Novel Complication of Nusinersen Treatment: Hyponatremia

There are variations in therapeutic regimens of different liver diseases. The accurate diagnosis ensNusinersen treatment is a novel therapy for spinal muscular atrophy (SMA) type 1; consequently, the adverse reactions of the therapy, have not been well known, yet. The present study is a case report that declares a hyponatremia development after the nursinersen therapy. Since the therapy is quite new one and has limited practice, we hope that this rare complication will contribute to the scientifi c literature. Case Report Novel Complication of Nusinersen Treatment: Hyponatremia Yasemin Coban* Sutcu Imam University, Medical Faculty, Department of Pediatrics, Division of Pediatric Intensive Care, Kahramanmaraş, Turkey *Address for Correspondence: Yasemin Coban, Sutçu Imam University, Medical Faculty, Department of Pediatrics, Division of Pediatric Intensive Care, Kahramanmaraş, Turkey, Email: yasemincoban83@gmail.com Submitted: 03 October 2018 Approved: 12 October 2018 Published: 15 October 2018 Copyright: © 2018 Coban Y. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited How to cite this article: Coban Y. Novel Complication of Nusinersen Treatment: Hyponatremia. J Clin Intensive Care Med. 2018; 3: 020-022. https://doi.org/10.29328/journal.jcicm.1001014 Introduction Nusinersen (SPINRAZA-Biogen; Cambridge, MA, USA) has received the irst global approval on 23 December 2016 for the treatment of SMA in paediatric and adult patients in the United States Food and Drug Administration (FDA) [1]. Most common adverse reactions are: lower respiratory tract infection, upper tract respiratory congestion, skin rash, back pain, proteinuria and postlumbar puncture syndrome. Severe hyponatremia was reported before in an infant SMA patient, treated with nusinersen. The researchers reported that, salt was added to his diet during 14 months because of severe and resistant hiponatremia [2]. The present report is another case of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), induced a single dose of nusinersen treatment. Case Report A 5-month-old boy diagnosed with SMA type 1 was admitted to our pediatric intensive care unit for the second dose nusinersen therapy. He received the irst nusinersen therapy two weeks ago. His physical examination and vital signs revealed no abnormalities. Laboratory indings on the day of admission, total blood count, renal and liver function test, random blood sugar, rutine urine examination, serebrospinal luid (CSF) examination, venous blood gas analysis and serum electrolits except sodium were within the normal limits. Serum sodium concentration in venous blood gas analysis was 110 mmol/L; and this result needed to be con irmed by a subsequent laboratory blood sample analyse. However, serum sodium level was found to be 109 mmol/L, again. There was no history of hyponatremia, suggestive water intake, vomiting or diarrhea, before nusinersen treatment. He was fed with breast milk by a nasogastric tube and gained only 500 gr during the last month. There were no signs of dehydration and generalize/ localize edema. His laboratory indings were as follows: lipid pro ile and blood sugar are within normal range; blood urea: 3,38 mg/dL; creatinin: 0,04 mg/dL; uric acide: 1,5 mg/dL; sodium: 110 mmol/L; potassium: 4,2 mmol/L; urine density: 1.002. His thyroid and adrenal functions were normal. His renal ultrasonography was reported as normal. Further investigations revealed low serum osmolarity (260 mOs/L), elevated urine Novel Complication of Nusinersen Treatment: Hyponatremia Published: October 15, 2018 21/22 osmolarity (110 mOs/L) and random urine sodium levels (30 mEq/L) based on which the diagnosis of SIADH was made. Antidiuretic hormone (ADH) level analyze could not be done at the hospital laboratory. His nutrition was added with table salt and he was discharged on day 5th. Follow-up blood tests a week later showed that the results had returned to normal ranges with serum sodium level 132 mmol/L, with added table salt. Firstly, water intake was restricted, then hipertonik salin given to increase the sodium level by 10mEq/L within 24 hours. The patient continues to get nusinersen treatment, and can only keeps normal sodium levels with added table salt. Another complication due to nusinersen did not develop. Discussion Spinal muscular atrophy is a genetic disease characterized by muscle weakness resulting from the degeneration of alpha motor neurons in the spinal cord and the brainstem [3]. Usually, SMA is caused by a homozygous deletion of the SMN1 gene, resulting in SMN protein de iciency. The SMN locus contains a paralog SMN2 due to an inverted duplication on human chromosome 5 [4]. Nusinersen is an antisense oligonucleotide that leads to splicing correction of the SMN2 gene [5]. The drug is administered intrathecally at 12 mg and 4 dose loading is recommended at the beginning. Nusinersen gets cleared from CSF into the systemic circulation and is guanti iable for 15-168 days after dosing. Autopsy data exposed the presence of nusinersen in liver, skeletal muscles, and kidney situation show that nusinersen gets cleared from CSF into the systemic circulation. Nusinersen is metabolized via exonucleasemediated hydrolysis. The mean half-life of nusinersen 63-87 days in the plasma. The primary route of elimination is thought to be via urinary excretion [6]. Adverse effects of novel therapy nusinersen were investigated by large clinical trials such as ENDEAR,CS3A,CHERISH and NURTURE [6]. CS3A clinic trials reported three cases, which developed hiponatremia. One of them is, a four month old girl, who diagnosed SMA type 2, had a developed hiponatremia on 89th days after treatment and on 231st day, Na level was determined as 96 meq/l. This patient was supported with table salt, during 14 months [7]. The other case was a 2 month old boy, a hiponatremi was determined on the 184th day of the treatment. However, the hiponatremia was not thought to be related with the drug and was attributed to bronchiolitis, levetiracetam and high fever [7]. The third patient was 7 month old baby and on 190th day of the treatment, hiponatremia was diagnosed. Since he had weight losses and diagnosed with pneumonia; hiponatremia was not recorded to be associated with nusinersen therapy [7]. Because of these three reports, Center for Drug Evaluation and Research, suggests to control serum sodium, both before and after nusinersen treatment. Nusinersen induced hiponatremia, was admitted in only one case and the mechanism was not explained [7]. In present case, our patient developed a hyponatremia following the irst nusinersen therapy and that occured at slowly onset. The patient was examined, with regard to inappropriate secretion of antidiuretic hormone etiological factors, as presented in table 1, such as pain, nausea, stress, and numerous pharmacological agents and diseases [8]. He was ventilated by using home ventilator, for 3 months but, hyponatremia had not developed until the nusinersen therapy. Consequently, no reason was found to explain the etiology of hiponatremia, except for nusinersen administration. In conclusion, it is suggested that when developing medicine like nusinersen and other oligonuclear ones, this rarely seen but signi icant complication that stated in present case should be taken into consideration. In addition, the case report is expected to contribute the related literature, for future implementations. Novel Complication of Nusinersen Treatment: Hyponatremia Published: October 15, 2018 22/22 Table 1: Causes Of Syndrome Of Inappropriate Secretion Of Antidiuretic Hormone In Children Acute Conditions Pulmonary Disease Neurological Diseases Medications Malignant Disease Hereditary Causes General anesthesia Positive pressure Ventilation Meningitis, encephalitis Carbamazepine Lymphoma Gain of function mutation V2R Stress Bronchiolitis Tumors Vincristine Ewing sarcoma Nausea Pneumonia Trauma Cyclophosphamide Carcinoma (lung, bladder, etc) Pain Asthma Hydrocephalus Tricyclic antidepressants Stress Cystic fi brosis Brain abscess Narcotics Rocky mountain spotted fever NSAIDs Cavernous sinus thrombosis MDMA (ecstasy) Guillain-Barré syndrome SSRI Cerebrovascular accident Desmopressin Subdural hematoma Ciprofl oxacin Amiodarone For a complete list, see references 1 and 2. MDMA1⁄43,4-methylenedioxymethamphetmine, NSAIDs1⁄4nonsteroidal antiinfl ammatory drugs, SSRI1⁄4selective serotonin reuptake inhibitor; V2R1⁄4vasopressin 2 receptor.


Introduction
Nusinersen (SPINRAZA-Biogen; Cambridge, MA, USA) has received the irst global approval on 23 December 2016 for the treatment of SMA in paediatric and adult patients in the United States Food and Drug Administration (FDA) [1]. Most common adverse reactions are: lower respiratory tract infection, upper tract respiratory congestion, skin rash, back pain, proteinuria and postlumbar puncture syndrome. Severe hyponatremia was reported before in an infant SMA patient, treated with nusinersen. The researchers reported that, salt was added to his diet during 14 months because of severe and resistant hiponatremia [2]. The present report is another case of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), induced a single dose of nusinersen treatment.

Case Report
A 5-month-old boy diagnosed with SMA type 1 was admitted to our pediatric intensive care unit for the second dose nusinersen therapy. He received the irst nusinersen therapy two weeks ago. His physical examination and vital signs revealed no abnormalities. Laboratory indings on the day of admission, total blood count, renal and liver function test, random blood sugar, rutine urine examination, serebrospinal luid (CSF) examination, venous blood gas analysis and serum electrolits except sodium were within the normal limits. Serum sodium concentration in venous blood gas analysis was 110 mmol/L; and this result needed to be con irmed by a subsequent laboratory blood sample analyse. However, serum sodium level was found to be 109 mmol/L, again. There was no history of hyponatremia, suggestive water intake, vomiting or diarrhea, before nusinersen treatment. He was fed with breast milk by a nasogastric tube and gained only 500 gr during the last month. There were no signs of dehydration and generalize/ localize edema. His laboratory indings were as follows: lipid pro ile and blood sugar are within normal range; blood urea: 3,38 mg/dL; creatinin: 0,04 mg/dL; uric acide: 1,5 mg/dL; sodium: 110 mmol/L; potassium: 4,2 mmol/L; urine density: 1.002. His thyroid and adrenal functions were normal. His renal ultrasonography was reported as normal. Further investigations revealed low serum osmolarity (260 mOs/L), elevated urine osmolarity (110 mOs/L) and random urine sodium levels (30 mEq/L) based on which the diagnosis of SIADH was made. Antidiuretic hormone (ADH) level analyze could not be done at the hospital laboratory. His nutrition was added with table salt and he was discharged on day 5 th . Follow-up blood tests a week later showed that the results had returned to normal ranges with serum sodium level 132 mmol/L, with added table salt. Firstly, water intake was restricted, then hipertonik salin given to increase the sodium level by 10mEq/L within 24 hours. The patient continues to get nusinersen treatment, and can only keeps normal sodium levels with added table salt. Another complication due to nusinersen did not develop.

Discussion
Spinal muscular atrophy is a genetic disease characterized by muscle weakness resulting from the degeneration of alpha motor neurons in the spinal cord and the brainstem [3]. Usually, SMA is caused by a homozygous deletion of the SMN1 gene, resulting in SMN protein de iciency. The SMN locus contains a paralog SMN2 due to an inverted duplication on human chromosome 5 [4].
Nusinersen is an antisense oligonucleotide that leads to splicing correction of the SMN2 gene [5]. The drug is administered intrathecally at 12 mg and 4 dose loading is recommended at the beginning. Nusinersen gets cleared from CSF into the systemic circulation and is guanti iable for 15-168 days after dosing. Autopsy data exposed the presence of nusinersen in liver, skeletal muscles, and kidney situation show that nusinersen gets cleared from CSF into the systemic circulation. Nusinersen is metabolized via exonuclease-mediated hydrolysis. The mean half-life of nusinersen 63-87 days in the plasma. The primary route of elimination is thought to be via urinary excretion [6].
Adverse effects of novel therapy nusinersen were investigated by large clinical trials such as ENDEAR,CS3A,CHERISH and NURTURE [6]. CS3A clinic trials reported three cases, which developed hiponatremia. One of them is, a four month old girl, who diagnosed SMA type 2, had a developed hiponatremia on 89 th days after treatment and on 231 st day, Na level was determined as 96 meq/l. This patient was supported with table salt, during 14 months [7]. The other case was a 2 month old boy, a hiponatremi was determined on the 184 th day of the treatment. However, the hiponatremia was not thought to be related with the drug and was attributed to bronchiolitis, levetiracetam and high fever [7]. The third patient was 7 month old baby and on 190 th day of the treatment, hiponatremia was diagnosed. Since he had weight losses and diagnosed with pneumonia; hiponatremia was not recorded to be associated with nusinersen therapy [7].
Because of these three reports, Center for Drug Evaluation and Research, suggests to control serum sodium, both before and after nusinersen treatment. Nusinersen induced hiponatremia, was admitted in only one case and the mechanism was not explained [7]. In present case, our patient developed a hyponatremia following the irst nusinersen therapy and that occured at slowly onset. The patient was examined, with regard to inappropriate secretion of antidiuretic hormone etiological factors, as presented in table 1, such as pain, nausea, stress, and numerous pharmacological agents and diseases [8]. He was ventilated by using home ventilator, for 3 months but, hyponatremia had not developed until the nusinersen therapy. Consequently, no reason was found to explain the etiology of hiponatremia, except for nusinersen administration.
In conclusion, it is suggested that when developing medicine like nusinersen and other oligonuclear ones, this rarely seen but signi icant complication that stated in present case should be taken into consideration. In addition, the case report is expected to contribute the related literature, for future implementations.