmology Society Complicated hereditary infantile optic Spinocerebellar ataxias atrophy (Behr syndrome) The spinocerebellar ataxias, previously called The designation of Behr syndrome reflects optic atrophy olivopontocerebellar atrophy (OPCA) and autosomal beginning in early childhood, associated with variable dominant cerebellar ataxia, include a group of pyramidal tract signs, ataxia, mental retardation, urinary dominantly-inherited ataxic disorders in which the ataxia incontinence, and pes cavus. Both sexes are affected and the is related more to degeneration of the cerebellum rather syndrome is usually inherited as an autosomal recessive trait. than the spinal cord (1,15,16). As of 2010, there were at Visual loss usually manifests before age 10 years, is moderate least 29 different genetic loci for the SCAs (SCA1 through to severe, and is frequently accompanied by nystagmus. In SCA31). The combination of SCA1 (chromosome 6p), most cases, the abnormalities do not progress after childhood. SCA2 (chromosome 12q), SCA3 (chromosome 14q), SCA6 Neuroimaging may demonstrate diffuse symmetric white (chromosome 19p), and SCA7 (chromosome 3p) comprises matter abnormalities. Clinicalfi ndings in some patients with approximately 80% of the autosomal dominant ataxias. Behr syndrome may be similar to those in cases of hereditary Most of the SCAs are caused by mutations involving the ataxia. Behr syndrome is likely heterogeneous, reflecting expansion of a CAG trinucleotide repeat in the protein- (1) different etiologic and genetic factors . coding sequences of specific genes. As with other diseases that involve abnormal repeats, the expanded regions can HEREDITARY ATAXIAS become larger with each successive generation, resulting The hereditary ataxias comprise a group of chronic in a younger age of onset in each generation, so-called progressive neurodegenerative conditions involving anticipation. Clinically, the SCAs are characterized by signs the cerebellum and its connections, and are sometimes and symptoms attributable to cerebellar degeneration associated with optic atrophy. A genomic classification and sometimes other neurologic dysfunction secondary by chromosomal location is available for many of these to neuronal loss. Loss of vision is usually mild but may disorders and the abnormal gene products involved be a prominent symptom, occurring in association are under investigation, many of them localized to the (1-3,15,16) with constricted visual fields and diffuse optic atrophy. mitochondria . However, it is not clear in some cases whether the primary process is retinal with secondary optic atrophy Friedreich ataxia or primarily involving the optic nerve. SCA7 is specifically Friedreich ataxia is inherited in an autosomal recessive associated with retinal degeneration, whereas optic manner, and the gene defect has been localized to the neuropathy is usually associated with SCA1 or SCA3. (15) proximal long arm of chromosome 9 (9q13–q21). The majority of cases are homozygous for a GAA trinucleotide HEREDITARY POLYNEUROPATHIES expansion in a gene designated FRDA/X25 that codes for a protein called frataxin, which regulates iron levels in Charcot-Marie-Tooth disease the mitochondria (2,3,16). The disease usually begins during Charcot-Marie-Tooth disease (CMT) encompasses a group the second decade of life and includes progressive ataxia, of heredofamilial disorders characterized by progressive dysarthria, loss of joint position and vibratory sensation, muscular weakness and atrophy that begins during the absent lower extremity tendon reflexes, and extensor plantar first two decades of life (1-4). This group of hereditary responses. Scoliosis, foot deformity, diabetes mellitus, polyneuropathies accounts for 90% of all hereditary and cardiac disease are common. Other manifestations neuropathies, with a prevalence of at least one in 2500 include pes cavus, distal wasting, deafness, nystagmus, individuals. Most forms of CMT begin between the ages eye movement abnormalities consistent with abnormal cerebellar function, and optic atrophy. The course is of 2 and 15 years, and the first signs may be pes cavus, progressive, with most patients unable to walk within 15 foot deformities, or scoliosis. There is slowly progressive years of onset, and death from infectious or cardiac causes weakness and wasting, first of the feet and legs, and then usually in the fourth or fifth decade. Although optic atrophy of the hands. Motor symptoms predominate over sensory is a common feature of Friedreich ataxia, most patients are abnormalities. As of 2011, causative mutations for the visually asymptomatic, and severe visual loss occurs only hereditary peripheral neuropathies have been identified (2,3) rarely. In a study of 26 patients with genetically-confirmed in more than 30 different genes . Numerous patients Friedreich ataxia, all patients were found to have an with CMT and optic atrophy have been reported. Taking underlying optic neuropathy, although 21 were completely into account both electrophysiologic and clinical data, up visually asymptomatic (17). Three symptomatic patients to 75% of patients with CMT have some afferent visual had slowly progressive central visual dysfunction, but two pathway dysfunction, demonstrating that subclinical patients presented with the sudden onset of bilateral optic neuropathy may occur in a high proportion of central scotomas, resembling LHON. A condition resembling patients with CMT. A subtype of CMT, hereditary motor Friedreich ataxia associated with decreased vitamin E and sensory neuropathy type VI (HMSN VI), is defined levels has been localized to chromosome 8. Vitamin E by the combination of axonal peripheral neuropathy and supplementation of these patients may be fief cacious early optic atrophy, and has both autosomal dominant and in the course of the disease. autosomal recessive forms of inheritance (1-4). The optic

2012 Annual Meeting Syllabus | 79 atrophy typically develops in late adolescence, a decade Other presumed mitochondrial disorders of both nuclear and or more after the peripheral neuropathy, with a subacute mitochondrial genomic origins may manifest optic atrophy as a visual decline, usually to below 20/400. As in LHON, a secondary clinical feature, often a variable manifestation of the subset of these patients may recover vision years after disease (1-4). Examples include cases of MELAS (mitochondrial the onset of optic neuropathy. The autosomal dominant myopathy, encephalopathy, lactic acidosis and stroke-like form of HMSN VI is caused by a mutation in the nuclear episodes, DCMA (dilated cardiomyopathy with ataxia), mitofusin-2 gene, and constitutes a subclass of CMT2A, the MERRF (myoclonic epilepsy and ragged red fibers), MNGIE most common autosomal dominant form of axonal CMT (mitochondrial neurogastrointestinal encephalomyopathy), (18). The mitofusin-2 protein is GTPase localized to the and chronic progressive external ophthalmoplegia, both with mitochondrial outer membrane, and shares many structural and without the full Kearns-Sayre phenotype. The other, and functional similarities with the OPA1 protein in DOA (2,3). more constant, phenotypic characteristics of all of these mitochondrial disorders usually distinguish them from diseases Familial dysautonomia (Riley-Day syndrome) such as LHON in which visual loss from optic nerve dysfunction Familial dysautonomia (Riley-Day syndrome) is an autosomal is the primary manifestation of the disorder (1-4). recessive disease that almost exclusively affects Ashkenazi Jews. Abnormalities of the peripheral nervous system Other familial-storage diseases and cause the clinical manifestations of sensory and autonomic cerebral degenerations of childhood dysfunction. Optic atrophy is very common in patients with associated with optic neuropathies familial dysautonomia, usually noted after thefi rst decade of life (1,19). In one recent study, optic nerve damage, especially Mucopolysaccharidoses (MPS IH, IS, IHS, IIA, IIB, IIIA, in the papillomacular bundle, was noted in all eyes of the 16 IIIB, IV, VI) patients examined, aged 12 to 61 years (19). However, in many Lipidoses (infantile and juvenile GM1-1 and GM1-2, cases, early mortality from the disease probably precludes the GM2, infantile Niemann-Pick disease) later development of optic atrophy (1,19). Metachromatic leukodystrophy Krabbe’s disease HEREDITARY SPASTIC PARAPLEGIAS Adrenoleukodystrophy The hereditary spastic paraplegias (Strumpell-Lorrain Zellweger syndrome disease) are inherited disorders characterized by progressive Pelizaeus-Merzbacher disease spasticity of the lower limbs with degeneration of the Infantile neuroaxonal dystrophy corticospinal system. The prevalence of these disorders is Hallervorden-Spatz disease about 3-10 per 100,000. As of 2011, there were at least Menkes syndrome 41 mapped loci for the hereditary spastic paraplegias, and Canavan’s disease 17 identified genes (2,3). Hereditary spastic paraplegia is Cockayne syndrome classified as pure, if spasticity is the only manifestation, or COFS as complicated if other features, such as optic atrophy, are Allgrove syndrome (“4A”) present. Complicated hereditary spastic paraplegia with Smith-Lemli-Opitz syndrome optic atrophy may result from several different nuclear GAPO syndrome DNA mutations. The SPG7 gene, found on chromosome 16 PEHO syndrome (16q24.3), encodes for a mitochondrial metalloproteinase, Blepharophimosis-mental retardation syndromes (BMR) paraplegin (20). Mutations in the SPG7 gene have been Cerebral palsy identified in an autosomal recessive form of hereditary MPS IH: Hurler; MPS IS: Sheie; MPS HIS: Hurler-Sheie; spastic paraplegia in which some patients have bilateral optic MPS IIA and IIB: Hunter; MPS IIIA and IIIB: Sanfilippo; atrophy as a prominent manifestation of their disorder (2,3). MPS IV: Morquio; MPS VI: Maroteaux-Lamy. PRIMARY MITOCHONDRIAL DISORDERS GM1-Gangliosidoses: GM1-1 and GM1-2. The subacute necrotizing encephalomyelopathy of Leigh GM2-Gangliosidoses: Tay-Sachs disease, Sandhoff results from multiple different biochemical defects that all disease, late infantile, juvenile and adult GM2- impair cerebral oxidative metabolism. (1-4). This disorder may Gangliosidose be inherited in an autosomal recessive, X-linked, or maternal COFS: Cerebro-oculo-facio-skeletal syndrome pattern, depending on the genetic defect. The onset of “4A”: Alacrine, achalasia, autonomic disturbance, and symptoms is typically between the ages of 2 months and 6 ACTH insensitivity. years, and consists of progressive deterioration of brainstem GAPO: Growth retardation, alopecia, pseudoanodontia, functions, ataxia, seizures, peripheral neuropathy, intellectual and optic atrophy. deterioration, impaired hearing, and poor vision. Visual loss PEHO: Progressive encephalopathy with edema, may be secondary to optic atrophy or retinal degeneration. The hypsarrythmia, and optic atrophy. syndrome of Leigh is likely a nonspecific phenotypic response to [Adapted from Newman NJ, Biousse V. Hereditary optic neuropathies. certain abnormalities of mitochondrial energy production. In: Taylor D and Hoyt CS, eds. Pediatric Ophthalmology. Elsevier Saunders. 4th ed. (in press).

80 | North American Neuro-Ophthalmology Society CME Answers 10. Chaussenot A, Bannwarth S, Rouzier C, et al. Neurologic features and genotype-phenotype correlation in Wolfram syndrome. Ann Neurol 1. false 2011;69:501-8. 2. false 11. Takei D, Ishihara H, Yamaguchi S, et al. WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. FEBS Lett 3. false 2006;580:5635-40. 12. Ajlouni K, Jarrah N, El-Zaheri M, et al. Wolfram syndrome: identification of a phenotypic and genotypic variant from Jordan. Am References J Med Genet 2002;115:61-5. 1. Newman NJ. Hereditary optic neuropathies. In: Miller NR, Newman NJ, 13. Macedo-Souza LI, Kok F, Santos S, et al. Spastic paraplegia, optic Biousse V, et al. editors. Walsh and Hoyt’s Clinical Neuro-ophthalmology. atrophy, and neuropathy: new observations, locus refinement, and 6th ed. Baltimore, MD: Williams & Wilkins. 2005, Vol I, pps 465-501. exclusion of candidate genes. Ann Hum Genet 2009;73:382-7. 2. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic 14. Delague V, Bareil C, Bouvagnet P, et al A new autosomal recessive neuropathies – disease mechanisms and therapeutic strategies. Prog non-progressive congenital cerebellar ataxia associated with mental Retin Eye Res 2011;30:81-114. retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze 3. Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of family. Neurogenetics 2002;4:23-7. mitochondrial disease. Surv Ophthalmol 2010;55:299-2010. 15. Pula JH, Gomez CM, Kattah JC. Ophthalmologic features of 4. Newman NJ, Biousse V. Hereditary optic neuropathies. In: Taylor D the common spinocerebellar ataxias. Curr Opin Ophthalmol and Hoyt CS, eds. Pediatric Ophthalmology. Elsevier Saunders. 4th 2010;21:447-453. ed. (in press). 16. Lynch Dr, Farmer JF. Practical approaches to neurogenetic disease. J 5. Carelli V, Schimpf S, Fuhrmann N, et al. A clinically complex form of Neuro-ophthalmol 2002; 22: 297–304. dominant optic atrophy (OPA8) maps on chromosome 16. Hum Mol Genet 2011;20:1893-1905. 17. Fortuna F, Barboni P, Liguori R, et al. Visual system involvement in patients with Friedreich’s ataxia. Brain 2009;132:116-23. 6. Hogewind BF, Pennings RJ, Hol FA, et al. Autosomal dominant optic neuropathy and sensorineural hearing loss associated with a novel 18. Zuchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy with mutation of WFS1. Mol Vis 2010;16:26-35. optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006;59:276-81. 7. Eiberg H, Hansen L, Kjer B, et al. Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation 19. Mendoza-Santiesteban CE, Hedges TR, Norcliffe-Kaufmann L, et al. caused by a missense mutation in the WFS1 gene. J Med Genet Clinical neuro-ophthalmologic findings in familial dysautonomia. J 2006;43:435-40. Neuro-ophthalmol (in press) 8. Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system 20. Casari G, de Fusco M, Ciarmatori S, et al. Spastic paraplegia and neurological disease is common in patients with OPA1 mutations. OXPHOS impairment caused by mutations in paraplegin, a nuclear- Brain 2010;133:771-786. encoded mitochondrial metalloproteinase. Cell 1998;93:973-83. 9. Yu-Wai-Man P, Shankar SP, Biousse V, et al. Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies. Ophthalmology 2011;118:558-63.

2012 Annual Meeting Syllabus | 81 82 | North American Neuro-Ophthalmology Society PLATFORM PRESENTATION

LEBER HEREDITARY OPTIC NEUROPATHY G11778A GENE THERAPY CLINICAL TRIAL: SERIAL PRETREATMENT EVALUATION FROM BASELINE TO TWO YEARS

Byron Lam, John Guy, Fawzi Abukhalil, Feuer William, Potyra Aroucha, Alexis Morante

Bascom Palmer Eye Institute, Miami, FL, USA

Introduction: The preparatory phase of the LHON gene therapy trial aims to characterize affected patients and carriers for the planned gene therapy study that will utilize “allotopic expression,” delivering copies of normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector. The normal ND4 protein expressed in the cytoplasm is then imported into the mitochondria.

Methods: LHON patients with acute or chronic visual loss and their asymptomatic maternally-related relatives undergo ocular examination, visual fields, pattern electroretinogram (PERG), Cirrus OCT and fundus photography every 6 months. Blood samples for phosphorylated neurofilament heavy chain (NfH) quantitation of axonal loss are obtained.

Results: 95 persons with G11778A have been recruited and more are needed. The two-year serial evaluations of 22 patients and 15 asymptomatic carriers are available. Mean two year LHON ETDRS acuity, 13.6, was within one letter of baseline). HVF mean defect (MD), –24.3, was within one dB of baseline. PNF-H was unchanged at year one with year two results pending (0.44 ng/ml one year, 0.41 baseline). Average RNFL was 55.2 µm year two, 55.1 µm year one, 64.2 µm baseline. PERG amplitudes, 0.51 µV, were within 0.05 µV of baseline. In carriers, acuity, 86.3, was within one letter of baseline. HVF MD, -1.8, was within one dB of baseline. PNF-H levels were pending year two, 0.67 ng/ml year one, 0.59 baseline (p=0.13). PERG was 0.72 µV year two, 0.77 µV year one, 0.99 µV baseline (p=0.034).

Conclusion: For affected LHON patients, clinical measures were stable through two years, and spontaneous improvement was rare (<5%), thus making gene therapy improvements with injection of AAV containing a normal ND4 easy to detect. For carriers, the PERG amplitudes continue to decrease in year two suggesting subclinical retinal ganglion cell dysfunction. Contact information for patient recruitment is available by googling “BPEI LHON”.

References: Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J. Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Arch Ophthalmol 2010;128:1129-1135.

Financial Disclosure: The authors had no disclosures.

2012 Annual Meeting Syllabus | 83 84 | North American Neuro-Ophthalmology Society HIV-Associated Optic Neuropathy Marie D. Acierno, MD LSU Health Sciences Center New Orleans, Baton Rouge, LA

Learning Objectives effects. The primary complications of HIV, encountered 1. HIV itself may be a cause of optic neuropathy in our neuro-ophthalmic practices, are retinopathy, optic neuropathy, and retrochiasmal visual field defects 3. 2. There is evidence to suggest direct degeneration of ganglion cell axons in the optic nerve primarily due to HIV infection HIV infection associated with optic neuropathy caused by secondary infections: 3. Human immunodeficiency virus infection should Most neuro-ophthalmologic manifestions of HIV infections be considered in the differential diagnosis of acute are secondary in nature. Patients with HIV infection who optic neuritis. present with unilateral or bilateral optic neuropathy will usually undergo an extensive work-up to rule out the presence of opportunistic infections. CME Questions 1. Does direct degeneration of ganglion cell axons in the Several of the herpesviruses, HSV, VZV, and CMV, may optic nerve of HIV infected patients suggest that there produce a severe retinitis or chorioretinitis as well as may be an AIDS associated primary optic neuropathy? have optic nerve involvement in HIV infected persons. In many, the process may be unilateral or bilateral. VZV may 2. Which antiretroviral agents used to treat HIV patients produce a non-specific retinal vasculitis or acute retinal have been associated with mitochondrial toxicity? necrosis (ARN) as the initial manifestation. There may be an associated anterior chamber reaction, vitritis, and papillits. 3. Are most cases of optic neuropathy in patients with HIV Patients with cytomegalovirus (CMV) may have severe infection considered to be a primary or secondary optic retinitis associated with optic disc swelling and peripapillary neuropathy? hemorrhages. Optic neuritis may result from contiguous spread of peripapillary retinitis to the optic nerve or it may occur as a primary process without associated retinits. 3,4. Keywords 1. HIV Optic Neuropathy Some HIV patients may have papilledema as a result of elevated intracranial pressure from a CNS infection or 2. HIV Infection tumor. Often there is meningeal inflammation with or 3. Primary HIV Infection without direct optic nerve invasion. AIDS patients may have involvement of the optic nerve with visual loss due 4. Secondary HIV Infection to cryptococcal meningitis. Most of these patients have chronic papilledema at the time vision becomes affected, 5. Axonal Degeneration although some initially have normal-appearing optic discs.

Syphilis can cause a neuroretinitis, optic neuritis and perineuritis Introduction in AIDS patients. Konjevic-Pernat et al report a case of bilateral The differential diagnosis of visual loss in patients optic neuritis as the initial manifestation of neurosyphilis in infected with the human immunodeficiency virus (HIV) is an HIV-positive patient. In this report, the patient presents rather extensive. There is a spectrum of ophthalmologic with bilateral decreased visual acuity. His Treponema pallidum findings in HIV infection that affects the anterior segment hemagglutination reactivity test was highly reactive and he was of the eye to the visual pathways. Most cases of optic HIV positive; therefore, he was given a working diagnosis of neuropathy in patients with HIV infection are associated optic neuritis and started on pulse corticosteroid therapy. This with opportunistic infections such as syphilis, cryptococcus, case was the first report of optic neuritis as the first and only 5 herpes zoster, toxoplasmosis, cytomegalovirus, manifestation of HIV and syphilis co-infection histoplasmosis, and tuberculosis 1,2. Ocular, orbital, and neuro-ophthalmologic complications can also occur as Some HIV infected patients may develop an optic neuritis a direct effect of HIV infection or from drug-related side secondary to the immune reaction of tuberculosis or to tuberculosis itself. The optic neuritis in HIV infection has

2012 Annual Meeting Syllabus | 85 been associated with histoplasmosis. There is a biopsy- observations suggest that AIDS-associated optic neuropathy proven case report of optic neuritis from sub-acute is a distinct primary optic nerve degeneration that is disseminated histoplamosis infection in a single patient with unrelated to secondary retinal or optic nerve infections; AIDS. Open biopsy of the optic nerve sheath and orbital however, the optic nerve degeneration may not be caused fat demonstrated H. capsulatum 6. Neuroretinits, optic disc by direct HIV viral infection of axons, but by HIV-infected edema with the development of a macular star composed of mononuclear phagocyte series cells and glial cells 10. lipid, may occur in patients with HIV infection. The underlying cause may be due to syphilis, Toxoplamosis or Bartonella Other case reports suggest HIV virus is a direct cause of the henselae 3. Toxoplasmic papillitis has occurred as the initial optic neuropathy. In 1992, Newman and Lessell reported manifestation of AIDS 7 or there may be a toxoplasma two HIV-positive men with bilateral retrobulbar optic retinochoroiditis and optic neuritis in AIDS patients 8. neuropathies. In both patients, compressive, infectious, and infiltrative processes were extensively ruled out 11. HIV virus Primary HIV-Associated Optic Neuropathy was postulated as the causative etiology. In 1993, Sweeney Although HIV may be a cause of optic neuropathy, there is et al reported another case of a patient with HIV-1 infection no well-recognized clinical syndrome of optic neuropathy or who developed a spontaneously remitting optic neuritis optic neuritis that is specifically attributed to the infection. associated with probable CNS lymphoma. The cause of Nevertheless, evidence suggests that direct degeneration of the optic neuritis remained obscure, but closely linked to ganglion cell axons in the optic nerve can be primarily due HIV infection itself 12. Larsen et al, 1998, reported a case of to the HIV virus itself. The extent and pattern of the axonal bilateral optic neuritis in which acute HIV infection is strongly loss in the optic nerves suggests that there may be an AIDS- suggested as the cause 13. The proposed mechanisms for associated primary optic neuropathy. Ninety percent of AIDS the clinical findings of the HIV-mediated optic neuropathy patients are estimated to have neurologic findings at autopsy include direct viral infection, HIV-mediated vasculitis, review; however, only half of these findings are recognized postviral-mediated immune attack, or autoimmune clinically. The purpose of the collaborative study of Drs destruction on neural and/or vascular structures as a result Tenhula, Shizao, Madigan, Heller, Freeman and Sadun was of the primary HIV infection. It may be that there are direct to demonstrate the degree of optic nerve axonal damage or indirect neurotoxic effects of the HIV-1 infection on the in patients with AIDS. The optic nerves of AIDS patients optic nerve similar to that seen in the CNS. This, too, could were morphometrically analyzed with a computer-assisted be the culprit in the development of primary HIV-associated image and measurement system. Compared to normal age- optic neuropathy 11-13. Hence, human immunodeficiency virus matched control optic nerve fibers, there was approximately infection should be considered in the differential diagnosis of 40% loss of optic nerve fibers in the AIDS patients. This study acute or chronic optic neuritis. provides important evidence that there is primary damage to the optic nerves of AIDS patients in the absence of Multiple Sclerosis-like illness with HIV opportunistic secondary infections. Furthermore, this study infection demonstrates that while many patients with AIDS have an Multiple sclerosis (MS)-like illnesses have been reported associated optic neuropathy, most are asymptomatic. As with in HIV-positive patients. Berger et al report seven other optic neuropathies, it may be merely a matter of time patients with relapsing and remitting neurologic disease before the extent of the axonal loss results in visual loss9. characteristic of multiple sclerosis occurring in the setting of HIV infection. All seven of these patients had no In later studies by Dr. Sadun et al, optic nerves in AIDS- evidence of the immunodeficiency virus or any other type related optic neuropathy were studied for their histological, of viral prodrome preceding their neurologic symptoms. virological and ultrastructural composition. Varying states In three of the patients, HIV-1 was detected within 3 of optic nerve axonal degeneration were found in patients months of the neurologic disorder. In the other four lacking retinal abnormalities or optic nerve infections. patients, MS had been suspected 41 months to 18 years Their study concluded that degeneration in the optic prior to HIV-1 infection detection. The close temporal nerve may be mediated by HIV-infected macrophages relationship between the onset of the MS-like illness and rather than by direct viral infection of the neurons. They the HIV infection in the three reported patients suggested documented that the axonal degeneration was patchy an association. It has been speculated that MS has a viral and scattered throughout the optic nerve. There was etiology. Although, the exact cause of the relapsing and astroglial proliferation and hypertrophy, degeneration of remitting neurologic disorders in Berger, et al case reports oligodendrocytes, activation of mononuclear phagocytes cannot be known, it is speculated that there may have been series cells and thickening of interfascicular septa. simultaneous occurrence of both MS and HIV infection. These findings are consistent with progressive diffuse Chronic experimental allergic encephalomyelitis (EAE) leukoencephalopathy, a non-inflammatory degeneration acting through cell-mediated immunity has been proposed observed in AIDS-infected brain tissue. Thus, mononuclear as a model for MS; however, these patients had progression phagocytes cells may be involved in producing the axonal of their demyelination despite lymphopenia and depressed degeneration and glial changes observed in optic nerves, T4 cell populations. Although the clinical syndromes may and the central nervous system, of AIDS patients. These be similar, the depletion of cell-mediated immunity in

86 | North American Neuro-Ophthalmology Society HIV infected patients suggests that there is a different the severity of visual loss in this type of optic neuropathy, pathogenesis. This alternatively raises the possibility that HIV infected patients should be warned of the potential risk the HIV infection was directly responsible for the remitting- especially if there is a family history suggestive of LHON. relapsing MS-like illness 14,15. NRTIs may need to be discontinued in an HIV infected patient who develops a monocular or binocular optic neuropathy of AION in AIDS Syndrome unknown etiology until LHON is excluded. Primary HIV infection has been postulated as the underlying mechanism in a case of anterior ischemic optic neuropathy Conclusion (AION). The case of AION reported by Brack et al was The evaluation of visual loss in AIDS patients is complex, often diagnosed clinically and confirmed by intravenous fluorescein requiring a detailed work-up to exclude infectious causes. angiography. Serological titers for infectious agents were Often, the etiology of the optic neuropathy in HIV patients is negative except for an elevated serum titer of antibodies not determined. Although in some instances, the cause may to HIV. This patient had ischemia of the optic nerve head be HIV infection itself. Therefore, human immunodeficiency caused by injury to the posterior ciliary arteries and changes virus infection should be considered in the differential in the retinal circulation 16. This correlates with the increased diagnosis of acute or chronic optic neuropathy. prevalence of retinal nerve fiber layer infarcts, hemorrhages, and focal non-perfusion of small retinal vessels found clinically in at least 50% of AIDS patients, and in a higher CME Answers 10 percentage of AIDS patients at autopsy . The case reported 1. Yes, the extent and pattern of the axonal loss in the optic by Laurent-Coriant et al in the French literature is an HIV nerves suggests that there may be an AIDS-associated patient with bilateral painless optic neuropathy who was primary optic neuropathy. There is some evidence to suggest unresponsive to antiretroviral and steroid treatments. His that direct degeneration of ganglion cell axons in the optic clinical course suggested a microvascular ischemia of the 17 nerve can be primarily due to the HIV virus itself Recent optic nerve head related to HIV infection . studies show that the optic nerve degeneration may not be caused by direct HIV viral infection of axons, but by HIV- Antiretroviral therapy for HIV as trigger infected mononuclear phagocyte series cells and glial cells for LHON Antiviral drugs such as nucleoside and nucleotide analogues 2. Nucleoside and nucleotide reverse transcriptase used in the management of HIV infection are known to inhibitors (NRTIs) used in the management of be associated with mitochondrial toxicity. Experimental HIV infection are known to be associated with evidence has demonstrated that nucleoside/nucleotide mitochondrial toxicity. reverse transcriptase inhibitors (NRTIs) affect DNA gamma 3. Most cases of optic neuropathy in patients with polymerase, the enzyme is involved in mitochondrial DNA HIV infection are associated with secondary (mtDNA) replication. Leber’s hereditary optic neuropathy (opportunistic) infections. (LHON), attributed to mtDNA mutations, causes acute, painless central visual loss. Visual loss does not occur in all patients with mtDNA mutations therefore, it has been References postulated that there are other genetic or environmental factors that may trigger the LHON-mutation. There are 1. Khadem M, Kalish SB, Goldsmith J, Fetkenhour C, O’Grady RB, Phair JP, Chrobak M. Ophthalmologic findings in acquired immune several case reports of Leber’s Hereditary Optic Neuropathy deficiency syndrome (AIDS). Arch Ophthalmol 1984; 102: 201-206. associated with the use of antiretroviral therapy in HIV 2. Winward KE, Hamed ALM, Glaser JS. The Spectrum of optic infected patients. The cases cited in the literature have been nerve disease in human immunodeficiency virus infection. Am J reported by Luke et al and Shaik et al who each reported a Ophthalmol 1989; 107: 373-380. case of an HIV patient with the 11778- mutation. Warner 3. Gordon LK. Retroviruses and retroviral diseases. In: Miller NR, and Ries reported a patient with the 14484-mutation, and Newman NJ., eds. Walsh & Hoyt’s Clinical Neuro-Ophthalmology 6th Mackey et al reported 2 other cases with the same mtDNA edition. Lippincott Willliams & Wilkins, 2005: 3323-3368. mutation. These clinical cases suggest that the effects of 4. Patel SS, Rutzen AR, Marx JL, Thach AB, Chong LP, Rao NA. antiretroviral treatments on the mitochondrial biogenesis Cytomegalovirus papillitis in patients with acquired immune incite LHON in susceptible individuals. Long-term treatment deficiency syndrome. Visual prognosis of patients treated with ganciclovir and/or foscarnet. Ophthalmol 1996; 103:1476-1482. with antiretroviral nucleoside analogues may result in acquired mitochondrial dysfunction. The reported cases 5. Konjevic-Pernar S, Bednar I, Novak-Laus K, Petric-Vickovic I, Mandic Z. Bilateral optic neuritis as initial manifestation of neurosyphilis in a imply that visual loss in these patients may be due to a HIV-positive patient. Acta Clin Croat 2008; 47: 97-100. combination of the LHON mutation and the antiretroviral 6. Yau TH, Rivera-Velazquez PM, Mark AS, et al. Unilateral optic neuritis therapy. Warner and Ries speculated that the onset of visual caused by Histoplamosia sapsulatum in a patient with the acquired loss is oxidative stress induced by mitochondrial toxicity immunodeficiency syndrome. Am J Ophthalmol 1996; 121: 324-326. in patients who already have mutated mtDNA. Due to the 7. Falcone PM, Notis C. Merhige K. Toxoplasmic papillitis as the initial possible mechanism of action of antiretroviral drugs of the manifestation of acquired immunodeficiency syndrome. Ann nucleoside/nucleotide analogue class triggering LHON and Ophthalmol 1993;25:56-7.

2012 Annual Meeting Syllabus | 87 8. Grossniklaus HE, Specht CS, Allaire G, Leavitt JA. Toxoplasma gondii 16. Brack MJ Cleland PG, Owen RI, Allen ED Anterior ischemic optic retinochoroiditis and optic neuritis in acquired immune deficiency neuropathy in the acquired immune deficiency syndrome Br Med J syndrome. Ophthalmology 1990; 97:1342-1346. 1987: 295;696-697. 9. Tenhula WN, Shizao X, Madigan MC, Heller K, Freeman WR, Sadun 17. Laurent-Coriant c, Tilikete c, Bouhour D, Boulliat J, Fleury J, Bernard AA. Morphometric Comparison of Optic Nerve Axon Loss in Acquired M, Vighetto A. Neuropathie optique bilaterale revelant une infection Immunodeficiency Syndrome Am J Ophthalmol 1992; 113:13-20. par le virus de l’immunodeficience humaine Rev Neuol (Paris) 2006;162:95-97. 10. Sadun AA, Pepose JS, Madigan MC, Laycock KA, Tenula WN, Freeman WR. AIDS-related optic neuropathy: a histological, virological and 18. Mackey SA, Fingert JH, Luzhansky JZ, McCluskey PJ, Howell N, Hall ultrastructural study Graefe’s Arch Clin Exp Ophthalmol 1995; AJH, Peirce AB, Hoy JF. Leber’s hereditary optic neuropathy triggered 233:387-398. by antiretroviral therapy for human immunodeficiency virus. Eye 2003; 17:312-317. 11. Newman NJ, Lessel S. Bilateral optic neuropathies with remission in two HIV-positive men. J Clin Neruo Ophthalmol 1992; 12:1-5. 19. Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial 12. Sweeney BJ. Manji H, Gilson RJC, Harrison MJG. Optic neuritis and HIV- toxicity as common pathway. AIDS 1998; 12:1735-1744. 1 infection. J Neurol, Neurosurg, and Psychiatry 1993; 56:705-707. 20. Luke C, Cornely OA, Fricke J, Lehrer E, Bartz-Schidt KU. Late onset of 13. Larsen M, Toft PB, Bernhard P, Herning M. Acta Ophthalmol Scand Leber’s hereditary optic neuropathy in HIV infection. Br J Ophthalol 1998; 76:737-738. 1999;83: 1204. 14. Berger JR, Sheremata WA, Resnick L, Atherton S, Fletcher MA, 21. Shaikh S, Ta C, Basham AA, Mansour S. Leber Hereditary Optic Norenberg M. Multiple sclerosis-like illness occurring with human Neuropathy associated with antiretroviral therapy for human immunodeficiency virus infection Neurology 1989; 39:324-329. immunodeficiency virus infection. Am J Ophthalmol 2001;131:143-145. 15. Rhodes RH. Histopathology of the central nervous system in the 22. Warner JEA, Ries KM. Optic Neuropathy in a Patient with Aids. J acquired immunodeficiency syndrome. Hum Pathol 1987: 18;636-643. Neuro-Ophthalmol 2001;21:92-94.

88 | North American Neuro-Ophthalmology Society Debates in Neuro-Ophthalmology Resolved: That optical coherence tomography (OCT) has “revolutionized our assessment, management, and understanding of neuro-ophthalmic disease (Subei and Eggenberger 2009).”

Deborah I. Friedman, MD, MPH: YES University of Texas Southwestern Dallas, Texas

Jonathan D. Trobe, MD: NO University of Michigan Ann Arbor, Michigan

Learning Objectives To make this issue more concrete, here are three cases 1. Determine the usefulness of OCT in various clinical in which OCT might be used. Each of these three cases situations presents a common diagnostic challenge in neuro- ophthalmology. Would OCT be helpful in the work-up? 2. Evaluate the limitations of OCT in the diagnosis of optic neuropathy Case 1: A 40-year-old man reports slowly progressive visual loss in both eyes for 6 months. He has a non- contributory history except for heavy alcohol consumption CME Questions in the past. There is no family history of visual loss or of 1. RNFL thinning is a hallmark of compressive optic neurologic disease. He does not particularly like his job as neuropathy a Ford assembly line worker. Best-corrected acuities are 20/50. Ishihara color plate scores are 5/11 OU. Pupils are a. True normal. Automated visual fields show non-clustered high b. False threshold points with mean deviations of -5 dB OU. The 2. Which of the following RNFL abnormalities may be optic discs are tilted with questionable temporal optic disc seen in patients with myopia and tilted optic nerves? pallor, but he is a 5-diopter myope.

a. RNFL thinning Friedman: b. Increased RNFL thickness Slowly, progressive, bilateral, symmetric visual loss raises c. Normal RNFL thickness several diagnostic possibilities. This man may have d. All of the above retinopathy, optic neuropathy, chiasmal disease or non- e. A and B organic visual loss. The visual field description essentially excludes a chiasmal problem. A great mnemonic for Keywords diagnosing unexplained visual loss, courtesy of Dr. Michael Slavin, is SOFA: Spectacles to Occiput (the visual system 1. Optical coherence tomography from anterior to posterior), Functional & Amblyopia. 2. Retinal nerve fiber layer analysis Nutritional (“tobacco-alcohol”) amblyopia seems unlikely 3. Macular disease given that his alcohol consumption was remote, although one never really knows for sure. Heavy drinkers are 4. Optic neuropathy often smokers, so a cancer associated retinopathy is a consideration. He is in the age range for demyelinating disease, which occasionally presents with slowly progressive visual loss. We are also given a clue about job dissatisfaction (although he is lucky to have a job these days if he works in the auto industry). Patients with “mid- level (20/40-20/80)” bilateral visual loss are the toughest to sort out with respect to functional visual loss, and the disc appearance doesn’t help us. His color vision loss may

2012 Annual Meeting Syllabus | 89 be real or feigned. As with many functional neurologic disorders, there may be a combination of real disease and My approach to this patient would be: non-organic embellishment. 1. Obtain old records to be sure that this isn’t OCT would definitely be helpful in the armamentarium longstanding amblyopia with recent delusions of of tools at our disposal. Pre-OCT, our options were: Workers Compensation review the old records, “brute force” refraction, various 2. Brute force refraction and other maneuvers to determine manipulations at the phoropter to try and prove 20/20 whether or not he can be coaxed into seeing 20/20 vision (more difficult when the visual loss is binocular than 3. OCT uniocular), visual evoked potentials (helpful if there is a delay in P100 but not if normal or unrecordable), ERG and a. If OCT shows buried drusen, follow the patient mfERG, neuroimaging (a structural lesion is highly unlikely b. If OCT shows macular abnormality, send for retinal in this case; perhaps helpful if demonstrates small optic evaluation nerves or buried disc drusen), orbital ultrasound (buried c. If OCT shows RNFL thinning, proceed with other drusen), fluorescein angiography, quantitative color vision testing to look for underlying cause of optic testing and genetic testing (e.g., atypical Leber, CAR). neuropathy While helpful, some of these tests are quite costly. d. If OCT is normal, consider CAR if he is a smoker and get an ERG Subtle manifestations of macular edema, intraretinal cysts, subtle detachments and macular degenerative changes Trobe: are discernible on OCT. An abnormal macular OCT with a The differential diagnosis is between a bilateral retinopathy, preserved RNFL scan in our patient would at least deflect a bilateral optic neuropathy from heavy alcohol him to the Retina service and likely avoid an expensive and consumption or from another cause, and malingering. time-consuming neuro-ophthalmic evaluation. I must concede that OCT has made a genuine contribution Moving on to the optic nerve, an abnormal OCT would help in the diagnosis of maculopathy, which often causes a us but there are a few possible confounders in our patient. visible structural alteration. But in this setting, how often He is a moderate myope with tilted optic nerves. OCT may is OCT positive when ophthalmoscopy is not? Is OCT the reveal increased temporal RNFL thickness compared to eyes preferred test over electroretinography (ERG)? Are they with non-tilted nerves (Hwang et al 2011). If that were the complimentary, one diagnosing structural alteration, the case, RFNL thinning in our patient would likely be significant. other dysfunction? I have sometimes ordered visual However, myopia and tilted optic nerves may be associated evoked potentials in this setting, but admit that they are with peripapillary atrophy (PPA). Abnormal retinal nerve often unreliable. Should OCT and ERG be performed before fiber layer (RNFL) structure is frequently present in eyes one would consider ordering brain/orbit MRI to rule out a with PPA with areas of both increased and decreased retinal bilateral optic nerve compressive lesion? thinning (Majnunath et al 2011). Additionally, increased axial length may affect RNFL thickness, with decreasing average In this case, I would probably order OCT, although it will 360 degree thickness with increasing axial length (Yoo et al, almost certainly not show a macular lesion. It might or 2011). This structural artifact associated with myopia may might not show a thinned retinal nerve fiber layer (RNFL), potentially classify a normal eye as abnormal. and then I would be left to decide whether to perform further work-up, including brain MRI, testing of blood Jeoung et al studied Stratus OCT and perimetry for for a thiamine level, and of urine for heavy metals (!). In the detection of diffuse RNFL atrophy in glaucoma truth, I have found that checking for gradient sensory loss suspects (which was originally described by neuro- in the lower extremities (part of nutritional peripheral ophthalmologists Hoyt, Frisen and NM Newman using neuropathy) is much the most helpful maneuver here! good old ophthalmoscopy!). They studied 102 eyes of 102 patients with diffuse RNFL atrophy and an equal number of Case 2: A 60-year-old woman with previous traumatic optic age-matched controls (Jeoung et al 2011). Specificity using neuropathy taking vision to no light perception in the OS, average RNFL thickness ranged from 61.5% (range 53.1- now complains of slowly progressive visual loss in the OD. 69.4) with abnormal values at the 5% level to 54.1% (range Best-corrected visual acuities are OD 20/40, OS NLP. There 45.7-62.3) with abnormal values at the 1% level and overall is an afferent pupil defect in the OS. Automated perimetry specificity approaching 100%. Having a corresponding shows some scattered high threshold points with a mean visual field defect increased the sensitivity considerably. deviation of -8 dB OD, but repeated testing shows that They concluded that using OCT with an internal normative the location of the high threshold points shifts and mean database should be evaluated with caution, especially in deviations vary between -5 and -10 dB. The right fundus the early stages of glaucoma with diffuse NFL thinning. appears normal but is slightly obscured by cataract. The left fundus shows a pale disc. Amblyopia does not affect the OCT (Walker et al 2011).

90 | North American Neuro-Ophthalmology Society Friedman: This case seems like a natural for OCT—a way to assess This patient has progressive visual loss in her only seeing eye whether the RNFL is of normal thickness. If OCT shows that and we don’t have the usual optic neuropathy calling cards the RNFL is thin, you would certainly have to order MRI (APD, optic atrophy) to make a diagnosis in the right eye. She imaging to rule out a compressive lesion. But here is the is a bit inconsistent with perimetry but there is no specific problem: if OCT shows that the RNFL is of normal thickness, pattern to her visual field loss. Let’s go back to the SOFA: you would still have to order the imaging study, because compressive lesions can damage optic nerve function Is her visual loss from cataract, retinal disease or optic without killing axons. neuropathy? (Any of these processes could be bilateral but we won’t know if it has affected her left eye. Likewise, it’s Suppose you found a compressive lesion, would OCT serve possible that posterior pathway disease could be the culprit as a predictor of how much visual recovery would occur with in a monocular patient but I am excluding a chiasmal or decompression? There is evidence that it might, but the post-chiasmal origin based on her visual field.) Functional studies (Jacob et al 2009, Danesh-Meyer et al 2008), although visual loss is always a possibility. She has likely been the intriguing, have limited clinical value. Jacob et al showed beneficiary of many years of ophthalmic follow-up after her that visual recovery eventually occurred months later even initial eye injury, so undiagnosed amblyopia is unlikely. in those with RNFL thinning. Thus, RFNL thinning cannot be an argument against surgery. Danesh-Meyer et al showed This woman wouldn’t be the first to present to a neuro- that those with severe visual field defects pre-operatively ophthalmologist for visual loss caused by a cataract. If the yet a normal RNFL had substantial visual improvement view of her right fundus was slightly obscured by a cataract post-operatively, indicating that visual dysfunction and (especially if viewed with the indirect ophthalmoscopy or RNFL thickness are not necessarily connected, even in using slit lamp bimicroscopy), the lens opacity may be the chronic compressive lesions! This finding exposes a major cause of her problem. drawback of OCT. That is, a normal OCT does not exclude an optic neuropathy! Would OCT serve as a useful baseline to There are a few things on the examination which might help follow such a patient post-operatively in lieu of conventional sort this out regarding retina vs. optic nerve. Color vision measures like visual acuity and visual field? Probably not, would likely be abnormal with an optic neuropathy. Amsler as we would be depending on axon death to thin the RNFL. grid testing may reveal metamorphopia, which would point me (The same argument could presumably be used in following toward the retina. Aside from the exam, my first step would patients with other chronic optic neuropathies like glaucoma be a slit lamp exam, view with a direct ophthalmoscope, and and idiopathic intracranial hypertension, where waiting for potential acuity meter testing to determine the extent of visual RNFL thinning might be a little too late.) impairment caused by the cataract. If the cataract is excluded as the source of her visual loss, an OCT would be helpful to In this case, I would not order OCT. Instead, I would go determine whether there may be a macular process (if the optic straight to brain/orbit MRI. nerve can’t be seen well on her exam, her macula probably can’t either). However, progressive monocular visual loss may Case 3: A 4-year-old boy complains of recent headaches. be caused by a mass lesion, and RNFL and macular thinning There is no pertinent history except that his mother has may occur from optic nerve or chiasmal compression. If the headaches. A pediatrician finds elevated discs. For your compression has either (1) not been present long enough or (2) examination, he is too squirrely to get a reliable acuity is relatively posterior along the course of the optic nerve such or confrontation fields. Pupils are normal. Optic discs that the retinal axons have not been damaged, the OCT may are both elevated without visible drusen. The neurologic be misleadingly normal. In this case, OCT could help define a examination is grossly normal. retinal process in a patient with a limited view of the fundus but would probably not hold up in court if she was later diagnosed Friedman: with a treatable tumor causing optic nerve compression… The combination of elevated optic nerves and headaches raises the alarming possibility of increased intracranial Trobe: pressure. Making the distinction of true papilledema from The patient is reporting progressive visual loss in her only pseudopapilledema can be challenging, even in the most sighted eye. An optical cause is not it. The loss of optic cooperative adult. However, one would not want to miss a function in the contralateral eye eliminates the use of brain tumor or hydrocephalus in a young child! the most valuable test for unilateral optic neuropathy: the swinging light test for an afferent pupil defect. Serial The fact that the pediatrician found elevated optic nerves in visual field testing yields fluctuating results, so that test is a child who is difficult to examine leads me to believe that probably not reliable. You are left to judge whether there is the optic nerve changes are not subtle. optic nerve damage on the basis of the appearance of the optic disc—hardly failsafe. Spectral-domain OCT is helpful in identifying optic nerve head drusen (ONHD) and distinguishing them from papilledema. One study of 45 patients with ONHD, 15

2012 Annual Meeting Syllabus | 91 patients with optic disc edema and 32 normal controls optic disc elevation from drusen and from acquired optic found that OCT showed characteristic changes in patients neuropathies to see if OCT could distinguish them. Using with ONHD: focal, hyperreflective, subretinal masses with TD-OCT, Johnson et al studied, among other patients, discrete margins, a deformed retinal nerve fiber layer with 11 with buried drusen and 10 with papilledema. They pseudoedema and high reflectance, and a hyporeflective could differentiate these conditions with approximately boot-shaped area adjacent to the drusen (Lee et al 2011). 65% sensitivity and specificity. The drusen cases were The peripapillary RNFL was thicker in all sections in optic affirmed by separate diagnostic criteria, including nerves with edema than in optic nerves with drusen. ultrasound and autofluorescence. Using SD-OCT, Lee et al found that all 45 patients with drusen had a focal But what if the drusen are buried? An OCT study of 21 eyes hyperreflective subretinal mass with discrete margins that with buried drusen (confirmed with ultrasound) and normal was not present in those with other causes of optic disc visual fields found focal RNFL defects in some eyes and normal elevation. However, they did did not disclose in what average RNFL thickness in all eyes (Katz and Pomeranz 2005). proportion of cases the drusen were buried. Moreover, Thus, patients with buried drusen may not affect the average the diagnosis of drusen was not independently verified RNFL and cannot be relied upon as a screening technique. with other modalities. Among those with other causes of optic disc elevation, only 4 had papilledema. With respect to our four-year-old, the presence of spontaneous venous pulsations would be reassuring for B-scan ultrasonography can detect buried drusen pseudopapilledema, although not 100% reliable. Venous (McNicholas et al 2004) but its sensitivity has never been pulsations may be absent with either papilledema or optic disc measured against a standard such as CT. No head-to-head drusen. The utility of an OCT is to quickly identify relatively study between OCT and ultrasound has been conducted. superficial disc drusen that may be hard to distinguish by ophthalmoscopy (or blurred fundus photographs if he was a Even if OCT were a sensitive detector of buried drusen, are “wiggle worm”). In that respect, OCT would save unnecessary there not cases in which the optic discs are congenitally testing, much of which would likely require that the child be elevated without drusen? I have many such patients in whom sedated. (Even an examination under anesthesia may not ultrasound and CT are negative for drusen, yet the discs add much to the diagnostic yield and cause further delays and are clearly elevated and detailed brain imaging and lumbar expense.) Orbital ultrasound with a 30 degree test is useful puncture opening pressures are normal. In such cases, would but not universally available; the child’s ability to cooperate OCT distinguish congenital from acquired optic disc elevation? may be a limiting factor. In the face of an inconclusive OCT, I We do not know. would proceed with additional evaluation with an MRI of the brain at least, and possibly a lumbar puncture. In this case, I would not order OCT. I would request a Trobe: B-scan ultrasound. If it were absolutely positive for buried drusen, I would do no further testing. If it were negative, The challenge is to distinguish congenital from acquired I would order brain MRI or follow for clinical change, optic disc elevation, a VERY common problem in clinical practice. I concede that I frequently cannot make depending on my mood. this distinction ophthalmoscopically. That history and neurological examination are overwhelmingly normal If you had told me 40 years ago that in 2011 we would still in these patients hardly excludes increased intracranial not have a reliable OBJECTIVE means of assessing visual pressure. Cerebral hemispheric tumors, especially those function, I would have been incredulous. And now we are originating in frontal and temporal lobes, may be clinically offered a highly sensitive way to measure RNFL thickness. silent for long periods. In children, supratentorial tumors It should be a terrific help in diagnosis. But somehow, are rare, with papilledema occurring much more commonly it almost never is. When it has already been performed from infratentorial masses that obstruct the fourth ventricle before I see the patient, I typically ignore it. But then, I or from aqueductal stenosis. Although such tumors usually barely know how to use a cell phone. produce an alteration in balance and consciousness, these manifestations are often delayed. Headache is also a late symptom. Surprisingly, low-grade meningitis can also be CME Answers clinically silent. And of course, idiopathic intracranial 1. b hypertension may have no other clinical manifestations. 2. d But is OCT a reliable differentiator of congenital from acquired optic disc elevation? Is it the best test? References 1. Danesh-Meyer HV, Papchenko T, Savino PJ, et al. In vivo retinal nerve One study using time-domain OCT (TD-OCT) (Johnson et al fiber layer thickness measured by optical coherence tomography 2009) and one study using spectral-domain OCT (SD-OCT) predicts visual recovery after surgery for parachiasmal tumors. (Lee et al 2011) have examined patients with congenital Invest Ophthalmol Vis Sci 2008;49:1879-1885.

92 | North American Neuro-Ophthalmology Society 2. Hwang YH, Yoo C, Kim YY. Characteristics of peripapillary retinal nerve fiber thickness in eyes with myopic optic disc tilt and rotation. J Glaucoma 2011; Sept 22 (PMID 21946540) 3. Jacob M, Raverot G, Jouanneau E, et al. Predicting visual outcome after treatment of pituitary adenomas with optical coherence tomography. Am J Ophthalmol 2009;147:64-70. 4. Jeoung JW, Kim SH, Park KH, Kim T-W, Kim DM. Diagnostic accuracy of OCT with normative database to detect diffuse retinal nerve fiber layer atrophy: diffuse atrophy imaging study. Invest Ophthalmol Vis Sci 2011;52:6074-6080. 5. Johnson LN, Diehl ML, Hamm CW et al. Differentiating optic disc edema from optic nerve head drusen on optical coherence tomography. Arch Ophthalmol 2009;127:45-49. 6. Katz BJ, Pomeranz HD. Visual field defects and retinal nerve fiber layer defects in eyes with buried optic disc drusen. Am J Ophthalmol 2006;141:248-253. 7. Lee KM, Woo SJ, Hwang J-M. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical coherence tomography. Ophthalmology 2011;118:971-977. 8. Manjunath V, Shah H. Fujimoto JG, Duker JS. Analysis of peripapillary atrophy using spectral domain optic cohererence tomography. Ophthalmology 2011; 118:531-536. 9. McNicholas MMJ, Power WJ, Griffin JF. Sonography in optic disk drusen: imaging findings and role in diagnosis when funduscopic findings are normal. AJR 1994;162:161-163. 10. Subei AM, Eggenberger ER. Optical coherence tomography: another tool in a neuro-ophthalmologist’s armamentarium. Curr Opin Ophthalmol 2009;20:462-466. 11. Walker RA, Rubab S, Voll AR, Erraguntla V, Murphy PH. Macular and peripapillary retinal nerve fibre layer thickness in adults with amblyopia. Can J Ophthalmol 2011;46:425-427. 12. Yoo YC, Lee CM, Park JH. Changes in peripapillary retinal nerve fiber layer distribution by axial length. Optom Vis Sci 2011, Oct 6 (PMID 21983121)

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