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 syn- dromes, 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 experi- enced 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- Ptain 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 (REPRINTED) ARCH NEUROL / VOL 59, MAR 2002 WWW.ARCHNEUROL.COM 464 ©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 expe- rience 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