High dose systemic methotrexate-associated acute neurologic dysfunction – docslide.com.br nanoxia deep silence

Medical and pediatric oncology 11: 159-161 (1983)

High dose systemic methotrexateassociated acute neurologic


Roger J. Packer, MD, robert 1. Grossman, MD, and jean bello belasco, MD

Two patients treated with high dose meth- of symptoms. Computed tomography in one

Otrexate with citrovorum rescue (HDMTX-CF) child disclosed a large low absorption abnor-

For osteogenic sarcoma developed the acute mality. This patient represents the first re-

Onset of neurologic deficits. Prior to the onset ported case of positive radiologic findings

Of symptoms, one child suffered brief epi- associated with this syndrome.

The two pa-

Sodes of altered consciousness. Both patients tients recovered completely and received fur-

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Developed hemiparesis and then steadily im- ther HDMTX-CF without sequelae. This

Proved over 72 hours. Laboratory evaluations condition may result from transient demyeli-

Disclosed normal coagulation parameters and nation or embolic cerebrovascular disease.

Nontoxic serum methotrexate levels at onset

Key words: high dose methotrexate, citrovorum rescue, acute neurologic

Dysfunction, stroke


Methotrexate (MTX) is a widely used chemotherapeu-

Tic agent with well documented acute, subacute, and

Chronic neurotoxicity [l]. MTX given in high doses (12

Mg/m2) with citrovorum rescue has proven to be an

Effective treatment for osteogenic sarcoma [2]. In 1978,

Allen and rosen 133 reported the occurrence of transient

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Cerebral dysfunction following the infusion of high dose

Methotrexate with citrovorum rescue (HDMTX-CF) .

Over the past year, we have cared for two similar pa-

Tients. In one patient there were dramatic changes on

Computed tomography; this has not been reported



A.S. Is a 6-year-old white female who was well until

July of 1981 when she developed stiffness of the left

Knee. Examination revealed her leg to be diffusely tender

Around the left distal femur with a palpable mass in the

Left supracondylar area. Biopsy of the lesion revealed an

Osteogenic sarcoma. Metastatic workup including chest

X-ray and computed tomography of the lungs was nega-

Tive. She received an above the knee amputation on

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September 8, 1981 and recovered uneventfully. She be-

Gan adjuvant chemotherapy with bleomycin, actinomy-

Cin, and cyclophosphamide in september of 1981. This

Was followed by three courses of HDMTX-CF (12 gm/

M2 per infusion). Serum MTX levels were monitored

During each infusion and were in the nontoxic range.

There were no signs of clinical MTX toxicity.

Five days after her third course of HDMTX-CF she

Began experiencing brief trance-like episodes without

Loss of postural tone or associated motor movements and

Intermittent episodes of visual loss. Twenty-four hours

Later she became unconscious and had the onset of left

Body tonic-clonic seizure activity. She was treated with

Intravenous valium, phenobarbital, and dilantin.Nanoxia deep silence within

One hour she was fully alert and oriented and seizure

Free. Examination disclosed a dense left hemiparesis in-

Volving face and arm greater than leg without sensory

Loss. Laboratory values included a normal CBC, platelet

Count (358,000/m3), prothornbin, partial thromboplastin

Time, and fibrinogen. Within 1 hour of seizure control,

Computed tomography of the brain was performed and

Disclosed a large noncontrast enhancing hypodense lesion

In the right posterior frontal lobe (see fig. 1) . Cerebral

Angiography, performed 2 hours later, was normal. Elec-

Troencephalography disclosed right frontal-central slow-

~ ~~

From the divisions of neurology (R.J.P.), and oncology (J.B.B.),

Childrenâs hospital of philadelphia, and the departments of pediat-

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Rics (R. J.P., J.B.B. ), neurology (R.J.P.), and neuroradiology

(R. I .G .), university of pennsylvania, philadelphia.

Address reprint requests to dr. Roger J. Packer, department of

Neurology, childrenâs hospital of philadelphia, 34th st. And civic

Center blvd., philadelphia, PA 19104.

0 1983 alan R. Liss. Inc.

160 packer, grossman, and belasco

Fig. 1. Low absorption in right fronto-parietal region.

Ing. Chest x-ray and echocardiography were normal. The

Child was maintained on anticonvulsants, remaining sei-

Zure free, and cleared her hemiparesis over 72 hours.

Repeat contrast-enhanced computerized tomography and

A brain scan performed 10 days later were normal.

HDMTX-CF treatments were resumed 1 week later and

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She has received multiple courses of HDMTX-CF over

The next 3 months without further neurological difficulty.

She had a recurrence of tumor in her left ileum in july of



S.G. Is an 18-year-old white female who developed

Pain and swelling of her left knee in february of 1982.

Biopsy of her left distal femur revealed an osteogenic

Sarcoma. Metastatic work-up disclosed several bilateral

Nodules in the lung on chest x-ray and lung computerized

Tomography. Because of presumed metastatic disease,

She underwent preoperative chemotherapy consisting of

HDMTX-CF (12 mg/m2). She received two courses of

HDMTX-CF without clinical toxicity. Serum MTX lev-

Els were in the nontoxic range. Six days following her

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Second dose of HDMTX-CF she suddenly developed left-

Sided weakness affecting her face, arm, and leg and

Decreased sensation in her left arm. Examination dis-

Closed slurred speech without aphasic difficulties and left

Hemiparesis involving her face, arm, and leg equally.

Laboratory evaluation disclosed a normal CBC, platelet

Count, prothombin time, partial thromboplastin time, and

Fibrinogen. Contrast-enhanced computerized tomography

Performed within 6 hours of onset of symptoms was

Normal. Electroencephalography disclosed bilateral

Slowing with right fronto-central accentuation. She im-

Proved over the next 4 days. Brain scan performed 4

Days after the onset of symptoms was normal. Her chest

X-ray was unchanged and echocardiography was normal.Nanoxia deep silence

Within 5 days after the onset of symptoms she was

Neurologically normal. Repeat contrast-enhanced com-

Puted tomography 10 days later was normal. Two weeks

Later she underwent a limb-saving resection for removal

Of her tumor. She then underwent thoracotomy for exci-

Sion and biopsy of the nodules. Pathology of the pulmo-

Nary nodules was consistent with histoplasmosis with no

Evidence for osteogenic sarcoma. She has since under-

Gone multiple treatments of HDMTX-CF without neuro-

Logic sequelae. She remains neurologically normal.


Our two patients developed sudden, focal neurologic

Deficits 6 days after completing their second and third

Course of HDMTX-CF, respectively. One child probably

Suffered intermittent absence seizures and possible hem-

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Ianopsia or cortical blindness several hours prior to the

Onset of hemiparesis. Once symptoms of focal neurologic

Compromise began, they tended to stabilize within a few

Hours and then steadily improved over the next 72 hours,

Without permanent sequelae. These findings are some-

What different than those patients reported by allen [3]

(see table I) who suffered from acute symptoms that

Fluctuated over the first 72 hours of illness and resulted

In permanent sequelae in 2 of 4 patients. The patients

TABLE I. Clinical and laboratorv findines

Allen et a1 [3]

Studv (N = 4)

Present study

(N = 2 )


Prodomal symptomsa 114 112

Acute onset 414 212

Symptoms and signs




Cranial nerve paresis

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Permanent sequelae

314 112

214 112

414 212

114 012

214 012

Abnormal laboratory studies

Platelet counts 014 012

Clotting function 014 012

Echocardiography ? I4 012

Computerized tomography 014 112

Cerebral angiography 012 01 1

(PT, PTT, fibrinogen)

Electroencephalopathy 414 (one 212 (both

Focal) focal

APrior transient symptoms of headache, transient alterations in

Consciousness, etc.

Methotrexate-associated neurologic dysfunction 161

Levels. The children did not have recurrent symptoms

After subsequent doses of HDMTX-CF; this suggests that

This is not a hypersensitivity phenomenon. The patients

Had localized disease and while osteogenic sarcoma does

Metastasize to the brain, this tends to occur late in the

Course of illness after pulmonary metastases and charac-

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Teristically shows an isodense or hyperdense lesion with

Marked contrast-enhancement on computerized tomog-

Raphy. Intracranial vasculitis, secondary to intravenous

MTX, seems very unlikely since arteriographic studies

Performed immediately after the onset of difficulties were

Normal. The two major considerations that remain are

Transient deniyelination or cmbolic disease. MTX cer-

Tainly results in cerebral white matter disease, and the

Computerized tomographic findings of hypodense, non-

Contrast-enhancing lesions have been seen in other types

Of demyelinating disease. However. The acute resolution

Of symptoms and radiographic findings is unusual. Mye-

Lin basic protein, a white-matter-specific protein was not

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Assayed in the cerebrospinal fluid in allenâs 131 patients

And may supply further information concerning the role

Of demyelination if it was measured. However since these

Patients seem to have symptoms of mass cortical lesions,

Lumbar puncture was not done in our patients. Finally,

Embolic disease remains a possibility, but one that has

Not been confirmed angiographically. 117 all patients re-

Ported so far, there has not been evidence for peripheral

Embolization, cardiac vegetation, or evidence for pul-

Monary metastatic disease predisposing to embolic dis-

Ease. The normal cerebral angiograms and lack of sources

For emboli, however. Does not rule out the possibility of



Previously reported and our patients underwent extensive

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Laboratory evaluation at the time of neurologic deterio-

Ration. Coagulation profiles have been normal in all pa-

Tients studied so far. Electroencephalography has been

Abnormal in all patients, but in the two patients seen here

There was definite focal slowing. Patient A.S. Is the only

Child reported with computerized tomographic abnormal-

Ity, disclosing a focal noncontrast enhancing lesion. This

Lesion seems most consistent with either an acute is-

Chemic or demyelinative lesion of the cerebral cortex.

Although the child may have suffered mild cerebral hy-

Poxia during her seizure, it would be difficult to invoke

Generalized hypoxia as the etiology of the radiographic

Findings since the lesion was unilateral and did not occur

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In the so-called âwatershedâ regions or in the basal

Ganglion (areas most sensitive to diffuse reduction in

Oxygen delivery to the cerebral cortex). Confirmation of

Cerebro-vascular occlusion or spasm was attempted by

Angiography within 2 hours of completion of computer-

Ized tomography and was normal. The significance of

This finding will be discussed below. Because of the

Findings of significant focal neurologic damage in these

Patients, possibly representing mass cortical lesions,

Cerebrospinal fluid analysis was not performed. In the

Patients who underwent lumbar puncture in allenâs series

No abnormalities were found.

One of the major issues in such children is the risk of

Delivery of further HDMTX-CF therapy.Nanoxia deep silence MTX has re-

Sulted, in significant neurotoxicity delivered intrave-

Nously, intrathecally, and intraventrically [ 11. Most acute

Neurotoxic effects of MTX, such as meningitis, radicu-

Lopathy, myelopathy, and encephalopathy, have been as-

Sociated with intraventricular or intrathecal instillation of

MTX, at times with concomitant obstruction of cerebro-

Spinal fluid flow and elevation of MTX level [l].

HDMTX-CF has been implicated as causing intellectual

Sequelae in children with leukemia [4] and has resulted

In leukoencephalopathy, with progressive intellectual and

Focal neurologic difficulties associated with white matter

Hypodensity on computerized tomography, in patients

With bone or soft tissue sarcoma [5].Nanoxia deep silence we attempted to

Determine the competence of the so-called blood-brain

Barrier prior to the infusion of further intravenous MTX,

So as not to deliver MTX in high doses to normal or

Partially compromised brain. Brain scan and computer-

Ized tomography with intravenous contrast enhancement

Did not show evidence for abnormal uptake of isotope or

Enhancement 4 and 10 days after neurologic compromise.

Further HDMTX-CF was given, as in the patients re-

Ported by allen, without sequelae.

The etiology of this transient neurologic syndrome

Remains unknown. During the same time period, 40 other

Children received HDMTX-CF delivered in an identical

Fashion for osteogenic sarcoma, without sequelae. Our

Patients had MTX levels monitored closely during infu-

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Sion and did not have inordinately elevated serum MTX

This study was supported in part by NCI grant CA

14489 and eagles fly for leukemia fund.


I . Young DF, posner JB: nervous system toxicity of chemotherapeu-

Tic agents. In vinken PJ, bruyn GW (eds): âhandbook of clinical

Neurology,â vol 39, part 11. New york, north holland publishing

2. Rosen G, caparros B, huvos AG, et al: preoperative chemother-

Apy for osteogenic sarcoma: selection of postoperative adjuvant

Chemotherapy based on the response of the primary tumor to

Preoperative chemotherapy. Cancer 49: 1221-1230, 1982.

3. Allen JC, rosen GR: transient cerebral dysfunction following

Chemotherapy for osteogenic sarcoma. Ann neurol 3:44-444,

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4. Bleyer W, griffen TW: white matter necrosis, mineralizing mi-

Croangiopathy and intellectual abilities in survivors of childhood

Leukemia: associations with central nervous system irradiation and

Methotrexate therapy. In gilbert HA, kagan AR (eds): âradiation

Damage to the nervous system. new york: raven press, 1980,

5. Allen JC, rosen G, mehta M, horten B: leukoencephalopathy

Following high dose IV methotrexate chemotherapy with leucovo-

Rin rescue. Cancer treat rep 64:1261-1273, 1980.

CO., 1979, pp 91-131.

Pp 155-174.