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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

REFERENCES D'Alecy LG, Rose CJ (1977) Parasympathetic cholinergic con­ trol of cerebral blood flow in dogs. Circ Res 41:324-331

Edvinsson L, Nielsen C, Owman C, Nielsen KC (1972) Cholin­ ergic mechanism in pial vessels. Histochemistry, electron

hypocapnia. Circ Res 41:350-356

Nanda RN, Wyper DJ, Harper AM, Johnson RH (1974) Cerebral blood flow in paraplegia. Paraplegia 12:212-218

Nielsen K. Owman C (1967) Adrenergic innervation of pial ar­

teries related to the circle of Willis in the cat. Brain Res

6:773-776

J Cereb Blood Flow Metabol, Vol. 4. No.3. 1984