- Email: [email protected]
Curtains
SURVEY OF OPHTHALMOLOGY
VOLUME 57 NUMBER 3 MAY–JUNE 2012
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
Curtains Paul H. Phillips, MD,1,2 Edgardo Angtuaco, MD,1 Rudy L. VanHemert, MD,1 and Rod Foroozan, MD3 1
University of Arkansas Medical Center, Little Rock, Arkansas; 2Arkansas Children’s Hospital, Little Rock, Arkansas; and 3Baylor College of Medicine, Houston, Texas, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report
examination showed bilateral, asymmetric, upper lid ptosis, OD O OS, with a marginal reflex distance of --3.0 mm OD and --1.0 mm OS (Fig. 1). There were mild adduction deficits OD O OS, 50% elevation deficits of both eyes, and an exophoria greater at near (Fig. 2). Prism and alternate cover testing in primary position disclosed 6 prism diopters of exophoria at distance and 12 prism diopters of exophoria at near. There was an adduction lag of both eyes with horizontal saccades and occasional abducting nystagmus. Lid closure, facial sensation, and the remainder of the neurological examination were normal. Where would you localize the patient’s neurologic deficits ? Are his findings consistent with myasthenia gravis? What tests would you do to further localize his deficit ?
A 55-year-old man presented with a 3-month history of headaches, nausea, photophobia, and tinnitus. Two weeks before presentation, he developed progressive, bilateral, upper lid ptosis; intermittent, horizontal diplopia on lateral gaze; and increased headache severity. He consulted his family physician who referred him to our neuroophthalmology service with a diagnosis of myasthenia gravis. Past medical history was remarkable for lower back pain from an injury 20 years prior to presentation, genital herpes, and rheumatic fever as a child. He had no known immunosuppressive condition. Medications included non-steroidal antiinflammatory drugs for back pain. He denied use of alcohol, tobacco, and recreational drugs. His occupation was that of a ‘‘bush-hogger’’, which consisted of driving a tractor with a device that cuts grass, trees, and hay. He was alert, oriented 3, and afebrile. Visual acuity was 20/20 OU, and automated Humphrey 24-2 visual fields were full. Pupillary, slit-lamp, and funduscopic examinations were normal. External
Comments COMMENTS BY ROD FOROOZAN, MD
Before answering these questions, it may be helpful to generate a list of conditions that may cause bilateral ptosis and ocular motility deficits. 284
Ó 2012 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter doi:10.1016/j.survophthal.2011.04.005
285
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Fig. 1. External photograph of patient at presentation shows upper lid ptosis, right O left.
Myasthenia gravis may cause any type of pupilsparing deficit and ptosis:8 third nerve palsy (either nuclear or bilateral to account for bilateral findings) with many different specific causes; bilateral findings suggest midbrain or bilateral nerve disease;12 Guillain-Barre´ syndrome (Fisher variant): less likely with no other neurologic deficits and sparing of the pupils;25 progressive syndromes of ptosis and opthalmoplegia such as chronic progressive external ophthalmoplegia and oculopharyngeal dystrophy: unlikely without a long progressive course;14 botulism (not only systemically, but also after periocular injections of toxin): less likely without exposure, given duration of symptoms, and without pupillary involvement;27 Wernicke encephalopathy: unlikely with no history of alcohol use and without history of malabsorption syndrome/dietary insufficiency;6 paraneoplastic syndromes: rare and no other clinical suggestion of disease;3 and Eaton-Lambert syndrome: rare, and no other clinical suggestion of disease.26 In a series of hospitalized patients with bilateral ocular motor paresis, Fisher variant, stroke, and myasthenia were the most common causes.10 The common theme is that the dysfunction results from involvement of the muscle, neuromuscular junction, and/or course of the third nerve (from the nucleus to the innervated structures). This patient has bilateral ptosis, adduction, and supraduction deficits. The third nerve is responsible for innervation of the levator palpebrae, superior rectus, medial rectus, inferior rectus, inferior oblique muscles, and pupil via the ciliary ganglion. However, the innervation is complicated as there are subnuclei (with a single subnucleus for both levators and crossed innervation from the superior rectus
subnuclei) in the midbrain for each extraocular muscle innervated by the third nerve.19 The third nerve splits into superior and inferior divisions, typically in the region of cavernous sinus/ orbital apex, with the superior division innervating the levator and superior rectus; this divisional arrangement can be manifested clinically by lesions from the brainstem to the orbit, however. In this patient the pupil, inferior rectus, and inferior oblique are spared on each side. This suggests that the superior division would be involved on each side or within the midbrain. While one would routinely expect multiple deficits (and perhaps even pupillary involvement) with midbrain lesions causing third nerve palsies, many varieties of deficits highlight the complexities of the anatomy in this region.15,23 If we take the ocular findings in isolation (eyelid, motility, and pupils), the deficits could be consistent with myasthenia gravis. Myasthenia gravis spares the pupils clinically and may cause virtually any type of ocular misalignment. Myasthenia may also cause a pattern of pseudo-internuclear ophthalmoplegia with ‘‘abducting nystagmus’’ that looks clinically similar to that caused by a brainstem lesion.13 Early on myasthenia may spare saccades and often does not cause the adduction lag that is more typical of paralytic/neurogenic processes. One can be mislead, however, by clinical findings when trying to distinguish myasthenia gravis from other causes of eyelid and ocular motility dysfunction, including disorders of the midbrain.2,20 Accepting all of this, his findings are not completely isolated. Apart from the ocular findings, his neurologic examination was said to be normal, but he has a 3-month history of headaches, nausea, photophobia, and tinnitus. It may be helpful to get additional history regarding these symptoms. Are they constant, intermittent, or associated with other symptoms? I am not aware of any specific risks of his occupation, but it may be helpful to ask him or look into this more extensively. One could perform other clinical tests (ice test, rest test, and others) for myasthenia gravis and ask about variability of symptoms. Myathenia gravis should not cause clinical pupillary dysfunction and should not directly cause headaches and his other symptoms. Nevertheless, I would start with an MRI of the brain and orbits with fat suppression and contrast and also get an acetylcholine receptor antibody. He could have more than one condition causing his findings if the headaches and other symptoms are coincidental.
Case Report (Continued) Cranial magnetic imaging of the brain with gadolinium showed enhancing extra-axial and
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Fig. 2. Patient at presentation. Composite ocular motility photograph shows limited elevation of both eyes and limited adduction, right eye O left eye.
intra-axial midbrain lesions (Fig. 3). The extra-axial lesion in the midbrain was an enhancing mass in the interpeduncular fossa where the right cranial nerve III exits the brainstem. The intra-axial lesions were in the midline tectum of the midbrain anterior to the sylvian aqueduct near the third nerve nucleus and medial longitudinal fasciculus. What is your differential diagnosis ? What is your recommended diagnostic work-up?
Comments (Continued) Before generating a list, I would discuss the findings with the neuroradiologist. I find that the interpretation of the images may be improved by sharing as many clinical details about the patient as I can provide. I had neuroradiologists review these images, and they helped generate a list for this enhancing lesion: sterile inflammatory (sarcoidosis, demyelination) infectious (syphilis, tuberculosis, fungus) neoplastic (including metastasis and lymphoma) I would add that at this point my view is that the ophthalmologist has done his job of determining
that there is a central problem causing the findings, and it is reasonable to suggest that other specialties get involved to help elucidate the specific etiology. A biopsy would be the definitive diagnostic test, but this would not be an easy area to biopsy. I would order blood tests for inflammatory and infectious causes (angiotensin converting enzyme, erythrocyte sedimentation rate, complete blood count, RPR, FTA-ABS, HIV, QuantiFERON-TB), computed tomography of the chest and abdomen for potential inflammatory or metastatic sites, and lumbar puncture with cell count, protein, glucose, culture, and Gram stain. Given our differential, it would be helpful to draw a large volume of cerebrospinal fluid to allow cytology looking for malignant cells and stains for acid-fast bacilli and fungal stains. I would also include oligocloncal bands, although their utility is controversial.
Case Report (Concluded) Laboratory testing including complete blood count, electrolytes, sedimentation rate, C-reactive protein, HIV titers, FTA-ABS, RPR, angiotensin converting enzyme, ANCA, compliment levels, and
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Fig. 3. Cranial magnetic resonance imaging of patient at presentation. A: Noncontrast T1-weighted sagittal view shows an isointense extra-axial lesion in the interpeduncular fossa (arrow). B: Contrast enhanced T1-weighted sagittal view shows enhancing lesions involving the interpeduncular fossa (arrow) and midbrain tectum anterior to the sylvian aqueduct (arrowhead). C: T1-weighted coronal view with gadolinium shows enhancing intra-axial midbrain lesion. D: T2-weighted axial view shows increased signal (arrow) anterior to sylvian aqueduct in the midbrain tectum at the region of the cranial nerve III nucleus and medial longitudinal fasciculus. E: T1-weighted axial view with gadolinium shows enhancing extra-axial lesion in the interpeduncular fossa (arrow) and the intra-axial tectal lesion (arrowhead). F: A more superior T1-weighted axial section shows the enhancing lesion in the interpeduncular fossa (arrow) and the linear enhancing lesion of the right cranial nerve III (arrowhead).
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T-cell helper/suppressor levels was unremarkable. A chest x-ray was normal. Lumbar puncture showed a mildly elevated opening pressure of 23 cm H2O, an elevated cell count of 464 mL with 72% lymphocytes and no red blood cells, an elevated protein of 140 mg/dL, and a glucose of 40 mg/dL. Gram stain and acid-fast bacillus smears showed no organisms. Bacterial and acid-fast bacillus cultures showed no growth. Polymerase chain reaction testing for tuberculosis, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus was negative. West Nile virus, enterovirus, and VDRL titers were negative. Angiotensin converting enzyme levels were normal. Cytology showed reactive cellular changes, primarily lymphocytes, with no sign of malignancy. Cerebrospinal fluid and serum cryptococcal antigen were positive. Cerebrospinal fluid fungal cultures grew Cryptococcus neoformans confirming a diagnosis of cryptococcal meningitis. He was treated with intravenous liposomal amphotericin B and flucytosine for several weeks, followed by oral fluconazole. His upper lid ptosis improved and his ocular motility deficits resolved (Fig. 4). Follow-up cranial magnetic resonance imaging and cerebrospinal fluid testing were normal (Fig. 5).
Discussion Cryptococcal meningitis often causes neuroophthalmologic dysfunction.30 Papilledema and cranial nerve VI palsy from elevated intracranial pressure are the most common neuro-ophthalmologic signs; cranial nerve III dysfunction is rare.18,29 Our patient was an apparently immunocompetent man who presented with bilateral cranial nerve III dysfunction from cryptococcal meningitis. He had multiple midbrain lesions that included the region of the interpeduncular fossa where the oculomotor nerve exits the brainstem, the third nerve nucleus, and the adjacent medial longitudinal fasciculus. The asymmetry of his bilateral upper lid ptosis favors bilateral cranial nerve III dysfunction from the lesion in the interpeduncular fossa. Ptosis from a lesion affecting the third nerve nucleus should be symmetric because of the midline location of the central caudal nucleus, the subnucleus that innervates the levator palpebrae of both eyes. His elevation and adduction deficits may be from bilateral cranial nerve III dysfunction as well—but his intra-axial lesions near the third nerve nucleus and the medial longitudinal fasciculus, however, could be responsible for some of his deficits. Indeed, he had bilateral adduction deficits and an associated abducting nystagmus on lateral gaze suggestive of bilateral internuclear ophthalmoplegia.
PHILLIPS ET AL
Cryptococcus neoformans is an encapsulated, yeastlike fungus that is found in pigeon droppings, soil, and food.30 Central nervous system infection occurs from inhalation of aerosolized organisms that travel from the lungs to the cerebrospinal fluid, resulting in a subacute or chronic meningoencephalitis. Although the organism is ubiquitous, the source of exposure in a given patient is often unknown, and person-to-person transmission is rare. It is possible that our patient’s occupation as a bush-hogger resulted in increased exposure to the organism; however, there is no known occupational predisposition to cryptococcal infection. Exposure to the organisms is common, but infection is rare, often related to immunosuppression from diseases such as AIDS, malignancy, diabetes, and immunosuppressive drugs.30 Cryptococcal meningitis does, however, occur in apparently healthy patients. In fact, many patients with cryptococcal meningitis described in the literature, especially prior to the AIDS epidemic, were apparently immunocompetent.17,18,22,24,29 This patient had no known immunosuppressive disease found in an extensive laboratory work-up. Cryptococcus causes neurological dysfunction via multiple mechanisms such as direct infiltration and inflammation induced by the organism, vasculitis with ischemia, mass effect from cryptococcomas, and elevated intracranial pressure. Virtually all neuro-ophthalmological signs have been described, including optic nerve dysfunction, frequently from papilledema, vertical field deficits from chiasmal and post-chiasmal involvement, cranial nerve palsies, internuclear ophthalmoplegia, supranuclear motility disorders such as skew deviation, and Horner syndrome.1,4,5,7,9,11,16,28--30 Our patient presented with bilateral cranial nerve III dysfunction. Cranial nerve III dysfunction is a relatively uncommon presentation of cryptococcal meningitis. In the series of 25 patients described by Tjia et al,29 the most common neuro-ophthalmologic findings were papilledema (8 patients) and cranial nerve VI palsy (7 patients) from elevated intracranial pressure. Only one patient had a cranial nerve III palsy. Similarly, among Okun and Butler’s18 series of 36 patients, the predominant findings were papilledema (12 patients) and cranial nerve VI palsy (4 patients). Although none of the patients had cranial nerve III dysfunction at presentation, one patient developed bilateral cranial nerve III dysfunction later in their clinical course. There are several case reports of third nerve dysfunction from cryptococcal meningitis. Azran et al1 described a patient who had episodic third nerve dysfunction. The episodes were attributed to vasculitis with variable ischemia. Keane described
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Fig. 4. External photograph of patient after 2 months of treatment shows improvement of upper lid ptosis and normal ocular motility. Examination after 4 months of treatment showed complete resolution of upper lid ptosis as well.
two patients with episodic third nerve dysfunction attributed to fluctuating intracranial pressure.11 Superior division cranial nerve III palsy and bilateral internal ophthalmoplegia have been described as well.4,16 Our patient also had bilateral adduction deficits with an abduction nystagmus suggestive of internuclear ophthalmoplegia. The intra-axial midbrain lesion involving the medial longitudinal fasciculus could account for this finding. Internuclear ophthalmoplegia from cryptococcal meningitis has been described in five patients and attributed to brainstem ischemia from vasculitis in two of these cases.7,9,21,28 Our patient had multiple enhancing intra-axial and extra-axial brainstem lesions consistent with meningitis from Cryptococcus or tuberculosis, or lymphoma. The diagnosis of cryptococcal meningitis was established from examination of the cerebrospinal fluid. Cranial neuroimaging in patients with cryptococcal meningitis may be normal or show non-specific intra-axial or extra-axial lesions, hydrocephalus, or both.30 Lumbar puncture typically discloses nonspecific findings of meningitis such as elevated intracranial pressure, elevated cell counts (mostly
lymphocytes), elevated protein, and a low glucose. Cryptococcal organisms may be demonstrated by India ink preparation that stains the capsule. However, the diagnosis is often suggested by the identification of the cryptococcal polysaccharide capsular antigen in the serum, cerebrospinal fluid, or both. The diagnosis should be confirmed by culture of the cryptococcal organism from cerebrospinal fluid. The organisms can also be identified from histology of affected tissue. Treatment of cryptococcal meningitis includes intravenous amphotericin with flucytosine, followed by oral fluconazole to prevent recurrence.30 Followup examination of the cerebrospinal fluid should be performed to confirm that fungal cultures of cerebrospinal fluid do not continue to grow Cryptococcus. Our patient was treated with intravenous liposomal amphotericin B and flucytosine followed by oral fluconazole. His neurological deficits, neuroimaging lesions, and cerebrospinal fluid abnormalities completely resolved. In summary, this case demonstrates that immunocompetent patients can present with bilateral cranial nerve III dysfunction from cryptococcal meningitis.
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Fig. 5. Cranial magnetic resonance imaging after 2 months of treatment. A: T1-weighted sagittal view with gadolinium. B: T1-weighted coronal view with gadolinium. C: T2-weighted axial view. D: T1-weighted axial view with gadolinium show resolution of lesions from cryptococcal meningitis.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this article was supported in part by an unrestricted grant from Research to Prevent Blindness (New York, New York) and the Pat & Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences (Little Rock, Arkansas).
References 1. Azran MS, Waljee A, Biousse V, et al. Episodic third nerve palsy with cryptococcal meningitis. Neurology. 2005;64:759--60 2. Barton JJ, Maguire J, Mezei M, et al. Mitochondrial pseudomyasthenia. J Neuroophthalmol. 2010;30(3):248--51 3. Berger JR, Bensalem M, Dalmau J. A brainstem paraneoplastic syndrome associated with prostate cancer. J Neurol Neurosurg Psychiatry. 2009;80(8):934--5 4. Chotmongkol V, Techasuknirun A. Superior division paresis of the oculomotor nerve caused by cryptococcal meningitis. J Med Assoc Thai. 1992;75:548--50
5. Custer P, Breen LA, Burde RM. Cryptococcal meningitis. An atypical presentation. J Clin Neuroophthalmol. 1982;2:33--7 6. Deramo VA, Jayamanne DG, Auerbach DB, et al. Acute bilateral ophthalmoplegia in a young woman. Surv Ophthalmol. 2000;44(6):513--7 7. Fay PM, Strominger MB. Wall-eyed bilateral internuclear ophthalmoplegia in central nervous system cryptococcosis. J Neuroophthalmol. 1999;19:131--5 8. Gilbert ME, Savino PJ. Ocular myasthenia gravis. Int Ophthalmol Clin. 2007;47(4):93--103, ix. 9. Gonyea EF, Heilman KM. Neuro-ophthalmic aspects of central nervous system cryptococcosis. Internuclear and Supranuclear ophthalmoplegia. Arch Ophthalmol. 1972;87: 164--8 10. Keane JR. Bilateral ocular paralysis: analysis of 31 inpatients. Arch Neurol. 2007;64(2):178--80 11. Keane JR. Intermittent third nerve palsy with cryptococcal meningitis. J Clin Neuroophthalmol. 1993;13:124--6 12. Keane JR. Third nerve palsy: analysis of 1400 personally examined inpatients. Can J Neurol Sci. 2010;37(5):662--70 13. Khanna S, Liao K, Kaminski HJ, et al. Ocular myasthenia revisited: insights from pseudo-internuclear ophthalmoplegia. J Neurol. 2007;254(11):1569--74 14. Lee MS, Kosmorsky GS, Cook JR, et al. My, what asthenia you have. Surv Ophthalmol. 2008;53(5):506--11 15. Lee AG, Tang RA, Wong GG, et al. Isolated inferior rectus muscle palsy resulting from a nuclear third nerve lesion as
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16. 17. 18. 19. 20. 21. 22. 23.
the initial manifestation of multiple sclerosis. J Neuroophthalmol. 2000;20(4):246--7 Lesser RL, Simon RM, Leon H, et al. Cryptococcal meningitis and internal ophthalmoplegia. Am J Ophthalmol. 1979;87:682--7 Nair KR, Jose J. Cryptococcal meningitis in unimmunocompromised patients. J Assoc Physicians India. 1995;43:222 Okun E, Butler WT. Ophthalmologic complications of cryptococcal meningitis. Arch Ophthalmol. 1964;71:86--91 Purvin V. Photo essay. Isolated fascicular third nerve palsy. J Neuroophthalmol. 2010;30(3):263--5 Ragge NK, Hoyt WF. Midbrain myasthenia: fatigable ptosis, ’lid twitch’ sign, and ophthalmoparesis from a dorsal midbrain glioma. Neurology. 1992;42(4):917--9 Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine. 1993;4:207--24 Sabetta JR, Andriole VT. Cryptococcal infection of the central nervous system. Med Clin North Am. 1985;69:333--44 Saeki N, Yamaura A, Sunami K. Bilateral ptosis with pupil sparing because of a discrete midbrain lesion: magnetic resonance imaging evidence of topographic arrangement within the oculomotor nerve. J Neuro-ophthalmol. 2000; 20(2):130--4
24. Sanchetee P. Cryptococcal meningitis in immunocompetent patients. J Assoc Physicians India. 1998;46:617--9 25. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barre´ syndrome (Fisher syndrome). J Neuro-ophthalmol. 2009;29(4):312--24 26. Spillane J, Beeson DJ, Kullmann DM. Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry. 2010;81(8):850--7 27. Stahl JS, Averbuch-Heller L, Remler BF, et al. Clinical evidence of extraocular muscle fiber-type specificity of botulinum toxin. Neurology. 1998;51(4):1093--9 28. Sung JY, Cheng PN, Lai KN. Internuclear ophthalmoplegia in cryptococcal meningitis. J Trop Med Hyg. 1991;94:116--7 29. Tjia TL, Yeow YK, Tan CB. Cryptococcal meningitis. J Neurol Neurosurg Psychiatry. 1985;48:853--8 30. Weinstein JM. Fungi and mycotic diseases, in Miller NR, Newman NJ (eds). Walsh & Hoyt’s Clinical Neuro-ophthalmology. Philadelphia, PA, Lippicott, Williams & Wilkins, ed 6 2005, pp 2817--52 Reprint address: Paul H. Phillips, MD, Department of Ophthalmology, Arkansas Children’s Hospital, Little Rock, AK 72202. e-mail: [email protected].
Abstract. A 55-year-old immunocompetent man presented with headache, nausea, progressive bilateral upper lid ptosis, and diplopia. Examination showed bilateral asymmetric upper lid ptosis with limited adduction and elevation of both eyes. Cranial magnetic resonance imaging revealed enhancing intra-axial and extra-axial midbrain lesions. Blood and cerebrospinal fluid were positive for cryptococcal antigen and cerebrospinal fluid fungal cultures grew Cryptococcus neoformans. Treatment with liposomal amphotericin B and flucytosine resulted in complete resolution of his neurological deficits and lesions on neuroimaging. Patients with cryptococcal meningitis may rarely present with bilateral cranial nerve III dysfunction. (Surv Ophthalmol 57:284--291, 2012. Ó 2012 Elsevier Inc. All rights reserved.) Key words.
cranial nerve III palsy
ptosis
cryptococcal meningitis
diplopia
VOLUME 57 NUMBER 3 MAY–JUNE 2012
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
Curtains Paul H. Phillips, MD,1,2 Edgardo Angtuaco, MD,1 Rudy L. VanHemert, MD,1 and Rod Foroozan, MD3 1
University of Arkansas Medical Center, Little Rock, Arkansas; 2Arkansas Children’s Hospital, Little Rock, Arkansas; and 3Baylor College of Medicine, Houston, Texas, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report
examination showed bilateral, asymmetric, upper lid ptosis, OD O OS, with a marginal reflex distance of --3.0 mm OD and --1.0 mm OS (Fig. 1). There were mild adduction deficits OD O OS, 50% elevation deficits of both eyes, and an exophoria greater at near (Fig. 2). Prism and alternate cover testing in primary position disclosed 6 prism diopters of exophoria at distance and 12 prism diopters of exophoria at near. There was an adduction lag of both eyes with horizontal saccades and occasional abducting nystagmus. Lid closure, facial sensation, and the remainder of the neurological examination were normal. Where would you localize the patient’s neurologic deficits ? Are his findings consistent with myasthenia gravis? What tests would you do to further localize his deficit ?
A 55-year-old man presented with a 3-month history of headaches, nausea, photophobia, and tinnitus. Two weeks before presentation, he developed progressive, bilateral, upper lid ptosis; intermittent, horizontal diplopia on lateral gaze; and increased headache severity. He consulted his family physician who referred him to our neuroophthalmology service with a diagnosis of myasthenia gravis. Past medical history was remarkable for lower back pain from an injury 20 years prior to presentation, genital herpes, and rheumatic fever as a child. He had no known immunosuppressive condition. Medications included non-steroidal antiinflammatory drugs for back pain. He denied use of alcohol, tobacco, and recreational drugs. His occupation was that of a ‘‘bush-hogger’’, which consisted of driving a tractor with a device that cuts grass, trees, and hay. He was alert, oriented 3, and afebrile. Visual acuity was 20/20 OU, and automated Humphrey 24-2 visual fields were full. Pupillary, slit-lamp, and funduscopic examinations were normal. External
Comments COMMENTS BY ROD FOROOZAN, MD
Before answering these questions, it may be helpful to generate a list of conditions that may cause bilateral ptosis and ocular motility deficits. 284
Ó 2012 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter doi:10.1016/j.survophthal.2011.04.005
285
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Fig. 1. External photograph of patient at presentation shows upper lid ptosis, right O left.
Myasthenia gravis may cause any type of pupilsparing deficit and ptosis:8 third nerve palsy (either nuclear or bilateral to account for bilateral findings) with many different specific causes; bilateral findings suggest midbrain or bilateral nerve disease;12 Guillain-Barre´ syndrome (Fisher variant): less likely with no other neurologic deficits and sparing of the pupils;25 progressive syndromes of ptosis and opthalmoplegia such as chronic progressive external ophthalmoplegia and oculopharyngeal dystrophy: unlikely without a long progressive course;14 botulism (not only systemically, but also after periocular injections of toxin): less likely without exposure, given duration of symptoms, and without pupillary involvement;27 Wernicke encephalopathy: unlikely with no history of alcohol use and without history of malabsorption syndrome/dietary insufficiency;6 paraneoplastic syndromes: rare and no other clinical suggestion of disease;3 and Eaton-Lambert syndrome: rare, and no other clinical suggestion of disease.26 In a series of hospitalized patients with bilateral ocular motor paresis, Fisher variant, stroke, and myasthenia were the most common causes.10 The common theme is that the dysfunction results from involvement of the muscle, neuromuscular junction, and/or course of the third nerve (from the nucleus to the innervated structures). This patient has bilateral ptosis, adduction, and supraduction deficits. The third nerve is responsible for innervation of the levator palpebrae, superior rectus, medial rectus, inferior rectus, inferior oblique muscles, and pupil via the ciliary ganglion. However, the innervation is complicated as there are subnuclei (with a single subnucleus for both levators and crossed innervation from the superior rectus
subnuclei) in the midbrain for each extraocular muscle innervated by the third nerve.19 The third nerve splits into superior and inferior divisions, typically in the region of cavernous sinus/ orbital apex, with the superior division innervating the levator and superior rectus; this divisional arrangement can be manifested clinically by lesions from the brainstem to the orbit, however. In this patient the pupil, inferior rectus, and inferior oblique are spared on each side. This suggests that the superior division would be involved on each side or within the midbrain. While one would routinely expect multiple deficits (and perhaps even pupillary involvement) with midbrain lesions causing third nerve palsies, many varieties of deficits highlight the complexities of the anatomy in this region.15,23 If we take the ocular findings in isolation (eyelid, motility, and pupils), the deficits could be consistent with myasthenia gravis. Myasthenia gravis spares the pupils clinically and may cause virtually any type of ocular misalignment. Myasthenia may also cause a pattern of pseudo-internuclear ophthalmoplegia with ‘‘abducting nystagmus’’ that looks clinically similar to that caused by a brainstem lesion.13 Early on myasthenia may spare saccades and often does not cause the adduction lag that is more typical of paralytic/neurogenic processes. One can be mislead, however, by clinical findings when trying to distinguish myasthenia gravis from other causes of eyelid and ocular motility dysfunction, including disorders of the midbrain.2,20 Accepting all of this, his findings are not completely isolated. Apart from the ocular findings, his neurologic examination was said to be normal, but he has a 3-month history of headaches, nausea, photophobia, and tinnitus. It may be helpful to get additional history regarding these symptoms. Are they constant, intermittent, or associated with other symptoms? I am not aware of any specific risks of his occupation, but it may be helpful to ask him or look into this more extensively. One could perform other clinical tests (ice test, rest test, and others) for myasthenia gravis and ask about variability of symptoms. Myathenia gravis should not cause clinical pupillary dysfunction and should not directly cause headaches and his other symptoms. Nevertheless, I would start with an MRI of the brain and orbits with fat suppression and contrast and also get an acetylcholine receptor antibody. He could have more than one condition causing his findings if the headaches and other symptoms are coincidental.
Case Report (Continued) Cranial magnetic imaging of the brain with gadolinium showed enhancing extra-axial and
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Fig. 2. Patient at presentation. Composite ocular motility photograph shows limited elevation of both eyes and limited adduction, right eye O left eye.
intra-axial midbrain lesions (Fig. 3). The extra-axial lesion in the midbrain was an enhancing mass in the interpeduncular fossa where the right cranial nerve III exits the brainstem. The intra-axial lesions were in the midline tectum of the midbrain anterior to the sylvian aqueduct near the third nerve nucleus and medial longitudinal fasciculus. What is your differential diagnosis ? What is your recommended diagnostic work-up?
Comments (Continued) Before generating a list, I would discuss the findings with the neuroradiologist. I find that the interpretation of the images may be improved by sharing as many clinical details about the patient as I can provide. I had neuroradiologists review these images, and they helped generate a list for this enhancing lesion: sterile inflammatory (sarcoidosis, demyelination) infectious (syphilis, tuberculosis, fungus) neoplastic (including metastasis and lymphoma) I would add that at this point my view is that the ophthalmologist has done his job of determining
that there is a central problem causing the findings, and it is reasonable to suggest that other specialties get involved to help elucidate the specific etiology. A biopsy would be the definitive diagnostic test, but this would not be an easy area to biopsy. I would order blood tests for inflammatory and infectious causes (angiotensin converting enzyme, erythrocyte sedimentation rate, complete blood count, RPR, FTA-ABS, HIV, QuantiFERON-TB), computed tomography of the chest and abdomen for potential inflammatory or metastatic sites, and lumbar puncture with cell count, protein, glucose, culture, and Gram stain. Given our differential, it would be helpful to draw a large volume of cerebrospinal fluid to allow cytology looking for malignant cells and stains for acid-fast bacilli and fungal stains. I would also include oligocloncal bands, although their utility is controversial.
Case Report (Concluded) Laboratory testing including complete blood count, electrolytes, sedimentation rate, C-reactive protein, HIV titers, FTA-ABS, RPR, angiotensin converting enzyme, ANCA, compliment levels, and
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Fig. 3. Cranial magnetic resonance imaging of patient at presentation. A: Noncontrast T1-weighted sagittal view shows an isointense extra-axial lesion in the interpeduncular fossa (arrow). B: Contrast enhanced T1-weighted sagittal view shows enhancing lesions involving the interpeduncular fossa (arrow) and midbrain tectum anterior to the sylvian aqueduct (arrowhead). C: T1-weighted coronal view with gadolinium shows enhancing intra-axial midbrain lesion. D: T2-weighted axial view shows increased signal (arrow) anterior to sylvian aqueduct in the midbrain tectum at the region of the cranial nerve III nucleus and medial longitudinal fasciculus. E: T1-weighted axial view with gadolinium shows enhancing extra-axial lesion in the interpeduncular fossa (arrow) and the intra-axial tectal lesion (arrowhead). F: A more superior T1-weighted axial section shows the enhancing lesion in the interpeduncular fossa (arrow) and the linear enhancing lesion of the right cranial nerve III (arrowhead).
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T-cell helper/suppressor levels was unremarkable. A chest x-ray was normal. Lumbar puncture showed a mildly elevated opening pressure of 23 cm H2O, an elevated cell count of 464 mL with 72% lymphocytes and no red blood cells, an elevated protein of 140 mg/dL, and a glucose of 40 mg/dL. Gram stain and acid-fast bacillus smears showed no organisms. Bacterial and acid-fast bacillus cultures showed no growth. Polymerase chain reaction testing for tuberculosis, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus was negative. West Nile virus, enterovirus, and VDRL titers were negative. Angiotensin converting enzyme levels were normal. Cytology showed reactive cellular changes, primarily lymphocytes, with no sign of malignancy. Cerebrospinal fluid and serum cryptococcal antigen were positive. Cerebrospinal fluid fungal cultures grew Cryptococcus neoformans confirming a diagnosis of cryptococcal meningitis. He was treated with intravenous liposomal amphotericin B and flucytosine for several weeks, followed by oral fluconazole. His upper lid ptosis improved and his ocular motility deficits resolved (Fig. 4). Follow-up cranial magnetic resonance imaging and cerebrospinal fluid testing were normal (Fig. 5).
Discussion Cryptococcal meningitis often causes neuroophthalmologic dysfunction.30 Papilledema and cranial nerve VI palsy from elevated intracranial pressure are the most common neuro-ophthalmologic signs; cranial nerve III dysfunction is rare.18,29 Our patient was an apparently immunocompetent man who presented with bilateral cranial nerve III dysfunction from cryptococcal meningitis. He had multiple midbrain lesions that included the region of the interpeduncular fossa where the oculomotor nerve exits the brainstem, the third nerve nucleus, and the adjacent medial longitudinal fasciculus. The asymmetry of his bilateral upper lid ptosis favors bilateral cranial nerve III dysfunction from the lesion in the interpeduncular fossa. Ptosis from a lesion affecting the third nerve nucleus should be symmetric because of the midline location of the central caudal nucleus, the subnucleus that innervates the levator palpebrae of both eyes. His elevation and adduction deficits may be from bilateral cranial nerve III dysfunction as well—but his intra-axial lesions near the third nerve nucleus and the medial longitudinal fasciculus, however, could be responsible for some of his deficits. Indeed, he had bilateral adduction deficits and an associated abducting nystagmus on lateral gaze suggestive of bilateral internuclear ophthalmoplegia.
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Cryptococcus neoformans is an encapsulated, yeastlike fungus that is found in pigeon droppings, soil, and food.30 Central nervous system infection occurs from inhalation of aerosolized organisms that travel from the lungs to the cerebrospinal fluid, resulting in a subacute or chronic meningoencephalitis. Although the organism is ubiquitous, the source of exposure in a given patient is often unknown, and person-to-person transmission is rare. It is possible that our patient’s occupation as a bush-hogger resulted in increased exposure to the organism; however, there is no known occupational predisposition to cryptococcal infection. Exposure to the organisms is common, but infection is rare, often related to immunosuppression from diseases such as AIDS, malignancy, diabetes, and immunosuppressive drugs.30 Cryptococcal meningitis does, however, occur in apparently healthy patients. In fact, many patients with cryptococcal meningitis described in the literature, especially prior to the AIDS epidemic, were apparently immunocompetent.17,18,22,24,29 This patient had no known immunosuppressive disease found in an extensive laboratory work-up. Cryptococcus causes neurological dysfunction via multiple mechanisms such as direct infiltration and inflammation induced by the organism, vasculitis with ischemia, mass effect from cryptococcomas, and elevated intracranial pressure. Virtually all neuro-ophthalmological signs have been described, including optic nerve dysfunction, frequently from papilledema, vertical field deficits from chiasmal and post-chiasmal involvement, cranial nerve palsies, internuclear ophthalmoplegia, supranuclear motility disorders such as skew deviation, and Horner syndrome.1,4,5,7,9,11,16,28--30 Our patient presented with bilateral cranial nerve III dysfunction. Cranial nerve III dysfunction is a relatively uncommon presentation of cryptococcal meningitis. In the series of 25 patients described by Tjia et al,29 the most common neuro-ophthalmologic findings were papilledema (8 patients) and cranial nerve VI palsy (7 patients) from elevated intracranial pressure. Only one patient had a cranial nerve III palsy. Similarly, among Okun and Butler’s18 series of 36 patients, the predominant findings were papilledema (12 patients) and cranial nerve VI palsy (4 patients). Although none of the patients had cranial nerve III dysfunction at presentation, one patient developed bilateral cranial nerve III dysfunction later in their clinical course. There are several case reports of third nerve dysfunction from cryptococcal meningitis. Azran et al1 described a patient who had episodic third nerve dysfunction. The episodes were attributed to vasculitis with variable ischemia. Keane described
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Fig. 4. External photograph of patient after 2 months of treatment shows improvement of upper lid ptosis and normal ocular motility. Examination after 4 months of treatment showed complete resolution of upper lid ptosis as well.
two patients with episodic third nerve dysfunction attributed to fluctuating intracranial pressure.11 Superior division cranial nerve III palsy and bilateral internal ophthalmoplegia have been described as well.4,16 Our patient also had bilateral adduction deficits with an abduction nystagmus suggestive of internuclear ophthalmoplegia. The intra-axial midbrain lesion involving the medial longitudinal fasciculus could account for this finding. Internuclear ophthalmoplegia from cryptococcal meningitis has been described in five patients and attributed to brainstem ischemia from vasculitis in two of these cases.7,9,21,28 Our patient had multiple enhancing intra-axial and extra-axial brainstem lesions consistent with meningitis from Cryptococcus or tuberculosis, or lymphoma. The diagnosis of cryptococcal meningitis was established from examination of the cerebrospinal fluid. Cranial neuroimaging in patients with cryptococcal meningitis may be normal or show non-specific intra-axial or extra-axial lesions, hydrocephalus, or both.30 Lumbar puncture typically discloses nonspecific findings of meningitis such as elevated intracranial pressure, elevated cell counts (mostly
lymphocytes), elevated protein, and a low glucose. Cryptococcal organisms may be demonstrated by India ink preparation that stains the capsule. However, the diagnosis is often suggested by the identification of the cryptococcal polysaccharide capsular antigen in the serum, cerebrospinal fluid, or both. The diagnosis should be confirmed by culture of the cryptococcal organism from cerebrospinal fluid. The organisms can also be identified from histology of affected tissue. Treatment of cryptococcal meningitis includes intravenous amphotericin with flucytosine, followed by oral fluconazole to prevent recurrence.30 Followup examination of the cerebrospinal fluid should be performed to confirm that fungal cultures of cerebrospinal fluid do not continue to grow Cryptococcus. Our patient was treated with intravenous liposomal amphotericin B and flucytosine followed by oral fluconazole. His neurological deficits, neuroimaging lesions, and cerebrospinal fluid abnormalities completely resolved. In summary, this case demonstrates that immunocompetent patients can present with bilateral cranial nerve III dysfunction from cryptococcal meningitis.
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Fig. 5. Cranial magnetic resonance imaging after 2 months of treatment. A: T1-weighted sagittal view with gadolinium. B: T1-weighted coronal view with gadolinium. C: T2-weighted axial view. D: T1-weighted axial view with gadolinium show resolution of lesions from cryptococcal meningitis.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this article was supported in part by an unrestricted grant from Research to Prevent Blindness (New York, New York) and the Pat & Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences (Little Rock, Arkansas).
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24. Sanchetee P. Cryptococcal meningitis in immunocompetent patients. J Assoc Physicians India. 1998;46:617--9 25. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barre´ syndrome (Fisher syndrome). J Neuro-ophthalmol. 2009;29(4):312--24 26. Spillane J, Beeson DJ, Kullmann DM. Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry. 2010;81(8):850--7 27. Stahl JS, Averbuch-Heller L, Remler BF, et al. Clinical evidence of extraocular muscle fiber-type specificity of botulinum toxin. Neurology. 1998;51(4):1093--9 28. Sung JY, Cheng PN, Lai KN. Internuclear ophthalmoplegia in cryptococcal meningitis. J Trop Med Hyg. 1991;94:116--7 29. Tjia TL, Yeow YK, Tan CB. Cryptococcal meningitis. J Neurol Neurosurg Psychiatry. 1985;48:853--8 30. Weinstein JM. Fungi and mycotic diseases, in Miller NR, Newman NJ (eds). Walsh & Hoyt’s Clinical Neuro-ophthalmology. Philadelphia, PA, Lippicott, Williams & Wilkins, ed 6 2005, pp 2817--52 Reprint address: Paul H. Phillips, MD, Department of Ophthalmology, Arkansas Children’s Hospital, Little Rock, AK 72202. e-mail: [email protected].
Abstract. A 55-year-old immunocompetent man presented with headache, nausea, progressive bilateral upper lid ptosis, and diplopia. Examination showed bilateral asymmetric upper lid ptosis with limited adduction and elevation of both eyes. Cranial magnetic resonance imaging revealed enhancing intra-axial and extra-axial midbrain lesions. Blood and cerebrospinal fluid were positive for cryptococcal antigen and cerebrospinal fluid fungal cultures grew Cryptococcus neoformans. Treatment with liposomal amphotericin B and flucytosine resulted in complete resolution of his neurological deficits and lesions on neuroimaging. Patients with cryptococcal meningitis may rarely present with bilateral cranial nerve III dysfunction. (Surv Ophthalmol 57:284--291, 2012. Ó 2012 Elsevier Inc. All rights reserved.) Key words.
cranial nerve III palsy
ptosis
cryptococcal meningitis
diplopia