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Contribution of Single-Photon Emission Computed Tomography in the Diagnosis and Follow-Up of CNS Toxicity of a Cytarabine-Containing Regimen in Pediatric Leukemia

From the Department of Nuclear Medicine, Charles Nicolle University Hospital, Henri Becquerel Center, Rouen; Departments of Pediatric Hematology and Radiology, Robert Debré Hospital, Paris; and Department of Nuclear Medicine, Beaujon Hospital, Clichy, France.

Address reprint requests to Pierre Véra, MD, PhD, 1 rue d'Amiens, 76000 Rouen, France; email pierre.vera{at}rouen.fnclcc.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Cytarabine (ara-C) is one of the most effective chemotherapeutic agents in patients with acute leukemia (AL), with a clear dose effect. Use of high-dose ara-C is hampered, however, by a noticeable toxicity, particularly to the CNS. We investigated the usefulness of CNS perfusion imaging with technetium-99m (^99mTc)-hexamethyl-propylene-amine oxime (HMPAO) single-photon emission computed tomography (SPECT) concurrent to magnetic resonance imaging (MRI) to specifically assess the effects of standard- and high-dose ara-C in children with AL.

PATIENTS AND METHODS: Twenty-six perfusion studies using ^99mTc-HMPAO SPECT were performed in 12 children (age range, 4 to 15 years) with AL after induction therapy, which consisted of a standard-dose ara-C, immediately after consolidation with high-dose ara-C, and later during follow-up (range, 6 to 44 months). The chemotherapy-related adverse events were monitored and correlated to SPECT and MRI.

RESULTS: After the induction phase, all children were neurologically normal on MRI. On SPECT imaging, four children displayed a slightly heterogeneous perfusion. After high-dose ara-C (4 to 36 g/m²), five children had regressive neurologic signs of potential toxic origin. Of these five children, only one had an abnormal MRI scan, whereas all patients showed evidence of diffuse cerebral and/or cerebellar heterogeneous perfusion on SPECT. The seven other patients without any neurologic symptoms had normal MRI scans; SPECT was normal for three patients and abnormal for four patients. On follow-up, for four children who had presented with clinical neurologic toxicity, SPECT improved in three patients and remained unchanged in one patients. In two of these four children, delayed abnormalities (T2 white matter hypersignal and cerebellar atrophy) appeared on MRI scans.

CONCLUSION: In our series, diffuse heterogeneous brain hypoperfusion is often the sole early objective imaging feature identified by SPECT of high-dose ara-C neurotoxicity, where MRI still demonstrates normal pictures.

	INTRODUCTION

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CYTARABINE (ARA-C) IS one of the most effective chemotherapeutic agents for acute leukemia and has been used at a conventional dose (100 to 200 mg/m²/d) or at a high dose (3 to 6 g/m²/d). High doses of ara-C (HD ara-C) are used to increase its therapeutic efficacy and to decrease resistance to the drug. HD ara-C has been used, in particular, in postremission acute myeloid leukemia and refractory leukemia treatment. Adverse side effects with conventional doses are well known.^1-5 The use of HD ara-C has been reported to have a CNS toxicity in 16% to 50% of the patients studied.⁶ Acute cerebral and cerebellar toxicity can be fatal.⁷ The main CNS toxicities are seizures, cerebral dysfunction, and acute cerebellar syndrome. CNS toxicity is related to high drug dose, renal and hepatic dysfunction, patients more than 60 years of age, and concurrent administration of neurotropic agents.^8,9 However, no individual factors are known to predict HD ara-C neurotoxicity. The physiopathology of CNS toxicity is unknown, and ancillary diagnostic evaluation has often not been helpful in detection. Electroencephalography revealed diffuse slow waves, and a CSF study revealed nonspecific elevated protein levels. Computed tomography of the brain is usually normal during the acute phase of toxicity. Vaughn et al,¹⁰ showed diffuse high-signal lesions in the central white matter on T2-weighted magnetic resonance imaging (MRI) that resolved with clinical improvement.

Technetium-99m hexamethyl-propylene-amine oxime (^99mTc-HMPAO) single photon emission computed tomography (SPECT), scan is a widely used method for cerebral perfusion studies and has been used to evaluate drug-induced neurotoxicity.^11-13 Recently, Osterlundh et al,¹⁴ and Karabacak et al,¹⁵ reported cases of brain ^99mTc-HMPAO SPECT abnormalities in children receiving methotrexate. However, no follow-up was available in these studies. Brain perfusion studies during HD ara-C treatment have not yet been reported in the literature. Here, we report a series of 12 children who underwent ^99mTc-HMPAO SPECT scan and MRI follow-up during conventional or HD ara-C treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Twelve children, seven males and five females (median age, 11 years; range, 4 to 16 years) treated for acute myeloid leukemia (AML, n = 11) or acute lymphoid leukemia (ALL, n = 1) and who received HD ara-C treatment, were prospectively studied and observed (median follow-up, 36 months). Informed consent was obtained from both parents after inclusion. Children younger than 4 years old were not included because of technical difficulties related to SPECT. Patients with Down syndrome or who presented at diagnosis with a neurologic disease were excluded.

The first patient of the series (patient no. 1) was an 11-year-old girl with high-risk ALL who underwent induction therapy according to the European Organization for Research and Treatment of Cancer children cooperative leukemia group (EORTC-CLCG) ALL protocol 58881. She presented neurologic complications associated with intensive consolidation treatment, which consisted of cyclophosphamide and HD methotrexate on day 1 followed by HD ara-C 1 g/m²/d on days 7 and 8 and on days 21 and 22.

The 11 children with AML were treated according to EORTC-CLCG protocol 58921 (Fig 1). One month after the induction, the first consolidation therapy was administered with a total HD ara-C dosage ranging from 18 to 36 g/m², depending on the individual leukemic risk factors, followed by methoxantrone or idarubicine.

View larger version (35K): [in this window] [in a new window]   Fig 1. Treatment (EORTC-CLCG protocol 58921) and study design. Abbreviations: IDA, idarubicin; MTZ, mitoxantrone; BMT, bone marrow transplantation. IDA or MTZ usage depended on randomization.

After the first consolidation therapy containing HD ara-C, all 12 patients received additional antileukemic therapy. Six patients (patient nos. 2, 5, 7, 10, 11, and 12) received a second therapeutic consolidation that included a standard dose of ara-C. The third consolidation combined HD ara-C at 2 g/m²/12 h on days 1 to 3 and etoposide 125 mg/m²/d on days 2 to 5. Three of the six patients (nos. 7, 10, and 12) underwent 18-Gy CNS radiotherapy after completion of the third consolidation. The six remaining patients underwent an allogenic bone marrow transplantation with a conditioning regimen that included hyperfractionated total-body irradiation (total dose, 12 Gy in six fractions) in five patients (nos. 1, 3, 4, 6, and 8) or misulban 16 mg/kg (in patient no. 9) combined with cyclophosphamide (120 to 200 mg/kg total dose) in all patients and etoposide 40 to 60 mg/kg in patients nos. 6 and 9.

Brain SPECT
The 12 children underwent 26 brain ^99mTc-HMPAO SPECT perfusion scans, eight after the induction, 12 just after the first intensification, and six during the follow-up. The injected activity of ^99mTc-HMPAO was 12 MBq/kg in all scans according to the Pediatric Task Group of the European Association of Nuclear Medicine.¹⁶ SPECT was carried out with a single-head rotating gamma-camera (Gammatomme II, Sophy-Camera; Sopha Medical Vision International, Buc, France) equipped with a high-resolution collimator. For each ^99mTc-HMPAO SPECT scan, 64 angular views of 30 seconds each) were recorded in a 64 x 64 matrix (pixel size 6.8 x 6.8 mm). Slices were then reconstructed from the raw data by the filtered back projection algorithm using a pseudo-Wiener filter. The planar full width of half-maximum at 10 cm in air (spatial resolution) was measured to be 14 mm. Reconstructed brain slices were then reoriented according to the bicommissural line with validated software.¹⁷ Then three sets of axial, sagittal, and coronal 1-cm thick slices were obtained for each study. The images were examined visually for heterogeneity and for regions of asymmetric perfusion by two independent nuclear physicians. Differences were resolved by consensus. The date of the examination was blind for the SPECT analysis and consensus. Because global heterogeneous perfusion was the more frequent feature of SPECT images, the images were classified by the observers as normal, slightly (+), or diffusely (++) heterogeneous. Side and localization of the perfusion abnormalities were classified as involving the cerebral cortex, basal ganglia, and cerebellum.

Brain MRI
The 12 children underwent 34 MRI scans of the brain, 12 at diagnosis, 12 after intensification, and 10 during the follow-up. Examinations were performed using a 0.5 Tesla magnetic resonance imager (Gyrex V; Elscint, Haïfa, Israel). Serial axial images were obtained with both T1- and T2-weighted spin echo pulse sequences at a section thickness of 5 mm, covering from medulla to the vertex: T1: 450/20 (in microseconds, repetition time/echo time) - T2: 3,000/20 to 90, 18 x 24 cm field of view, 170 x 256 matrix. In some cases, FLAIR sequence was also obtained (5000/2000/20 msec, repetition time/inversion time/echo time) in the axial plane, allowing better delineation of paraventricular or cortical lesions. Intravenous contrast material was administered when recurrence or infection were questionable. MRI studies were reviewed by two radiologists. Signal anomalies were classified as involving the cerebral cortex, white matter, basal ganglia, and cerebellum.

	RESULTS

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Results of the initial neurologic examination were normal in all patients. Patient eye fundus, CSF, leukemic involvement, therapeutics, and SPECT, and MRI results are listed in Table 1.

View larger version (27K): [in this window] [in a new window]   Table 1. Neurologic Examination, Eye Fundus, CSF, Leukemic Involvement, Therapeutics, and SPECT and MRI Imaging for the 12 Children

Treatment Induction
In all the patients, the neurologic examination results were normal. However, the eye fundus was abnormal in four patients (nos. 1, 5, 8, and 12), and there was a meningeal leukemic involvement in five patients (nos. 1, 7, 8, 10, and 12). The brain MRI scans were always normal at diagnosis, except for one patient (no. 1) who showed meningeal hypersignal compatible with leukemic infiltration. Brain SPECT imaging was performed in eight patients between induction and the first consolidation. Four of eight SPECT scans were slightly (+) heterogeneous (nos. 3, 4, 5, and 12). Abnormalities were located exclusively in the cerebral cortex without lobar or vascular systematization. Perfusion was normal in the basal ganglia and cerebellum in these patients. Diffuse (++) heterogeneous perfusion was never observed. SPECT imaging was normal in the four remaining patients (nos. 6, 7, 8, and 10).

First Consolidation With HD ara-C
Six patients (nos. 1, 2, 3, 5, 8, and 11) experienced severe organ toxicity as a result of the first consolidation regimen. Five of these patients presented neurologic symptoms, which appeared during the HD ara-C infusions (nos. 1, 2, 5, 8, and 11). The main symptom was acute cerebellar syndrome (nos. 1, 2, 5, and 11), accompanied in patients no. 1 and no. 2 by cerebral dysfunction and in patient no. 5 by upper limb paresthesia. Evolution was rapidly favorable in patients no. 2 and no. 5, whereas patients no. 1 and no. 11 remained neurologically impaired for several weeks. Patient no. 8 presented only enhanced osteotendinous reflexivity. Two patients, no. 2 and no. 8, experienced multiorgan dysfunction, related to HD ara-C, involving the pancreas. One patient (no. 3) had skin and kidney toxicity without neurologic dysfunction.

Among the five patients with HD ara-C–related neurotoxicity, only one patient (no. 11) showed abnormal MRI results with diffuse T2 hypersignals in the white matter, basal ganglia, and cerebellum. In contrast, SPECT were diffusely (nos. 1, 2, 5, and 11) or slightly (no. 8) heterogeneous. Perfusion abnormalities involved the cortex and the cerebellum in three patients (nos. 1, 2, and 11) and only the cortex in patients no. 5 and no. 8. No cerebral systematization or basal ganglia impairment was observed.

The seven patients who did not present neurologic complications had normal MRI results after the consolidation. SPECT could be performed in these seven patients. Four of the patients had diffusely (no. 12) or slightly (nos. 3, 4, and 10) cerebral heterogeneous perfusion. Cerebellar abnormalities were observed in two (nos. 4 and 10). The three remaining patients had normal SPECT scans (nos. 6, 7, and 9).

Follow-Up
Among the five patients with neurologic symptoms after the first consolidation (nos. 1, 2, 5, 8, and 11), long-term follow-up was available for four patients (one relapse-related death, no. 8). In two patients, sequelae were confirmed at 60 (no. 1) and 27 (no. 11) months. In the first child (no. 1), whose SPECT remained diffusely heterogeneous, a diffuse T2 hypersignal appeared in the white matter, and the patient still presents an impaired memory. It is noteworthy that this patient received 12-Gy total body irradiation during the allogenic bone marrow transplantation conditioning. For patient no. 11, who had sequela motor clumsiness, MRI and SPECT results remained abnormal at 18 months.

Symptoms have completely resolved in the other two patients (nos. 2 and 5) even after they received an additional 12 g ara-C–containing regimen during the third intensification. In patient no. 2, a child with initial severe cerebellar syndrome, a vermix atrophy appeared on the MRI follow-up, consistent with a SPECT cerebellar hypoperfusion, that persisted 42 months after the neurologic episode (Fig 2). In patient no. 5, the MRI scan remained normal and the SPECT abnormalities were resolved at 14 months (Fig 3).

View larger version (80K): [in this window] [in a new window]   Fig 2. Example of an 11-year-old boy (patient no. 2) with M2 AML. During acute cerebellar syndrome, 99mTc-HMPAO SPECT scan was very abnormal. The MRI scan was normal. Forty-two months later, 99mTc-HMPAO SPECT scan showed slightly heterogeneous perfusion and relative hypoperfusion in the cerebellum. The MRI scan displayed cerebellar atrophy.

View larger version (47K): [in this window] [in a new window]   Fig 3. Example of a 10-year-old boy (patient no. 5) with AML type 1. 99mTc-HMPAO SPECT scan was abnormal after induction and during intensification. Perfusion remains normal at 14 months. The MRI scan remained normal.

A complete imaging follow-up was available for two of the four surviving patients (nos. 10 and 12) who had abnormal SPECT scan without neurologic signs during HD ara-C treatment. The two SPECT scans have normalized at 20 months and MRI scans remained normal. Two patients (nos. 7 and 9) who had normal SPECT scans after HD ara-C treatment only underwent an MRI during follow-up, the results of which remained normal.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We report a series of 12 children who received HD ara-C treatment and underwent ^99mTc-HMPAO SPECT brain perfusion and MRI follow-up. Most children with acute leukemia had an abnormal brain perfusion scan after receiving an ara-C–containing regimen, although these abnormalities frequently disappeared at long-term follow-up. All the children who experienced CNS toxicity had an abnormal brain perfusion scan during or just after the neurologic episode. These SPECT abnormalities occurred more frequently and before MRI abnormalities.

Study Methodology
For ethical reasons, ^99mTc-HMPAO SPECT was not performed in a control group of healthy children. Therefore, a follow-up study was initiated to specifically evaluate the dynamics of clinical and imaging features after completion of therapy. Moreover, a previous study demonstrated that ^99mTc-HMPAO perfusion scans were generally normal in patients with ALL before any treatment.¹⁸

Children underwent one to three ^99mTc-HMPAO SPECT scans. Therefore, estimated absorbed radiation doses for each ^99mTc-HMPAO SPECT scan, assuming 500 MBq of ^99mTc by SPECT, were 2.1 mGy for the whole body, 3.8 mGy for the brain, and 0.6 mGy for the gonads. In comparison, one computed tomography scan delivers 30 mGy to 50 mGy to the brain and 0.1 mGy to the gonads.¹⁹

SPECT images were qualitatively examined for regions of asymmetric perfusion and for heterogeneity. This type of subjective evaluation has, in fact, proven to be accurate.²⁰ Moreover, two independent observers, blinded from the date of the SPECT examination, interpreted the SPECT scans. This approach has proven to be reproducible.²¹

SPECT-MRI Correlations
Five patients (nos. 1, 2, 5, 8, and 11) experienced severe neurologic events. Early ^99mTc-HMPAO SPECT scans were abnormal in all of these patients. MRI scans were normal in all but one case, which showed diffuse T2 hypersignal abnormalities (no. 11). Thus, brain ^99mTc-HMPAO SPECT seems to be more sensitive than MRI for early detection of treatment-related neurotoxicity, as previously suggested for other drugs.¹⁸ In the follow-up, MRI abnormalities were consistent with those found with SPECT, arguing for nonreversible lesions in these cases.

Etiologic Hypothesis
In our series, heterogeneous perfusion was the main ^99mTc-HMPAO SPECT abnormality. Three hypotheses may be considered to explain the brain perfusion abnormalities in leukemic patients: the leukemic process, radiation therapy, and the drug-induced neurotoxicity. In leukemia, brain damage is mainly related to either CNS hemorrhage (facilitated by thrombocytopenia and disseminated intravascular coagulation) or hyperleukocytosis. None of these factors were noted in our series. In addition, a recent study including children with acute leukemia showed normal brain SPECT scans in eight out of nine patients before any treatment.¹⁸ Therefore, the leukemic process does not explain the brain perfusion abnormalities. Radiation therapy also does not explain the ^99mTc-HMPAO brain scan abnormalities, because severe abnormalities occurred before cerebral irradiation or in children who did not receive cerebral or total-body irradiation (nos. 2, 5, and 11). Therefore, drug-related toxicity seems to be the more likely cause, as previously described for methotrexate.^14,15 Among the drugs used, idarubicin and mitoxantrone do not exhibit a noticeable neurotoxicity at the conventional dosage. Therefore, etoposide, methotrexate (no. 1), and ara-C are drugs that might explain the abnormalities observed after induction therapy. The occurrence of neurotoxicity exclusively after the conventional dose of anthracyclin and HD ara-C–containing regimens underscores the main responsibility of ara-C. Moreover, HD ara-C has a well-described dose-related neurotoxicity, even in children, and up to 50% of patients treated with HD ara-C–containing regimens may have experienced CNS side effects.^6,22 Spontaneous complete clinical and MRI resolution of the syndrome observed after HD ara-C treatment, suggests a reversible drug-related neurotoxicity and supports this hypothesis.^10,23 In our series, the partial (nos. 2 and 11) or complete (nos. 5, 10, and 12) reversibility of brain SPECT abnormalities was observed in five children, as was the case for patient no. 5 (Fig 3).

Physiopathology
Heterogeneous supratentorial cortex perfusion was the main brain ^99mTc-HMPAO SPECT abnormality. No cerebral vascular distribution was observed. This phenomenon suggested a global cerebral involvement and not a large-vessel ischemic process. In postmortem studies, various nonspecific histologic changes, including multifocal leukoencephalopathy, small vessel ischemia, and paraneoplasic encephalomyelitis, have been described after ara-C treatment.^24-26 The heterogeneous pattern of ^99mTc-HMPAO SPECT may be related to local or remote consequences of those histologic changes.

In our study, SPECT cerebellar abnormalities were observed in five children (nos. 1, 2, 4, 10, and 11). Cerebellar dysfunction in HD ara-C–treated patients has previously been described.^6,23,27-29 The most consistent finding is a loss of Purkinje cells in the cerebellar hemispheres and in the vermix. A reactive proliferation of glial cells and astrocytes has been observed in response to Purkinje cell injury.^6,27 Moreover, a previous study has shown cerebellar atrophy on computed tomography scan in patients receiving HD ara-C treatment.³⁰ Patient no. 2 is particularly interesting because ^99mTc-HMPAO SPECT scan showed a diffuse cerebral heterogeneity with a cerebellar hyperperfusion 2 days after an acute cerebellar syndrome. Consecutively, MRI showed cerebellar atrophy 1 year after the acute neurologic episode (Fig 2).

Cortical and/or cerebellar perfusion abnormalities were found in children who did not exhibit clinical neurotoxicity (nos. 3, 4, 10, and 12) and were even found after ara-C treatment at a conventional dosage. This phenomenon may be explained by minimal or microscopic cerebral damage not responsible for neurologic signs and not detectable on MRI scans. In a pathologic study, Winkelman and Hines²⁷ showed minimal cerebellar damage in patients who where treated with HD ara-C but suffered no clinical neurotoxicity and in patients who even received conventional doses of cytarabine. Therefore, long-term follow-up in those patients seems crucial to detect any neuropsychologic impairment consecutive to these possible infraclinical damages.

Even if poorly understood, our results suggest that abnormal brain perfusion appears as soon as the induction therapy containing conventional doses of ara-C is initiated. After HD ara-C–containing intensification, these abnormalities seemed to be marked in children who have experienced neurologic toxicity, even when the MRI scans remained normal.

	ACKNOWLEDGMENTS

 
We thank R. Medeiros for his assistance in editing the manuscript.

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Submitted December 1, 1998; accepted May 18, 1999.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Véra, P. Articles by Vilmer, E. Search for Related Content PubMed PubMed Citation Articles by Véra, P. Articles by Vilmer, E.