The Hypothalamus in Parkinson Disease J. William Langston, MD, and Lysia S. Forno, MD
T h e hypothalamus was systematically examined in 30 patients with pathologically documented idiopathic parkinsonism. Using J i w y body formation as a marker for nerve cell degeneration, we observed abnormalities in every hypothalamus examined. O f t h e thirteen hypothalamic nuclei that could be individually identified, none were exempt from Lewy body degeneration. T h e tuberomamillary nucleus and the lateral and posterior hypothalamic nuclei demonstrated the highest average Lewy body counts (16, 9, and 3, respectively); they were also the most frequently involved nuclei. These findings may aid in interpretation of the autonomic and endocrine abnormalities in patients with Parkinson disease. Langston JW, Forno LS: The hypothalamus in Parkinson disease. Ann Neurol 3:129-133, 1978
A number of investigators, including Lewy himself, IS, 11, 19, 251, have noted pathological changes in the hypothalamus in Parkinson disease. To date, a systematic assessment of these changes has not been carried out, leaving doubt as to their true frequency. W e now report a quantitative study designed to resolve this question. Our results indicate that t h e hypothalamus is consistently involved in Parkinson disease. I n addition, w e have discovered a predilection for certain nuclear groups not traditionally considered to have important aminergic functions.
Materials and M e t h o d s Sections of the hypothalamus were obtained from patients who died with a diagnosis of parkinsonism at the Palo Alto Veterans Administration Hospital between 196 1 and 1974. Patient material was included in the study when (1) at least two of the three classic clinical findings of parkinsonism (bradykinesia, tremor, and rigidity) had been present during life, (2) neuropathological examination confirmed degeneration of pigmented nuclei with Lewy body inclusions, and ( 3 ) adequate sections of the hypothalamus were available. Autopsy material from 30 patients met these criteria. The average age of these patients at the time of death was 70.4 years, with a range of 49 to 87 years. Almost half (14 of 30) died in their seventies. Only 1 patient was female, reflecting the predominantly male population at the Vererans Administration Hospital. The duration of illness ranged from less than 1 year to 12 years, except for 1 patient in whom the duration was 22 years. Only 1 patient had received L-dopa for a prolonged period. One patient had Shy-Drager syndrome. We were able to consistently identify thirteen separate hypothalamic nuclei (Table), using the classification of Nauta and Haymaker [24]; the works of Rioch et a1 [27] and Ingram [18] were also of value in delineating the various From the Department of Neurology, Stanford University School of Mehcine, the Department of Pathology (Neuropathology),Vererans Administration Hospital and Stanford University School of Medicine, Palo Alto, and the Division of Neurology, Sanca Clara Valley Medical Center, San Jose, CA.
nuclei of the human hypothalamus. Hematoxylin and eosin stains as well as stains for myelin, axons, and glial fibers were used. The Table lists these nuclei and shows the number of brains in which each nucleus could be identified. Lewy bodies were used as a marker for nerve cell degeneration because they were easier to quantitate than nerve cell loss or gliosis. We counted the number of Lewy bodies per nucleus in each hematoxylin and eosin stained slide. In most cases, two or more levels of the hypothalamus were available for study. If the same nuclear group was seen in more than one slide, the highest count was used. Lewy bodies counted included typical eosinophilic intracytoplasmic inclusions with a peripheral halo as well as round and elongated forms outside the perikaryon (Fig 1). The latter are probably located in nerve cell processes [8, 121 and have an ultrastructure similar to Lewy bodies in the sympathetic ganglia [12]. A filamentous Lewy body in the hypothalamus is illustrated in Figure 2.
Results Every hypothalamus studied in this series showed at least some degree of Lewy body degeneration (see the Table). W h e n w e added together the highest Lewy body counts for each nucleus within an individual hypothalamus, a total of more than 60 Lewy bodies per hypothalamus was encountered in 20% (6 of 30) of the patient material. T h e remaining 80% had from 2 to 60 Lewy bodies p e r hypothalamus. A n unexpected predilection for certain nuclei was also encountered (see the Table). T h e tuberomamillary nucleus and t h e lateral and posterior hypothalamic nuclei contained by far the highest concentrations of Lewy bodies, with average counts per nucleus of 16, 9, and 3 , respectively. T h e medial preoptic and anterior nuclei had the lowest average Lewy body counts. No n u d e u s was consistently free Accepted for publication July 25, 1977.
Address reprint requests to Dr Langston, Division of Neurology, Santa Clara Valley
Center, 7 5 South Bascorn Ave, Sari
Jose, CA 95128.
0364-5 134/78/0003-0206$01.25 @ 1978 by the American Neurological Association 129
Hypothalamic Nuclei Identified in the Brains of 30 Patients Who Died with Parkinson Disease Hypothalamic Nudeus
No. Examined
Tuberomamillary Lsteral Posterior Mamilkry body Lateral preoptic Tuberis lateralis Dorsal Ventromedial Dormmedial Arcuate Supraoptic Anterior Medial preoptic
24 29 18 20 14 22 13 25 19 18 23 7 14
LE3
=
No. of Cases with LB Counts in Ranges:
No.
Percent Positive
Average No. of LB per
withLB
form
Nudeus
None
1-5
6-10
11-20
21-30
19 25 15 9
79 86 83 45 25 36 46 36 42 33 26 14 14
16 9 3
5 4 3 11 6 14 7 16 11 12 17 6 12
5
2 5 3
6
2 5
8 8 6 9 8 6 6 1 2
1!4
1% 1!4 1!4 1
1
1 1
T h e hypothalamus was systematically examined in 30 patients with pathologically documented idiopathic parkinsonism. Using J i w y body formation as a marker for nerve cell degeneration, we observed abnormalities in every hypothalamus examined. O f t h e thirteen hypothalamic nuclei that could be individually identified, none were exempt from Lewy body degeneration. T h e tuberomamillary nucleus and the lateral and posterior hypothalamic nuclei demonstrated the highest average Lewy body counts (16, 9, and 3, respectively); they were also the most frequently involved nuclei. These findings may aid in interpretation of the autonomic and endocrine abnormalities in patients with Parkinson disease. Langston JW, Forno LS: The hypothalamus in Parkinson disease. Ann Neurol 3:129-133, 1978
A number of investigators, including Lewy himself, IS, 11, 19, 251, have noted pathological changes in the hypothalamus in Parkinson disease. To date, a systematic assessment of these changes has not been carried out, leaving doubt as to their true frequency. W e now report a quantitative study designed to resolve this question. Our results indicate that t h e hypothalamus is consistently involved in Parkinson disease. I n addition, w e have discovered a predilection for certain nuclear groups not traditionally considered to have important aminergic functions.
Materials and M e t h o d s Sections of the hypothalamus were obtained from patients who died with a diagnosis of parkinsonism at the Palo Alto Veterans Administration Hospital between 196 1 and 1974. Patient material was included in the study when (1) at least two of the three classic clinical findings of parkinsonism (bradykinesia, tremor, and rigidity) had been present during life, (2) neuropathological examination confirmed degeneration of pigmented nuclei with Lewy body inclusions, and ( 3 ) adequate sections of the hypothalamus were available. Autopsy material from 30 patients met these criteria. The average age of these patients at the time of death was 70.4 years, with a range of 49 to 87 years. Almost half (14 of 30) died in their seventies. Only 1 patient was female, reflecting the predominantly male population at the Vererans Administration Hospital. The duration of illness ranged from less than 1 year to 12 years, except for 1 patient in whom the duration was 22 years. Only 1 patient had received L-dopa for a prolonged period. One patient had Shy-Drager syndrome. We were able to consistently identify thirteen separate hypothalamic nuclei (Table), using the classification of Nauta and Haymaker [24]; the works of Rioch et a1 [27] and Ingram [18] were also of value in delineating the various From the Department of Neurology, Stanford University School of Mehcine, the Department of Pathology (Neuropathology),Vererans Administration Hospital and Stanford University School of Medicine, Palo Alto, and the Division of Neurology, Sanca Clara Valley Medical Center, San Jose, CA.
nuclei of the human hypothalamus. Hematoxylin and eosin stains as well as stains for myelin, axons, and glial fibers were used. The Table lists these nuclei and shows the number of brains in which each nucleus could be identified. Lewy bodies were used as a marker for nerve cell degeneration because they were easier to quantitate than nerve cell loss or gliosis. We counted the number of Lewy bodies per nucleus in each hematoxylin and eosin stained slide. In most cases, two or more levels of the hypothalamus were available for study. If the same nuclear group was seen in more than one slide, the highest count was used. Lewy bodies counted included typical eosinophilic intracytoplasmic inclusions with a peripheral halo as well as round and elongated forms outside the perikaryon (Fig 1). The latter are probably located in nerve cell processes [8, 121 and have an ultrastructure similar to Lewy bodies in the sympathetic ganglia [12]. A filamentous Lewy body in the hypothalamus is illustrated in Figure 2.
Results Every hypothalamus studied in this series showed at least some degree of Lewy body degeneration (see the Table). W h e n w e added together the highest Lewy body counts for each nucleus within an individual hypothalamus, a total of more than 60 Lewy bodies per hypothalamus was encountered in 20% (6 of 30) of the patient material. T h e remaining 80% had from 2 to 60 Lewy bodies p e r hypothalamus. A n unexpected predilection for certain nuclei was also encountered (see the Table). T h e tuberomamillary nucleus and t h e lateral and posterior hypothalamic nuclei contained by far the highest concentrations of Lewy bodies, with average counts per nucleus of 16, 9, and 3 , respectively. T h e medial preoptic and anterior nuclei had the lowest average Lewy body counts. No n u d e u s was consistently free Accepted for publication July 25, 1977.
Address reprint requests to Dr Langston, Division of Neurology, Santa Clara Valley
Center, 7 5 South Bascorn Ave, Sari
Jose, CA 95128.
0364-5 134/78/0003-0206$01.25 @ 1978 by the American Neurological Association 129
Hypothalamic Nuclei Identified in the Brains of 30 Patients Who Died with Parkinson Disease Hypothalamic Nudeus
No. Examined
Tuberomamillary Lsteral Posterior Mamilkry body Lateral preoptic Tuberis lateralis Dorsal Ventromedial Dormmedial Arcuate Supraoptic Anterior Medial preoptic
24 29 18 20 14 22 13 25 19 18 23 7 14
LE3
=
No. of Cases with LB Counts in Ranges:
No.
Percent Positive
Average No. of LB per
withLB
form
Nudeus
None
1-5
6-10
11-20
21-30
19 25 15 9
79 86 83 45 25 36 46 36 42 33 26 14 14
16 9 3
5 4 3 11 6 14 7 16 11 12 17 6 12
5
2 5 3
6
2 5
8 8 6 9 8 6 6 1 2
1!4
1% 1!4 1!4 1
1
1 1
