 |
|
Familial Diffuse Lewy Body Disease, Eye Movement Abnormalities, and Distribution of Pathology
Francesca M. Brett, MD, FRCPath;
Craig Henson, BS;
Hugh Staunton, PhD, FRCP
Arch Neurol. 2002;59:464-467.
ABSTRACT
| |
Background Familial diffuse Lewy body disease (DLBD) is rare and not yet associated
with a defect in the synuclein gene. In the differential diagnosis of the
parkinsonian syndromes, defects in vertical gaze tend to be identified with
progressive supranuclear palsy. False-positive diagnosis of progressive supranuclear
palsy can occur, and defects in vertical gaze have been reported in DLBD,
although so far a pure vertical gaze palsy associated with pathological abnormalities
in the substrate for vertical gaze has not been described.
Objectives To report the clinical and pathological findings in 2 siblings with
DLBD, and to relate the distribution of the pathological abnormalities in
the brainstem to centers for vertical gaze.
Materials For several years, 2 Irish siblings experienced a progressive parkinsonism-dementia
complex associated in one with a defect in vertical gaze and in both with
visual hallucinations.
Results In both patients, results of pathological examination revealed (1) Lewy
bodies positive for ubiquitin and  -synuclein together with cell loss
and gliosis in the substantia nigra, locus ceruleus, and neocortex; and (2)
similar findings in the rostral interstitial nucleus of the medial longitudinal
fasciculus, the posterior commissure, and the interstitial nucleus of Cajal
(substrates for vertical gaze).
Conclusions Familial DLBD (not shown to be genetically as distinct from environmentally
transmitted) has been shown to exist in an Irish family. Caution should be
enjoined in the interpretation of defects in vertical gaze in the differential
diagnosis of the parkinsonian syndromes.
INTRODUCTION
PARKINSONISM IS a feature of a number of disorders. The distinction
of other conditions from Parkinson disease (PD) requires the presence of certain
features atypical for PD. Diagnosis in elderly people and early PD cause additional
problems.1-2 Autopsy studies suggest
that accurate distinction is frequently not made, and many patients dying
with a clinical diagnosis of PD may have parkinsonism due to another cause.3-4 Those syndromes that cause differential
difficulty include progressive supranuclear palsy (PSP), diffuse Lewy body
disease (DLBD), multiple system atrophy, and corticobasal ganglionic degeneration.
The true relative frequency of these conditions is difficult to obtain. Prevalence
studies are usually clinical, of necessity, whereas autopsy studies represent
sampling. Thus, epidemiological conclusions based on clinicopathologic correlations
prove difficult.2-5
Like PD, they are all degenerative disorders for which there is no reliable
laboratory or imaging test. Considerable overlap may exist in symptomatology,
which is a function of topographic distribution.6
Autopsy demonstration of the appropriate pathological features remains the
gold standard for accurate diagnosis.7 Even
here, the "specific" bodies seen in some of these conditions represent neurotubular
and filamentous breakdown products and may not be responsible for either pathogenesis
or clinical symptomatology. A recent review has suggested that the density
distribution ratios of Lewy bodies is constant, independent of the clinical
mode of presentation (eg, cortical vs subcortical).8
The diagnostic terminology, which may include clinical and pathological elements
(eg, dementia with diffuse Lewy bodies, dementia of Alzheimer type with Lewy
bodies), underlines a relative unspecificity.
Therefore, clinical diagnosis as a predictor of pathology is open to
error. For instance, the clinical diagnosis of PSP, in which impairment of
vertical eye movement receives particular significance, appears to be made
more frequently than the clinical diagnosis of DLBD, whereas, at a pathological
level, dementia associated with Lewy bodies may be the second most common
form of dementia after dementia of Alzheimer type. This finding implies a
significant false-positive level of diagnosis of PSP.6, 9-10
Clinically, vertical supranuclear palsy with postural instability, associated
with mild dementia, is regarded as a reliable combination for predicting a
diagnosis of PSP,11-12 but vertical
gaze impairment may occur in DLBD13-15
and is a frequent accompaniment of aging.16-19
In this report, we present clinical and pathological details of 2 siblings
who had DLBD and who experienced a parkinsonism-dementia complex. One sibling
manifested vertical (upward and downward) gaze palsy. Systematic examination
of the brainstem revealed, in both patients, cell loss, gliosis, and Lewy
bodies affecting the pathways for vertical gaze, in addition to the pathological
features of DLBD.
REPORT OF CASES
PATIENT 1
A 66-year-old man, previously healthy, began to experience deterioration
in his golf game, largely due to impaired balance when swinging a club. This
imbalance continued and progressed up to his death 14 years later. His memory
had also become mildly impaired, and his bridge game had suffered. When seen
6 years after onset, he had a stiff gait with poor arm swinging. Bilateral
cogwheeling and mild rigidity were present. He was treated with levadopa (300
mg/d) and carbidopa monohydrate (30 mg/d) with little response. He began to
experience visual hallucinations, eg, he began to see numerous black balls
scattered around him while playing golf. Other hallucinations were less clearly
formed and could be articulated less clearly. Although the hallucinations
persisted, they did not increase when the levadopa dosage was increased to
600 mg/d (to which he made some physical response). A defect in upward gaze
gradually developed. This became accompanied by a defect in downward gaze
of greater degree, of which he independently complained when he found that
he could not read when holding a book beneath eye level. He had brisk doll's-eye
movements. There were no upper motor signs. On the Wechsler Memory Scale–Revised,
he achieved a verbal memory score of 81, a visual memory score below the basal
level of 50, and a general memory score of 58. On the Warrington Recognition
Memory Test, verbal and facial memory aspects were defective, the latter more
severely. The one area of unaffected function was attentional memory, with
a score of 112. His physical condition progressed to the point of incapacity.
For the 2 years before his death, his intellectual deficit, which had been
fluctuant, became more prominent.
PATIENT 2
A 73-year-old woman, a sister of patient 1, experienced a slow and steady
decline in physical and mental function. She also had visual hallucinations,
as reported by her family, although their time of onset could not be dated
retrospectively. Her clinical signs included bradykinesia and rigidity, but
not tremor. She had been treated with levadopa without effect. During the
illness, which progressed for about 11 years, she also had intermittently
high blood pressure, and Doppler ultrasonography revealed bilateral carotid
bifurcation atherosclerosis. She underwent progressive severe physical and
cognitive (not fluctuant) decline. When first seen by one of us (H.S.) 2 months
before her death, she was permanently bed bound and not communicating. It
proved impossible to test eye movements. All limbs were severely rigid, with
cogwheeling. Arm reflexes were brisk, and due to the rigidity, could not be
elicited in the legs. There was small-muscle wasting in the hands and feet.
Review of the family history revealed that the mother had died in the
middle of her fourth decade of life, and the father had died in his ninth
decade. Stepsiblings have not demonstrated any neurologic deficit. No previous
record of a neurologic illness in either family was found.
RESULTS
NEUROPATHOLOGIC EXAMINATION
Postmortem examination was limited in each case (by request) to examination
of the brain. Macroscopic examination in both patients revealed no significant
cerebral atrophy. Pallor was noted in the substantia nigra in both. Representative
sections were taken from the midfrontal area; the superior and middle temporal,
inferior parietal, and occipital cortices; anterior cingulate; amygdala; hippocampus;
striatum; thalamus; midbrain (levels of the superior colliculus and pretectal
regions); pons; medulla; and cerebellum. Midbrain regions related to vertical
eye movement, including the rostral interstitial nucleus of the medial longitudinal
fasciculus (riMLF), posterior commissure, and interstitial nucleus of Cajal,
were examined. Sections were stained with hematoxylin-eosin, and the following
immunocytochemical markers were used: glial fibrillary acidic protein (1:1000;
Dako, Cambridge, United Kingdom), BA4 (1:100; Dako), tau (1:90; Immunogenetics,
Ghent, Belgium), ubiquitin (1:60; Novocastra, Newcastle, United Kingdom),
and -synuclein (1:3000; Chemicon, Harrow, United Kingdom).
Gliosis in the region of riMLF, interstitial nucleus of Cajal, and posterior
commissure were graded semiquantitatively in conjunction with hematoxylin-eosin
and glial fibrillary acidic protein staining, where 0 indicates absent; 1,
mild; 2, moderate; and 3, severe.
NEUROPATHOLOGIC FINDINGS
Concentric hyaline intracytoplasmic eosinophilic inclusions (Lewy bodies)
were found in the substantia nigra and locus ceruleus of both patients (Figure 1). In both locations, Lewy bodies
were associated with cell loss, gliosis, and pigmentary incontinence of cells
with extracellular melanin deposition. Occasional Lewy bodies were identified
in the periaqueductal gray matter, oculomotor nucleus, riMLF, interstitial
nucleus of Cajal, and dorsal vagal nucleus in both patients (Figure 2). In addition, both patients demonstrated cell loss and
moderate gliosis in the posterior commissure and medial longitudinal fasciculus
(Figure 3).
|
|
|
|
Figure 1. Intracytoplasmic Lewy body in
the pigmented cells of the substantia nigra (hematoxylin-eosin, original magnification
x40).
|
|
|
|
|
|
|
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 x40).
|
|
|
|
|
|
|
Figure 3. Gliosis in the posterior commissure
(glial fibrillary acidic protein, original magnification x40).
|
|
|
Less well-defined eosinophilic inclusions were identified in neurons
of the neocortex in both patients (Figure
4). They were found in small neurones in the middle and lower cortical
laminae of parahippocampal, insular, and occipital cortices and cingulate
gyrus. These inclusions stained positively with ubiquitin and -synuclein,
but not with tau protein (Figure 5).
Occasional tau-positive neurofibrillary tangles were identified in the hippocampus
of patient 1, but numbers were insufficient for a diagnosis of dementia of
Alzheimer type.
|
|
|
|
Figure 4. Lewy body in the neocortex (hematoxylin-eosin,
original magnification x40).
|
|
|
|
|
|
|
Figure 5. Lewy body in neocortex (-synuclein,
original magnification x40).
|
|
|
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 movement. Although the precise
mechanism of symptom production 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, the posterior commissure,
and the interstitial nucleus of Cajal indicates some degree of clinicopathologic
correlation. Vertical eye movement abnormalities have been previously described
in DLBD, and a difficulty in separating the parkinsonian syndromes lies in
the fact that the phenotype will be determined by the topographic distribution
of the abnormality. In 3 previously described patients with DLBD and defects
in vertical gaze,13-15
the eye signs were not pure, in that 2 had an associated defect in horizontal
gaze,13-14 whereas 2 appeared
to have little defect in downward gaze.13, 15
Possibly in part for technical reasons, the pathological changes were found
in the appropriate substrate for vertical gaze in only one of these patients.13 No hallucinations were described in any of these
patients, and a diagnosis of PSP was made. Although in the patients under
current study, the presence of visual hallucinations suggested Lewy body disease,
their absence, as can occur in Lewy body disease (they are not demanded as
a sine qua non in the consensus guidelines),20
or their late appearance may lead to an erroneous diagnosis. Furthermore,
medication-induced hallucinations are well recognized in PD.21
Marked concordance was found between both siblings in the appearance
and distribution of the pathological changes. It seems reasonable to assume
that they both expressed the same synucleinopathy. In view of their mother's
early death, it is difficult to know if the synucleinopathies were genetic
in origin, and, if so, what was the mode of inheritance. A limited number
of familial DLBD cases have been reported.22-24
A dominant form of inheritance has been described in at least 2 families,22 whereas consanguinity appeared to play a part in
one extended pedigree23 and in another smaller
pedigree,24 although the pattern of inheritance
did not appear typical in the latter. In view of the fact that most cases
of DLBD are sporadic, taking into account the unspecific nature of Lewy bodies,
and given the range and heterogeneity of the synucleinopathies,25
different genotypes may well exist.
AUTHOR INFORMATION
Accepted for publication July 19, 2001.
Author contributions: Study
concept and design (Dr Staunton); acquisition of
data (Mr Henson and Dr Staunton); analysis and interpretation
of data (Drs Brett and Staunton); drafting of the
manuscript (Drs Brett and Staunton); critical revision
of the manuscript for important intellectual content (Drs Brett and
Staunton and Mr Henson); and administrative, technical,
and material support (Dr Brett and Mr Henson).
Mr Henson was supported by a Health Research Board summer student fellowship.
We wish to thank John Connolly, PhD, for the neuropsychological evaluation
of patient 1.
Corresponding author and reprints: Francesca M. Brett, MD, FRCPath,
Department of Clinical Neurological Sciences, Royal College of Surgeons, Beaumont
Hospital, Dublin 9, Ireland (e-mail: fmbrett{at}iol.ie).
From the Department of Clinical Neurological Sciences, Royal College
of Surgeons, Beaumont Hospital, Dublin, Ireland.
REFERENCES
| |
1. Jankovic J, Rajput AH, McDermott MP, Perl DP for the Parkinson Study Group. The evolution of diagnosis in early Parkinson disease. Arch Neurol. 2000;57:369-372.
FREE FULL TEXT
2. Meara J, Bhowmick BK, Hobson P. Accuracy of diagnosis in patients with presumed Parkinson's disease. Age Ageing. 1999;28:99-102.
FREE FULL TEXT
3. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a
clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181-184.
ABSTRACT
4. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism: a prospective study. Can J Neurol Sci. 1991;18:275-278.
ISI
| PUBMED
5. Jellinger KA. The frequency of Lewy bodies in a consecutive autopsy series. Clin Neuropathol. 1999;18:214-215.
ISI
| PUBMED
6. Litvan I, Campbell G, Mangone CA, et al. Which clinical features differentiate progressive supranuclear palsy
(Steele-Richardson-Olszewski syndrome) from related disorders? a clinicopathological
study. Brain. 1997;120:65-74.
FREE FULL TEXT
7. Quinn N. Accuracy of clinical diagnosis in early Parkinson's disease. Arch Neurol. 2001;58:316-317.
FREE FULL TEXT
8. Gomez-Tortosa E, Irizarry MC, Gomez-Isla T, Hyman BT. Clinical and neuropathological correlates of dementia with Lewy bodies. Ann N Y Acad Sci. 2000;920:9-15.
FREE FULL TEXT
9. Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome). Neurology. 1996;46:922-930.
FREE FULL TEXT
10. Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal features in 31 pathologically confirmed
cases of diffuse Lewy body disease and 34 pathologically confirmed cases of
Parkinson's disease. Neurology. 1997;48:376-380.
FREE FULL TEXT
11. Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological spectrum of Steel Richardson-Olszewski
syndrome (progressive supranuclear palsy): a reappraisal. Brain. 1995;118:759-770.
FREE FULL TEXT
12. Morris HR, Wood NW, Lees AJ. Progressive supranuclear palsy (Steele-Richsrdson-Olszewski syndrome). Postgrad Med J. 1999;75:579-584.
FREE FULL TEXT
13. Lewis AJ, Gawel MJ. Diffuse Lewy body disease with dementia and oculomotor dysfunction. Mov Disord. 1990;5:143-147.
FULL TEXT
|
ISI
| PUBMED
14. Fearnley JM, Revesz T, Brooks DJ, Frackowiak RS, Lees AJ. Diffuse Lewy body disease presenting with a supranuclear gaze palsy. J Neurol Neurosurg Psychiatry. 1991;54:159-161.
ABSTRACT
15. de Bruin VMS, Lees AJ, Daniel SE. Diffuse Lewy body disease presenting with supranuclear gaze palsy,
parkinsonism, and dementia: a case report. Mov Disord. 1992;7:355-358.
FULL TEXT
|
ISI
| PUBMED
16. Chamberlain W. Restriction in upward gaze with advancing age. Am J Ophthalmol. 1971;1:341-346.
PUBMED
17. Kokemon E, Bossemeyer RW Jr, Barney J, Williams WJ. Neurological manifestations of aging. J Gerontol. 1977;32:411-419.
ISI
| PUBMED
18. Benassi G, D'Allesandro R, Gallassi R, Morreale A, Lugaresi E. Neurological signs, aging, and the neurodegenerative syndromes. Neuroepidemiology. 1990;9:27-38.
FULL TEXT
|
ISI
| PUBMED
19. Waite LM, Broe GA, Creasey H, Grayson D, Edelbrock D, O'Toole B. Neurological signs, aging, and the neurodegenerative syndromes. Arch Neurol. 1996;53:498-502.
ABSTRACT
20. 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;47:1113-1124.
FREE FULL TEXT
21. Okada K, Suyama N, Oguro H, Yamaguchi S, Kobayashi S. Medication-induced hallucinations and cerebral blood flow in Parkinson's
disease. J Neurol. 1999;246:365-368.
FULL TEXT
|
ISI
| PUBMED
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.
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 Neurol. 1997;42:638-643.
FULL TEXT
|
ISI
| PUBMED
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.
ISI
| PUBMED
25. Galvin JE, Lee VM, Trojanowski JQ. Synucleinopathies: clinical and pathological implications. Arch Neurol. 2001;58:186-190.
FREE FULL TEXT
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2002;59(3):492-494.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Familial Occurrence of Dementia With Lewy Bodies
Tsuang et al.
AJGP 2004;12:179-188.
ABSTRACT
| FULL TEXT
|
