Brief Communication
Spinal Primitive Neuroectodermal Tumor Mimicking as Chronic Inflammatory Demyelination Polyneuropathy: A Case Report and Review of Literature
Journal of Child Neurology 2015, Vol. 30(2) 254-258 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814527160 jcn.sagepub.com
Sophelia H. S. Chan, FHKAM1, Dickson S. F. Tsang, FHKAM2, Virginia C. N. Wong, FHKAM1, and Godfrey C. F. Chan, FHKAM1
Abstract We report a young boy who presented with progressive weakness of lower extremities associated with areflexia and abnormal electrophysiological findings initially suggestive of chronic inflammatory demyelinating polyneuropathy. Initial lumbosacral spinal magnetic resonance imaging (MRI) showed thickened descending spinal nerve roots only. Immunomodulating therapy was given but with limited clinical response. Repeated spine magnetic resonance imaging showed cauda equina and also new spinal cord extramedullary contrast enhancement. The initial extensive investigations including open biopsy did not point to any specific diagnosis. Only through pursuing a repeated biopsy, the diagnosis of the spinal peripheral primitive neuroectodermal tumor was confirmed. This case highlights the diagnostic challenges of the spinal peripheral primitive neuroectodermal tumor that could have an initial chronic inflammatory demyelinating polyneuropathy-like presentation. The literature review confirms that this is a rare condition and cauda equina origin has only been reported in adults and teenagers, and this is the first reported case in a young child. Keywords chronic inflammatory demyelinating polyneuropathy, spinal primitive neuroectodermal tumor Received June 16, 2013. Received revised August 17, 2013, and December 09, 2013. Accepted for publication February 13, 2014.
Primitive neuroectodermal tumors are malignant neoplasm and the primary tumor location can be infratentorial or supratentorial inside the brain. Spinal cord or peripheral nerves origin is extremely rare. Primitive neuroectodermal tumor of the cauda equina is extremely rare, with only 13 reported cases found in the literature involving adults and teenagers,1-9 and so far there are no similar presenting features reported in young children. Chronic inflammatory demyelinating polyneuropathy is a rare condition in childhood and commonly presents as symmetrical proximal and distal weakness with hyporeflexia or areflexia over at least 4 weeks. It is clinically heterogeneous and under the revised diagnostic criteria for childhood chronic inflammatory demyelinating polyneuropathy, the classical form of chronic inflammatory demyelinating polyneuropathy has both sensorimotor involvement and the variant forms can have only pure motor or sensory involvement.10 Although the differential diagnosis of a chronic inflammatory demyelinating polyneuropathy-like presentation in a child includes specific infectious, metabolic, vasculitic, neoplastic (myeloma), and pharmacologic causes, a presentation due to a primary tumor derived from nerve roots is extremely rare. We describe a 7-year-old boy with spinal peripheral primitive neuroectodermal tumor arising from cauda equina whose
initial presentation suggests possible chronic inflammatory demyelinating polyneuropathy, the variant form with pure motor involvement.
Case Report A 7-year-old boy presented with a 1-month history of progressive walking difficulty. Initial magnetic resonance imaging (MRI) of the lumbosacral spine showed nerve root swelling with thickening (Figure 1), and nerve conduction studies showed increased distal latencies of both peroneal and tibial nerves but preserved conduction velocities. Muscle MRI of 1
Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China 2 Department of Radiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China Corresponding Author: Sophelia H. S. Chan, FHKAM, Room 115, New Clinical Building, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. Email: [email protected]
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Figure 1. (A) T2-weighted sagittal image of the lumbosacral spine shows thickened descending spinal nerves. (B) T2-weighted axial image of the lumbar spine at the L4 level shows clumping of the spinal nerves.
both lower extremities was normal. He was then referred to our hospital for suspected chronic inflammatory demyelinating polyneuropathy. After admission, he had persistent lower limb weakness involving both proximal and distal muscles of Medical Research Council grade 3. Knee and ankle jerks were absent. He complained of pain over the legs. Upper limbs did not have major weakness and had preserved deep tendon reflexes. Pain, light touch, proprioception, and vibration senses were all normal. Bladder and bowel control was preserved. Initial investigations including erythrocyte sedimentary rate, C-reactive protein, liver and renal function, random glucose, venous blood gas, creatine kinase, rheumatoid factors, complement 3 and 4, antinuclear antibodies, antiextractable nuclear antigens antibodies, antineutrophil cytoplasmic antibodies, and immunoglobulin pattern were normal. Initially, antidouble-stranded DNA antibodies were elevated at 201 IU/mL (normal reference: 0-35 IU/mL) but normalized on rechecking 1 month later. His first lumbar puncture showed numerous blood cells from a suspected traumatic tap, so cytoalbumin dissociation could not be studied. The cerebrospinal fluid showed markedly elevated protein of more than 6 g/L (norm reference: 0.12-0.6 g/L) but low glucose of 1.9 mmol/L (34% of blood level). In view of these abnormal biochemical findings, extensive infective screening of the cerebrospinal fluid included molecular analysis using polymerase chain reaction for mycoplasma, varicella zoster, and mycobacterium tuberculosis complex, and culture for fungal, bacterial, mycobacterium tuberculosis, and viral infection were all negative. There were no abnormal tumor cells. The lactate in the cerebrospinal fluid was markedly elevated at 5.7 mmol/L (norm reference:
0.45-2.1) whereas the blood lactate level was normal at 1.4 mmol/L (norm reference: 2.2-3.9). Metabolic workup including blood for acetoacetate, beta-hydroxybutyrate, pyruvate, lactate and plasma amino acid profile, and oral glucose loading test, as well as urine organic acid profile were all normal. Anti-ganglioside antibodies GA1, GM1, GM2, GD1a, GD1b, and GQ1b and oligoclonal bands in both serum and cerebrospinal fluid were all negative. Repeated nerve conduction studies in our hospital showed increased distal latencies of the right tibial (4.8 ms, reference: 5 mV]). The norm reference for the nerve conduction study is based on the study by Cai and colleagues.11 There was no response from the left peroneal nerve. Findings on sural nerves and the median and ulnar nerves were normal. Needle electromyography of the right quadriceps showed an acute denervation pattern. Although the symmetrical lower limb weakness last over a month and the nerve conduction studies suggested demyelinating involvement of lower limb motor nerves, and with a supporting MRI evidence of nerve root thickening in the lumbosacral region, possible chronic inflammatory demyelinating
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Figure 2. T1-weighted sagittal post-gadolinium image of the spine taken 9 weeks after the onset of weakness that show thickening and clumping of the cauda equina (thick arrow). There is dural thickening and leptomeningeal enhancement from L1/2 to the S2 vertebral level (thin arrow).
polyneuropathy was suspected. Intravenous immunoglobulin at 2 gram/kg was given over 5 days. There was some initial improvement of the lower limb power in the first 2 weeks and then the power deteriorated again. Follow-up nerve conduction studies showed further reduction of the compound muscle action potentials’ amplitude of right tibial motor nerve to 1.7 mV with similar prolonged distal latency of 5 ms but further increase in F-wave latency to 68.1 ms, and decrease in conduction velocity to 38 m/s. There was no response from left tibial and both peroneal motor nerves upon maximal stimulation. A course of intravenous pulse methylprednisolone at 30 mg/kg for 3 days was given but with no improvement. Follow-up contrast MRI spine showed persistent caudal equina contrast enhancement with nerve root thickening but with additional patchy leptomeningeal enhancement extending from the mid thoracic to the lumbar spinal region and the conus medullaris (Figure 2). Further imaging including brain MRI with contrast and spectroscopy were normal. An 18F-flurodeoxyglucose positron emission tomography (PET) whole body contrast-enhanced 64-MDCT study was arranged. It showed a hypermetabolic intradural extramedullary thickening and enhancement in the spine and posterior to the medulla. There were no hypermetabolic lesions in the brain or other parts of the body. Important differential diagnoses, including lymphoma, leukemia, leptomeningeal, or pachymeningeal metastases as well as tuberculosis are considered. An open biopsy was carried out
in the lumbar region. During the procedure, a gelatinous-like tissue around the cauda equina was found. The pathology came back as reactive changes with no tumor cells identified. Repeated cerebrospinal fluid for cytology and infective screening were negative. Paired serology titers of encephalitis panels, human immunodeficiency virus (HIV) antibodies, and cryptococcal antigen were all negative. Gastric lavage and early morning urine for acid-fast bacilli smear were negative. Betahuman chorionic gonadotropin, alpha-fetoprotein, and urate were negative. Although the extensive studies failed to obtain any specific diagnosis, his lower limb power further reduced. Another course of combined intravenous immunoglobulin and methylprednisolone was given but with minimal effect. Follow-up contrast MRI of the spine confirmed increased pachymeningeal enhancement in the spinal canal and also affecting the brainstem, whereas the cauda equina enhancement showed clumping of swollen nerve roots. MRI of the brain showed new onset of hydrocephalus, and so an urgent ventriculoperitoneal shunt was performed. Sural nerve and dural biopsy were performed and both findings came back normal. Parents initially strongly refused further open biopsy and after repeated counseling they eventually agreed. The second open biopsy at the lumbar region showed tumor cells of divergent differentiation with glial, neuronal and epithelial components, and immunostaining of the cells were positive for cytokeratin, vimentin and synaptophysin, with focal positivity for glial fibrillary acidic protein and epithelial membrane antigen but negative for smooth muscle actin, cluster of differentiation 99 antigen (CD 99), neurofilament, alpha-fetoprotein, and human chorionic gonadotropin. No loss of staining for nuclear antigen integrase interactor 1 (INI-1) was noted. Less than 10% of the tumor cells were positive for the proliferative marker Ki-67. The findings are compatible to primitive neuroectodermal tumor. The child completed active course of chemotherapy with radiotherapy according to the central nervous system primitive neuroectodermal tumor protocol modified from Packer.12 During treatment, his condition was stabilized. His lower limb weakness persisted and he required intermittent catheterization for neurogenic bladder involvement. Repeated brain and spine MRIs after treatment showed no lesion in the brain, but leptomeningeal and pachymeningeal enhancement around the brainstem and spinal dural extramedullary space from cervical level to cauda equina. He had been stable for more than 2 years and he returned to school on a wheelchair. At 2½ years after the diagnosis of primitive neuroectodermal tumor, his disease relapsed and the condition progressed rapidly. He died shortly after his disease disseminated.
Discussion The initial presentation of progressive lower limb weakness more than 1 month with areflexia, and investigation including electrophysiological studies suggesting motor demyelinating polyneuropathy and MRI findings of nerve root thickening led to the initial suspicion of chronic inflammatory demyelinating polyneuropathy. However, the atypical disease course led us to
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Table 1. Previous Reported Cases of Primitive Neuroectodermal Tumor With Cauda Equina Involvement Upon Presentation. Patient
Sex/onset age Initial location
Symptoms
1
M/24
In caudal equina at L4 to L5
2
M/56
In cauda equina L2 to L3
3
M/39
In cauda equina L5 to S1 with thickened nerve roots L3 to sacrum, extending along nerve roots with invasion of L3 neural arch and first sacral foramen In cauda equina involved 1 of the nerve root Right S1 nerve root tumor with invasion of nerve ganglion In cauda equina from L3 to L5, extension into paraspinal muscles In cauda equina from L2 to L5, encasing the spinal nerve roots
4
M/47
5
M/14
6
M/32
7
M/17
8
M/52
9
F/18
10
F/49
11
F/31
12 13
M/27 F/16
In cauda equina from L4 to L5 In cauda equina from L2 to S1
14
M/7
In cauda equina with nerve root thickening
In cauda equina from L3 to L5 involving the L5 spinal root In cauda equina closely related to L1 nerve root extend to L2 In cauda equina from L1 to S2, encasement of the spinal nerve roots
Reference
Sciatica, left foot dragging, followed by numbness and Keppes et al (1985)6 tingling of left calf Increase leg weakness, back pain, limited straight leg raising Difficulty walking and climbing stairs Sciatica, low back pain, difficulty in straight leg raising McDermott et al (1994)7 Perineal anaesthesia, lower limb weakness, decrease sensation, difficulty in passing urine Low back pain, lower limb pain, difficulty in standing Hisaoka et al (1997)8 and walking Right sciatica, numbness of right leg Dorfmu¨ller et al (1999)3 Bilateral sciatica, numbness and progressive weakness of both legs Low back pain, limitation in straight leg raising, walking Isotalo et al (2000)4 difficulty, left leg weakness, numbness in caudal area, decreased pinprick sensation of both legs, postvoiding urinary incontinence, laxed anal tone Bilateral sciatica, lower limb weakness with left foot Yavuz et al (2002)9 drop, sensory level at L5 Right sciatica. Paresthesias of both legs Albrecht et al (2003)2 Bilateral sciatica, difficulty in walking, paraesthesia and Akyu¨z et al (2004)1 progressive weakness of both legs, decreased pinprick sensation, decreased anal tone, postvoiding urinary incontinence Intermittent leg pain Perry et al (2007)5 Bilateral sciatica, bilateral paraesthesia and progressive lower limb weakness, unable to walk Bilateral progressive lower limb weakness, areflexia Present study
consider other possible differential diagnoses, including central nervous system infection, neurometabolic disorders, vasculitic disease, and also malignancies including primary or secondary tumors of the nervous system. The extensive diagnostic investigations in this patient excluded the above-mentioned important causes, and confirmed no primary central nervous system tumor or non–central nervous system tumor. While the first open biopsy yielded only nonspecific findings, this case posed a major diagnostic challenge, and the importance in pursuing another open biopsy if a progressive lesion is highly suspected. The initial abnormal cerebrospinal fluid findings could be explained by the fact that the initial fluid obtained was close to the nerve root tumor with expected extensive reactive inflammatory changes. This child was subsequently confirmed to have spinal primitive neuroectodermal tumor. Primitive neuroectodermal tumor with spinal involvement is a very rare condition. So far, there are fewer than 50 cases of intraspinal primitive neuroectodermal tumor reported in the literature.13 Among these cases, there are only 13 reported cases of primitive neuroectodermal tumor originating from the cauda equina. These patients presented frequently with back pain, sciatica, progressive lower limb
weakness and sensory loss, and sometimes also with bladder and bowel sphincter problems. Eleven of these patients were adults and 2 were teenagers (Table 1). The tumors can be intramedullary, extramedullary, intradural, and extradural and appear as contrast-enhancing lesions with or without nerve root encasement. They are frequently described as soft, friable, vascular, and poorly demarcated masses on biopsy. The differentiation of the primitive neuroectodermal tumor of the nervous system based on their origin is not that straightforward. It has been proposed that those arising in the spinal cord may be derived from the central nervous system and those arising in the cauda equina may be developed from the peripheral nervous system.14 However, the terminology should not be mistaken with non–nervous system peripheral primitive neuroectodermal tumors belonging to the Ewing family of tumors. Peripheral primitive neuroectodermal tumor can be found in many non-neuronal soft tissues and often has a specific translocation involving the Ewing sarcoma breakpoint region 1 gene. In conclusion, primitive neuroectodermal tumor of the cauda equina is a very rare and progressive condition with poor prognosis. Despite treatment with surgery, radiotherapy, and chemotherapy, most patients have a dismal outcome. Our
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patient has demonstrated that early presentation of such a condition can mimic chronic inflammatory demyelinating polyneuropathy. Even though this is a very rare condition, primitive neuroectodermal tumors should be considered as an important differential diagnosis for chronic inflammatory demyelinating polyneuropathy presentation, especially in those patients refractory to immunomodulating therapy, and having a slowly deteriorating course with follow-up spine MRI shows additional leptomeningeal enhancement. Despite the high false positive rate, a hypermetabolic lesion found in PET scan should also alert us to the possibility of a tumor. Acknowledgments We are sincerely grateful to the patient and the parents. We would also like to thank Dr H. Royden Jones (Department of Neurology, Boston, Children’s Hospital, Harvard Medical School, Boston, and Lahey Clinic, Burlington, MA) and Dr Basil T. Darras (Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston) for their invaluable advice for this patient and the helpful comments when preparing this manuscript.
Author Contributions All the authors have been involved in the care of this patient. The manuscript was prepared by SHSC. The figures of the spine MRI and the comments were provided by DSFT. VCNW and GCFC provided expert advice during manuscript review.
Authors’ Note This is a nonfunded single case study with review of the past reported case series.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval As this is only a single case study, no specific ethical approval has been applied.
References 1. Akyu¨z M, Demiral AN, Gu¨rer IE, Ucar T, Tuncer R. Primary primitive neuroectodermal tumour of cauda equina with intracranial seeding. Acta Neurochir (Wien). 2004;146:525-528.
2. Albrecht CF, Weiss E, Schulz-Schaeffer WJ, et al. Primary intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature. J Neurooncol. 2003;61:113-120. 3. Dorfmu¨ller G, Wu¨rtz FG, Umschaden HW, Kleinert R, Ambros PF. Intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature. Acta Neurochir (Wien). 1999; 141:1169-1175. 4. Isotalo PA, Agbi C, Davidson B, Girard A, Verma S, Robertson SJ. Primary primitive neuroectodermal tumor of the cauda equina. Hum Pathol. 2000;31:999-1001. 5. Perry R, Gonzales I, Finlay J, Zacharoulis S. Primary peripheral primitive neuroectodermal tumours of the spinal cord: report of two cases and review of the literature. J Neurooncol. 2007;81: 259-264. 6. Keppes JJ, Belton K, Roessmann U, Ketcherside WJ. Primitive neuroectodermal tumors of the cauda equine in adults with no detectable primary intracranial neoplasm—three case studies. Clin Neuropathol. 1985;4:1-11. 7. McDermott VG, El-Jabbour JN, Sellar RJ, Bell J. Primitive neuroectodermal tumour of the cauda equina. Neuroradiology. 1994; 36:228-230. 8. Hisaoka M, Hashimoto H, Murao. Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina. Virchows Arch. 1997;431:365-369. 9. Ysvuz AA, Yaris N, Yavuz MN, Sari A, Reis AK, Aydin F. Primary intraspinal primitive neuroectodermal tumor: case report of a tumor arising from the sacral spinal nerve root and review of the literature. Am J Clin Oncol. 2002;25:135-139. 10. Nevo Y, Topaloglu H. 88th ENMC international workshop: childhood chronic inflammatory demyelinating polyneuropathy (including revised diagnostic criteria), Naarden, The Netherlands, December 8-10, 2000. Neuromuscul Disord. 2002;12:195-200. 11. Cai F, Zhang J. Study of nerve conduction and later responses in normal Chinese infants, children, and adults. J Child Neurol. 1997;12:13-18. 12. Packer RJ, Finlay JL. Chemotherapy for childhood medulloblastoma and primitive neuroectodermal tumors. Oncologist. 1996;1: 381-393. 13. Jingyu C, Jinning S, Hui M, Hua F. Intraspinal primitive neuroectodermal tumors: report of four cases and review of the literature. Neurol India. 2009;57:661-668. 14. Kampman WA, Kros JM, De Jong THR, Lequin MH. Primitive neuroectodermal tumors (PNETs) located in spinal canal; the relevance of classification as central or peripheral PNET: case report of a primary spinal PNET occurrence with a critical literature review. J Neurooncol. 2006;77:65-72.
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Spinal Primitive Neuroectodermal Tumor Mimicking as Chronic Inflammatory Demyelination Polyneuropathy: A Case Report and Review of Literature
Journal of Child Neurology 2015, Vol. 30(2) 254-258 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814527160 jcn.sagepub.com
Sophelia H. S. Chan, FHKAM1, Dickson S. F. Tsang, FHKAM2, Virginia C. N. Wong, FHKAM1, and Godfrey C. F. Chan, FHKAM1
Abstract We report a young boy who presented with progressive weakness of lower extremities associated with areflexia and abnormal electrophysiological findings initially suggestive of chronic inflammatory demyelinating polyneuropathy. Initial lumbosacral spinal magnetic resonance imaging (MRI) showed thickened descending spinal nerve roots only. Immunomodulating therapy was given but with limited clinical response. Repeated spine magnetic resonance imaging showed cauda equina and also new spinal cord extramedullary contrast enhancement. The initial extensive investigations including open biopsy did not point to any specific diagnosis. Only through pursuing a repeated biopsy, the diagnosis of the spinal peripheral primitive neuroectodermal tumor was confirmed. This case highlights the diagnostic challenges of the spinal peripheral primitive neuroectodermal tumor that could have an initial chronic inflammatory demyelinating polyneuropathy-like presentation. The literature review confirms that this is a rare condition and cauda equina origin has only been reported in adults and teenagers, and this is the first reported case in a young child. Keywords chronic inflammatory demyelinating polyneuropathy, spinal primitive neuroectodermal tumor Received June 16, 2013. Received revised August 17, 2013, and December 09, 2013. Accepted for publication February 13, 2014.
Primitive neuroectodermal tumors are malignant neoplasm and the primary tumor location can be infratentorial or supratentorial inside the brain. Spinal cord or peripheral nerves origin is extremely rare. Primitive neuroectodermal tumor of the cauda equina is extremely rare, with only 13 reported cases found in the literature involving adults and teenagers,1-9 and so far there are no similar presenting features reported in young children. Chronic inflammatory demyelinating polyneuropathy is a rare condition in childhood and commonly presents as symmetrical proximal and distal weakness with hyporeflexia or areflexia over at least 4 weeks. It is clinically heterogeneous and under the revised diagnostic criteria for childhood chronic inflammatory demyelinating polyneuropathy, the classical form of chronic inflammatory demyelinating polyneuropathy has both sensorimotor involvement and the variant forms can have only pure motor or sensory involvement.10 Although the differential diagnosis of a chronic inflammatory demyelinating polyneuropathy-like presentation in a child includes specific infectious, metabolic, vasculitic, neoplastic (myeloma), and pharmacologic causes, a presentation due to a primary tumor derived from nerve roots is extremely rare. We describe a 7-year-old boy with spinal peripheral primitive neuroectodermal tumor arising from cauda equina whose
initial presentation suggests possible chronic inflammatory demyelinating polyneuropathy, the variant form with pure motor involvement.
Case Report A 7-year-old boy presented with a 1-month history of progressive walking difficulty. Initial magnetic resonance imaging (MRI) of the lumbosacral spine showed nerve root swelling with thickening (Figure 1), and nerve conduction studies showed increased distal latencies of both peroneal and tibial nerves but preserved conduction velocities. Muscle MRI of 1
Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China 2 Department of Radiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China Corresponding Author: Sophelia H. S. Chan, FHKAM, Room 115, New Clinical Building, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. Email: [email protected]
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Figure 1. (A) T2-weighted sagittal image of the lumbosacral spine shows thickened descending spinal nerves. (B) T2-weighted axial image of the lumbar spine at the L4 level shows clumping of the spinal nerves.
both lower extremities was normal. He was then referred to our hospital for suspected chronic inflammatory demyelinating polyneuropathy. After admission, he had persistent lower limb weakness involving both proximal and distal muscles of Medical Research Council grade 3. Knee and ankle jerks were absent. He complained of pain over the legs. Upper limbs did not have major weakness and had preserved deep tendon reflexes. Pain, light touch, proprioception, and vibration senses were all normal. Bladder and bowel control was preserved. Initial investigations including erythrocyte sedimentary rate, C-reactive protein, liver and renal function, random glucose, venous blood gas, creatine kinase, rheumatoid factors, complement 3 and 4, antinuclear antibodies, antiextractable nuclear antigens antibodies, antineutrophil cytoplasmic antibodies, and immunoglobulin pattern were normal. Initially, antidouble-stranded DNA antibodies were elevated at 201 IU/mL (normal reference: 0-35 IU/mL) but normalized on rechecking 1 month later. His first lumbar puncture showed numerous blood cells from a suspected traumatic tap, so cytoalbumin dissociation could not be studied. The cerebrospinal fluid showed markedly elevated protein of more than 6 g/L (norm reference: 0.12-0.6 g/L) but low glucose of 1.9 mmol/L (34% of blood level). In view of these abnormal biochemical findings, extensive infective screening of the cerebrospinal fluid included molecular analysis using polymerase chain reaction for mycoplasma, varicella zoster, and mycobacterium tuberculosis complex, and culture for fungal, bacterial, mycobacterium tuberculosis, and viral infection were all negative. There were no abnormal tumor cells. The lactate in the cerebrospinal fluid was markedly elevated at 5.7 mmol/L (norm reference:
0.45-2.1) whereas the blood lactate level was normal at 1.4 mmol/L (norm reference: 2.2-3.9). Metabolic workup including blood for acetoacetate, beta-hydroxybutyrate, pyruvate, lactate and plasma amino acid profile, and oral glucose loading test, as well as urine organic acid profile were all normal. Anti-ganglioside antibodies GA1, GM1, GM2, GD1a, GD1b, and GQ1b and oligoclonal bands in both serum and cerebrospinal fluid were all negative. Repeated nerve conduction studies in our hospital showed increased distal latencies of the right tibial (4.8 ms, reference: 5 mV]). The norm reference for the nerve conduction study is based on the study by Cai and colleagues.11 There was no response from the left peroneal nerve. Findings on sural nerves and the median and ulnar nerves were normal. Needle electromyography of the right quadriceps showed an acute denervation pattern. Although the symmetrical lower limb weakness last over a month and the nerve conduction studies suggested demyelinating involvement of lower limb motor nerves, and with a supporting MRI evidence of nerve root thickening in the lumbosacral region, possible chronic inflammatory demyelinating
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Figure 2. T1-weighted sagittal post-gadolinium image of the spine taken 9 weeks after the onset of weakness that show thickening and clumping of the cauda equina (thick arrow). There is dural thickening and leptomeningeal enhancement from L1/2 to the S2 vertebral level (thin arrow).
polyneuropathy was suspected. Intravenous immunoglobulin at 2 gram/kg was given over 5 days. There was some initial improvement of the lower limb power in the first 2 weeks and then the power deteriorated again. Follow-up nerve conduction studies showed further reduction of the compound muscle action potentials’ amplitude of right tibial motor nerve to 1.7 mV with similar prolonged distal latency of 5 ms but further increase in F-wave latency to 68.1 ms, and decrease in conduction velocity to 38 m/s. There was no response from left tibial and both peroneal motor nerves upon maximal stimulation. A course of intravenous pulse methylprednisolone at 30 mg/kg for 3 days was given but with no improvement. Follow-up contrast MRI spine showed persistent caudal equina contrast enhancement with nerve root thickening but with additional patchy leptomeningeal enhancement extending from the mid thoracic to the lumbar spinal region and the conus medullaris (Figure 2). Further imaging including brain MRI with contrast and spectroscopy were normal. An 18F-flurodeoxyglucose positron emission tomography (PET) whole body contrast-enhanced 64-MDCT study was arranged. It showed a hypermetabolic intradural extramedullary thickening and enhancement in the spine and posterior to the medulla. There were no hypermetabolic lesions in the brain or other parts of the body. Important differential diagnoses, including lymphoma, leukemia, leptomeningeal, or pachymeningeal metastases as well as tuberculosis are considered. An open biopsy was carried out
in the lumbar region. During the procedure, a gelatinous-like tissue around the cauda equina was found. The pathology came back as reactive changes with no tumor cells identified. Repeated cerebrospinal fluid for cytology and infective screening were negative. Paired serology titers of encephalitis panels, human immunodeficiency virus (HIV) antibodies, and cryptococcal antigen were all negative. Gastric lavage and early morning urine for acid-fast bacilli smear were negative. Betahuman chorionic gonadotropin, alpha-fetoprotein, and urate were negative. Although the extensive studies failed to obtain any specific diagnosis, his lower limb power further reduced. Another course of combined intravenous immunoglobulin and methylprednisolone was given but with minimal effect. Follow-up contrast MRI of the spine confirmed increased pachymeningeal enhancement in the spinal canal and also affecting the brainstem, whereas the cauda equina enhancement showed clumping of swollen nerve roots. MRI of the brain showed new onset of hydrocephalus, and so an urgent ventriculoperitoneal shunt was performed. Sural nerve and dural biopsy were performed and both findings came back normal. Parents initially strongly refused further open biopsy and after repeated counseling they eventually agreed. The second open biopsy at the lumbar region showed tumor cells of divergent differentiation with glial, neuronal and epithelial components, and immunostaining of the cells were positive for cytokeratin, vimentin and synaptophysin, with focal positivity for glial fibrillary acidic protein and epithelial membrane antigen but negative for smooth muscle actin, cluster of differentiation 99 antigen (CD 99), neurofilament, alpha-fetoprotein, and human chorionic gonadotropin. No loss of staining for nuclear antigen integrase interactor 1 (INI-1) was noted. Less than 10% of the tumor cells were positive for the proliferative marker Ki-67. The findings are compatible to primitive neuroectodermal tumor. The child completed active course of chemotherapy with radiotherapy according to the central nervous system primitive neuroectodermal tumor protocol modified from Packer.12 During treatment, his condition was stabilized. His lower limb weakness persisted and he required intermittent catheterization for neurogenic bladder involvement. Repeated brain and spine MRIs after treatment showed no lesion in the brain, but leptomeningeal and pachymeningeal enhancement around the brainstem and spinal dural extramedullary space from cervical level to cauda equina. He had been stable for more than 2 years and he returned to school on a wheelchair. At 2½ years after the diagnosis of primitive neuroectodermal tumor, his disease relapsed and the condition progressed rapidly. He died shortly after his disease disseminated.
Discussion The initial presentation of progressive lower limb weakness more than 1 month with areflexia, and investigation including electrophysiological studies suggesting motor demyelinating polyneuropathy and MRI findings of nerve root thickening led to the initial suspicion of chronic inflammatory demyelinating polyneuropathy. However, the atypical disease course led us to
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Table 1. Previous Reported Cases of Primitive Neuroectodermal Tumor With Cauda Equina Involvement Upon Presentation. Patient
Sex/onset age Initial location
Symptoms
1
M/24
In caudal equina at L4 to L5
2
M/56
In cauda equina L2 to L3
3
M/39
In cauda equina L5 to S1 with thickened nerve roots L3 to sacrum, extending along nerve roots with invasion of L3 neural arch and first sacral foramen In cauda equina involved 1 of the nerve root Right S1 nerve root tumor with invasion of nerve ganglion In cauda equina from L3 to L5, extension into paraspinal muscles In cauda equina from L2 to L5, encasing the spinal nerve roots
4
M/47
5
M/14
6
M/32
7
M/17
8
M/52
9
F/18
10
F/49
11
F/31
12 13
M/27 F/16
In cauda equina from L4 to L5 In cauda equina from L2 to S1
14
M/7
In cauda equina with nerve root thickening
In cauda equina from L3 to L5 involving the L5 spinal root In cauda equina closely related to L1 nerve root extend to L2 In cauda equina from L1 to S2, encasement of the spinal nerve roots
Reference
Sciatica, left foot dragging, followed by numbness and Keppes et al (1985)6 tingling of left calf Increase leg weakness, back pain, limited straight leg raising Difficulty walking and climbing stairs Sciatica, low back pain, difficulty in straight leg raising McDermott et al (1994)7 Perineal anaesthesia, lower limb weakness, decrease sensation, difficulty in passing urine Low back pain, lower limb pain, difficulty in standing Hisaoka et al (1997)8 and walking Right sciatica, numbness of right leg Dorfmu¨ller et al (1999)3 Bilateral sciatica, numbness and progressive weakness of both legs Low back pain, limitation in straight leg raising, walking Isotalo et al (2000)4 difficulty, left leg weakness, numbness in caudal area, decreased pinprick sensation of both legs, postvoiding urinary incontinence, laxed anal tone Bilateral sciatica, lower limb weakness with left foot Yavuz et al (2002)9 drop, sensory level at L5 Right sciatica. Paresthesias of both legs Albrecht et al (2003)2 Bilateral sciatica, difficulty in walking, paraesthesia and Akyu¨z et al (2004)1 progressive weakness of both legs, decreased pinprick sensation, decreased anal tone, postvoiding urinary incontinence Intermittent leg pain Perry et al (2007)5 Bilateral sciatica, bilateral paraesthesia and progressive lower limb weakness, unable to walk Bilateral progressive lower limb weakness, areflexia Present study
consider other possible differential diagnoses, including central nervous system infection, neurometabolic disorders, vasculitic disease, and also malignancies including primary or secondary tumors of the nervous system. The extensive diagnostic investigations in this patient excluded the above-mentioned important causes, and confirmed no primary central nervous system tumor or non–central nervous system tumor. While the first open biopsy yielded only nonspecific findings, this case posed a major diagnostic challenge, and the importance in pursuing another open biopsy if a progressive lesion is highly suspected. The initial abnormal cerebrospinal fluid findings could be explained by the fact that the initial fluid obtained was close to the nerve root tumor with expected extensive reactive inflammatory changes. This child was subsequently confirmed to have spinal primitive neuroectodermal tumor. Primitive neuroectodermal tumor with spinal involvement is a very rare condition. So far, there are fewer than 50 cases of intraspinal primitive neuroectodermal tumor reported in the literature.13 Among these cases, there are only 13 reported cases of primitive neuroectodermal tumor originating from the cauda equina. These patients presented frequently with back pain, sciatica, progressive lower limb
weakness and sensory loss, and sometimes also with bladder and bowel sphincter problems. Eleven of these patients were adults and 2 were teenagers (Table 1). The tumors can be intramedullary, extramedullary, intradural, and extradural and appear as contrast-enhancing lesions with or without nerve root encasement. They are frequently described as soft, friable, vascular, and poorly demarcated masses on biopsy. The differentiation of the primitive neuroectodermal tumor of the nervous system based on their origin is not that straightforward. It has been proposed that those arising in the spinal cord may be derived from the central nervous system and those arising in the cauda equina may be developed from the peripheral nervous system.14 However, the terminology should not be mistaken with non–nervous system peripheral primitive neuroectodermal tumors belonging to the Ewing family of tumors. Peripheral primitive neuroectodermal tumor can be found in many non-neuronal soft tissues and often has a specific translocation involving the Ewing sarcoma breakpoint region 1 gene. In conclusion, primitive neuroectodermal tumor of the cauda equina is a very rare and progressive condition with poor prognosis. Despite treatment with surgery, radiotherapy, and chemotherapy, most patients have a dismal outcome. Our
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Journal of Child Neurology 30(2)
patient has demonstrated that early presentation of such a condition can mimic chronic inflammatory demyelinating polyneuropathy. Even though this is a very rare condition, primitive neuroectodermal tumors should be considered as an important differential diagnosis for chronic inflammatory demyelinating polyneuropathy presentation, especially in those patients refractory to immunomodulating therapy, and having a slowly deteriorating course with follow-up spine MRI shows additional leptomeningeal enhancement. Despite the high false positive rate, a hypermetabolic lesion found in PET scan should also alert us to the possibility of a tumor. Acknowledgments We are sincerely grateful to the patient and the parents. We would also like to thank Dr H. Royden Jones (Department of Neurology, Boston, Children’s Hospital, Harvard Medical School, Boston, and Lahey Clinic, Burlington, MA) and Dr Basil T. Darras (Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston) for their invaluable advice for this patient and the helpful comments when preparing this manuscript.
Author Contributions All the authors have been involved in the care of this patient. The manuscript was prepared by SHSC. The figures of the spine MRI and the comments were provided by DSFT. VCNW and GCFC provided expert advice during manuscript review.
Authors’ Note This is a nonfunded single case study with review of the past reported case series.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval As this is only a single case study, no specific ethical approval has been applied.
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