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Show ORIGINAL CONTRIBUTION Periodic Alternating Nystagmus and Periodic Alternating Skew Deviation in Spinocerebellar Ataxia Type 6 Chaim B. Colen, MD, PhD, Anastasia Ketko, MD, Edwin George, MD, and Gregory P. Van Stavern, MD Abstract: The combination of periodic alternating nystagmus (PAN) and periodic alternating skew deviation (PASD) is rare. We report a case of PAN and PASD in a patient with spinocerebellar ataxia type 6 (SCA-6) and discuss the role of the cerebellum as a plausible mechanism for this combined pathologic condition. (J Neuro-Ophthalmol 2008;28:287-288) Various conditions have been reported to cause com-bined periodic alternating nystagmus (PAN) and perio-dic alternating skew deviation (PASD), including brainstem abscess (1), multiple sclerosis (MS) (2), degenerative vascular disease, vertebral artery compression (3), midbrain infarction (4), and iatrogenic vermian biopsy causing injury to the uvula (5). PAN without PASD has previously been reported to occur with spinocerebellar ataxia type 6 (SCA-6) (6). We have found only one other reported case of a patient with combined PAN and PASD (7); that patient had presumed hereditary cerebellar ataxia but no specific genetic diagnosis. Combined PAN and PASD have not been reported in the clinical setting of a genetically confirmed spinocerebellar ataxia syndrome. This association would strengthen the argument that cerebellar dysfunction is a focal point in the pathogenesis of PAN and PASD. CASE REPORT A 58-year-old African-American man presented with worsening vision over at least 6 months. He had progressed Departments of Neurological Surgery (CBC, AK, EG, GPVS), Ophthalmology (GPVS), and Neurology (GPVS), Wayne State University, Detroit, Michigan. Address correspondence to Gregory P. Van Stavern, MD, Kresge Eye Institute/Wayne State University, 4717 St. Antoine Street, Detroit, MI 48201; E-mail: gvanstaver@med.wayne.edu This study was supported by an unrestricted grant from the Research to Prevent Blindness to the Department of Ophthalmology at Wayne State University. to wheelchair dependence over 6 years because of worsening ataxia. He had developed severe extremity tremors and dysarthria. His family history suggested the presence of a ‘‘balance problem'' in his father and a paternal uncle but neither had a genetic diagnosis, and the patient had lost contact with his family. He had two sons who were reportedly neurologically normal. In an earlier evaluation in a movement disorders clinic, molecular genetic testing had shown an expansion on the SCA-6 gene of 22 repeats, confirming a diagnosis of SCA-6. A recent MRI had shown only pancerebellar atrophy, which was unchanged. Neuro-ophthalmologic examination showed a best-corrected visual acuity of 20/100 in both eyes. Confron-tation and Goldmann visual fields were normal. Pupils were normal. He had full versions but markedly impaired smooth pursuit and dysmetric saccades. He had PAN with a cycle of about 120 seconds and a right-beating nystagmus, a still period of about 10-15 seconds, and then a left-beating nystagmus. The cycle repeated itself through the exami-nation. He also had a periodic alternating hypertropia, typically a left hypertropia when the nystagmus was right-beating and a right hypertropia when the nystagmus was left-beating. The duration of the hypertropia would vary between cycles and did not follow a rhythmic pattern. Intraocular pressures were normal. Slit-lamp examination revealed mild nuclear cataracts. Ophthalmoscopy was normal. The visual acuity loss was attributed to oscillopsia, and low-dose baclofen was started, which produced improvement in oscillopsia. He was then lost to follow-up. DISCUSSION We report here the first case of combined PAN and PASD in a patient with genetically confirmed SCA-6. The combination of PAN and PASD is itself quite rare, and the association with a specific, well-characterized cerebellar ataxia lends insight into the pathophysiology of PAN and PASD. Skew deviation is a vertical misalignment of the eyes caused by damage to prenuclear vestibular input to the ocular motor nuclei. When it occurs on an interchanging J Neuro-Ophthalmol, Vol. 28, No. 4, 2008 287 J Neuro-Ophthalmol, Vol. 28, No. 4, 2008 Colen et al cyclic basis, the abnormality is called PASD. Acute hydrocephalus, tumors, strokes, and MS are the most frequent causes of PASD, followed by spinocerebellar degeneration and tentorial herniation (8). PAN, a spontane-ous conjugate nystagmus that involves regular cycles of "active" and "quiet" phases, has a differential diagnosis similar to that for PASD (5). A cycle of PAN includes a left-beating nystagmus, a quiet or transitional phase, a right-beating nystagmus, and a second transitional phase. SCA-6 is a progressive, degenerative, autosomal dominant condition resulting in late-onset adult cerebellar ataxia, dysarthria, and ocular motor disorders such as nystagmus (9,10). It is characterized by trinucleotide CAG expansions occurring within the gene CACNA1A on chromosome 19p13, which encodes for the 1A voltage-dependent subunit of the calcium channel (11). In SCA-6, the most affected calcium channels are of the Cav2.1 p-type, a subtype most prominent within the cerebellar Purkinje cells (12). The dramatic Purkinje cell loss and dysfunction that results from SCA-6 occurs predominantly within the vermis, flocculus, nodulus, and uvula (13,14). This preferential involvement of cerebellar structures could explain a predisposition to the rare concurrence of PAN and PASD. Radtke et al (5) described PASD in a patient who underwent biopsy of the inferior cerebellar vermis, resulting in destruction of the uvula. The periodic rhythmic ocular oscillation of PAN has been associated with various cerebellar disorders and has been attributed to an instability or increased gain in the vestibulo-ocular reflex (VOR) (9,15). The VOR circuit is regulated by three main components: Purkinje fibers from the archicerebellum, mossy fibers from the pontine nucleus prepositus hypoglossi (integrator for horizontal eye position), and the interstitial nucleus of Cajal (vertical integrator in the midbrain) (16). The cerebellar nodulus and uvula are essential in habituating and stabilizing the VOR. Selective ablation of these areas has resulted in PAN (5). The VOR model postulates neuroelectrical relays that conduct information regarding head position from the otolith organs and semicircular canals to the contralateral sixth cranial nerve nucleus and ipsilateral third cranial nerve nucleus, eventually stimulating the contralateral lat-eral rectus and the ipsilateral medial rectus to stabilize images on the retina during head movement. However, stability of the VOR depends on cerebellar sampling of this information. The mechanism of PASD is unknown but may involve pathways from both utricles to the vertical-rotatory ocular motor neurons, loss of cerebellar control of vertical vergence, or both. Once thought to be associated only with brainstem lesions and extensive cerebellar destruction, skew deviation has now been described with a localized lesion in the ventral caudal portion of the vestibular complex (17). PASD has previously been described in a patient with presumed hereditary cerebellar degeneration (18) in a report predating molecular genetic testing, so the specific syndrome was not identified. The combination of PAN and PASD in spinocerebellar ataxia might be under-reported owing to lack of an accurate diagnosis. Hereditary spinocerebellar ataxias should be considered as part of the differential diagnosis of patients with this finding. Careful examination of these patients might refine the anatomical definition of otolith-ocular pathways. Clinicopathological study of discrete cerebellar lesions associated with skew deviation should help resolve the causative role of the cerebellum in skew deviation. REFERENCES 1. Hedges TR III, Hoyt WF. Ocular tilt reaction due to an upper brainstem lesion: paroxysmal skew deviation, torsion, and oscillation of the eyes with head tilt. Ann Neurol 1982;11:537-40. 2. Rabinovitch HE, Sharpe JA, Sylvester TO. 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