Dural Venous Sinus Thrombosis in Acute Lymphoblastic Leukemia

(1)

Dural

Venous

Sinus

Thrombosis

in Acute

Lymphoblastic

Leukemia

Lawrence

A. Lockman,

MD,

Angeline

Mastri,

MD,

John

R. Priest,

MD, and

Mark

Nesbit,

MD

From the Division of Pediatric Neurology and Departments of Neurology, Pediatrics,

and Laboratory Medicine, University of Minnesota School of Medicine, Minneapolis

ABSTRACT.

Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One pa-tient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic cells. Attention is drawn to this potentially treatable cause of central nervous system symptoms in childhood leukemia. Angiography is the diagnostic test of choice and can also demonstrate intracerebral hematoma and subdural hematoma, if pres-ent. Sinus thrombosis can occur either during exacerba-tion or remission of the basic leukemic process. The possibility that chemotherapeutic techniques predispose toward this complication is raised. Pediatrics 66:943-947, 1980; dural, venous, sinus, thrombosis, leukemia.

The common central nervous system complica-tions of acute lymphoblastic leukemia (ALL) con-sist of leukemic inifitration,’ infections of the nerv-ous system and its coverings, and intracerebral and subarachnoid hemorrhage resulting from thrombo-cytopenia or disseminated intravascular coagula-tion.2 Because at least half of patients with ALL risk leukemic infiltration of the arachnoid during the illness that may be unrelated to the state of bone marrow remission, presymptomatic treatment of the craniospinal axis to prevent infiltration has become commonplace. A number of protocols have been utilized: radiation alone, radiation plus in-trathecal methotrexate, and intrathecal methotrex-ate alone.

The spectrum of CNS involvement in ALL is

changing as a result of altered treatment. Some

Received for publication Dec 10, 1979; accepted March 24, 1980. Reprint requests to (L.A.L.) Division of Pediatric Neurology, University of Minnesota School of Medicine, Minneapolis, MN

55455.

complications

may

be

seen

because

of improved

survival

while

others

are

to the

therapy;

the

course may be altered by changing the mode of

treatment.5 It is necessary to expand the differ-ential diagnosis of CNS complications of ALL so that potentially treatable conditions are correctly diagnosed and hazardous therapy is avoided.

It is the

purpose

of this

report

to document

the

occurrence of sagittal sinus thrombosis, a poten-tially treatable condition, in three children with

ALL, two of whom received presymptomatic ther-apy.

A recently reported case of dural sinus occlusion

in ALL6 called attention to this problem. The

di-agnosis was established by angiography. At post-mortem examination, infiltration

of the

walls

of the

sagittal sinus and the dura by leukemic cells was noted. In another report7 of a patient with ALL and dural sinus thrombosis, the postmortem examina-tion showed no leukemic infiltration of the sagittal sinus

although

the

patient

had

received

1,400

rads

of cranial irradiation between the time of clinical onset and death. Thus, the possibility of CNS leu-kemia in this patient, who was otherwise in remis-sion, is not excluded.

In

the

patients

reported

here

no

such

leukemic

inifitration was noted on postmortem examination

of the

two

patients

who

died

and

another

mecha-nism must be postulated.

Of seven adults with systemic cancer and non-metastatic superior sagittal sinus thrombosis re-ported by Sigsbee et al,8 two had ALL. A 26-year-old woman received prednisone, vincristine, and

intrathecal methotrexate; thrombosis occurred 2#{189} weeks

later.

A 17-year-old

female

adolescent

with

277,000 WBC/cu mm (90% lymphoblasts) was

treated with prednisone, vincristine, and intrathecal

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CASE

REPORTS

Case 1

This 7#{189}-year-old girl had been diagnosed as having ALL at the age of 4 years. The total WBC count at the time of diagnosis was 4,200/cu mm. A spinal tap was not done and the patient did not receive presymptomatic therapy of the CNS. Remission was induced with

vincris-tine and prednisone. Fourteen months after diagnosis she developed increased intracranial pressure and had

mono-nuclear cell count of 1,800/cu mm of spinal fluid. Her

CNS leukemia was treated with intrathecal methotrexate

and 1,200 rads to the entire CNS axis. She remained well

on a regimen of prednisone and vincristine until 28

months after diagnosis when another CNS relapse was

treated with intrathecal methotrexate, intrathecal

cyto-sine arabinoside, and 1,200 rads to the brain alone. At 32

months after diagnosis, a bone marrow relapse was

treated with cytosine arabinoside and L-asparagmase. Thirty-six months after diagnosis a CNS relapse was treated with intrathecal methotrexate and 1,200 rads to

the neuraxis. Five months later she received mtrathecal methotrexate, cytosine arabinoside, and intrathecal hy-drocortisone plus 1,200 rads to the brain. During the 44th

month following diagnosis, a bone marrow relapse was treated with L-asparaglnase, prednisone, and cytosine arabinoside. Spinal fluid examination at that time re-vealed no cells.

Forty-eight months after beginning therapy, the

pa-tient experienced two days of bifrontal headache,

vomit-ing, and lethargy, which prompted a spinal tap at her local hospital. The cerebrospinal fluid was xanthochromic

and contained 3,300 RBC/cu mm and 179 WBC/cu mm

of which 42 were mononuclear cells and 58%

polymor-phonuclear leukocytes; the sugar was 52 mg/100 ml.

On admission she was lethargic and slightly irritable but able to follow simple commands. Nuchal rigidity was present. There was a right homonymous hemianopsia. The right pupil was slightly larger than the left. She had conjugate deviation of the eyes to the left, but they would

move across the midline with forceful head turning. Pap-illedema was present with absent venous pulsations and

blurred disc margins; no hemorrhages or exudates were seen. Upon painful stimulation, she moved only her left

extremities. Toe sign was extensor on the right.

Hemoglo-bin was 7.4 gm/100 ml; WBC count was 2,850/cu mm with 71% polymorphonuclear leukocytes, 12%

lympho-cytes, and 5% monocytes. Platelets numbered 130,000/cu mm. The spinal fluid contained: RBC 400/cu mm, and WBC 800/cu mm of which 80% were polymorphonuclear leukocytes and 20% mononuclear cells; no blast forms were present. Gram stain and India ink preparation of the spinal fluid were negative. Results of throat, spinal fluid,

and blood cultures were negative. Tests of coagulation

were not obtained. A technetium 99m brain scan showed increased uptake in the left frontoparietal area. Electro-encephalogram was markedly abnormal because of dii-fuse slowing with preponderance of slowing on the left and a delta focus in the left frontoparietal area.

The patient was treated with ampidillin and gentamicin for presumed septicemia and with dexamethasone and oral glycerol to reduce intracranial pressure. Fluid

restnc-tion was instituted for inappropriate antidiuretic hormone secretion. She became more responsive within two days. Headache remained mild and the right hemiparesis

per-sisted. She was able to take fluids by mouth and her antibiotics were discontinued. Five days after admission she became obtunded and incontinent of urine. The fol-lowing day she deteriorated with Cheyne-Stokes respi-ration, dilation of the left pupil, and subsequently died.

The autopsy was limited to examination of the brain. The superior sagittal and left transverse sinuses and the torcular were filled with a blood clot which was partly laminated and adherent to the sinus wall. Many of the dural veins were enormously distended by thrombi, some of which were invaded by fibroblasts. There was no

evidence of leukemic infiltration in the dura, sinuses, or veins or in the leptomeninges, cerebral vessels, or brain

parenchyma. The left temporal lobe was swollen and diffuse subarachnoid hemorrhage was noted over the left

parietal, temporal, and occipital regions. Extensive

hem-orrhagic softening of almost the entire left cerebral

hem-isphere was present; only the frontal and temporal poles

were spared (Fig 1). The right cerebral hemisphere was

compressed and showed focal softening and hemorrhage in the superior and middle frontal gyri. There was also extensive hemorrhagic softening of the superior aspect of the right cerebellar hemisphere and a small area of similar change in the superior aspect of the left cerebellar

hemi-sphere.

Case 2

This 12-year-old white boy was admitted to the

Urn-versity of Minnesota Hospitals because of disorientation

and hemiparesis. ALL had been diagnosed 10 months earlier. At the time of diagnosis the hemoglobin was 3.6

gm/100 ml, the WBC count 2,950/cu mm and the platelet count 10,000/cu mm. His spinal fluid examination at diagnosis revealed one red blood cell and no white blood

cells. Induction therapy was with prednisone and

vincris-tine. L-Asparaglnase was started on the 22nd day of

treatment.

Six months before this admission he had a relapse with WBC count 94,000/cu mm, 74% of which were

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blasts. The platelet count was 73,000. Antileukemic ther-apy was begun with vincristine, hydrea, and prednisone.

6-Mercaptopurmne (6-MP) was started after 15 days.

Spinal fluid contained no white blood cells. He received 2,400 rads of presymptomatic radiation therapy to the skull and spinal axis and was maintained on 6-MP, pred-nisone, and vincristine.

Twenty-six days before admission CNS leukemia was

diagnosed with 1,970 cells/cu mm, a protein level of 134 mg/100 ml and a glucose level of 27 mg/100 ml of spinal fluid. No differential white cell count was done. Metho-trexate was given intrathecally and prednisone was con-tinued. Two days later the spinal fluid cell count had dropped to 715/cu mm and four days after that to 233/cu mm. Seventeen days prior to admission the white cell count in the spinal fluid had dropped to 93; an attempt at lumbar puncture failed six days later.

On admission the patient was confused and disoriented to place and situation, but not to time or person. He was unable to follow verbal commands, but able to follow visual cues. There was a mild right facial paresis. Corneal reflexes were absent bilaterally. Initially there was a flaccid paralysis of the right extremities. Reflexes were

depressed on the right side and there was an extensor toe sign. Lumbar puncture showed normal pressure; there were 1 1 mononuclear cells, 1 polymorphonuclear leuko-cyte, and 23 RBC per cubic millimeter. The prothrombin time was 13.9 seconds. That night he became unrespon-sive to verbal commands but did respond to pain with a grimace. He did not withdraw. Pupils were dilated but reactive. Tonic-clonic and multifocal motor seizures en-sued. A brain scan on the third hospital day showed a

large area of uptake in the right posterior parietal area, suggestive of a hemorrhagic lesion. The hemoglobin was

13.7 gm/100 ml; white blood count was 1,750/cu mm with 90% neutrophils and no lymphoblasts; platelet count was 60,000/cu mm. Prothrombin time was 13.9 seconds, par-tial thromboplastin time 53.5 seconds, and thrombin time

14.9/15.2 sec. Radiation therapy to the brain was begun on the third hospital day with 150 rads/day.

He slowly

deteriorated over the next few days and died on the seventh hospital day.

At autopsy, there were small leukemic foci in the testes but no other leukemic infiltrations were found in the

body. Additional findings were focal bronchopneumorna, and pituitary scarring and testicular atrophy secondary to ionizing radiation. Only a portion of the cerebral dura was available for examination and this

showed

thrombo-sis of the superior sagittal sinus extending into the tribu-tary veins. The cerebrum was swollen, particularly the right hemisphere. Many of the superficial veins were greatly distended and thrombosed. There was focal, fresh, subarachnoid hemorrhage over the frontal, parietal,

and

occipital lobes bilaterally. There was extensive hemor-rhagic infarction involving the right parietal, occipital, and posterior frontal lobes (Fig 2). Similar, less extensive, changes were noted in the left frontal lobe. Herniation of the right uncus into the incisura of the tentorium com-pressed the midbrain. Microscopic examination showed the superior sagittal sinus to be occluded by fresh throm-bus in which only a few fibroblasts were seen at the

periphery adjoining the endothelium. A few small sinuses

Fig 2. Case 2: Hemorrhages and infarction in the

pan-etal lobes are the result of superior sagittal sinus throm-bosis with thrombosis of the draining veins.

or veins near the superior sagittal sinus also were throm-bosed or showed swelling of the intima. There was no evidence of leukemic infiltration in the dura, the cerebral blood vessels, leptomeninges, or in the parenchyma of the brain. Many of the cerebral leptomeningeal veins were occluded by thrombi which showed no evidence of orga-rnzation.

Case 3

This 14-year-old white male adolescent was diagnosed as having acute lymphoblastic leukemia 39 days prior to his CNS episode. He was originally seen with a

three-week history of fatigue and results of physical examina-tion were normal except for pallor and lethargy; there was no organomegaly or adenopathy. At the time of diagnosis white blood cell count was 2,600/cu mm with 20% neutrophils and 77% lymphocytes; there were no peripheral lymphoblasts. Platelet count was 157,000/cu

mm

but fell to 45,000 two days later. His marrow induc-tion therapy consisted of prednisone 40 mg/sq rn/day for one month, L-asparagmase 6,000 units/sq rn/dose

intra-muscularly (IM) for nine doses

and

weekly

vincristine,

1.5 mg/sq m, for five doses. Normal spinal fluid was obtained at the time of the diagnosis and at the time of the first dose of intrathecal methotrexate on the 35th day of therapy. Partial thromboplastin time was 41.6 seconds initially and rose to greater than 180 seconds on the 28th day of therapy. The prothrombin time rose from 11.2 to

13.9 seconds. The thrombin time was 15.3 seconds.

Fi-brinogen level dropped to 10 mg/100 ml on the 29th day.

On the 38th day of therapy the patient complained of headache which decreased when he became recumbent. The following day he had his first dose of prophylactic radiation, 200 rads, to the right cerebral hemisphere. Immediately following his radiation the patient corn-plained of numbness and clumsiness of the right upper

extremity especially in the hand. Results of examination were normal at that time, and he took a nap. When he arose he was dysarthric and very weak on the right side.

(4)

and thrashing in bed. There was no spontaneous speech and no facial movement except when he cried out. His speech to command was dysarthric and mostly consisted of “I can’t.” He could follow simple commands. There was a positive Brudzinski’s sign. There was a dense

horn-onyrnous hernianopsia on the right side and the optic discs were very pale. There was no volitional tongue movement. There was a flaccid paralysis on the right side with only minimal withdrawal of the right upper extrem-ity to pain. Reflexes were depressed except at the right knee and the right toe sign was extensor.

The prothrornbin time was 12.6 seconds, the partial thromboplastin time, 32.5 seconds, and thrornbin time, 13.6 seconds. Fibrinogen was 300 mg/i#{174} ml.

An angiogram

of the

left carotid

(Fig 3) showed

non-filling of the sagittal sinus even on late films, compatible with sagittal sinus thrombosis. There was slight shift of the anterior cerebral arteries from left to right. There was no evidence of arterial occlusive disease. The veins in the mid- and posterior-frontal and throughout much of the left parietal regions were never visualized throughout the filming sequence while the veins in the posterior parietal and occipital region emptied in normal sequence. Hence the appearance was that of a cortical venous thrornbosis with probable sagittal sinus thrombosis. The sagittal sinus was not visualized on the dynamic portion of a brain scan; the static portion of the study was normal. (Eleven days later, the brain scan was normal.)

Electro-encephalogram was markedly abnormal because of exces-sive diffuse slowing of higher voltage over the left hemi-sphere, localized left paietal and posterior temporal slow-ing, and slow spikes occurring frontocentrally on the left.

An electrical

seizure

was noted

in the left

parietal area. The record indicated diffuse CNS dysfunction and was suggestive of a left parietotemporal structural lesion.

On the next day the patient had an 18-minute seizure on the right side which was treated with 5 mg of

intra-Fig 3. Case 3: Left carotid angiogram. In this late film the deep venous structures are well demonstrated, but no contrast has been seen in the superior sagittal sinus.

venous diazeparn. Dexarnethasone and phenytoin therapy was started. Two days later he was

able

to identify pictures and objects and to move the right leg and foot

on command.

The

patient

continued

to show improve-ment; he had good neurologic recovery and returned to school. Three years later he died after several marrow relapses without any evidence of meningeal leukemia.

No

autopsy was performed.

DISCUSSION

Dural sinus thrombosis is uncommon in children. This disorder is associated

with

severe

dehydration

in infancy, trauma, and localized or systemic

infec-tions.9

Cases

associated

with

leukemia

were

de-scribed

by Gowers

in the

19th

century.’#{176}The

report

of

the

dural

sinus

occlusion

in a 7-year-old

boy

with

leukemia

in

relapse

is the

first

well

studied

case

occurring

in leukemia

which

was

treated

with

mul-tiple drugs6; CNS leukemia could not be ruled out.

The

second

patient7

raised

the

possibility

that

sinus

thrombosis may not be related to leukemic

infiltra-tion

of the

dural

sinus.

The

addition

of

our

three

patients,

one

of whom

was

in remission,

raises

the

possibility that certain aspects of treatment are

predisposing

these

children

to

this serious and usu-ally fatal

complication.

The

diagnosis

of dural

sinus

thrombosis

is

diffi-cult

and often

not

made

until

postmortem

exami-nation.

The

differential

diagnosis includes intracer-ebral hemorrhage, subarachnoid hemorrhage,

cere-bral

abscess,

and

pseudotumor

cerebri.

Subdural

hematoma

may

also

occur

in acute

lymphoblastic

1

The

clinical

course

may

be

divided

into

two

stages for clinical convenience, based on symptoms

and

signs

with

neuropathologic

correlates.’2

In the

early

stages

of sinus

thrombosis

the

signs

are presumably related to thrombosis of the sinus itself. This early stage is characterized clinically by fever, headache, dilation of the vessels over the

scalp

with

possible

scalp

edema,

and signs of in-creased intracranial pressure.

The

second

stage

is

presumably related to extension of the thrombus to

the

veins

of the

cerebral

cortex.

Seizures,

coma,

and hemiplegia occur during this

stage.

The

character-istics of spinal fluid are of help in establishing the diagnosis.

The

pressure,

protein,

and red cell count

are

often

elevated.

Diagnosis

is established

by

an-giography with particular attention paid to the rate

of flow

of contrast

material

through

the

brain.

Dur-ing

the

late

venous

phase,

contrast

material does not appear in the superior sagittal sinus; collateral

venous

drainage

channels

may

be demonstrated.’3

Therapy

is directed

at reducing

intracranial

pres-sure

and

at

interrupting

the

propagation

of

the

(5)

as well as with glucocorticoids such as dexametha-sone.’4 The problem of prevention of thrombus propagation is more difficult. There is substantial risk of enlargement of a hemorrhagic infarction with the use of anticoagulants. On the other hand, the prognosis for survival is so poor that their use may be indicated. It would seem that the risk would

be diminished

if treatment

could

be initiated

before

the cortical veins have been affected.

In

a classic

report

of dural

vein

thrombosis

in

infancy and childhood, Byers and Hass’5

studied

50

cases of thrombosis of the intracranial sinuses, many of which were related to infection. None were attributable to leukemia. The course of patients with cryptogenic thrombosis was highly variable although convulsions of focal onset were frequently noted. Following a period of improvement, a second

series

of convulsions

might

occur

which

appeared

to indicate

an extension

of the

original thrombosis.

Spinal

fluid

abnormalities

were

highly

variable,

the

most common single finding

being

an

increase

in

protein. The fluid was normal only in those few instances in which the thrombosis was minimal.

Treatment of meningeal leukemic infiltration has been vigorous in contrast to that for intracerebral

hematoma. Subdural hematoma and sagittal sinus

thrombosis, which can present the same clinical picture as an intracerebral hematoma, are poten-tially treatable, carry a

more

favorable

prognosis,

and therefore should be diagnosed during life. Cere-bral angiography remains the diagnostic test most likely to differentiate among these entities.’6”7

The cause of the dural sinus thromboses in the three children reported here is not known

but

may

be related to hemostatic abnormalities caused by their recent marrow induction therapy. Patients 1

and

3 had

just

completed

courses

of marrow

induc-tion therapy when the CNS events occurred. Their therapy included vincristine, prednisone, and

L-as-paraginase;

several

abnormalities

in the

hemostatic

system are associated with this

therapy

regimen

and have been attributed to L-asparaginase. Ram-say et al’8 reported hypofibrinogenemia in 26 of 26 children receiving vincristine, prednisone, and

L-asparaginase; in addition most had prolonged

plasma clotting times and low factor IX and

XI

levels.’8 Concomitant deficiencies of antithrombin

and

plasminogen

also occur during L-asparaginase therapy.’2’ Prednisone raises factor VIII levels and, following marrow induction therapy, produc-tion of new platelets is abundant. The sum

of these

hemostatic changes may, in certain patients,

pre-dispose to thrombosis,’9 especially in the uniquely

turbulent

flow

in the

superior

sagittal sinus.’2 The coagulation issues in leukemic children require con-tinued investigation.

REFERENCES

1. Price RA, Johnson WW: The central nervous system in childhood leukemia. I. The arachnoid. Cancer 31:520, 1973 2. Robson GS, Anderson R McD: Central nervous system

lesions in childhood leukemia. Med JAust 1:1134, 1973 3. Flament-Durand J, Ketelbant-Balasse P, Maurus R, et al:

Intracerebral calcifications appearing during the course of acute lymphocytic leukemia treated with methotrexate and x-rays. Cancer 35:319, 1975

4. Rubinstein U, Herman MM, Long TF, et al: Disseminated necrotizing leukoencephalopathy: A complication of treated central nervous system leukemia and lymphoma. Cancer 35: 291, 1975

5. Hendin B, DeVivo DC, Torack R, et al: Parenchymatous degeneration of the central nevous system in childhood leukemia. Cancer 33:468, 1974

6. David RB, Hadfield MG, Vines FS, et a!: Dural sinus occlu-sion in leukemia. Pediatrics 56:793, 1975

7. Ganick DJ, Robertson WC, ViSeSkU1 C, et al: Dural sinus thrombosis in leukemia. Am JDiS Child 132:1040, 1978 8. Sigsbee B, Deck MDF, Posner JB: Noninetastatic superior

sagittal sinus thrombosis complicating systemic cancer. Neu-rology 29:139, 1979

9. Yang DC, Sohn D, Anand HK: Thrombosis of superior longitudinal sinus during infancy. J Pediatr 74:570, 1969 10. Gowers WR, cited by Kendall D: Thrombosis of intracranial

veins. Brain 71:386, 1948

11. Pitner SE, Johnson WW: Chronic subdural hematoma in childhood acute leukemia. Cancer 32:185, 1973

12. Kalbag RM, Woolf AL: Cerebral Venous Thrombosis. Lon-don, Oxford University Press, 1967

13. Scotti LN, Goldman RL, Hardman DR, et al: Venous throm-bosis in infants and children. Radiology 112:393, 1974 14. Rosman NP: Elevated intracranial pressure, in Swaiman KF,

Wright FS (eds): The Practice of Pediatric Neurology. St Louis, CV Mosby Co, 1975, pp 144-145

15. Byers RK, Hass GM: Thrombosis ofthe dural venous sinuses in infancy and in childhood. Am JDIS Child45:1161, 1933 16. Averback P: Primary cerebral venous thrombosis in young

adults: The diverse manifestations of an unrecognized dis-ease. Ann Neurol 3:81, 1978

17. Kingsley DPE, Kendall BE, Moseley IF: Superior sagittal sinus thrombosis: An evaluation of the changes demon-strated on computed tomography. J Neurol Neurosurg Pay-chiatry 41:1065, 1978

18. Ramsay NKC, Coccia PF, Krivit W, et al: The effect of L-asparaginase on plasma coagulation factors in acute lympho-blastic leukemia. Cancer 40:1398, 1977

19. Priest JR, Ramsey NKC, Latchaw RE, et al: Thrombotic and hemorrhagic strokes complicating remission induction chemotherapy for childhood acute lymphoblastic leukemia.

Cancer 48:1548, 1980

20. Deutsch E, Fischer M, Frischauf H, et al: Blood coagulation changes under L-asparagmase therapy, in Grundmann E, Oettgen HF (eds): Recent Results in Cancer Research. New York, Springer-Verlag, 1970, vol 33, pp 331-341

21. Conrad J, Durnad J, Feger J, et al: Acquired abnormal antithrombin III in L-asparaglnase treated patient? (abstract 193), in IVth International Congress on Thrombosis and Haemostasis, Vienna, 1973, p 228

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1980;66;943

Pediatrics

Lawrence A. Lockman, Angeline Mastri, John R. Priest and Mark Nesbit

Dural Venous Sinus Thrombosis in Acute Lymphoblastic Leukemia

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