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Show The Ocular Motor Features of Adult-Onset Alexander Disease: A Case and Review of the Literature Gerald Pfeffer, MD, Mathias Abegg, MD, A. Talia Vertinsky, MD, Isabella Ceccherini, PhD, Francesco Caroli, Jason J. S. Barton, MD, PhD Abstract: A 51-year-old Chinese man presented with gaze-evoked nystagmus, impaired smooth pursuit and vestibular ocular reflex cancellation, and saccadic dys-metria, along with a family history suggestive of late-onset autosomal dominant parkinsonism. MRI revealed abnormalities of the medulla and cervical spinal cord typ-ical of adult-onset Alexander disease, and genetic testing showed homozygosity for the p.D295N polymorphic allele in the gene encoding the glial fibrillary acidic protein. A review of the literature shows that ocular signs are fre-quent in adult-onset Alexander disease, most commonly gaze-evoked nystagmus, pendular nystagmus, and/or oculopalatal myoclonus, and less commonly ptosis,miosis, and saccadic dysmetria. These signs are consistent with the propensity of adult-onset Alexander disease to cause medullary abnormalities on neuroimaging. Journal of Neuro-Ophthalmology 2011;31:155-159 doi: 10.1097/WNO.0b013e31820ecb28 2011 by North American Neuro-Ophthalmology Society Alexander disease is a rare leukoencephalopathy char-acterized pathologically by Rosenthal fibers and cytoplasmic inclusions that contain glial fibrillary acidic protein (GFAP). A variety of mutations in the GFAP gene have recently been described in many, but not all, patients with this disorder (1-3). Infantile, juvenile, and adult-onset variants are recognized. The classic pediatric variant presents with spasticity, mental retardation, megalencephaly, and seizures, accompanied by extensive frontal and posterior fossa white matter changes on MRI. In contrast, patients with the adult-onset variant have mainly bulbar dysfunc-tion, ataxia, and/or spasticity, notably without cognitive impairment, optic atrophy, or megalencephaly (4). Their MRI shows minimal, if any, cerebral white matter changes; rather, there is an unusual atrophy and hyperintensity in the medulla and cervical cord that are virtually diagnostic of the condition (5). Given the importance of medullary structures in ocular motor control, it is likely that abnormal eye movements will be found in a significant number of patients with adult-onset Alexander disease. We recently encountered a patient with the classic MRI features of this disorder, who presented with balance problems and visual symptoms. In this report, we describe his features and review the literature on the ocular motor signs of adult-onset Alexander disease. CASE REPORT A 51-year-old Chinese man reported mild imbalance for 2 years. For the past year he has also noted tingling in his neck, both hands and feet, left trunk and inner arm, and blurred vision momentarily after a saccade. He was not taking medication. His father, paternal aunt, and paternal grandfather had a parkinsonian syndrome that began in their 50s. Records indicated that the aunt's condition was associated with dementia, vertical gaze palsy, pseudobulbar palsy with dysarthria, and diffuse muscle atrophy. Her CT at age 74 showed only cerebral atrophy, and nerve conduction studies were normal. All 3 had died without autopsy. The patient also has 2 younger brothers, 2 younger sisters, a daughter, and 2 sons, all well, but he declined to Division of Neurology, Department of Medicine (GP, MA, JJSB) and Departments of Ophthalmology and Visual Sciences (MA, JJSB) and Radiology (ATV), University of British Columbia, Vancouver, British Columbia, Canada; and Laboratory of Molecular Genetics (IC, FC), Institute Giannina Gaslini, Genova, Italy. J. J. S. Barton was supported by a Canada Research Chair and Senior Scholar Award from the Michael Smith Foundation for Health Re-search. M. Abegg was supported by a fellowship award from the Stiftung fuer Medizinisch-Biologische Stipendien. The authors re-port no financial conflicts of interest related to this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Address correspondence to Jason J. S. Barton, MD, PhD, Neuro- Ophthalmology Section K, VGH Eye Care Centre, 2550 Willow Street, Vancouver, British Columbia V5Z 3N9, Canada; E-mail: jasonbarton@ shaw.ca Pfeffer et al: J Neuro-Ophthalmol 2011; 31: 155-159 155 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. have them examined or imaged. There was no consan-guinity or family history of ocular problems. Visual acuity and funduscopy were normal, without optic atrophy. He was orthotropic with full range of eye move-ments. There was a fine, left-beating, horizontal nystagmus in primary position, horizontal gaze-evoked nystagmus, and rebound nystagmus (Fig. 1) (see Video 1, Supplemental Digital Content 1, http://links.lww.com/WNO/A15). (Video 1 shows floccular signs in the patient. This begins with a demonstration of low-gain pursuit horizontally and then vertically. It then shows gaze-evoked nystagmus in right gaze, followed by subtle rebound nystagmus on return to primary [most evident in the left eye], and then gaze-evoked nystagmus in left gaze.) Saccades were dysmetric with occasional macrosaccadic oscillations, and his visual symp-toms coincided with the occurrence of hypermetric saccades. Pursuit and cancellation of the vestibulo-ocular reflex were impaired. There was mild gait ataxia but no parkinsonism, dysarthria, or scoliosis. These eye movements were documented, and saccades were analyzed with an Eyelink 1000 video-based system (SR Research; http://www.eyelinkinfo.com). Horizontal sac-cades to 20 targets had a mean hypermetria of 1.3 6 2.1 , but the peak velocity/amplitude and duration/amplitude relationships of both the horizontal and vertical saccadic velocities were normal. Thus, horizontal saccades of 25-30 had a mean peak velocity of 558 s21 (SE = 13) and a mean duration of 92 milliseconds (SE = 1), while vertical saccades of 15-25 had a mean peak velocity of 471 s21 (SE = 17) and a mean duration of 81 milliseconds (SE = 3). These values are all within the normal range of published data (6). The patient returned 1 year later. After being treated with systemic steroids, clindamycin, and ceftriaxone for facial cel-lulitis, he began having new bouts of spontaneous oscillopsia lasting 5-10 seconds. He still had subtle left-beating nystag-mus in the primary position, which changed intermittently to right-beating horizontal nystagmus for 5-15 seconds, which was associated with the oscillopsia (see Video 2, Supple-mental Digital Content 2, http://links.lww.com/WNO/A16). (The patient returns complaining of recurrent brief bouts of oscillopsia lasting minutes. The video captures him in the midst of a symptomatic spell, with right-beating nystagmus in the primary position that gradually subsides by the end of the video.) This occurred several times at irregular intervals during his examination. After several weeks, he reported that the oscillopsia had gradually abated and stopped. Brain MRI (Figs. 2, 3) showed changes consistent with adult-onset Alexander disease. Nerve conduction studies re-vealed a mild left ulnar neuropathy but no generalized neuropathy or radiculopathy. Somatosensory potentials were delayed in the arms and legs. Auditory-evoked potentials had low amplitudes and prolonged latencies. Genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, and 7 was negative. DNA sequencing showed that he was homozygous for the p.D295N polymorphic allele of the GFAP gene. The ex-pected heterozygous state of the proband's parents could not be confirmed so that the possibility of a hemizygous con-dition due to an interstitial deletion could not be ruled out. DISCUSSION The presentation of adult-onset Alexander disease in our patient was characterized by a predominance of ocular motility disturbances, which correlated well with the dis-tribution of MRI signal abnormalities within the medulla. Poor tracking of moving objects, gaze-evoked nystagmus, and rebound nystagmus indicate impairment of ocular motor control circuits involving the flocculus and medullary structures, such as the medial vestibular nuclei and nuclei prepositus hypoglossi (7,8). The primary position nystag-mus could indicate dysfunction in central vestibular FIG. 1. Representative horizontal eye movements show-ing eye position (top trace of each pair) and velocity (bottom trace of each pair). By convention, right is at top and left is at bottom of each trace. Top: Primary position, there is fine, left-beating, horizontal nystagmus. Middle: Right gaze reveals right-beating gaze-evoked nystagmus. Bottom: Hypermetric saccade sequence. An excessively large leftward saccade is followed by corrective rightward saccade and then another smaller corrective leftward saccade. 156 Pfeffer et al: J Neuro-Ophthalmol 2011; 31: 155-159 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. pathways. His recurrent unprovoked episodes of right-beating nystagmus a year later are highly unusual. Although the patient attributed his several-week episode of oscillopsia and nystagmus to the use of steroids and antibiotics to treat his cellulitis, this may have been coincidental. Regardless, this period of episodic nystagmus also likely indicates a time of unstable central vestibular function. Saccadic dysmetria implicates circuits within the dorsal vermis and fastigial nuclei, some of which project to pontine structures (9) and others to the lateral medullary region (10,11). Abnormal auditory-evoked responses also support pontine in-volvement. Gait ataxia, sensory symptoms, and abnormal somatosensory potentials are consistent with structural changes in the medullary tegmentum or cervical cord. Our patient presented with cerebellar findings and a family history of parkinsonism. This raises the diagnostic possibility of a spinocerebellar atrophy (SCA), such as SCA- 2 or SCA-3 (12,13). Genetic testing ruled out the common forms of SCA and the neuroimaging findings proved di-agnostic. Our patient had medullary and cervical cord at-rophy consistent with adult-onset Alexander disease. Brain MRI showed no cerebellar abnormalities that would be seen in SCA (14). Mutations in the GFAP gene are found in approximately 95% of cases with infantile or adult-onset Alexander disease (2-4). Since normal GFAP can aggregate into Rosenthal fibers when overproduced (15), genetic abnormalities that affect normal GFAP expression may be responsible in pa-tients carrying no mutation of the coding gene portion. The role of the p.D295N variant, regarded as a polymorphism and for which our patient was homozygous, is not clear. This polymorphism occurs in 3% of control subjects (16), and its protein product forms normal-appearing GFAP filaments (15). However, this polymorphism has been as-sociated with other mutations of known pathogenicity, in a homozygous state in one patient with adult-onset FIG. 2. Axial scans at level of the medulla demonstrate small olives (white arrows) just anterior to deep horizontal medullary clefts (black arrowheads). The cerebellum ap-pears normal. T1 (A) and FLAIR (C) sequences show de-creased signal within the olives and clefts, while T2 MRI (B) demonstrates hyperintense signal in these regions. On FLAIR (C), the medulla also demonstrates a brighter signal than the cerebellum. FIG. 3. Midline T2 sagittal MRI shows a lateral medullary cleft (white arrow) and decreased volume of the medulla and upper cervical spinal cord. Basis pontis and cerebellar folia are normal. Pfeffer et al: J Neuro-Ophthalmol 2011; 31: 155-159 157 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Alexander disease (2) and in a heterozygous state in another (1). Hence, it is possible that this polymorphism may play a modulatory role in the development of this disorder. A review of 44 patients with adult-onset Alexander disease (3,4,17-32) showed that ocular symptoms are unusual at presentation, with only 3 patients noting dip-lopia and 2 oscillopsia (Table 1). Yet ocular motor signs commonly develop at some point in adult-onset Alexander disease, being present in 26 (59%) of the reported cases. The most frequent ocular finding is nystagmus, which was present in 22 patients (50%). Pendular nystagmus and gaze-evoked nystagmus were most common, and in at least some cases, the pendular form was part of oculopalatal myoclo-nus. Eight patients (18%) reported diplopia at some point in their course, but insufficient detail was given to determine if this was due to ocular motor nerve palsy or brainstem involvement. There is a single case reported with bilateral internuclear ophthalmoplegia (32). In summary, ocular motor signs are common in adult-onset Alexander disease due to involvement of the medulla and upper cervical cord. This results in damage to vestibular pathways, structures important for gaze-holding, and olivary pathways required for gaze stabilization. In our case, there was also evidence of damage to circuits involving the cerebellar vermis that determines saccadic accuracy. ACKNOWLEDGMENTS The authors thank Drs M. Wong, J. Beckman, and A. J. Stoessl for kindly providing them with previous records and K. Mohaseb for referring the patient. REFERENCES 1. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001;27:117-120. 2. 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