Extraocular muscle dystonia due to acquired (non-Wilsonian) hepatocerebral degeneration

Movement Disorders Vol. 23, No. 6, 2008, pp. 875–915 Ó 2008 Movement Disorder Society

Brief Reports

Extraocular Muscle Dystonia Due to Acquired (non-Wilsonian) Hepatocerebral Degeneration

prior hepatic encephalopathy with asterixis; however, she had no history of encephalitis and denied antecedent use of dopamine receptor blocking medications or other drugs known to precipitate dyskinesias. Neurological examination revealed a normal level of consciousness with preserved orientation and attention; she had no difficulties with language, calculation or abstraction and no obsessive-compulsive symptoms. Cranial nerve testing revealed episodes of tonic ocular deviation, upward and to the patient’s right side, interrupted by compensatory eye movements. These episodes would last for several hours and then remit for only minutes at a time. The oro-facial chorea was constant, nonrhythmic, and involved her lips, tongue, and jaw. In addition, there were involuntary vocalizations (predominantly squeaking) as well as patterned, longer-duration dystonic muscle contractions producing platysmal spasm, grimacing, jaw opening, blepharospasm, and brow elevation. The patient denied an urge to perform the movements and was unable to suppress them for any period of time. No other cranial nerve abnormalities were noted except slow, dysarthric, highpitched speech (Fig. 1, video segment). Motor examination revealed normal bulk, power and tone without rest, postural or kinetic tremor. She had appendicular and gait ataxia, but her sensory and reflex examinations were unremarkable. Her serum manganese concentration was 1.5 ng/mL (normal, 0.40–0.85), and magnetic resonance (MR) imaging revealed homogenously increased T1 signal within the pallidal nuclei and nigra (Fig. 2). T2-weighted and gadolinium enhanced sequences were normal. A normal slit-lamp ophthalmologic examination, hepatic copper level and serum ceruloplasmin concentration excluded Wilson’s disease. Cirrhotic patients may develop a neurodegenerative syndrome-acquired hepatocerebral degeneration (AHD)with ataxia, cognitive decline, myelopathy, dysarthria, and various extrapyramidal signs such as orofaciolingual dyskinesias, craniocervical dystonia, chorea, and parkinsonism.1–3 While AHD is generally regarded as an uncommon disease, recent evidence suggests that 20% of patients with advanced liver failure develop parkinsonism often with cranial dystonia.3 Abnormalities of eye movement, however, are rarely encountered

Joseph Ferrara, MD, Deepak Gupta, MD, Emily Foster, MD, Katherine Garman, MD, and Mark Stacy, MD* Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, North Carolina Video

Abstract: We present a video report of a patient with advanced non-Wilsonian cirrhotic liver disease who developed extraocular muscle dystonia (oculogyric crisis) and severe orofaciolingual dyskinesias. Acquired hepatocerebral degeneration causes choreic movements, especially of cranial muscles, but dystonic ocular spasm is an infrequent manifestation of this disorder. This case illustrates that AHD should be considered in the differential diagnosis of extraocular muscle dystonia. Ó 2008 Movement Disorder Society Key words: oculogyric crisis; extraocular muscle dystonia; hepatocerebral degeneration

A 56-year-old woman with cirrhosis, Child-Pugh Score 9 (Class B), from biopsy-proven alpha-1 antitrypsin deficiency and nonalcoholic steatohepatitis presented with a 10-day history of gradual-onset dysarthria and involuntary facial movements accompanied by anxiety, retroocular discomfort, and neck paresthesias. The patient’s neurological history was notable for

This article includes supplementary video clips, available online at http://www.interscience.wiley.com/jpages/0885-3185/suppmat *Correspondence to: Dr. Mark Stacy, Associate Professor of Neurology, 932 Morreene Rd, MS 3333, Durham, NC 27705. E-mail: [email protected] Received 7 July 2007; Revised 31 August 2007; Accepted 12 October 2007 Published online 24 March 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21841

875

876

J. FERRARA ET AL. patients.6,10,11 Manganese levels are also elevated in other brain regions, including the striatum, but usually to a lesser degree.6,11

FIG. 1. Extraocular muscle dystonia and involuntary grimacing. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

in AHD, including the extraocular muscle dystonia seen in this patient.4 The pathogenesis of AHD is not well understood. It develops independent of the etiology of hepatic dysfunction, but almost5 always occurs in patients with chronic liver disease and portosystemic vascular shunts. AHD shares pathological and some clinical features with Wilsonian hepatolenticular degeneration but without the significant copper accumulation typical of Wilson’s disease.1,6 AHD may improve following liver transplantation, but otherwise current treatments, including conventional therapies for hepatic encephalopathy, are often inadequate.7 Clinicians have recently hypothesized that AHD, like Wilson’s disease, is a form of metal intoxication, but in this case manganese, not copper, is the active metal.7 Normally, excess dietary manganese-over 95% of that absorbed-is quickly cleared by the liver before reaching the systemic circulation.8,9 In cirrhotic patients with portosystemic shunting, the first-pass elimination of manganese is bypassed, leading to systemic overload. The paramagnetic properties of manganese produce a distinct MR imaging signature-increased T1 signal in the basal ganglia without corresponding changes on T2-weighted sequences. This pattern of MR imaging is nearly ubiquitous in cirrhotic patients and correlates with excess manganese levels present at autopsy.6 Pallidal manganese concentrations in persons who expire from hepatic coma are approximately threefold to ninefold higher than in control

Movement Disorders, Vol. 23, No. 6, 2008

FIG. 2. T1-weighted MR imaging demonstrates symmetrical pallidal and nigral hyperintensities. Other MR imaging sequences (not shown) are normal.

EXTRAOCULAR MUSCLE DYSTONIA It is unclear whether manganese deposition is responsible for the extrapyramidal signs of AHD. Other potential causes include ammonia, which is a known contributor to hepatic encephalopathy, and aromatic amino acids, which theoretically could disrupt the dopaminergic pathways that modulate movement.4 A role for manganese in AHD is conceivable considering its reputation as an occupational neurotoxin. The metal is known to collect in glial cells at a concentration of approximately 200 times that of the extracellular compartment, and the majority of intracellular manganese is found within mitochondria where it may compromise energy metabolism.12 Historically, about 1 to 4% of miners who were exposed to high levels of manganese-laden dust developed dystonia and parkinsonism.13 Additionally, a possible link between manganese and neurological disease may exist in arc welders who are exposed to fumes containing the metal. Rare case reports of welders with parkinsonism and basal ganglia T1 hyperintensity on MR imaging support this association14-16; however, as with AHD, this link remains speculative, and no connection between welding and idiopathic Parkinson’s disease has been established.17 If AHD and occupational manganism genuinely share a common pathogenesis, then differences in their clinical features require explanation: for example, oro-facial chorea is a feature of AHD but is not found in manganese ore workers, while limb dystonia is common in occupational manganism but an uncommon feature of AHD. This patient’s clinical phenotype is interesting in that extraocular muscle dystonia is an uncommon disorder but is reported as a symptom of manganism.13 Early last century, postencephalitic parkinsonism was a major cause of extraocular muscle dystonia. Presently, most cases are the result of acute druginduced dystonia, often from dopamine receptor blocking medications and infrequently from other agents such as acetylcholinesterase inhibitors,18,19 cetirizine,20 lithium,21 and carbamazepine.22 Briefly sustained ocular deviations are also a common form of dystonic tic in patients with Tourette’s syndrome, but other causes of dystonic ocular deviation—brief or sustained—are rare. These disorders include basal ganglia stroke,23 hemorrhage,24 calcification,25 and demyelination26; thirdventricular glioma (causing a positional variant)27; infections including herpes virus,28 Japanese encephalitis29 and syphilis30; disorders of neurotransmitter metabolism such as guanosine triphosphate cyclohydrolase I deficiency,31 tyrosine hydroxylase deficiency32 Sepiapterin reductase deficiency33 and aromatic L-amino acid decarboxylase deficiency34; rapid-onset dystonia-

877

parkinsonism35; Rett syndrome36; Chediak–Higashi syndrome37; ataxia-telangiectasia38; Wilson’s disease39; neurodegeneration with brain iron accumulation40; paraneoplasia associated with anti-Ta antineuronal antibodies41; tardive dystonia42,43 and levodopa-induced dyskinesias in Parkinson’s disease.44 Paroxysms of tonic upgaze may also occur as a self-limited disorder of childhood, associated with ataxia or cognitive impairment in half of patients. In these children its etiology appears heterogeneous: most cases are sporadic, some familial and occasional patients have fetal exposure to valproic acid or structural lesions of the midbrain.45 Involuntary dystonic ocular deviations may also be a form of idiopathic focal dystonia-either in isolation46 or with accompanying blepharospasm.30 The present case highlights the need for including AHD among the infrequent causes of extraocular muscle dystonia. LEGEND TO THE VIDEO Video: Dystonic and choreic movements of cranial muscles and involuntary vocalizations. Acknowledgments: All authors have no financial disclosures.

REFERENCES 1. Victor M, Adams R, Cole M. The acquired (non wilsonian) type of chronic hepatocerebral degeneration. Medicine 1965;44:345– 396. 2. Finlayson MH, Superville B. Distribution of cerebral lesions in acquired hepatocerebral degeneration. Brain 1981;104:79–95. 3. Burkhard PR, Delavelle J, Du Pasquier R, Spahr L. Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003;60:521–528. 4. Jog MS, Lang AE. Chronic acquired hepatocerebral degeneration: case report and new insights. Mov Disord 1995;10:714– 722. 5. Aggarwal A, Vaidya S, Shah S, Singh J, Desai S, Bhatt M. Reversible Parkinsonism and T1W pallidal hyperintensities in acute liver failure. Mov Disord 2006;21:1986–1990. 6. Klos KJ, Ahlskog JE, Kumar N, Campburn J, et al. Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity. Neurology 2006;67:1984–1989. 7. Pomier-Layrargues GP. Movement dysfunction and hepatic encephalopathy. Metab Brain Dis 2001;16:27–35. 8. Cotzia GC, Horiuchi K, Fuenzalida S, Mena I. Chronic Manganese poisoning: clearance of tissue manganese concentrations with persistence of the neurological picture. Neurology 1968;18: 376–382. 9. Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci 2004;1012:115–128. 10. Pomier-Layrargues G, Spahr L, Butterworth RF. Increased manganese concentrations in pallidum of cirrhotic patients. Lancet 1995;345:735. 11. Maeda H, Sato M, Yoshikawa A, et al. Brain MR imaging in patients with hepatic cirrhosis: relationship between high intensity signal in basal ganglia on T1-weighted images and elemental concentrations in brain. Neuroradiology 1997;39:546–550.

Movement Disorders, Vol. 23, No. 6, 2008

878

J. FERRARA ET AL.

12. Normandin L, Hazell AS. Manganese neurotoxicity: an update of pathophysiologic mechanisms. Metab Brain Dis 2002;17:375– 387. 13. Pal PK, Samii A, Calne DB. Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 1999;20:227–238. 14. Sadek AH, Rauch R, Schulz PE. Parkinsonism due to manganism in a welder. Int J Toxicol 2003;22:393–401. 15. Kenangil G, Ertan S, Sayilir I, Ozekmekci S. Progressive motor syndrome in a welder with pallidal T1 hyperintensity on MRI: a two-year follow-up. Mov Disord 2006;21:2197–2200. 16. Discalzi G, Pira E, Herrero Hernandez E, Valentini C, Turbiglio M, Meliga F. Occupational Mn parkinsonism: magnetic resonance imaging and clinical patterns following CaNa2-EDTA chelation. Neurotoxicology 2000;21:863–866. 17. Jankovic J. Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology 2005;64:2021– 2028. 18. Nucci P, Brancato R. Oculogyric crisis after the Tensilon test. Graefes Arch Clin Exp Ophthalmol 1990;228:384–385. 19. Hsieh BH, Deng JF, Ger J, Tsai WJ. Acetylcholinesterase inhibition and the extrapyramidal syndrome: a review of the neurotoxicity of organophosphate. Neurotoxicology 2001;22:423– 427. 20. Fraunfelder FW, Fraunfelder FT. Oculogyric crisis in patients taking cetirizine. Am J Ophthalmol 2004;137:355–357. 21. Sandyk R. Oculogyric crisis induced by lithium carbonate. Eur Neurol 1984;23:92–94. 22. Arnstein E. Oculogyric crisis: a distinct toxic effect of carbamazepine. J Child Neurol 1986;1:289–290. 23. Liu GT, Carrazana EJ, Macklis JD, Mikati MA. Delayed oculogyric crises associated with striatocapsular infarction. J Clin Neuroophthalmol 1991;11:198–201. 24. Shimpo T, Fuse S, Yoshizawa A. Retrocollis and oculogyric crisis in association with bilateral putaminal hemorrhages. Rinsho Shinkeigaku 1993;33:40–44. 25. Kis B, Hedrich K, Kann M, Schwinger E, Kompf D, Klein C, Pramstaller PP. Oculogyric dystonic states in early-onset parkinsonism with basal ganglia calcifications. Neurology 2005;65: 761. 26. Barton JJ, Cox TA, Calne DA. Involuntary ocular deviations and generalized dystonia in multiple sclerosis. A case report. J Neuroophthalmol 1994;14:160–162. 27. Stechison MT. Cystic glioma with positional oculogyric crisis. J Neurosurg 1989;71:955–957. 28. Matsumura K, Sakuta M. Oculogyric crisis in acute herpetic brainstem encephalitis. J Neurol Neurosurg Psychiatry 1987;50: 365–366. 29. Kalita J, Misra UK. Markedly severe dystonia in Japanese encephalitis. Mov Disord 2000;15:1168–1172. 30. Aramideh M, Bour LJ, Koelman JH, Speelman JD, Ongerboer de Visser BW. Abnormal eye movements in blepharospasm and involuntary levator palpebrae inhibition. Clinical and pathophysiological considerations. Brain 1994;117:1457–1474. 31. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 2003;54 (Suppl 6):S32–S45. 32. Swoboda KJ, Hyland K, Goldstein DS, et al. Clinical and therapeutic observations in aromatic l-amino acid decarboxylase deficiency. Neurology 1999;53:1205–1211. 33. Neville BG, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain 2005;128:2291–2296. 34. Hoffmann GF, Assmann B, Bra¨utigam C, et al. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. Ann Neurol 2003;54 (Suppl 6): S56–S65. 35. Dobyns WB, Ozelius LJ, Kramer PL, et al. Rapid-onset dystonia-parkinsonism. Neurology 1993;43:2596–2602.

Movement Disorders, Vol. 23, No. 6, 2008

36. FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement disorders. Mov Disord 1990;5:195–202. 37. Uyama E, Hirano T, Ito K, et al. Adult Chediak-Higashi syndrome presenting as parkinsonism and dementia. Acta Neurol Scand 1994;89:175–183. 38. Urra DG, Campose J, Ruiz PG, Varela de Seijas E, de Yebenes JG. Movement disorders in ataxia telangiectasia: review of six patients [abstract]. Neurology 1989;39 (Suppl 1):321. 39. Lee MS, Kim YD, Lyoo CH. Oculogyric crisis as an initial manifestation of Wilson’s disease. Neurology 1999;52:1714– 1715. 40. Zupanc ML, Chun RW, Gilbert-Barness EF. Osmiophilic deposits in cytosomes in Hallervorden-Spatz syndrome. Pediatr Neurol 1990;6:349–352. 41. Bennett JL, Galetta SL, Frohman LP, et al. Neuro-ophthalmologic manifestations of a paraneoplastic syndrome and testicular carcinoma. Neurology 1999;52:864–867. 42. FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neurology 1989;39:1434–1437. 43. Sachdev P. Tardive and chronically recurrent oculogyric crises. Mov Disord 1993;8:93–97. 44. LeWitt PA. Conjugate eye deviations as dyskinesias induced by levodopa in Parkinson’s disease. Mov Disord 1998;13:731– 734. 45. Ouvrier R, Billson F. Paroxysmal tonic upgaze of childhood-a review. Brain Dev 2005;27:185–188. 46. Galardi G, Volonte´ MA, Maderna L, Amadio S, Nemni R, Comi G. Oculomotor focal dystonia. Mov Disord 2001;16:366–370.