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Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma
Journal of Pediatric Surgery (2009) 44, E5–E7
www.elsevier.com/locate/jpedsurg
Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma Anthony S. de Buys Roessingh ⁎, Marie-Hélène Loriot, Chad Wiesenauer, Michel Lallier Department of General Pediatric Surgery, University Hospital, Hôpital Sainte-Justine, Montréal, Quebec, Canada H3T 1C5 Received 12 October 2008; revised 5 March 2009; accepted 17 April 2009
Key words: Neuroblastoma; Paraneoplastic; Myasthenic syndrome; Lambert-Eaton
Abstract Lambert-Eaton myasthenic syndrome is a paraneoplastic syndrome that may reveal a primitive tumor. Neuroblastoma in children and small cell lung carcinoma in adults are the leading tumors revealed or expressed by paraneoplastic phenomena. The clinical neurologic manifestations of Lambert-Eaton myasthenic syndrome are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Neurologic manifestations are explained by the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor. Neurologic paraneoplastic disorders may also be the result of toxicity of drugs, coagulopathy, infection, or metabolic diseases. We describe the case of a 13-month-old child with unusual neurologic symptoms because of the presence of an abdominal neuroblastoma. © 2009 Elsevier Inc. All rights reserved.
Lambert-Eaton myasthenic syndrome (LEMS) is a prototype of a presynaptic autoimmune disorder of the neuromuscular transmission. In this syndrome, circulating antibodies react with voltage-gated calcium channels at the presynaptic neuromuscular junction. This stimulation provokes severe neurologic manifestations such as autonomic dysfunction, muscular weakness, and decreased tendon reflexes. These symptoms may be the presenting feature of an otherwise undiagnosed tumor. Normally, early diagnosis of the etiology of these manifestations maximizes the likelihood of the treatment of the tumor along with the disappearance of the neurologic manifestations.
⁎ Corresponding author. MER Service de chirurgie pédiatrique Centre Hospitalier Universitaire Vaudois (CHUV) CH-1011 Lausanne, Switzerland. Tel.: +1 41 21 314 31 26; fax: +1 41 21 314 30 76. E-mail address: [email protected] (A.S. de Buys Roessingh). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.04.023
1. Case report A 13-month-old adolescent girl was brought by her parents to the emergency ward for abdominal pain after a long period of constipation and for right ocular paresis and somnolence present for about 1 week according to the parents. The girl slept all through the physical examination. It was difficult to wake her up during the day. She refused to stand straight and experienced an extreme weakness of the legs. She did not react during venous puncture. Her head was oriented toward the right direction. A weakness of the right eyelid and a right ocular paresis were present. She was hospitalized for neurologic and ophthalmologic investigations. Bilateral ptosis was noted soon after her hospitalization, and the girl showed no reaction to any stimulation. The movements of her limbs were normal without spasticity. A computed tomography (CT) scan of the brain was normal except for a Chiari type II malformation. Magnetic resonance
E6
A.S. de Buys Roessingh et al.
imaging of the brain was also normal. An abdominal ultrasound (US) revealed a right abdominal mass measuring 6 by 5 by 5 cm, situated above the superior pole of the kidney and causing a compression of the inferior vena cava. The mass was compatible with a neuroblastoma. A paraneoplastic LEMS was diagnosed. Electromyography showed normal conduction. A Tensilon test was also normal. The child was tested negative for antiacetylcholine receptor antibodies. The staging evaluation began with a CT scan of the abdomen, which showed a right retroperitoneal resectable tumor (Fig. 1). Bone CT scan findings showed no osseous metastases. Bone marrow aspiration specimens from the iliac crests did not contain tumor cells. Metaiodobenzylguanidine I 131 scan uptake was limited to the abdominal mass. Serum ferritin level was less than 142 ng/mL, serum neuron-specific enolase was less than 100 ng/mL, serum lactate dehydrogenase was less than 1500 U/L, and the urine vanillylmandelic acid/homovanillic acid ratio was less than 1. The abdominal mass was resected, and the diagnosis of neuroblastoma was confirmed. The tumor was intact, with free margins and normal lymph nodes. The mass measured 7 by 5.5 by 4 cm and weighed 53 g. The histology of the specimen was compatible with a neuroblastoma and was not favorable, with a mitosis karyorrhexis index of more than 200, a high MYCN (oncogenic transcription factor) amplification within more than 80% of nuclei, and cell diploidy. Tumor cell chromosomal findings were normal with intact chromosomes 1p and 11q. One day after the surgical removal of the tumor, the girl woke up without any persistent neurologic symptoms. She could move normally. The weakness of the right eyelid and the right ocular paresis had totally disappeared. She left the hospital a few days after the operation. Two months later, she returned to the hospital because of a protruding right eye. A CT scan revealed the presence of a mass behind the right eye, and the 131I-metaiodobenzylguanidine scan uptake was positive for a mass in the right retroocular region. Chemotherapy was started. The child was treated according to the Pediatric Oncology Group recommendations [1].
Fig. 1 mass.
Compute tomography scan showing the right abdominal
2. Discussion Early symptoms of the presence of a neuroblastoma are usually weight loss, weakness, or fever. The clinical presentation depends on the location of the tumor. In the abdomen, the mass is retroperitoneal and is most often detected in the course of routine clinical examinations. A pelvic mass may provoke urinary retention or constipation. In the thorax, the tumor is most often discovered on chest radiographs. Occasionally, the tumor is revealed by symptoms because of the compression of the sympathetic innervation leading to a Horner syndrome or by various neurologic paraneoplastic manifestations such as opsoclonus-myoclonus-ataxia [2]. Clinical ocular manifestations with ptosis may even be present. Lambert-Eaton myasthenic syndrome is extremely rare in young children. Its clinical manifestations are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Dysautonomia is the dysfunction of the autonomic nervous system that concerns the 3 subsystems, the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. The autonomic nervous system regulates in an autonomous manner the activities of the cardiac muscle, the smooth muscle, the endocrine glands, and the exocrine glands [3]. Paraneoplastic disorders can affect both central and peripheral nervous systems. The symptoms of these disorders may be because of the stimulation of different parts of the nervous system, thus, inducing different manifestations. This explains why no neurologic manifestation is in itself absolutely pathognomonic for a paraneoplastic syndrome because of a tumor. Neuromuscular junction disorders are usually categorized either as presynaptic or postsynaptic. Lambert-Eaton myasthenic syndrome is typically a presynaptic autoimmune disorder of neuromuscular transmission as opposed to myasthenia gravis (MG), which is postsynaptic. These 2 disorders can be differentiated by electromyography, which shows an increase of the response to muscle stimulation in LEMS and a decrease of the response to muscle stimulation in MG and by a Tensilon test, which is an injection of edrophonium chloride used to diagnose MG. Edrophonium blocks the action of the enzyme acetylcholinesterase, which takes an important part in the regulation of the neuromuscular transmission. A nerve cell (neuron) releases the chemical acetylcholine to stimulate a muscle. Acetylcholine is broken down by acetylcholinesterase after the muscle is stimulated to prevent prolonged muscle response to a single nerve signal. The presence of different and specific autoantibodies may also help to differentiate these 2 illnesses [3]. The mechanisms of neurologic manifestations because of a paraneoplastic syndrome are not well understood. The leading theory describes the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor as well as in some types of neurons [4]. When these antigens are expressed in a nonnervous
LEMS revealing an abdominal neuroblastoma system, the immune system produces autoantibodies that can damage these particular neurons. One of the best-known autoantibodies is the antineuronal nuclear antibody (anti-Hu), which is related to neuroblastoma and also to lung carcinoma [5]. However, autoantibodies are not always associated with a tumor or with neurologic manifestations and are not always present in patients who present these syndromes [6]. In vitro testing has even produced some evidence that autoantibodies such as the anti-Hu may not cause injury to neurons [7]. Because we consider that paraneoplastic syndromes are autoimmune diseases, it follows that their manifestations should disappear either after the excision of the tumor or in response to an immunosuppressive treatment. The resection of the tumor in our patient led to the suppression of the neurologic symptoms. But in fact, the response to treatment of different paraneoplastic syndromes can vary considerably, and in most of the adult cases, the recovery may not be complete and neurologic symptoms can persist. The addition of immunosuppressive therapy to treat neurologic paraneoplastic symptoms after removal of the tumor does not seem to improve the reduction of the neurologic symptoms, and, especially in LEMS, patients are left with permanent neurologic deficits [8]. Although some neuronal injury by unknown mechanisms may already be present and irreversible, a prompt diagnosis may play a role in the recovery and early treatment may be correlated with a faster abatement of the neurologic paraneoplastic symptoms. We could not ascertain whether a prompt diagnosis in children could be of importance in reducing neurologic sequelae. But in any case, the presence of unexplained
E7 neurologic manifestations in an otherwise healthy child should raise the suspicion of a possible paraneoplastic syndrome because of the presence of an undiagnosed tumor.
Acknowledgment The authors are grateful to Annette Wagnière for reviewing the English text.
References [1] Castleberry RP. Biology and treatment of neuroblastoma. Pediatr Clin North Am 1997;44:919-37. [2] Pranzatelli MR, Tate ED, Wheeler, et al. Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia. Pediatr Neurol 2002; 27:384-7. [3] Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2002;73:766-8. [4] Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol 2005;18:331-6. [5] Pittock SJ, Kryzer VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56:715-9. [6] Bataller L, Rosenfeld MR, Graus F, et al. Autoantigen diversity in the opsoclonus-myoclonus syndrome. An Neurol 2003;53:347-53. [7] Tanaka K, Tanaka M. Effects of antineuronal antibodies from patients with paraneoplastic syndrome on primary cultured neurons. J Neurol Sci 2004;217:2-30. [8] Bosdure E, Attarian S, Mancini J, et al. Lambert-Eton myasthenic syndrome revealing neuroblastoma in 2 children. Arch Pediatr 2006; 13:1121-4.
www.elsevier.com/locate/jpedsurg
Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma Anthony S. de Buys Roessingh ⁎, Marie-Hélène Loriot, Chad Wiesenauer, Michel Lallier Department of General Pediatric Surgery, University Hospital, Hôpital Sainte-Justine, Montréal, Quebec, Canada H3T 1C5 Received 12 October 2008; revised 5 March 2009; accepted 17 April 2009
Key words: Neuroblastoma; Paraneoplastic; Myasthenic syndrome; Lambert-Eaton
Abstract Lambert-Eaton myasthenic syndrome is a paraneoplastic syndrome that may reveal a primitive tumor. Neuroblastoma in children and small cell lung carcinoma in adults are the leading tumors revealed or expressed by paraneoplastic phenomena. The clinical neurologic manifestations of Lambert-Eaton myasthenic syndrome are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Neurologic manifestations are explained by the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor. Neurologic paraneoplastic disorders may also be the result of toxicity of drugs, coagulopathy, infection, or metabolic diseases. We describe the case of a 13-month-old child with unusual neurologic symptoms because of the presence of an abdominal neuroblastoma. © 2009 Elsevier Inc. All rights reserved.
Lambert-Eaton myasthenic syndrome (LEMS) is a prototype of a presynaptic autoimmune disorder of the neuromuscular transmission. In this syndrome, circulating antibodies react with voltage-gated calcium channels at the presynaptic neuromuscular junction. This stimulation provokes severe neurologic manifestations such as autonomic dysfunction, muscular weakness, and decreased tendon reflexes. These symptoms may be the presenting feature of an otherwise undiagnosed tumor. Normally, early diagnosis of the etiology of these manifestations maximizes the likelihood of the treatment of the tumor along with the disappearance of the neurologic manifestations.
⁎ Corresponding author. MER Service de chirurgie pédiatrique Centre Hospitalier Universitaire Vaudois (CHUV) CH-1011 Lausanne, Switzerland. Tel.: +1 41 21 314 31 26; fax: +1 41 21 314 30 76. E-mail address: [email protected] (A.S. de Buys Roessingh). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.04.023
1. Case report A 13-month-old adolescent girl was brought by her parents to the emergency ward for abdominal pain after a long period of constipation and for right ocular paresis and somnolence present for about 1 week according to the parents. The girl slept all through the physical examination. It was difficult to wake her up during the day. She refused to stand straight and experienced an extreme weakness of the legs. She did not react during venous puncture. Her head was oriented toward the right direction. A weakness of the right eyelid and a right ocular paresis were present. She was hospitalized for neurologic and ophthalmologic investigations. Bilateral ptosis was noted soon after her hospitalization, and the girl showed no reaction to any stimulation. The movements of her limbs were normal without spasticity. A computed tomography (CT) scan of the brain was normal except for a Chiari type II malformation. Magnetic resonance
E6
A.S. de Buys Roessingh et al.
imaging of the brain was also normal. An abdominal ultrasound (US) revealed a right abdominal mass measuring 6 by 5 by 5 cm, situated above the superior pole of the kidney and causing a compression of the inferior vena cava. The mass was compatible with a neuroblastoma. A paraneoplastic LEMS was diagnosed. Electromyography showed normal conduction. A Tensilon test was also normal. The child was tested negative for antiacetylcholine receptor antibodies. The staging evaluation began with a CT scan of the abdomen, which showed a right retroperitoneal resectable tumor (Fig. 1). Bone CT scan findings showed no osseous metastases. Bone marrow aspiration specimens from the iliac crests did not contain tumor cells. Metaiodobenzylguanidine I 131 scan uptake was limited to the abdominal mass. Serum ferritin level was less than 142 ng/mL, serum neuron-specific enolase was less than 100 ng/mL, serum lactate dehydrogenase was less than 1500 U/L, and the urine vanillylmandelic acid/homovanillic acid ratio was less than 1. The abdominal mass was resected, and the diagnosis of neuroblastoma was confirmed. The tumor was intact, with free margins and normal lymph nodes. The mass measured 7 by 5.5 by 4 cm and weighed 53 g. The histology of the specimen was compatible with a neuroblastoma and was not favorable, with a mitosis karyorrhexis index of more than 200, a high MYCN (oncogenic transcription factor) amplification within more than 80% of nuclei, and cell diploidy. Tumor cell chromosomal findings were normal with intact chromosomes 1p and 11q. One day after the surgical removal of the tumor, the girl woke up without any persistent neurologic symptoms. She could move normally. The weakness of the right eyelid and the right ocular paresis had totally disappeared. She left the hospital a few days after the operation. Two months later, she returned to the hospital because of a protruding right eye. A CT scan revealed the presence of a mass behind the right eye, and the 131I-metaiodobenzylguanidine scan uptake was positive for a mass in the right retroocular region. Chemotherapy was started. The child was treated according to the Pediatric Oncology Group recommendations [1].
Fig. 1 mass.
Compute tomography scan showing the right abdominal
2. Discussion Early symptoms of the presence of a neuroblastoma are usually weight loss, weakness, or fever. The clinical presentation depends on the location of the tumor. In the abdomen, the mass is retroperitoneal and is most often detected in the course of routine clinical examinations. A pelvic mass may provoke urinary retention or constipation. In the thorax, the tumor is most often discovered on chest radiographs. Occasionally, the tumor is revealed by symptoms because of the compression of the sympathetic innervation leading to a Horner syndrome or by various neurologic paraneoplastic manifestations such as opsoclonus-myoclonus-ataxia [2]. Clinical ocular manifestations with ptosis may even be present. Lambert-Eaton myasthenic syndrome is extremely rare in young children. Its clinical manifestations are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Dysautonomia is the dysfunction of the autonomic nervous system that concerns the 3 subsystems, the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. The autonomic nervous system regulates in an autonomous manner the activities of the cardiac muscle, the smooth muscle, the endocrine glands, and the exocrine glands [3]. Paraneoplastic disorders can affect both central and peripheral nervous systems. The symptoms of these disorders may be because of the stimulation of different parts of the nervous system, thus, inducing different manifestations. This explains why no neurologic manifestation is in itself absolutely pathognomonic for a paraneoplastic syndrome because of a tumor. Neuromuscular junction disorders are usually categorized either as presynaptic or postsynaptic. Lambert-Eaton myasthenic syndrome is typically a presynaptic autoimmune disorder of neuromuscular transmission as opposed to myasthenia gravis (MG), which is postsynaptic. These 2 disorders can be differentiated by electromyography, which shows an increase of the response to muscle stimulation in LEMS and a decrease of the response to muscle stimulation in MG and by a Tensilon test, which is an injection of edrophonium chloride used to diagnose MG. Edrophonium blocks the action of the enzyme acetylcholinesterase, which takes an important part in the regulation of the neuromuscular transmission. A nerve cell (neuron) releases the chemical acetylcholine to stimulate a muscle. Acetylcholine is broken down by acetylcholinesterase after the muscle is stimulated to prevent prolonged muscle response to a single nerve signal. The presence of different and specific autoantibodies may also help to differentiate these 2 illnesses [3]. The mechanisms of neurologic manifestations because of a paraneoplastic syndrome are not well understood. The leading theory describes the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor as well as in some types of neurons [4]. When these antigens are expressed in a nonnervous
LEMS revealing an abdominal neuroblastoma system, the immune system produces autoantibodies that can damage these particular neurons. One of the best-known autoantibodies is the antineuronal nuclear antibody (anti-Hu), which is related to neuroblastoma and also to lung carcinoma [5]. However, autoantibodies are not always associated with a tumor or with neurologic manifestations and are not always present in patients who present these syndromes [6]. In vitro testing has even produced some evidence that autoantibodies such as the anti-Hu may not cause injury to neurons [7]. Because we consider that paraneoplastic syndromes are autoimmune diseases, it follows that their manifestations should disappear either after the excision of the tumor or in response to an immunosuppressive treatment. The resection of the tumor in our patient led to the suppression of the neurologic symptoms. But in fact, the response to treatment of different paraneoplastic syndromes can vary considerably, and in most of the adult cases, the recovery may not be complete and neurologic symptoms can persist. The addition of immunosuppressive therapy to treat neurologic paraneoplastic symptoms after removal of the tumor does not seem to improve the reduction of the neurologic symptoms, and, especially in LEMS, patients are left with permanent neurologic deficits [8]. Although some neuronal injury by unknown mechanisms may already be present and irreversible, a prompt diagnosis may play a role in the recovery and early treatment may be correlated with a faster abatement of the neurologic paraneoplastic symptoms. We could not ascertain whether a prompt diagnosis in children could be of importance in reducing neurologic sequelae. But in any case, the presence of unexplained
E7 neurologic manifestations in an otherwise healthy child should raise the suspicion of a possible paraneoplastic syndrome because of the presence of an undiagnosed tumor.
Acknowledgment The authors are grateful to Annette Wagnière for reviewing the English text.
References [1] Castleberry RP. Biology and treatment of neuroblastoma. Pediatr Clin North Am 1997;44:919-37. [2] Pranzatelli MR, Tate ED, Wheeler, et al. Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia. Pediatr Neurol 2002; 27:384-7. [3] Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2002;73:766-8. [4] Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol 2005;18:331-6. [5] Pittock SJ, Kryzer VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56:715-9. [6] Bataller L, Rosenfeld MR, Graus F, et al. Autoantigen diversity in the opsoclonus-myoclonus syndrome. An Neurol 2003;53:347-53. [7] Tanaka K, Tanaka M. Effects of antineuronal antibodies from patients with paraneoplastic syndrome on primary cultured neurons. J Neurol Sci 2004;217:2-30. [8] Bosdure E, Attarian S, Mancini J, et al. Lambert-Eton myasthenic syndrome revealing neuroblastoma in 2 children. Arch Pediatr 2006; 13:1121-4.