Journal of the Neurological Sciences 193 Ž2001. 53–57 www.elsevier.comrlocaterjns Short communication Reversible parkinsonism in systemic lupus erythematosus E.K. Tan a,) , L.L. Chan b, A.P. Auchus a a Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore b Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore Received 5 March 2001; received in revised form 27 July 2001; accepted 6 August 2001 Abstract Parkinsonism as a manifestation of central nervous system ŽCNS. lupus is extremely rare. We report the first patient with systemic lupus erythematosus ŽSLE. who developed a reversible parkinsonian syndrome associated with enhancing subcortical lesions on magnetic resonance imaging ŽMRI.. Following treatment with prednisolone and cyclophosphamide, her bradyphrenia, bradykinesia, hypophonia, rigidity, and abnormal gait progressively improved. Three months after she commenced treatment, repeat MRI scanning demonstrated resolution of the abnormal subcortical white matter enhancement. Our case illustrates unusual clinico-radiologic correlates of reversible parkinsonism in a SLE patient; these findings suggest that disruption of the subcortical frontal pathways may be a possible pathophysiologic mechanism for parkinsonism in cerebral lupus. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Parkinsonism; MRI; Systemic lupus erythematosus 1. Introduction Systemic lupus erythematosus ŽSLE. is an autoimmune, multiorgan disease that primarily affects young women. Neuropsychiatric manifestations, such as psychosis and seizures, are common in SLE, and may present in isolation or in association with other signs of systemic involvement w1x. Movement disorders Žsuch as chorea, ataxia, and hemiballism. complicating SLE are uncommon. Chorea usually occurs early in the course of the disease and may be associated with anticardiolipin antibodies w1x. Parkinsonism as a manifestation of central nervous system ŽCNS. lupus is extremely rare. In this report, we review the literature on parkinsonism in SLE and present the acute and convalescent clinico-radiologic correlates of reversible parkinsonism in a patient with CNS lupus. 2. Case report A 57-year-old Chinese woman with an 18-year history of SLE complicated by nephropathy and hypertension was receiving maintenance doses of prednisolone at 3 mg daily. She was well until several weeks before admission when ) Corresponding author. Fax: q65-220-3321. E-mail address: gnrtek@sgh.com.sg ŽE.K. Tan.. she became less communicative and increasingly passive and disinterested in her daily affairs. She also had difficulty swallowing, and the volume of her voice decreased. She did not complain of limb weakness or numbness, giddiness, diplopia, tinnitus, fever, urinary or bowel dysfunction. She consulted her physician who diagnosed depression and counselled the patient. However, she was subsequently hospitalised as her symptoms worsened. Neurologic examination revealed that she was fully oriented and demonstrated no evidence of cognitive dysfunction, aphasia, signs of meningism or any lateralizing neurological deficits. However, she had an expressionless facies and was hypophonic. In addition, there was marked rigidity and bradykinesia in her extremities. She also had a festinating gait with little arm swing, turn and start hesitation, and severe postural instability. Both rest and action tremor were absent. There was no associated postural hypotension, supranuclear gaze palsy or involuntary movements. There was no history of exposure to heavy metals or toxins. On T1-weighted brain magnetic resonance imaging ŽMRI. scans with intravenous gadolinium administration, prominent areas of enhancement were seen in the subcortical white matter areas of the corona radiata and centrum semiovale. There was no abnormal meningeal enhancement. On the T2-weighted MRI scans, mild bilateral subcortical white matter signal hyperintensities were seen. A brain CT scan revealed basal ganglia calcifications. Blood 0022-510Xr01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X Ž 0 1 . 0 0 6 0 4 - 9 54 E.K. Tan et al.r Journal of the Neurological Sciences 193 (2001) 53–57 investigations showed mildly elevated creatinine Ž114 umrl., decreased levels of total complements ŽCH50. and C4, a positive antinuclear antibody Ž1:800, homogenous., positive anti-Ro ŽSSA. antibody, elevated anti-dsDNA Ž95.51 IUrml., and elevated erythrocyte sedimentation rate Ž57 mmrh.. Thyroid and parathyroid hormonal levels, serum calcium, phosphate, and magnesium were within normal limits. On lumbar puncture, the opening pressure and the cerebrospinal fluid ŽCSF. examination was within normal limits Žwhite cell count 0 per mm3 , glucose 3.5 Fig. 1. Ža. MRI scans on admission. An axial T1-weighted scan at the level of the body of the lateral ventricles following gadolinium enhancement reveals intense enhancement of the subcortical white matter. Žb. Coronal contrast enhanced T1-weighted image showing enhancement in the frontal subcortical white matter Žarrows.. Note the basal ganglionic calcifications demonstrated as areas of hyperintensity due to the presence of hydrated calcium ions. Žc and d. Axial and coronal enhanced T1-weighted MRI scans at the same level showing interval resolution of subcortical enhancement 3 months later. E.K. Tan et al.r Journal of the Neurological Sciences 193 (2001) 53–57 mmolrl, chloride 125 mmolrl, protein 0.2 Grl, globulins negative.. On the basis of her laboratory findings and abnormal white matter enhancement on MRI, a diagnosis of active CNS lupus was made, and she was treated with high-dose intravenous methylprednisolone Ž1 grday. for 3 days. This was subsequently converted to oral prednisolone at 1 mgrkgrday for 2 weeks and gradually tapered according to her clinical response. In addition, she received monthly infusions of cyclophosphamide Ž10 mgrkg. for 3 months. Following treatment with prednisolone and cyclophosphamide, her bradyphrenia, bradykinesia, hypophonia, rigidity, and abnormal gait progressively improved. Three months after she commenced treatment, repeat MRI scanning demonstrated resolution of the abnormal subcortical white matter enhancement ŽFig. 1.. 3. Discussion Headache, seizures, and psychiatric symptoms are the most common manifestations of CNS lupus w1–3x. However, parkinsonism as a manifestation of SLE is extremely rare w4–9x. There have been only a few case reports of children w4,5x and adults w6–9x with parkinsonian features as a manifestation of SLE ŽTable 1.. The American College of Rheumatology Nomenclature for neuropsychiatric SLE recently provided case definitions of 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests w10x. However, probably due to its rarity, parkinsonian features were not part of this classification. Our patient had quiescent SLE for many years, and presented with parkinsonian features that were initially misdiagnosed as depression. Her MRI showed abnormal enhancement in the frontal lobe white matter that resolved following anti-inflammatory and immunosuppressive treatments. This is the first report of enhancing subcortical lesions on MRI in a SLE patient presenting with parkinsonism. The resolution of these lesions coinciding with the clinical improvement suggests that these abnormalities were the likely cause of patient’s signs. To our knowledge, there have been only three published case reports of abnormal MRI findings in SLE patients with parkinsonism, and in only two of these did imaging abnormalities correlated with clinical improvement w4,9x. However, neither of these two cases reported enhancing brain lesions. The first was a 9-year-old girl who presented with seizures and mutism, and her MRI showed T2weighted hyperintensities in bilateral caudate nuclei, putamen, and external capsules w4x. These resolved with treatment. The second case was a 24-year-old man who had left hemiparesis and parkinsonism w9x. Hyperintensities were noted in the brainstem, both parietal lobes, left thalamus, right internal capsule, and right occipital lobe on T2weighted MRI. He responded to oral prednisolone, fol- 55 lowed by oral cyclophosphamide. At follow-up 6 months later, the hyperintensities resolved, but he developed lefthand dystonia. The pathogenesis of CNS lupus is not fully understood. However, based on the varied clinical spectrum, more than one pathophysiologic mechanism may be involved. The most common finding in autopsy series is the presence of multiple microinfarcts, but pathologic findings have not always correlated well with antemortem clinical signs. Immunological mechanism may play a role in the pathogenesis of parkinsonism in SLE w1x. The autoantibodies that reacted with neuronal membrane antigens have been demonstrated in serum and CSF of SLE patients. Presence of these autoantibodies frequently correlated with levels of anti-DNA antibodies w1x. Kunas et al. w6x reported the presence of antidopamine antibodies in a SLE patient with parkinsonism. These antibodies were not detected in other active SLE patients. The authors postulated that these antibodies may be cytotoxic to dopaminergic neurones. Some authors w11–13x reported that the level of interleukin-6 Žwhich can induce synthesis of acute phase proteins, differentiation of neuronal cells, and improves catecholaminergic and cholinergic cell survival in the brain. was elevated in CSF and may be correlated with CNS lupus activity w13x. Mogi et al. w14x previously described elevated levels of interleukin-1b and interleukin-6 in brains from parkinsonian patients, and Kluter et al. w15x found defective leucocyte production of interleukin-2 in idiopathic Parkinson’s disease. These interleukins may therefore play a role in the pathogenesis of parkinsonism in SLE patients. The MRI findings in our patient supported the hypothesis that inflammatory changes with disruption of the blood–brain barrier produced dysfunction within subcortical frontal brain regions. The clinical and imaging response to therapy suggested that this subcortical dysfunction may be reversible. AVascularB or AatheroscleroticB parkinsonism can occur following brain infarction in these same brain regions w16–19x. Winikates and Jankovic w16x found more than 75% of their patients with vascular parkinsonism had evidence of periventricular andror subcortical white matter changes on neuroimaging studies. This was significantly higher than the 16% found in their Parkinson’s disease patients. Similarly, Zijlmans et al. w19x reported a greater volume of MRI subcortical lesions in patients with suspected vascular parkinsonism compared with both Parkinson’s disease and hypertensive controls. In vascular parkinsonism, it is postulated that disruption of frontal subcortical pathways produces lower-body bradykinesia, rigidity, and gait difficulty. However, unlike our presumably vasculitic case, the signs in parkinsonism following subcortical frontal brain infarction are usually irreversible. Intravenous glucocorticoids and cyclophosphamide have been used successfully to treat cerebral lupus w20x. However, it is uncertain which is the best form of treatment in 56 Table 1 Reported cases of cerebral lupus with parkinsonism Duration of SLE before neurologic symptoms Žyears. Signs at presentation MRI CSF Treatment Outcome 1r9rF 0.7 seizure, mutism ≠protein 2r12rF 2 seizure, loss of consciousness T2 hyperintensities in caudate, putamen, external capsule T2 hyperintensities in right lentiform, external capsule pulse prednisolone, cyclophosphamide, immunoglobulins pulse prednisolone, cyclophosphamide, immunoglobulins 3r15rF ? psychosis Normal ? levodopa, amantadine 4r16rF 0.5 progressive motor slowing Normal ? 5r34rF 11 progressive motor slowing Normal ≠IgG 6r39rF 7r20rF 3 10 Normal Normal ≠protein, ≠cells ≠cells 8r24rM diagnosed at the same time progressive motor slowing spastic paraplegia initially, progressive motor slowing 2 months later progressive motor slowing, left hemiparesis normal 9r57rF Žpresent study. 18 progressive motor slowing T2 hyperintensities in brainstem, occipital and parietal lobes, thalamus, internal capsule T1 gadolinium enhancement in subcortical frontal white matter levodopa, amantadine, bromocriptine levodopa, bromocriptine, selegiline pulse prednisolone plasmapharesis cyclophosphamide, evodopa levodopa, prednisolone complete recovery, repeat MRI normal repeat MRI at 2 weeks no improvement, clinical recovery at 2 months complete recovery at 3 months some recovery ≠protein normal pulse methyl-prednisolone, cyclophosphamide some recovery some recovery complete recovery 9 months complete recovery from parkinsonism, but had left-hand dystonia almost complete recovery at 3 months E.K. Tan et al.r Journal of the Neurological Sciences 193 (2001) 53–57 No.rager gender E.K. Tan et al.r Journal of the Neurological Sciences 193 (2001) 53–57 patients with cerebral lupus manifesting parkinsonism. Levodopa, bromocriptine, selegiline, and amantadine have been used with varying degrees of success ŽTable 1.. Our patient responded to pulse steroids and cyclophosphamide without receiving any antiparkinsonian medications. Kwong et al. w4x reported the effective use of intravenous immunoglobulins Žfollowing failed methylprednisolone and cyclophosphamide. in treating parkinsonism in two young SLE patients. Both had complete clinical recovery within a few months. At present, it is difficult to conclusively state the most effective therapy for parkinsonism in SLE. In conclusion, we highlight that parkinsonism, although rare, can be a manifestation of cerebral lupus. Our report illustrates unusual clinico-radiologic correlates of reversible parkinsonism in a SLE patient. These findings suggest that disruption of the subcortical frontal pathways may be a possible pathophysiologic mechanism for parkinsonism in cerebral lupus. References w1x Systemic lupus erythematosus. In: Schumacher HR, Klippel JH, Koopman WJ, editors. Primer on rheumatic disease. 10th edn. Atlanta, GA: Arthritis Foundation; 1993. p. 100–16. w2x Parikh S, Swaiman KF, Kim Y. Neurologic characteristics of childhood lupus erythematosus. Pediatr Neurol 1995;13:198–201. w3x Steinlin MI, Blaster SI, Gilday DL, et al. Neurologic manifestations of systemic lupus erythematosus. Pediatr Neurol 1995;13:191–7. w4x Kwong KL, Chu R, Wong SN. Parkinsonism as unusual neurologic complication in childhood systemic lupus erythematosus. Lupus 2000;9:474–7. w5x Shahar E, Goshen E, Tauber Z, Lahat E. Pediatr Neurol 1998; 18:456–8. w6x Kunas RC, McRae A, Kesselring J, Villiger PM. Antidopaminergic antibodies in a patient with complex autoimmune disorder and rapidly progressing Parkinson’s disease. J Allergy Clin Immunol 1995;96:688–90. 57 w7x Miyoshi Y, Atsumi T, Kitagawa H, et al. Parkinson-like symptoms as a manifestation of systemic lupus erythematosus. Lupus 1993;2: 199–201. w8x Osawa H, Yamabe H, Kaizuka M, et al. Systemic lupus erythematosus associated with transverse myelitis and parkinsonian symptoms. Lupus 1997;6:613–5. w9x Lim SM, Oldfield M, Abbott RJ. Systemic lupus erythematosus presenting with steroid-responsive parkinsonism and post-hemiplegic dystonia. Eur J Neurol 1998;5:309–12. w10x The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599–608. w11x Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T. Interleukin ŽIL.-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 1996; 211:13–6. w12x Muller T, Blum-Degen D, Przuntek H, Kuhn W. Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson’s disease. Acta Neurol Scand 1998;2:142–4. w13x Hirohata S, Miyamoto T. Elevated levels of interleukin 6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum 1990;33:644– 9. w14x Mogi M, Harada M, Kondo T, et al. Interleukin 1b, interleukin 6, epidermal growth factor and transforming growth factor-a are elevated in the brain from parkinsonian patients. Neurosci Lett 1994; 180:147–50. w15x Kluter H, Vieregge P, Stolze H, Kirchner H. Defective production of interleukin 2 in patients with idiopathic Parkinson’s disease. J Neurol Sci 1995;133:134–9. w16x Winikates J, Jankovic J. Clinical correlates of vascular parkinsonism. Arch Neurol 1999;56:98–102. w17x Jankovic J. Lower body Žvascular. parkinsonism. Arch Neurol 1990;47:728. w18x Fitz Gerald PM, Jankovic J. Lower body parkinsonism: evidence of vascular etiology. Mov Disord 1989;4:249–60. w19x Zijlmans JCM, Thijssen HOM, Vogels OJM, et al. MRI in patients suspected of vascular parkinsonism. Neurology 1995;45:2183–8. w20x West SG. Lupus and the nervous system. Curr Opin Rheumatol 1996;8:408–14.