Leber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms
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REFERENCES 1. Kirkham Th, Sander MD, Sapp GA. Unilateral papilledema in benign intracranial hypertension. Can J Ophthalmol 1973; 8:533–538. 2. Sedwick LA, Burde RM. Unilateral and asymmetric optic disk swelling with intracranial abnormalities. Am J Ophthalmol 1983;96:484 – 487. 3. Strominger MB, Weiss GB, Mehler MF. Asymptomatic uni- lateral papilledema in pseudotumor cerebri. J Clinical Neuro- Ophthalmol 1992;12:238 –241. 4. Walsh FB, Hoyt WF. Clinical neuro-ophthalmology. Vol. 1. Baltimore: Williams and Wilkins; 1979:569 –574. 5. Killer HE, Laeng HR, Groscurth P. Lymphatic capillaries in the meninges of the human optic nerve. J Neuro-Ophthalmol 1999;19:222–228. Leber Hereditary Optic Neuropathy, Progressive Visual Loss, and Multiple- Sclerosis-like Symptoms Mai Tran, Ravi Bhargava, MD, and Ian M. MacDonald, MD, CM PURPOSE: To report a case of Leber hereditary optic neuropathy with multiple-sclerosis-like symptoms. METHODS: Observational case report. A 34-year-old man was found to have Leber hereditary optic neuropathy and a mutation at position 11778 of the mitochondrial genome. The progression of vision loss and onset of weakness in the right leg warranted neuroimaging. RESULTS: Magnetic resonance imaging documented mul- tiple lesions in the brain and spinal cord. CONCLUSION: Although rarely reported, progression of optic neuropathy over months has been previously doc- umented in Leber hereditary optic neuropathy. The emergence of multiple sclerosis-like symptoms and signs in our patient may be part of the spectrum of Leber hereditary optic neuropathy or a coincidental occurrence. (Am J Ophthalmol 2001;132:591–593. © 2001 by Elsevier Science Inc. All rights reserved.) L EBER HEREDITARY OPTIC NEUROPATHY [MIM 535000] IS characterized by sudden loss of central vision in other- wise healthy individuals in the second or third decade of life. All mutations found thus far have been missense mutations and affect the mitochondrial respiratory chain: complex I, III, and IV subunits. 1 The clinical features of the disorder include sequential or simultaneous bilateral subacute optic neuropathy, resulting in large central visual field defects, poor visual acuity ( 6/60), and poor color vision. 2,3 ● CASE: A 34-year-old man had loss of visual acuity in his right eye to counting fingers in December 1989. Deterio- ration continued, and 6 months later, visual acuity in his left eye declined rapidly to counting fingers. Neuroimaging did not suggest multiple sclerosis. The onset of symptoms was not associated with excessive alcohol intake or smok- ing. He was found to have Leber hereditary optic neurop- athy and was subsequently treated with vitamin B12 injections. Visual field testing done in consecutive years 1991 to 1993 showed decreasing visual fields with increas- ingly dense central scotomas in each eye. At the same time, he subjectively reported worsening visual function. Examination revealed visual acuity of counting fingers in both eyes, and fundus examination demonstrated marked optic atrophy in both eyes. Mutation analysis confirmed that the patient had a mutation at 11778 of the mitochondrial genome. The mother of the patient was a carrier of the mutation, but healthy at 79 years of age with no noticeable visual or neurologic problems. His matrilineal aunts were not carri- ers of the mutation. However, his sister was a carrier of the mutation, and her daughters were heteroplasmic for the mutation. In 1998, he observed some weakness in his right leg and a tendency to stumble to his right side, which worsened with physical exertion. Although he did not have any obvious sensory loss on examination, he complained of having “cold hands and feet.” The power, tone, and reflexes in his upper limbs were normal. He displayed slight weakness in the lower limbs with brisk knee and ankle reflexes and extensor plantar reflexes. In July 1999, magnetic resonance imaging (MRI) ob- tained three sequences of the brain and three sequences of the cervical and thoracic spinal cord (Figures 1 and 2). Saggital T1-weighted and axial turbo spin echo T2- weighted and axial T2 fluid-attenuated inversion recovery studies of the brain revealed several lesions measuring less than 1 cm each. The lesions demonstrated low signal characteristics on the T1-weighted images and high signal characteristics on the T2-weighted images and were found throughout the white matter, predominantly in a callosal septal distribution, with evidence of periventricular exten- sion (Figure 1). Additionally, bilateral lesions were noted in the medulla and the cerebral peduncles with several subtle lesions in the posterior fossa. None of these lesions demonstrated mass effect. Axial T1-weighted and turbo spin echo T2-weighted images of the cervical and thoracic spine were obtained (Figure 2). Multiple areas of subtle signal alteration were located scattered throughout the cervical and upper thoracic spinal cord. An oblong-shaped hyperintense lesion on T2-weighted MRI was seen at the C2 to C3 level, measuring 2 cm in size with no enlarge- ment or narrowing of the spinal cord. Accepted for publication Apr 19, 2001. From the Department of Ophthalmology (M.T., I.M.M.) and the Department of Radiology and Diagnostic Imaging (R.B.), University of Alberta, Edmonton, Alberta, Canada. Inquiries to Ian M. MacDonald, MD, CM, University of Alberta, 8-32 Medical Sciences Bldg, Edmonton, Alberta T6G 2H7, Canada; fax: (780) 492-6934; e-mail: [email protected] BRIEF REPORTS VOL. 132,NO. 4 591
Transcript of Leber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms
REFERENCES
1. Kirkham Th, Sander MD, Sapp GA. Unilateral papilledemain benign intracranial hypertension. Can J Ophthalmol 1973;8:533–538.
2. Sedwick LA, Burde RM. Unilateral and asymmetric optic diskswelling with intracranial abnormalities. Am J Ophthalmol1983;96:484–487.
3. Strominger MB, Weiss GB, Mehler MF. Asymptomatic uni-lateral papilledema in pseudotumor cerebri. J Clinical Neuro-Ophthalmol 1992;12:238–241.
4. Walsh FB, Hoyt WF. Clinical neuro-ophthalmology. Vol. 1.Baltimore: Williams and Wilkins; 1979:569–574.
5. Killer HE, Laeng HR, Groscurth P. Lymphatic capillaries inthe meninges of the human optic nerve. J Neuro-Ophthalmol1999;19:222–228.
Leber Hereditary Optic Neuropathy,Progressive Visual Loss, and Multiple-Sclerosis-like SymptomsMai Tran, Ravi Bhargava, MD, andIan M. MacDonald, MD, CM
PURPOSE: To report a case of Leber hereditary opticneuropathy with multiple-sclerosis-like symptoms.METHODS: Observational case report. A 34-year-old manwas found to have Leber hereditary optic neuropathy anda mutation at position 11778 of the mitochondrialgenome. The progression of vision loss and onset ofweakness in the right leg warranted neuroimaging.RESULTS: Magnetic resonance imaging documented mul-tiple lesions in the brain and spinal cord.CONCLUSION: Although rarely reported, progression ofoptic neuropathy over months has been previously doc-umented in Leber hereditary optic neuropathy. Theemergence of multiple sclerosis-like symptoms and signsin our patient may be part of the spectrum of Leberhereditary optic neuropathy or a coincidental occurrence.(Am J Ophthalmol 2001;132:591–593. © 2001 byElsevier Science Inc. All rights reserved.)
LEBER HEREDITARY OPTIC NEUROPATHY [MIM 535000] IS
characterized by sudden loss of central vision in other-wise healthy individuals in the second or third decade oflife. All mutations found thus far have been missensemutations and affect the mitochondrial respiratory chain:complex I, III, and IV subunits.1 The clinical features ofthe disorder include sequential or simultaneous bilateralsubacute optic neuropathy, resulting in large central visual
field defects, poor visual acuity (� 6/60), and poor colorvision.2,3
● CASE: A 34-year-old man had loss of visual acuity in hisright eye to counting fingers in December 1989. Deterio-ration continued, and 6 months later, visual acuity in hisleft eye declined rapidly to counting fingers. Neuroimagingdid not suggest multiple sclerosis. The onset of symptomswas not associated with excessive alcohol intake or smok-ing. He was found to have Leber hereditary optic neurop-athy and was subsequently treated with vitamin B12injections. Visual field testing done in consecutive years1991 to 1993 showed decreasing visual fields with increas-ingly dense central scotomas in each eye. At the sametime, he subjectively reported worsening visual function.Examination revealed visual acuity of counting fingers inboth eyes, and fundus examination demonstrated markedoptic atrophy in both eyes.
Mutation analysis confirmed that the patient had amutation at 11778 of the mitochondrial genome. Themother of the patient was a carrier of the mutation, buthealthy at 79 years of age with no noticeable visual orneurologic problems. His matrilineal aunts were not carri-ers of the mutation. However, his sister was a carrier of themutation, and her daughters were heteroplasmic for themutation.
In 1998, he observed some weakness in his right leg anda tendency to stumble to his right side, which worsenedwith physical exertion. Although he did not have anyobvious sensory loss on examination, he complained ofhaving “cold hands and feet.” The power, tone, andreflexes in his upper limbs were normal. He displayed slightweakness in the lower limbs with brisk knee and anklereflexes and extensor plantar reflexes.
In July 1999, magnetic resonance imaging (MRI) ob-tained three sequences of the brain and three sequences ofthe cervical and thoracic spinal cord (Figures 1 and 2).Saggital T1-weighted and axial turbo spin echo T2-weighted and axial T2 fluid-attenuated inversion recoverystudies of the brain revealed several lesions measuring lessthan 1 cm each. The lesions demonstrated low signalcharacteristics on the T1-weighted images and high signalcharacteristics on the T2-weighted images and were foundthroughout the white matter, predominantly in a callosalseptal distribution, with evidence of periventricular exten-sion (Figure 1). Additionally, bilateral lesions were notedin the medulla and the cerebral peduncles with severalsubtle lesions in the posterior fossa. None of these lesionsdemonstrated mass effect. Axial T1-weighted and turbospin echo T2-weighted images of the cervical and thoracicspine were obtained (Figure 2). Multiple areas of subtlesignal alteration were located scattered throughout thecervical and upper thoracic spinal cord. An oblong-shapedhyperintense lesion on T2-weighted MRI was seen at theC2 to C3 level, measuring 2 cm in size with no enlarge-ment or narrowing of the spinal cord.
Accepted for publication Apr 19, 2001.From the Department of Ophthalmology (M.T., I.M.M.) and the
Department of Radiology and Diagnostic Imaging (R.B.), University ofAlberta, Edmonton, Alberta, Canada.
Inquiries to Ian M. MacDonald, MD, CM, University of Alberta, 8-32Medical Sciences Bldg, Edmonton, Alberta T6G 2H7, Canada; fax: (780)492-6934; e-mail: [email protected]
BRIEF REPORTSVOL. 132, NO. 4 591
The appearance of widespread white matter changesfound predominantly in a callosal septal distributionwithin the brain and multiple lesions with similar signalcharacteristics in the spinal cord were most consistent witha diffuse demyelinating process such as multiple sclerosis.
Presently, 18 missense mutations have been found thateither in isolation or in combination with each other causeLeber hereditary optic neuropathy. Although some disputeremains over the actual consequences of some of thesemutations, consensus exists that three mutations at base-pairs 11778, 3460, and 14484 are primarily causative.These mutations are found in at least 90% of Leberhereditary optic neuropathy families.3
Multiple sclerosis-like symptomology has been describedin combination with Leber hereditary optic neuropathyfamilies with the 11778 mutation.2,4 Although multiplesclerosis-like symptoms in Leber hereditary optic neurop-athy appear to be reported more frequently in femalepatients, cases in male patients have also been reported.5Here, we report a man with the 11778 mutation whodisplayed multiple sclerosis-like symptoms that developedapproximately a decade after the onset of Leber hereditaryoptic neuropathy. Patients should not be immediatelylabeled as having multiple sclerosis when a preexisting
mutation has been detected for Leber hereditary opticneuropathy. The signs and symptoms experienced by ourpatient may represent the spectrum of Leber hereditaryoptic neuropathy or alternatively the chance occurrence ofmultiple sclerosis in a patient with Leber hereditary opticneuropathy.
In Leber hereditary optic neuropathy, vision loss canoccur in both eyes simultaneously or sequentially. Al-though the progression of the disorder varies considerably,ranging from sudden and complete vision loss to progres-sive decline up to 2 years, progressive loss of vision in ourpatient over 4 years was highly unusual.
ACKNOWLEDGMENTS
We would like to thank D. C. Wallace, PhD, Center forMolecular Medicine, Emory University School of Medi-cine, for performing the mutational analysis, confirmingthe 11778 mutation in the male Leber hereditary opticneuropathy patient. Accession numbers and URLs for datain this article are as follows: Online Mendelian Inheri-tance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for Leber optic atrophy [MIM 535000]).
FIGURE 1. Axial fluid-attenuated inversion recovery image ofthe brain shows ellipsoid periventricular (arrowheads) andsubcortical (arrows) white matter hyperintensities in bothcerebral hemispheres. FIGURE 2. A Turbo spin echo T2-weighted image of the
cervical and thoracic spine shows linear hyperintensity (arrow-head) in the ventral aspect of the spinal cord at the C3 and C4levels.
AMERICAN JOURNAL OF OPHTHALMOLOGY592 OCTOBER 2001
REFERENCES
1. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNAmutation associated with Leber’s hereditary optic neuropathy.Science 1988;242:1427–1430.
2. Harding AE, Sweeney MG, Miller DH, et al. Occurrence of amultiple sclerosis-like illness in women who have a Leber’shereditary optic neuropathy mitochondrial DNA mutation.Brain 1992;115:979–989.
3. Riordan-Eva P, Harding AE. Leber’s hereditary optic neurop-athy: the clinical relevance of different mitochondrial DNAmutations. J Med Genet 1995;32:81–87.
4. Newman NJ, Lott MT, Wallace DC. The clinical character-istics of pedigrees of Leber’s hereditary optic neuropathy withthe 11778 mutation. Am J Ophthalmol 1991;111:750–762.
5. Olsen NK, Hansen AW, Nørby S, et al. Leber’s hereditaryoptic neuropathy associated with a disorder indistinguishablefrom multiple sclerosis in a male harbouring the mitochondrialDNA 11778 mutation. Acta Neurol Scand 1995;91:326–39.
Isolated Bilateral Trochlear NervePalsy as the First Clinical Sign of aMetastasic Bronchial CarcinomaChristine Mielke, MD,Mark S. M. Alexander, FRCR, andNitin Anand, FRCS
PURPOSE: To report a case with isolated, nontraumaticbilateral fourth nerve palsy as the first clinical sign of ametastatic lung carcinoma.METHODS: Case report. A 56-year-old man presentedwith isolated, nontraumatic bilateral fourth nerve palsy.Magnetic resonance imaging (MRI) of the brain andorbits and, subsequently, chest x-ray and a computertomographic (CT)-scan of the thorax, the abdomen, andthe pelvis were performed.RESULTS: Magnetic resonance imaging confirmed thepresence of a midline brain stem lesion in the region ofdecussation of the trochlear nerves. Computed tomo-graphic scan of the chest revealed that the lesion wascaused by a metastatic lung carcinoma.CONCLUSION: The findings of isolated bilateral fourthnerve palsy in the absence of trauma should alert theclinician to the possibility of a posterior fossa lesion inthe region of the trochlear nerves. Besides urgent scan-ning of the dorsal midbrain, investigations should bedirected to search for the primary tumor. (Am J Oph-thalmol 2001;132:593–594. © 2001 by Elsevier ScienceInc. All rights reserved.)
A56-YEAR-OLD CAUCASIAN MAN WAS REFERRED TO THE
eye clinic with a 4-week history of double vision whilereading and walking down the stairs. He avoided doublevision by depressing his chin. He was a heavy smoker since15 years of age.
Corrected visual acuity was RE: 6/6 and LE: 6/9. Ocularmotility examination revealed a V pattern esotropia. TheBielschowsky test was positive for both sides. The Hesscharts confirmed an underaction of both superior obliquemuscles and a slight overaction of both inferior obliquemuscles, which suggested bilateral trochlear nerve palsy.Pupil responses were normal. Anterior segment and fundusexamination were within normal limits in both eyes.
On systemic examination, no other neurologic deficitwas noted. Cardiovascular examination was also withinnormal limits. A magnetic resonance imaging (MRI)-scanwith contrast (IV Gadolinium-DTPA 10 ml) of the brainand the orbits was arranged. T1-weighted sagittal, axial,and coronal sections after contrast enhancement showedthree intracranial mass lesions, the largest was lying in theanterolateral aspect of the left frontal cortex. The secondlesion was lying toward the vertex in the left para-falcineregion, and the third was in the brain stem lying inproximity to the cerebral aqueduct and slightly to the leftof the midline close to the oculomotor nucleus (Figures 1and 2). Because of their enhancing characteristics andtheir location, it was concluded that the lesions were likelyto represent metastasis.
Hence, a chest x-ray and a computer tomographic(CT)-scan of the thorax, the abdomen, and the pelvis were
Accepted for publication Apr 6, 2001.From the Department of Ophthalmology (C.M., N.A.) and the
Department of Radiology (M.S.M.A.), The Luton and Dunstable Hospi-tal NHS Trust, Luton, United Kingdom.
Inquiries to N. Anand, Department of Ophthalmology, Luton andDunstable Hospital, Luton LU4 0DZ, UK; fax: 44-1582-497174; e-mail:[email protected]
FIGURE 1. Coronal postcontrast (Gadolinium) T1 magneticresonance image shows a 2-cm enhancing midline mass (blackarrow) in the brain stem.
BRIEF REPORTSVOL. 132, NO. 4 593
