Journal of Neuro-Ophthalmology, December 1999, Volume 19, Issue 4

Microvascular Cranial Nerve Palsies in an Arabic Population

OBJECTIVES: The incidence of microvascular ocular cranial nerve palsies may be increasing with the prevalence of diabetes in the developing world. We review this problem for the first time in an Arabic population. MATERIALS AND METHODS: This is a prospective nonrandomized study of all patients with the diagnosis of microvascular cranial mononeuropathy seen in the Neuro-ophthalmology Clinic at the King Khaled Eye Specialist Hospital between September 1997 and April 1998. RESULTS: Forty-seven patients with microvascular palsies of cranial nerves 3, 4, or 6 were seen in this 8-month period. Compared to previous studies, this group had a stronger association with previously diagnosed diabetes mellitus, more males affected, and a longer duration of the cranial nerve palsy before complete resolution. Five patients had an unusual clinical course that included a second microvascular cranial mononeuropathy before the first palsy completely resolved. CONCLUSIONS: Microvascular cranial nerve palsies may occur more frequently in this Arabic population than elsewhere and may have certain unusual features.

Journal of Neuro- Ophthalmology 19( 4): 252- 256, 1999. © 1999 Lippincott Williams & Wilkins, Inc., Philadelphia Microvascular Cranial Nerve Palsies in an Arabic Population Mona al Saleh, M. D., and Thomas M. Bosley, M. D. Objectives: The incidence of microvascular ocular cranial nerve palsies may be increasing with the prevalence of diabetes in the developing world. We review this problem for the first time in an Arabic population. Materials and Methods: This is a prospective nonrandomized study of all patients with the diagnosis of microvascular cranial mononeuropathy seen in the Neuro- ophthalmology Clinic at the King Khaled Eye Specialist Hospital between September 1997 and April 1998. Results: Forty- seven patients with microvascular palsies of cranial nerves 3, 4, or 6 were seen in this 8- month period. Compared to previous studies, this group had a stronger asso­ciation with previously diagnosed diabetes mellitus, more males affected, and a longer duration of the cranial nerve palsy before complete resolution. Five patients had an unusual clini­cal course that included a second microvascular cranial mono-neuropathy before the first palsy completely resolved. Conclusions: Microvascular cranial nerve palsies may occur more frequently in this Arabic population than elsewhere and may have certain unusual features. Key Words: Abducens nerve- Arabic population- Cranial nerve palsy- Diabetes- Oculomotor nerve- Trochlear nerve- Vascular risk factors. Microvascular cranial nerve ( CN) palsies are one im­portant manifestation of small vessel atherosclerotic dis­ease ( 1). Because vascular risk factors, particularly dia­betes mellitus, are a growing health problem in develop­ing countries ( 2- 5), we decided to investigate the frequency and characteristics of microvascular CN pal­sies at the largest eye facility in the Middle East. De­scriptions of microvascular CN palsies are scarce in the developing world, and the prevalence and features of this problem have not been reported in an Arabic population. MATERIALS AND METHODS This study was performed at the King Khaled Eye Specialist Hospital ( KKESH), a tertiary ophthalmologic center with approximately 100,000 outpatient visits per Manuscript received May 28, 1999; accepted July 20, 1999. From the Neuro- ophthalmology Division, King Khaled Eye Special­ist Hospital, Riyadh, Saudi Arabia. Address correspondence to Dr. Thomas M. Bosley, Neuro-ophthalmology Division, King Khaled Eye Specialist Hospital, P. O. Box 7191, Riyadh 11462, Saudi Arabia. year from all portions of Saudi Arabia ( 6). The enroll­ment period for this study was September 1997 to April 1998, with a follow- up period extending through No­vember 1998. Inclusion criteria were 1) presentation to the KKESH Neuro- ophthalmology Service during the enrollment period with an isolated palsy of CN 3, 4, or 6 without pupillary involvement, orbital signs, or other re­cent neurologic history; 2) maximum neurologic deficit within 2 weeks of onset and complete resolution of the motility abnormality during the enrollment or follow- up period without treatment; 3) a history of vascular risk factors including diabetes mellitus, hypertension, hyper-lipidemia, coronary artery disease, or age > 60 years; and 4) no history or evidence of a medical problem implying another possible etiology of diplopia, such as trauma, stroke, myasthenia gravis, thyroid eye disease, malig­nancy, or vasculitis. During the enrollment period, 60 patients were seen with diplopia possibly caused by isolated CN palsies. Excluded from the study group were three patients who were lost to follow- up before the diagnosis was definite, two patients whose eye motility abnormality did not re­solve sufficiently during the enrollment or follow- up pe­riod, three patients who were diagnosed with nasopha­ryngeal cancer, one patient with probable recurrent com­plicated migraine, one patient with active systemic lupus erythematosus, two patients with probable ocular myas­thenia gravis, and one patient with a history of mono­neuritis multiplex affecting peripheral nerves elsewhere as well. An additional 22 patients returned for follow- up ap­pointments during the enrollment period with a previous history of resolved microvascular CN injuries well docu­mented in hospital records. The characteristics of this group ( age, sex, incidence of diabetes, distribution of CN injuries, duration of symptoms, etc.) were very similar to those of patients presenting with acute microvascular CN injuries. These patients were excluded because they did not experience acute cranial mononeuropathies during the enrollment period. Each study patient received a complete ophthalmo­logic and neurologic examination. A focused history was taken and hospital records were reviewed for evidence of previous resolved CN palsies or other small vessel dis­ease ( such as diabetic retinopathy or nephropathy). Blood testing was performed on every patient, including 252 CRANIAL NERVE PALSIES 253 TABLE 1. Patients ( no.) Acute palsies ( no.) Age ( mean) Sex ( male: female) Right: left DM (%) Duration of palsy ( wks) CN 2 ( percent of presentations) CN 3 ( percent of presentations) CN 4 ( percent of presentations) CN 6 ( percent of presentations) CN 7 ( percent of presentations)" Demographic and clinical data Single 41 41 20- 95 ( 59.9) 3.1: 1 0.78: 1 80% 4- 36( 12.3) 14( 34%) 2 ( 5%) 25 ( 61%) Multiple 6 12 44- 72 ( 57.9) 6: 0 1: 1 83% 4- 28 ( 14.6) 1 ( 8%) 3 ( 25%) 0 6 ( 50%) 2 ( 17%) Total 47 53 20- 95 ( 59.9) 3.7: 1 0.88: 1 81% 4- 36( 12.4) 1 ( 2%) 17 ( 32%) 2 ( 4%) 31 ( 60%) 2 ( 4%) DM, diabetes mellitus; CN, cranial nerve. " Facial palsy was not one of the inclusion criteria for this study. These two patients developed facial palsies after an initial palsy of the 6th cranial nerve. Westergren erythrocyte sedimentation rate ( ESR), anti-nuclear antibodies ( ANA), and VDRL. Neuroimaging, including computed tomographic ( CT) scanning, mag­netic resonance imaging ( MRI), or both, was performed on 64% ( 30 of 47 patients). RESULTS The demographic characteristics of the study group are summarized in Table 1. Forty- one patients presented during the enrollment period with an isolated acute CN palsy meeting the above criteria (" Single" column). Two of these patients had a prior history of a resolved 6th CN palsy, whereas six patients had a previous history of one or more Bell's palsy and an examination demonstrating varying degrees of recovery of facial strength with ab­errant regeneration. One patient was seen during the enrollment period with an abduction deficit on the left and the complaint of recent onset of diplopia and mildly reduced vision OS. When first seen, he had excellent visual acuity OS with a mild afferent pupillary defect and nerve fiber bundle visual field loss on that side. During the next several months, he developed mild pallor of the left optic disk while his left abduction deficit resolved completely, im­plying that his left optic nerve and 6th CN may have undergone a simultaneous microvascular injury. Figure 1 shows this patient's right Humphrey visual field, and this patient is also included as Patient 1 in Table 2. Five other patients were seen during the enrollment period with microvascular cranial nerve palsies that re­solved completely during the study period; in addition, each of these patients developed a second cranial mono-neuropathy during the study period, as detailed in Table 2 ( patients 2- 6) by date of onset of initial symptoms. These patients were evaluated with CT scan ( five pa­tients), vasculitis and coagulopathy blood studies ( five patients), lumbar puncture ( two patients), and Tensilon test ( two patients), all of which were unremarkable. The second CN palsy also resolved completely except for aberrant regeneration of a facial nerve palsy ( patient 5). This group met the inclusion criteria for this study and was demographically similar to the larger group with single microvascular CN palsies. Therefore, the group was included in the analysis of Table 1 (" Multiple" col­umn). Table 3 details vascular risk factors in the study group and shows that diabetes mellitus was the most common atherosclerotic risk factor, encountered in 81% of pa­tients. Duration of diabetes ranged from 6 months to 25 years, with an average duration of 12.7 years. Diabetic complications such as retinopathy and nephropathy were quite common. Hypertension was present in 28% of the study group, whereas diagnosed hyperlipidemia and coronary artery disease were less frequent. Twenty- one patients ( 44%) had some degree of ipsi- PUPIL OlflMETER: 4.0 MM VISUAL ACUITY: RX: + 5.25 OS + 1.50 DC X 170 OftTE: 14- 07- 98 TIME: 8: « AH AGE: 60 FIG. 1. Humphrey Visual Field OS of patient with simultaneous left 6th cranial nerve palsy and optic neuropathy. J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 254 M. AL SALEH AND T. M. BOSLEY TABLE 2. Multiple cranial nerve palsies Patient 1 2 3 4 5 6 Age 60 53 44 53 58 72 Sex M M M M M M Risk factors DM DM Previous ri; DM; HBP DM DM ght Bell palsy Side L L R L R L R L R R L R CN 6 2 6 6 6 7 3 3 6 7 3 6 Date 12/ 97 12/ 97 8/ 97 10/ 97 10/ 97 11/ 97 10/ 97 1/ 98 11/ 97 1/ 98 12/ 97 4/ 98 Resolution Complete No Complete Complete Complete Ab. regeneration Complete Complete Complete Ab. regeneration Complete Complete Duration ( wk) 20 4 28 12 8 12 8 24 12 CN, cranial nerve; M, male; F, female; DM, diabetes mellitus; HBP, hypertension; R, right; L, left; Ab. regeneration, aberrant regeneration. lateral periorbital pain at the time of onset of their cranial nerve palsy. One patient had a previous history of an internuclear ophthalmoplegia in 1992 that was thought to be caused by a pontine infarct. Neuroimaging in the study group was significant only for age- related changes. Three patients had an ESR elevated above 60. One of these patients had diabetic nephropathy, whereas another had arthritis and the third underwent a normal temporal artery biopsy. None of these patients developed symp­toms or visual sequelae of giant- cell arteritis. Other blood testing was unremarkable in the study group. DISCUSSION The isolated cranial nerve palsies reported here meet the accepted diagnostic criteria for microvascular injury to cranial nerves 3, 4, and 6 ( 7- 11) with abrupt onset ( often with periorbital pain) and spontaneous resolution of an isolated mononeuropathy in patients with no prob­able etiology other than microvascular atherosclerotic in­jury. This group of patients was similar to previous re­ports ( 7- 10,12,13) with age at onset of approximately 60 years, a high incidence of vascular risk factors, equal involvement of right and left eyes, and comparable dis­tribution of cranial nerve injuries ( 6th > 3rd > 4th). Eye motility abnormalities resolved spontaneously, and sub­sequent follow- up did not reveal an alternative diagnosis. In particular, there was no history of malignancy or sys­temic inflammatory disease, no variable or generalized weakness that might imply myasthenia gravis, and no associated neurologic signs that accompany a stroke or less common neurologic phenomena such as chronic meningitis or the Miller Fisher variant of Guillain Barre syndrome. Neuroimaging, blood testing, and studies such as lumbar puncture tailored to the clinical setting did not bring to light additional information. Some differences were present between the group de­scribed here and previous reports. Compared to previous studies, we found substantially more men than women ( more than 3: 1 male: female ratio versus approximately 1: 1), more diabetic patients ( approximately 80% diabetic patients versus less than 50%), and a somewhat longer duration of the resolution phase ( average duration of 3 months and maximum of 7 months versus a maximum of 3 months). Demographics of the patient population of this hospital do not explain these differences. Approxi­mately one- third of the patients seen at this medical cen­ter are diabetic, but this proportion is probably equal in other major eye facilities in the world. The sex ratio of patients is equal in the hospital as a whole. Further stud­ies are planned to evaluate this patient population more carefully for evidence of vascular risk factors, subclinical coagulopathy, and/ or vasculitis. Microvascular cranial nerve palsies may be more fre­quent in Saudi Arabia than appreciated elsewhere. The series of Mayo Clinic studies covering 44 years ( 10,14- 16) included 646 patients with microvascular cranial nerve palsies, or approximately 15 patients per year at a major referral center. The current study enrolled three times as many patients in less than a year. Referral pat­terns to different facilities are impossible to compare, but this striking difference raises the possibility that micro­vascular mononeuropathies may be more common in this Arabic population than in previous reports. The occurrence of multiple microvascular cranial nerve injuries in a subpopulation of patients is also note­worthy. Simultaneous microvascular injury to multiple cranial nerves has been reported previously ( 8,9,12,13, 17- 24). Some of these reported patients have had severe visual loss with VF defects typical of ischemic optic neuropathy ( 12,21). Jabs and colleagues ( 21) reported TABLE 3. Total patients Diabetes Diabetic treatment Insulin Oral agents None Summary Diabetic complications Retinopathy Nephropathy Hypertension Hyperlipidemia Coronary artery di: ^ ease of atherosclerotic No. of patients 47 38 15 21 2 30 22 8 13 3 5 risk factors Percent 100 81 40 55 5 64 47 17 28 6 11 J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 CRANIAL NERVE PALSIES 255 histology of one patient in which the optic nerve injury had the appearance of ischemic infarction, presumably because of microangiopathic injury similar to that re­ported to cause 3rd CN injury ( 1,25). Interestingly, the patient in the current series had much milder visual loss, although his optic nerve injury was also permanent. Recurrent CN palsies involving the ocular motor nerves have been reported less frequently, particularly recurrent palsies occurring during a brief period. Table 4 includes all previously reported patients of which we are aware who experienced recurrent microvascular palsies, emphasizing those patients experiencing two palsies dur­ing a period of 4 months or less, similar to our patients. No previous report contains more than two such patients, whereas in the current series, five patients meeting these criteria were evaluated in an 8- month enrollment period, implying that rapidly recurrent palsies, and perhaps mi­crovascular CN palsies in general, are more frequent in Saudi Arabia. A releatively high incidence of small ves­sel atherosclerotic disease might be expected because the prevalence of diabetes mellitus has increased dramati­cally in recent years in Saudi Arabia ( 4) and in much of the Middle East ( 3). Other vascular risk factors such as obesity, high- density lipoprotein cholesterolemia, and hypertriglyceridemia are also becoming more prevalent ( 5) and are expected to increase in frequency as the popu­lation ages. Sergott et al. ( 22) observed in 1984 that microvascular cranial neuropathies are almost always isolated and that exceptions to this rule, either more than one motor nerve palsy per eye or simultaneous bilateral cranial palsies, make an investigation mandatory for other possible etio-logic mechanisms including myasthenia gravis, giant-cell arteritis, thyroid eye disease, Miller Fisher variant of Guillain Barre, neoplasm, basilar artery aneurysm or oc­clusion, and chronic meningeal inflammation. They sug­gested that the diagnostic evaluation for patients with multiple simultaneous or sequential cranial nerve palsies should include neuroimaging, ESR, forced duction test­ing. Tensilon test, glucose tolerance test, and cerebrospi­nal analysis. Our experience with the current patient population suggests that, under certain circumstances, multiple cra­nial nerve palsies may not be a sign of undiagnosed serious medical problems. The following protocol would be appropriate for the diagnosis and follow- up of the current patient population with microvascular palsies of cranial nerves 3, 4, and 6: TABLE 4. Recurrent cranial nerve palsy literature Author, year ( reference no.) Collier, 1930 ( 12) Weinstein, 1948 ( 26) Eareckson and Miller, 1952 ( 27) Goldstein and Cogan, 1960 ( 7) Ross, 1962 ( 19) Green et al., 1964 ( 9) Eshbaugh et al., 1995 ( 24) Total 1 3 1 5 2 7 2 Interval ( wk) 24 NA 7 NA 2 NA 4 NA, not available. 1. A patient meeting the diagnostic criteria listed above should have a test for syphilis and an ESR drawn to evaluate the possibility of giant- cell arteritis ( which may be less frequent than in other populations). Ad­ditional evaluation appropriate for the clinical sce­nario should be performed if the patient does not have atherosclerotic risk factors or if there is a history or suspicion of additional serious medical problems such as immunosuppression, infection, or malignancy. 2. The patient should be followed carefully to confirm that resolution of the neurologic deficit begins within 4- 6 weeks and that the deficit resolves completely in less than 5- 7 months. Any patient who deviates from the expected clinical course requires a complete evaluation tailored to the clinical situation. 3. If a second cranial nerve palsy develops before com­plete resolution of the first cranial nerve injury, the patient requires neuroimaging and blood testing that includes at least ESR, ANA, and tests for syphilis. More testing than this is probably not necessary if the second cranial nerve involved is 3, 4, 6, or 7 and if resolution of both cranial nerve palsies continues in a fashion compatible with microvascular injury. This clinical situation obviously requires careful follow- up and additional testing, such as suggested by Sergott et al, if the patient deviates from a course compatible with simultaneous or sequential microvascular cranial nerve injuries. 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