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Show Journal of Neuro- Ophthalmology 15( 4): 219- 224, 1995. > 1995 Lippincott- Raven Publishers, Philadelphia Simultaneous, Multiple Cranial Neuropathies in Diabetes Mellitus Calvin G. Eshbaugh, M. D., R. Michael Siatkowski, M. D., J. Lawton Smith, M. D., and Lanning B. Kline, M. D. Cranial mononeuropathies, particularly ophthalmoplegia and facial palsy, are common entities in the diabetic population. Simultaneous multiple cranial neuropathies due to diabetes are much less common, however. We present three patients with this entity. Key Words: Diabetes- Cranial neuropathy. Manuscript received March 17, 1995. From the University of Miami School of Medicine ( C. G. E.) and the Bascom Palmer Eye Institute ( R. M. S., J. L. S.), Miami, Florida; and the Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama ( L. B. K.). Address correspondence and reprint requests to Dr. R. M. Siatkowski, Bascom Palmer Eye Institute, P. O. Box 016880, Miami, FL 33101, U. S. A. CASE REPORTS Casel A 73- year- old man with a 2- year history of non-insulin- dependent diabetes developed a right facial palsy in September 1991, for which he was treated with prednisone. In December of the same year, he experienced the acute onset of binocular diplopia and was found by his local ophthalmologist to have right third and sixth nerve palsies; the pupil and lid were normal at that time. One month later, right ptosis developed. Past medical history was significant for hypercholesterolemia and a left cerebellar infarction 2 years previously with no sequelae. In 1982 he had a pupil- sparing left third nerve palsy, which cleared in 2 months. In 1985 he developed left trigeminal neuralgia for which he underwent rhizotomy 3 years later. On examination in January 1992, visual acuity was 20/ 30 OD, 20/ 20 OS. Pupils were 3.5 mm, round, and 3+ reactive to light without afferent defect. The right lid fissure measured 3 mm, left 9 mm. A peripheral right facial nerve palsy was present with a paralytic ectropion. The left eye had full motility. In the right eye there was a 75% abduction deficit, inability to adduct past the midline, and 80- 90% limitation of both depression and elevation ( Fig. 1A- D). Forced ductions were negative. On attempted gaze down and left, there was no intorsion of the right eye, consistent with paresis of the superior oblique. Trigeminal sensation was equal in all three divisions bilaterally. The fundi were normal with no sign of diabetic retinopathy. Tensilon test, Lyme titers, RPR, FTA- Abs, CBC, and lumbar puncture were all normal. Two MRIs of the brain revealed an old left cerebellar infarct, but normal cavernous sinuses and brain stem. On follow- up examination 2 months later, the right lid fissure measured 7.5 mm, and the facial 219 220 C. G. ESHBAUGH ET AL. FIG. 1. Case 1, a 73- year- old male. A: Right ptosis and peripheral facial palsy, B: significant limitation todowngaze OD, C: no elevation past midline OD, and D: poor eyelid closure OD despite full effort. nerve paresis had almost completely resolved. Abduction of the right eye was 90- 95% of normal, depression and elevation were full, and adduction was approximately 90% of normal ( Fig. 2A- C). Motility in the field of action of the right superior oblique muscle was full, and no cyclodeviation was noted on double Maddox rod testing. The patient showed complete resolution of all ocular findings after an additional 2 months. Case 2 A 58- year- old white male with no significant past medical history developed binocular diplopia on December 25, 1991. In January 1992 he noted drooping of the left upper eyelid, followed by left facial drooping one month later. Examination revealed visual acuity of 20/ 25 OD, 20/ 30 OS. Pupils were 4 mm, round, and 3 + reactive to light bilaterally without afferent defect. The right lid fissure measured 9 mm, the left 4 mm. A peripheral right facial nerve paresis was present. Abduction was 25% of normal bilaterally. The left eye did not adduct past midline and had 50% elevation and depression deficits. No intor-sion of the left eye was noted in gaze down and right. Trigeminal function was intact bilaterally. / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEUROPATHIES IN DIABETES 221 FIG. 2. Same patient ( case 1) two months later. A: Essentially full downgaze OD, B: essentially full up-gaze OD, and C: marked improvement of right facial paresis. The fundi were normal with no sign of diabetic retinopathy. Two months after his initial presentation, pupils were 4.5 mm, round, and 3+ reactive. He had a mild residual right facial nerve palsy with only slight flattening of the right nasolabial fold. Motility was normal but for 10% abduction deficits bilaterally. Forced ductions, Tensilon test, and brain CT and MRI were normal. Serum RPR, FTA- Abs, Lyme titers, and CBC were all normal, but serum glucose was 482 mg/ dl. Lumbar puncture revealed an elevated glucose of 190 mg/ dl, but was otherwise normal. The patient was hospitalized and glycemic control achieved in 3 days. He had complete clearing of his ophthalmic findings within 5 months after onset. Case 3 A 71- year- old man with an 8- year history of insulin- dependent diabetes developed the sudden onset of diplopia followed by complete left ptosis in May 1985. Visual acuity was 20/ 30 OU. The pupils measured 3.5 mm OD and 4.5 mm OS, but were equally reactive to light without afferent defect. There was complete left ptosis. The right eye moved normally but the left had total abduction and adduction deficits, as well as no function in the field of the inferior rectus. Trigeminal function was intact bilaterally. The fundi showed no signs of diabetic retinopathy. Forced ductions were negative. Brain CT was normal. By mid- September 1985, ocular motility and levator function were normal. DISCUSSION The first reported case of diabetic ophthalmoplegia was in 1866 ( 1). Although diabetic cranial neuropathy is commonly encountered in ophthalmologic practice, data on its prevalence are scarce. Waite and Beetham reported a 0.4% prevalence ( 16 of 4,001 patients) of paresis of one or more extraocular muscles over a 10- year period following the initial diagnosis of diabetes ( 2). A large retrospective series from the Institute for Diabetes Care and Research in Tokyo showed a 0.97% incidence of cranial nerve 3, 4, 6, or 7 palsies in the diabetic population over a 25- year period ( 3), 7.5 times more frequent than in the nondiabetic control group. Only two of their patients had simultaneous neuropathies, both oculomotor and ab-ducens. All patients experienced complete, spontaneous recoveries, with the mean recovery time for the ophthalmoplegia being 11.9 weeks. If approximately 0.5- 1.0% of diabetics will sustain a cranial neuropathy over a 25- year period, the next question becomes: Of all patients with cranial nerve palsies, how many are secondary to diabetes? The Mayo Clinic has reported a large series of patients with cranial neuropathies affecting cranial nerves 3, 4, and 6. Their cumulative experience to date consists of over 4,000 patients ( 4). Of all cases, the abducens nerve was by far the most commonly / Neuro- Ophthaltnol, Vol. 15, No. 4, 1995 222 C. G, ESHBAUGH ET AL. involved ( 43.9% of cases), followed by the oculomotor nerve ( 28.0%), trochlear nerve ( 15.0%), and multiple simultaneous ocular motor palsies ( 13.1%). After excluding 102 cases due to congenital insults, just over 15% of the remaining cranial neuropathies were attributed to vascular causes ( including diabetes, hypertension, atherosclerosis, vasculitis). Of the patients with multiple simultaneous ocular motor palsies, neoplasm was by far the most common cause ( 35.3%), with vascular being significantly rarer ( 4.1%). [ These data pertain to adults only, as in the pediatric population, vascular cranial neuropathies are exceedingly rare ( 5).] From further calculation, one can determine that 20% of patients with multiple simultaneous cranial neuropathies attributed to a vascular cause had diabetes mellitus at the onset of ophthalmoplegia ( 0.8% of all patients with simultaneous polyneuropathy). One should note that the Mayo series, if anything, underestimates the frequency of diabetes in their group, because information is included only for those patients with previously diagnosed disease; in all likelihood, some patients had their cranial neuropathies as the initial manifestation of diabetes. Even if a patient is not a known diabetic and has a negative workup at the onset of the cranial neuropathy, the future development of diabetes mellitus remains a distinct possibility. Goldstein and Cogan reported on 33 patients with isolated oculomotor nerve palsy ( 6). Thirty percent of them were previously diagnosed diabetics. In three of the 33 ( 10%), the third nerve palsy was the presenting sign of diabetes. Another 20% of them would have glucose intolerance by today's definition, with one of these patients going on to develop frank diabetes within 4 years. [ Glucose intolerance is defined as serum glucose: 115- 140 mg/ dl at fasting, or 0.5 h after a 75- g carbohydrate load; and/ or > 200 mg/ dl 1 h after similar load; and/ or 140- 199 mg/ dl 1.5, 2, or 3 h after similar load ( 7).] Since at least 25% of patients with abnormal glucose- tolerance testing will develop diabetes within 5 years ( 8) and up to 50% within 16 years ( 7), then by these criteria at least 35% of patients with third nerve palsy of vascular or undetermined origin will become diabetic. Green attributed almost 20% of 130 cases of third nerve palsy to diabetes ( 9). In half of these cases, the oculomotor nerve palsy was the first sign of diabetes. Glucose tolerance testing is thus necessary during the initial workup of a patient with a cranial neuropathy of unknown etiology, and diabetes mellitus must be continually considered as long as the cause of the neuropathy remains obscure. The recurrent nature of diabetic cranial neuropathy has been well described and is evidenced by our first case. One of the most fascinating cases reported describes a woman who suffered 13 separate episodes of single or multiple cranial nerve palsies over an 18- year period, all with full recovery ( 10). The recurrent nature of cranial nerve palsies in diabetics does not seem to bode poorly for their prognosis. Most of these patients also recover fully; in fact, the mean recovery time was briefer for the later episodes than for the first ( 6,11,12)! Although simultaneous diabetic cranial polyneuropathy is much rarer, when it occurs, the third cranial nerve seems to be the most frequently involved. Table 1 shows the cases of multiple simultaneous diabetic cranial neuropathies in the literature. To our knowledge, only nine other patients with this entity have been previously described ( 1,3,10,12- 14). The mean age of the patients ( 57.6 years) and mean recovery time ( 13.7 weeks) do not significantly differ from those patients with isolated or recurrent diabetic cranial mononeuropathy. Sergott et al. have elucidated the following clinical dictum: " . . . a diabetic is permitted one cranial neuropathy at a time. Exceptions to this rule, either more than one motor nerve per eye, or simultaneous bilateral cranial palsies, make investigation mandatory" ( 12). Therefore, clinical considerations in a patient with simultaneous multiple cranial neuropathies must include but are not limited to: myasthenia gravis, cranial arteritis, thyroid eye disease, Miller- Fischer variant of Guillain- Barre, neoplasm, basilar artery aneurysm or occlusion, chronic meningeal inflammation, and diabetes mellitus. Appropriate diagnostic workup would include forced ductions, Tensilon test, erythrocyte sedimentation rate, glucose tolerance testing, neu-roimaging, and CSF analysis. The culprit lesions in diabetic cranial neuropathy may occur anywhere from the brain stem to the orbit. Dreyfus et al. reported histopathology showing myelin sheath and axonal destruction in the oculomotor nerve of a diabetic who died before resolution of a third nerve palsy ( 15). Involvement of the intracavernous portion ( 16), as well as the subarachnoid segment of the nerve ( 17), has been reported. There is also evidence that the lesions in diabetic cranial neuropathies may be intraparen-chymal. Hopf and Gutmann described 24 diabetics with oculomotor nerve palsies ( 75% pupil- sparing), impaired masseter reflex, and brain stem involvement based on MRI findings ( 18). Fukutake and Hirayama reported a case of an abducens nerve palsy in a diabetic from a pontine infarct ( 19). / Neuro- Ophthalmol, Vol. 15, No. 4, 1995 NEUROPATHIES IN DIABETES 223 TABLE 1. Reported cases of simultaneous multiple diabetic cranial neuropathies Author, year Cranial nerves involved8 Age of patient ( years) Recovery time ( weeks) Eshbaugh, 1995 Eshbaugh, 1995 Eshbaugh, 1995 Luco, 1990 Watanabe, 1990 Watanabe, 1990 Sergott, 1984 Sergott, 1984 Ross, 1962 Ross, 1962 ( same patient) ( same patient) ( same patient) Larson, 1950 Larson, 1950 Larson, 1950 Jordan, 1936 Means R 3, 4, 6, R6; L3, L3, 6 R 3, 4, 6, L3, 6 L3, 6 BILAT 3 BILAT 3 R 3, 4, 6 R 3, 4, 6 R 3, 4, 6 L 3, 4, 6 L3, 6 BILAT 3, BIIAT 3, ! BILAT 3, BILAT 3; 7 4,6, 7 5,7, 5,7, 5,6, L6 7 9, 9, 7, 10 10; L6 9, 10, 11 73 58 71 69 71 79 62 67 54 44 45 46 47 36 33 61 64 57.6 16 20 16 16 12 unavailable 8 20 unavailable 8 12 1 3 28 24 8 unavailable 13.7 ' BILAT, bilateral; R, right; L, left. Breen et al. noted two cases of midbrain infarcts causing pupil- sparing oculomotor nerve palsies ( 20). Usui et al. ( 21) reported on a diabetic with right third and fourth nerve palsies. At postmortem examination, the intracavernous portions of the oculomotor, trochlear, and abducens intraneural vasculature revealed marked thickening and proliferation within the intimal layers ( 21). Breg-man and Harbour reported a superior division diabetic oculomotor nerve palsy ( 22), and Cunningham and Good a corollary case of inferior branch oculomotor palsy ( 23), implicating orbital involvement of the nerve. Without histopathology, the exact site and nature of the lesions responsible for simultaneous diabetic cranial neuropathies remain unknown. Luco and Valenzuela ( 13) speculated that since the ocular motor nerves have common nutrient vessels in the cavernous sinus ( specifically the meningohy-pophysial trunk and the inferior artery of the cavernous sinus, both branches of the internal carotid artery), an occlusion of one of these vessels could lead to ischemia of all three ocular motor nerves. Alternatively, diffuse posterior fossa ischemia is another possible pathogenesis. Of note is that none of our three patients had severe hyperglycemia or evidence of diabetic ketoacidosis or nonketotic hyperosmolar coma. Similarly, none of our patients had any diabetic retinopathy. It thus seems likely that the occurrence of simultaneous multiple cranial neuropathies is related more to the location of the lesion( s) rather than to the diffuse long- term effects of diabetes on vascular integrity. Although the proximity of the ocular motor nerves in the cavernous sinus tends to implicate this area anatomically, it does not account for the concomitant occurrence of peripheral facial palsies in these patients. Diabetes mellitus is a rare but benign cause of multiple and/ or bilateral simultaneous cranial neuropathies. This entity may be the presenting sign of diabetes and often occurs in the complete absence of diabetic retinopathy. Although the prognosis is excellent, it remains a diagnosis of exclusion and retrospection. REFERENCES 1. Jordan WR. 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