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CLINICOPATHOLOGIC CONFERENCE *
L. W. DIGGS, M.D., AND RUSSELL S. JONES, M.D.
Department of Medical Laboratories and Institute of Pathology, University of Tennessee,
42 North Dunlap Street, Memphis 7, Tennessee
HISTORY
R. N., a 48-year-old Negro woman, picked cotton on the day before admission
and felt well. After supper she drank approximately 4 ounces of whiskey, became
mildly inebriated and went to bed. Five hours later she was awakened abruptly
with stabbing pains in the lower back and perianal region. The pains radiated
to the hips and thighs and gradually extended to include the abdomen, thorax,
shoulders and arms. Deep respirations and movements of the body caused an
exaggeration of the pain. There was recurrent vomiting, with regurgitation of
food previously eaten. The patient became drowsy and her general condition
progressively worsened. She was brought to the John Gaston Hospital 7 hours
after the onset of symptoms.
On 2 occasions, approximately 4 years previously and again 4 months before
admission to the hospital, the patient had experienced similar episodes that
came on during sleep and were characterized by severe pains in the back and
abdomen, with associated cramping of muscles, fever, nausea and vomiting.
Following the attacks there was residual muscle soreness lasting for several days.
On both occasions she returned to work and suffered no apparent disability or
personality change.
The review of systems and past history revealed no relevant information.
Except for a transient attack of "rheumatism" in the left knee and elbow a few
years previously, there had been no joint or bone symptoms. For the past months
the patient had worked steadily as a farm laborer.
The patient was a moderately obese woman with good muscular development.
The sensorium was dull, but she was able to answer questions and to follow
simple instructions. She lay in bed with her knees flexed, the muscles tense, and
in obvious pain. At intervals there were severe cramplike seizures. The abdominal muscles were rigid, and the muscles of the back firm and tender on
pressure. The temperature was 100 F., the pulse rate 100, the respiratory
rate 24 per minute, and the blood pressure 140/85. The heart and lungs revealed
no significant abnormality. The liver and spleen could not be palpated. The
tendon reflexes were hyperactive; the position and vibratory senses were normal.
The initial laboratory examinations revealed a white-cell count of 18,900 and
a red-cell count of 3,120,000 per cu. mm., and a hemoglobin of 11 Gm. per 100 ml.
The erythrocytes in the stained blood smear varied in size and shape, the platelets were normal and the differential count was reported as neutrophilic bands
2 per cent, neutrophilic segmented forms 83 per cent and lymphocytes 15 per
cent. A drop of blood, sealed under a coverslip and allowed to stand, revealed
* Received for publication, June 30, 1952.
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characteristic sickle-cell transformation. The specific gravity of the urine was
1.020; the albumin, sugar, acetone and microscopic tests were negative. The
cerebrospinal fluid was clear and colorless. The initial manometric pressure was
220 mm. of water and the final pressure, 110 mm.; the hydrodynamics were
normal. There were 2 lymphocytes per cu. mm. but no red blood cells. The protein was 29 mg. per 100 ml., the glucose 90 mg. and the sodium chloride concentration 740 mg. A Kahn test for syphilis and a spinal fluid culture were negative.
On the day after admission to the hospital the patient became mentally confused and semistuporous, and gradually lapsed into a deep coma that persisted
until death on the fifth hospital day. The temperature remained within the range
of 102-105 F. On the third day of illness it was noted that the neck was stiff and
that there were multiple petechiae of the skin, mucosal surfaces and retinae.
Lumbar puncture at this time revealed an initial cerebrospinal fluid pressure
of 110 mm. of water and yielded a clear, colorless fluid with a normal white-cell
count and occasional red cells. The protein concentration was 20 mg., the glucose 102 mg. and the sodium chloride 700 mg. per 100 ml. A culture of the cerebrospinal fluid was negative. The white-cell count on the blood on the third hospital day was 22,500 per cu. mm., the sedimentation rate 59 mm. in 1 hour
(Wintrobe) and the total serum bilirubin 2.6 mg. per 100 ml. Three blood cultures and agglutination tests for typhoid fever, brucellosis, tularemia and rickettsial disease (Proteus OX19) were negative. Roentgenograms of the chest
revealed a heart of normal size and shape and clear lung fields. The films of the
vertebrae revealed no evidence of bone disease. An electrocardiogram revealed
sinus tachycardia with a rate of 128 per minute, PR interval 0.12 and QRS interval 0.07 second and nonspecific abnormalities of ST segments and T waves
suggesting myocardial disease.
Blood smears made on the fourth hospital day revealed anisocytosis, numerous
target and oval cells, occasional double-pointed elongated cells, numerous diffusely basophilic cells and cells with nuclear fragments. There were 63 nucleated
red cells per 100 white cells and 2-4 thrombocytes per oil-immersion field. The
differential count was reported as neutrophilic myelocytes 1 per cent, neutrophilic metamyelocytes 1 per cent, neutrophilic band forms 6 per cent, neutrophilic segmented forms 73 per cent, lymphocytes 17 per cent and monocytes
2 per cent. The sickle-cell trait was confirmed by the sodium bisulfite method.
Penicillin therapy was started on the third hospital day, with no apparent
effect on the fever or the patient's general condition.
CLINICAL DISCUSSION
Dr. L. W. Diggs: The admitting diagnosis was "renal calculus." Other recorded
diagnoses by various staff members included acute gastritis, herniation of nucleus pulposus, spontaneous fracture of a lumbar vertebra, tabes dorsalis, conversion hysteria, aneurysm of the abdominal aorta, dissecting aneurysm, blackwidow spider bite and encephalitis. These conditions can be excluded by the
laboratory findings and the subsequent clinical course.
The petechiae and cerebral meningeal signs suggested thrombocytopenic pur-
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pura and thrombotic thrombopenia, but the platelets were not decreased and
there was no spontaneous bleeding from mucous surfaces.
Bacterial endocarditis with cerebral embolism was also considered but the
absence of heart murmurs and pericardial signs and the negative blood and cerebrospinal fluid cultures exclude this possibility. The sudden onset of symptoms
and the failure to respond to antibiotics are also against the diagnosis of endocarditis or septicemia.
The blood picture was typical for sickle-cell anemia, for sickled cells and target
cells were present in the stained blood smear, the leukocyte count was increased,
there were numerous nucleated red cells and low-grade jaundice. The sudden
onset, the severe pains all over the body, the nausea and vomiting and the fever
and cerebral manifestations favor the diagnosis of sickle-cell anemia.
On the other hand, there were many features that were not characteristic of
sickle-cell anemia. The patient was 48 years of age and had been in good health
most of her life, whereas patients with sickle-cell anemia are in chronic ill health
and few live beyond the third decade. The patient was fat and well developed,
whereas most patients with chronic sickle-cell anemia are asthenic. The patient
was. able to work regularly in the fields, whereas patients with sickle-cell anemia
cannot "carry their row of cotton." There were no leg ulcers or scars of previous
ulcers. The heart in patients with sickle-cell anemia is usually enlarged, but in
this patient the heart was of normal size. Roentgenograms did not show the
flattening, osteoporosis and cupping of the vertebral bodies that are common in
patients with sickle-cell anemia of long standing. There was no past history of
migratory joint and bone.pains, recurrent febrile illnesses, jaundice or symptoms
of anemia. Also, petechiae are rare in sickle-cell anemia.
It is obvious that we are dealing with a patient with sickle-cell trait, who does
not have the past history of sickle-cell anemia, but who has in association with
an acute illness a mild anemia of the hemolytic type with sickle cells in the
circulating blood.
In the literature of sickle-cell disease one finds occasional reports of a syndrome
that closely resembles the one presented by this patient. 1-4 This syndrome occurs in adults with the sickle-cell trait who have no anemia or mild anemia and
no history suggestive of chronic sickle-cell anemia. Usually these patients have
an abrupt onset, backache and severe pains all over the body, fever, nausea and
vomiting, petechiae, leukocytosis with a leukemoid blood picture, low-grade
jaundice, splenomegaly, lethargy, varied central nervous system signs and symptoms and often death within a few days. In my opinion we are dealing with a
patient with the sickle-cell trait, who, as the result of hypoxia associated with
slumber and the alcoholic state, developed massive sickling of erythrocytes all
over the body with degenerative and hemorrhagic lesions secondary to vascular
occlusion.
DISCUSSION O F PATHOLOGIC
FINDINGS
Dr. Russell S. Jones: The pathologic diagnoses were sickle-cell disease with
agglomeration of sickle cells in dilated vessels; focal hemorrhages and necroses
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of brain; petechial hemorrhages in conjunctivae, gastrointestinal mucosa, epicardium, pleurae, lungs, bone marrow and skin; small focal hepatic necroses and
acute congestive splenomegaly.
The clinical and pathologic findings in this case are ascribable in their entirety
to the sickling of erythrocytes, with associated increased viscosity of blood, the
agglomeration of the sickled cells in many vessels throughout the body and the
occurrence of petechial hemorrhages and small necroses.
F I G . 1 (left). Section through brain showing focal hemorrhagic and necrotic lesions
in ii patient with the sickle-cell trait.
F i e . 2 (right). Section of the brain showing hemorrhagic lesions in the subcortical
white m a t t e r .
The liver and brain suffered the greatest injury. Numerous small hemorrhages were seen on gross examination' throughout the brain (Fig. 1). Nearly
all of the hemorrhages lay within the white matter (Fig. 2), although a few
could be seen in the basal ganglia and within the cerebellar cortex. Such gross
changes are similar to those observed in some forms of encephalitis, carbon
monoxide poisoning, malaria, thrombocytopenic acroangiothrombosis and embolism from fat or bacterial endocarditis. No large arteries 01 venous sinuses
were thrombosed. Sickled erythrocytes distended the capillaries and small vessels
in all areas, and frequently filled the perivascular Virchow-Robin spaces. In
many areas the hemorrhage extended into the brain substance. In some areas a
ring of hemorrhage surrounded a central area of vacuolated brain tissue and a
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few gitter cells were observed. No macrophagic phagocytosis or hemosiderin was
encountered.
The liver weighed 1740 Gm. and the spleen 400 Gm. The dark mahogany
color of the liver and spleen and the petechial hemorrhages in the brain so impressed one pathologist with the possibility of malaria that immediate impression
smears of these organs were made. The stained smears failed to demonstrate
malarial parasites. Sections of the liver revealed marked sinusoidal congestion
with sickle cells. Small focal areas of necroses not confined to any particular
part of the liver lobule were found. In the areas of necrosis the hepatic cord
cells were replaced by macrophages whose abundant cytoplasm often contained
small particles of golden-brown pigment. In the distended sinusoids away from
the small zones of necrosis, very few Kupffer cells could be found.
There was no evidence of fibrosis, either grossly or microscopically, in the
enlarged spleen. A small band of lymphocytes about the arterioles constituted
the malpighian bodies. The sickled erythrocytes about the remnant of the malpighian bodies were better preserved than those in the pulp. No evidence of
hemosiderin or of increase in reticuloendothelial cells was noted.
Sections of bone marrow from ribs, sternum, vertebra, tibia and ilium showed
the usual proportion of fat to hematopoietic tissue and of granulocytic to erythrocytic cells. No hemosiderin phagocytosis was seen, but scattered recent
hemorrhages of moderate size were encountered. Erythrocytes within the hemorrhages and within adjacent distended vessels were sickled.
Fat embolism has been described in patients with sickle-cell disease. 3-6 The
findings in these patients were similar in many respects to those in our patient,
but fat stains revealed only a minimal amount of lipoid material in the pulmonary and brain capillaries. There is nothing to suggest that fat embolism is a
significant factor in the production of lesions in this patient.
The other viscera showed no important changes except for distention of vessels
with sickled cells and the petechial hemorrhages.
The etiologic agent responsible for the decreased oxygen tension, crystallization of hemoglobin, agglomeration of sickled erythrocytes, petechial hemorrhages and cerebral lesions is not obvious. Factors producing no significant
morphologic changes such as alcohol, insect bite and mild infection might serve
as "trigger" mechanisms.
GENERAL DISCUSSION
Question: How do the tissue changes in this patient differ from those found
in sickle-cell anemia?
Dr. Jones: The spleen was not small or scarred, but enlarged and free of
siderofibrosis. The bone marrow contained much fat. The hyperplasia of cellular
elements usually observed in sickle-cell anemia was lacking. There was no scarring of the kidneys or liver, and there were no leg ulcers. The brain lesions in
sickle-cell anemia usually involve the gray matter and there are thromboses of
the meningeal vessels, including arteries and larger dural veins. In this patient
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the lesions were principally in the subcortical white matter and were characterized by necroses and hemorrhages, without demonstrable thrombi.
Reputably patients with sickle-cell anemia differ from those with the trait in
having a greater proportion of abnormal hemoglobin that crystallizes under
conditions of decreased oxygen tension; but all of the erythrocytes in any patient with the sickle-cell trait, with or without anemia, are capable of sickling
if the proper chemical conditions leading to the reduction of hemoglobin are
present.
Question: Since the brain lesions described closely simulate those seen in
carbon monoxide poisoning, how do you exclude this condition?
Dr. Diggs: The patient was conscious when admitted to the hospital and became comatose while in the hospital under supervision. There is no histoiy of
•exposure to fumes.
Carbon monoxide poisoning, fat embolism and massive sickling of erythrocytes all produce tissue anoxia, and the anatomic lesions produced by these
different etiologic agents are similar. The medicolegal importance of the sicklecell trait and the necessity of considering this condition in patients dying without obvious cause and having focal degenerative lesions and petechial hemorrhages are obvious.
At the Armed Forces Institute of Pathology, Lt. Col. Vorder Bruegge and I
have reviewed the autopsy material of patients with the sickle-cell trait and
have found multiple instances of unexpected and often sudden death. In this
series the blood vessels were distended with sickled erythrocytes, the spleen was
enlarged and resembled a "bag of blood" and there were microscopic areas of
ischemic necrosis in the brain, liver and other organs. This patient differs from
those usually seen in that she lived for 5 days after the onset of symptoms, and
the lesions were hemorrhagic. It is probable that the tissue changes in those
persons dying suddenly and those dying several days after onset are not different but represent different stages in the same process. It is visualized that the
first reaction of the vascular bed to hypoxia and sudden and severe decrease
in blood flow is vasoconstriction and ischemic necrosis as described by Kimmelsteil. Hemorrhages probably occur after the cells of the vessel wall and
the tissue supplied by the vessels have become injured, the vessels dilated and
the blood flow partially restored.
Question: Why do you regard alcohol as a possible etiologic factor in this case?
Dr. Diggs: The part played by alcohol is conjectural but it is known that
alcohol depresses the nerve centers, favors acidosis and increases the depth of
slumber, all of which would favor the deoxygenation of the blood and crystallization of hemoglobin. We have obtained from occasional patients with sickle-cell
anemia a story of painful febrile episodes after drinking bouts.
Question: Since the patient gave a history of attacks coming on during sleep
and associated with muscle cramps, jaundice and regenerative anemia, how do
you exclude paroxysmal nocturnal hemoglobinuria?
Dr. Jones: Paroxysmal nocturnal hemoglobinuria is excluded by the facts
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that urinalysis revealed no abnormal pigment and that there was an absence
of the characteristic hemosiderin pigment in the proximal tubules of the kidney.
REFERENCES
1. BRIDGERS, W. H . : Cerebral vascular disease accompanying sickle cell anemia. Am. J .
Clin. P a t h . , 15: 353-362, 1930.
2. THOMPSON, R. K., WAGNER, J . A., AND M C L E O D , C. E . : Sickle cell disease: Report of
a case with cerebral manifestations in the absence of anemia. Ann. I n t . Med., 29:
921-92S, 1948.
3. VANCE, B . M., AND F I S H E R , R. C : Sickle cell disease. Two cases, one presenting fat
embolism as a fatal complication. Arch. P a t h . , 32: 378-386, 1941.
4. W A D E , L. J., AND STEVENSON, L. D . : Necrosis of the bone marrow with fat embolism in
sickle cell anemia. Am. J. Clin. P a t h . , 17: 47-54, 1941.
5. WERTHAM. F . , M I T C H E L L , N . , AND ANGRIST, A.: The brain in sickle cell anemia. Arch.
Neurol. & Psychiat., 47: 752-767, 1942.
6. WYATT, J. P . , AND ORRAHOOD, M. D . : Massive fat embolism following marrow infarction
' in sickle cell anemia. Arch. P a t h . , 53: 233-238, 1952.