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Limbic Encephalitis in a Child: An Atypical Presentation
Pediatric Neurology 49 (2013) 501e504
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Limbic Encephalitis in a Child: An Atypical Presentation Adel A.H. Mahmoud MD FRCP MRCPCH a, *, Fouad A.S. Al Ghamdi MD a, b, Michael V. Johnston MD c a
King Fahad Medical City, Riyadh, Saudi Arabia King Fahad Specialist Hospital, Dammam, Saudi Arabia c Kennedy Krieger Institute, Broadway, Baltimore, Maryland b
abstract BACKGROUND: Limbic encephalitis is a rare disorder with a generally subacute onset evolving over days to weeks. Patients present with a variable combination of memory loss, seizures, and psychiatric disturbance, and it is not rare for patients to be initially misdiagnosed. PATIENT: We describe a previously healthy 12-year-old boy who developed his first seizures at 8 years of age. He had a total of eight prolonged focal seizures, each followed by a month of behavioral changes and short-term memory loss. There was no family history of seizures or other neurological disorders, and he had an otherwise unremarkable neonatal and medical history. RESULTS: Magnetic resonance imaging during each episode of seizures showed alternating unilateral brain hemispheric involvement consistent with limbic encephalitis that was followed by resolution for a total of six times. Despite a negative laboratory evaluation for a large panel of paraneoplastic antibodies, the clinical scenario and exclusion of other possible disorders made recurrent limbic encephalitis the most likely diagnosis. CONCLUSION: Limbic encephalitis is a rare disorder that is diagnosed primarily on the basis of clinical criteria and is often associated with the presence of a paraneoplastic antibody. However, lack of a positive paraneoplastic antibody in a patient with a triad of seizure, behavioral changes, and short-term memory loss does not exclude the diagnosis. The unique presentation in a seronegative patient may indicate an unrecognized antibody. Keywords: limbic encephalitis, seizure, memory, antibodies, magnetic resonance imaging (MRI)
Pediatr Neurol 2013; 49: 501-504 Ó 2013 Elsevier Inc. All rights reserved.
Case Report A 12-year-old boy was previously well with normal cognitive function until age 8, when he developed his first attack of seizure. The patient’s first seizure developed as sudden awakening from sleep with confusion. He vomited once and immediately developed rightsided clonic seizure with head and eye deviation to the right. This was followed by secondary generalization with loss of consciousness. It was aborted by anticonvulsant medication after 30 minutes. Magnetic resonance imaging (MRI) brain was normal (Fig 1A). Within 4 years, the child had a total of eight status epilepticus episodes starting as focal seizures with secondary generalization. Each seizure was requiring an antiepileptic medication to be aborted and was followed by 3 weeks to a month of behavioral changes and short-term memory loss. His behavioral changes were in the form of
Article History: Received 1 February 2013; Accepted in final form 27 May 2013 * Communications should be addressed to: Dr. Mahmoud; Pediatric Neurology; King Fahd Hospital; Dabab, Riyadh 11393, Saudi Arabia. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.05.009
apathy and unusual disrespect to his parents and people around him. He improved gradually after each attack, but never returned back to baseline. His focal onset seizures were always accompanied by changes on brain imaging in the opposite hemisphere. Seizures one, two, three, five, and seven were right-sided with left temporal or temporoparietal lesions. His fourth, sixth, and eighth attacks were left-sided with rightsided temporoparietal lesions as per imaging (Figs 1 and 2). After the first year of seizures, the patient started to have daily short seizures that were not associated with behavioral changes or short-term memory loss. MRI of the brain one year after the sixth attack revealed bilateral temporal lobe abnormal signal intensity, loss of volume, and scattered cortical hyperintensities with evidence of meso-temporal sclerosis (Fig 2B). Positron emission tomography (PET) scan revealed mild diffuse bilateral cortical hypometabolism with small areas of relative hypermetabolism in the bitemporoparietal and mesial temporal cortices (Fig 3). Neonatal and medical history was unremarkable. A maternal uncle had brief controllable seizures. Parents are not consanguineous, but they are from the same tribe. The child had normal development and good school performance until he developed his first seizure. Currently, he is
502
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504
FIGURE 1. (A) A normal magnetic resonance imaging (MRI) scan of the brain after the second attack. (B) Computed tomography (CT) scan brain after the third attack, revealed extensive white matter hypodensity in left temporal lobe. (C) An MRI scan of the brain after the fourth attack revealed new development of a large right temporal lobe lesion with of improvement of the previous left hemispheric lesion. (D) CT scan of the brain after the fifth attack revealed redevelopment of the left temporoparietal hypodense area with significant improvement of the previous right hemispheric lesion.
in 7th grade with poor performance and multiple school absences. He is fully vaccinated. He has unremarkable systemic examination apart from large 5- 6-cm café au lait spot on the medial side of his right thigh. Neurological evaluation after each attack revealed orientation impairment to time, place, and persons, with loss of spontaneous speech and inability to repeat phrases. Recent memory was impaired for about a month, which was confirmed by neuropsychiatric evaluation. Remote memory was intact. Examination of cranial nerves was normal, with temporarily, motor weakness, and exaggerated reflexes contralateral to the brain lesion. Sensory and cerebellar examination was difficult to perform during the illness because of a lack of cooperation, but it was normal between the attacks. Hematological, biochemical, immunological, and infectious evaluations were unremarkable. Serum paraneoplastic antibodies including ANNA-1 (anti-neuronal nuclear antibodies), ANNA-2, ANNA-3, AGNA (anti-glial nuclear antibodies), PCA (Purkinje cell cytoplasmic antibodies)-1, PCA-2, PCA-Tr, CRMP (collapsin response mediator protein)-5-immunoglobulin G, amphiphysin antibody (Ab), striated muscle Ab, P/Q-type calcium channel Ab, N-type calcium channel Ab, Ach receptor muscle-binding Ab, AchR ganglionic neuronal Ab, neuronal voltage-gated Kþ channel
Ab, anti-NMDA (N-Methyl-D-aspartate), and anti-AMPA (2-amino-3[3-hydroxy-5-methyl-isoxazol-4-yl]propanoic acid) Ab were all negative. Cerebrospinal fluid (CSF) oligoclonal bands and polymerase chain reaction herpes simples virus tests were negative, but CSF albumin and immunoglobulin G were high. Repeated electroencephalogram showed generalized slowing in some studies and focal slowing in others, with very rare epileptiform discharges. Computed tomography of the chest, abdomen, and pelvis were unremarkable apart from right undescended testis, which showed no malignancy in pathological examination. PET scan of the whole body revealed mildly hypermetabolic right paracolic and right groin lymph nodes. Visual- and auditory-evoked potentials during the attacks were normal. Brain biopsy from the right temporal lobe revealed significant profuse infiltration of the brain parenchyma with CD3- and CD8-positive T cells. Based on the clinical scenario of memory loss, seizures, and psychiatric symptoms, the diagnosis of limbic encephalitis was considered and the child was treated accordingly by intravenous methylprednisolone for 5 days (30 mg/kg/day) and tapering doses of prednisolone. He showed good improvement.
FIGURE 2. (A) Computed tomography scan of the brain after the sixth attack revealed reappearance of right temporoparietal lesion and regression of the previous left hemispheric lesion. (B) A magnetic resonance imaging (MRI) of the brain a year after the sixth attack revealed bilateral temporal lobe abnormal signal intensity with evidence of mediotemporal sclerosis. (C) An MRI scan of the brain after the seventh attack showed reappearance of left temporoparietal lesion and regression of the previous right hemispheric lesion. (D) An MRI scan of the brain after the eighth attack revealed reappearance of right temporoparietal lesion and regression of the previous left hemispheric lesion.
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504
FIGURE 3. Positron emission tomography scan; arrows point to areas of hypermetabolism in the bitemporoparietal and mesial temporal cortices.
Discussion
Limbic encephalitis is autoimmune inflammatory encephalitis characterized by a subacute impairment of shortterm memory, psychiatric features, and seizures. It is often associated with a variety of other neurological symptoms. It was first described in 1968.1 Limbic encephalitis can be broadly divided into three major groups.2,3 (1) Limbic encephalitis associated with classical onconeural antibodies (antibodies to intracellular antigens). (2) Limbic encephalitis associated with antibodies against neuronal surface/synaptic antigens. (3) Limbic encephalitis associated with no known antibody (i.e., seronegative limbic encephalitis).4 Antibodies to intracellular antigens are Hu, Ma2, CV2, amphiphysin, and glutamic acid decarboxylase. They are associated with underlying malignancies, but usually do not reflect the presence of a tumor. They cause irreversible neuronal damage by cytotoxic T-cell mechanisms and they usually carry a poor prognosis.5 Glutamic acid decarboxylase antibodies are exceptions in this group because tumors are uncommon, and recovery is possible.3 Antibodies to neuronal surface/synaptic antigens are voltage-gated potassium channel complex (LGI1, CASPR2, contactin-2) and the NMDA, AMPA, gamma-aminobutyric acid type B, and glycine receptors. These are increasingly recognized categories, having much less associated malignancies and better response to immunotherapy with better prognosis.6,7 Seronegative limbic encephalitis is a group having the responsible antibody unrecognized. It is likely that new antibodies are yet to be discovered. It could be associated with an underlying tumor.4 Differential diagnoses of limbic encephalitis could include infectious, demyelinating, neoplastic, degenerative, neurotoxin, metabolic, or neurological manifestations of either systemic or connective tissue diseases. Diagnostic criteria of limbic encephalitis include: (1) acute or subacute onset of short-term memory loss,
503
seizures, confusion, and psychiatric symptoms; (2) pathological or radiological evidence of limbic system involvement; (3) CSF evidence of inflammation; and (4) exclusion of other possible etiologies of limbic dysfunctions.8 Normal CSF and MRI brain studies do not exclude the diagnosis. Electroencephalogram reveals either generalized or focal slowing. Epileptiform discharges can be seen.3 All patients with limbic encephalitis should be widely screened for underlying tumors, including mammography for women, testicular ultrasound, beta human chorionic gonadotropin, and alpha-fetoprotein for men. To date, fluorodeoxyglucose PET represents the most sensitive technique for detecting even small neoplasms.9,10 In some cases, identified paraneoplastic antibody may provide a guide for subsequent tumor screening.2 However, there is no paraneoplastic antibody that is unique for a specific neoplasm. In 2009, at the European Paediatric Neurologic Society meeting, multiple groups reported individual children with, and pediatric patient case series of, NMDA receptor encephalitis, none of whom had evidence of malignancy; most of them had a favorable neurologic outcome.11,12 The three main facets of treating patients with paraneoplastic limbic encephalitis include removing or treating the tumor (if one can be detected), initiating therapy at the earliest, and using appropriate immune modality options. It is clear that not all children will have a detectable tumor as is the situation in the case being discussed.13 The recommended first-line immune therapies are intravenous methylprednisolone with either intravenous immunoglobulin or plasma exchange followed by tapering oral prednisolone.14e16 Supplementary symptomatic treatment such as antiepileptic drugs is sometimes highly needed. Second-line treatment including either rituximab17 or cyclophosphamide or both may be required.18 Because patients with detected paraneoplastic antibodies are highly prone to having a tumor, close follow-up in a previously screened patient with no tumor detected is crucial. In our patient, despite the fact that antibodies done were negative, the clinical picture of recurrent seizures associated with recent memory loss and behavioral changes made the diagnosis of limbic encephalitis very likely. Conclusion
Limbic encephalitis is a rare disease, and our patient’s unusual relapsing-remitting presentation with alternating brain lesion has not been reported previously. Our patient fulfills clinical criteria for limbic encephalitis, although he was seronegative for all the usual antibodies previously reported. References 1. Corsellis JA, Goldberg GJ, Norton AR. “Limbic encephalitis” and its association with carcinoma. Brain. 1968;91:481-496. 2. Asztely F, Kumlien E. The diagnosis and treatment of limbic encephalitis. Acta Neurol Scand. 2012;126:365-375. 3. Machado S, Pinto AN, Irani SR. What should you know about limbic encephalitis? Arq Neuropsiquiatr. 2012;70:817-822. 4. Ahmed SA, Archer HA, Rice CM, Gerhand S, Bradley M, Wilkins A. Seronegative limbic encephalitis: case report, literature review
504
5.
6.
7.
8.
9.
10.
11.
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504 and proposed treatment algorithm. Pract Neurol. 2011;11: 355-361. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 2011;10:759-772. Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology. 2008;70:1883-1890. Mori M, Kuwabara S, Yoshiyama M, Kanesaka T, Ogata T, Hattori T. Successful immune treatment for nonparaneoplastic limbic encephalitis. J Neurol Sci. 2002;201:85-88. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135-1140. Younes-mhenni S, Janier MF, Cinotti L, et al. FDGPET improves tumour detection in patient with paraneoplastic neurological syndromes. Brain. 2004;127:2331-2338. Mckeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010;67:322-329. Poloni C, Korff CM, Ricotti V. Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for
12.
13. 14.
15.
16. 17.
18.
anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2010;52:e78-e82. http://dx.doi.org/10.1111/j.1469-8749.2009.03542.x. Gowda V, Mukhtyar B, Pike MG, Hewertson J, McShane MA, Vincent A. Two children with NMDAr þve limbic encephalitis. United Kingdom: European Pediatric Neurology Society; 2009: S102. Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet Rare Dis. 2007;2:22. Grisold W, Giometto B, Vitaliani R, Oberndorfer S. Current approaches to the treatment of paraneoplastic encephalitis. Ther Adv Neurol Disord. 2011;4:237-248. Pelosof LC, Gerber De. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010; 85:838-854. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13:261-271. Shams’ili S, De Beukelaar J, Gratama JW, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol. 2006;253:16-20. Dalmau J, Tüzün E, Hy Wu, et al. Paraneoplastic anti-N-methyl-Daspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25-36.
I cannot give you the formula for success, but I can give you the formula for failure e which is: Try to please everybody. Herbert Swope
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Limbic Encephalitis in a Child: An Atypical Presentation Adel A.H. Mahmoud MD FRCP MRCPCH a, *, Fouad A.S. Al Ghamdi MD a, b, Michael V. Johnston MD c a
King Fahad Medical City, Riyadh, Saudi Arabia King Fahad Specialist Hospital, Dammam, Saudi Arabia c Kennedy Krieger Institute, Broadway, Baltimore, Maryland b
abstract BACKGROUND: Limbic encephalitis is a rare disorder with a generally subacute onset evolving over days to weeks. Patients present with a variable combination of memory loss, seizures, and psychiatric disturbance, and it is not rare for patients to be initially misdiagnosed. PATIENT: We describe a previously healthy 12-year-old boy who developed his first seizures at 8 years of age. He had a total of eight prolonged focal seizures, each followed by a month of behavioral changes and short-term memory loss. There was no family history of seizures or other neurological disorders, and he had an otherwise unremarkable neonatal and medical history. RESULTS: Magnetic resonance imaging during each episode of seizures showed alternating unilateral brain hemispheric involvement consistent with limbic encephalitis that was followed by resolution for a total of six times. Despite a negative laboratory evaluation for a large panel of paraneoplastic antibodies, the clinical scenario and exclusion of other possible disorders made recurrent limbic encephalitis the most likely diagnosis. CONCLUSION: Limbic encephalitis is a rare disorder that is diagnosed primarily on the basis of clinical criteria and is often associated with the presence of a paraneoplastic antibody. However, lack of a positive paraneoplastic antibody in a patient with a triad of seizure, behavioral changes, and short-term memory loss does not exclude the diagnosis. The unique presentation in a seronegative patient may indicate an unrecognized antibody. Keywords: limbic encephalitis, seizure, memory, antibodies, magnetic resonance imaging (MRI)
Pediatr Neurol 2013; 49: 501-504 Ó 2013 Elsevier Inc. All rights reserved.
Case Report A 12-year-old boy was previously well with normal cognitive function until age 8, when he developed his first attack of seizure. The patient’s first seizure developed as sudden awakening from sleep with confusion. He vomited once and immediately developed rightsided clonic seizure with head and eye deviation to the right. This was followed by secondary generalization with loss of consciousness. It was aborted by anticonvulsant medication after 30 minutes. Magnetic resonance imaging (MRI) brain was normal (Fig 1A). Within 4 years, the child had a total of eight status epilepticus episodes starting as focal seizures with secondary generalization. Each seizure was requiring an antiepileptic medication to be aborted and was followed by 3 weeks to a month of behavioral changes and short-term memory loss. His behavioral changes were in the form of
Article History: Received 1 February 2013; Accepted in final form 27 May 2013 * Communications should be addressed to: Dr. Mahmoud; Pediatric Neurology; King Fahd Hospital; Dabab, Riyadh 11393, Saudi Arabia. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.05.009
apathy and unusual disrespect to his parents and people around him. He improved gradually after each attack, but never returned back to baseline. His focal onset seizures were always accompanied by changes on brain imaging in the opposite hemisphere. Seizures one, two, three, five, and seven were right-sided with left temporal or temporoparietal lesions. His fourth, sixth, and eighth attacks were left-sided with rightsided temporoparietal lesions as per imaging (Figs 1 and 2). After the first year of seizures, the patient started to have daily short seizures that were not associated with behavioral changes or short-term memory loss. MRI of the brain one year after the sixth attack revealed bilateral temporal lobe abnormal signal intensity, loss of volume, and scattered cortical hyperintensities with evidence of meso-temporal sclerosis (Fig 2B). Positron emission tomography (PET) scan revealed mild diffuse bilateral cortical hypometabolism with small areas of relative hypermetabolism in the bitemporoparietal and mesial temporal cortices (Fig 3). Neonatal and medical history was unremarkable. A maternal uncle had brief controllable seizures. Parents are not consanguineous, but they are from the same tribe. The child had normal development and good school performance until he developed his first seizure. Currently, he is
502
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504
FIGURE 1. (A) A normal magnetic resonance imaging (MRI) scan of the brain after the second attack. (B) Computed tomography (CT) scan brain after the third attack, revealed extensive white matter hypodensity in left temporal lobe. (C) An MRI scan of the brain after the fourth attack revealed new development of a large right temporal lobe lesion with of improvement of the previous left hemispheric lesion. (D) CT scan of the brain after the fifth attack revealed redevelopment of the left temporoparietal hypodense area with significant improvement of the previous right hemispheric lesion.
in 7th grade with poor performance and multiple school absences. He is fully vaccinated. He has unremarkable systemic examination apart from large 5- 6-cm café au lait spot on the medial side of his right thigh. Neurological evaluation after each attack revealed orientation impairment to time, place, and persons, with loss of spontaneous speech and inability to repeat phrases. Recent memory was impaired for about a month, which was confirmed by neuropsychiatric evaluation. Remote memory was intact. Examination of cranial nerves was normal, with temporarily, motor weakness, and exaggerated reflexes contralateral to the brain lesion. Sensory and cerebellar examination was difficult to perform during the illness because of a lack of cooperation, but it was normal between the attacks. Hematological, biochemical, immunological, and infectious evaluations were unremarkable. Serum paraneoplastic antibodies including ANNA-1 (anti-neuronal nuclear antibodies), ANNA-2, ANNA-3, AGNA (anti-glial nuclear antibodies), PCA (Purkinje cell cytoplasmic antibodies)-1, PCA-2, PCA-Tr, CRMP (collapsin response mediator protein)-5-immunoglobulin G, amphiphysin antibody (Ab), striated muscle Ab, P/Q-type calcium channel Ab, N-type calcium channel Ab, Ach receptor muscle-binding Ab, AchR ganglionic neuronal Ab, neuronal voltage-gated Kþ channel
Ab, anti-NMDA (N-Methyl-D-aspartate), and anti-AMPA (2-amino-3[3-hydroxy-5-methyl-isoxazol-4-yl]propanoic acid) Ab were all negative. Cerebrospinal fluid (CSF) oligoclonal bands and polymerase chain reaction herpes simples virus tests were negative, but CSF albumin and immunoglobulin G were high. Repeated electroencephalogram showed generalized slowing in some studies and focal slowing in others, with very rare epileptiform discharges. Computed tomography of the chest, abdomen, and pelvis were unremarkable apart from right undescended testis, which showed no malignancy in pathological examination. PET scan of the whole body revealed mildly hypermetabolic right paracolic and right groin lymph nodes. Visual- and auditory-evoked potentials during the attacks were normal. Brain biopsy from the right temporal lobe revealed significant profuse infiltration of the brain parenchyma with CD3- and CD8-positive T cells. Based on the clinical scenario of memory loss, seizures, and psychiatric symptoms, the diagnosis of limbic encephalitis was considered and the child was treated accordingly by intravenous methylprednisolone for 5 days (30 mg/kg/day) and tapering doses of prednisolone. He showed good improvement.
FIGURE 2. (A) Computed tomography scan of the brain after the sixth attack revealed reappearance of right temporoparietal lesion and regression of the previous left hemispheric lesion. (B) A magnetic resonance imaging (MRI) of the brain a year after the sixth attack revealed bilateral temporal lobe abnormal signal intensity with evidence of mediotemporal sclerosis. (C) An MRI scan of the brain after the seventh attack showed reappearance of left temporoparietal lesion and regression of the previous right hemispheric lesion. (D) An MRI scan of the brain after the eighth attack revealed reappearance of right temporoparietal lesion and regression of the previous left hemispheric lesion.
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504
FIGURE 3. Positron emission tomography scan; arrows point to areas of hypermetabolism in the bitemporoparietal and mesial temporal cortices.
Discussion
Limbic encephalitis is autoimmune inflammatory encephalitis characterized by a subacute impairment of shortterm memory, psychiatric features, and seizures. It is often associated with a variety of other neurological symptoms. It was first described in 1968.1 Limbic encephalitis can be broadly divided into three major groups.2,3 (1) Limbic encephalitis associated with classical onconeural antibodies (antibodies to intracellular antigens). (2) Limbic encephalitis associated with antibodies against neuronal surface/synaptic antigens. (3) Limbic encephalitis associated with no known antibody (i.e., seronegative limbic encephalitis).4 Antibodies to intracellular antigens are Hu, Ma2, CV2, amphiphysin, and glutamic acid decarboxylase. They are associated with underlying malignancies, but usually do not reflect the presence of a tumor. They cause irreversible neuronal damage by cytotoxic T-cell mechanisms and they usually carry a poor prognosis.5 Glutamic acid decarboxylase antibodies are exceptions in this group because tumors are uncommon, and recovery is possible.3 Antibodies to neuronal surface/synaptic antigens are voltage-gated potassium channel complex (LGI1, CASPR2, contactin-2) and the NMDA, AMPA, gamma-aminobutyric acid type B, and glycine receptors. These are increasingly recognized categories, having much less associated malignancies and better response to immunotherapy with better prognosis.6,7 Seronegative limbic encephalitis is a group having the responsible antibody unrecognized. It is likely that new antibodies are yet to be discovered. It could be associated with an underlying tumor.4 Differential diagnoses of limbic encephalitis could include infectious, demyelinating, neoplastic, degenerative, neurotoxin, metabolic, or neurological manifestations of either systemic or connective tissue diseases. Diagnostic criteria of limbic encephalitis include: (1) acute or subacute onset of short-term memory loss,
503
seizures, confusion, and psychiatric symptoms; (2) pathological or radiological evidence of limbic system involvement; (3) CSF evidence of inflammation; and (4) exclusion of other possible etiologies of limbic dysfunctions.8 Normal CSF and MRI brain studies do not exclude the diagnosis. Electroencephalogram reveals either generalized or focal slowing. Epileptiform discharges can be seen.3 All patients with limbic encephalitis should be widely screened for underlying tumors, including mammography for women, testicular ultrasound, beta human chorionic gonadotropin, and alpha-fetoprotein for men. To date, fluorodeoxyglucose PET represents the most sensitive technique for detecting even small neoplasms.9,10 In some cases, identified paraneoplastic antibody may provide a guide for subsequent tumor screening.2 However, there is no paraneoplastic antibody that is unique for a specific neoplasm. In 2009, at the European Paediatric Neurologic Society meeting, multiple groups reported individual children with, and pediatric patient case series of, NMDA receptor encephalitis, none of whom had evidence of malignancy; most of them had a favorable neurologic outcome.11,12 The three main facets of treating patients with paraneoplastic limbic encephalitis include removing or treating the tumor (if one can be detected), initiating therapy at the earliest, and using appropriate immune modality options. It is clear that not all children will have a detectable tumor as is the situation in the case being discussed.13 The recommended first-line immune therapies are intravenous methylprednisolone with either intravenous immunoglobulin or plasma exchange followed by tapering oral prednisolone.14e16 Supplementary symptomatic treatment such as antiepileptic drugs is sometimes highly needed. Second-line treatment including either rituximab17 or cyclophosphamide or both may be required.18 Because patients with detected paraneoplastic antibodies are highly prone to having a tumor, close follow-up in a previously screened patient with no tumor detected is crucial. In our patient, despite the fact that antibodies done were negative, the clinical picture of recurrent seizures associated with recent memory loss and behavioral changes made the diagnosis of limbic encephalitis very likely. Conclusion
Limbic encephalitis is a rare disease, and our patient’s unusual relapsing-remitting presentation with alternating brain lesion has not been reported previously. Our patient fulfills clinical criteria for limbic encephalitis, although he was seronegative for all the usual antibodies previously reported. References 1. Corsellis JA, Goldberg GJ, Norton AR. “Limbic encephalitis” and its association with carcinoma. Brain. 1968;91:481-496. 2. Asztely F, Kumlien E. The diagnosis and treatment of limbic encephalitis. Acta Neurol Scand. 2012;126:365-375. 3. Machado S, Pinto AN, Irani SR. What should you know about limbic encephalitis? Arq Neuropsiquiatr. 2012;70:817-822. 4. Ahmed SA, Archer HA, Rice CM, Gerhand S, Bradley M, Wilkins A. Seronegative limbic encephalitis: case report, literature review
504
5.
6.
7.
8.
9.
10.
11.
A.A.H. Mahmoud et al. / Pediatric Neurology 49 (2013) 501e504 and proposed treatment algorithm. Pract Neurol. 2011;11: 355-361. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 2011;10:759-772. Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology. 2008;70:1883-1890. Mori M, Kuwabara S, Yoshiyama M, Kanesaka T, Ogata T, Hattori T. Successful immune treatment for nonparaneoplastic limbic encephalitis. J Neurol Sci. 2002;201:85-88. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135-1140. Younes-mhenni S, Janier MF, Cinotti L, et al. FDGPET improves tumour detection in patient with paraneoplastic neurological syndromes. Brain. 2004;127:2331-2338. Mckeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010;67:322-329. Poloni C, Korff CM, Ricotti V. Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for
12.
13. 14.
15.
16. 17.
18.
anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2010;52:e78-e82. http://dx.doi.org/10.1111/j.1469-8749.2009.03542.x. Gowda V, Mukhtyar B, Pike MG, Hewertson J, McShane MA, Vincent A. Two children with NMDAr þve limbic encephalitis. United Kingdom: European Pediatric Neurology Society; 2009: S102. Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet Rare Dis. 2007;2:22. Grisold W, Giometto B, Vitaliani R, Oberndorfer S. Current approaches to the treatment of paraneoplastic encephalitis. Ther Adv Neurol Disord. 2011;4:237-248. Pelosof LC, Gerber De. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010; 85:838-854. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13:261-271. Shams’ili S, De Beukelaar J, Gratama JW, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol. 2006;253:16-20. Dalmau J, Tüzün E, Hy Wu, et al. Paraneoplastic anti-N-methyl-Daspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25-36.
I cannot give you the formula for success, but I can give you the formula for failure e which is: Try to please everybody. Herbert Swope