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CASE OF THE MONTH

ABSTRACT: A 3-year-old girl with acute lymphocytic leukemia (ALL) in remission developed lower extremity paraparesis and areflexia 15 days after receiving intrathecal methotrexate, cytarabine, and hydrocortisone. Cerebrospinal fluid protein was 107 mg/dl. Compound muscle action potential amplitudes were reduced, F waves were absent, and sensory conduction studies were normal. Needle electromyography (EMG) revealed reduced motor unit potential recruitment. Magnetic resonance imaging (MRI) showed lumbosacral ventral root enhancement. She was treated with intravenous immunoglobulin and slowly recovered. Nerve conduction and EMG abnormalities correlated with MRI root enhancement, facilitated early diagnosis, and distinguished this from a myelopathy or distal polyneuropathy. These findings could represent selective ventral nerve root vulnerability to intrathecal chemotherapy. A selective autoimmune process cannot be excluded.
2002 John Wiley & Sons, Inc. Muscle Nerve 25: 106110, 2002

VENTRAL POLYRADICULOPATHY WITH PEDIATRIC ACUTE LYMPHOCYTIC LEUKEMIA


STEPHEN C. ANDERSON, MD,1,2 GEORGE D. BAQUIS, MD,1 ANTHONY JACKSON, MD,2 PHILIP MONTELEONE, MD,3 and J. ROBERT KIRKWOOD, MD4
1

Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA Department of Pediatrics, Baystate Medical Center, Springfield, Massachusetts, USA 3 Department of Child Health, University of Missouri Health Sciences Center, Columbia, Missouri, USA 4 Department of Radiology, Baystate Medical Center, Springfield, Massachusetts, USA
2

Accepted 26 July 2001

Intrathecal

chemotherapy is commonly administered for prophylaxis or treatment of leukemic meningitis. Paraparesis is an uncommon complication of intrathecal methotrexate and cytarabine (Ara-C), and acute polyradiculopathy has rarely been reported as a cause of this syndrome. We describe clinical characteristics, magnetic resonance imaging (MRI) abnormalities, and electrodiagnostic findings of a child with acute lymphocytic leukemia (ALL) in remission who developed an acute ventral polyradiculopathy after treatment with intrathecal methotrexate, Ara-C, and hydrocortisone.

CASE REPORT

A 3-year-old girl with ALL in remission on maintenance chemotherapy developed progressive lower
Abbreviations: ALL, acute lymphocytic leukemia; Ara-C, cytarabine; CSF, cerebrospinal fluid; EMG, electromyography; MRI, magnetic resonance imaging Key words: intrathecal chemotherapy; paraparesis; pediatric acute lymphocytic leukemia; ventral polyradiculopathy; ventral root enhancement Correspondence to: S. Anderson, Belchertown Wellness Center, 95 Sargent Street, Belchertown, MA 01199; e-mail: sanderso@massmed.org 2002 John Wiley & Sons, Inc. DOI 10.1002/mus.1219

extremity flaccid weakness, inability to walk, and mild upper extremity weakness over a 2-week period. Chemotherapy 12 days prior to onset of symptoms included intrathecal methotrexate, Ara-C, and hydrocortisone, along with intravenous vincristine. This treatment was part of Childrens Cancer Group Protocol 1952, which also included L-asparaginase, cyclophosphamide, oral methotrexate, and 6-mercaptopurine. She had received no radiation therapy. She had a mild fever and upper respiratory infection 1 month prior to the onset of her symptoms. Examination revealed lower extremity flaccid paralysis, mild upper extremity weakness, absent patellar and ankle tendon reflexes, and normal sensation. Serum creatine kinase, thyroid-stimulating hormone, calcium, electrolytes, erythrocyte sedimentation rate, complete blood count, and blood cultures were normal. Cerebrospinal fluid (CSF) showed 0 white blood cells/mm3, absence of malignant cells, elevated total protein concentration (107 mg/dl), normal glucose level (55 mg/dl), and normal electrophoresis. Campylobacter jejuni, Borrelia burgdorferi, mycoplasma, human immunodeficiency viruses 1

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and 2, cytomegalovirus, GM1, asialo-GM1, GD1B, and GQ1B antibody titers were normal. A bone scan was normal. Spinal MRI with gadolinium showed abnormal enhancement of multiple ventral nerve roots within the conus medullaris (Figs. 1 and 2). Electrodiagnostic abnormalities were present, consistent with an acute multilevel intraspinal disorder affecting motor nerves in all extremities. Lower extremity nerve conduction velocities were normal, F waves were absent, and compound muscle action potentials were reduced in amplitude distally without multifocal conduction block (Table 1). Needle EMG showed absence of lower extremity muscle activation, a reduced motor unit potential recruitment pattern with normal insertional activity, absent spontaneous activity, and motor unit potentials of normal configuration in the proximal and distal right arm muscles. She was empirically treated with 1.7 g/kg of intravenous immunoglobulin, divided into two doses given on 2 consecutive days, for a possible acute immune demyelinating polyradiculopathy, and within 3 days proximal leg strength improved. After 4 months she could walk without assistance and her tendon reflexes were normal. Findings consistent with denervation and early reinervation were present on repeat electromyographic (EMG) study performed 5 months after onset of symptoms. After 12 months, her examination was normal with the ex-

FIGURE 2. Gadolinium enhancement of the cauda equina.

ception of a slightly wide-based gait while running. She continues to receive oral methotrexate, 6-mercaptopurine, and dexamethasone. Her CSF has been persistently negative for malignant cells and no further intrathecal treatments have been given.
DISCUSSION

FIGURE 1. Selective ventral lumbar nerve root gadolinium enhancement (arrows).

Our patient developed a polyradiculopathy after systemic and intrathecal chemotherapy treatment of ALL (in remission). Multiple reports have described polyradiculopathy as a cause of flaccid bilateral leg paralysis associated with intrathecal methotrexate and Ara-C.15,17,18,25,37 These cases describe motor syndromes, occurring primarily in children with elevated CSF protein levels. EMG studies have shown motor axonal polyneuropathies with normal sensory conduction tests. Interpretation of the clinical findings is sometimes complicated by conditions that can mask the presence of a polyradiculopathy such as myelopathic features and simultaneous treatment with vincristine. In our case, initial electrodiagnostic testing was consistent with an acute diffuse intraspinal disorder affecting predominantly lower extremity nerve roots or anterior horn cells. Although the absence of F waves has been described with myelopathies (anterior spinal artery syndrome34 and transverse myelitis35), this abnormality in conjunction with MRI gadolinium enhancement of ventral nerve roots is consistent with a polyradiculopathy. Her subsequent electrodiagnostic studies demonstrated mo-

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Table 1. Nerve conduction study. Response amplitude (mV, motor; V, sensory) Study 1 ( 0.9) 0.5* 0.4 ( 7.0) 0.6* 0.4 ( 3.2) 4.6 3.7 ( 2.8) 5.5 4.9 4.8 ( 7) 22 ( 13) 19 5 ( 8) 26 9 Study 2 Conduction velocity (m/s) Study 1 ( 42.2) 1.5 1.3 4.8* 4.3 39.5* ( 42.3) 41.3* ( 38.2) 45.6 ( 44.8) 7.3 6.7 6.6 52.3 54.6 57 55.3 ( 3.8) 1.6 ( 3.0) 1.7 ( 2.2) 1.4 63 43.8 ( 3.1) 3.5* 52.7 ( 3.5) 2.9 ( 2.5) 1.9 20 3.6* NR 30 Study 2 Latency (ms) Study 1 ( 4.5) 4.5 Study 2 F-wave latency (minimum, ms) Study 1 Study 2

Nerve and stimulation site Motor R. peroneal Ankle Fibular head R. tibial Ankle Knee R. median Wrist Elbow R. ulnar Wrist Below elbow Above elbow Sensory R. sural Calf R. median Wrist Elbow R. ulnar Wrist Below elbow

3.6

NR

NR

2.0

18

18

26 ( 47.6) 54.5 ( 55.8) 36 10 63

1.6

1.3

Normal limits in parentheses. *Abnormal values.

tor axonal loss, rather than demyelination, as the cause of her weakness, with improvement secondary to muscle reinnervation. There are several reports of paraparesis, some with encephalopathy, attributed to myelopathy due to intrathecal methotrexate or Ara-C. 4,5,79,12,20,23,25,26,31,33,38,39 Some have described abnormal peripheral nerve conduction studies with muscle denervation. Autopsy pathology has shown inflammatory changes in the spinal cord with nerve root involvement, including demyelination of the spinal roots.22 The pathogenesis of her syndrome is unclear. She had previously received intrathecal methotrexate and Ara-C uneventfully. As her CSF levels were not measured, the possibility of direct toxicity secondary to reduced clearance and prolonged nerve root exposure to elevated levels of methotrexate, a previously described mechanism of toxicity, cannot be excluded.3 Because the pathology of intrathecal methotrexate toxicity is similar to that of subacute combined degeneration of the spinal cord caused by cobalamine deficiency, localized folate deficiency has been postulated as a cause of this condition.22 Methotrexate toxicity studies using cerebellar explants from rats suggest that methotrexate is primarily a neurotoxin and that demyelination is a conse-

quence of axonal loss.10 However, electrodiagnostic studies after a single intrathecal methotrexate administration in 20 patients with non-Hodgkins lymphoma revealed no alterations of F waves or peripheral motor nerve conduction values.13 Ara-C has a long CSF elimination half-life compared with plasma, which is related to low Ara-C deaminase activity in CSF and brain and could contribute to central nervous system toxicity.16 Although our patient received systemic chemotherapy with vincristine, the absence of sensory symptoms or sensory nerve conduction abnormalities would be atypical for the generalized axonal sensorimotor polyneuropathy associated with vincristine toxicity.24 Nerve root toxicity secondary to the chemotherapy diluent has also been described, but our patient received a preservative-free diluent.14 MRI has demonstrated nerve root damage in a variety of diseases.36,37 Hingtgen and Garg and Pisani et al. report two similar cases of paralysis in children with ALL receiving similar intrathecal chemotherapy with ventral root enhancement on MRI.15,29 In addition, several series have reported MRI findings with ventral root enhancement in cases of Guillain-Barre syndrome.6,11,40 Our patients clinical presentation, electrodiag-

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nostic studies, elevated CSF protein level, and MRI imaging were also potentially consistent with an acute immune-mediated polyradiculopathy. The possibility exists of an immune-mediated polyradiculopathy triggered by chemotherapy. In addition, acute leukemia has been associated with polyneuropathy and GuillainBarre syndrome in the absence of chemotherapy.1,19,28,30,32 McKhann et al. described an acute motor axonal polyneuropathy in children and young adults with electrodiagnostic features similar to our patient, which they termed Chinese paralytic syndrome.21 This syndrome has been associated with prior Campylobacter jejuni infection.2 It has been hypothesized that chemotherapy results in the release of antigens with development of an autoimmune reaction, or that younger patients with immature nervous systems may be at greater risk for development of methotrexate neurotoxic complications.10 Immunosuppression, secondary to either leukemia or systemic chemotherapy, could potentially contribute to the development of an immunemediated polyradiculopathy.18,27
The authors thank Dr. Maura Brennan for translating the Japanese reference article. This study was presented at the annual meeting of the American Association of Electrodiagnostic Medicine, Vancouver, British Columbia, Canada, October 1999.

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