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Review of Dextromethorphan Administration in 18 Patients With Subacute Methotrexate Central Nervous System Toxicity
Pediatric Neurology 50 (2014) 625e629
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Review of Dextromethorphan Administration in 18 Patients With Subacute Methotrexate Central Nervous System Toxicity Maryam Afshar MD a, *, Daniel Birnbaum MD b, Carla Golden MD c a
Department of Pediatrics, Children’s Hospital & Research Center Oakland, Oakland California Department of Pediatric Neurology, Children’s Hospital & Research Center Oakland, Oakland California c Department of Pediatric Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland California b
abstract BACKGROUND: The pathogenesis of methotrexate central nervous system toxicity is multifactorial, but it is likely
related to central nervous system folate homeostasis. The use of folinate rescue has been described to decrease toxicity in patients who had received intrathecal methotrexate. It has also been described in previous studies that there is an elevated level of homocysteine in plasma and cerebrospinal fluid of patients who had received intrathecal methotrexate. Homocysteine is an N-methyl-D-aspartate receptor agonist. The use of dextromethorphan, noncompetitive N-methyl-D-aspartate receptor receptor antagonist, has been used in the treatment of sudden onset of neurological dysfunction associated with methotrexate toxicity. It remains unclear whether the dextromethorphan impacted the speed of recovery, and its use remains controversial. This study reviews the use of dextromethorphan in the setting of subacute methotrexate central nervous system toxicity. METHODS: Charts of 18 patients who had sudden onset of neurological impairments after receiving methotrexate and were treated with dextromethorphan were reviewed. RESULT: The use of dextromethorphan in most of our patients resulted in symptomatic improvement. In this patient population, earlier administration of dextromethorphan resulted in faster improvement of impairments and led to prevention of recurrence of seizure activity induced by methotrexate central nervous system toxicity. CONCLUSIONS: Our study provides support for the use of dextromethorphan in patients with subacute methotrexate central nervous system toxicity. Keywords: methotrexate CNS toxicity, dextromethorphan, homocysteine, NMDA receptor
Pediatr Neurol 2014; 50: 625-629 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Methotrexate is a folic acid antagonist; it blocks the synthesis of purines and pyrimidines by inhibiting several key enzymes. A well-known and clinically important side effect of methotrexate is its associated central nervous system (CNS) toxicity, which presents most frequently after intrathecal methotrexate administration; however, it can be observed after intravenous methotrexate at low and high doses. The CNS toxicity has been categorized as being acute,
Article History: Received December 4, 2013; Accepted in final form January 27, 2014 * Communications should be addressed to: Dr. Maryam Afshar; Department of Pediatrics; Children’s Hospital & Research Center Oakland; 747 52nd Street; Oakland, CA 94609. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.048
subacute, or chronic.1 Acute CNS toxicity occurs within a few hours after methotrexate administration, and patients usually exhibit signs of chemical meningitis: somnolence, confusion, headache, nausea, vomiting, and dizziness. Subacute CNS toxicity is observed within days to weeks of methotrexate therapy, and a patient may exhibit seizures or stroke-like signs including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Chronic CNS toxicity occurs months to years after methotrexate therapy, and patients exhibit signs of cognitive dysfunction, behavioral abnormalities, and spasticity.1 A possible mechanism of methotrexate CNS toxicity is through methotrexate’s disruption of remethylation of homocysteine to methionine. Homocysteine is directly toxic to vascular endothelium, and its metabolites are excitatory agonists of N-methyl-D-aspartate (NMDA) receptors.2 Here, we will review cases of 18 patients with subacute
626
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
TABLE 1. Clinical Features and Details of Therapy of 18 Patients With Subacute Methotrexate CNS Toxicity S.No
Dx
Patient’s Protocol
Age (yr)
Sex
Time Since Last MTX (days)
Dose of MTX
Physical Examination Findings
Group A 1 2 3
ALL ALL ALL
CCG 1961 AALL02P2 CCG 1961
14 3.5 15
M M F
12 6 4
12 mg IT 12 mg IT 12 mg IT
4
ALL
CCG 1961
18
F
4
12 mg IT
5
ALL
CCG 1991
8
F
4
12 mg IT
6
VWD ALL
CCG 1961
5.5
M
3
12 mg IT
7
ALL
CCG 1961
14
F
7
12 mg IT
8 9 10
ALL ALL OS
AALL02P2 CCG 1922 AOST0791
15 6 14
M F F
7 5 2
5 g/m2 IV 12 mg IT 12 g/m2 IV
Convulsions followed by slurred speech Confusion Right sided weakness, dysarthria, expressive dysphagia, and incontinence Confusion, slurred speech, obsessive compulsive behavior, and rumination. Slurred speech, drooling, difficulty moving left arm, difficulty with word finding, ataxia, agitation and complaint of dizziness, and headaches Ataxia, dysmetria with right lower extremity weakness and emotional labiality Mental status changes, decrease alertness, slurred speech, left facial droop, inability to speak, and right-sided weakness Slurred speech and left-sided weakness Right limb and face weakness Waxing and waning sensorium and mild dysmetria
ALL
CCG 1961
6
M
8
12 mg IT
12 13
ALL ALL
AALL0232 AALL0232
16 17
M M
3 8
7.5 mg IT 15 mg IT
14
ALL
AALL0232
10
F
7
15 mg IT
15 16 17 18
ALL ALL ALL ALL
CCG CCG CCG CCG
13 2 10 15
M M F F
3 3 3 9
12 mg IT 8 mg IT 12 mg IT 12 mg IT
Group B 11
1961 1991 1961 1961
Seizure, disconjugate gaze, ataxia, clumsiness, and cognitive slowing Right hemiparesis, aphasia, and facial droop Mental status changes and left-sided hemiparesis Left facial numbness and left arm and leg weakness and numbness Seizure Lower extremity trembling and unsteady gait Disorientation and acute right-sided weakness Difficulty swallowing, talking, right hemiparesis, and increase in agitation with eventual somnolence and aphasia
Abbreviations: ALL ¼ Acute lymphoblastic leukemia Ara C ¼ Cytarabine b.i.d ¼ Twice a day CNS ¼ Central nervous system DM ¼ Dextromethorphan Dx ¼ Diagnosis F ¼ Female HC ¼ Hydrocortisone IT ¼ Intrathecal M ¼ Male MTX ¼ Methotrexate OS ¼ Osteogenic sarcoma PPx ¼ Prophylaxis q.d ¼ Once a day VWD ¼ Von Willebrand Disease * Resolved ¼ Resolved before DM administration
methotrexate CNS toxicity treated with dextromethorphan at different time intervals after start of their dysfunction. Patients and Methods The charts of 18 patients, at various time points of treatment protocol, who had sudden onset of neurological impairments after receiving methotrexate from 2000 to 2012 and were treated with dextromethorphan were reviewed (Table 1). None of the patients had any prior cranial radiation therapy. The dose of dextromethorphan ranged from 1 to 3 mg/ kg per day. No adverse reactions to dextromethorphan were noted. Parents and patients were provided information about dextromethorphan and the reasoning behind its off-label use. The mean age of patients reviewed was 11.2 years. Twelve of 18 patients were noted to be Hispanic based on their own reporting. Most patients (17/18) had the diagnosis of acute lymphoblastic leukemia. All the patients had imaging studies done at the time of presentation that ruled out other intracranial processes, such as hemorrhage, ischemia, masses, or thrombosis, which could have explained their impairments.
Neurological deficits noted in the patients ranged from seizure activity to unresponsiveness. The mean time from receiving methotrexate to development of neurological deficit was 5.4 days. Eight of 18 patients started dextromethorphan 24 hours after start of their findings, titled group A. The remaining 10 patients (group B) received their first dose of dextromethorphan on average within 7.6 hours after start of their findings. One of the 10 patients in group B, Patient 9, had resolution of impairments before receiving dextromethorphan. After dextromethorphan administration, he did not have any recurrence of his impairments. The remaining nine patients in group B improved within 3.5 hours of receiving dextromethorphan. The average response time for group A patients who received dextromethorphan 24 hours or later after start of impairments was 13.9 hours. Patients 1 and 15 presented with seizure activity without fever or other etiologies for seizure. The seizure of Patient 1 lasted 2 minutes. After his seizure, he was noted to have slurred speech. He was started on dextromethorphan about an hour after start of his seizure activity and development of slurred speech. His slurred speech was noted to improve within about 12 minutes after start of dextromethorphan administration and resolved after 2 hours. He also did not suffer any recurrence of
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
627
TABLE 1. Clinical Features and Details of Therapy of 18 Patients With Subacute Methotrexate CNS Toxicity (Continued) Time to Initial Dose of DM (hr)
DM Dose
Duration of DM
1 3 5
1 mg/kg b.i.d. 1 mg/kg q.d. 1 mg/kg b.i.d.
24 hr 2 days 8 days
6
1 mg/kg b.i.d.
6.5
Time to Resolution of impairments after initial onset
MTX changed to
0.2 2.5 1
2 hr 6 hr 7 days
Ara C/HC MTX with DM PPx Ara C/HC
7 days
7
7 days
Ara C/HC
1 mg/kg b.i.d.
4 days
2
3 days
Ara C/HC
6.5
1 mg/kg b.i.d.
3 days
5.5
Ara C/HC
7
1 mg/kg b.i.d.
6 days
1
1 modimproved dramatically. Continues to have ataxia 9 yr later. 1.5 mo
Ara C/HC
9 16 16
1.5 mg/kg q.d. 1 mg/kg b.i.d. 2.5 mg/kg q.d.
1 wk 1.5 days 2 days
26 hr 4 hr 24 hr
MTX with DM PPx Ara C/HC MTX with DM PPx
24
1 mg/kg b.i.d.
4 days
3
5 days
Ara C/HC
24 27
1.5 mg/kg q.d. 0.9 mg/kg b.i.d.
3 days 20 days
11 16
MTX with DM PPx Ara C/HC
28
2 mg/kg q.d.
2 days
12
3 days 8 wkdimproved with residual left-sided weakness 4 mo later. 40 hr
1 mg/kg b.i.d. 1.5 mg/kg b.i.d. 1 mg/kg b.i.d. 1 mg/kg b.i.d.
4 4 1 6
15 4 43 7
2.5 days 7 days 20 days 2 mo
Ara Ara Ara Ara
48 48 96 240
days days day days
Time to Initial Response After DM (hr)
4 Resolved* 8
seizure activity and did not receive anticonvulsants. Patient 15 was started on dextromethorphan 48 hours after his first seizure activity, and he suffered two more episodes of seizures. He had one 8 hours before start of dextromethorphan and another about 12 hours after start of dextromethorphan. He was started on antiepileptics after his second episode of seizure. Sixteen of 18 patients fully recovered. Patient 6 has continued to have ataxia and has also been noted to have speech and learning disabilities 9 years after the initial episode of subacute methotrexate CNS toxicity. Patient 13 has continued to have residual left-sided weakness at 16 weeks from his initial event. A summary of data is provided in Table 2.
Discussion
With the improvement in overall cure rate for pediatric malignancies, it has become imperative to decrease the long-term toxicity of treatment regimens. The use of intrathecal methotrexate and intravenous methotrexate
MTX with DM PPx C/HC C/HC C/HC C/HC
instead of cranial radiotherapy has been described to effectively decrease CNS relapse in low-risk acute lymphoblastic leukemia.3 With the increased use of methotrexate, a wide range of toxicities affecting the CNS has been noted. Winick et al.4 in 1992 were the first to highlight the role of elevated homocysteine level in development of methotrexate CNS toxicity. Although etiology of the CNS toxicity is likely multifactorial, we also hypothesize that elevated homocysteine plays an integral role in development of methotrexate-associated CNS toxicity. Homocysteine is a very reactive amino acid, and it is metabolized to excitatory amino acid neurotransmitters.5 Hyperhomocystinemia as a result of methotrexate is due to cellular depletion of reduced folates, including 5-methyltetrahydrofolate, which is a carbon donor in conversion of homocysteine to methionine.6 Hyperhomocystinemia has been reported in patients after
628
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
TABLE 2. Summary of 18 Patients Reviewed in the Study
Mean age of group A þ B patients Mean time from receiving MTX to development of CNS toxicity in group A þ B Hispanic ethnicity (based on Self reporting) in group A þ B Number of patients in group A Average time to first dose of Dex in group A after development of CNS toxicity Average initial response time for group A Number of patients in group B Average time to first dose of Dex in group B after development of CNS toxicity Average initial response time for 9/10* of group B
11.2 yr 5.4 days 12/18 8 66.9 hr 13.9 hr 10 7.6 hr 3.5 hr
Abbreviations: CNS ¼ Central nervous system Dex ¼ dextromethorphan MTX ¼ Methotrexate Group A: Patients who received dextromethorphan 24 hour after developing MTX CNS toxicity. Group B: Patients who received dextromethorphan <24 hours after developing MTX CNS toxicity. * Patient 2 was excluded because he recovered before receiving dextromethorphan.
methotrexate therapy in plasma, urine,6-10 and cerebrospinal fluid (CSF).5 The plasma concentration of homocysteine has been revealed to be higher in patients who developed methotrexate CNS toxicity.6 CSF studies of animals after four doses of intrathecal methotrexate have revealed a significant increase in homocysteine and homocysteic acid concentration in association with recognition and spatial memory deficits.11 An increase in level of excitatory amino acid neurotransmitters has also been noted in CSF of a patient who suffered seizure after receiving methotrexate.12 Hyperhomocystinemia has been recognized as a known risk factor for neurodegeneration.13 Cytotoxic effects of homocysteine on neurons have been evaluated both in vitro and also in vivo studies. Zieminska et al.13 incubated rat cerebellar granular cell culture with homocysteine and measured homocysteine toxicity through propidium iodide staining, which was evident after a 24-hour incubation. In animal models, induction of seizure has been accomplished through intraventricular infusion of homocysteic acid.14 Homocysteine and its excitotoxic amino acids are agonists at ionotropic glutamate receptors, including the NMDA receptors.11 Neuronal damage including neuronal apoptosis occurs with excessive excitation at the NMDA receptors through causing an influx of NaCl and water and causing acute neuronal swelling and injury.15 NMDA receptors have been implicated in homocysteine-induced CNS toxicity. In vitro work done by Zieminska and Lazarewicz16 has shown that use of uncompetitive NMDA receptor antagonist in combination with ionotropic glutamate receptor antagonist provides protection against chronic homocysteine toxicity in cell culture exposed to homocysteine. It is reasonable to hypothesize that methotrexate-associated CNS toxicity is secondary to the excitotoxic property of homocysteine metabolites on NMDA receptors. Attenuation of the excitatory effects of homocysteine on the NMDA receptors presents as a possible mechanism to indirectly ameliorate the toxic properties of methotrexate. Dextromethorphan is a nonopioid morphinan derivative that acts as a noncompetitive antagonist of NMDA receptors.11 In vivo study using mice that had sustained
cognitive deficits secondary to methotrexate has shown that use of dextromethorphan can reverse the methotrexate-induced cognitive deficits.11 Drachtman et al.2 noted resolution of impairments in five patients with severe subacute methotrexate-induced CNS toxicity after administration of dextromethorphan. Our case review provides further support for the use of dextromethorphan in patients with methotrexate CNS toxicity. The use of dextromethorphan in most of our patients resulted in symptomatic improvement. This was especially prominent in Patient 18 who was continuously symptomatic for 10 days and started to improve within 7 hours of dextromethorphan administration. Patient 16 also improved within hours of dextromethorphan administration after having been symptomatic for 48 hours. Patients who received dextromethorphan within the first 24 hours of becoming symptomatic (group B) exhibited improvement four times faster as compared with patients who had a delay of 24 hours or more in receiving dextromethorphan. Comparing Patients 1 and 15, both of the same age, same diagnosis, and without any family history of seizure disorders, points to the possibility that early administration of dextromethorphan to patients who present with seizure activity thought related to methotrexate CNS toxicity could be effective in preventing recurrence of seizure activity. Patient 1 was given dextromethorphan within an hour of his first seizure activity, whereas Patient 15 received his first dose of dextromethorphan 48 hours after his first episode of seizure activity. Patient 1 did not have recurrence of seizure activity and did not require any antiepileptics, whereas Patient 15 had two more episodes of seizures: one before dextromethorphan administration and one after dextromethorphan administration and required antiepileptics. The use of intrathecal methotrexate was replaced with intrathecal cytarabine (Ara C) with hydrocortisone in 13 of 18 patients. This change in therapy was discussed at length with the families and patients because there has never been a pediatric oncology trial directly comparing intrathecal methotrexate versus Ara C with hydrocortisone as CNS prophylaxis in patients with leukemia. There has not been any reported recurrence of disease or repeat neurological complications in this group of patients, which suggests that the use of intrathecal Ara C with hydrocortisone is as safe as methotrexate in this setting. We have not observed an increased relapse in patients treated this way. Five of the 18 patients were continued on methotrexate with dextromethorphan prophylaxis. This group has also done well without any recurrence of signs of CNS toxicity with methotrexate. We acknowledge the possibility of placebo effect and the limitation of this retrospective, nonplacebo-controlled, nonrandomized review. Nevertheless, dextromethorphan appears to be a potential therapeutic option for treatment of the methotrexate CNS toxicity. Although most patients with methotrexate CNS toxicity spontaneously recover, the dysfunction may cause great distress for the patient and their family, and as observed in patients 6 and 13, some individuals experience long-term neurological deficits as a result of severe leukoencephalopathy. Consequently, future prospective randomized placebo-controlled studies are needed to further investigate role of dextromethorphan in reversing or preventing subacute methotrexate CNS toxicity
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
and whether there is any effect on the incidence of late methotrexate CNS toxicity.
9.
References 1. Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy. 2003;49:92-104. 2. Drachtman RA, Cole PD, Golden CB, et al. Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatric Hematology and Oncology. 2002;19:319-327. 3. Schrappe M, Reiter A, Riehm H. Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. J Neurooncol. 1998;38:159-165. 4. Winick NJ, Bowman WP, Kamen BA, et al. Unexpected acute neurologic toxicity in the treatment of children with acute lymphoblastic leukemia. J Natl Cancer Inst. 1992;19:252-256. 5. Quinn CT, Griener JC, Bottiglieri T, Hyland K, Farrow A, Kamen BA. Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer. J Clin Oncol. 1997;15: 2800-2806. 6. Kishi S, Greiner J, Cheng C, et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. Journal of Clinical Oncology. 2003;21:3084-3091. 7. Refsum H, Ueland PM, Kvinnsland S. Acute and long-term effects of high-dose methotrexate treatment on homocysteine in plasma and urine. Cancer Res. 1986;46:5385-5391. 8. Refsum H, Helland S, Ueland PM. Fasting plasma homocysteine as a sensitive parameter of antifolate effect: a study of psoriasis patients
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12. 13.
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15.
16.
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receiving low-dose methotrexate treatment. Clin Pharmacol Ther. 1989;46:510-520. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer Res. 1991;51:828-835. Broxson EH Jr, Stork LC, Allen RH, Stabler SP, Kolhouse JF. Changes in plasma methionine and total homocysteine levels in patients receiving methotrexate infusions. Cancer Res. 1989;49:5879-5883. Vijayanathan V, Gulinello M, Ali N, Cole PD. Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res. 2011;225:491-497. Quinn CT, Griener JC, Bottiglieri T, Kamen BA. Methotrexate, homocysteine, and seizures. J Clin Oncol. 1998;16:393-394. Zieminska E, Stafiej A, Lazarewicz JW. Role of group I metabotropic glutamate receptors and NMDA receptors in homocysteine-evoked acute neurodegeneration of cultured cerebellar granule neurones. Neurochem Int. 2003;43:481-492. Folbergrova J, Haugvicova R, Mares P. Seizures induced by homocysteic acid in immature rats are prevented by group III metabotropic glutamate receptoragonist (R,S)-4-phosphonophenylglycine. Exp Neurol. 2003;180:46-54. Collins RC, Dobkin BH, Choi DW. Selective vulnerability of the brain: new insights into the pathophysiology of stroke. Ann Intern Med. 1989;110:992-1000. Zieminska E, Lazarewicz JW. Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studies in vitro: the role of NMDA and group I metabotropic glutamate receptors. Acta Neurobiol Exp. 2006; 66:301-309.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Review of Dextromethorphan Administration in 18 Patients With Subacute Methotrexate Central Nervous System Toxicity Maryam Afshar MD a, *, Daniel Birnbaum MD b, Carla Golden MD c a
Department of Pediatrics, Children’s Hospital & Research Center Oakland, Oakland California Department of Pediatric Neurology, Children’s Hospital & Research Center Oakland, Oakland California c Department of Pediatric Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland California b
abstract BACKGROUND: The pathogenesis of methotrexate central nervous system toxicity is multifactorial, but it is likely
related to central nervous system folate homeostasis. The use of folinate rescue has been described to decrease toxicity in patients who had received intrathecal methotrexate. It has also been described in previous studies that there is an elevated level of homocysteine in plasma and cerebrospinal fluid of patients who had received intrathecal methotrexate. Homocysteine is an N-methyl-D-aspartate receptor agonist. The use of dextromethorphan, noncompetitive N-methyl-D-aspartate receptor receptor antagonist, has been used in the treatment of sudden onset of neurological dysfunction associated with methotrexate toxicity. It remains unclear whether the dextromethorphan impacted the speed of recovery, and its use remains controversial. This study reviews the use of dextromethorphan in the setting of subacute methotrexate central nervous system toxicity. METHODS: Charts of 18 patients who had sudden onset of neurological impairments after receiving methotrexate and were treated with dextromethorphan were reviewed. RESULT: The use of dextromethorphan in most of our patients resulted in symptomatic improvement. In this patient population, earlier administration of dextromethorphan resulted in faster improvement of impairments and led to prevention of recurrence of seizure activity induced by methotrexate central nervous system toxicity. CONCLUSIONS: Our study provides support for the use of dextromethorphan in patients with subacute methotrexate central nervous system toxicity. Keywords: methotrexate CNS toxicity, dextromethorphan, homocysteine, NMDA receptor
Pediatr Neurol 2014; 50: 625-629 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Methotrexate is a folic acid antagonist; it blocks the synthesis of purines and pyrimidines by inhibiting several key enzymes. A well-known and clinically important side effect of methotrexate is its associated central nervous system (CNS) toxicity, which presents most frequently after intrathecal methotrexate administration; however, it can be observed after intravenous methotrexate at low and high doses. The CNS toxicity has been categorized as being acute,
Article History: Received December 4, 2013; Accepted in final form January 27, 2014 * Communications should be addressed to: Dr. Maryam Afshar; Department of Pediatrics; Children’s Hospital & Research Center Oakland; 747 52nd Street; Oakland, CA 94609. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.048
subacute, or chronic.1 Acute CNS toxicity occurs within a few hours after methotrexate administration, and patients usually exhibit signs of chemical meningitis: somnolence, confusion, headache, nausea, vomiting, and dizziness. Subacute CNS toxicity is observed within days to weeks of methotrexate therapy, and a patient may exhibit seizures or stroke-like signs including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Chronic CNS toxicity occurs months to years after methotrexate therapy, and patients exhibit signs of cognitive dysfunction, behavioral abnormalities, and spasticity.1 A possible mechanism of methotrexate CNS toxicity is through methotrexate’s disruption of remethylation of homocysteine to methionine. Homocysteine is directly toxic to vascular endothelium, and its metabolites are excitatory agonists of N-methyl-D-aspartate (NMDA) receptors.2 Here, we will review cases of 18 patients with subacute
626
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
TABLE 1. Clinical Features and Details of Therapy of 18 Patients With Subacute Methotrexate CNS Toxicity S.No
Dx
Patient’s Protocol
Age (yr)
Sex
Time Since Last MTX (days)
Dose of MTX
Physical Examination Findings
Group A 1 2 3
ALL ALL ALL
CCG 1961 AALL02P2 CCG 1961
14 3.5 15
M M F
12 6 4
12 mg IT 12 mg IT 12 mg IT
4
ALL
CCG 1961
18
F
4
12 mg IT
5
ALL
CCG 1991
8
F
4
12 mg IT
6
VWD ALL
CCG 1961
5.5
M
3
12 mg IT
7
ALL
CCG 1961
14
F
7
12 mg IT
8 9 10
ALL ALL OS
AALL02P2 CCG 1922 AOST0791
15 6 14
M F F
7 5 2
5 g/m2 IV 12 mg IT 12 g/m2 IV
Convulsions followed by slurred speech Confusion Right sided weakness, dysarthria, expressive dysphagia, and incontinence Confusion, slurred speech, obsessive compulsive behavior, and rumination. Slurred speech, drooling, difficulty moving left arm, difficulty with word finding, ataxia, agitation and complaint of dizziness, and headaches Ataxia, dysmetria with right lower extremity weakness and emotional labiality Mental status changes, decrease alertness, slurred speech, left facial droop, inability to speak, and right-sided weakness Slurred speech and left-sided weakness Right limb and face weakness Waxing and waning sensorium and mild dysmetria
ALL
CCG 1961
6
M
8
12 mg IT
12 13
ALL ALL
AALL0232 AALL0232
16 17
M M
3 8
7.5 mg IT 15 mg IT
14
ALL
AALL0232
10
F
7
15 mg IT
15 16 17 18
ALL ALL ALL ALL
CCG CCG CCG CCG
13 2 10 15
M M F F
3 3 3 9
12 mg IT 8 mg IT 12 mg IT 12 mg IT
Group B 11
1961 1991 1961 1961
Seizure, disconjugate gaze, ataxia, clumsiness, and cognitive slowing Right hemiparesis, aphasia, and facial droop Mental status changes and left-sided hemiparesis Left facial numbness and left arm and leg weakness and numbness Seizure Lower extremity trembling and unsteady gait Disorientation and acute right-sided weakness Difficulty swallowing, talking, right hemiparesis, and increase in agitation with eventual somnolence and aphasia
Abbreviations: ALL ¼ Acute lymphoblastic leukemia Ara C ¼ Cytarabine b.i.d ¼ Twice a day CNS ¼ Central nervous system DM ¼ Dextromethorphan Dx ¼ Diagnosis F ¼ Female HC ¼ Hydrocortisone IT ¼ Intrathecal M ¼ Male MTX ¼ Methotrexate OS ¼ Osteogenic sarcoma PPx ¼ Prophylaxis q.d ¼ Once a day VWD ¼ Von Willebrand Disease * Resolved ¼ Resolved before DM administration
methotrexate CNS toxicity treated with dextromethorphan at different time intervals after start of their dysfunction. Patients and Methods The charts of 18 patients, at various time points of treatment protocol, who had sudden onset of neurological impairments after receiving methotrexate from 2000 to 2012 and were treated with dextromethorphan were reviewed (Table 1). None of the patients had any prior cranial radiation therapy. The dose of dextromethorphan ranged from 1 to 3 mg/ kg per day. No adverse reactions to dextromethorphan were noted. Parents and patients were provided information about dextromethorphan and the reasoning behind its off-label use. The mean age of patients reviewed was 11.2 years. Twelve of 18 patients were noted to be Hispanic based on their own reporting. Most patients (17/18) had the diagnosis of acute lymphoblastic leukemia. All the patients had imaging studies done at the time of presentation that ruled out other intracranial processes, such as hemorrhage, ischemia, masses, or thrombosis, which could have explained their impairments.
Neurological deficits noted in the patients ranged from seizure activity to unresponsiveness. The mean time from receiving methotrexate to development of neurological deficit was 5.4 days. Eight of 18 patients started dextromethorphan 24 hours after start of their findings, titled group A. The remaining 10 patients (group B) received their first dose of dextromethorphan on average within 7.6 hours after start of their findings. One of the 10 patients in group B, Patient 9, had resolution of impairments before receiving dextromethorphan. After dextromethorphan administration, he did not have any recurrence of his impairments. The remaining nine patients in group B improved within 3.5 hours of receiving dextromethorphan. The average response time for group A patients who received dextromethorphan 24 hours or later after start of impairments was 13.9 hours. Patients 1 and 15 presented with seizure activity without fever or other etiologies for seizure. The seizure of Patient 1 lasted 2 minutes. After his seizure, he was noted to have slurred speech. He was started on dextromethorphan about an hour after start of his seizure activity and development of slurred speech. His slurred speech was noted to improve within about 12 minutes after start of dextromethorphan administration and resolved after 2 hours. He also did not suffer any recurrence of
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
627
TABLE 1. Clinical Features and Details of Therapy of 18 Patients With Subacute Methotrexate CNS Toxicity (Continued) Time to Initial Dose of DM (hr)
DM Dose
Duration of DM
1 3 5
1 mg/kg b.i.d. 1 mg/kg q.d. 1 mg/kg b.i.d.
24 hr 2 days 8 days
6
1 mg/kg b.i.d.
6.5
Time to Resolution of impairments after initial onset
MTX changed to
0.2 2.5 1
2 hr 6 hr 7 days
Ara C/HC MTX with DM PPx Ara C/HC
7 days
7
7 days
Ara C/HC
1 mg/kg b.i.d.
4 days
2
3 days
Ara C/HC
6.5
1 mg/kg b.i.d.
3 days
5.5
Ara C/HC
7
1 mg/kg b.i.d.
6 days
1
1 modimproved dramatically. Continues to have ataxia 9 yr later. 1.5 mo
Ara C/HC
9 16 16
1.5 mg/kg q.d. 1 mg/kg b.i.d. 2.5 mg/kg q.d.
1 wk 1.5 days 2 days
26 hr 4 hr 24 hr
MTX with DM PPx Ara C/HC MTX with DM PPx
24
1 mg/kg b.i.d.
4 days
3
5 days
Ara C/HC
24 27
1.5 mg/kg q.d. 0.9 mg/kg b.i.d.
3 days 20 days
11 16
MTX with DM PPx Ara C/HC
28
2 mg/kg q.d.
2 days
12
3 days 8 wkdimproved with residual left-sided weakness 4 mo later. 40 hr
1 mg/kg b.i.d. 1.5 mg/kg b.i.d. 1 mg/kg b.i.d. 1 mg/kg b.i.d.
4 4 1 6
15 4 43 7
2.5 days 7 days 20 days 2 mo
Ara Ara Ara Ara
48 48 96 240
days days day days
Time to Initial Response After DM (hr)
4 Resolved* 8
seizure activity and did not receive anticonvulsants. Patient 15 was started on dextromethorphan 48 hours after his first seizure activity, and he suffered two more episodes of seizures. He had one 8 hours before start of dextromethorphan and another about 12 hours after start of dextromethorphan. He was started on antiepileptics after his second episode of seizure. Sixteen of 18 patients fully recovered. Patient 6 has continued to have ataxia and has also been noted to have speech and learning disabilities 9 years after the initial episode of subacute methotrexate CNS toxicity. Patient 13 has continued to have residual left-sided weakness at 16 weeks from his initial event. A summary of data is provided in Table 2.
Discussion
With the improvement in overall cure rate for pediatric malignancies, it has become imperative to decrease the long-term toxicity of treatment regimens. The use of intrathecal methotrexate and intravenous methotrexate
MTX with DM PPx C/HC C/HC C/HC C/HC
instead of cranial radiotherapy has been described to effectively decrease CNS relapse in low-risk acute lymphoblastic leukemia.3 With the increased use of methotrexate, a wide range of toxicities affecting the CNS has been noted. Winick et al.4 in 1992 were the first to highlight the role of elevated homocysteine level in development of methotrexate CNS toxicity. Although etiology of the CNS toxicity is likely multifactorial, we also hypothesize that elevated homocysteine plays an integral role in development of methotrexate-associated CNS toxicity. Homocysteine is a very reactive amino acid, and it is metabolized to excitatory amino acid neurotransmitters.5 Hyperhomocystinemia as a result of methotrexate is due to cellular depletion of reduced folates, including 5-methyltetrahydrofolate, which is a carbon donor in conversion of homocysteine to methionine.6 Hyperhomocystinemia has been reported in patients after
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M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
TABLE 2. Summary of 18 Patients Reviewed in the Study
Mean age of group A þ B patients Mean time from receiving MTX to development of CNS toxicity in group A þ B Hispanic ethnicity (based on Self reporting) in group A þ B Number of patients in group A Average time to first dose of Dex in group A after development of CNS toxicity Average initial response time for group A Number of patients in group B Average time to first dose of Dex in group B after development of CNS toxicity Average initial response time for 9/10* of group B
11.2 yr 5.4 days 12/18 8 66.9 hr 13.9 hr 10 7.6 hr 3.5 hr
Abbreviations: CNS ¼ Central nervous system Dex ¼ dextromethorphan MTX ¼ Methotrexate Group A: Patients who received dextromethorphan 24 hour after developing MTX CNS toxicity. Group B: Patients who received dextromethorphan <24 hours after developing MTX CNS toxicity. * Patient 2 was excluded because he recovered before receiving dextromethorphan.
methotrexate therapy in plasma, urine,6-10 and cerebrospinal fluid (CSF).5 The plasma concentration of homocysteine has been revealed to be higher in patients who developed methotrexate CNS toxicity.6 CSF studies of animals after four doses of intrathecal methotrexate have revealed a significant increase in homocysteine and homocysteic acid concentration in association with recognition and spatial memory deficits.11 An increase in level of excitatory amino acid neurotransmitters has also been noted in CSF of a patient who suffered seizure after receiving methotrexate.12 Hyperhomocystinemia has been recognized as a known risk factor for neurodegeneration.13 Cytotoxic effects of homocysteine on neurons have been evaluated both in vitro and also in vivo studies. Zieminska et al.13 incubated rat cerebellar granular cell culture with homocysteine and measured homocysteine toxicity through propidium iodide staining, which was evident after a 24-hour incubation. In animal models, induction of seizure has been accomplished through intraventricular infusion of homocysteic acid.14 Homocysteine and its excitotoxic amino acids are agonists at ionotropic glutamate receptors, including the NMDA receptors.11 Neuronal damage including neuronal apoptosis occurs with excessive excitation at the NMDA receptors through causing an influx of NaCl and water and causing acute neuronal swelling and injury.15 NMDA receptors have been implicated in homocysteine-induced CNS toxicity. In vitro work done by Zieminska and Lazarewicz16 has shown that use of uncompetitive NMDA receptor antagonist in combination with ionotropic glutamate receptor antagonist provides protection against chronic homocysteine toxicity in cell culture exposed to homocysteine. It is reasonable to hypothesize that methotrexate-associated CNS toxicity is secondary to the excitotoxic property of homocysteine metabolites on NMDA receptors. Attenuation of the excitatory effects of homocysteine on the NMDA receptors presents as a possible mechanism to indirectly ameliorate the toxic properties of methotrexate. Dextromethorphan is a nonopioid morphinan derivative that acts as a noncompetitive antagonist of NMDA receptors.11 In vivo study using mice that had sustained
cognitive deficits secondary to methotrexate has shown that use of dextromethorphan can reverse the methotrexate-induced cognitive deficits.11 Drachtman et al.2 noted resolution of impairments in five patients with severe subacute methotrexate-induced CNS toxicity after administration of dextromethorphan. Our case review provides further support for the use of dextromethorphan in patients with methotrexate CNS toxicity. The use of dextromethorphan in most of our patients resulted in symptomatic improvement. This was especially prominent in Patient 18 who was continuously symptomatic for 10 days and started to improve within 7 hours of dextromethorphan administration. Patient 16 also improved within hours of dextromethorphan administration after having been symptomatic for 48 hours. Patients who received dextromethorphan within the first 24 hours of becoming symptomatic (group B) exhibited improvement four times faster as compared with patients who had a delay of 24 hours or more in receiving dextromethorphan. Comparing Patients 1 and 15, both of the same age, same diagnosis, and without any family history of seizure disorders, points to the possibility that early administration of dextromethorphan to patients who present with seizure activity thought related to methotrexate CNS toxicity could be effective in preventing recurrence of seizure activity. Patient 1 was given dextromethorphan within an hour of his first seizure activity, whereas Patient 15 received his first dose of dextromethorphan 48 hours after his first episode of seizure activity. Patient 1 did not have recurrence of seizure activity and did not require any antiepileptics, whereas Patient 15 had two more episodes of seizures: one before dextromethorphan administration and one after dextromethorphan administration and required antiepileptics. The use of intrathecal methotrexate was replaced with intrathecal cytarabine (Ara C) with hydrocortisone in 13 of 18 patients. This change in therapy was discussed at length with the families and patients because there has never been a pediatric oncology trial directly comparing intrathecal methotrexate versus Ara C with hydrocortisone as CNS prophylaxis in patients with leukemia. There has not been any reported recurrence of disease or repeat neurological complications in this group of patients, which suggests that the use of intrathecal Ara C with hydrocortisone is as safe as methotrexate in this setting. We have not observed an increased relapse in patients treated this way. Five of the 18 patients were continued on methotrexate with dextromethorphan prophylaxis. This group has also done well without any recurrence of signs of CNS toxicity with methotrexate. We acknowledge the possibility of placebo effect and the limitation of this retrospective, nonplacebo-controlled, nonrandomized review. Nevertheless, dextromethorphan appears to be a potential therapeutic option for treatment of the methotrexate CNS toxicity. Although most patients with methotrexate CNS toxicity spontaneously recover, the dysfunction may cause great distress for the patient and their family, and as observed in patients 6 and 13, some individuals experience long-term neurological deficits as a result of severe leukoencephalopathy. Consequently, future prospective randomized placebo-controlled studies are needed to further investigate role of dextromethorphan in reversing or preventing subacute methotrexate CNS toxicity
M. Afshar et al. / Pediatric Neurology 50 (2014) 625e629
and whether there is any effect on the incidence of late methotrexate CNS toxicity.
9.
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