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Show Midbrain Cleft as a Cause of Chronic Internuclear Ophthalmoplegia, Progressive Ataxia, and Facial Weakness Omar Ahmad, FRACP, Stephen Reddel, FRACP, Christian J. Lueck, PhD, FRCP, FRACP Abstract: A 44-year-old man with progressive ataxia, fa-cial weakness, bilateral adduction deficits, and abducting nystagmus was initially misdiagnosed and treated for multiple sclerosis because a midbrain anatomic cleft had been overlooked on brain MRI. Six cases of ‘‘midbrain (or mesencephalic) cleft'' or ‘‘keyhole aqueduct syndrome'' have been previously reported. This developmental ana-tomic abnormality always manifests bilateral internuclear ophthalmoplegia (INO), often together with ataxia, which may be progressive and debilitating. Because the INO is chronic, patients may have no visual symptoms. The cause of a midbrain cleft is uncertain, but it may be the midbrain version of a syrinx. There is no known effective treatment. Journal of Neuro-Ophthalmology 2010;30:145-149 doi: 10.1097/WNO.0b013e3181da2ceb 2010 by North American Neuro-Ophthalmology Society Midbrain (or mesencephalic) clefts are cerebrospinal fluid (CSF)-containing slit-like ventral extensions of the cerebral aqueduct lined by a combination of ependymal and neuroglial tissues. Although rostral extension is most often seen, complete bisection of the midbrain is also possible. The cause is unknown, and there is currently no useful treatment. These clefts have been reported to cause ataxia and bilateral internuclear ophthalmoplegia (INO), together with other ocular motor abnormalities, usually giving rise to very long-standing symptomatology (1-4). Previous authors (1-4) have shown that although the most prominent findings relate to midbrain involvement, more widespread brainstem and cerebellar manifestations can also be seen, often leading to misdiagnosis. We present a case of a midbrain cleft, which differs from previous reports by presenting mostly as an ataxic syndrome with an incidental finding of INO without visual symptoms. CASE REPORT A 44-year-old man was referred to our department with progressive ataxia and facial weakness. Bilateral INO had also been noted, but he had no visual complaints. The patient had first come to medical attention 7 years earlier when a neurologist described bilateral INO in assessing the patient after he had fainted following a routine inguinal hernia repair. The patient had no diplopia or other visual symptoms. The patient manifested mild ataxia. He acknowledged then that he had been uncoordinated for at least 10 years in doing sporting activities. He was given a tentative diagnosis of multiple sclerosis (MS), although brain MRI, lumbar puncture, and visual evoked responses were reported as normal. He was treated with 2 courses of intravenous methylprednisolone without symptomatic improvement. Over the 2 years preceding our examination, he had begun to notice a drunken gait and had experienced several falls. He believed that his arms were better coordinated than his legs. During the year prior to consulting us, he had also developed bilateral facial weakness with difficulty whistling, blowing out his cheeks, and closing his right eye. There was no history of excessive alcohol intake. He had been adopted as a child and had no knowledge of his family history. Visual acuity, visual fields, pupillary responses, and ophthalmoscopy were normal. There was an adduction deficit in both eyes, nystagmus of the abducting eyes, and upbeat nystagmus on upgaze. There was a mild exotropia in primary position. Convergence was retained, and his eye Department of Neurology, The Canberra Hospital and Australian National University Medical School (OA, CJL), Canberra, Australia; and Departments of Neurology and Molecular Medicine, Concord Hospital and University of Sydney (SR), Sydney, Australia. Address correspondence to Christian J. Lueck, PhD, FRCP, FRACP, Department of Neurology, The Canberra Hospital, P.O. Box 11, Woden ACT 2611, AUSTRALIA; E-mail: christian.lueck@act.gov.au Ahmad et al: J Neuro-Ophthalmol 2010; 30: 145-149 145 Original Contribution Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. movements were otherwise normal. Mild bilateral facial weakness was also apparent, with incomplete closure of the right eye. The remainder of the neurological examination revealed normal strength in all limbs, normal sensation, sym-metrically depressed reflexes, and flexor plantar responses. There was no ataxia in the upper limbs, but he had a wide-based casual gait and an inability to perform tandem gait. No oculocutaneous features of neurofibromatosis were present. Negative or normal laboratory studies included vitamin B12; vitamin E; phytanic acid and hexosaminidase levels; serum angiotensin-converting enzyme; autoantibody screen; antineuronal antibodies; anti-GM1 antibodies; and genetic studies for spinocerebellar ataxias types 1, 2, 3, and 6. A repeat brain MRI revealed a midline cleft at the level of the midbrain (Figs. 1, 2). The cleft was in continuity with the fourth ventricle, which was somewhat expanded and showed a rectangular appearance. The cerebral hemi-spheres, cerebellum, cisterns, and foramen magnum were unremarkable, but there was a small syrinx in the cervical spinal cord (Fig. 3). High-resolution 3T images of the aqueduct and fourth ventricle did not reveal any other anatomic abnormalities. Review of the previous MRI indi-cated that the cleft had been present but overlooked. The cleft appeared to have increased slightly in size over the years, but this might have been an artifact of the technical improvements in MRI scanning. Intraventricular pressure monitoring and cerebrospinal infusion testing were normal. We have followed the patient for 2 years, during which the ophthalmological findings have not progressed but the degree of ataxia has clearly worsened. DISCUSSION We believe that our patient's neurologic manifestations are the result of the midbrain cleft. This abnormality was evident on the first brain MRI but was overlooked, perhaps FIG. 1. Axial T2 (A) and FLAIR (B) MRI of our patient show a midline cleft in the midbrain (arrows). Sagittal T2 (C) shows a cleft (arrow) in open communication with the fourth ventricle and aqueduct. D. Axial T2 image at the level of the fourth ventricle shows its expansion and rectangular appearance. Original Contribution 146 Ahmad et al: J Neuro-Ophthalmol 2010; 30: 145-149 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. because clinicians and radiologists are unfamiliar with this entity. As a consequence, the patient was initially misdiagnosed as having MS. Six other cases of midbrain cleft have been reported (1-4) (Table 1). Three cases were labeled ‘‘mesencephalic clefts'' (1,2). Two other cases were labeled ‘‘keyhole aqueduct syndrome'' (Cases 4 and 5 in Table 1) (3) and 1 had a similar keyhole aqueduct (4) (Case 6 in Table 1). A recent report (5) of a midbrain cleft in the context of bilateral INO is not included as the ocular motor abnor-malities were described as acute in onset and the apparent cleft decreased in size with time, suggesting a different pathological mechanism. Also excluded was a much older case of a ‘‘posterior diverticulum of the cerebral aqueduct'' associated with diplopia from childhood and diagnosed on the basis of pneumoencephalography (6). It was excluded because the patient did not have INO or ataxia, and there was no pathological examination. Of the 6 cases, 3 (Cases 4, 5, and 6) were examined pathologically (Table 1; Fig. 4) (3,4). Case 5 had developed relentlessly progressive ataxia, which ultimately led to pro-found immobility and death. Case 4 died of a myocardial infarction; Case 6 died of urinary tract infection. Patho-logical examination showed a keyhole-shaped cleft at the pontomesencephalic junction that was lined by ependyma and compressed glial tissue. Varying degrees of distortion/ destruction of several midbrain nuclei and tracts was seen, particularly involving the medial longitudinal fasciculus (MLF). Atrophy of the pons and cerebellum was noted, and, in Cases 4 and 5, slit-like cavities were observed in the pons, some of which were in communication with the fourth ventricle. Cerebellar degeneration was confirmed by the loss of cortical neurons, gliosis of subcortical white matter, and atrophy of cerebellar nuclei. Of the 7 reported patients, 4 presented with long-standing symptoms of double vision (1,2,4). In Case 1, this FIG. 3. Sagittal T2 spine MRI of our patient showing a small syrinx. FIG. 2. Sequence of axial T2 images from diencephalon to medulla shows the full rostral (A1) to caudal (A6) extent of the cleft in our patient. Original Contribution Ahmad et al: J Neuro-Ophthalmol 2010; 30: 145-149 147 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. was the only symptom (1), but the other patients went on to develop other neurological features including ataxia and/or dysarthria. In 3 cases, including the 1 presented here, the initial presentation was with long-standing ataxia and dysarthria. In the other 2 cases, ocular motor involvement appears to have been a late development, unlike our case in which the INO was found on initial examination (3). Although ocular findings have been somewhat varied, INO has been documented in all 7 reported cases. The authors of the 2 original keyhole aqueduct cases described INO without specifying whether it was unilateral or bilateral (3). The clefts are thought to cause the INO through destruction of the MLF at the level of the midbrain (1,2). In addition to INO, upgaze paresis and fourth nerve and partial third nerve palsies have been reported. Four cases had a progressive clinical course with death attributed to complications of progressive ataxia. By com-parison, 2 cases had a relatively static clinical course. In most cases, symptom onset was in the fourth decade, the latest presentation occurring at 49 years of age. Brain MRI has revealed abnormalities similar to those found in our patient. The midline clefts were partial or complete (Fig. 4). Mis-diagnosis of MS has been common, as in our patient. The ‘‘keyhole aqueduct syndrome,'' (3) a description applied to cases reported before the availability of brainMRI, is probably another label for midbrain cleft. All cases had INO and marked ataxia. The radiological and pathological findings of both conditions correlate closely (Figs. 4A, C). The etiology of this condition is unknown. A congenital cause seems unlikely since presentation is usually delayed until the fourth decade, with subsequent clinical progression seen in the majority of cases. Familial occurrence has not been reported. The time course is consistent with a de-generative process, supported by the fact that there are usually clinical or pathological abnormalities remote from the midbrain, including the pons and cerebellum (3,4). The cause of the clefts might be disruption of CSF flow through the aqueduct, an idea supported by the finding of compression and edema of structures surrounding the clefts and the pathological cavities in the 3 histological studies (3,4). This process might be analogous to the slow expan-sion of a syrinx in the spinal cord or brainstem. Inter-estingly, the histological features of keyhole aqueducts are very similar to those of syringes, which mainly affect the cervicothoracic spine and lower brainstem and almost never extend above the pons (7). One pathogenetic theory about the development of a syrinx is that it is related to disrupted CSF flow via a craniospinal pressure dissociation produced during Valsalva maneuvers (8). Unlike syringes in the spinal cord, which are typically ovoid in cross section, syringes in the medulla or pons typically have a cleft-like appearance. These clefts usually project laterally rather than in an Table 1. Summary of cases of mesencephalic cleft and keyhole aqueduct Case Year Age (Yr)*/Sex Age at Onset of Symptoms and Their Duration Prior to Initial Examination Clinical Course INO Ataxia Other Ocular Findings Mesencephalic clefts Current study 2008 44/M Age 34, ataxia 10 yr Progressive Bilateral Yes Vertical nystagmus 1(1) 1996 43/F Age 30, diplopia (horizontal and vertical) 13 yr Static Bilateral No Right fourth cranial nerve palsy, upgaze nystagmus, reduced convergence, mild right ptosis 2(1) 1996 59/M Unknown, diplopia ‘‘very chronic'' Uncertain Bilateral Yes Downgaze nystagmus, reduced upgaze and convergence 3(2) 1997 67/M Unknown, diplopia and ptosis since early adulthood, ataxia 10 yr Progressive Bilateral Yes Bilateral ptosis, upbeat nystagmus Keyhole aqueduct 4(3) 1986† 59/M Age 32, ataxia 27 yr, ptosis 13 yr, diplopia 10 yr Static, death from unrelated cause Yes‡ Yes Bilateral ptosis, upbeat and rotatory nystagmus, ocular bobbing 5(3) 1986† 58/M Age 48, ataxia 10 yr Progressive leading to death Yes‡ Yes Vertical nystagmus, anisocoria, horizontal nystagmus 6(4) 1983† 59/F Age 32, diplopia and ataxia 27 yr Progressive, death in 60 s from unrelated cause Bilateral Yes Vertical nystagmus, possible bilateral abducens palsies later in illness *Age at last report. †Autopsy-confirmed cases. ‡No information as to whether INO was unilateral or bilateral. Original Contribution 148 Ahmad et al: J Neuro-Ophthalmol 2010; 30: 145-149 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. anteroposterior direction (Fig. 4E) (7,9). Why syringes in the brainstem should differ in appearance from those in the spinal cord is not clear, but the answer may lie in differing anatomical structures. Disruption would be likely to extend along lines of greatest weakness such as regions of de-velopmental fusion (10). It is conceivable, therefore, that midbrain clefts are syringes isolated to the midbrain. In our patient, the finding of normal intraventricular pressures and CSF flow on intraventricular monitoring argues against a generalized abnormality of CSF dynamics but would not exclude a local abnormality of CSF flow restricted to the region of the aqueduct. Also, the fact that there was a small syrinx in the cervical cord of our patient is suggestive of a more widespread disorder of CSF flow. REFERENCES 1. Lagre`ze WD, Warner JE, Zamani AA, Gouras GK, Koralnik IJ, Bienfang DC. Mesencephalic clefts with associated eye movement disorders. Arch Ophthalmology. 1996;114: 429-432. 2. Burgett RA, Kawasaki A. Mesencephalic clefts and eye movement disorders. Arch Ophthalmology. 1997;115:824. 3. de la Monte SM, Horowitz SA, Laroque AA, Richardson EP Jr. Keyhole aqueduct syndrome. Arch Neurology. 1986;43: 926-929. 4. Samples JR, Howard FM Jr, Okazaki H. Syringomesencephalia. Report of a case. Arch Neurology. 1983;40:757-759. 5. Chen CM, Lin SH. Wall-eyed bilateral internuclear ophthalmoplegia from lesions at different levels in the brainstem. J Neuroophthalmol. 2007;27:9-15. 6. Fredericks EJ, Van Nuis C. Diverticulum of the rostral cerebral aqueduct with ocular dysfunctions. Arch Neurology. 1967;16:32-36. 7. Love S, Louis DN, Ellison DW. Greenfield's Neuropathology, 8th edition. New York: Oxford University Press, 2008. 8. Sung WS, Chen YY, Dubey A, Hunn A. Spontaneous regression of syringomyelia-review of the current aetiological theories and implications for surgery. J Clin Neuroscience. 2008;15:1185-1188. 9. Riaz G, Campbell WW, Carr J, Ghatak N. Facial myokymia in syringobulbia. Arch Neurol. 1990;47:472-474. 10. Morgan D, Williams D. Syringobulbia: a surgical appraisal. J Neurol, Neurosurg Psychatry. 1992;55: 1132-1141. FIG. 4. Sample of images from previously reported cases of midbrain cleft. A. Axial T2 MRI shows a partial midbrain cleft (arrow) (1). B. Axial precontrast T1 MRI shows a complete midbrain cleft (2). C. Photomicrograph of ‘‘keyhole aqueduct syndrome'' at the level of the midbrain (3). D. Photomicrograph of laterally extending slit-like cavities at the level of the pontine tegmentum in a patient with ‘‘keyhole aqueduct syndrome.'' The fourth ventricle is to the top and left of the picture, and the slit is interrupting fibers of the superior cerebellar peduncle (3). E. Photomicrograph of medullary clefts (arrows) in a case of syringobulbia. Reprinted with permission from Lagre`ze et al (1), Burgett et al (2), and de la Monte et al (3). Original Contribution Ahmad et al: J Neuro-Ophthalmol 2010; 30: 145-149 149 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. |
