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Table. 
Causes of Internuclear Ophthalmoplegia
Causes of Internuclear Ophthalmoplegia
1.
Spiller  WG Ophthalmoplegia internuclearis anterior: a case with necropsy. Brain 1924;47345- 357Article
2.
Cogan  DG Internuclear ophthalmoplegia, typical and atypical. Arch Ophthalmol 1970;84583- 589
PubMedArticle
3.
Fotzsch  R Die internukleare ophthalmoplegia. Ophthalmologica 1971;162331- 342
PubMedArticle
4.
Gonyea  EF Bilateral internuclear ophthalmoplegia. Arch Neurol 1974;31168- 173
PubMedArticle
5.
Thomke  FK The internuclear ophthalmoplegias.  In: Caplan  LR, Hopf  HC, eds. Brainstem Localization and Function. Berlin, Germany: Springer-Verlag; 1993:119-132
6.
Frohman  EMGoodin  DSCalabresi  PA  et al.  The utility of MRI in suspected MS: report of the subcommittee of the American Academy of Neurology. Neurology 2003;61602- 611
PubMedArticle
7.
Keane  JR Locked-in syndrome after head and neck trauma. Neurology 1986;3680- 82
PubMedArticle
8.
Devereaux  MWBrust  JCMKeane  JR Internuclear ophthalmoplegia caused by subdural hematoma. Neurology 1979;29251- 255
PubMedArticle
9.
Keane  JR Bilateral ocular motor signs after tentorial herniation in 25 patients. Arch Neurol 1986;43806- 807
PubMedArticle
10.
Shanzer  S Neuro-ophthalmology in 19th century Paris: pioneering work on conjugate gaze.  In: Rose  FC, ed. Neuroscience Across the Centuries. London, England: Smith-Gordon & Co Ltd; 1989:151-156
11.
Freeman  W Paralysis of associated lateral movements of the eyes: a symptom of intrapontile lesion. Arch Neurol Psychiatry 1922;7454- 487Article
12.
Paton  L Ocular palsies. Br J Ophthalmol 1921;5250- 271Article
13.
Holmes  G Palsies of the conjugate ocular movements. Br J Ophthalmol 1921;5241- 250Article
14.
Savitsky  NRangell  L The ocular findings in multiple sclerosis. Res Publ Assoc Res Nerv Ment Dis 1950;28403- 413
PubMed
15.
Cogan  DGKubik  CHSmith  WC Unilateral Internuclear ophthalmoplegia: report on eight cases with one postmortem study. Arch Ophthalmol 1950;44783- 796Article
16.
Madonick  MJ Ophthalmoplegia internuclearis anterior without a lesion of the posterior longitudinal bundle. Arch Neurol Psychiatry 1957;66338- 345Article
17.
Leigh  RJZee  DS The Neurology of Eye Movements. 3rd ed. New York, NY: Oxford University Press; 1999
18.
Keane  JR Neuro-ophthalmologic signs of AIDS: 50 patients. Neurology 1991;41841- 845
PubMedArticle
19.
Keane  JR Eye movement abnormalities in systemic lupus erythematosus. Arch Neurol 1995;521145- 1149
PubMedArticle
20.
Galindo  MPablos  JLGomez-Reino  JJ Internuclear ophthalmoplegia in systemic lupus erythematosus. Semin Arthritis Rheum 1998;28179- 186
PubMedArticle
21.
Alexander  ELMalinow  KLejewski  JE  et al.  Primary Sjogren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med 1986;104323- 330
PubMedArticle
22.
Patten  BMPages  M Severe neurological disease associated with hyperparathyroidism. Ann Neurol 1984;15453- 456
PubMedArticle
23.
Barnes  DMisra  VPYoung  EPThomas  PHarding  AE An adult onset hexosaminidase A deficiency syndrome with sensory neuropathy and internuclear ophthalmoplegia. J Neurol Neurosurg Psychiatry 1991;541112- 1113
PubMedArticle
24.
Al-Din  SNAnderson  MEeg-Olofsson  OTrontelf  JV Neuro-ophthalmic manifestation of ophthalmoplegia, ataxia and areflexia: a review. Acta Neurol Scand 1994;89157- 163
PubMedArticle
25.
Mastaglia  FLGrainger  MR Internuclear ophthalmoplegia in progressive supranuclear palsy. J Neurol Sci 1975;25303- 308
PubMedArticle
Neurological Review
May 2005

Internuclear OphthalmoplegiaUnusual Causes in 114 of 410 Patients

Author Affiliations

Author Affiliations: Department of Neurology, University of Southern California School of Medicine, Los Angeles.

 

DAVID E.PLEASUREMD

Arch Neurol. 2005;62(5):714-717. doi:10.1001/archneur.62.5.714
Abstract

Internuclear ophthalmoplegia (INO) is a sign of exquisite localizing value, often due to either multiple sclerosis or infarction. To demonstrate that unusual causes of INO are more common than the 11% reported in previous series, this review considers a case series of 410 inpatients whom I personally examined during a 33-year period. In this series, the cause of INO was infarction in 157 patients (38%), multiple sclerosis in 139 (34%), and unusual causes in 114 (28%). Unusual causes included trauma (20 cases), tentorial herniation (20 cases), infection (17 cases), tumor (17 cases), iatrogenic injury (12 cases), hemorrhage (13 cases), vasculitis (7 cases), and miscellaneous (8 cases). Internuclear ophthalmoplegia was unilateral in 136 of the infarct cases (87%), 38 of those with multiple sclerosis (27%), and 48 of the unusual cases (42%). Because unusual causes compose more than one quarter of the cases, the differential diagnosis of INO should be tripartite: multiple sclerosis, stroke, and other causes.

Internuclear ophthalmoplegia (INO), arguably the most discrete localizing sign in medicine, has considerable value in predicting multiple sclerosis (MS) or stroke, depending on whether the INO is bilateral or unilateral and on whether the patient is young or old. Although some of the earliest reported cases of INO were due to trauma, tuberculoma, encephalitis, and tumor,1 unusual causes tend to be obscured by these dichotomies. In 4 case series of INO,25 “other causes” compose less than 11% (Table). My experience in working with unselected neurologic inpatients, which demonstrated that “unusual” causes of INO are common, prompted this review.

PATIENTS

I examined all the patients in this study on the wards of the Los Angeles County/University of Southern California Medical Center and Rancho Los Amigos Hospital (rehabilitation) during a 33-year period. I reviewed my notes on all patients, still photographs (n = 171), motion pictures (n = 39), videotapes (n = 35), and selected hospital records and radiographs.

Internuclear ophthalmoplegia was defined as medial rectus limitation or obvious slowing, often accompanied by dissociated nystagmus and preserved convergence, and not better explained on any other basis than medial longitudinal fasciculus injury. Patients with the one-and-a-half syndrome were included, as were those with limited abduction in the same eye or lesser abduction limitation in the opposite eye. Of 435 patients with possible INO, 25—usually those with complex horizontal or fragmentary third nerve eye movement abnormalities—were excluded.

The cause of INO was determined using clinical criteria and appropriate course, laboratory studies of blood and cerebrospinal fluid, and the best contemporary radiologic studies. Multiple sclerosis was diagnosed using Poser or McDonald criteria.6 Tumors were diagnosed using biopsy findings in 9 cases, were inferred from biopsy findings of an associated metastasis in 4 cases, and were diagnosed using clinical and radiologic criteria in 3 pontine gliomas and 1 AIDS-related lymphoma. Cysticercosis was diagnosed using epidemiologic analysis, imaging studies, and cerebrospinal fluid cysticercal antibody titers, and presence of eosinophilia. Patients with syphilis had cerebrospinal fluid pleocytosis and a positive cerebrospinal fluid VDRL test. Systemic lupus erythematosus was diagnosed using the modified criteria of the American Rheumatological Association.

RESULTS

Of 410 cases of INO, 157 (38%) were caused by infarction (from cardiac emboli in 5 cases), 139 (34%) were caused by MS, and 114 (28%) were due to unusual causes (Table). Infarction was considered definite in 133 of 157 patients, and MS was considered definite in 99 of 139 cases. Unilateral INO occurred in 136 infarcts (87%), 38 MS cases (27%), and 48 unusual cases (42%).

Blunt head injury was the cause of INO in 16 patients, a gunshot wound with an occipital-to-quadrigeminal plate cistern course in 1 patient, and shock from blood loss in a patient with multiple stab wounds. Two victims of motor vehicle crashes sustained traumatic C5-6 spinal injury, resulting in vertebral artery damage, which led to brainstem infarction after 1- and 2-day intervals.7 Causes of blunt head trauma were motor vehicle crashes (5 patients), pedestrians hit by cars (4 patients), motorcycle crashes (3 patients), bicycle crashes (2 patients), a fall (1 patient), and a fight (1 patient).

Tentorial herniation8,9 was associated with infections in 2 cases. In 1 patient, a blow to the head resulted in decompensation of a chronic subdural empyema associated with intravenous drug use and endocarditis. The other patient had chronic bilateral subdural hematomas after tuberculous meningitis.

Of 6 patients with AIDS, 2 had toxoplasmosis involving the brainstem, 1 had a possible lymphoma (lymphoma was highly likely in another patient with AIDS tallied as a tumor), and 3 had probable viral brainstem encephalitis. Three of 4 patients with cysticercosis had enhancing cysts in the caudal aqueduct, and 1 had a large inflammatory cyst in the fourth ventricle that produced intense brainstem edema. Two patients (without AIDS) had meningovascular syphilis and strokes, and meningitis was due to tuberculosis and an unknown chronic condition in 1 patient each. In 2 patients, infection was an indirect cause: septic shock with brainstem infarction and a diabetic leg infection that progressed to sepsis with meningeal reaction and basilar artery occlusion.

Of 12 patients with iatrogenic injury, 7 involved neurosurgery and 5 involved vascular mishaps (2 angiography and 1 each tumor embolization, carotid endarterectomy, and cardiac catheterization). The 8 miscellaneous cases consisted of 2 patients each with hydrocephalus (1 with Chiari malformation) and probable Wernicke syndrome and 1 each congenital with fixed brainstem atrophy, carbamazepine overdose, cerebellar hemorrhagic infarct with pontine compression, and spinocerebellar atrophy with pigmentary retinopathy.

By comparison, during the period of this study, convincing pseudo-INO was seen in 27 (15%) of 182 patients with myasthenia, in 2 patients with Guillain-Barré syndrome, and in 1 of 38 patients with Fisher syndrome. A single patient with abetalipoproteinemia had typical ophthalmoplegia with weakness and nystagmus of the medial rectus muscles. An INO pattern on caloric testing was seen occasionally in comatose patients.

COMMENT

Foville’s landmark 1859 study of pontine gaze palsy identified the sixth nerve nucleus as a gaze center, introduced the concept of yoked eye muscles, and postulated a crossed pathway connecting the pons and midbrain to coordinate horizontal gaze.10 Although illustrated in Stilling’s atlas of 1846, the posterior (medial) longitudinal fasciculus was not identified as the connecting gaze pathway until 1873.11

Clinical recognition of INO lagged far behind the anatomy and theory of horizontal eye movements. By 1910, 4 clearly recognizable cases of INO and 4 cases of the one-and-a-half syndrome had been published.11(p478) In 1921, the year that Lhermitte named INO,12 Gordon Holmes13(p247) wrote that he had seen only 2 dissociated medial rectus palsies in his career. Spiller,1 in describing the first clinicopathologic case in 1924, accepted only 8 reported cases of INO. Internuclear ophthalmoplegia continued to be reported as “partial third nerve palsies” or “supranuclear third nerve palsies” for another quarter century.14 In 1950, Cogan and colleagues15 found fewer than 10 cases of unilateral INO in the literature, and in 1957, at least half of “all 20 reported cases of INO” had horizontal gaze palsies with preserved convergence.16 Finally, however, Cogan’s appreciation of the distinctive features and relatively common incidence of INO established the diagnosis and allowed him to accumulate approximately 200 personal cases by 1970.2

Although 4 series25 of approximately 400 combined cases of INO (Table 1) contain only 2 cases due to trauma, at least 32 case reports of traumatic INO have been published.13,11,17 AIDS18 has replaced tuberculosis1,16 and syphilis4 as an infectious cause of brainstem disease. Cysticercosis, the most common infection on our neurology ward, is a rare cause of INO, as are cryptococcus,4 herpes zoster, aspergillus, borrelia, listeria, Whipple disease, and prion disease.17 Systemic lupus erythematosus19,20 and Sjögren syndrome21 are the principal vasculitic causes of INO. Temporal arteritis was first reported to cause INO as late as 1989, but at least 5 cases, and several cases of periarteritis, have now been published.

Drug overdose from a variety of medicines causes INO in the absence of structural lesions of the medial longitudinal fasciculus.17(pp561-564) Single cases of hyperparathyroidism,22 a great imitator of posterior fossa disease; Fabry disease,17 known to cause lacunar infarcts; and hexosaminidase deficiency23 have been reported with INO.

Although myasthenia is the usual cause of pseudo-INO, a review of 243 cases of Fisher syndrome found 15 cases of apparent INO.24 Preferential weakness of the medial rectus muscle with generalized ophthalmoplegia may occur in progressive supranuclear palsy,25 but improvement with vestibular stimulation suggests pseudo-INO. Similarly, localization of the INO pattern with spinocerebellar atrophies and reverse dissociated nystagmus in abetalipoproteinemia is uncertain. Selective medial rectus limitation on caloric testing in comatose patients can represent a stage of general anesthesia and may reflect the depth of coma rather than a focal medial longitudinal fasciculus lesion.

In summary, unusual causes of INO are responsible for more than a quarter of inpatient cases and merit serious consideration in differential diagnosis.

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Article Information

Correspondence: James R. Keane, MD, Department of Neurology, University of Southern California School of Medicine, 1200 N State St, Room 5441, Los Angeles, CA 90033.

Accepted for Publication: April 23, 2004.

References
1.
Spiller  WG Ophthalmoplegia internuclearis anterior: a case with necropsy. Brain 1924;47345- 357Article
2.
Cogan  DG Internuclear ophthalmoplegia, typical and atypical. Arch Ophthalmol 1970;84583- 589
PubMedArticle
3.
Fotzsch  R Die internukleare ophthalmoplegia. Ophthalmologica 1971;162331- 342
PubMedArticle
4.
Gonyea  EF Bilateral internuclear ophthalmoplegia. Arch Neurol 1974;31168- 173
PubMedArticle
5.
Thomke  FK The internuclear ophthalmoplegias.  In: Caplan  LR, Hopf  HC, eds. Brainstem Localization and Function. Berlin, Germany: Springer-Verlag; 1993:119-132
6.
Frohman  EMGoodin  DSCalabresi  PA  et al.  The utility of MRI in suspected MS: report of the subcommittee of the American Academy of Neurology. Neurology 2003;61602- 611
PubMedArticle
7.
Keane  JR Locked-in syndrome after head and neck trauma. Neurology 1986;3680- 82
PubMedArticle
8.
Devereaux  MWBrust  JCMKeane  JR Internuclear ophthalmoplegia caused by subdural hematoma. Neurology 1979;29251- 255
PubMedArticle
9.
Keane  JR Bilateral ocular motor signs after tentorial herniation in 25 patients. Arch Neurol 1986;43806- 807
PubMedArticle
10.
Shanzer  S Neuro-ophthalmology in 19th century Paris: pioneering work on conjugate gaze.  In: Rose  FC, ed. Neuroscience Across the Centuries. London, England: Smith-Gordon & Co Ltd; 1989:151-156
11.
Freeman  W Paralysis of associated lateral movements of the eyes: a symptom of intrapontile lesion. Arch Neurol Psychiatry 1922;7454- 487Article
12.
Paton  L Ocular palsies. Br J Ophthalmol 1921;5250- 271Article
13.
Holmes  G Palsies of the conjugate ocular movements. Br J Ophthalmol 1921;5241- 250Article
14.
Savitsky  NRangell  L The ocular findings in multiple sclerosis. Res Publ Assoc Res Nerv Ment Dis 1950;28403- 413
PubMed
15.
Cogan  DGKubik  CHSmith  WC Unilateral Internuclear ophthalmoplegia: report on eight cases with one postmortem study. Arch Ophthalmol 1950;44783- 796Article
16.
Madonick  MJ Ophthalmoplegia internuclearis anterior without a lesion of the posterior longitudinal bundle. Arch Neurol Psychiatry 1957;66338- 345Article
17.
Leigh  RJZee  DS The Neurology of Eye Movements. 3rd ed. New York, NY: Oxford University Press; 1999
18.
Keane  JR Neuro-ophthalmologic signs of AIDS: 50 patients. Neurology 1991;41841- 845
PubMedArticle
19.
Keane  JR Eye movement abnormalities in systemic lupus erythematosus. Arch Neurol 1995;521145- 1149
PubMedArticle
20.
Galindo  MPablos  JLGomez-Reino  JJ Internuclear ophthalmoplegia in systemic lupus erythematosus. Semin Arthritis Rheum 1998;28179- 186
PubMedArticle
21.
Alexander  ELMalinow  KLejewski  JE  et al.  Primary Sjogren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med 1986;104323- 330
PubMedArticle
22.
Patten  BMPages  M Severe neurological disease associated with hyperparathyroidism. Ann Neurol 1984;15453- 456
PubMedArticle
23.
Barnes  DMisra  VPYoung  EPThomas  PHarding  AE An adult onset hexosaminidase A deficiency syndrome with sensory neuropathy and internuclear ophthalmoplegia. J Neurol Neurosurg Psychiatry 1991;541112- 1113
PubMedArticle
24.
Al-Din  SNAnderson  MEeg-Olofsson  OTrontelf  JV Neuro-ophthalmic manifestation of ophthalmoplegia, ataxia and areflexia: a review. Acta Neurol Scand 1994;89157- 163
PubMedArticle
25.
Mastaglia  FLGrainger  MR Internuclear ophthalmoplegia in progressive supranuclear palsy. J Neurol Sci 1975;25303- 308
PubMedArticle
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