PATHOGENESIS
OF
LESIONS
IN
THE
NERVOUS
SYSTEM
IN
HYPERNATREMIC
STATES
I. Clinical
Observations
of
Infants
By Laurence Finberg, M.D.
Pediatric Division of the Baltimore City Hospitals, Johns Hopkins University School of Methcine
(Accepted July 9, 1958; submitted April 30.)
ADDRESS: Baltimore City Hospitals, 4940 Eastern Avenue, Baltimore 24, Maryland.
PEDIATRICS, January 1959
40
A
RELATIONSHIP between hypernatremiaand central nervous system disease has
been documented by a number of authors
beginning with tile report of The
occurrence of disturbances of the nervous
system during tile course of hypernatremic
dehydration in infants has been noted and
the clinical significance stressed more
re-cently.36 The pathogenesis of the lesions
of the nervous system has remained
ob-scure and some confusion has arisen
be-cause injury to the central nervous system
may give rise to a hypernatremic state. This
may occur as a result of specific injury to
the brain altering the regulatory
mecha-nisms for homeostasis of water and
electro-lytes.’ 8 An altered state of consciousness
after injury to the brain may lead indirectly
to hypernatremia since the normal thirst
mechanism cannot operate. Such patients
are dependent upon their attendants who
may underestimate water requirements;
another type of dependent patient, the
pre-verbal infant, may fare similarly.” ‘ There
is reason to believe that hypernatremia
may cause injury to the central nervous
system and this aspect of the problem will
be discussed here.
The purpose of the present
communica-tion is to extend the clinical observations
previously made, by demonstration of the
occurrence of subdural effusions and
hem-orrhage in infants with hypernatremic
de-hydration, and to add to the evidence that
hypernatremia may be the cause of severe
and irreversible brain damage. A second
report’#{176} will deal with the anatomic and
chemical changes in experimentally induced
hypernatremia in animals. Seven infants
have been observed in whom either
sub-dural hematoma or hygroma was found
during tile course of an illness marked by
the occurrence of hypernatremic
dehydra-tion. The salient features of these cases are
summarized in Table . The first case
il-lustrates a number of important points
which are detailed in the following case
report:
History
CASE REPORT
MB., a Negro male infant 5 weeks of age,
was admitted to Baltimore City Hospitals on
April 30, 1956. The parents were in good
health as were three older siblings. There were
110 SigilifiCant familial illnesses, and the patient
had seemed normal before the present illness.
He had been born uneventfully at Baltimore
City Hospitals, weighing 4,475 gm. On April
28 the mother made the formula, consisting of
13 oz of evaporated milk, 17 oz of water and
2 tablespoons of sugar, while in the home of
the patient’s grandmother. It was subsequently
learned that sugar and salt were kept ill
identi-cal canisters and that salt had inadvertently
been substituted for sugar. The patient took
between 360 and 600 ml of this mixture during
the next 12 hours before beginning to vomit.
The excessive ingestion of salt is estimated to
have been 30 to 40 gm or approximately 500 to
700 meq of sodium chloride. After the vomiting
he became febrile and on the next day began
to have labored breathing. Late in the evening
of April 29 he was brought to the accident room
of Baltimore City Hospitals because of these
symptoms. It was not known at that time that
the excessive ingestion of salt had occurred but
the infant appeared sick and he was admitted
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Physical Findings
The weight was 4,810 gm. Temperature was
39.2#{176}C, pulse rate, 145/mm and respiratory
rate, 80/mm. Respirations were labored and
there was inspiratory stridor. He was lethargic
but hyperirritable when stimulated and muscle
tone was increased. There were bursts of
tremors involving the muscles of the extremities
and extraocular muscles. The peripheral
circu-latory status was excellent.
Course and Laboratory Findings
In the absence of an accurate history, the
correct diagnosis was not appreciated and the
patient was initially considered to have
respira-tory infection and managed accordingly. About
2 hours later a generalized convulsion occurred
which was finally controlled with barbiturates.
A lumbar puncture revealed clear fluid which
contained no cells and proved sterile. The
con-centration of protein was 100 mg/100 ml and
that of glucose, 50 mg/100 ml. Concentrations
of chloride and sodium were 195 and 205
meq/l, respectively. Subdural taps were
per-formed and 15 ml of fluid were obtained on the
right side and 6 ml on the left. The fluid was
clear, the concentration of protein was 254
mg/100 ml and that of sodium 197 meq/l.
Concentrations of electrolytes in the serum are
summarized along with subsequent values in
Table II. Intravenous administration of fluids
of low content of electrolytes was carried out
during the next 3 days while the patient
re-mained stuporous. On the fourth day he began
to take a solution of glucose with added
po-tassium chloride (3 meq/kg/day) by mouth and
the next day he ingested a milk feeding with
low content of electrolytes (Lonolac#{174}) which
was administered for 4 days before a more
usual evaporated milk feeding was given. On
May 7 he weighed 5,560 gm, a gain of 750 gm
in 8 days. Table II also summarizes the output
of urine in terms of volume, concentration of
electrolytes and of total solutes. The urinary
concentration of sodium remained rather low
after collection of the initial specimen despite
the persistently high concentrations of sodium
in the serum.
The subsequent course has been that of a
severely brain-damaged child. There have been
recurrent convulsions which necessitate
con-tinuous anticonvulsant therapy. At 15 months
of age he cannot sit up, muscle tone is markedly
hypertonic and he makes no response to people.
An electroencephalogram performed on March
22, 1957, was reported as grossly abnormal
with continuous generalized seizure discharges
consisting of very fast spikes. There were no
normal patterns seen on an 18-electrode
trac-ing.
DISCUSSION
The foregoing case illustrates that
poison-ing with salt with concomitant anorexia
produces a state of hypernatremic
dehy-dration with manifestations in the central
nervous system similar to those which have
been described in hypernatremic
dehydra-tion occurring with diarrheal (or other)
dis-ease in infants. The development of
sub-dural hygroma in this infant as well as in
six others is of particular interest from
TABLE II
SUMMARY OF FINDINGS OF ELECTROLYTES IN SERUM AND URINE OF INFANT M.B. (CASE 1)
Day
Concentrations in Serum Volume and Concentrations of Urine
Urea
Na Cl !ICO K Nitrogen
(meq/l) (meq/l (meq/l) (meq/l) (mg/100 ml)
Volume Na Cl K
Osmo-(nil/day) (meq/l) (meq/l) (meq/l) laritti moe , I 2 3 4 5 6 8
193 157 3 4.8
-161 135 17 4.2 48
- - - -
-161 127 - - 32
- - - -
-154 115 20 5.6 26
142 105 - 5.3 16
40 188 155 74 720
120 96 84 20 446
285 70 54 6 249
- - - -
-771 28 19 34 230
- - - -
both the clinical and theoretic point of
view. In six instances the lesion was looked
for after a convulsion; the other patient
had hemiparesis. A subdural hygroma or
hematoma has not invariably occurred in
our experience with infants who have
hy-pernatremic dehydration. The precise
mci-dence of this complication is not known
since subdural taps have only been
per-formed in a small number of infants upon
clinical indication. The very high incidence
of abnormal concentrations of protein in
cerebrospinal fluid in hypernatremic infants
with clinical evidence of involvement of the
nervous system has been documented.4
Ap-proximately half of the known
hyperna-tremic infants have had sufficient
manifes-tations clinically to warrant doing a lumbar
puncture. During the period over which
tile first six cases of Table I were collected,
19 other infants with hypernatremic
dehy-dration had examinations of cerebrospinal
fluid which revealed abnormal
concentra-tioiis of protein, and 22 infants with
hyper-natremia were seen in whom tile
cerebro-spinal fluid was not examined. Previous
ex-1)eriellce has shown that dehydrated infants
vith normal concentrations of sodium in the
serum may have abnormal findings in tile
Cerel)roSpillal fluid hut to a much lesser
ex-telit than those w’ith iiypernatremia.’ To
date we have not observed subdural
effu-sions in dehydration without hypernatremia
but no systematic program of subdural taps
has been attempted, nor does it seem
jtlsti-fled.
In the group of cases reported here
neither needle aspiration nor surgical
ex-ploration has been shown to have any clear
therapeutic benefit. For the present it would
seem that each patient should he assessed
in(lividually with respect to the iroper
clinical management of the lesion of the
nervous system until such time as criteria
for paracentesis and/or surgery can be
established. In a previous report4 two
fatali-ties with subarachnoid hemorrhage were
cited as were four cases of permanent
neu-rologic residua in previously normal infants
who developed hypernatremic dehydration.
The fact that moderate to severe residual
damage is noted in six of the seven patients
in the present study and that in three of
these the infants were previously thought to
be normal, further indicates the importance
as vell as the severity of the damage
in-curred.
The origin of the symptoms related to the
central nervous system and of the findings
just described can be conveniently
dis-cussed under three headings, the cellular
changes or chemical anatomy of the
nerv-ous system, changes in concentrations of
ions in tile extracellular fluid which might
affect excitability of nerves and, finally,
factors which might predispose to vascular
lesions and hemorrhage, i.e., gross anatomic
changes. Changes in chemical anatomy at
the level of the cell and its immediate
en-vironment is a very complex subject, but a
few of the factors which are involved in
hypernatremia are pertinent here. An
in-crease ill the extracellular concentration of
an ion such as sodium, which has limited
net entry to water within the cell,
necessi-tates osmotic readjustment between the
cellular water and the interstitial fluid.
There are at least three mechanisms by
which this may he accomplished: water
may leave the cell; sodium ions may
in-crease in concentration within the cell; there
may be a change of cellular constituents to
increase osmolar concentration either by
dissociation of bound electrolytes or by
breakdown of complex poiyvalent ions.
There is reason to believe that all of these
mechanisms take place in the brain,
particu-larly the first and last mentioned.
Experi-mental studies bearing on this point will be
presented in the second portion of this
work.’#{176}Hyperosmolarity per se without
con-comitant shifts of water can be produced
by injection of a nontoxic substance which
freely permeates the cell (e.g., urea) and
does not seem to produce symptoms related
to the central nervous system.’#{176}
Changes in concentrations of specific ions
in the extracellular fluid may have a bearing
on excitability of nervous tissue. It is
the sodium and chloride ions from their
Os-motic roles which have been previously
discussed. Changes in extracellular
concen-trations of potassium are very variable in
these patients46 and seem unlikely to be
involved in the major symptomatology. An
interesting finding has been the frequent
hypocalcemia.” This disturbance may be
aggravated by poor renal excretion of
phos-phate but has been shown to be
independ-ent of
Experimen-tat studies have indicated that loading with
sodium in the presence of concomitant
cel-lular deficit of potassium leads to a
moder-ate hypocaicemia.hI This disturbance, while
it may contribute to the manifestations
re-lated to the central nervous system ill
hyper-natremic dehydration, is not always or even
usually present in patients when the
mani-festations are the most severe.
Finally, gross anatomic changes in the
re-gion of the brain may occur, as has been
shown by the case material discussed.
Gi-rard” produced intracranial hemorrhages
in experimental animals by the injection of
hypertonic
solutions of sodium chloride andthese observations have been repeated and
extended in our laboratory.’#{176} The
mecha-nism is incompletely understood. ‘
believes that reduction in intracerebral
pres-sure is the key step in the pathogenesis of
the hemorrhages. Whatever the mechanism,
it is apparent that symptoms and signs often
occur before such gross changes are present
and, indeed, without having them occur at
all. The patients discussed in this report,
however, all did have evidence of anatomic
lesions and it is perhaps noteworthy that
the residual damage was unusually severe.
In view of the variety of mechanisms known
to produce symptoms referable to the
cen-tral nervous system in hypernatremic
de-hydration, it is not surprising that the time
of occurrence varies from early in the illness
to the point of near recovery from
dehydra-tion.
Manifestations in tile central nervous
sys-tem may accompany dehydration because
of circulatory disturbances regardless of the
concentration of sodium. While it has often
been stated that subdural hematoma may
complicate dehydration without
specifica-tion of the type of disturbance of
electro-lytes, it has been our experience that such
dehydrated infants have been
hyperna-tremic. While this may not be invariably
true, the knowledge of preponderant
occur-rence is clinically valuable. Likewise, one
does not expect every patient with
hyper-natremic dehydration to have demonstrable
effusions nor is there close correlation with
the degree of hypernatremia;4 the rate of
development of the disturbance is probably
important and contents of electrolyte and
water, as distinguished from concentrations,
may be determining factors which are not
easily
assessed from usual clinical data. Theimportant thing to the clinician at present
is the existence of correlation between
hypernatremia and lesions of the central
nervous system and as much understanding
of pathogenesis as present data afford.
SUMMARY
Seven infants with hypernatremic
de-hydration developed subdural effusions or
bleeding. One of these was a previously
normal infant accidentally poisoned by
ex-cessive ingestion of salt. This infant and five
of the others had significant neurologic
damage, ranging from moderate to severe.
It appears that the hypernatremic
dehydra-tion was responsible for the subdural lesions
in these patients and responsible for
per-manent damage in at least three of them.
Changes in chemical anatomy and lesions
of the cerebral vessels are discussed with
regard to producing lesions of the central
nervous system in hypernatremic
dehydra-tion.
At present no salutary therapeutic
ap-proach to the complication of subdural
effu-sions occurring during hypernatremic
dehy-dration has been found.
REFERENCES
1. Aliott, E. N.: Sodium and chloride
reteii-tion without renal disease. Lancet, 1:
1035, 1939.
2. Welt, L. G., Seldin, D. W., Nelson, W. P.,
ARTICLES
Role of the central nervous system in
metabolism of electrolytes and water.
Arch.
mt.
Med., 90:355, 1952.3. Rapoport, S.: Hvperosmolaritv and
hv-perelectrolytemia in pathologic
condi-tions of childhood. Am.
J.
Dis. Child.,74:682, 1947.
4. Finberg, L., and Harrison, H. E.:
Hyper-natremia in infants. PEDIATRICS, 16:1,
1955.
5. Weil, W. B., and Wallace, W. M.:
Hy-pertonic dehydration in infancy.
PEDI-ATRICS, 17:171, 1956.
6. Skinner, A. L., and Moll, F. C.:
Hyper-natremia accompanying infant diarrhea.
Am.
J.
Dis. Child., 92:562, 1956.7. MacCart>’, C. S., and Cooper, I. S.:
Neuro-logic and metabolic effect of bilateral
ligation of the anterior cerebral arteries
ill man. Proc. Staff Meet., Mayo Clin.,
26:185, 1951.
8. Higgins, G., Lewin, W., O’Brien,
J.
R. B.,and Taylor, W. H.: Metabolic disorders
in head injury. Lancet, 1:61, 1954.
9. Engle, F. L., and Jaeger, C.: Dehydration
with hypernatremia, hyperchioremia and
azotemia complicating nasogastric tube
feeding. Am.
J.
Med., 17:196, 1954.10. Finberg, L., Luttrell, C., and Redd, H.:
Pathogenesis of lesions in the nervous
system in hpernatremic states. II.
Ex-perimental studies of gross anatomic
changes and alterations of chemical
com-position of the tissues. PEDIATRICS, 23:
46, 1958.
11. Finberg, L.: Experimental studies of the
mechanisms producing hvpocalcemia in
hypernatremic states.
J.
Ciin. Invest., 36:434, 1957.
12. Girard, F.: Les hCmatomes sous-duraux.
ltude exp#{233}rimentale. Acta paediat., 45:
618, 1956.
TEACHING MACHINES, B. F. Skinner. (Science, 128:969, October 24, 1958.)
Many thouglltful nlembers of the teaching staff of a department of pediatrics must
have wondered whetller SOIll mechanical invention could be of assistance in drilling
students on esseiltial facts, thus leaving the instructor free to play a more effective
role in tile cultivation of thinking, which should be the prime objective of education.
As what appear to be basic facts become more numerous, the dilemma facing the
teacher secns to iecone more difficult to resolve. How can one get the student to
acquire esseiltial facts without interfering with the more important aspect of
educa-tion-learning to use tile niinci critically in the evaluation of material and to develop
a capacity for integrative and creative thinking?
This article Oil Teaching Machines by a professor of psychology in Harvard
Uni-versity will acquaint the interested reader with developments in machines designed
to enable the student to undertake some self instruction. The machines are based on
current cOllceptS of the learning process; although mechanical, they require more thin
passive co-operation from the student. A full discussion of the results thus far achieved,
and the limitations which ilave been encountered, are presented in what appears to
be a fair and objective fashion.
The machine discussed is supposed to serve as a means of re-enforcement in tile
learning process. The machine is not intended to replace teachers hut to liberate
them for greater realization of their indispensable roles in the educational process. The
programming of material for the niachines and their use seem to allow particularly
for the differences in rates of learning of individual students.
It would be an interesting experinlent if some department of pediatrics would give
