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Biochemical findings in a case of parkinsonism secondary to brain tumor.

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BRIEF COMMUNICATIONS A N D CASE REPORTS
Biochemical Findings
in a Case of Parkinionism
Secondary to Brain Tumor
J. Garcia d e Yebenes, MD," J. J. Gervas, M D , t
J. Iglesias, MD,: M. A. Mena, P h D , t
R. Martin del Rio, M D , t and E. Somoza, MDt
Neuropathological and biochemical studies were performed in a patient with craniopharyngioma and a
long history of parkinsonism. Morphological examination revealed atrophy of the substantia nigra without
Lewy bodies. Both the caudate and putamen nuclei
showed moderate loss of large cells with glial proliferation. There was a notable decrease in dopamine and
its metabolites and a reduction in norepinephrine content in both the caudate and putamen nuclei. Less consistent changes were found in serotonin and amino
acid levels. Dopamine receptors, evaluated as "Hspiperone binding sites, were unchanged in the putamen but decreased to 30% of control values in the
caudate. The findings suggest that parkinsonism was
caused by the brain tumor, which damaged both the
presynaptic dopaminergic nigrostriatal neurons and
the postsynaptic dopamine receptors.
Garcia d e Yebenes J, Gervas JJ, lglesias J, Mena
MA, Martin del Rio R, Somoza E: Biochemical
findings in a case of parkinsonism secondary to
brain tumor. Ann Neurol ll:313-316, 1982
Parkinsonism is occasionally associated with brain tumors, but biochemical data from such cases have not
been reported. We present the clinical, pathological,
and biochemical findings in a patient with craniopharyngioma and a parkinsonian syndrome.
A 70-year-old white man had a 15-month history of weakness in both legs and intermittent tremor at rest. He coinplained of progressive difficulty in walking, loss of vision in
both lateral margins of the optic field, and loss of appetite
and weight during the previous four months. General
physical examination was unremarkable. The patient was
alert and oriented but severely bradykinetic and amimic;
his speech was dysarthric. He had bilateral temporal
hemianopia and paleness of both optic nerve heads. Other
cranial nerves appeared normal. Muscle strength was preserved. There was slight resting rremor in both hands,
more prominent on the right, and severe cogwheel rigidity
From the Departments of "Neurology, tResearch, and SPathology, Centro Ramon y Cajal, Carretera de Colrnenar, Km 9, 1, Madrid 4 , Spain.
Received Ftb 24, 198 1, and i n revised form June 19. Accepted for
publication June 20, 1981.
Address reprint requests to Dr Garcia d e Ykbenes.
in the neck muscles and about both wrists. Voluntary
movements were slow and walking was difficuit, accomplished in small steps in a flexed posture without associated
arm movements. Laboratory data were normal except for
mild anemia. C T scan disclosed enlargement of the third
and lateral ventricles, a small calcified area over the left
putamen, and an area of low density over the optic chiasm.
A vetriculoperitoneal shunt was implanted. Four months
later the patient developed an episode of aseptic lymphocytic meningitis with inadequate antidiuretic hormone
secretion, followed by progressive deterioration of gait, vision, and mental acuity with occasional hallucinations.
Rigidity and bradykinesia worsened. A course of tr'eatment
with amantadine (200 mglday), levodopa (up to 1,000 m d
day) plus carbidopa (up to 100 mgiday), and bromocriptine
(60 mg/day) was unsuccessful.
Six months after admission the patient developed generalized tonic-clonic convulsions that were treated with
phenytoin (300 mg/day). His rigidity and akinesia worsened and he became blind. Fifteen months after admission
he died.
Neuroputhologicul and Biochemical Methods
The patient's body was refrigerated at 5°C and autopsy was
performed five hours after death. Fresh brain was sliced
and two portions of the left caudate and putamen were dissected, frozen, weighed, and stored at -80°C until
biochemical analyses were performed. T h e rest of the brain
was used for microscopic examinations. For controls, caudate and putamen from four patients aged 68 to 7 2 years old
who were without clinical or neutopathological evidence of
nervous system disease were obtained with similar postmortem delay and autopsy conditions.
Amino acid levels were measured with a Beckman 121
M B automatic amino acid analyzer; monoamines and
metabolites were estimated by fluorometry after separation
in an ion-exchange column chromatograph according to
previously described techniques [l-3, 6, 20, 211, and
dopamine receptors were measured by binding assays of
3H-spiperone to the synaptosomal-mitochondria1 (P2)
fractions [ l o , 131 according to Creese et a1 191. Final nominal
concentration for "H-spiperone was 4 nM.
Binding values were obtained as disintegrations per minute per milligram of pellet [24]. Measured values were corrected for the presence of nonspecific binding by including
a high concentration ( 2 5 p M ) of nonradioactive haloperidol in the media in some experiments. The quantity of radioactive ligand detected in the pellet in the presence of the 25 p M nonradioactive ligand was subtracted
from total binding to obtain specific binding.
Neurochemical values three or more standard deviations
from the mean of control values were considered abnormal.
Results
Neuropathological Findings
Postmortem examination of the brain revealed a cystic cavity measuring 40 x 25 mm located behind the
olfactory bulbs and extending to the exit of t h e displaced third cranial nerves. Neither the pituitary
0364-5 134/82/030313-04$01.25 @ 1981 by the American Neurological Association
313
ventricle had a granular proliferation (ependymitis
granularis). T h e histological diagnosis was cranioph ar y ngi oma.
Microscopic examination in other brain areas revealed marked loss of neurons in the substantia nigra
(Fig 2) with granules of melanin pigment within the
macrophages or neuropil and with glial proliferation.
The caudate and putamen nuclei had undergone
moderate loss of large cells with slight glial proliferation. Diffuse neuron loss was evident in other brain
areas but it was not excessive for the patient’s age.
Fig 1. Axial section of brain through the tumor mass and
brainstem. A large tumor occupies the interpeduncular and
perichiasmatic &tern and compresseJ the brainstem.
gland nor the infundibulum was located. T h e optic
chiasm was narrow and the optic nerves were atrophic. Both internal carotid arteries were displaced
laterally and the anterior cerebral arteries were
shifted frontally. The tumor occupied the interpeduncular and perichiasmatic cisterns (Fig 1) as well
as a portion of the third ventricle, displacing its wall
and causing ventricular enlargement. T h e cavity
contained many small cysts filled with a gelatinous
liquid. Inside one cyst was a 5 mm cauliflower-shaped
tumor with a granular, coral-like wall. Both lateral
ventricles were dilated and the ependyma of the third
314
Annals of Neurology
Vol I 1
No 3
March 1982
Biochemical Findings
Amino acids were not significantly altered from control levels (data not shown). Norepinephrine was reduced in the parkinsonian caudate and putamen to
10% of control levels. Dopamine, 3-methoxytyramine, and homovanillic acid were markedly decreased in both areas of the patient’s brain. 5-Hydroxytryptophan values were unrevealing. 3Hspiperone binding sites were severely decreased
in the caudate and moderately reduced in the putamen (Table).
Discussion
Extrapyramidal syndromes, characterized by rigidity
and tremor, have been reported as a rare symptom of
brain tumor. Most reports concern tumors compress-
F i g 2. Paraffin section of right Jubstantici nigra howing loss
of neurons and accumulation o f melanin pigment in the
neuropil. (HGE; X100.)
Monoamines, Dopamine Metabolites, and 3H-SpiperoneBinding Sites
in Cazldate and Putamen of the Puukinsonian Patient and Contuo.olsa
Parkinson
Control
Determination
Caudate
Putamen
Caudate
Putamen
5-HT
NE
275
35
1,810
74
18
816
Trace
123
13.1 -+ 1.5
Trace
502
15.4
1.9
217 ? 45
194 ? 32
3,796 ? 485
385 t 66
2,726 ? 628
46.97 ? 6.3
279 ? 4 9
146 2 17
3,923 ? 611
443 5 7 0
2,788 ? 360
29.3 -+ 4.3
DA
3-MT
HVA
"H-sDiDerone
*
"Values are expressed as nanograms per gram wet tissue for monoamines and metabolites and as picomoles per gram of protein for binding.
All data from controls are means and standard deviation for four normal brains. Each point of binding data is the mean of four determinations.
5-HT
=
5-hydroxytryptophan; NE
=
norepinephrine; DA
=
dopamine; 3-MT
ing or infiltrating the basal ganglia or compressing the
brainstem [ l l , 12, 17, 26, 27, 29-31, 33, 36, 37,
40-421. Pressure o n the brainstem could be caused
directly by the tumor mass or indirectly by torsion or
displacement of brain structures and herniation
through the tentorial notch [18, 25, 381. The tumors
most often associated with parkinsonism are the large
meningiomas growing at the base of the skull or over
the convexity, but there are also craniopharyngioma,
glioma, ependymoma, and other types; even syringobulbia have been associated with extrapyramidal
syndromes, probably by the same mechanisms of
brainstem compression.
Craniopharyngioma is very seldom associated with
parkinsonism. Van Bogaert [40]reported two cases:
one patient with a histologically confirmed craniopharyngioma and a typical parkinsonian syndrome,
the other with tremor, rigidity, and a suprasellar
mass of unknown type. Orzechowski and Mitkus
[32] described another patient with craniopharyngioma and parkinsonism, but reports of large series of craniopharyngioma [4, 7, 14, 35, 391 d o not
mention parkinsonism even as a rare symptom.
Theoretically, a parkinsonian syndrome can be
produced by: (1) damage to nigral dopaminergic
neurons or their axons, the nigrostriatal dopaminergic pathways; or (2) a lesion of postsynaptic cells at
the striatum [18]. A biochemical indication of the
first cause would be a decrease in dopamine and its
metabolites in the striatum and substantia nigra [5,
15, 16, 23, 341. The second mechanism is evidenced
by a change in postsynaptic dopamine receptors. In
both cases there may be some changes in other
neurotransmitrers.
O u r patient showed a prominent decrease in
dopamine and its metabolites 3-methoxytyramine
and homovanillic acid, while norepinephrine was also
reduced. These findings suggest that the parkinsonian symptoms were produced by compression of
=
3-methoxytyramine; HVA
=
homovanillic acid.
the substantia nigra or its dopaminergic projection
to the striatum and that the norepinephrine-rich projection from the lower brainstem was also damaged.
The decrease in dopaminergic postsynaptic receptors in the putamen and caudate may explain the
poor clinical response to L-dopa and bromocriptine.
There is evidence for several types of dopaminergic
receptors in the brain [19, 281. Dopaminergic supersensitivity accompanies postsynaptic dopamine receptor binding enhancement [8, 221 secondary to
striatal denervation in Parkinson disease. The decreased number of dopaminergic receptors in the
striatum in our patient suggests direct compression of
this area by the tumor mass and is not explained by
damage to nigrostriatal dopaminergic pathways.
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