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Severe Neutropenia and Anemia in a Child With Epilepsy and Copper Deficiency on a Ketogenic Diet
Accepted Manuscript Title: Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet Author: Houman Rashidian, YM Christiana Liu, Michael T Geraghty, Jeff Kobayashi, Elizabeth J. Donner, Robert J. Klaassen PII: DOI: Reference:
S0887-8994(17)30792-0 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.08.007 PNU 9212
To appear in:
Pediatric Neurology
Please cite this article as: Houman Rashidian, YM Christiana Liu, Michael T Geraghty, Jeff Kobayashi, Elizabeth J. Donner, Robert J. Klaassen, Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet Houman Rashidian B.Sc, YM Christiana Liu, RD2, Michael T Geraghty, MB, Jeff Kobayashi, MD2, Elizabeth J. Donner, MD2, Robert J. Klaassen, MD6 2Division
of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto 6 Division of Hematology/Oncology, The Children’s Hospital of Eastern Ontario Correspondence: Dr. Robert Klaassen The Children’s Hospital of Eastern Ontario 401 Smyth Rd. Ottawa, ON K1H 8L1 Phone: 613-737-7600 Ext. 2210 Fax: 613-738-4828 [email protected] Key words: bicytopenia, copper, epilepsy, Ketogenic Running head: bicytopenia in copper deficiency Abstract word count: 130 Main text word count (excluding title page, abstract, References, and Tables): 600 Number of tables: 1 Abbreviation Table: Abbreviation Hb ANC CBC
Full term hemoglobin absolute neutrophil count complete blood count
Page 1 of 4
The Ketogenic diet is a medical treatment for drug-resistant epilepsy in children. Other than one previous case depicting hemolytic anemia (Ballaban et al., 1998), there is no evidence linking this treatment to hematological abnormalities. This report will expand upon this. We present a patient who developed bicytopenia, in the setting of a Ketogenic diet. Case Report: A female patient was diagnosed at the age of three years with a seizure disorder called Lennox-Gastaut Syndrome. After being refractory to antiepileptic medications, she was prescribed the Ketogenic diet. There was a noticeable improvement within four months where the duration, frequency, and intensity of her seizures decreased. She was on this diet for eight years without any complications. She was also taking levetiracetam and clonazepam. Her other medical history includes learning disabilities and asthma. At the age of eleven, she presented to the emergency department with a fever of 38.5 0C, increased seizure frequency, fatigue, and epistaxis. CBC done in the community ten days prior showed anemia and neutropenia (Table 1). At the hospital, she had Hb of 62 g/L, white blood cell count of 2.1 x109/L, an absolute neutrophil count of 0.2 x109/L, and a platelet count of 188 x109/L. She was admitted to hospital and treated with intravenous ceftriaxone and one unit of packed red blood cells. She was discharged three days later. No indication of hemolysis was found with a low reticulocyte count, normal bilirubin level and a negative direct antiglobulin test. Viral etiology was unlikely as blood work ten days prior to onset of the fever already showed abnormalities. The only anomaly found was a significantly decreased serum copper level of 0.5 umol/L. After discharge, she was started on copper supplementation. As her copper levels increased so did her blood counts and after one month her Hb and neutrophil values were normal again (Table 1). Also, after a year her serum copper levels normalized at 12.1. Discussion: The severity of the copper deficiency and the response of the bicytopenia to copper supplementation supports copper deficiency as the most likely cause of her marrow suppression. This is also consistent with previous reports showing that low serum copper can result in anemia and neutropenia, while thrombocytopenia is rare (Halfdanarson, Kumar, Phyliky, & Hogan, 2008). That being said, what is the etiology of her copper deficiency? Even prior to her presentation, she was receiving above her daily-required intake of copper via multivitamins and diet. Even when she was started on supplementation, surmounting to eleven times her daily-required intake, her copper level was still low for almost a year. Neurotransmitter testing detected no issues and analysis of whole exome sequencing data did not detect any pathogenic changes in genes linked to copper metabolism. Excess zinc supplementation was likely not a factor as she
Page 2 of 4
had normal serum zinc levels. More holistically, children with epilepsy are not reported to be deficient in serum copper (Seven, Basaran, Cengiz, Unal, & Yuksel, 2012; Wojciak, Mojs, Stanislawska-Kubia, & Samborski, 2013). Further, levetiracetam or clonazepam are not linked to copper abnormalities. In conclusion, there could be an association between the Ketogenic diet and our patient’s copper deficiency. One study by Caraballo et al (2011), reported one child among 216 prescribed the diet, to be low in copper. The exact role and mechanism is not confirmed. Nonetheless, as witnessed with our patient, undetected copper deficiency can have serious consequences. By being aware that this treatment can potentially present with this complication, health-care practitioners can screen for copper deficiency if there is any abnormalities on routine CBC or complete periodic screening of copper levels. This being said, this is only the second case of reported copper deficiency in association with the Ketogenic diet, and the first with bone marrow suppression. Further research is warranted. References Ballaban-Gill, K., Callahan, C., O’Dell, C., et al. (1998). Complications of the Ketogenic Diet. Epilepsia, 39: 744-748. Caraballo, R., Vaccarezza, M., Cersosimo, R., Rios, V., Soraru, A., Arroyo,…Panico, L. (2011). Long-term follow-up of the ketogenic diet for refractory epilepsy: Multicenter Argentinean experience in 216 pediatric patients. Seizure, 640-645. Halfdanarson, T. R., Kumar, N., Li, C. Y., Phyliky, R. L., & Hogan, W. J. (2008). Hematological manifestations of copper deficiency: a retrospective review. [Article]. European Journal of Haematology, 80(6), 523-531. Seven, M., Basaran, S,Y., Cengiz, M., Unal, S., & Yuksel, A. (2012). Deficiency of selenium and zinc as causative factor for idiopathic intractable epilepsy. Epilepsy Research, 104, 35-39. Wojciak, R.W., Mojs, E., Stanislawska-Kubiak, M., & Samborski, W. (2013). The serum zinc, copper, iron, and chromium concentrations in epileptic children. Epilepsy Research, 104, 40-44.
Page 3 of 4
Table #1: Complete blood cell counts and differential and serum copper levels in our patient over time Date Hemoglobin Neutrophils Platelets Serum Copper (105 - 135 (1.5 - 8.0 (130 - 380 Copper Supplementation g/L) 109/L) 109/L) (12.9 (mg; 18.9 daily umol/L) requirement = 0.7 mg) th August 28 , 76 0.5 2015 – 10 days prior to emergency visit September 7th, 62 0.2 188 2015 – Presents to emergency department September 9th, 86 0.4 225 2015 September 10th, 92 0.2 261 0.5 2015 September 16th, 99 0.7 355 8 2015 September 30th, 116 1.3 263 7.1 8 2015 October 28th, 134 1.7 308 10.0 8 2015 – approximately one month after initiation of copper supplementation February 22nd, 125 1.1 240 8.8 8 2016 April 20th, 2016 137 1.3 244 9.4 6 May 24th, 2016
138
2.1
Oct 10th, 2016 one year followup.
139
1.97
297
10.8
3
12.1
2
Page 4 of 4
S0887-8994(17)30792-0 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.08.007 PNU 9212
To appear in:
Pediatric Neurology
Please cite this article as: Houman Rashidian, YM Christiana Liu, Michael T Geraghty, Jeff Kobayashi, Elizabeth J. Donner, Robert J. Klaassen, Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Severe Neutropenia and Anemia in a Child with Epilepsy and Copper Deficiency on a Ketogenic Diet Houman Rashidian B.Sc, YM Christiana Liu, RD2, Michael T Geraghty, MB, Jeff Kobayashi, MD2, Elizabeth J. Donner, MD2, Robert J. Klaassen, MD6 2Division
of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto 6 Division of Hematology/Oncology, The Children’s Hospital of Eastern Ontario Correspondence: Dr. Robert Klaassen The Children’s Hospital of Eastern Ontario 401 Smyth Rd. Ottawa, ON K1H 8L1 Phone: 613-737-7600 Ext. 2210 Fax: 613-738-4828 [email protected] Key words: bicytopenia, copper, epilepsy, Ketogenic Running head: bicytopenia in copper deficiency Abstract word count: 130 Main text word count (excluding title page, abstract, References, and Tables): 600 Number of tables: 1 Abbreviation Table: Abbreviation Hb ANC CBC
Full term hemoglobin absolute neutrophil count complete blood count
Page 1 of 4
The Ketogenic diet is a medical treatment for drug-resistant epilepsy in children. Other than one previous case depicting hemolytic anemia (Ballaban et al., 1998), there is no evidence linking this treatment to hematological abnormalities. This report will expand upon this. We present a patient who developed bicytopenia, in the setting of a Ketogenic diet. Case Report: A female patient was diagnosed at the age of three years with a seizure disorder called Lennox-Gastaut Syndrome. After being refractory to antiepileptic medications, she was prescribed the Ketogenic diet. There was a noticeable improvement within four months where the duration, frequency, and intensity of her seizures decreased. She was on this diet for eight years without any complications. She was also taking levetiracetam and clonazepam. Her other medical history includes learning disabilities and asthma. At the age of eleven, she presented to the emergency department with a fever of 38.5 0C, increased seizure frequency, fatigue, and epistaxis. CBC done in the community ten days prior showed anemia and neutropenia (Table 1). At the hospital, she had Hb of 62 g/L, white blood cell count of 2.1 x109/L, an absolute neutrophil count of 0.2 x109/L, and a platelet count of 188 x109/L. She was admitted to hospital and treated with intravenous ceftriaxone and one unit of packed red blood cells. She was discharged three days later. No indication of hemolysis was found with a low reticulocyte count, normal bilirubin level and a negative direct antiglobulin test. Viral etiology was unlikely as blood work ten days prior to onset of the fever already showed abnormalities. The only anomaly found was a significantly decreased serum copper level of 0.5 umol/L. After discharge, she was started on copper supplementation. As her copper levels increased so did her blood counts and after one month her Hb and neutrophil values were normal again (Table 1). Also, after a year her serum copper levels normalized at 12.1. Discussion: The severity of the copper deficiency and the response of the bicytopenia to copper supplementation supports copper deficiency as the most likely cause of her marrow suppression. This is also consistent with previous reports showing that low serum copper can result in anemia and neutropenia, while thrombocytopenia is rare (Halfdanarson, Kumar, Phyliky, & Hogan, 2008). That being said, what is the etiology of her copper deficiency? Even prior to her presentation, she was receiving above her daily-required intake of copper via multivitamins and diet. Even when she was started on supplementation, surmounting to eleven times her daily-required intake, her copper level was still low for almost a year. Neurotransmitter testing detected no issues and analysis of whole exome sequencing data did not detect any pathogenic changes in genes linked to copper metabolism. Excess zinc supplementation was likely not a factor as she
Page 2 of 4
had normal serum zinc levels. More holistically, children with epilepsy are not reported to be deficient in serum copper (Seven, Basaran, Cengiz, Unal, & Yuksel, 2012; Wojciak, Mojs, Stanislawska-Kubia, & Samborski, 2013). Further, levetiracetam or clonazepam are not linked to copper abnormalities. In conclusion, there could be an association between the Ketogenic diet and our patient’s copper deficiency. One study by Caraballo et al (2011), reported one child among 216 prescribed the diet, to be low in copper. The exact role and mechanism is not confirmed. Nonetheless, as witnessed with our patient, undetected copper deficiency can have serious consequences. By being aware that this treatment can potentially present with this complication, health-care practitioners can screen for copper deficiency if there is any abnormalities on routine CBC or complete periodic screening of copper levels. This being said, this is only the second case of reported copper deficiency in association with the Ketogenic diet, and the first with bone marrow suppression. Further research is warranted. References Ballaban-Gill, K., Callahan, C., O’Dell, C., et al. (1998). Complications of the Ketogenic Diet. Epilepsia, 39: 744-748. Caraballo, R., Vaccarezza, M., Cersosimo, R., Rios, V., Soraru, A., Arroyo,…Panico, L. (2011). Long-term follow-up of the ketogenic diet for refractory epilepsy: Multicenter Argentinean experience in 216 pediatric patients. Seizure, 640-645. Halfdanarson, T. R., Kumar, N., Li, C. Y., Phyliky, R. L., & Hogan, W. J. (2008). Hematological manifestations of copper deficiency: a retrospective review. [Article]. European Journal of Haematology, 80(6), 523-531. Seven, M., Basaran, S,Y., Cengiz, M., Unal, S., & Yuksel, A. (2012). Deficiency of selenium and zinc as causative factor for idiopathic intractable epilepsy. Epilepsy Research, 104, 35-39. Wojciak, R.W., Mojs, E., Stanislawska-Kubiak, M., & Samborski, W. (2013). The serum zinc, copper, iron, and chromium concentrations in epileptic children. Epilepsy Research, 104, 40-44.
Page 3 of 4
Table #1: Complete blood cell counts and differential and serum copper levels in our patient over time Date Hemoglobin Neutrophils Platelets Serum Copper (105 - 135 (1.5 - 8.0 (130 - 380 Copper Supplementation g/L) 109/L) 109/L) (12.9 (mg; 18.9 daily umol/L) requirement = 0.7 mg) th August 28 , 76 0.5 2015 – 10 days prior to emergency visit September 7th, 62 0.2 188 2015 – Presents to emergency department September 9th, 86 0.4 225 2015 September 10th, 92 0.2 261 0.5 2015 September 16th, 99 0.7 355 8 2015 September 30th, 116 1.3 263 7.1 8 2015 October 28th, 134 1.7 308 10.0 8 2015 – approximately one month after initiation of copper supplementation February 22nd, 125 1.1 240 8.8 8 2016 April 20th, 2016 137 1.3 244 9.4 6 May 24th, 2016
138
2.1
Oct 10th, 2016 one year followup.
139
1.97
297
10.8
3
12.1
2
Page 4 of 4