Brief Report
Valproate-induced hyperammonaemic encephalopathy in a neonate: Treatment with carglumic acid
Encefalopatía hiperamoniémica inducida por ácido valproico en un neonato. Tratamiento con ácido carglúmico
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Fernández Colomer, S. Rekarte García, J.E. García López, C. Pérez González, M. Montes Granda, G.D. Coto Cotallo" "autores" => array:6 [ 0 => array:4 [ "nombre" => "B." "apellidos" => "Fernández Colomer" "email" => array:1 [ 0 => "bcolomer@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Rekarte García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.E." "apellidos" => "García López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "C." "apellidos" => "Pérez González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "M." "apellidos" => "Montes Granda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "G.D." "apellidos" => "Coto Cotallo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neonatología, AGC de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "AGC de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Encefalopatía hiperamoniémica inducida por ácido valproico en un neonato. Tratamiento con ácido carglúmico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1728 "Ancho" => 2178 "Tamanyo" => 340137 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Urea cycle. CA carbonic anhydrase; NAG, N-acetylglutamate; VA, valproic acid.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Valproic acid (VA) is an anticonvulsant that, while not being the first-line treatment for convulsions in neonates, is used as a second- or third-line treatment in Spain for convulsions refractory to phenobarbital treatment.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Valproate-induced hyperammonaemic encephalopathy (VHE) is rare (<1/10,000), but it is serious and potentially fatal.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> The main physiopathological mechanism that leads to VHE is a gradual elevation of serum ammonia levels, leading to a clinical syndrome characterised by vomiting, progressive impairment of consciousness up to coma, focal neurological deficits, and increased seizure frequency.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> There is no evidence that the incidence and severity of VHE are associated to blood VA levels, since in most published cases the levels were within therapeutic ranges, although there is evidence suggesting that anticonvulsant polytherapy (phenobarbital, phenytoin, and VA) may contribute to VHE.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Treatment consists of discontinuation of VA and management of ammonia levels to prevent neurotoxicity, especially in neonates.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> N-carbamylglutamate (NCG), also known as carglumic acid, is a synthetic analogue of N-acetylglutamate (NAG), one of the cofactors essential to the proper functioning of the urea cycle. NCG is indicated for treatment of hyperanaemia secondary to N-acetylglutamate-synthetase (NAGS) deficiency, although it has also been used to treat hyperanaemia of different aetiologies, such as VHE.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a neonate with VHE treated successfully with NCG and other measures against hyperammonaemia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical case</span><p id="par0020" class="elsevierStylePara elsevierViewall">A male neonate, 20 days old, was admitted for a skull fracture and subdural haematoma secondary to occipital trauma, with no family history of metabolic disorders or consanguinity. He had been born at full term in a normal delivery and had an Apgar score of 9/10. The general examination at admission found a left parietal cephalohaematoma and neurological examination found only increased somnolence (Glasgow Coma Scale score 13/15). A computer tomography (CT) scan of the head revealed multiple diastatic skull fractures, extensive right subdural haematoma, and subgaleal fluid collections in the left parietal region (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). At 24<span class="elsevierStyleHsp" style=""></span>h after admission, he had partial seizures that were resolved with phenobarbital (initial bolus 20<span class="elsevierStyleHsp" style=""></span>mg/kg, maintenance 5<span class="elsevierStyleHsp" style=""></span>mg/kg/day) and midazolam. He had a new episode that consisted of a prolonged secondarily generalised partial seizure, so VA was added to the treatment regimen (initial bolus 15<span class="elsevierStyleHsp" style=""></span>mg/kg, maintenance 1<span class="elsevierStyleHsp" style=""></span>mg/kg/h). The electroencephalograph (EEG) at admission was normal, but after the seizures it detected focal activity in posterior regions of the right hemisphere that coincided with the location of the subdural haematoma (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). At 48<span class="elsevierStyleHsp" style=""></span>h after initiation of VA therapy, the patient started showing signs of decreased level of consciousness, decreased spontaneous movement, and marked hypotonia and hyporeflexia. Examination did not reveal signs of intracranial pressure and a surveillance CT scan of the head did not show any changes. A new EEG showed generalised low-voltage slow activity compatible with cerebral oedema (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). Phenobarbital levels were normal and VA levels were slightly elevated (104.9<span class="elsevierStyleHsp" style=""></span>μg/mL). Basic laboratory testing (complete blood count, electrolyte panel, liver function) yielded normal results, and gasometry showed respiratory alkalosis. The serum ammonia level was 398<span class="elsevierStyleHsp" style=""></span>μmol/L. In light of these findings, treatment with VA was discontinued and treatment with carglumic acid (loading dose 100<span class="elsevierStyleHsp" style=""></span>mg/kg, maintenance 25<span class="elsevierStyleHsp" style=""></span>mg/kg/6<span class="elsevierStyleHsp" style=""></span>h orally) and carnitine (25<span class="elsevierStyleHsp" style=""></span>mg/kg/6<span class="elsevierStyleHsp" style=""></span>h orally) was initiated. Five hours later the level of ammonia had not decreased fast enough (374<span class="elsevierStyleHsp" style=""></span>μmol/L), so oral phenylbutyrate (125<span class="elsevierStyleHsp" style=""></span>mg/kg/6<span class="elsevierStyleHsp" style=""></span>h) and oral L-arginine (600<span class="elsevierStyleHsp" style=""></span>mg/kg/day) were added to the regimen. At 10<span class="elsevierStyleHsp" style=""></span>h, the ammonia level had dropped by half (182<span class="elsevierStyleHsp" style=""></span>μmol/L) and the VA level was within the normal range (69.8<span class="elsevierStyleHsp" style=""></span>μg/mL). At 18<span class="elsevierStyleHsp" style=""></span>h, the level of ammonia was normal (102<span class="elsevierStyleHsp" style=""></span>μmol/L) and the patient had improved considerably, so medication for hyperammonaemia was discontinued. A broad metabolic screening was done on a heel prick blood sample, the results of which were normal. The patient was monitored on an outpatient basis and evolved favourably. Phenobarbital treatment was discontinued at 4 months of age, and at age 1 year he showed normal psychomotor development, with no further episodes of convulsions.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Although the treatment of neonatal convulsions has hardly changed in the past few decades, it remains a controversial subject because there are no evidence-based guidelines for their management. There is a general consensus that phenobarbital is the first-line treatment,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> followed by phenytoin and benzodiazepines. Instances of treatment with other drugs, such as topiramate or levetiracetam, are starting to be published.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Valproate is also used as a second-line treatment after phenobarbital treatment failure with positive results, although it should be used with caution because there is limited experience in its use in neonatology.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">VHE is a rare and serious condition, especially in neonates. The main physiopathological mechanism involved is an increased serum ammonia level that causes an acute or subacute clinical presentation characterized by vomiting and decreasing level of consciousness that progresses towards coma and that may be associated to focal neurological deficits and increased seizure frequency.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Ammonia is highly toxic to the central nervous system, as it diffuses freely through the blood–brain barrier, reaching concentrations higher than those found in the blood. The developing brain is much more susceptible to the harmful effects of ammonia than a mature brain.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Its toxicity is associated to the elevation of extracellular glutamate levels and the development of cerebral oedema with increased intracranial pressure.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The urea cycle is the main metabolic pathway to eliminate ammonia, transforming it into urea that is later excreted by the kidney.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Several mechanisms have been postulated to explain how VA and its metabolites cause hyperammonaemia. One is direct action in the kidney by stimulation of renal glutaminase, and indirect action in the liver by inhibition of NAGS, which reduces the availability of NAG, a cofactor required for the activity of carbamoyl phosphate synthetase (CPS I), the first enzyme in the urea cycle.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> They also cause carnitine depletion, affecting the beta-oxidation of fatty acids and resulting in decreased levels of acetyl-CoA, which is necessary for NAG synthesis<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Although a positive correlation between ammonia levels and the dosage and serum levels of AV has been reported recently,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> a significant association between the daily dosage of VA and the development and severity of VHE has not been found, in fact the levels of VA are within therapeutic<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> or supratherapeutic<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> ranges in most of the published cases. On the other hand, mild elevations in the level of ammonia that did not cause any symptoms have been observed in patients treated with VA in whom medication did not need to be discontinued.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Thus, we do not believe that levels of ammonia need to be monitored in all patients treated with VA, although they should be monitored in those who develop neurological symptoms.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Several factors may be associated to the development of VHE, but the most important are polytherapy and deficiency of ornithine transcarbamylase (OTC) and of carnitine. Some anticonvulsant drugs, such as phenobarbital, phenytoin, carbamazepine, and topiramate, increase the toxicity of VA.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> OTC deficiency (an X-linked disease) is the most common inherited cause of hyperammonaemia. Male homozygotes usually die in the neonatal period, while female heterozygotes may be asymptomatic and develop hyperammonaemia secondary to VA therapy.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Treatment of VHE consists of discontinuation of valproate therapy and control of ammonia levels using carnitine and N-carbamoylglutamate, to prevent neurotoxicity.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> NCG, a synthetic analogue of NAG, is indicated for treatment of hyperammonaemia secondary to NAGS deficit, but has been used in hyperammonaemia of other (organic acidemias, beta-oxidation disorders) or unknown aetiologies with good results.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,17</span></a> Giner and cols, report two cases in adolescents in which VA was discontinued and who were treated successfully with NCG over 24–48<span class="elsevierStyleHsp" style=""></span>h,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and recently a case of a preschooler treated for 2 months with NCG while the dose of VA was tapered off.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">We report this case due to its rarity and the difficulty of its diagnosis. We also want to emphasise that while VHE is a rare condition, it needs to be considered in the diagnosis of any neonate undergoing VA therapy with an unexplained impairment of consciousness. In our case, polytherapy could have been a contributing factor; other possible causes of hyperammonaemia were ruled out. Finally, we ought to emphasise the therapeutic efficacy of discontinuing VA therapy and administering NCG combined with other drugs in normalising ammonia levels, which resulted in full resolution of the condition without short- or medium-term sequelae.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "xres375166" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec354308" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres375167" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec354309" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical case" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-05-08" "fechaAceptado" => "2013-09-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec354308" "palabras" => array:6 [ 0 => "Valproate" 1 => "Hyperammonaemia" 2 => "Newborn" 3 => "Adverse effect" 4 => "Carglumic acid" 5 => "Infant" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec354309" "palabras" => array:5 [ 0 => "Valproico" 1 => "Hiperamoniemia" 2 => "Neonato" 3 => "Efecto adverso" 4 => "Ácido carglúmico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Valproate-induced hyperammonaemic encephalopathy (VHE) is an unusual and serious complication of valproate (VA) treatment. When an early diagnosis is made, it can be reversed with VA withdrawal and early treatment for hyperammonaemia. We describe the case of a 20-day-old male, who developed a serious VHE after receiving VA for refractory neonatal seizures. The VHE was resolved with VA withdrawal in association with carglumic acid and other measures for hyperammonaemia treatment.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La encefalopatía hiperamoniémica inducida por ácido valproico (EHV) es una entidad grave e inusual. Para su diagnóstico, precisa un elevado índice de sospecha, pues resulta reversible con la retirada del fármaco y el tratamiento precoz de la hiperamoniemia. Presentamos el caso de un neonato tratado con valproico (AV) por convulsiones refractarias, que desarrolló una EHV grave que revirtió con la retirada del AV y el tratamiento con ácido carglúmico, junto con otras medidas para control de la hiperamoniemia.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Fernández Colomer B, Rekarte García S, García López JE, Pérez González C, Montes Granda M, Coto Cotallo GD. Encefalopatía hiperamoniémica inducida por ácido valproico en un neonato. Tratamiento con ácido carglúmico. An Pediatr. (Barc). 2014;81:251–255.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 557 "Ancho" => 1002 "Tamanyo" => 54599 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Multiple diastatic skull fractures, extensive right subdural haematoma, and subgaleal fluid collections in the left parietal region.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2432 "Ancho" => 3194 "Tamanyo" => 747353 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">EEG showing focal epileptiform activity in posterior regions of the right hemisphere on an integrated background pattern (A). EEG showing very low voltage diffuse activity formed by a combination of slow frequencies with no clear topographic differentiation or response to external stimuli. The tracing shows focal epileptiform activity in the right posterior temporal region (B).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1728 "Ancho" => 2178 "Tamanyo" => 340137 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Urea cycle. CA carbonic anhydrase; NAG, N-acetylglutamate; VA, valproic acid.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Convulsions and epileptic syndromes of the newborn infant. Forms of presentation, study and treatment protocols" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. 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| 2022 August | 74 | 47 | 121 |
| 2022 July | 59 | 29 | 88 |
| 2022 June | 61 | 41 | 102 |
| 2022 May | 67 | 27 | 94 |
| 2022 April | 48 | 31 | 79 |
| 2022 March | 102 | 53 | 155 |
| 2022 February | 61 | 27 | 88 |
| 2022 January | 84 | 28 | 112 |
| 2021 December | 77 | 38 | 115 |
| 2021 November | 62 | 44 | 106 |
| 2021 October | 65 | 45 | 110 |
| 2021 September | 41 | 29 | 70 |
| 2021 August | 41 | 30 | 71 |
| 2021 July | 41 | 33 | 74 |
| 2021 June | 56 | 26 | 82 |
| 2021 May | 68 | 28 | 96 |
| 2021 April | 115 | 51 | 166 |
| 2021 March | 99 | 17 | 116 |
| 2021 February | 71 | 14 | 85 |
| 2021 January | 63 | 13 | 76 |
| 2020 December | 50 | 25 | 75 |
| 2020 November | 73 | 13 | 86 |
| 2020 October | 53 | 13 | 66 |
| 2020 September | 37 | 13 | 50 |
| 2020 August | 53 | 8 | 61 |
| 2020 July | 81 | 23 | 104 |
| 2020 June | 71 | 19 | 90 |
| 2020 May | 54 | 18 | 72 |
| 2020 April | 33 | 15 | 48 |
| 2020 March | 49 | 18 | 67 |
| 2020 February | 41 | 15 | 56 |
| 2020 January | 58 | 15 | 73 |
| 2019 December | 55 | 11 | 66 |
| 2019 November | 42 | 12 | 54 |
| 2019 October | 49 | 20 | 69 |
| 2019 September | 45 | 18 | 63 |
| 2019 August | 43 | 25 | 68 |
| 2019 July | 37 | 20 | 57 |
| 2019 June | 50 | 25 | 75 |
| 2019 May | 129 | 35 | 164 |
| 2019 April | 106 | 46 | 152 |
| 2019 March | 59 | 26 | 85 |
| 2019 February | 60 | 26 | 86 |
| 2019 January | 59 | 21 | 80 |
| 2018 December | 61 | 26 | 87 |
| 2018 November | 130 | 37 | 167 |
| 2018 October | 179 | 23 | 202 |
| 2018 September | 83 | 21 | 104 |
| 2018 August | 4 | 0 | 4 |
| 2018 July | 8 | 0 | 8 |
| 2018 June | 8 | 0 | 8 |
| 2018 May | 11 | 0 | 11 |
| 2018 April | 55 | 0 | 55 |
| 2018 March | 101 | 0 | 101 |
| 2018 February | 43 | 0 | 43 |
| 2018 January | 60 | 0 | 60 |
| 2017 December | 46 | 0 | 46 |
| 2017 November | 95 | 0 | 95 |
| 2017 October | 46 | 0 | 46 |
| 2017 September | 43 | 0 | 43 |
| 2017 August | 38 | 0 | 38 |
| 2017 July | 48 | 2 | 50 |
| 2017 June | 69 | 12 | 81 |
| 2017 May | 72 | 9 | 81 |
| 2017 April | 73 | 45 | 118 |
| 2017 March | 75 | 6 | 81 |
| 2017 February | 138 | 6 | 144 |
| 2017 January | 49 | 8 | 57 |
| 2016 December | 98 | 13 | 111 |
| 2016 November | 112 | 10 | 122 |
| 2016 October | 120 | 9 | 129 |
| 2016 September | 165 | 12 | 177 |
| 2016 August | 75 | 4 | 79 |
| 2016 July | 34 | 5 | 39 |
| 2016 March | 4 | 0 | 4 |
| 2016 February | 1 | 0 | 1 |
| 2016 January | 3 | 0 | 3 |
| 2015 December | 2 | 0 | 2 |
| 2015 November | 2 | 13 | 15 |
| 2015 October | 9 | 16 | 25 |
| 2015 August | 3 | 13 | 16 |
| 2015 June | 2 | 0 | 2 |
| 2015 May | 2 | 10 | 12 |
| 2015 April | 2 | 10 | 12 |
| 2015 March | 3 | 0 | 3 |
| 2015 February | 7 | 0 | 7 |
| 2015 January | 1 | 0 | 1 |
| 2014 December | 2 | 1 | 3 |
| 2014 November | 4 | 1 | 5 |
Show all
