Accepted Manuscript Title: Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy Author: Pauli Ylikotila Raimo A. Ketola Susanna Timonen Heli Malm Jori O. Ruuskanen PII: DOI: Reference:

S0890-6238(15)30002-2 http://dx.doi.org/doi:10.1016/j.reprotox.2015.07.068 RTX 7160

To appear in:

Reproductive Toxicology

Received date: Revised date: Accepted date:

16-4-2015 7-6-2015 6-7-2015

Please cite this article as: Ylikotila Pauli, Ketola Raimo A, Timonen Susanna, Malm Heli, Ruuskanen Jori O.Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy.Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2015.07.068 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.

Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy Pauli Ylikotila1,2, Raimo A. Ketola3, Susanna Timonen4, Heli Malm5,6, Jori O. Ruuskanen1,2,7 1

Institute of Clinical Medicine, Department of Neurology, University of Turku, Turku, Finland

2

Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland

3

Department of Forensic Medicine, Hjelt Institute, Faculty of Medicine, University of Helsinki,

Finland 4

Institute of Clinical Medicine, Department of Gynaecology and Obstetrics, University of Turku,

Turku, Finland 5

Teratology Information Service, HUSLAB and Helsinki University Central Hospital, Helsinki,

Finland 6

Department of Clinical Pharmacology, Helsinki University, Helsinki, Finland

7

Medbase Ltd, Turku, Finland

Corresponding author. Tel: +358 44 550 9391(mobile), +35823135879 (office). E-mail: [email protected]

Keywords : Lacosamide; Pregnancy; Lactation; Cerebral venous thrombosis; Status epilepticus

Abstract Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, accounting to less than 1% of all strokes. We describe a pregnant woman with a massive CVT in early pregnancy, complicated by status epilepticus. The mother was treated with levetiracetam, lacosamide and enoxaparin throughout pregnancy. A male infant was born on pregnancy week 36, weighing 2.2 kilogram. Both levetiracetam and and lacosamide were present in cord blood in levels similar to those in maternal blood. The infant was partially breast-fed and experienced poor feeding and sleepiness, starting to

resolve after two first weeks. Milk samples were drawn five days after the delivery and a blood sample from the infant three days later. Lacosamide level in milk was low, resulting in an estimated relative infant dose of 1.8% of the maternal weight-adjusted daily dose in a fully breast-fed infant. This is the first case describing lacosamide use during pregnancy and lactation.

1. Introduction

Cerebral venous thrombosis (CVT) accounts for 0.5 to 1.0% of all strokes [1] . Predisposing factors include female sex, prothrombotic conditions, pregnancy and puerperium, use of oral contraceptives, certain drugs, and cancer. Presentation of CVT depends on the size and location of the thrombi, the extent of oedema and collateral circulation. Typical symptoms and signs in superior sagittal sinus thrombi are headache, nausea, elevation of intracranial pressure, and papilloedema.

Only about 30 % of CVT cases can be identified with non-contrast CT, necessitating the use of angiography (CTA or MRA) [2] . D-dimer can be used as a screening tool in the emergency setting. However, the specificity of D-dimer decreases during pregnancy [3] .

Approximately 2% of strokes during pregnancy are caused by CVT. The risk of CVT increases in the third trimester and postpartum, with about 75% of cases occurring postpartum [4] . Only few cases of CVT in early pregnancy have been reported, with variable outcomes [5,6] .

Variables associated with poor prognosis in CVT include age over 37 years, male sex, lowered consciousness, seizures, status epilepticus, ICH, deep vein thrombosis, venous infarction, CNS infection, cancer, and underlying thrombophilia [7,8] . In the International Study on Cerebral Vein and Dural Sinus Thrombosis trial (ISCVT) mortality within 30 days of disease onset was 3.4 % [9] . Other trials have reported higher mortality, up to 15 % [10,11] .

Levetiracetam appears to be relatively safe both during pregnancy and lactation [12,13,14] . In experimental animal studies performed for the registration of lacosamide, exposures similar to those used in humans on a plasma concentration basis did not increase malformations in rats and rabbits (Vimpat SPC. UCB Pharma Limited 2014). However, human data on lacosamide during pregnancy and lactation is lacking.

2. Case

A 36-year-old pregnant woman with inborn femur aplasia, a history of migraine and severe preeclampsia in a previous pregnancy, was admitted to the emergency ward because of headache, leftsided weakness and dysarthria. Estimated pregnancy week was 8.

Laboratory testing revealed anaemia (haemoglobin 84 g/L, MCV 62 and elevated fibrin D-dimer, 3.1 mg/L. Contrast CT revealed sinus thrombosis in the superior sagittal sinus, left sigmoid and transversal sinuses. There were two small intracranial haemorrhages (ICH) in the cranial part of the right frontal lobe. Intravenous heparin was started.

Next morning the patient had a focal secondarily generalised seizure, treated initially with intravenous diazepam (10 mg) and levetiracetam (1000 mg). Due to repeated seizures and low consciousness, suggesting status epilepticus (SE), she was sedated and admitted to the intensive care unit (ICU). CT scan showed no new findings. As she was still restless in the ICU, midazolam infusion was started, in addition to ongoing propofol. Because of occasional epileptic jerks lorazepam and a loading dose of fosphenytoin was administered. Fosphenytoin was continued 250 mg twice daily and levetiracetam 1000 mg twice daily. Heparin was switched to low molecular weight heparin (LMWH) enoxaparin (60 mg twice daily).

During days 2 and 3, fosphenytoin and levetiracetam doses were increased, and lacosamide as well as lorazepam started due to epileptiform EEG and seizures during sedation pauses. Chest radiograph revealed pneumonia, treated with ceftriaxone. Free phenytoin concentration was 5.8 mM (therapeutic range 3-10).

On day 4, daily doses of antiepileptic drugs were 600 mg fosphenytoin, 3000 mg levetiracetam, 300 mg lacosamide and 6 mg lorazepam. EEG was no longer epileptiform. Ultrasound revealed a normal intrauterine pregnancy, corresponding to 7 weeks of gestation.

On day 7, CT showed slight resorption of the ICH. Lorazepam was gradually discontinued and the patient was extubated on day 12. A slight left-sided hemiparesis was still present. The patient could have a short meaningful conversation.

Levetiracetam 1000 mg bid and lacosamide 100 mg bid were continued as the only antiepileptic drugs throughout the rest of the pregnancy. Because of high blood pressure, labetalol was continued during the whole pregnancy. After four weeks she was discharged from the hospital.

Thrombophilia testing was normal. Enoxaparin 40 mg bid was continued. Ultrasound of the foetus was repeated several times, and indicated normal growth and no abnormalities. Serum alfafetoprotein was normal. Maternal head MRI two months after sinusthrombosis onset, at pregnancy week 17, showed resorption of the ICH and recanalization of superior sagittal sinus and left transverse sinus.

A planned caesarean section was performed on pregnancy week 36. A boy weighing 2.2 kilogram (2 SD) was born with Apgar points 8/9/9, no malformations, and umbilical cord arterial blood pH 7.33. Blood samples from the mother and from cord blood were drawn immediately after the delivery. The mother started breast-feeding her infant. Milk samples were drawn 5 days after the delivery and a blood sample from the infant three days later. During the first week, approximately half of the milk ingested by the infant was from the mother. There were no detectable levels of levetiracetam in the milk or in the infant blood, and lacosamide levels were very low (Table). Based on lacosamide concentration in breast milk, the estimated relative infant dose (RID) of a fully breast-fed infant would be 1.8% of the maternal weight adjusted dose (actual daily dose 200 mg), assuming maternal weight of 60 kg and infant feeding 0.15 L/kg of breast-milk (0.4 x 0.15 x 60 / 200 = 0.018).

However, the mother decided to discontinue breast-feeding due to poor feeding and sleepiness of the infant at day 15 post-partum. Before that, pauses held in breast-feeding did not improve the infant’s condition. The problems with feeding and alertness resolved gradually. The infant showed

normal developmental milestones at calendar age of seven months, and follow-up in tertiary care was discontinued.

Enoxaparin was continued for three months after the delivery. Lacosamide was gradually discontinued and the patient has been continuing levetiracetam monotherapy. Testing for thrombophilia three months after the delivery was normal. The patient has recovered well with only slight neuropsychological disturbances and minimal impressive aphasia.

Reagents, chemical, and analytical information

All reagents used were of pure analytical grade. Lacosamide was obtained from Chemtec Leuna, Leuna, Germany, and levetiracetam from UCP Pharma Sector S.A., Braille-l’Allend, Belgium.

The analysis of lacosamide was performed using a gas chromatograph equipped with two nitrogenphosphorus detectors (Agilent Technologies, Waldbronn, Germany). Two analytical columns were used: HP-5 and DB-17 (J&W Scientific, Agilent). 0.5 g of a blood or breast milk sample was weighed into a disposable tube, the internal standard (dibenzepine), TRIS buffer, and butyl acetate were added, the sample was vortexed and centrifuged. An aliquot of the organic phase was transferred into GC sample vial for analysis. Bovine whole blood was used as a blank matrix.

The analysis of levetiracetam was performed using gas chromatography-mass spectrometry (Agilent). The analytical column was DB-5MS. Mass spectrometric parameters were the following: electron ionization (70 eV), target ion at m/z 126.0 and qualifier ion at m/z 112.0 for levetiracetamTMS, and target ion at m/z 353.3, and qualifier ions at m/z 312.2 and 325.2 for the internal standard (butalbital-2TMS). 0.5 g of a blood or breast milk sample was weighed into a disposable tube, the internal standard, NH4Cl solution, and ethyl acetate were added. The sample was vortexed and centrifuged. The organic phase was transferred to a vial, the solvent was evaporated, a silylation reagent (N-methyl-N-trimethylsilyl-trifluoroacetamide:trimethylchlorosilane, 99:1) was added and the sample was heated at 85 °C for 30 min prior to analysis.

* the limit of quantitation was 3 mg/L 3. Comment

This is the first report describing lacosamide use during pregnancy, and drug levels in cord blood, breast milk and a breast-fed infant. Lacosamide appears to cross the near-term placenta freely. The infant was born without malformations but was small for gestational age, raising the concern of mother’s multiple medications and possibly status epilepticus and its consequences having a deleterious impact on his development. Due to low molecular weight and minimal binding to plasma proteins, lacosamide could also be expected to pass into milk in significant amounts. Lacosamide is primarily eliminated by kidneys, and could accumulate in a breast-fed infant due to lower renal excretion. However, drug level in breast milk was low, and lacosamide concentration in the blood of the breast-fed infant eight days after the delivery was approximately 5 % of the cord blood level. Levetiracetam was present in cord blood in levels similar to those in the mother, but was undetectable in the breast milk and in infant blood, which is partially in contrast to previous studies showing approximately 1:1 blood:milk ratios, but also very low levels in breast-fed infants [12]. Current, limited evidence argues against a teratogenic or neurotoxic potential for levetiracetam, also compatible with breast-feeding [12,14].

Conflicts of interests The authors declare that they have no competing interests.

Consent Written informed consent was obtained from the patient for publication of this Case presentation and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. References [1] Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005 Apr 28;352(17):1791-1798. [2] Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol 2007 Feb;6(2):162-170. [3] Lapner ST, Kearon C. Diagnosis and management of pulmonary embolism. BMJ 2013 Feb 20;346:f757. [4] James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005 Sep;106(3):509-516. [5] Oktem M, Erdem A, Demirdag E, Cenksoy C, Erdem M, Bozkurt N. Cerebral venous sinus thrombosis during the first trimester after superovulation and intrauterine insemination with recombinant follicle-stimulating hormone: a case report. Eur J Obstet Gynecol Reprod Biol 2013 May;168(1):118-119. [6] Yamamoto J, Kakeda S, Takahashi M, Idei M, Nakano Y, Soejima Y, et al. Severe subarachnoid hemorrhage associated with cerebral venous thrombosis in early pregnancy: a case report. J Emerg Med 2013 Dec;45(6):849-855. [7] Appenzeller S, Zeller CB, Annichino-Bizzachi JM, Costallat LT, Deus-Silva L, Voetsch B, et al. Cerebral venous thrombosis: influence of risk factors and imaging findings on prognosis. Clin Neurol Neurosurg 2005 Aug;107(5):371378.

[8] Stolz E, Rahimi A, Gerriets T, Kraus J, Kaps M. Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and long-term outcome. Clin Neurol Neurosurg 2005 Feb;107(2):99-107. [9] Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004 Mar;35(3):664-670. [10] Azin H, Ashjazadeh N. Cerebral venous sinus thrombosis--clinical features, predisposing and prognostic factors. Acta Neurol Taiwan 2008 Jun;17(2):82-87. [11] Boncoraglio G, Carriero MR, Chiapparini L, Ciceri E, Ciusani E, Erbetta A, et al. Hyperhomocysteinemia and other thrombophilic risk factors in 26 patients with cerebral venous thrombosis. Eur J Neurol 2004 Jun;11(6):405-409. [12] Tomson T, Palm R, Kallen K, Ben-Menachem E, Soderfeldt B, Danielsson B, et al. Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation. Epilepsia 2007 Jun;48(6):1111-1116. [13] Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology 2013 Jan 22;80(4):400-405. [14] Chaudhry SA, Jong G, Koren G. The fetal safety of Levetiracetam: a systematic review. Reprod Toxicol 2014 Jul 46:40-5.

Table. Measured concentrations ± relative standard deviation (RSD), as calculated directly using the total measure imprecision of the method. Sample

Lacosamide

Levetiracetam

(mg/L±RSD)

(mg/L±RSD)

Mother, blood, Day 0

3.8 ± 1.1

17 ± 5

Child, cord blood, Day 0

3.9 ± 1.2

23 ± 7

Mother, breast milk, Day 5

0.4 ± 0.2

not detected*

Child, blood, Day 8

0.2 ± 0.1

not detected*

* the limit of quantitation was 3 mg/L

Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy.

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, accounting to less than 1% of all strokes. We describe a pregnant woman with a massiv...
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