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Central neurogenic hyperventilation in an awake patient with brainstem astrocytoma.

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Report of a Case
Central Neurogenic
Hyperventilation in an
Awake Patient with
Brainstem Astrocytoma
Moses Rodriguez, MD,* Philippe L. Baele, MD,?
H . Michael Marsh, MB, BS,t and Haruo Okazaki, MDS
A patient had the rare combination of central
neurogenic hyperventilation (PaCol of 9 torr) and a
normal level o f consciousness f o r eight days. M o r p h i n e
attenuated b u t never corrected the hyperventilation.
Experimental effects of hypocapnia, w h i c h decreases
both cerebral blood flow and metabolism in humans,
are at odds w i t h the normal mentation initially seen
i n this patient despite her m a r k e d and persistent hypocapnia. Death occurred after progressive
brainstem dysfunction. Pathological study showed a
well-differentiated astrocytoma involving primarily
the medulla and pons, with scattered t u m o r foci
t h r o u g h o u t the e n t i r e neuraxis. Possible mechanisms
f o r central neurogenic hyperventilation are discussed
briefly i n relation to the pathological findings and the
observed response to morphine.
Rodriguez M, B a d e PL, Marsh H M , Okazaki H:
Central neurogenic hyperventilation in an awake
patient with brainstem asi-rocytoma.
Ann Neurol 11:625-628, 1982
Central
neurogenic
hyperventilation
has
been
defined by P l u m and Swanson 1121 as a s y n d r o m e
comprising elevated arterial oxygen tension (Pao,),
decreased arterial carbon dioxide tension (Paco,),
and respiratory alkalosis i n t h e absence of roentgenographic evidence of p u l m o n a r y congestion.
The combination of central neurogenic hyperventilation with n o r m a l levels of consciousness is rare a n d
has b e e n r e p o r t e d i n only t w o previous cases. We describe a third p a t i e n t who h a d central neurogenic
hyperventilation associated with a n infiltrating
brainstem astrocytoma, and w h o had normal l u n g
function on admission a n d r e m a i n e d conscious for
eight days d e s p i t e a persistent decline in P a c o , levels
t o as low as 9 torr. T h i s patient h a d a decreased respiratory r a t e with a n increase i n PaCO, i n r e s p o n s e
t o m o r p h i n e . Possible mechanisms underlying this
rare disorder a r e reviewed.
From the Departments of "Neurology, t Anesthesiology (Section
of Respiratory and Intensive Care), and $Pathology, Mayo Clinic
and Mayo Foundation, 200 First St SW, Rochester, MN 55905.
Received Sept 16, 1981. Accepted for publication Sept 21, 1981.
Address reprint requests to Dr Marsh.
A 53-year-old woman (weight 75.6 kg, height 165 cm) was
seen at our clinic on June 23, 1980, with a seven-month
history of stiffness in her lower extremities and gait unsteadiness. Results of the general medical and neurological
examinations were normal except for moderately severe
ataxia of gait, speech, and extremities associated with
hyperreflexia. Roentgenograms of the skull and computed
tomography (CT scan) of the head showed no abnormalities.
O n November 25, the cerebellar deficit worsened and
bilateral Babinski signs developed. Visual evoked potentials were normal. Brainstem auditory evoked potentials
were abnormal o n the right, with prolongation of
stimulus-to-peak I latency and I-V interpeak latency.
Cerebrospinal fluid examination showed a total protein
value of 7 1 m d d l (normal, 14 to 45) and normal immunoglobulin G and cell count. A presumptive diagnosis
of demyelinating disease was made, and therapy with prednisone was started.
O n December 7 the patient returned with a three-day
history of uncontrollable hyperpnea. She had tried rebreathing from a paper bag before admission, without
change in her breathing pattern. She was alert, oriented,
and able to answer questions appropriately. Respirations
were sustained, rapid (22 breathsimin), regular, deep, and
unaltered during sleep. Results of examination were unchanged since her previous evaluation. Arterial blood gases
o n room air were Pao, 121 torr, Paco, 9 tom, p H 7.74,
base deficit 7 mEq/liter, bicarbonate 11 mEq/liter, hemoglobin 12.5 gm/dl, hemoglobin saturation 97%, and carboxyhemoglobin 2%. The lactate level was 4.9 mM/liter
(normal, < 1.65), and the value for plasma salicylate was 4
mg/dl 3 hours after the patient took 600 mg of aspirin. The
accuracy of the carbon dioxide electrode at low CO, tensions was assessed and confirmed using tonometered samples of saline to a Paco, of 13.4 tom. Supplemental oxygen
did not affect the respiration rate or the PaCO,. There was
no clinical or radiographic evidence of upper or lower respiratory tract disease. Other abnormal findings were
hypophosphatemia, with a phosphate level of 1.1 mg/dl
(normal, 2.5 to 4.5); hypokalemia, with a potassium level of
2.8 mEq/liter (normal, 3.7 to 4.5); and a urine p H of 7.90.
Cerebrospinal fluid, blood, urine, and sputum cultures
were all negative. The cerebrospinal fluid was unchanged
since November 25, disclosing no malignant cells.
Morphine (14 mg) was administered intravenously, and
the respiration rate decreased to 16 breathsimin. Arterial
blood gases 90 minutes later were Pao, 103 tom, Paco, 2 1
tori-, p H 7.50, base deficit 6 mEq/liter, and bicarbonate 16
mEq/liter. Morphine (4 to 10 mg) was needed every 4 to 6
hours to maintain the p H below 7.60. O n December 9 the
respiratory rate was 19 breathdmin, tidal volume 811 cc
ATPS, oxygen consumption 207 cc/min STPD, and carbon
dioxide production 230 ml/min STPD. The patient remained alert but began to exhibit more evidence of
brainstem dysfunction. She developed a mild left central
facial nerve palsy, dysphagia, and gaze-evoked horizontal
and vertical nystagmus. In the evening she showed sustained ankle clonus and increasing difficulty with oral secretions, requiring nasotracheal suctioning. The next day
0364-5134/82/060625-04$01.25 @ 1981 by the American Neurological Association 625
there were bilateral abducens palsies with skew deviation,
flaccid quadriplegia, flaccid dysarthria, and absence of gag
reflex.
She then aspirated gastric contents, and was intubated
and placed o n intermittent mechanical ventilation. A CT
scan of the head showed poor visualization of the lateral
medullary prepontine cisterns and was suggestive of decreased attenuation within the brainstem without midline
shift. The respiratory status worsened rapidly; antibiotics
were withheld. O n December 11, she was awake but
“locked in” and only able to move her eyes to verbal commands. Throughout the day she slowly became less responsive. The electroencephalogram showed background symmetrical polymorphic 1 to 3 Hz delta activity. Verbal or
noxious stimuli elicited an arousal response with brief runs
of rhythmic 5 Hz components associated with eye opening.
A respiration rate of 22 breathshin persisted until 2 hours
before death. She died on December 14, from aspiration
pneumonia and circulatory collapse. Bilateral necrotizing
bacterial bronchopneumonia was the immediate cause of
death and was confirmed at autopsy.
Neuropathological Findings
The brain showed no external abnormalities. The
internal structures of the medulla and upper pontine
tegmentum were obscured, without increase in size.
The brachia conjunctiva were mildly enlarged, and
their structural markings were obscured. The white
matter of the cerebellar hemispheres appeared
slightly mottled, containing multiple small areas of
increased pallor and translucency.
Microscopic examination of the brainstem showed
extensive diffuse but patchy infiltration, with welldifferentiated astrocytes that were bipolar and fibril-
626 Annals of Neurology Vol 11 No 6 June 1982
lary when in nerve fiber tracts (Fig 1) but plump and
stellate elsewhere. There was no derangement of
nuclei or tracts.
The entire extent of the medulla was involved (Fig
2), as were the tegmentum of the pons (Fig 3 ) , the
brachia conjunctiva, and the white matter of the
cerebellar hemisphere. The trigeminal nerve fibers
were also heavily infiltrated. In the midbrain, the
substantia nigra bilaterally was most involved. Scattered foci of similar astrocyte infiltration, at most a
few millimeters in diameter, were seen in the basal
gray matter, in the cerebral white matter, and rarely
in the cerebral cortex. Below the medulla, the pattern of infiltration was patchy in both the gray and
white matter throughout the length of the spinal
cord.
Discussion
There have been only two previous reports of patients who presented with central neurogenic hyperventilation in an awake state. An awake patient with
central neurogenic hyperventilation was described
by Goulon and associates [7] to have a primary
brainstem astrocytoma infiltrating both the medulla
and the lower pontine tegmentum. Lange and Laszlo
[9] reported a patient with malignant cerebral re-
F i g 1 . Section of ventral raphe region of the medulla, demonstrating an increase in well-differentiated bipolar fibrillary
astrocytes arranged along exiJting nerve fiber bundles. (H&E;
x 160 before 15 q)reduction.)
F i g 2. Cross section of the medulla at its midpoint, stained for
astrocyticfibers, with darker areas indicating heavy concentration offibrillary astrocytes. (Holzer; ~ 4 . before
5
15 % redu ction .)
F i g 3 . Upper pons and cerebellum showzng difluse infiltration
of astrocytes, predominantly of the pontine tegmentum, brachia
conjunctiva, and cerebellar white matter, as indicated by
patchy pallor of myelinated areas. (Luxolfast blue-iiesyl violet; ~2 before 15 % reduction.)
ticulosis infiltrating the midbrain and pons but sparing the medulla, who remained alert for 41 days with
central neurogenic hyperventilation before death. By
comparison with these two patients, our patient presented with an extraordinarily low Paco,.
Cerebral metabolism is affected by hyperventilation. Studies done in anesthetized volunteers and
dogs have shown that acute respiratory alkalosis
significantly decreases cerebral blood flow and shifts
the oxyhemoglobin dissociation curve to the left, and
that both factors increase anaerobic metabolism of
glucose in the brain [l, 101. In one study, hypoxic
electroencephalographic changes were noted in all
volunteers [l]. Our patient had a normal level of
mentation despite maintaining a PaCO, below 15 torr
for a long period.
Morphine decreased the respiratory rate and increased but never completely corrected the PacOz to
normal levels. Morphine decreases the respiratory
rate and tidal volume in normal subjects, but the sites
of action are controversial. Opiate receptor binding
in humans and in primates is distributed diffusely
throughout the neuraxis [ 8 ] . Autoradiographic techniques in rats have shown high concentrations of receptors associated with the respiratory centers of the
dorsal medulla: nucleus ambiguus, tractus solitarius,
and nucleus commisuralis [ 1-31. Application of morphine [4] and met-enkephalin [ 5 , 61 to the ventral
surface of the brainstem overlying the central
chemoreceptors in cats depresses respiration. Theoretically, morphine may act on these chemoreceptors, on the medullary centers, or at higher
levels. No conclusion may be drawn in that respect
from the present case.
Sparing of the dorsal medulla has been considered
necessary for the development of central neurogenic
hyperventilation, particularly in association with head
injury [ 113. The mechanism proposed by Plum and
Swanson [ 121 for central neurogenic hyperventilation
is disconnection of otherwise normal medullary respiratory centers from regulatory control originating
in the cortex, thalamus, or pons. Autopsy study in
their cases showed involvement from the caudal part
of the midbrain to the lower third of the pons with
extensive damage to the reticular formation ventral
to the aqueduct and above the level of the obex,
sparing the medulla. However, both Goulon’s patient
and our own had diffuse infiltration of the medulla
and pons by tumor. The wide extent of the tumorous
infiltration in these cases makes it difficult to identify
whether destruction of specific nuclei or tracts could
account for the unusual clinical pattern of central
neurogenic hyperventilation in an otherwise awake
and alert patient. However, the pathological findings
in our case showed relatively little derangement of
the normal anatomy of nuclei and tracts in the
brainstem. Loss of neurons could not be ruled out.
Unfortunately, we did not check the p H of the
cerebrospinal fluid in our patient, nor did we measure lactate or pyruvate levels in the central venous
or jugular blood, or estimate cortical flows o r cerebral metabolic rates for glucose consumption. Such
studies would be of great interest to ascertain
whether a central chemoreceptor mechanism is triggering central neurogenic hyperventilation in cases in
Case Report: Rodriguez et al: Central Neurogenic Hyperventilation
627
which the metabolic rate in the brainstem is increased, or whether an enhanced interaction between
medullary neurons or decreased extrabulbar inhibitory influence is responsible.
we thank Dr L. H. Phillips, 11, for helpful discussion in the management of this case and Miss Ellen A. Graupmann for her secretarial assistance.
References
1. Alexander SC, Cohen PJ, Wollman H , et al: Cerebral carbohydrate metabolism during hypocarbia in man: studies
during nitrous oxide anesthesia. Anesthesiology 26:624-632,
1965
2. Atweh SF, Kuhar MJ: Autoradiographic localization of opiate
receptors in rat brain. 1. Spinal cord and lower medulla. Brain
Res 124153-67, 1977
3. Atweh SF, Kuhar MJ: Autoradiographic localization of opiate
receptors in rat brain. 11. The brainstem. Brain Res 129:l-12,
1977
4. Berger AJ, Mitchell RA, Severinghaus JW: Regulation of
respiration. N Engl J MeJ 297:92-97, 138-143, lcl4-201.
1977
5. Flbrez J, McCarthy LE, Borison HL: A comparative study in
the cat of the respiratory effects of morphine injected intravenously and into the cerebrospinal fluid. J Pharmacol Exp
Ther 163:448-455, 1968
6. Florez J , Mediavilla A : Respiratory and cardiovascular effects
of met-enkephalin applied to the ventral surface of the brain
stem. Brain Res 138:585-590, 1977
7. Goulon M, Escourolle R, Augustin P, et al: Hyperventilation
primitive par gliome bulbo-protubPrantie1. Rev Neurol (Paris)
121~636-639, 1969
8. Kuhar MJ, Pert CB, Snyder SH: Regional distribution of
opiate receptor binding in monkey and human brain. Nature
245:447-450, 1973
9. Lange LS, Laszlo G: Cerebral tumour presenting with hyperventilation. J Neurol Neurosurg Psychiatry 28:3 17-3 19,
1965
10. Michenfelder JD, Theye RA: The effects of profound
hypocapnia and dilutional anemia on canine cerebral
metabolism and blood flow. Anesthesiology 3 1:449-457,
1969
11. Plum F, Posner JB: The Diagnosis of Stupor and Coma. Third
edition. Philadelphia, Davis, 1980, pp 30-41
12. Plum F, Swanson AG: Central neurogenic hyperventilation in
man. Arch Neurol Psychiatry 81:535-549, 1959
Encephalomy eloneuropathy
with Ganglionitis of the
Myenteric Plexuses in the
Absence of Cancer
Dikran S. Horoupian, MD,* and Yehum Kim, M D " t
A 5 5-year-old woman presented with rapidly progressive brainstem dysfunction which led to death within a
month. She also had constipation for three weeks, and
barium enema showed ileus. Subacute encephalomyelitis predominantly involving the medulla and
pons correlated with the patient's initial symptoms.
In addition, ganglionitis of the myenteric plexuses
explained the constipation and ileus. Ganglioradiculoneuropathy was another finding. The presence of
abundant neuronophagia in the brainstem, dorsal root
ganglia, and myenteric plexuses raised the speculation
that a putative virus, toxic agent, or immune reaction possessed special affinity for neurons and ganglion cells. The neuropathological findings were
similar to paraneoplastic changes, but no neoplasm
was found.
Horoupian DS, Kim Y: Encephalomyeloneuropathy
with ganglionitis of the myenteric plexuses in the
absence of cancer. Ann Neurol 11:628-632, 1982
Ganglionitis of the myenteric plexus has been reported only once in a patient who had an occult primary tumor with an undifferentiated metastasis in a
cervical lymph node [8]. We recently observed the
phenomenon in a patient in whom postmortem examination failed to reveal any neoplastic process.
T h e condition was associated with extensive neuronophagia throughout the central nervous system,
especially in the brainstem but also in the posterior
horns of the spinal cord and dorsal root ganglia.
A 55-year-old black woman was admitted on July 1, 1 9 7 9 ,
because of weakness, easy fatigability, and chest pains with
shortness of breath for one week. She also complained of
double vision and unsteadiness of gait in the preceding
three days. H e r family had noticed facial twitchings. She
was known to have arteriosclerotic heart disease with angina pectoris, and had lost weight in the previous month.
From the *Department of Pathology (Neuroparhology), Rose F.
Kennedy Center for Mental Retardation and Human Development, Albert Einstein College of Medicine, 1300 Morris Park
Ave, Bronx, N Y 10461, and ?Bronx Lebanon Hospital.
Received Aug 13, 1981, and in revised form Sept 24. Accepted for
publication Sept 27, 1981.
Address reprint requests to Dr Horoupian.
628 0364-5 134/82/060628-05501.25 @ 1981 by the American Neurological Association
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