Drager syndrome, which manifests severe general ized impairment of the central autonomic nervous system (Gotoh ... Medical University Hospital in November 1982 for diarrhea .... Iwayama T, Furness JB, Burnstock G (1970) Dual adrenergic.
Journal of Cerebral Blood Flow and Metabolism
4:470-473 © 1984 Raven Press, New York
Short Communication
Dysautoregulation of the Cerebral Circulation in Primary Systemic Amyloidosis
Shotai Kobayashi, Tomoko Katsube, Shuhei Yamaguchi, Mitsuhiro Kitani, Kazunori Okada, and Tokugoro T sunematsu Department of Internal Medicine, Shimane Medical University, Izumo, Shimane, Japan
Summary: A case of primary systemic amyloidosis as
lation was spared. To our knowledge, this is the first case
sociated with marked dysautoregulation of the cerebral
to demonstrate that amyloid peripheral autonomic neu
circulation in response to hypotension is reported, T he
ropathy can be accompanied by dysautoregulation of the
major amyloid protein was immunoglobulin A lambda
cerebral circulation. Key Words: Autonomic nervous
type, An autonomic nerve function test showed severe
system - Autoregulation - Cerebral
and extensive disturbances of the autonomic nervous
mary systemic amyloidosis.
circulation -Pri
system. The cerebrovascular reactivity to 5% CO2 inha-
Neurogenic control of the cerebral circulation has
CASE REPORT
been suggested from observations made in the Shy
A 49-year-old man was admitted to Shimane
Drager syndrome, which manifests severe general
Medical University Hospital in November 1982 for
ized impairment of the central autonomic nervous
diarrhea and dizziness. Starting 4 years prior to ad
system (Gotoh et aI., 1971-72). However, partial
mission, he suffered from watery diarrhea and had
interruption of sympathetic pathways, such as
lost 12 kg since around the end of 1979. Two years
spinal cord transection above T6, does not interfere
before admission, the patient began to have bouts
with the autoregulation of the cerebral circulation
of dizziness and blurring of vision precipitated or
(Nanda et al., 1974). Although many experimental
aggravated by assuming erect posture from the
studies of neurogenic control have been reported,
lying or sitting position. He had been impotent for
there is no general agreement as to whether or not
2 years. On general examination, multiple petechial
the peripheral autonomic nerves play a major role
bleedings and small, brownish papules were ob
in cerebrovascular autoregulation. Severe general
served in the axilla and neck. His blood pressure
ized impairment of the peripheral autonomic ner
was 126/78 mm Hg in the supine position and fell to
vous system is known in primary systemic amyloi
80/56 mm Hg after he stood quietly in one spot for
dosis, especially in the familial type (Glenner et al.,
I min. His pulse rate remained at 80 beats/min. He
1978). We report here a patient with primary amy
complained of dizziness at this time.
loidosis who showed marked dysautoregulation of
On neurological examination, the patient was
the cerebral circulation.
found to be alert, cooperative, and well oriented. Examination of the cranial nerves including those of the pupils revealed entirely normal results.
Address correspondence and reprint requests to Dr. Kobay ashi at Department ofInternal Medicine, Shimane Medical Uni
Motor strength was normal, and no muscle atrophy
versity, Izumo, Shimane 693, Japan.
was observed. Deep tendon reflexes were abol
Abbreviations used: AVD-OzSAT, Arteriovenous difference of
ished. Coordination was normal. Pain and thermal
oxygen saturation; rCBF, regional cerebral blood flow.
470
DYSAUTOREGULATION OF CBF IN AMYLOIDOSIS sensation were diminished in the whole body, but touch and deep sensation were normal. Laboratory investigations
The hemogram, urinalysis, hepatic function, elec trolyte, lipid, and blood urea nitrogen levels, and erythrocyte sedimentation rate were normal. The oral glucose tolerance test showed a normal pat tern. The immunoglobulin A increased markedly by 2,500 mg/dl and that of other immunoglobulins was decreased slightly. The major amyloid protein was of lambda light-chain origin. Bence Jones protein was negative. Bone marrow examination revealed normal nuclear cell counts with 3.8% plasma cells.
471
Autonomic nerve function tests
The Aschner's and the Czermak-Hering tests failed to reduce the pulse rate, and the heart rate showed no change following the administration of 0.5 mg atropine sulfate. Variation of the RR inter vals on the ECG was markedly reduced, as the vari ation coefficient was 0.45%. A significant fall of the MABP from 93 to 63 mm Hg during tilting up of the head was observed by continuous recording of the blood pressure measured by a transducer connected to an intraarterial catheter. Overshooting of the blood pressure was also observed when the patient returned to the horizontal position.
There were no findings of myeloma. Bone scinti grams were normal. Skin biopsy revealed deposits
Examination of cerebrovascular reactivity
of amyloid in the small vessels by Congo red stain,
Autoregulation of the cerebral circulation was ex
as shown in Fig. 1. This amyloid showed a negative
amined at admission by the arteriovenous differ
reaction in the immunohistochemical enzyme anti
ence of oxygen saturation (AV D-02SAT) before and
body assay using anti-AA serum to amyloid protein
after tilting the head upward. The blood was sam
AA. These findings indicated that this case should
pled from the internal jugular vein and femoral ar
not be one of secondary amyloidosis. The sensory
tery, and (Po2, Pco2, pH, and 02SAT were mea
conduction velocity was delayed in the distal por
sured by a blood gas analyzer (Corning 175). The
tion of the bilateral median nerves. The cerebro
change of the CBF was represented by the per
spinal fluid was normal. The EEG and brain com
centage change of the AV D-02SAT in place of the
puted tomography were normal. The ECG showed
absolute value of the CBF. Arterial blood Po2, Pco2,
left ventricular hypertrophy and T inversion in V 4-
pH, and 02SAT at rest were 74 mm Hg, 40 mm Hg,
6. Radiographs of the chest and abdomen were
7.41, and 95%, respectively. The MABP was re
normal. The stomach, small intestine, and colon
duced by 27 mm Hg, associated with the marked
were morphologically normal, but the passing time
reduction of the CBF by 42.5% after 5 min of tilting
of barium was shortened.
the head upward. The patient complained of mild
FIG. 1. Deposition of amyloid is observed in the small vessels of the skin (Congo red stain, x 100).
J Cereb Blood Flow Me/abol, Vol. 4, No.3, 1984
472
S. KOBAYASHI ET AL.
dizziness and blurred vision during the examma
DISCUSSION
tion. Plasma noradrenaline was increased from 260
Disturbance of the peripheral autonomic nervous
to 460 pg/ml (+ 77%) by tilting up the head, and
system is the main neurological symptom in pri
nonesterified fatty acids rose from 0.27 to 0.43 mgl
mary systemic amyloidosis, especially in the fa
dl. The CBF increased by 27.5% during 5% CO2
milial type. The pathological change in the periph
inhalation without any rise of the blood pressure.
eral nerve is axonal degeneration with amyloid de
Two years after the first admission, the autoreg
position in the vasa vasorum and the interstitial
ulatory response of the cerebral circulation was
space of the nerve fibers. Deposition of amyloid is
reexamined
inhalation
more prominent in the sympathetic ganglion and
method. At the second admission, the patient could
parasympathetic nerves than in other peripheral
using
the
xenon-133
not sit on the chair because of severe orthostatic
nerves. CNS involvement is generally restricted to
hypotension. The regional CBF (rCBF) was exam
asymptomatic infiltration of the leptomeninges
ined in the supine position and at 35° of tilting the
(Glenner et aI., 1978). Therefore, this case is an
upper half of the body upward. The interval be
appropriate model for investigating the relationship
tween the two measurements was 30 min, and the
between the peripheral autonomic nervous system
second measurement started 5 min after the tilting
and neurogenic control of the cerebral circulation.
up. The mean rCBF was reduced from 57.7 to 39.6
It has been reported that the cerebral pial vessels
ml/l00 g/min ( - 31%) by tilting the head upward, as
are innervated by adrenergic nerves originating
sociated with an 8 mm Hg reduction of the MABP
from cervical sympathetic (Nielsen and Owman,
(from 78/52 to 60150 mm Hg; Fig. 2). The Pco2 re
1967; lwayama et aI., 1970) and parasympathetic
mained constant at 32 mm Hg. The patient com
(Edvinsson et aI., 1972) nerves in animals. Re
plained of mild blurred vision during the examina
cently, central noradrenergic innervation of paren chymal vessels from the locus ceruleus has been
tion.
demonstrated (Edvinsson et aI., 1973), but the role of this nervous system in the cerebral circulation has not been fully elucidated. It has been reported
Family history
There were no persons who showed similar symptoms or who had been diagnosed as having amyloidosis in the patient's family. The serum pro tein fraction, electroimmunophoresis, and nerve conduction velocity were normal in his brothers and sons.
that stimulation of the cervical sympathetic nerves has protective effects against injury of the blood brain barrier induced by excessive hypertension (Edvinsson et aI., 1976). On the other hand, cholin ergic nerves have been considered to have a vaso dilating action in the cerebral vessels (James et aI., 1969). It has also been reported that the stimulation of the greater superficial petrosal nerve or the in
MABP mmHe
rCBF ml/100e/min 70
70
traarterial injection of acetylcholine induced dila tion of the pial arteries, and that these responses were blocked by premedication with atropine sul fate (D'Alecy and Rose, 1977), Therefore, cholin ergic nerves have been considered as cerebral va sodilating nerves, but this origin remains uncertain. In this case, the circulating noradrenaline (Kanda
50
50
et aI., 1980) and nonesterified fatty acid levels in creased normally by the tilting up of the head, in contrast to no response of the heart rate to atropine sulfate injection or the Achner's test. However, the existence of severe orthostatic hypotension despite
30
30 supine
tilt-up
FIG. 2. Change of the mean regional cerebral blood flow (rCBF) by tilting up of the head at the second admission (filled circles) and that of the mean arterial blood pressure (MABP; open circles). The change of the rCBF parallels that of the MABP.
J Cereb Blood Flow Metabol, Vol. 4. No.3, 1984
a large increase in circulating noradrenaline may indicate that the postsynaptic sympathetic nerves had been severely affected. This suggests that an increase in circulating noradrenaline would not con tribute to a diminution of autoregulation of the ce rebral circulation in this case. We examined the au toregulatory response of the cerebral circulation by AV D-02SAT at the first admission because the
DYSAUTOREGULATION OF CBF IN AMYLOIDOSIS
tilting table was not applicable for our xenon-133 inhalation instruments. This method, however, has the possibility of errors caused by the change in the cerebral metabolic rate for oxygen during the ex amination, but the change in the relative CBF was consistent with that in the rCBF by the xenon-l33 inhalation method at the second admission. These results suggest that the peripheral autonomic ner vous system may have a role in the autoregulation of the cerebral circulation in response to hypoten sion. This hypothesis is consistent with the report of Mchedlishvili and Nikolaishvili (1970) that dem onstrated cerebral dysautoregulation in response to hypotension by intraarterial atropine sulfate injec
473
microscopy and pharmacology. Z Zeliforsch Mikrosk Anat 134:311-325 Edvinsson L, Lindvall M, Nielsen C, Owman CH (1973) Are brain vessels innervated also by central (non-sympathetic)
adrenergic neurons? Brain Res 63:496-499
Edvinsson L, Owman C, Siesjo B (1976) Physiological role of cerebrovascular sympathetic nerves in the autoregulation of cerebral blood flow. Brain Res 117:519-523
Glenner GG, Ignaczak TF, Page DL (1978) The inherited sys
temic amyloidosis and localized amyloid deposits. In: The
Metabolic Basis of Inherited Disease, 4th ed. (Stansbury JB, Wyngaarden JB, Fredrickson DS, eds). New Y ork, McGraw-Hill, pp. 1308-1339
Gotoh F, Ebihara S, Toyoda M, Shinohara Y (1971-72) Role of autonomic nervous system in autoregulation of human ce
rebral circulation. Eur Neurol 6:203-207
Iwayama T, Furness JB, Burnstock G (1970) Dual adrenergic and cholinergic innervation of the cerebral arteries of the
rat. eirc Res 26:635-646
tion, but contradictory opinions have also been pre
James 1M, Millar RA, Purves MJ (1969) Observation on the ex
sented (Kawamura et a!., 1975). Dysautoregulation
trinsic neuronal control of cerebral blood flow in the baboon.
of the cerebral circulation in response to hypoten sion could be induced by fusaric acid (a dopamine l3-hydroxylase inhibitor) (Kobayashi et a!., 1980), whereas cervical sympathectomy does not affect the cerebral autoregulation in response to hypoten sion (Mueller et a!., 1977). There have been many experimental studies of cerebral autoregulation and diverse results have been reported. We believe this to be due to the difficulties in making an extensive dysautonomic model as represented by the patient reported in this article. Acknowledgment: We are grateful to Dr. T. lsobe (De partment of Internal Medicine, Kobe University) for the immunohistochemical enzyme antibody assay of amy loid.
Circ Res 25:77-93
Kanda T, Tazaki Y, Furuhashi N, Kobayashi S, Hayakawa I, Hayashi H (1980) Plasma norepinephrine levels in patients
with dysautoregulation of cerebral circulation. In: Patho
physiolofU and Pharmacotherapy of Cerebrovascular Dis orders (Betz E, Grote J, Heuser D, Willlenweber R, eds).
Baden-Baden, Verlag Gerhard Witzstrock, pp. 44-47 Kawamura Y, Meyer JS, Hiromoto H, Aoyagi M, Tagashira Y, Ott EO (1975) Neurogenic control of cerebral blood flow in the baboon. J Neurosurg 43:676-688
Kobayashi S, Kitamura A, Furuhashi N, Kanda T, Tazaki Y (1980) T he effect of inhibition of dopamine beta hydroxylase on cerebrovascular CO, reactivity and autoregulation. In:
PathophysiolofU and Pharmacotherapy of Cerebrovascular Disorders (Betz E, Grote J, Heuser D, Willlenweber R, eds). Baden-Baden, Verlag Gerhard Witzstrock, pp. 48-51 Mchedlishvili GI, Nikolaishvili LS (1970) Evidence of a cholin ergic nervous mechanism mediating the autoregulatory dilatation of the cerebral blood vessels. Pflugers Arch 315: 27-37 Mueller SM, Heistad DD, Marcus ML (1977) Total and regional cerebral blood flow during hypotension, hypertension and
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J Cereb Blood Flow Metabol, Vol. 4. No.3. 1984