STUDIES
IN SICKLE
CELL
ANEMIA
XXI.
CIinicoPathoIogicaI
Aspects
of
Neurological
Manifestations
Robert L. Baird, M.D., Daniel 1. Weiss, M.D., Angella D. Ferguson, M.D.,
Joseph H. French, M.D., and Roland B. Scott, M.D.
Department of Pediatrics, Howard University College of Medicine and the Pediatric Sereice of Freedmen’s Hospital and the Pediatric Service and tile Department of Pathology of the
District of Columbia General Hospital
(Submitted November 23, 1962; revision accepted for publication January 27, 1964.)
D.L.W. : Presently professor in the Department of Pathology at the University of Kentucky School of
Medicine.
J.H.F. : Presently assistant professor (Neurology) Department of Pediatrics at the University of Colorado School of Medicine.
ADDRESS: (R.B.S.) Department of Pediatrics, Howard University of Medicine, Washington 1, D.C.
92
PEDIATRICS, July 1964
S
INCE the first description of sickle cellanemia (SCA) as a clinical entity in
1910,1 comprehensive reviews2 of its
clini-cal manifestations and reports of extensive
research into the genetic,717
biochemi-cal,#{176}20 and pathological2t24 nature of
clini-cal syndromes caused by sickled
erythno-cytes have appeared in the medical
litera-tune. Notwithstanding these advances, SCA, on occasion, presents as a diagnostic
prob-lem because it can mimic on simulate so many other clinical conditions.
This report proposes to focus attention
OIl selected cases in which the presenting
signs and symptoms were predominantly associated with the central nervous system.
Because of these unusual clinical
manifesta-tions the true diagnosis was often delayed.
The cases presented here include known
“sicklers” or variants thereof as vell as
pa-tients previously undiagnosed as having
sickle cell disease.#{176} In these patients, the
sudden unexpected appearance of bizarre
neurological symptomatology necessitated
extensive investigation and clinical ap-l)raisal of the nervous system.
CASE MATERIAL
Case histories of eight children with erythrocytic sickling who, at the time of
hos-0 Sickle cell disease will be used broadly to include all of the disorders in which clinical maui-festations are attributed to the presence of S hemoglobin in hoiriozygous or heterozygous forns.
pitalization or study, demonstrated abnor-mal neurological symptoms and signs were reviewed. Seven had homozygous SS
dis-ease (SCA) and one had sickle cell trait. The
ages at the onset of symptoms ranged from 42,42 years to 9 years. There were 6
fe-males and 2 males. The diagnosis of SCA or its variant forms was made from a positive
sickling test, analysis of hemoglobin by the
use of paper electrophoresis, and supporting
hematologic data.
In most instances, further work-up during the acute episode included selected blood
chemistry, bone marrow examination, lum-bar puncture, roentgenognams of the chest and skull, electroencephalograms, and neu-rological examination. In some cases
follow-lip electroencephalograms and neurological
examinations were perfornied after
dis-charge from the hospital. A few patients
had further evaluation consisting of hearing
tests, psychometric and school evaluations.
Fiiially, a retrospective study of the
ana-tornical changes I)nesent ill the brains of
individuals who had died in sickle cell crises or with sickle cell disease as the
pni-many condition was undertaken. Five
rep-resentative cases were chosen (in addition
to the 8 described above) at various age
levels in order to assess the effect of age on
the progression of the pathological findings
in the nervous system. The patiellts, whose
ages naiiged from 15 nionths to 32 years,
abnor-TABLE I
Ca8L Age
3
4
5
15 run
10
() yr
() yr 32 yr
“seurological Finding
(‘onvulsious, lethargy
Grand ma! type seizures ; transient unresponsiveness
Transient episodes of disorientation, transient weakness of ex-tremities
Increased deep tendon reflexes, restlessness, coma Recurrent headache, recurrent motor weakness
hemoglobin Types
S-F S-S S-S
5-Thalassemia S -Ihalassenna
malities similar to those to be described in
the presentatioii (Table I).
RESU LTS
Clinical Material
The 8 children selected for presentation
were observed Oil the pediatric service of
two metropolitan hospitals. No statistical
analysis as to general incidence was
at-tempted because only those cases in which
unexpected, abnormal neurological
symp-toms and signs had confused the clinical picture of sickle cell disease were reviewed.
The following types of crises in SS patients
were noted: 4 thrombotic, 2 aplastic, and 1 lieniolytic. The patient with sickle cell
trait exhibited findings consistent with a
thrombotic crisis. Two patients, both with
SS disease, died subsequently as a result of
repeated SCA crises with neurological find-ings of central nervous system involvement.
The precipitating factors and the symp-toms preceding the onset of neurological signs in these patients consisted of delirium, headache, anorexia, infection, fever,
ab-dominal and joint pain, and anesthesia.
There was n detectable precipitating
fac-ton in some cases.
Neurological examination, in general,
suggested diffuse and focal involvement of
the cerebral hemispheres. The striking
find-ings were : hemiparesis and hemiplegia,
paresthesia of the extremities, ataxia, con-vulsions, aphasia of motor and sensory type, hemianopsia, weakness of tile mouth, tongue and facial muscles, and loss of
muscle tone.
Generally, examination of the cerebro-spinal fluid revealed xanthochromia with
increase in pressure, protein, and cells. The
appearance of the spinal fluid varied from one patient to another, from normal to
grossly bloody. Roentgenograms of the skull, in most instances, revealed the usual bone changes associated with a chronic hemolytic anemia, but in some cases they were normal.
Electroencephalograms were done on 6 of the 8 patients. In 5 patients an abnormal tracing was obtained and revealed tile fol-lowing: poor organization, marked
irregu-larity, high microvoltage with ventilation, multiple slow wave foci and biphasic sharp
waves with occasional bursts and spikes. Abnormal tracings in these 5 patients were
associated with abnormal neurological
find-ings on admission, permanent neurological sequelae in 4 patients, and transient
find-ings in one case. One patient, who exhibited
signs of neurological impairment on
admis-sion, had a tracing which was interpreted
as normal for tile age period. This patient
had transient right-sided hemiplegia. One
case with an abnormal tracing at tile time of the acute episode had a follow-up elec-troencephalognam done 4 months after
dis-charge. Although the second record showed
improvement over the previous tracing, this
patient exhibited permanent neurological sequelae.
In general, treatment consisted of
symp-tomatic measures such as intravenous fluids and/or blood transfusions and antibiotics
when indicated. Patients who showed evi-dence of permanent neurological sequelae received occupational and physiotherapy. Special schooling had to be arranged for
2 patients. Intelligence quotients deter-mined on school-aged patients ranged from
Review of these 8 case histories showed the following points of interest: two cases illustrated that insult to the central nervous system by sickling may or may not be repeti-tive and may result in the appearance of
permanent neurological deficits. In one case, anesthesia administered to a “sickler”
pre-cipitated the appearance of unexpected, bizarre neurological findings. Two cases in-eluded in this study were unusual in that almost identical neurological manifestations (hemiplegia) occurred within a period of 24
hours in identical twins with SCA.
PATHOLOGICAL MATERIAL
Pathological examination of the brains of 5 individuals who had died in sickle cell
crisis or with sickle cell disease as the
pni-mary condition revealed anatomical changes
which were divisible into two categories,
vascular and parenchymal.
1. Vascular Changes
In all cases, death in crisis was accom-panied by a severe generalized congestion of all fine vessels in all parts of the brain. The most prominent vascular divisions
in-volved were the capillaries, precapillary artenoles and small venules. The larger
arteries had masses of sickled erythrocytes, but were not dilated or occluded as were the smaller vessels. Study of the smaller vessels revealed the following changes:
ARTERIOLES, PARTICULARLY
PRECAPIL-LARY: The diameter of these vessels varied
from 1% to 4 times their normal diameter,
but the dilatations were segmental in
dis-tnibution. This was especially evident in the
segment of the precapillary arteriole
im-mediately preceding bifurcation into
capil-lary branches (Fig. 1 A, B). The dilated seg-ments were impacted with sickled
erythro-cytes which were clumped together, oblit-crating the lumina of the vessels in the fixed state (Fig. 2). No thromboses, in the
classic sense, were seen. No fibrin could be identified in the erythrocyte masses. The
clumps of impacted cells were interpreted
as sickled cells adherent to one another and
to the arteriolar wall.
CAPILLARIES: The capillary diameters
distal to the segmentally dilated precapil-lary arterioles were generally of normal caliber. The masses of impacted cells seen in the dilated segments extended as fine
streamers into the capillary lumina. The further from the dilated segment, the less evidence of luminal occlusion was
avail-able. Beyond the area of occlusion sickled cells appeared consistently in small groups
or singly, but total luminal obstruction was not a prominent feature.
Random longitudinal sections of capil-lanes and precapillary arterioles showed a typical and consistent pattern. Localized
dilations containing impacted cells tapered
abruptly into the trailing capillary struc-ture. The resemblance to a tadpole form was striking.
At no point was necrosis of any small vessel wall recognizable. At several points
of vasodilatation, diapedesis of erythrocytes was evident in the immediate penivascular zone.
VENULES : The postcapillary small
venu-lan structures were very difficult to identify. When they could be clearly seen, the
di-ameter of these vessels was normal, but the lumina were filled with masses of sickled erythrocytes.
PERIVASCULAR SPACES : In all cases, iron
pigment in both the free state and within
macrophages was found around vessels. This was most prominent around arterioles, although some was seen around larger
yes-sels, even to the small pial arterial size. This was interpreted to be evidence of
prior episodes of perivascular bleeding and of in situ destruction of erythrocytes during
or
following the sickle cell crisis.Very frequently, penivascular accumula-tions of lipid-filled macrophages were found (Fig. 3). The finely divided lipid
gave positive reactions with Oil Red 0 but did not stain for myelin. The lipid material
may have arisen from a variety of sources.
Wertham, Mitchell, and Angrist24 suggested that this lipid represents the lipid compo-nent of destroyed erythrocytic stroma. An
alternative explanation is that it came from the destruction of myelin and mobilization
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Fic. 1. A, B. Focal arteriolar dilatation, precapillary segment. H. & E. x32
phages. The foci of lipid accumulation were seen with and without anatomical evidence of parenchymal destruction. Nevertheless, the material was interpreted as the result
of minute areas of old myelin destruction. The absence of any absolute correlation of areas of iron deposition and lipid accumu-lation tends to reinforce the latter interpre-tation.
2. Parenchymal Changes
Anatomical changes in the parenchyma of
the central nervous system were scattered throughout the brain with no particular
areas of predilection. In only one case were
these areas grossly manifest in the form of small infarcts along the medial surface of
the left occipital lobe. These were less than 0.5 cm in maximum diameter. All other Ic-sions were found only by microscopic sun-vey.
WHrni MATTER: Numerous microinfarcts
of white matter were seen. The anatomical picture was one of spongioform transfor-mation of minute foci in the deep white matter associated with a minimal to
FIG. 2. Sickled ervthrocvtes impacted in arteriolar lumen.
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Fic. 3. Perivascular lipid-filled macrophages are seen.
areas of mineralization which reacted
posi-tively for both calcium and iron. Axonal
discontinuity as well as loss of myelin
stain-ing were consistent features of the
spongio-form lesion. Such microinfarcts were found
in the cortical grey matter in only one case.
NEURONAL CHANGES: In only one of tile
five cases was loss of neurones seen in the
Purkinje cell layer of the cerebellum. In that instance, focal disappearance of
Pun-kinje cells occurred in an irregular pattern
of distribution.
In two cases, isolated groups of neurones in the olive and the thalamus showed pe-nipheral margination of Nissl substance and central chromatolysis (Fig. 5). In these cells, the pallor of the nuclei and prominence of the nucleoli gave an owl’s eye pattern to the cell structure. No neunonal destruction or glial reaction was present in these areas.
These latter minimal neuronal changes
sug-gest an acute and minimal hypoxic reaction.
Since this degree of damage is probably
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II. & E. x.32
loss of netirones suggest that in sickle cell
crisis the neuronal damage is transient and that reconstitution of neuronal integrity follows clearing of the vascular obstruction.
The changes in the deep white matter,
on the other hand, suggest that damage is
severe in areas in which collateral blood
supply is minimal. The microinfarcts may
be the expression of repeated or
cumula-tive injury to the white matter included by
hypoxic crises. This is further reflected in
the focal penivascular accumulations of lipid-filled macrophages.
SUMMARY OF PATHOLOGICAL FINDINGS:
The vascular findings, in the absence of any
intrinsic changes of the vessel walls, appear to be based upon occlusive impaction of
erythrocytes, hypoxia, and conseqtieiit focal
vasodilatation. The impedance to the circu-lation caused by these phenomena probably
opens diversionary channels for blood flow,
explaining the absence of evidence of
occlu-
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I!sion proximal to the fine arterioles. Such a diversion of blood flow can be expected to
further compound the hypoxic injury to the brain substance instituted by the occlusive impaction of sickled erythrocytes and to
further increase the sickling phenomenon.
The events which permit the reopening of
vascular channels and relief of the hypoxic brain are not clear and have not been dem-onstrated.
A. Clinical
COMMENT
Sydenstnicker, NI ulhenin, and Houseal,25 the first American authors to record nervous
system manifestations in a patient with
SCA, reported a case of a 5-year-old Negro male with generalized rigidity, recurring painful tonic convulsions, left spastic hemi-plegia, and marked mental dullness. The initial impression was meningitis. The deep reflexes were hyperactive, especially on the left. The cerebrospinal fluid was normal. Findings suggesting a thnombotic crisis (i.e., pains and swelling in the joints of the
cx-tremities) were also noted. Death occurred during a convulsion on the 8th day. Patho-logical examination of the brain was not
done.
Subsequently, numerous reports and more
comprehensive reviews2636 of the cerebral manifestations and pathological findings as-sociated with sickle cell disease appeared in the medical literature.
Our data and the observations mentioned above indicate that neurologic manifesta-tions are frequent in patients who have sickle cell disease; that the lesions are
multiple; that the location of the lesions is variable; and that the onset of symptoms is often sudden and extensive enough to cause grave manifestations such as convulsions, meningeal signs, headache, aphasia, paraly-sis, and coma. This vulnerability of the central nervous system is not surprising. Sickle cell disease is systemic in nature and
tile tissues of the central nervous system are
tile most sensitive to even temporary anoxia.
Other nervous system symptoms observed were variable disturbances of reflexes, facial weakness, nystagmus, transitory blindness,
homonymous hemianopsia, anesthesia and
analgesia of various parts of the body,
drooling, urinary incontinence, and
disturb-ances of speech. With findings such as these, the following diagnoses had to be considered in these patients : meningitis, epilepsy, subdural hematoma, subarachnoid
hemmorrhage, neoplasms, hypertoxic
dehy-dration, and congenital malformations of the brain.
B. Clinical-Pathological Correlation
Previous investigators have never
in-dicated whether these neurological
compli-cations were predictable on the type of
crisis involved. Two of our patients (identi-cal twins who presented with similar neuro-logical manifestations within a short period of each other) had laboratory studies which
revealed that an aplastic type of crisis was involved. Clinical and laboratory studies on the remaining patients suggested that these patients, in most instances, were
expenienc-ing “thrombotic” (pain) crises at the time of
admission. A hemolytic crisis was seen in one case. The pathological material pre-sented here (although on different cases,
similar abnormal neurological findings were found clinically) failed to reveal “throm-boses.” The striking findings were
infarc-tion and small hemorrhages and these ap-parently are responsible for the varied neurological findillgs these patients cx-hibited.
Neurological examination in our 8 cases at the time of admission and following discharge suggested diffuse and focal in-volvement of the cerebral hemispheres.
More accurate location of the occluded vessel by cerebral angiography was not
possible because permission to perform
this procedure was not given. This pro-cedure was used by Ende et al.#{176}in one of
their cases but it revealed only what was thought to be a mid-temporal panietal space
occupying lesion. Again, employing
The pathological findings and the clinical
manifestations demonstrate that damage to the central nervous system leads to
tran-sient or permanent neurological sequelae
and may thus be considered either revens-ible or irreversible. The transient findings disappeared in hours or gradually cleared up in a matter of days and were associated in each instance, except one, with normal cerebrospinal findings and normal
electro-encephalographic tracings. There were no
recurrences and no evidence of residual
damage to the central nervous system fol-lowing the insult.
The irreversible group includes those pa-tients who died or in whom severe neuro-logical deficits were associated with
per-manent sequelae. These patients seemed, on subsequent occasions, to experience recur-rent crises in which abnormal neurological
findings of a more severe nature dominated the clinical picture. Death in 2 such cases
came during the crisis and was sudden and
without apparent cause. On the other hand, in the patients who survived, the later
at-tacks did not seem to be more severe, but rather the neurological findings became more variable and unpredictable and re-sidual damage became slightly more cvi-dent after each episode. The sequelae noted in these patients were hemiparesis,
spas-ticity of extremities, abnormal reflexes, poor bladder control, and atrophy of the muscles of the extremities.
Finally, all the patients with permanent
neurological findings had abnormal
electro-encephalographic readings. On the other hand, the records for the patients in the
reversible group varied from normal to ab-normal. No correlation was possible be-tween electroencephalographic changes and cerebrospinal fluid findings.
Referral to physiotherapy and occupa-tional therapy was necessary because of the sequelae mentioned above. Psychomet-nc evaluation revealed that two of these patients were trainable, but not educable,
and that one was a slow learner. Intelli-gence quotients obtained in 3 cases were
40-50, 99, and 50-55 respectively. These poor results do not necessarily indicate
that SCA complicated by neurological
mani-festations is a cause of mental retardation. Additional factors to be considered are
pro-longed and recurrent periods of
absentee-ism from school together with the tension and psychological problems which surround patients with a chronic debilitating disease.
SUMMARY
Neurologic manifestations are frequent
in patients who have sickle cell disease.
These manifestations may be the earliest presenting signs and symptoms and they are
so variable that the patient may be
errone-ously diagnosed as having conditions such as meningitis, poliomyelitis, subdunal hema-toma, neoplasm, subarachnoid hemorrhage, lead encephalitis, subacute bacterial endo-carditis, and congenital malformations of the brain. Furthermore, development of these manifestations cannot be predicted on the basis of the type of crisis involved.
Prognosis following neurological
involve-ment is unpredictable, but recurrent epi-sodes, together with abnormal electroen-cephalographic readings suggest a poor out-come. Such patients die or are the victims of rather severe neurological deficits.
Neurological examination of these
pa-tients suggests diffuse involvement of the
cerebral hemispheres. Examination of the pathological material, however, often fails to reveal thromboses. The striking findings are infarcts in the white matter and pen-vascular hemorrhages.
The thesis that the abnormal neurological findings in these patients are actually due
to sickle cell disease is supported by the fact tilat all such symptoms appear in as-sociation with clinical circumstances known to induce sickling. These include surgery and anesthesia, fever and infection.
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Acknowledgment
Dr. Charles E. Edwards of the Department of
Neurology, District of Columbia General
