Familial Diffuse Lewy Body Disease, Eye Movement Abnormalities, and Distribution of Pathology

OBSERVATION Familial Diffuse Lewy Body Disease, Eye Movement Abnormalities, and Distribution of Pathology

Francesca M. Brett, MD, FRCPath; Craig Henson, BS; Hugh Staunton, PhD, FRCP

Background: Familial diffuse Lewy body disease (DLBD) sociated in one with a defect in vertical gaze and in both is rare and not yet associated with a defect in the synuclein with visual hallucinations. gene. In the differential diagnosis of the parkinsonian syndromes, defects in vertical gaze tend to be identified with Results: In both patients, results of pathological exami- progressive supranuclear palsy. False-positive diagno- nation revealed (1) Lewy bodies positive for ubiquitin and sis of progressive supranuclear palsy can occur, and de- ␣-synuclein together with cell loss and gliosis in the sub- fects in vertical gaze have been reported in DLBD, al- stantia nigra, locus ceruleus, and neocortex; and (2) simi- though so far a pure vertical gaze palsy associated with lar findings in the rostral interstitial nucleus of the medial pathological abnormalities in the substrate for vertical longitudinal fasciculus, the posterior commissure, and the gaze has not been described. interstitial nucleus of Cajal (substrates for vertical gaze).

Objectives: To report the clinical and pathological find- Conclusions: Familial DLBD (not shown to be geneti- ings in 2 siblings with DLBD, and to relate the distribu- cally as distinct from environmentally transmitted) has been tion of the pathological abnormalities in the brainstem shown to exist in an Irish family. Caution should be en- to centers for vertical gaze. joined in the interpretation of defects in vertical gaze in the differential diagnosis of the parkinsonian syndromes. Materials: For several years, 2 Irish siblings experienced a progressive parkinsonism-dementia complex as- Arch Neurol. 2002;59:464-467

ARKINSONISM IS a feature of a Considerable overlap may exist in symp- number of disorders. The dis- tomatology, which is a function of topo- tinction of other conditions graphic distribution.6 Autopsy demonstra- from Parkinson disease (PD) tion of the appropriate pathological features requires the presence of cer- remains the gold standard for accurate di- tainP features atypical for PD. Diagnosis in agnosis.7 Even here, the “specific” bodies elderly people and early PD cause addi- seen in some of these conditions repre- tional problems.1,2 Autopsy studies sug- sent neurotubular and filamentous break- gest that accurate distinction is fre- down products and may not be respon- quently not made, and many patients dying sible for either pathogenesis or clinical with a clinical diagnosis of PD may have symptomatology. A recent review has sug- parkinsonism due to another cause.3,4 gested that the density distribution ratios Those syndromes that cause differential of Lewy bodies is constant, independent of difficulty include progressive supra- the clinical mode of presentation (eg, cor- nuclear palsy (PSP), diffuse Lewy body dis- tical vs subcortical).8 The diagnostic ter- ease (DLBD), multiple system atrophy, and minology, which may include clinical and corticobasal ganglionic degeneration. The pathological elements (eg, dementia with true relative frequency of these condi- diffuse Lewy bodies, dementia of Alzhei- tions is difficult to obtain. Prevalence mer type with Lewy bodies), underlines a studies are usually clinical, of necessity, relative unspecificity. whereas autopsy studies represent sam- Therefore, clinical diagnosis as a pre- From the Department of pling. Thus, epidemiological conclu- dictor of pathology is open to error. For Clinical Neurological Sciences, sions based on clinicopathologic correla- instance, the clinical diagnosis of PSP, in 2-5 Royal College of Surgeons, tions prove difficult. Like PD, they are which impairment of vertical eye move- Beaumont Hospital, Dublin, all degenerative disorders for which there ment receives particular significance, ap- Ireland. is no reliable laboratory or imaging test. pears to be made more frequently than the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 clinical diagnosis of DLBD, whereas, at a pathological level, retrospectively. Her clinical signs included bradykine- dementia associated with Lewy bodies may be the sec- sia and rigidity, but not tremor. She had been treated with ond most common form of dementia after dementia of levadopa without effect. During the illness, which pro- Alzheimer type. This finding implies a significant false- gressed for about 11 years, she also had intermittently positive level of diagnosis of PSP.6,9,10 Clinically, vertical high blood pressure, and Doppler ultrasonography re- supranuclear palsy with postural instability, associated vealed bilateral carotid bifurcation atherosclerosis. She with mild dementia, is regarded as a reliable combina- underwent progressive severe physical and cognitive (not tion for predicting a diagnosis of PSP,11,12 but vertical gaze fluctuant) decline. When first seen by one of us (H.S.) 2 impairment may occur in DLBD13-15 and is a frequent ac- months before her death, she was permanently bed bound companiment of aging.16-19 and not communicating. It proved impossible to test eye In this report, we present clinical and pathological movements. All limbs were severely rigid, with cogwheel- details of 2 siblings who had DLBD and who experi- ing. Arm reflexes were brisk, and due to the rigidity, could enced a parkinsonism-dementia complex. One sibling not be elicited in the legs. There was small-muscle wast- manifested vertical (upward and downward) gaze palsy. ing in the hands and feet. Systematic examination of the brainstem revealed, in both Review of the family history revealed that the mother patients, cell loss, gliosis, and Lewy bodies affecting the had died in the middle of her fourth decade of life, and pathways for vertical gaze, in addition to the pathologi- the father had died in his ninth decade. Stepsiblings have cal features of DLBD. not demonstrated any neurologic deficit. No previous re- cord of a neurologic illness in either family was found. REPORT OF CASES RESULTS PATIENT 1 NEUROPATHOLOGIC EXAMINATION A 66-year-old man, previously healthy, began to experience deterioration in his golf game, largely due to im- Postmortem examination was limited in each case (by paired balance when swinging a club. This imbalance con- request) to examination of the brain. Macroscopic ex- tinued and progressed up to his death 14 years later. His amination in both patients revealed no significant cere- memory had also become mildly impaired, and his bridge bral atrophy. Pallor was noted in the substantia nigra in game had suffered. When seen 6 years after onset, he had both. Representative sections were taken from the mid- a stiff gait with poor arm swinging. Bilateral cogwheel- frontal area; the superior and middle temporal, inferior ing and mild rigidity were present. He was treated with parietal, and occipital cortices; anterior cingulate; amyg- levadopa (300 mg/d) and carbidopa monohydrate (30 dala; hippocampus; striatum; thalamus; midbrain (lev- mg/d) with little response. He began to experience vi- els of the superior colliculus and pretectal regions); pons; sual hallucinations, eg, he began to see numerous black medulla; and cerebellum. Midbrain regions related to ver- balls scattered around him while playing golf. Other hal- tical eye movement, including the rostral interstitial lucinations were less clearly formed and could be articu- nucleus of the medial longitudinal fasciculus (riMLF), lated less clearly. Although the hallucinations persisted, posterior commissure, and interstitial nucleus of Cajal, they did not increase when the levadopa dosage was in- were examined. Sections were stained with hematoxylin- creased to 600 mg/d (to which he made some physical eosin, and the following immunocytochemical markers response). A defect in upward gaze gradually devel- were used: glial fibrillary acidic protein (1:1000; Dako, oped. This became accompanied by a defect in down- Cambridge, United Kingdom), BA4 (1:100; Dako), tau ward gaze of greater degree, of which he independently (1:90; Immunogenetics, Ghent, Belgium), ubiquitin (1: complained when he found that he could not read when 60; Novocastra, Newcastle, United Kingdom), and holding a book beneath eye level. He had brisk doll’s- ␣-synuclein (1:3000; Chemicon, Harrow, United eye movements. There were no upper motor signs. On Kingdom). the Wechsler Memory Scale–Revised, he achieved a ver- Gliosis in the region of riMLF, interstitial nucleus bal memory score of 81, a visual memory score below of Cajal, and posterior commissure were graded semi- the basal level of 50, and a general memory score of 58. quantitatively in conjunction with hematoxylin-eosin and On the Warrington Recognition Memory Test, verbal and glial fibrillary acidic protein staining, where 0 indicates facial memory aspects were defective, the latter more se- absent; 1, mild; 2, moderate; and 3, severe. verely. The one area of unaffected function was atten- tional memory, with a score of 112. His physical condi- NEUROPATHOLOGIC FINDINGS tion progressed to the point of incapacity. For the 2 years before his death, his intellectual deficit, which had been Concentric hyaline intracytoplasmic eosinophilic inclu- fluctuant, became more prominent. sions (Lewy bodies) were found in the substantia nigra and locus ceruleus of both patients (Figure 1). In both PATIENT 2 locations, Lewy bodies were associated with cell loss, gliosis, and pigmentary incontinence of cells with extracel- A 73-year-old woman, a sister of patient 1, experienced lular melanin deposition. Occasional Lewy bodies were a slow and steady decline in physical and mental func- identified in the periaqueductal gray matter, oculomo- tion. She also had visual hallucinations, as reported by tor nucleus, riMLF, interstitial nucleus of Cajal, and dor- her family, although their time of onset could not be dated sal vagal nucleus in both patients (Figure 2). In addi-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Figure 1. Intracytoplasmic Lewy body in the pigmented cells of the Figure 4. Lewy body in the neocortex (hematoxylin-eosin, original substantia nigra (hematoxylin-eosin, original magnification ϫ40). magnification ϫ40).

A B

Figure 2. Whole-mount photograph of the midbrain (A) at the level of the superior colliculus showing the interstitial nucleus of Cajal (arrow). Lewy body (arrow) is seen in the interstitial nucleus of Cajal (B) (hematoxylin-eosin, original magnification ϫ40).

Figure 5. Lewy body in neocortex (␣-synuclein, original magnification ϫ40).

COMMENT This report demonstrates, in 2 siblings, the presence of pathologic abnormalities specific for Lewy body disease, in addition to gliosis, in the areas that subserve vertical gaze. One of the patients, in addition to exhibiting parkinsonism, dementia, and visual hallucinations, demonstrated initially a defect in upward gaze followed by a more significant impairment in downward gaze. The other patient underwent assessment too late in the course of the disease for observations to be made about eye move- Figure 3. Gliosis in the posterior commissure (glial fibrillary acidic protein, ment. Although the precise mechanism of symptom pro- original magnification ϫ40). duction in Lewy body diseases is not known, and the presence of ␣-synuclein and ubiquitin in Lewy body disease represents a secondary effect, such presence in the riMLF, tion, both patients demonstrated cell loss and moderate the posterior commissure, and the interstitial nucleus of gliosis in the posterior commissure and medial longitu- Cajal indicates some degree of clinicopathologic corre- dinal fasciculus (Figure 3). lation. Vertical eye movement abnormalities have been Less well-defined eosinophilic inclusions were iden- previously described in DLBD, and a difficulty in sepa- tified in neurons of the neocortex in both patients rating the parkinsonian syndromes lies in the fact that (Figure 4). They were found in small neurones in the the phenotype will be determined by the topographic dis- middle and lower cortical laminae of parahippocampal, tribution of the abnormality. In 3 previously described insular, and occipital cortices and cingulate gyrus. These patients with DLBD and defects in vertical gaze,13-15 the inclusions stained positively with ubiquitin and eye signs were not pure, in that 2 had an associated de- ␣-synuclein, but not with tau protein (Figure 5). Oc- fect in horizontal gaze,13,14 whereas 2 appeared to have casional tau-positive neurofibrillary tangles were iden- little defect in downward gaze.13,15 Possibly in part for tech- tified in the hippocampus of patient 1, but numbers were nical reasons, the pathological changes were found in the insufficient for a diagnosis of dementia of Alzheimer type. appropriate substrate for vertical gaze in only one of these

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 patients.13 No hallucinations were described in any of these 2. Meara J, Bhowmick BK, Hobson P. Accuracy of diagnosis in patients with pre- patients, and a diagnosis of PSP was made. Although in sumed Parkinson’s disease. Age Ageing. 1999;28:99-102. 3. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idio- the patients under current study, the presence of visual pathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol hallucinations suggested Lewy body disease, their ab- Neurosurg Psychiatry. 1992;55:181-184. sence, as can occur in Lewy body disease (they are not de- 4. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinson- manded as a sine qua non in the consensus guidelines),20 ism: a prospective study. Can J Neurol Sci. 1991;18:275-278. 5. Jellinger KA. The frequency of Lewy bodies in a consecutive autopsy series. Clin or their late appearance may lead to an erroneous diag- Neuropathol. 1999;18:214-215. nosis. Furthermore, medication-induced hallucinations 6. Litvan I, Campbell G, Mangone CA, et al. Which clinical features differentiate pro- are well recognized in PD.21 gressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from re- Marked concordance was found between both sib- lated disorders? a clinicopathological study. Brain. 1997;120:65-74. lings in the appearance and distribution of the pathologi- 7. Quinn N. Accuracy of clinical diagnosis in early Parkinson’s disease. Arch Neu- rol. 2001;58:316-317. cal changes. It seems reasonable to assume that they both 8. Gomez-Tortosa E, Irizarry MC, Gomez-Isla T, Hyman BT. Clinical and neuropatho- expressed the same synucleinopathy. In view of their moth- logical correlates of dementia with Lewy bodies. AnnNYAcadSci.2000;920:9-15. er’s early death, it is difficult to know if the synucleinopa- 9. Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of thies were genetic in origin, and, if so, what was the mode progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neu- rology. 1996;46:922-930. of inheritance. A limited number of familial DLBD cases 10. Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal features in 31 22-24 have been reported. A dominant form of inheritance has pathologically confirmed cases of diffuse Lewy body disease and 34 pathologi- been described in at least 2 families,22 whereas consanguin- cally confirmed cases of Parkinson’s disease. Neurology. 1997;48:376-380. ity appeared to play a part in one extended pedigree23 and 11. Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological spectrum of Steel in another smaller pedigree,24 although the pattern of in- Richardson-Olszewski syndrome (progressive supranuclear palsy): a reap- praisal. Brain. 1995;118:759-770. heritance did not appear typical in the latter. In view of the 12. Morris HR, Wood NW, Lees AJ. Progressive supranuclear palsy (Steele- fact that most cases of DLBD are sporadic, taking into ac- Richsrdson-Olszewski syndrome). Postgrad Med J. 1999;75:579-584. count the unspecific nature of Lewy bodies, and given the 13. Lewis AJ, Gawel MJ. Diffuse Lewy body disease with dementia and oculomotor range and heterogeneity of the synucleinopathies,25 differ- dysfunction. Mov Disord. 1990;5:143-147. 14. Fearnley JM, Revesz T, Brooks DJ, Frackowiak RS, Lees AJ. Diffuse Lewy body ent genotypes may well exist. disease presenting with a supranuclear gaze palsy. J Neurol Neurosurg Psychia- try. 1991;54:159-161. Accepted for publication July 19, 2001. 15. de Bruin VMS, Lees AJ, Daniel SE. Diffuse Lewy body disease presenting with Author contributions: Study concept and design supranuclear gaze palsy, parkinsonism, and dementia: a case report. Mov Dis- (Dr Staunton); acquisition of data (Mr Henson and Dr ord. 1992;7:355-358. 16. Chamberlain W. Restriction in upward gaze with advancing age. Am J Ophthal- Staunton); analysis and interpretation of data (Drs Brett mol. 1971;1:341-346. and Staunton); drafting of the manuscript (Drs Brett and 17. Kokemon E, Bossemeyer RW Jr, Barney J, Williams WJ. Neurological manifes- Staunton); critical revision of the manuscript for impor- tations of aging. J Gerontol. 1977;32:411-419. tant intellectual content (Drs Brett and Staunton and Mr 18. Benassi G, D’Allesandro R, Gallassi R, Morreale A, Lugaresi E. Neurological signs, aging, and the neurodegenerative syndromes. Neuroepidemiology. Henson); and administrative, technical, and material sup- 1990;9:27-38. port (Dr Brett and Mr Henson). 19. Waite LM, Broe GA, Creasey H, Grayson D, Edelbrock D, O’Toole B. Neurological Mr Henson was supported by a Health Research Board signs, aging, and the neurodegenerative syndromes. Arch Neurol. 1996;53:498-502. summer student fellowship. 20. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and We wish to thank John Connolly, PhD, for the neuropathologic diagnosis of dementia with Lewy bodies (DLB): report of the consor- tium on DLB international workshop. Neurology. 1996;47:1113-1124. psychological evaluation of patient 1. 21. Okada K, Suyama N, Oguro H, Yamaguchi S, Kobayashi S. Medication-induced Corresponding author and reprints: Francesca M. Brett, hallucinations and cerebral blood flow in Parkinson’s disease. J Neurol. 1999; MD, FRCPath, Department of Clinical Neurological Sci- 246:365-368. ences, Royal College of Surgeons, Beaumont Hospital, 22. Ishikawa A, Takahashi H, Tanaka H, Hayashi T, Tsuji S. Clinical features of familial diffuse Lewy body disease. Eur Neurol. 1997;38(suppl 1):34-38. Dublin 9, Ireland (e-mail: [email protected]). 23. Denson MA, Wszolek ZK, Pfeiffer RF, Wszolek EK, Paschall TM, McComb RD. Familial parkinsonism, dementia, and Lewy body disease: study of family G. Ann REFERENCES Neurol. 1997;42:638-643. 24. Ohara K, Takauchi S, Kokai M, Morimura Y, Nakajima T, Morita Y. Familial dementia with Lewy bodies (DLB). Clin Neuropathol. 1999;18:232-239. 1. Jankovic J, Rajput AH, McDermott MP, Perl DP, for the Parkinson Study Group. The 25. Galvin JE, Lee VM, Trojanowski JQ. Synucleinopathies: clinical and pathological evolution of diagnosis in early Parkinson disease. Arch Neurol. 2000;57:369-372. implications. Arch Neurol. 2001;58:186-190.

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