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5. Shahani BT, Halperin JJ, Boulu P, Cohen J. Sympathetic skin response: a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J Neurol Neurosurg Psychiatry 1984;47: 536 542. 6. Claus D. Schondorf R. Sympathetic skin response. Electroencephogr Clin Neurophysiol 1999;(Suppl. 52):277282. 7. Vetrugno R, Liguori R, Cortelli P, Montagna P. Sympathetic skin response. Basic mechanisms and clinical applications. Clin Auton Res 2003;13:256 270. 8. Mano Y, Nakamuro T, Takayanagi T, Mayer RF. Sweat function in Parkinsons disease. J Neurol 1994;241:573576. 9. Bordet R, Benhadjal J, Destee A, Hurtevent JF, Bourriez L, Guieu JD. Sympathetic skin response and R-R interval variability in multiple system atrophy and idiopathic Parkinsons disease. Mov Disord 1996;11:268 272. 10. Braune HJ. Autonomic dysfunction in Parkinsons disease assessed by sympathetic skin response: a prospective clinical and neurophysiological trial on 50 patients. Acta Neurol Scand 1997; 95:293297. 11. Chen HJ, Chen MH, Lin TH, Chee ECY. Recording pre- and post-operative sympathetic skin response in patients with palmar hyperhidrosis. Stereotact Funct Neurosurg 1995;64:214 220. 12. Lefaucheur JP, Fitoussi M, Becquemin JP. Abolition of sympathetic skin responses following endoscopic thoracic sympathectomy. Muscle Nerve 1996;19:581586. 13. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:3339. 14. Johnsen B, Fuglsang-Frederiksen A. Electrodiagnosis of polyneuropathy. Neurophysiol Clin 2000;30:339 351. 15. Toyokura M, Takeda H. Waveform of sympathetic skin response in diabetic patients. Clin Neurophysiol 2001;112:1229 1236. 16. Goldstein DS. Dysautonomia in Parkinsons disease: neurocardiological abnormalities. Lancet Neurol 2003;2:669 676. 17. Sharabi Y, Li ST, Dendi R, Holmes C, Goldstein DS. Neurotransmitter specicity of sympathetic denervation in Parkinsons disease. Neurology 2003;60:1036 1039. 18. Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H. Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 2005;15:29 34. 19. Spector RH, Bachman DL. Bilateral Adies tonic pupil with anhidrosis and hyperthermia. Arch Neurol 1984;41:342343. 20. Valls-Sole J, Monforte R, Estruch R. Abnormal sympathetic skin response in alcoholic subjects. J Neurol Sci 1991;102:233237. 21. Rousseaux M, Hurtevent JF, Benaim C, Cassim F. Late contralateral hyperhidrosis in lateral medullary infarcts. Stroke 1996;27: 991995. 22. Brasil-Neto JP, Carneiro CR. Monophasic negative sympathetic skin responses and autonomic dysfunction in carpal tunnel syndrome. Muscle Nerve 2004;29:330 331. 23. Mitani H, Ishiyama Y, Hashimoto I. Equivalent current dipole estimated from SSR potential distribution over the human hand. Clin Neurophysiol 2003;114:233238.

Fulminant Lewy Body Disease

Isabelle Momjian-Mayor, MD,1 Gian Paolo Pizzolato, MD,2 Karim Burkhardt, MD,2 Theodor Landis, MD,1 Alessandra Coeytaux, MD,1 and Pierre R. Burkhard, MD1*
1 Department of Neurology, Geneva University Hospitals and Medical School, Geneva, Switzerland; 2Neuropathology Unit, Department of Pathology, Geneva University Hospitals and Medical School, Geneva, Switzerland

Abstract: The clinical distinction between Parkinsons disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB) is challenged by most neuropathological studies showing nearly identical changes in both conditions. We report an unusual case of PD evolving into a rapidly progressive dementia leading to death within 3 months that showed nearly all clinical features of DLB. At autopsy, numerous Lewy bodies and Lewy neurites were found in several areas of the brainstem, the limbic system, and the neocortex, consistent with pure DLB. This case demonstrates that Lewy body disease may exhibit a dramatic course without any coexisting pathology and exemplies that PD, PDD, and DLB may sometimes represent sequential, yet overlapping, phenotypes of a same clinicopathological entity. 2006 Movement Disorder Society Key words: Parkinsons disease; dementia; Lewy body

Lewy body (LB) disease is a generic term that encompasses a variety of clinical phenotypes sharing a unique neuropathological marker, the intraneuronal inclusion of aggregated -synuclein. LB diseases include Parkinsons disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), among others. Despite extensive research, there is still considerable debate as to whether PDD1 and DLB2 are similar, overlapping, or separate entities.3 The problem is further complicated by the frequent co-occurrence of Alzheimers disease (AD) or vascular pathology in both conditions. Nearly indistinguishable on a neuropathological basis, PDD and DLB are clinically separated according to the duration of Parkinsonism preceding dementia, which, in DLB, is required not to exceed 1 year.4 Although purely empirical, this 1-year rule is used worldwide and considered practical by most clinicians to separate late versus early dementia associated with PD-type Parkinsonism. It has led some authors to emphasize clinical features that

*Correspondence to: Dr. Pierre R. Burkhard, Department of Neurology, Geneva University Hospitals, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: pierre.burkhard@hcuge.ch Received 10 March 2006; Accepted 15 March 2006 Published online 7 July 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21034

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FULMINANT LEWY BODY DISEASE appear more prominent in one condition compared to the other. For example, executive impairment, hallucinations, and delusions were found more severe5 and Parkinsonism more symmetrical6 in DLB than in PDD. Another issue involves disease progression and survival in LB diseases. While most authors agree that PD without dementia has a much longer disease duration than PDD and DLB, it is unclear whether evolution of these two conditions differs signicantly, yet two studies have suggested that some DLB patients may experience a more rapid course.7,8 We here report a unique case of typical PD followed by PDD and autopsy-conrmed diffuse LB disease similar to pure DLB, evolving over a dramatically brief course. CASE REPORT A 79-year-old man developed since 1993 typical features of PD including akinesia, rigidity, and resting tremor, all of which were more prominent on the left side and remarkably well responsive to levodopa (LD). His past history included type II diabetes and recurrent pulmonary embolism treated by chronic anticoagulant therapy. Over a 10-year course, evolution of PD was slowly progressive, with the recent development of mild motor uctuations and dyskinesia. In July 2003, the patient experienced some worsening of motor uctuations, gait difculties, and mild hallucinations. At that time, PD severity was rated Hoehn and Yahr stage 2.5. Adding tolcapone 100 mg tid to increased LD dosage (carbidopaLD 50/200 mg tid) and discontinuing dopamine agonists (cabergoline and pergolide) allowed prompt improvement of all motor symptoms and hallucinations completely disappeared. One month later, in the absence of any change of his current treatment, he suddenly presented repeated falls and generalized tremor. On neurological evaluation, features of Parkinsonism have considerably changed with severe hypomimia, dysarthria, axial rigidity, and a coarse action tremor mixed with myoclonus involving all limbs and massively interfering with gait and postural stability. There was no tremor at rest. Besides increasing apathy and major weight loss, he developed a rapidly progressive cognitive decline with recurrent episodes of confusion, uctuations of cognition with pronounced variations in attention and alertness, recurrent well-formed visual hallucinations, delusions, and severe anxiety with sleep disturbances. Trials with quetiapine and donepezil were unsuccessful, whereas conventional neuroleptics were intentionally avoided. Tremor exacerbated, balance and gait became increasingly difcult, and he was bedridden within 6 weeks. A detailed neuropsychological assessment demonstrated prominent frontosubcortical and visuospatial dysfunction

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with minimal memory impairment, all of which being absent 2 months earlier. An extensive workup excluded drug-induced, toxic, or metabolic delirium, but failed to provide clear explanations for this unexpected evolution. Notably, brain CT and MRI scans, besides diffuse brain atrophy, were unremarkable; repeated EEGs were all normal, as was CSF analysis, except for an increased expression of the 14-3-3 protein. Autoimmune, tumoral, or paraneoplastic disorders were ruled out by appropriate tests. While DLB was initially considered, sporadic CreutzfeldtJakob disease (CJD) became the more likely diagnosis based on the extremely rapid dementia, myoclonus, and a positive 14-3-3 test. After a short period of stupor complicated by bilateral aspiration pneumonia, the patient died, about 3 months after initial cognitive decline. Family gave consent for an autopsy to be performed. Neuropathology The brain was xed for 15 days in 4% buffered formalin and cut into 8 to 10 mm thick coronal slices. Samples were taken from the following areas: midbrain, pons, medulla oblongata, cerebellum; frontal, temporal, parietal, and occipital lobes; striatum, amygdala, entorhinal cortex, and thalamus. Several stains were performed on the aforementioned samples including hematoxylin eosin, Luxol van Gieson, Gallyas, and -synuclein immunostain (Novocastra Lab, Newcastle, U.K.). Macroscopic study showed moderate enlargement of frontal sulci, marked enlargement of lateral ventricles, and depigmentation of the substantia nigra and locus ceruleus. Histological analysis showed marked neuronal loss in both structures, where -synuclein immunostaining revealed numerous LBs and a moderate number of Lewy neurites. LBs and neuritis were also present in other parts of the brainstem, including the periaqueducal gray matter, oculomotor nuclei, reticularis nucleus, and tegmentum pontis. Gallyas stain of the frontal, temporal, parietal, occipital, and entorhinal cortices and amygdala showed no AD pathology, in particular no senile plaques, yet rare neurobrillary tangles were noticed in the subiculum, the CA1 sector of the hippocampus, the amygdala, and the entorhinal cortex. -synuclein immunostain showed the presence of LBs and neurites in the superior and middle gyri of the frontal and temporal lobes, hippocampus, cingulate gyrus, entorhinal cortex, and amygdala. Illustrative examples are provided on Figure 1. There was neither spongiform change nor any histological evidence of prion disease. Vascular changes were minimal.

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FIG. 1. Presence of numerous Lewy bodies (arrows) and Lewy neurites (arrowheads) in various brainstem, limbic, and neocortical areas. A: Substantia nigra. B: Hippocampus. C: Cingulate gyrus. D: Amygdala. E: Entorhinal cortex. F: Temporal cortex. -synuclein immunostain. Magnication: 160. [Color gure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

DISCUSSION Over a decade, this patient presented the typical course and cardinal features of PD followed by an abrupt and massive motor and cognitive decline unrelated to any secondary cause, in particular therapeutic modications. Following clinical criteria, he should be labeled as PDD. However, with the single exception of the 1-year-rule, he also fullled all core diagnostic features of DLB, as dened by the widely accepted McKeiths consensus criteria, including Parkinsonism, uctuating cognition, and recurrent visual hallucinations.4 Confusion, delusions, apathy, and anxiety on a background of progressive deterioration were also present as well as repeated falls. Interestingly, while more prominent on the left side during the PD stage of LB disease, the pattern of Parkinsonism evolved rapidly toward more axial, LD-unresponsive involvement with greater postural instability, gait impairment, dysarthria, and amimia. This particular phenotype has been frequently reported in DLB.2 Similarly, unilateral resting tremor, which was present initially, tended to disappear as a new severe action tremor developed symmetrically in four limbs. Neuropsychological testing was also in agreement with cognitive features reported in DLB.3 On the other hand, extremely rapid disease progression, leading to death within 3 months, is highly unusual for both PDD and DLB1,2 and, to the best of our knowledge, has not been reported yet. In fact, this

fulminant course appeared consistent with sporadic CJD at the time, the more so as the 14-3-3 test was found positive. While confounding, the latter result may not have been unexpected since a positive 14-3-3 test has been previously reported in a variety of degenerative nonprion dementias, including AD, frontotemporal dementia, and DLB.9,10 Indeed, the appearance of this neuronal protein in CSF is likely to reect the extent and rapidity of brain damage rather than prion-specic mechanisms, as suggested not only by this case but also by reports of positive 14-3-3 tests found in acute conditions as diverse as transverse myelitis,11 multiple sclerosis,12 paraneoplastic neurological disorders,13 Hashimotos encephalopathy,14 and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.15 Diagnosis of LB disease was unambiguously conrmed by neuropathological ndings showing extensive deposition of LBs and neurites within neocortical, limbic, and brainstem structures (Fig. 1). The neuropathological formula was in accordance with the consensus guideline for DLB4 and ts the recently dened criteria for a pure form.16 Interestingly, compared to the few cases of rapidly progressive DLB reported in the literature,7,8 all of which associated with senile plaques and neurobrillary tangles deposition, this case exhibited virtually no AD pathology. This appears consistent with disease progression of DLB being not merely determined

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DISTURBANCE OF REM SLEEP IN SCA2 by the burden of coexisting AD or vascular lesions and with Lewy pathology alone being sufcient to drive a fulminant evolution. Providing that the progression of Lewy pathology is reliably reected by clinical features, our case is likely to have presented a rapid brainstem to cerebrum extension of Lewy pathology, clinically expressed as PD initially and DLB thereafter. Supporting this view, deposition of LBs and neuritis was found in nearly all structures selectively involved in PD, even in the early stage of the disease (reticular formation and locus ceruleus), and recapitulated the stages of PD-related pathology recently revisited by Braak and colleagues,17 our case corresponding to Braaks stage 6. Our patient illustrates the problematic relationship between PD, PDD, and DLB, as, at one stage or another, he has fullled clinical criteria for either three conditions. In our opinion, this case exemplies the limited practical usefulness of distinguishing PDD and DLB, at least in some patients. In fact, it suggests that PDD and DLB may share so many clinical, pathological, and biological similarities that they are most certainly similar, if not identical, clinical expressions of a same, Lewy pathologyrelated, disease spectrum. If the recent reassessment of the incidence of dementia in PD, according to which 60% to 80% of PD patients will ultimately become demented after 15 years,18 is correct, then the clinical observation reported here will probably prove quite frequent and the 1-year rule established as the single criteria distinguishing PDD and DLB become obsolete. REFERENCES
1. Emre M. Dementia associated with Parkinsons disease. Lancet Neurol 2003;2:229 237. 2. McKeith I, Mintzer J, Aarsland D, et al. Dementia with Lewy bodies. Lancet Neurol 2004;3:19 28. 3. Aarsland D, Ballard CG, Halliday G. Are Parkinsons disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol 2004;17:137145. 4. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:11131124. 5. Aarsland D, Ballard C, Larsen JP, McKeith IG. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinsons disease with and without dementia. Int J Geriatr Psychiatry 2001;16:528 536. 6. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook MA, Bannister P. Motor and cognitive function in Lewy body dementia: comparison with Alzheimers and Parkinsons diseases. J Neurol Neurosurg Psychiatry 1997;62:243252. 7. Armstrong TP, Hansen LA, Salomon DP, et al. Rapidly progressive dementia in a patient with Lewy body variant of Alzheimers disease. Neurology 1991;41:1178 1180. 8. Lopez OL, Wisniewski S, Hamilton RL, et al. Predictors of progression in patients with AD and Lewy bodies. Neurology 2000; 54:1774 1779.

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9. Burkhard PR, Sanchez JC, Landis T, Hochstrasser DF. CSF detection of the 14-3-3 protein in unselected patients with dementia. Neurology 2001;56:1528 1533. 10. Huang N, Marie SK, Livramento JA, Chammas R, Nitrini R. 14-3-3 protein in the CSF of patients with rapidly progressive dementia. Neurology 2003;61:354 357. 11. Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal uid of patients with acute transverse myelitis. Lancet 2000;355:901. 12. Colucci M, Roccatagliata L, Capello E, et al. The 14-3-3 protein in multiple sclerosis: a marker of disease severity. Mult Scler 2004; 10:477 481. 13. Saiz A, Graus F, Dalmau J, Pifarre A, Marin C, Tolosa E. Detection of 14-3-3 brain protein in the cerebrospinal uid of patients with paraneoplastic neurological disorders. Ann Neurol 1999;46: 774 777. 14. Hernandez Echebarria LE, Saiz A, Graus F, et al. Detection of 14-3-3 protein in the CSF of a patient with Hashimotos encephalopathy. Neurology 2000;54:1539 1540. 15. Fujii K, Tanabe Y, Kobayashi K, Uchikawa H, Kohno Y. Detection of 14-3-3 protein in the cerebrospinal uid in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. J Neurol Sci 2005;239:115118. 16. Iseki E. Dementia with Lewy bodies: reclassication of pathological subtypes and boundary with Parkinsons disease and Alzheimers disease. Neuropathology 2004;24:7278. 17. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinsons disease. Neurobiol Aging 2003;24: 197211. 18. McKeith I. Dementia in Parkinsons disease: common and treatable. Lancet Neurol 2004;3:456.

Disturbance of Rapid Eye Movement Sleep in Spinocerebellar Ataxia Type 2

Sylvia M. Boesch, MD, Birgit Frauscher, MD, Elisabeth Brandauer, MD, Gregor K. Wenning, MD, PhD, Birgit Ho gl, MD, and Werner Poewe, MD*
Clinical Department of Neurology, Innsbruck Medical University, Austria Abstract: Five genetically conrmed spinocerebellar ataxia type 2 (SCA2) patients were admitted to our sleep laboratory for two all-night video-polysomnographies. A standard montage was used, including electroencephalography, vertical and horizontal electrooculography, electromyography of mental, submental, and tibialis anterior muscles, and

*Correspondence to: Dr. Werner Poewe, Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: werner.poewe@uibk.ac.at Received 3 January 2006; Revised 15 March 2006; Accepted 17 March 2006 Published online 7 July 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21036

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