Brief Communication
Wernicke Encephalopathy in Pediatric Neuro-oncology: Presentation of 2 Cases and Review of Literature
Journal of Child Neurology 2014, Vol. 29(12) NP181-NP185 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510355 jcn.sagepub.com
Maria Giuseppina Cefalo, MD1, Maria Antonietta De Ioris, MD1, Antonella Cacchione, MD1, Daniela Longo, MD1, Susanna Staccioli, MD1, Francesco Arcioni, MD2, Bruno Bernardi, MD1, and Angela Mastronuzzi, MD1
Abstract Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations. Wernicke encephalopathy is rare and under-recognized in childhood and may be fatal. Few cases have been documented in pediatric oncology. We report on 2 Wernicke encephalopathy cases that occurred in children having a brain tumor. The diagnosis of Wernicke encephalopathy was suggested by clinical manifestations associated with the typical radiologic findings and a laboratory evidence of thiamine deficiency. No large series have been published to support the evidence that pediatric malignancies represent a demonstrated factor of increased risk to develop a Wernicke encephalopathy. Moreover, the diagnosis may be even more difficult in brain tumors, considering the overlapping symptoms and the risk of encephalopathy related to both the disease and the treatment. Wernicke encephalopathy should be considered in all children with cancer presenting a neurologic deterioration, mainly in brain tumors. An early diagnosis is imperative for a prompt therapy that might prevent or minimize the irreversible brain damage related to this condition. Keywords Wernicke encephalopathy, brain cancer, childhood Received May 08, 2013. Received revised June 29, 2013; July 25, 2013; August 29, 2013; September 05, 2013. Accepted for publication October 03, 2013.
Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations that appears in patients with multifactorial thiamine (vitamin B1) deficiency1; this condition is associated with high morbidity and mortality.2 The classical clinical triad is mental status changes, ophthalmoplegia, and ataxia, although atypical presentations have been reported. The acute neurologic injury of Wernicke encephalopathy can evolve into Korsakoff syndrome, an impairment of formation of new memories with sufficient preservation of other mental functions. The disorder may be fatal if unrecognized. Wernicke encephalopathy is rare in children and is always associated with malabsorption. Few cases have been documented in pediatric oncology.3
was continued, with good tolerance and no side effects. During the 11th week of treatment, the patient acutely developed restlessness, truncal ataxia, slurred speech, and bilateral visual disorders. He was afebrile and there were no meningeal signs. Vital signs were stable. Routine investigations—complete blood count, biochemistry, and C-reactive protein—were within normal range. Cerebrospinal fluid was normal. At ophthalmologic examination, asymmetrical paralysis of both lateral recti muscles was found. Brain magnetic resonance imaging (MRI) showed global volumetric growth of the well-known expansive lesion in the brainstem region, with a new fluid area in the tumor. Furthermore, fluid-attenuated inversion recovery image showed bilateral hyperintensity signal and symmetric areas involving the dorsal medial nucleus of the thalamus,
Case Presentation 1
1
We present a 6-year-old boy with diffuse intrinsic pontine glioma, treated with radiotherapy (delivered dose 5400 cGy) and chemotherapy (vinorelbine 20 mg/m2 and nimotuzumab 100 mg/m2 weekly) achieving partial response with reduction of the lesion and decreased contrast enhancement. Therefore, chemotherapy with vinorelbine 25 mg/m2 and nimotuzumab 100 mg/m2 every 2 weeks
2
Ospedale Pediatrico Bambino Gesu` Children’s Hospital IRCCS, Rome, Italy University of Perugia, S.M. Misericordia University Hospital, Perugia, Rome, Italy
Corresponding Author: Angela Mastronuzzi, MD, Ospedale Pediatrico Bambino Gesu` IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. Email: [email protected]
NP182
Journal of Child Neurology 29(12)
Figure 1. A 6-year-old boy with diffuse intrinsic bulbopontine lesion. (A) Sagittal T1-weighted images; (B) coronal T2-weighted image: brain stem expansive lesion; (C-F) fluid-attenuated inversion recovery images: symmetric hyperintensity areas in periaqueductal gray matter, mammillary bodies, periventricular regions of the third ventricle, and dorsal medial nucleus of thalami.
the periventricular region of the third ventricle, the periaqueductal gray matter, and mammillary bodies were detected (Figure 1). Diagnosis of Wernicke encephalopathy, in addition to cancer progression, was suspected as confirmed by a low blood thiamine level, that is 33.7 nM/L (normal values 66.5-200) although the patient had not been vomiting and had varied nutritional intake, with adequate content of carbohydrates, vegetable and animal proteins, vitamins, and minerals. Thiamine supplementation at 20 mg/kg by oral administration was given for 75 days. Magnetic resonance imaging performed after 2 weeks showed a stable brainstem lesion, whereas the multiple alterations related to Wernicke encephalopathy had partially disappeared. A normal blood thiamine level, 213 nM/L, was obtained after 9 days of supplementation. The child became fully conscious, while ataxia and ocular abnormalities improved, but were not completely restored. Seven months later, the child died as a result of tumor progression.
Case Presentation 2 The second patient is a 12-year-old boy who was referred to our hospital for an acute hemiparesis. The workup revealed a fronto-parietal expansive lesion. He underwent a partial
surgical resection, followed by total tumor removal at a second-look procedure. Pathology showed a primitive neuroectodermal tumor. After surgery, the patient received chemotherapy based on high-dose methotrexate, etoposide, cyclophosphamide, and carboplatinum plus radiotherapy (delivered dose 5400 cGy).4 After radiotherapy, 1 course of high-dose thiotepa followed by autologous peripheral hemopoietic stem cell rescue was administered. The procedure was complicate by grade IV mucositis that required prolonged parenteral nutrition. Maintenance chemotherapy based on vincristine and lomustine was started, but it had to be stopped after 1 cycle because of prolonged hematologic toxicity. The patient showed prolonged anorexia and needed nocturnal parenteral nutrition. Two months after the end of the last course of maintenance chemotherapy, the child showed an acute and rapidly progressive alteration of mental status consisting of hallucinations, aphasia, dysphagia, tremors, bilateral mydriasis, and impairment of consciousness. The magnetic resonance imaging features included bilateral and symmetric high-T2 signal in the thalamic region and the mammillary bodies, confirming previous bilateral white matter high-T2 signal (Figure 2A-C). The diagnosis of Wernicke encephalopathy was made on the basis of the
Cefalo et al
NP183
Figure 2. A 12-year-old boy affected by frontoparietal primitive neuroectodermal tumor. (A-C) T2-weghted axial images: symmetric hyperintense areas in thalamic regions, mammillary bodies, periaqueductal gray matter, and supratentorial white matter hyperintensity. (D-F) Four weeks after thiamine replacement/supplementation: T2-weighted axial images demonstrate reduction in signal intensity in the previously hyperintense regions.
low thiamine level of 31.6 nM/L. Intravenous thiamine supplementation (500 mg for 5 days) was started, followed by intramuscular injection (100 mg/day for 20 days and then 100 mg 3 times a week) with slight neurologic improvement, probably because of the late diagnosis. After oral benzodiazepine treatment (lorazepam, 0.08 mg/kg) was started, an abrupt change in vigilance was observed, with a full consciousness, recovery of spontaneous speech, progressive capability of oral alimentation, increase of movements, and postural changes. Clinical improvement was confirmed by magnetic resonance imaging that documented partial disappearance of the images characteristic of Wernicke encephalopathy (Figure 2D-F).
Discussion Wernicke encephalopathy is a metabolic disorder caused by thiamine deficiency. It is likely under-recognized in children and it may be fatal if untreated. According to autopsy studies performed on adult cancer series, the prevalence of Wernicke encephalopathy lesions was 0.8%-2.8%, higher than suspected on clinical presentation.5 Indeed, about 58% of pediatric cases
have been unrecognized at clinical examination.6 Mortality ranged from 10% to 20%. Prevalence data of Wernicke encephalopathy in children affected by brain tumors are not currently available. As for the pathophysiology of the condition, brain damage is thought to be dependent on an alteration of the metabolism of glial cells and neurons due to deficiency of thiamine, a water-soluble vitamin necessary for glucose metabolism.7 In the absence of thiamine, glucose cannot be metabolized in the Kreb cycle and the pentose phosphate pathway, inducing intracellular accumulation of glutamate, which is subsequently released into the extracellular spaces following homeostatic imbalance and excitotoxic damage. Excess extracellular glutamate may bind to either N-methyl-Daspartate (NMDA) receptors, allowing entry of calcium ions into the cells, with resulting cellular injury and death due to necrosis or apoptosis, or to non-NMDA receptors, allowing entry of sodium, with resulting cellular injury and cell death due to edema. Alteration of the osmotic gradients across cell membranes leads to simultaneous cytotoxic and vasogenic edema. Wernicke encephalopathy brain injury is confined to selective regions, particularly sensitive to thiamine deficiency because of their high oxidative metabolism, such as the paraventricular
NP184 regions of the third ventricle, the dorsal medial nucleus of thalami, the hypothalamus, the mammillary bodies, the periaqueductal region, and the floor of the fourth ventricle.8 In pediatric patients, additional sites, such as the nuclei of the oculomotor nerves, the red nuclei, the cerebellar dentate nuclei, and above all, the basal nuclei may be involved, probably as a result of the high thiamine-dependent metabolism of the nuclear-basal regions in children.9 Both of our patients, affected by central nervous system cancer, presented classical brain involvement of Wernicke encephalopathy. In affected children, the classical triad of symptoms is present at onset in a minority of patients, as it was in our cases; atypical presentations have been reported.10 Uncommon presenting symptoms include hypotension and tachycardia, related to a defect in efferent sympathetic outflow; hypothermia, caused by involvement of the hypothalamic regions; and seizures, resulting from excessive glutamatergic activity.11 Despite being the most common presenting symptom of Wernicke encephalopathy, changes in consciousness are nonspecific in acutely ill patients. So the ‘‘classic triad’’ of symptoms has been shown to be misleading in the pediatric population: in children with brain tumor, a differential diagnosis of Wernicke encephalopathy includes postchemotherapy angiopathy,12 leukoencephalopathy, posterior reversible encephalopathy syndrome,13 chemical arachnoiditis, and infections of the central nervous system. Currently, magnetic resonance imaging is considered the most reliable method to diagnose this disorder because it has a high specificity (93%); however, sensitivity has been reported to be only 53%.14 In adults, Wernicke encephalopathy is commonly associated with chronic alcoholism, whereas in childhood the thiamine deficit is due to different malnutrition or malabsorption conditions, such as prolonged parenteral nutrition without addition of thiamine, gastrointestinal surgical procedures, anticancer therapies, systemic diseases, severe sepsis, and unbalanced nutrition.15–19 The first of our patients was affected by a diffuse intrinsic pontine glioma that had been treated with radiotherapy and nimotuzumab. Nimotuzumab is a humanized monoclonal antibody targeting the epidermal growth factor receptor; it prevents dimerization of the receptor, inhibiting tyrosine kinase activity and interfering with cell signaling pathways involved in cell proliferation.20 It significantly decreases tumor growth, reduces the tumor proliferation, and inhibits angiogenesis.21 No relevant side effects related to nimotuzumab has been reported so far.22 On the basis of medical history, the etiology of thiamine deficit in our child was not attributable to malnutrition. To our knowledge, thiamine deficit has not been shown in other patients, either in adults or children, treated with this monoclonal antibody. The second patient had been on parenteral nutrition, without thiamine supplementation for more than 2 months, leading to the classical Wernicke encephalopathy symptomatology. Wernicke encephalopathy has previously been described in 13 children with tumor: the diagnosis was made at autopsy in 6 cases, observation of radiologic features suggestive of the disease and laboratory dosing of serum thiamine in 3 cases, and with a combination of clinical signs and magnetic resonance findings in 2 cases.23 In both our cases, the diagnosis of
Journal of Child Neurology 29(12) Wernicke encephalopathy was suggested by clinical manifestations associated with typical radiologic findings and was confirmed by laboratory evidence of thiamine deficiency. In the various cases published so far, full recovery was obtained in most children after thiamine replacement; however, timely treatment is crucial to optimize the chance of recovery because early therapy can affect the reversibility of the clinical symptoms and radiologic features.24 Efficacy of benzodiazepine treatment, as documented in the second patient, might be related to an increased density of binding sites for the ‘‘peripheral type’’ benzodiazepine receptor ligand. This may reflect glial proliferation and is consistent with an excitotoxic mechanism in the pathogenesis of neuronal cell loss in thiamine deficiency encephalopathy.25
Conclusion Wernicke encephalopathy may develop at any age. Moreover, malignancy is one of the potential underlying disorders in which Wernicke encephalopathy occurs in the pediatric population. Larger series need to show the prevalence of this disorder in children with cancer. In the case of patients with brain tumor or infectious or toxic encephalopathies, the diagnosis may be even more difficult considering that the initial symptoms are not easily differentiated from the symptoms due to the original disease. In childhood cancer, factors that contribute to the thiamine deficiency also include the consumption of thiamine by fastgrowing neoplastic cells, poor dietary intake, and the use of several therapeutic agents, including antineoplastic drugs, immunosuppressants, and antibiotics, that could potentially cause or worsen the neurotoxicity. An early diagnosis and treatment is imperative, in order to prevent or minimize irreversible brain damage. Indeed, Wernicke encephalopathy should be considered as differential diagnosis in all cancer children presenting a neurologic deterioration, mainly in patients affected by brain tumor. In this situation, we also suggest a prompt empirical thiamine replacement, even in the absence of documented malnutrition conditions. Acknowledgments We are grateful to Prof. Franco Locatelli for his substantial contribution to the conception, critical supervision, and clinical support in realizing this manuscript.
Author Contributions MGC and MADI wrote the first draft and the manuscript revisions. SS, AC, and FA cared for the patients. DL and BB selected the neuroimaging and realized figure and legends. AM has been crucial in designing the work and supervising the draft revision.
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.
Cefalo et al Ethical Approval A written consent for publication has been obtained from the children’s parents.
References 1. Pearce JM. Wernicke-Korsakoff encephalopathy. Eur Neurol. 2008;59:101-104. 2. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoffsyndrome: under-recognized and under-treated. Psychosomatics. 2012;53:507-516. 3. Ahmed R. Wernicke like encephalopathy in a child: a reversible cause. J Pediatr Neurosci. 2012;7:146-148. 4. Massimino M, Giangaspero F, Garre` ML, et al. Childhood medulloblastoma. Crit Rev Oncol Hematol. 2011;79:65-83. 5. Onishi H, Kawanishi C, Onose M, et al. Successful treatment of Wernicke encephalopathy in terminally ill cancer patients: report of 3 cases and review of the literature. Support Care Cancer. 2004;12: 604-608. 6. Vasconcelos MM, Silva KP, Vidal G, et al. Early diagnosis of pediatric Wernicke’s encephalopathy. Pediatr Neurol. 1999;20: 289-294. 7. Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke’s encephalopathy and Korsakoff’s psychosis. Alcohol Alcohol. 2006;41:151-158. 8. Zuccoli G, Pipitone N. Neuroimaging findings in acute Wernicke’s encephalopathy: review of the literature. AJR Am J Roentgenol. 2009;192:501- 508. 9. Zuccoli G, Siddiqui N, Bailey A, et al. Neuroimaging findings in pediatric Wernicke encephalopathy: a review. Neuroradiology. 2010;52:523-529. 10. Cooke CA, Hicks E, Page AB, et al. An atypical presentation of Wernicke’s encephalopathy in an 11-year-old child. Eye (Lond). 2006;20:1418-1420. 11. Doss A, Mahad D, Romanowski CA. Wernicke’s encephalopathy: unusual findings in nonalcoholic patients. J Comput Assist Tomogr. 2003;27:235-240. 12. Ross CS, Brown TM, Kotagal S, Rodriguez V. Cerebral venous sinus thrombosis in pediatric cancer patients: long-term neurological outcomes. J Pediatr Hematol Oncol. 2013;35:299-302.
NP185 13. de Laat P, Te Winkel ML, Devos AS, et al. Posterior reversible encephalopathy syndrome in childhood cancer. Ann Oncol. 2011; 22:472-478. 14. Chung SP, Kim SW, Yoo IS, et al. Magnetic resonance imaging as a diagnostic adjunct to Wernicke’s encephalopathy in the ED. Am J Emerg Med. 2003;21:497-502. 15. Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of Wernicke-Korsakoff syndrome. Alcohol Alcohol Suppl. 2000;35:2-7. 16. Francini-Pesenti F, Brocadello F, Famengo S, et al. Wernicke’s encephalopathy during parenteral nutrition. JPEN J Parenter Enteral Nutr. 2007;31:69-71. 17. Lim YJ, Kim HJ, Lee YJ, et al. Clinical features of encephalopathy in children with cancer requiring cranial magnetic resonance imaging. Pediatr Neurol. 2011;44:433-438. 18. Xin Y, Wan DH, Chu Q, et al. Severe sepsis as an initial presentation in children with Wernicke’s encephalopathy: report of a case and literature review. Zhonghua Er Ke Za Zhi. 2011;49:612-616. 19. Peters TE, Parvin M, Petersen C, et al. A case report of Wernicke’s encephalopathy in a pediatric patient with anorexia nervosa– restricting type. J Adolesc Health. 2007;40:376-383. 20. Massimino M, Bode U, Biassoni V, et al. Nimotuzumab for pediatric diffuse intrinsic pontine gliomas. Expert Opin Biol Ther. 2011; 11:247-256. 21. Bode U, Massimino M, Bach F, et al. Nimotuzumab treatment of malignant gliomas. Expert Opin Biol Ther. 2012;12:1649-1659. 22. Wolff JE, Rytting ME, Vats TS, et al. Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J Neurooncol. 2012;106:391-397. 23. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6:442-655. 24. Perko R, Harreld JH, Helton KJ, et al. What goes around comes around? Wernicke encephalopathy and the nationwide shortage of intravenous multivitamins revisited. J Clin Oncol. 2012;1;30: e318-e320. 25. Leong DK, Therrien G, Swain MS, et al. Densities of binding sites for the ‘‘peripheral-type’’ benzodiazepine receptor ligand 3H-PK11195 are increased in brain 24 hours following portacaval anastomosis. Metab Brain Dis. 1994;9:267-273.
Wernicke Encephalopathy in Pediatric Neuro-oncology: Presentation of 2 Cases and Review of Literature
Journal of Child Neurology 2014, Vol. 29(12) NP181-NP185 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510355 jcn.sagepub.com
Maria Giuseppina Cefalo, MD1, Maria Antonietta De Ioris, MD1, Antonella Cacchione, MD1, Daniela Longo, MD1, Susanna Staccioli, MD1, Francesco Arcioni, MD2, Bruno Bernardi, MD1, and Angela Mastronuzzi, MD1
Abstract Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations. Wernicke encephalopathy is rare and under-recognized in childhood and may be fatal. Few cases have been documented in pediatric oncology. We report on 2 Wernicke encephalopathy cases that occurred in children having a brain tumor. The diagnosis of Wernicke encephalopathy was suggested by clinical manifestations associated with the typical radiologic findings and a laboratory evidence of thiamine deficiency. No large series have been published to support the evidence that pediatric malignancies represent a demonstrated factor of increased risk to develop a Wernicke encephalopathy. Moreover, the diagnosis may be even more difficult in brain tumors, considering the overlapping symptoms and the risk of encephalopathy related to both the disease and the treatment. Wernicke encephalopathy should be considered in all children with cancer presenting a neurologic deterioration, mainly in brain tumors. An early diagnosis is imperative for a prompt therapy that might prevent or minimize the irreversible brain damage related to this condition. Keywords Wernicke encephalopathy, brain cancer, childhood Received May 08, 2013. Received revised June 29, 2013; July 25, 2013; August 29, 2013; September 05, 2013. Accepted for publication October 03, 2013.
Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations that appears in patients with multifactorial thiamine (vitamin B1) deficiency1; this condition is associated with high morbidity and mortality.2 The classical clinical triad is mental status changes, ophthalmoplegia, and ataxia, although atypical presentations have been reported. The acute neurologic injury of Wernicke encephalopathy can evolve into Korsakoff syndrome, an impairment of formation of new memories with sufficient preservation of other mental functions. The disorder may be fatal if unrecognized. Wernicke encephalopathy is rare in children and is always associated with malabsorption. Few cases have been documented in pediatric oncology.3
was continued, with good tolerance and no side effects. During the 11th week of treatment, the patient acutely developed restlessness, truncal ataxia, slurred speech, and bilateral visual disorders. He was afebrile and there were no meningeal signs. Vital signs were stable. Routine investigations—complete blood count, biochemistry, and C-reactive protein—were within normal range. Cerebrospinal fluid was normal. At ophthalmologic examination, asymmetrical paralysis of both lateral recti muscles was found. Brain magnetic resonance imaging (MRI) showed global volumetric growth of the well-known expansive lesion in the brainstem region, with a new fluid area in the tumor. Furthermore, fluid-attenuated inversion recovery image showed bilateral hyperintensity signal and symmetric areas involving the dorsal medial nucleus of the thalamus,
Case Presentation 1
1
We present a 6-year-old boy with diffuse intrinsic pontine glioma, treated with radiotherapy (delivered dose 5400 cGy) and chemotherapy (vinorelbine 20 mg/m2 and nimotuzumab 100 mg/m2 weekly) achieving partial response with reduction of the lesion and decreased contrast enhancement. Therefore, chemotherapy with vinorelbine 25 mg/m2 and nimotuzumab 100 mg/m2 every 2 weeks
2
Ospedale Pediatrico Bambino Gesu` Children’s Hospital IRCCS, Rome, Italy University of Perugia, S.M. Misericordia University Hospital, Perugia, Rome, Italy
Corresponding Author: Angela Mastronuzzi, MD, Ospedale Pediatrico Bambino Gesu` IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. Email: [email protected]
NP182
Journal of Child Neurology 29(12)
Figure 1. A 6-year-old boy with diffuse intrinsic bulbopontine lesion. (A) Sagittal T1-weighted images; (B) coronal T2-weighted image: brain stem expansive lesion; (C-F) fluid-attenuated inversion recovery images: symmetric hyperintensity areas in periaqueductal gray matter, mammillary bodies, periventricular regions of the third ventricle, and dorsal medial nucleus of thalami.
the periventricular region of the third ventricle, the periaqueductal gray matter, and mammillary bodies were detected (Figure 1). Diagnosis of Wernicke encephalopathy, in addition to cancer progression, was suspected as confirmed by a low blood thiamine level, that is 33.7 nM/L (normal values 66.5-200) although the patient had not been vomiting and had varied nutritional intake, with adequate content of carbohydrates, vegetable and animal proteins, vitamins, and minerals. Thiamine supplementation at 20 mg/kg by oral administration was given for 75 days. Magnetic resonance imaging performed after 2 weeks showed a stable brainstem lesion, whereas the multiple alterations related to Wernicke encephalopathy had partially disappeared. A normal blood thiamine level, 213 nM/L, was obtained after 9 days of supplementation. The child became fully conscious, while ataxia and ocular abnormalities improved, but were not completely restored. Seven months later, the child died as a result of tumor progression.
Case Presentation 2 The second patient is a 12-year-old boy who was referred to our hospital for an acute hemiparesis. The workup revealed a fronto-parietal expansive lesion. He underwent a partial
surgical resection, followed by total tumor removal at a second-look procedure. Pathology showed a primitive neuroectodermal tumor. After surgery, the patient received chemotherapy based on high-dose methotrexate, etoposide, cyclophosphamide, and carboplatinum plus radiotherapy (delivered dose 5400 cGy).4 After radiotherapy, 1 course of high-dose thiotepa followed by autologous peripheral hemopoietic stem cell rescue was administered. The procedure was complicate by grade IV mucositis that required prolonged parenteral nutrition. Maintenance chemotherapy based on vincristine and lomustine was started, but it had to be stopped after 1 cycle because of prolonged hematologic toxicity. The patient showed prolonged anorexia and needed nocturnal parenteral nutrition. Two months after the end of the last course of maintenance chemotherapy, the child showed an acute and rapidly progressive alteration of mental status consisting of hallucinations, aphasia, dysphagia, tremors, bilateral mydriasis, and impairment of consciousness. The magnetic resonance imaging features included bilateral and symmetric high-T2 signal in the thalamic region and the mammillary bodies, confirming previous bilateral white matter high-T2 signal (Figure 2A-C). The diagnosis of Wernicke encephalopathy was made on the basis of the
Cefalo et al
NP183
Figure 2. A 12-year-old boy affected by frontoparietal primitive neuroectodermal tumor. (A-C) T2-weghted axial images: symmetric hyperintense areas in thalamic regions, mammillary bodies, periaqueductal gray matter, and supratentorial white matter hyperintensity. (D-F) Four weeks after thiamine replacement/supplementation: T2-weighted axial images demonstrate reduction in signal intensity in the previously hyperintense regions.
low thiamine level of 31.6 nM/L. Intravenous thiamine supplementation (500 mg for 5 days) was started, followed by intramuscular injection (100 mg/day for 20 days and then 100 mg 3 times a week) with slight neurologic improvement, probably because of the late diagnosis. After oral benzodiazepine treatment (lorazepam, 0.08 mg/kg) was started, an abrupt change in vigilance was observed, with a full consciousness, recovery of spontaneous speech, progressive capability of oral alimentation, increase of movements, and postural changes. Clinical improvement was confirmed by magnetic resonance imaging that documented partial disappearance of the images characteristic of Wernicke encephalopathy (Figure 2D-F).
Discussion Wernicke encephalopathy is a metabolic disorder caused by thiamine deficiency. It is likely under-recognized in children and it may be fatal if untreated. According to autopsy studies performed on adult cancer series, the prevalence of Wernicke encephalopathy lesions was 0.8%-2.8%, higher than suspected on clinical presentation.5 Indeed, about 58% of pediatric cases
have been unrecognized at clinical examination.6 Mortality ranged from 10% to 20%. Prevalence data of Wernicke encephalopathy in children affected by brain tumors are not currently available. As for the pathophysiology of the condition, brain damage is thought to be dependent on an alteration of the metabolism of glial cells and neurons due to deficiency of thiamine, a water-soluble vitamin necessary for glucose metabolism.7 In the absence of thiamine, glucose cannot be metabolized in the Kreb cycle and the pentose phosphate pathway, inducing intracellular accumulation of glutamate, which is subsequently released into the extracellular spaces following homeostatic imbalance and excitotoxic damage. Excess extracellular glutamate may bind to either N-methyl-Daspartate (NMDA) receptors, allowing entry of calcium ions into the cells, with resulting cellular injury and death due to necrosis or apoptosis, or to non-NMDA receptors, allowing entry of sodium, with resulting cellular injury and cell death due to edema. Alteration of the osmotic gradients across cell membranes leads to simultaneous cytotoxic and vasogenic edema. Wernicke encephalopathy brain injury is confined to selective regions, particularly sensitive to thiamine deficiency because of their high oxidative metabolism, such as the paraventricular
NP184 regions of the third ventricle, the dorsal medial nucleus of thalami, the hypothalamus, the mammillary bodies, the periaqueductal region, and the floor of the fourth ventricle.8 In pediatric patients, additional sites, such as the nuclei of the oculomotor nerves, the red nuclei, the cerebellar dentate nuclei, and above all, the basal nuclei may be involved, probably as a result of the high thiamine-dependent metabolism of the nuclear-basal regions in children.9 Both of our patients, affected by central nervous system cancer, presented classical brain involvement of Wernicke encephalopathy. In affected children, the classical triad of symptoms is present at onset in a minority of patients, as it was in our cases; atypical presentations have been reported.10 Uncommon presenting symptoms include hypotension and tachycardia, related to a defect in efferent sympathetic outflow; hypothermia, caused by involvement of the hypothalamic regions; and seizures, resulting from excessive glutamatergic activity.11 Despite being the most common presenting symptom of Wernicke encephalopathy, changes in consciousness are nonspecific in acutely ill patients. So the ‘‘classic triad’’ of symptoms has been shown to be misleading in the pediatric population: in children with brain tumor, a differential diagnosis of Wernicke encephalopathy includes postchemotherapy angiopathy,12 leukoencephalopathy, posterior reversible encephalopathy syndrome,13 chemical arachnoiditis, and infections of the central nervous system. Currently, magnetic resonance imaging is considered the most reliable method to diagnose this disorder because it has a high specificity (93%); however, sensitivity has been reported to be only 53%.14 In adults, Wernicke encephalopathy is commonly associated with chronic alcoholism, whereas in childhood the thiamine deficit is due to different malnutrition or malabsorption conditions, such as prolonged parenteral nutrition without addition of thiamine, gastrointestinal surgical procedures, anticancer therapies, systemic diseases, severe sepsis, and unbalanced nutrition.15–19 The first of our patients was affected by a diffuse intrinsic pontine glioma that had been treated with radiotherapy and nimotuzumab. Nimotuzumab is a humanized monoclonal antibody targeting the epidermal growth factor receptor; it prevents dimerization of the receptor, inhibiting tyrosine kinase activity and interfering with cell signaling pathways involved in cell proliferation.20 It significantly decreases tumor growth, reduces the tumor proliferation, and inhibits angiogenesis.21 No relevant side effects related to nimotuzumab has been reported so far.22 On the basis of medical history, the etiology of thiamine deficit in our child was not attributable to malnutrition. To our knowledge, thiamine deficit has not been shown in other patients, either in adults or children, treated with this monoclonal antibody. The second patient had been on parenteral nutrition, without thiamine supplementation for more than 2 months, leading to the classical Wernicke encephalopathy symptomatology. Wernicke encephalopathy has previously been described in 13 children with tumor: the diagnosis was made at autopsy in 6 cases, observation of radiologic features suggestive of the disease and laboratory dosing of serum thiamine in 3 cases, and with a combination of clinical signs and magnetic resonance findings in 2 cases.23 In both our cases, the diagnosis of
Journal of Child Neurology 29(12) Wernicke encephalopathy was suggested by clinical manifestations associated with typical radiologic findings and was confirmed by laboratory evidence of thiamine deficiency. In the various cases published so far, full recovery was obtained in most children after thiamine replacement; however, timely treatment is crucial to optimize the chance of recovery because early therapy can affect the reversibility of the clinical symptoms and radiologic features.24 Efficacy of benzodiazepine treatment, as documented in the second patient, might be related to an increased density of binding sites for the ‘‘peripheral type’’ benzodiazepine receptor ligand. This may reflect glial proliferation and is consistent with an excitotoxic mechanism in the pathogenesis of neuronal cell loss in thiamine deficiency encephalopathy.25
Conclusion Wernicke encephalopathy may develop at any age. Moreover, malignancy is one of the potential underlying disorders in which Wernicke encephalopathy occurs in the pediatric population. Larger series need to show the prevalence of this disorder in children with cancer. In the case of patients with brain tumor or infectious or toxic encephalopathies, the diagnosis may be even more difficult considering that the initial symptoms are not easily differentiated from the symptoms due to the original disease. In childhood cancer, factors that contribute to the thiamine deficiency also include the consumption of thiamine by fastgrowing neoplastic cells, poor dietary intake, and the use of several therapeutic agents, including antineoplastic drugs, immunosuppressants, and antibiotics, that could potentially cause or worsen the neurotoxicity. An early diagnosis and treatment is imperative, in order to prevent or minimize irreversible brain damage. Indeed, Wernicke encephalopathy should be considered as differential diagnosis in all cancer children presenting a neurologic deterioration, mainly in patients affected by brain tumor. In this situation, we also suggest a prompt empirical thiamine replacement, even in the absence of documented malnutrition conditions. Acknowledgments We are grateful to Prof. Franco Locatelli for his substantial contribution to the conception, critical supervision, and clinical support in realizing this manuscript.
Author Contributions MGC and MADI wrote the first draft and the manuscript revisions. SS, AC, and FA cared for the patients. DL and BB selected the neuroimaging and realized figure and legends. AM has been crucial in designing the work and supervising the draft revision.
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.
Cefalo et al Ethical Approval A written consent for publication has been obtained from the children’s parents.
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