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Isolated Abducens Nerve Palsy Complicating Cytomegalovirus Infection
Isolated Abducens Nerve Palsy Complicating Cytomegalovirus Infection Filippo Greco, MD, Rosaria Garozzo, MD, and Giovanni Sorge, MD This report describes an immunocompetent 5-yearold female with isolated abducens nerve palsy complicating a cytomegalovirus infection and documented with polymerase chain reaction performed on cerebrospinal fluid; treatment with ganciclovir was associated with rapid clinical improvement. It may be the first report of cytomegalovirus detected in the central nervous system as a cause of isolated abducens nerve palsy. © 2006 by Elsevier Inc. All rights reserved. Greco F, Garozzo R, Sorge G. Isolated Abducens Nerve Palsy Complicating Cytomegalovirus Infection. Greco F, Garozzo R, Sorge G. Isolated abducens nerve palsy complicating cytomegalovirus infection. Pediatr Neurol 2006;35:229-230.
Introduction Abducens nerve palsy can be associated in children with different clinical pictures underlying significant pathology. This report presents a 5-year-old female affected with acute isolated abducens nerve palsy complicating cytomegalovirus infection, diagnosed on the basis of polymerase chain reaction carried out on cerebrospinal fluid. Treatment with ganciclovir, 10 mg/kg per day intravenously for 14 days, was associated with rapid improvement and complete recovery.
From the Department of Pediatrics, University of Catania, Catania, Italy.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.03.008 ● 0887-8994/06/$—see front matter
Case Report The patient is a firstborn female to nonconsanguineous parents; the mother is affected with bronchial asthma, and two cousins are affected with celiac disease. She was born at 39 weeks of gestation by normal delivery after uncomplicated pregnancy. Birth weight was 2900 gm, length 49 cm, and head circumference 34 cm. The perinatal period was uneventful; psychomotor development was normal. At the age of 4 years and 10 months, the patient developed low-grade fever, sore throat, cough, and mild cervical lymphoadenopathy lasting 3 days. She was treated with paracetamol. Within 6 days she experienced headache and diplopia. She had no history of trauma or recent vaccination. After 1 month from the onset of symptoms, she was admitted at the Department of Pediatrics of the University of Catania; weight was 17 kg (10th percentile), length 106 cm (25th percentile), and head circumference 50 cm (25th percentile). On examination she was alert and not febrile; cardiovascular and respiratory inspection was normal. Abdomen was normotensive and tractable; liver and spleen were within normal limits. Neurologic examination revealed a right sixth nerve palsy. All other cranial nerves were intact, and there was no evidence of nystagmus; dilated funduscopic examination was unremarkable with no evidence of papilledema, and corneal reflexes were normal. There were no signs of meningeal irritation; muscle tone and strength were normal, as were deep tendon reflexes and cerebellar function. Magnetic resonance imaging of the brain and optic nerves was normal. On laboratory investigations, peripheral white blood cell count was 11,500/mm3 leukocytes, lymphocytes 8,000/mm3, hemoglobin 12.2 gm/dL, and erythrocyte sedimentation rate 30 mm. The following clinical investigations were all within the normal range: chest radiography, urinalysis, red blood cell count, platelet count, glucose, serum urea, serum electrolytes, transaminase, bleeding time, fibrinogen, immunoglobulins, lymphocyte subpopulations, immunoglobulin A and immunoglobulin G antigliadin antibodies, immunoglobulin A antiendomysium antibodies, antitransglutaminase antibodies, anti-GQ1b antibodies, anti-GM1 and GM2 antibodies, antibodies to Mycoplasma pneumoniae, Campylobacter jejuni, Epstein-Barr virus, Toxoplasma gondii, human immunodeficiency virus, Borrelia burgdorferi, and Chlamydia pneumoniae. The antibody immunoglobulin M titers against cytomegalovirus were 10.79 I.R. (0-0.9) and immunoglobulin G were 9.2 UI/mL (0.7-35), suggesting the possibility of an acute cytomegalovirus infection; thus further immunologic studies were performed. Polymerase chain reaction carried out on serum and saliva was positive. On examination of cerebrospinal fluid, there were no cells, glucose and protein concentrations were normal, and microbiologic culture was negative. Testing of viral deoxyribonucleic acid for cytomegalovirus, performed with nested polymerase chain reaction, was indeed positive. Therefore specific therapy with ganciclovir was initiated at a dosage of 10 mg/kg/day intravenously for 14 days with weekly control of transaminase, hemoglobin, and serum urea. In the next 7 days the child presented a progressive clinical improvement with complete recovery.
Communications should be addressed to: Dr. Greco; Department of Pediatrics; Via S. Sofia 78; 95123 Catania, Italy. E-mail: [email protected] Received December 28, 2005; accepted March 14, 2006.
Greco et al: Abducens Palsy Complicating CMV 229
Discussion In its long and tortuous course from pontine somatic motor nucleus, the abducens nerve runs through different anatomic structures including subarachnoid space, temporal bone, cavernous sinus, and orbit and thus is susceptible to a variety of insults. Lateral rectus palsy is usually caused by tumors, hemorrhages, head trauma, and inflammations such as meningitis, Miller Fisher syndrome, and Gradenigo’s syndrome [1] and may rarely occur as a complication of ophthalmoplegic migraine [2]. Benign isolated abducens nerve palsy is a rare clinical entity characterized by spontaneous resolution within 6 months. Diagnosis is determined retrospectively after exclusion of the main conditions of sixth nerve palsy in childhood [3], and is different from benign recurrent forms [4]. The first description dates back to Knox et al. who in 1967 reported 12 children who presented with a sixth nerve palsy as their main symptom; three of them had a prior history of otitis media and then were affected with Gradenigo syndrome, whereas for the other nine patients the investigators assumed that the benign palsy was due to antecedent viral febrile or upper respiratory illness [5]. Several viral or bacterial agents reported in the literature were correlated to isolated abducens palsy. Particularly some reports were described secondary to immunizations (measles, measles-mumps-rubella, diphtheria-tetanus-pertussis vaccines) [6-8], others to Epstein-Barr, varicella, herpes zoster ophthalmicus, Mycoplasma pneumoniae, and Chlamydia pneumoniae infections [9-13]. Only one patient previously reported in the literature of lateral rectus palsy and cytomegalovirus infectious concerns a 4-year-old male child, who in the course of a mononucleosis-like syndrome suddenly developed diplopia; serologic studies indicated increasing titers of anticytomegalovirus serum antibodies, but test for antibody on cerebrospinal fluid was negative and the role of the virus was only presumed [14]. Acquired cytomegalovirus infections cause various acute, subacute, and chronic disorders of the central and peripheral nervous system that mainly include encephalitis, meningitis, cranial nerve palsies, myelitis, polymyeloradiculitis, and Guillain-Barré syndrome [15]. In childhood, neurologic involvement by cytomegalovirus occurs usually in immunocompromised patients, above all in those with acquired immunodeficiency syndrome. To our knowledge, the patient reported is the first immunocompetent child described in the literature associated with cytomegalovirus infection, in which the virus was detected in cerebrospinal fluid with polymerase chain reaction. The presence of cytomegalovirus deoxyribonucleic acid in the cerebrospinal fluid likely
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implies primary infection, not reactivation of a persistent cytomegalovirus infection in a subject without immunologic abnormalities in immunoglobulins and lymphocyte subpopulations. Treatment with intravenous ganciclovir was associated with rapid clinical improvement, even if the natural history of abducens palsy is one of eventual recovery. With respect to pathogenic mechanism, normal cerebrospinal fluid protein did not exclude completely a demyelination, but a neuritis probably must also be considered. The lack of serum anti-ganglioside antibodies (anti-GM, -GM2, and -GQ1b) seems to exclude at the moment molecular mimicry between virus surface epitopes and cranial nerve gangliosides, as has been documented in other peripheral nervous disorders such as Guillain-Barré and Miller Fisher syndrome. Further clinical and microbiologic studies are necessary to analyze the relationships between viral infections, immunologic assessment, and central and peripheral nervous system.
References [1] Afifi AK, Bell WE, Menezes AH. Etiology of lateral rectus palsy in infancy and childhood. J Child Neurol 1992;7:295-9. [2] Levin M, Ward TN. Ophthalmoplegic migraine. Curr Pain Headache Rep 2004;8:306-9. [3] Cohen HA, Nussinovitch M, Ashkenazi A, Straussberg R, Kaushansky A. Benign abducens nerve palsy of childhood. Pediatr Neurol 1993;9:394 –5. [4] Knapp CM, Gottlob I. Benign recurrent abducens (6th) nerve palsy in two children. Strabismus 2004;12:13-6. [5] Knox DL, Clark DB, Schister FF. Benign VI nerve palsies in children. Pediatrics 1967;40:560 – 4. [6] Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:574-9. [7] Werner DB, Savino PJ, Schatz NJ. Benign recurrent sixth nerve palsies in childhood secondary to immunization or viral illness. Arch Ophthalmol 1983;101:607-8. [8] Rosen E. A postvaccinial ocular syndrome. Am J Ophthalmol 1948;31:1443-53. [9] Neuberger J, Bone I. Bilateral sixth cranial nerve palsy in infectious mononucleosis. Postgrad Med J 1979;55:433-4. [10] Nemet P, Ehrlich D, Lazar M. Benign abducens palsy in varicella. Am J Ophthalmol 1974;78:859. [11] Herman JS. Isolated abducens paresis complicating herpes zoster ophthalmicus. Am J Ophthalmol 1962;54:298-301. [12] Wang CH, Chou ML, Huang CH. Benign isolated abducens nerve palsy in Mycoplasma pneumoniae infection. Pediatr Neurol 1998; 18:71-2. [13] Vanden Eijnden S, Borza D, Cautron V, Cavatorta E. Isolated 6th nerve palsy in a child associated with asymptomatic Chlamydia pneumoniae infection and elevated anti-GQ1b antibody. Eur J Pediatr 2001;160:400. [14] George JL, Abellan P, Gehin JC, Toussaint M, Toussaint D. Regressive abducens palsy in a child: A cytomegalovirus infection presumed. Rev Otoneuroophthalmol 1984;56:67-70. [15] Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 2001;11:440-51.
Introduction Abducens nerve palsy can be associated in children with different clinical pictures underlying significant pathology. This report presents a 5-year-old female affected with acute isolated abducens nerve palsy complicating cytomegalovirus infection, diagnosed on the basis of polymerase chain reaction carried out on cerebrospinal fluid. Treatment with ganciclovir, 10 mg/kg per day intravenously for 14 days, was associated with rapid improvement and complete recovery.
From the Department of Pediatrics, University of Catania, Catania, Italy.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.03.008 ● 0887-8994/06/$—see front matter
Case Report The patient is a firstborn female to nonconsanguineous parents; the mother is affected with bronchial asthma, and two cousins are affected with celiac disease. She was born at 39 weeks of gestation by normal delivery after uncomplicated pregnancy. Birth weight was 2900 gm, length 49 cm, and head circumference 34 cm. The perinatal period was uneventful; psychomotor development was normal. At the age of 4 years and 10 months, the patient developed low-grade fever, sore throat, cough, and mild cervical lymphoadenopathy lasting 3 days. She was treated with paracetamol. Within 6 days she experienced headache and diplopia. She had no history of trauma or recent vaccination. After 1 month from the onset of symptoms, she was admitted at the Department of Pediatrics of the University of Catania; weight was 17 kg (10th percentile), length 106 cm (25th percentile), and head circumference 50 cm (25th percentile). On examination she was alert and not febrile; cardiovascular and respiratory inspection was normal. Abdomen was normotensive and tractable; liver and spleen were within normal limits. Neurologic examination revealed a right sixth nerve palsy. All other cranial nerves were intact, and there was no evidence of nystagmus; dilated funduscopic examination was unremarkable with no evidence of papilledema, and corneal reflexes were normal. There were no signs of meningeal irritation; muscle tone and strength were normal, as were deep tendon reflexes and cerebellar function. Magnetic resonance imaging of the brain and optic nerves was normal. On laboratory investigations, peripheral white blood cell count was 11,500/mm3 leukocytes, lymphocytes 8,000/mm3, hemoglobin 12.2 gm/dL, and erythrocyte sedimentation rate 30 mm. The following clinical investigations were all within the normal range: chest radiography, urinalysis, red blood cell count, platelet count, glucose, serum urea, serum electrolytes, transaminase, bleeding time, fibrinogen, immunoglobulins, lymphocyte subpopulations, immunoglobulin A and immunoglobulin G antigliadin antibodies, immunoglobulin A antiendomysium antibodies, antitransglutaminase antibodies, anti-GQ1b antibodies, anti-GM1 and GM2 antibodies, antibodies to Mycoplasma pneumoniae, Campylobacter jejuni, Epstein-Barr virus, Toxoplasma gondii, human immunodeficiency virus, Borrelia burgdorferi, and Chlamydia pneumoniae. The antibody immunoglobulin M titers against cytomegalovirus were 10.79 I.R. (0-0.9) and immunoglobulin G were 9.2 UI/mL (0.7-35), suggesting the possibility of an acute cytomegalovirus infection; thus further immunologic studies were performed. Polymerase chain reaction carried out on serum and saliva was positive. On examination of cerebrospinal fluid, there were no cells, glucose and protein concentrations were normal, and microbiologic culture was negative. Testing of viral deoxyribonucleic acid for cytomegalovirus, performed with nested polymerase chain reaction, was indeed positive. Therefore specific therapy with ganciclovir was initiated at a dosage of 10 mg/kg/day intravenously for 14 days with weekly control of transaminase, hemoglobin, and serum urea. In the next 7 days the child presented a progressive clinical improvement with complete recovery.
Communications should be addressed to: Dr. Greco; Department of Pediatrics; Via S. Sofia 78; 95123 Catania, Italy. E-mail: [email protected] Received December 28, 2005; accepted March 14, 2006.
Greco et al: Abducens Palsy Complicating CMV 229
Discussion In its long and tortuous course from pontine somatic motor nucleus, the abducens nerve runs through different anatomic structures including subarachnoid space, temporal bone, cavernous sinus, and orbit and thus is susceptible to a variety of insults. Lateral rectus palsy is usually caused by tumors, hemorrhages, head trauma, and inflammations such as meningitis, Miller Fisher syndrome, and Gradenigo’s syndrome [1] and may rarely occur as a complication of ophthalmoplegic migraine [2]. Benign isolated abducens nerve palsy is a rare clinical entity characterized by spontaneous resolution within 6 months. Diagnosis is determined retrospectively after exclusion of the main conditions of sixth nerve palsy in childhood [3], and is different from benign recurrent forms [4]. The first description dates back to Knox et al. who in 1967 reported 12 children who presented with a sixth nerve palsy as their main symptom; three of them had a prior history of otitis media and then were affected with Gradenigo syndrome, whereas for the other nine patients the investigators assumed that the benign palsy was due to antecedent viral febrile or upper respiratory illness [5]. Several viral or bacterial agents reported in the literature were correlated to isolated abducens palsy. Particularly some reports were described secondary to immunizations (measles, measles-mumps-rubella, diphtheria-tetanus-pertussis vaccines) [6-8], others to Epstein-Barr, varicella, herpes zoster ophthalmicus, Mycoplasma pneumoniae, and Chlamydia pneumoniae infections [9-13]. Only one patient previously reported in the literature of lateral rectus palsy and cytomegalovirus infectious concerns a 4-year-old male child, who in the course of a mononucleosis-like syndrome suddenly developed diplopia; serologic studies indicated increasing titers of anticytomegalovirus serum antibodies, but test for antibody on cerebrospinal fluid was negative and the role of the virus was only presumed [14]. Acquired cytomegalovirus infections cause various acute, subacute, and chronic disorders of the central and peripheral nervous system that mainly include encephalitis, meningitis, cranial nerve palsies, myelitis, polymyeloradiculitis, and Guillain-Barré syndrome [15]. In childhood, neurologic involvement by cytomegalovirus occurs usually in immunocompromised patients, above all in those with acquired immunodeficiency syndrome. To our knowledge, the patient reported is the first immunocompetent child described in the literature associated with cytomegalovirus infection, in which the virus was detected in cerebrospinal fluid with polymerase chain reaction. The presence of cytomegalovirus deoxyribonucleic acid in the cerebrospinal fluid likely
230
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implies primary infection, not reactivation of a persistent cytomegalovirus infection in a subject without immunologic abnormalities in immunoglobulins and lymphocyte subpopulations. Treatment with intravenous ganciclovir was associated with rapid clinical improvement, even if the natural history of abducens palsy is one of eventual recovery. With respect to pathogenic mechanism, normal cerebrospinal fluid protein did not exclude completely a demyelination, but a neuritis probably must also be considered. The lack of serum anti-ganglioside antibodies (anti-GM, -GM2, and -GQ1b) seems to exclude at the moment molecular mimicry between virus surface epitopes and cranial nerve gangliosides, as has been documented in other peripheral nervous disorders such as Guillain-Barré and Miller Fisher syndrome. Further clinical and microbiologic studies are necessary to analyze the relationships between viral infections, immunologic assessment, and central and peripheral nervous system.
References [1] Afifi AK, Bell WE, Menezes AH. Etiology of lateral rectus palsy in infancy and childhood. J Child Neurol 1992;7:295-9. [2] Levin M, Ward TN. Ophthalmoplegic migraine. Curr Pain Headache Rep 2004;8:306-9. [3] Cohen HA, Nussinovitch M, Ashkenazi A, Straussberg R, Kaushansky A. Benign abducens nerve palsy of childhood. Pediatr Neurol 1993;9:394 –5. [4] Knapp CM, Gottlob I. Benign recurrent abducens (6th) nerve palsy in two children. Strabismus 2004;12:13-6. [5] Knox DL, Clark DB, Schister FF. Benign VI nerve palsies in children. Pediatrics 1967;40:560 – 4. [6] Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:574-9. [7] Werner DB, Savino PJ, Schatz NJ. Benign recurrent sixth nerve palsies in childhood secondary to immunization or viral illness. Arch Ophthalmol 1983;101:607-8. [8] Rosen E. A postvaccinial ocular syndrome. Am J Ophthalmol 1948;31:1443-53. [9] Neuberger J, Bone I. Bilateral sixth cranial nerve palsy in infectious mononucleosis. Postgrad Med J 1979;55:433-4. [10] Nemet P, Ehrlich D, Lazar M. Benign abducens palsy in varicella. Am J Ophthalmol 1974;78:859. [11] Herman JS. Isolated abducens paresis complicating herpes zoster ophthalmicus. Am J Ophthalmol 1962;54:298-301. [12] Wang CH, Chou ML, Huang CH. Benign isolated abducens nerve palsy in Mycoplasma pneumoniae infection. Pediatr Neurol 1998; 18:71-2. [13] Vanden Eijnden S, Borza D, Cautron V, Cavatorta E. Isolated 6th nerve palsy in a child associated with asymptomatic Chlamydia pneumoniae infection and elevated anti-GQ1b antibody. Eur J Pediatr 2001;160:400. [14] George JL, Abellan P, Gehin JC, Toussaint M, Toussaint D. Regressive abducens palsy in a child: A cytomegalovirus infection presumed. Rev Otoneuroophthalmol 1984;56:67-70. [15] Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 2001;11:440-51.