Visual, Ocular Motor, and Cochleo-Vestibular Loss in Patients With Heteroplasmic, Maternally-Inherited Diabetes Mellitus and Deafness (MIDD), 3243 Transfer RNA Mutation

Orbital apex syndrome is a rare complication of herpes zoster ophthalmicus. In addition to our case, we review the clinical presentation, imaging findings, treatment options, and prognosis of 14 other reported cases. Magnetic resonance imaging of our patient demonstrated diffuse enhancement of the orbit involving the orbital apex, optic nerve and/or nerve sheath, extraocular muscles, and orbital soft tissues. There was significant clinical improvement with acyclovir and systemic corticosteroids, which seems to be preferred treatment for this disorder.

Original Contribution Visual, Ocular Motor, and Cochleo-Vestibular Loss in Patients With Heteroplasmic, Maternally-Inherited Diabetes Mellitus and Deafness (MIDD), 3243 Transfer RNA Mutation Simon Cardenas-Robledo, MD, Ali Saber Tehrani, MD, Gregory Blume, MD, Jorge C. Kattah, MD Background: Mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS) and MIDD (maternallyinherited diabetes mellitus and deafness) are caused by A3243G transfer RNA mutations that affect mitochondrial function. Hearing loss and early onset diabetes mellitus constitute the main MIDD phenotype. Regarding the ophthalmologic manifestations of MIDD, we hypothesized that decreased vestibulo-ocular reflex (VOR) gain in patients with MIDD may contribute to impaired dynamic visual acuity. Methods: Neuro-ophthalmologic, neuroimaging, and neurootologic evaluations were performed in 2 nonrelated patients with MIDD who complained of oscillopsia with head movement. We obtained quantitative recording of the horizontal and the vertical VOR, using the video head impulse test device. Results: In the 2 patients, we detected visual, ocular motor, and vestibular abnormalities. Decreased VOR gain in the planes of all 3 semicircular canals and impaired dynamic visual acuity was demonstrated in both cases. Conclusions: MIDD patients are primarily recognized by their advanced hearing loss or deafness, early onset diabetes mellitus, and lactic acidosis. Decreased vision in these patients relates primarily to peri-macular retinal atrophy. In addition, loss of vestibular function causes poor dynamic visual acuity. Both patients, in their late fifties, had evidence of progressive central and peripheral nervous system dysfunction. Journal of Neuro-Ophthalmology 2016;36:134-140 doi: 10.1097/WNO.0000000000000340 © 2016 by North American Neuro-Ophthalmology Society A s a result of tissue heteroplasmy, many phenotypes of hereditary mitochondrial DNA mutations are highly variable, even among family members who share the same mutant DNA. This phenomenon has been observed in the transfer RNA 3243 A to G mutation (A3243G) associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS) syndrome. In contrast, the initial clinical manifestations of maternally-inherited diabetes mellitus and deafness (MIDD) syndrome initially are subtle. The insidious nature of MIDD, in addition to the high prevalence of diabetes mellitus (DM) in the general population, makes the mitochondrial etiology of the patient's symptoms potentially overlooked. However, over time, MIDD patients show multisystem compromise and develop a more characteristic presentation of a systemic mitochondrial disorder. We report 2 patients from 2 nonrelated families who presented with visual complaints, bilateral cochlea-vestibular loss, and early onset DM. Both parents had significant loss of horizontal and posterior canal vestibulo-ocular reflex gain. This was the contributing factor to blurred vision with head movements. The clinical suspicion of a mitochondrial disorder was confirmed by muscle biopsy and the A3243G mutation was identified by biochemical analysis. REPORT OF CASES Patient 1 Department of Neurology (SC-R), Universidad Nacional Facultad de Medicina, Bogota, Colombia; and Illinois Neurologic Institute (AST, GB, JCK), University of Illinois College of Medicine, Peoria, Illinois. Address correspondence to Jorge C. Kattah, MD, 530 North Glen Oak Avenue, Department of Neurology, Peoria, IL 61637; E-mail: [e-mail] 134 A 58-year-old, right-handed man presented with a 2-year history of loss of balance, diplopia, and blurred vision that increased with head movement. He did not report any falls and was able to walk up to 3 miles on a paved trail, but his gait worsened in the dark. He did not recall having vertigo, nausea, vomiting, headache, or motion intolerance. His symptoms were triggered by changing positions such as Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution rising from a sitting position or walking. He was diagnosed with bilateral, symmetric sensori-neural hearing loss approximately 30 years before and with insulin-dependent DM at the age of 34. He had hypertension, a family history of diabetes, and one niece who died from complications of MELAS at the age of 15. Two of his siblings have hearing impairment, but were not formally tested. There was no personal or family history of treatment with aminoglycosides. On physical examination, he was alert and oriented. Static visual acuity was 20/20 in each eye, and he read the J1 line with the Rosenbaum near card. His dynamic visual acuity was significantly impaired; he could only read the J16 line with side-to-side head oscillations (frequency: 2 Hz). Pupillary testing and ophthalmoscopy were normal. Eye movements were full but there was an esophoria measuring 6 prism diopters in left gaze. Visual fixation was steady; saccades, pursuit, and clinical vestibulo-ocular reflex (VOR) in light were intact. The visual-VOR (VVOR) was also normal. We suspected a low VOR gain associated with covert saccades causing decreased visual performance under dynamic conditions. Central and eccentric eye positions were monitored with the eyes open in total darkness, as the patient wore goggles equipped with an infrared camera for each eye (fixation block). He had an up-beating nystagmus on primary and lateral gaze, which increased in response to mastoid vibration and decreased with the head hanging on the left side during the Dix-Hallpike maneuver. His muscle strength was normal, but he had areflexia in both lower limbs and significant dysmetria on heel-to-shin test. Sensory examination demonstrated normal position and vibratory sense and mildly decreased distal pin prick in both feet. Although he was unsteady while testing the Romberg sign, he could maintain a standing posture without assistance. He could not perform tandem gait or the Fukuda step test. Pure tone audiometry disclosed a severe sensori-neural hearing loss, with thresholds at 80 and 85 dB for the left and right ears, respectively, and a speech discrimination of 60%. Video-nystagmography showed normal saccade main sequence (velocity, latency and accuracy), slightly impaired pursuit, and low VOR gain and phase lead for slow chair oscillation and impulsive rotation, and decreased time constant. We used a video head impulse (v-HIT) device to measure the VOR gain (ICS impulse; GN-Otometrics, Taastrup, Denmark). The horizontal (h) gain (h-VOR) was calculated by recording the ratio between the head and eye movement velocity during random right (R) and left (L) horizontal head rotations, which were performed as the patient was staring at a fixed target. The vertical (v) VOR gain (v-VOR) was tested by performing vertical head impulses with the head turned 45° to the right (left anterior, right posterior semicircular canals) and to the left (right anterior and left posterior semicircular canals). The patient's horizontal and posterior canal gain values were bilaterally decreased; mean horizontal gain was R: 0.31; L: 0.37 (normal: 0.7-1.0), mean vertical gain in the plane of the posterior canals was R: 0.58; L: 0.58 (normal: 0.7-1.0). In contrast, FIG. 1. Patient 1. Video-oculography (VOG) montage. Response to head impulses performed in the plane of the horizontal and vertical semicircular canals, recorded as the patient fixates on a central target. The horizontal canal gains were, right: 0.31 and left: 0.37 (normal 0.7). Posterior canal vestibulo-ocular reflex (VOR) gain was also decreased (0.58 for both right and left canals). Overt refixation saccades are present. Anterior canal gain was normal. Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the v-VOR gain the plane of the anterior canals was bilaterally normal, R: 0.83; L: 0.94 (normal 0.7-1.0). The v-HIT device VOR tracings detected mostly covert saccades and a few overt saccades. The low h-VOR gain could have been undetected without graphic recording (Fig. 1). The combined VVOR was normal. Vestibular evoked myogenic potentials (VEMPs) were bilaterally absent. Serum lactate level was slightly elevated at 2.2 mmol/L (normal: 0.7-24 mmol/L). Nerve conduction studies showed a sensory motor, axonal polyneuropathy that was length dependent. His bilateral sural sensory nerve action potentials were less than 3 mV in amplitude (normal 6-12 mV). His right peroneal compound muscle action potential was 1.5 mV in amplitude (normal 3.5-6 mV). Brain magnetic resonance imaging (MRI) showed moderate generalized brain atrophy and small vessel ischemic changes in the supratentorial white matter, with no abnormalities found in the vessels of the neck and brain on magnetic resonance angiography. Biopsy from the right deltoid muscle showed few scattered trichrome stained ragged red fibers and several cytochrome oxidase negative and succinate dehydrogenase hyper-reactive fibers. The presence of an A3243G mutation with 90% heteroplasmy was identified. Patient 2 A 58-year-old woman with a history of bilateral hearing loss since the age of 13 years, experienced sudden, enduring deafness in the left ear at age 36, despite a 2-week course of systemic corticosteroids. An exploratory tympanotomy did not detect a perilymphatic fistula or other explanation for the cause of deafness. Although there was a family history of hearing loss, there was no personal or family history of exposure to aminoglycosides. The sensori-neural hearing loss was quantified as symmetric and significant, 60 dB across all frequencies, and was attributed to a "viral illness." She also had a history of insulin-dependent DM, which was first detected during a brief steroid treatment she received for her sudden hearing loss. She has 5 siblings. The eldest is affected with bilateral hearing loss, as are 1 of her 2 daughters and her mother. Twenty-two years before, when the patient was 36 years old and evaluated for a cochlear implant, her general physical examination was unremarkable. At that time, visual acuity, color vision, and pupillary testing were normal. Automated visual fields were reported to show mild central depression bilaterally and pigmenting changes were seen in each macula (Fig. 2A). We did not test the h-VOR or v-VOR and there were no abnormalities on her neurological examination. Brain MRI showed symmetric and bilateral increased signal intensities in the posterior thalami. Additional testing revealed elevated cerebrospinal fluid protein of 77.1 mg/dL (normal: 15-40 mg/dL), increased serum lactate of 3.3 mmol/L (normal: 0.5-2.2 mmol/L) and fasting blood glucose of 156 mg/dL (normal 77-99 mg/L). One daughter in her early teens had bilateral 30-DB sensorineural hearing loss. FIG. 2. Patient 2. A. Fundus appearance at age 36 years reveals peripapillary pigment changes with pigment clumping in each macula. B. At age 56 years, there is progression in pigmentary changes yet less pigment clumping. 136 Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Patient 2. Automated perimetry (Humphrey 30-2). A. At age 50 years, there is general depression of both visual fields and a paracentral scotoma in the right eye. B. At age 56 years, there is progression of field loss bilaterally. A right deltoid muscle biopsy was positive for ragged red fibers and the patient was found to have a mutation of the transfer RNA at the 3243 position. An analysis of the degree of heteroplasmy was not provided. She had a cochlear implant and was able to hear and function well. She was not seen for 14 years and the only remarkable health issue was related to an episode of rhabdomyolysis triggered by the use of statins to lower cholesterol. At age 50 years, the patient had visual acuity of 20/20 in the right eye, and 20/25 in the left eye. Color vision and pupillary reactions were normal. Automated perimetry showed bilateral visual field loss (mean deviation: Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 right eye, 25.53 dB; left eye, 26.02 dB) with elevated foveal thresholds (right eye, 33 dB; left eye, 33 dB) (Fig. 3A). Ophthalmoscopy revealed bilateral, symmetric mild optic disc pallor and peripapillary retinal atrophy. Previously observed macular pigmenting changes were less conspicuous. The ocular motor examination was intact and the h-HIT was normal bilaterally. Dynamic visual acuity was not tested. The neurologic examination was normal and brain computed tomography showed the right cochlear implant, moderate cerebral and more marked cerebellar atrophy, and calcifications in the basal ganglia (Fig. 4). 137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution On her most recent examination at age 56 years, the patient reported increasing difficulties with vision which interfered with her ability to read, particularly with head movement. Although her visual acuity was 20/20 in each eye, she had paracentral visual loss that affected her reading efficiency. Static visual acuity at near was J1 bilaterally; dynamic visual acuity with 2 Hz head oscillations fell to worse than J15 (20/800 Snellen equivalent). Color vision was impaired in each eye but pupillary testing was normal. Automated perimetry showed progressive, bilateral visual field loss (mean deviation: right eye, 212.63 dB; left eye, 28.91 dB) (Fig. 3B). Funduscopy demonstrated altered pigmentation in each maculae but less evidence of pigment clumping (Fig. 2B). Eye movements were normal. The h- and the v-VOR were tested with the v-HIT device with the same protocol described in Patient 1. The mean h-VOR gain was significantly low bilaterally R: 0.07; L: 0.32 (normal 0.7-1.0), with overt corrective saccades (Fig. 5). The mean vertical gains were low; R: 0.58 and L: 0.58 for the posterior canals, and normal for the anterior canals R: 0.83; L 0/80 (normal: 0.7-1.0). The combined vestibular visual VOR was normal. The rest of her neurological examination was intact. DISCUSSION MELAS is a multisystem disease with varied manifestations, among which the neurological, metabolic (diabetes mellitus), lactic acidosis, and cardiovascular disturbances are prominent (1). A milder clinical phenotype related to tissue heteroplasmy has been recognized (MIDD) (2) and is the subject of this report. Our 2 patients in their late fifties had DM and progressive hearing loss, beginning at age 28 in Patient 1 and at age 13 in Patient 2. Patient 1 wears hearing aids and finds them marginally helpful, whereas Patient 2 became deaf and underwent successful cochlear implantation. Both reported visual symptoms triggered by head movement. Decreased VOR gain due to bilateral peripheral vestibulopathy caused oscillopsia during head movement and decreased dynamic visual acuity as a factor responsible for impaired vision. Neuro-ophthalmic complications affecting the afferent visual system are frequent in the fully expressed MELAS and in the MIDD phenotypes. The most common is pigmentary retinopathy, that may remain mild and asymptomatic as observed in our Patient 2 for several years (2,3). Less common ocular manifestations include macular degeneration (4), central retinal vein occlusion (5), and optic neuropathy (6). Patients with MIDD may develop peri-macular annular retinal/choroidal atrophy (3,4). The retinopathy in MELAS and MIDD is best identified by auto fluorescence (4). In patient 2, retinal pigmentary changes became less marked over time, possibly reflecting retinal pigment epithelium atrophy. Many of the clinical manifestations of our 2 patients were subtle and seemingly nonsyndromic. Both patients had a family history of hearing loss and deafness but no known history of a mitochondrial disorder or exposure to aminoglycosides. Cochlear involvement in mitochondrial DNA disorders and, specifically in MELAS, has been well recognized (2). Steadily progressive sensori-neural hearing loss and DM were the 2 main findings that left to the initial diagnostic consideration of a mitochondriopathy. In Patient 1, ophthalmoplegia, a positive head impulse test, loss of balance with gait ataxia and a length dependent sensori-motor neuropathy further supported the need for additional investigation. In Patient 2, pigmentary retinopathy, lactic acidosis, and MRI changes involving the posterior thalami suggested a systemic metabolic disorder and justified further testing. Our patients had increased baseline serum lactic acid levels and muscle biopsy demonstrated ragged red fibers. The A3243G mutation of the transfer RNA was found in both FIG. 4. Patient 2. Contiguous noncontrast axial computed tomography shows bilateral basal ganglia calcifications and atrophy of the superior cerebellar peduncle with enlargement of the fourth ventricle. The beam hardening artifact is from right cochlear implant. 138 Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Patient 2. Video-oculography (VOG) montage. Response to head impulses performed in the plane of the horizontal and vertical semicircular canals is recorded as the patient fixates on a central target. The horizontal canal gains were, right: 0.32 and left: 0.20 (normal 0.7). Posterior canal gains were also decreased. Overt refixation saccades are present. Anterior canal gains were normal. patients, yet with a remarkable difference in their phenotype. This may be explained by DNA heteroplasmy and by variable tissue mutation. It is surprising that vestibular dysfunction, and specifically impaired VOR gain, has been infrequently reported in MELAS and MIDD, despite pathologic evidence of selective degeneration of the saccule (7). To our knowledge, clinical involvement of the vestibular system was reported only once in a previous case series (8). Those patients had episodic vertigo, uni- or bilaterally-hypoactive caloric responses and abnormal myogenic, cervical cVEMPs. Bilateral vestibular loss is an infrequent clinical finding and has multiple etiologies including ototoxic drug effect, systemic, autoimmune, and degenerative diseases (9,10). In a significant number of cases, it is idiopathic. When evaluating bilateral vestibular loss, it is crucial to bear in mind that vestibular and/or cochlear loss in response to aminoglycoside exposure is more likely in some mitochondrial mutations (11- 14). In such cases, a small dose may cause irreversible ototoxicity. None of our patients were treated with medications with potential ototoxicity. To our knowledge, this is the second report of the A3243G mutation of the transfer RNA causing bilateral vestibular loss. The absence of vertigo in our patients suggests that the loss of VOR was slow and symmetric. More commonly reported ocular motor abnormalities in MELAS and MIDD include nystagmus (15) and extraocular muscle paresis, ranging from subtle (16) to overt ophthalmoplegia (17,18). Although our patients Cardenas-Robledo et al: J Neuro-Ophthalmol 2016; 36: 134-140 did not have these findings, they did have decreased VOR gain, resulting in oscillopsia during head movement and impaired dynamic visual acuity. Brain neuroimaging abnormalities in MIDD differ from the large cerebral stroke-like lesions found in MELAS. Cerebral and cerebellar atrophy were present in our patients. In Patient 2, this was followed by white matter signal changes and extensive calcification of the basal ganglia and thalami, suggesting progressive neurodegeneration. In conclusion, the initial diagnosis in our patients could have easily been idiopathic bilateral cochlear-vestibular loss. However, the family history of deafness and early onset DM, coupled with search of family records in Patient 1 and a careful evaluation of both patients, uncovered physical findings and laboratory data suggestive of a syndromic mitochondrial disorder. Our 2 patients with MIDD are now in their late fifties and encephalopathy and stroke-like episodes have not occurred. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. C. Kattah; b. Acquisition of data: S. Cardenas-Robledo, A. Saber Tehrani, G. Blume, and J. C. Kattah; c. Analysis and interpretation of data: A. Saber Tehrani, G. Blume, and J. C. Kattah. Category 2: a. Drafting the manuscript: S. Cardenas-Robledo, A. Saber Tehrani, and J. 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