Letter to the Editor
Progressive myoclonus epilepsies: description of a case of Lafora disease with autopsy
Epilepsia mioclónica progresiva: Descripción de un caso de enfermedad de Lafora con autopsia
P.E. Jiménez Caballero
Servicio de Neurología, Hospital San Pedro de Alcántara, Cáceres, Spain
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Jiménez Caballero" "autores" => array:1 [ 0 => array:3 [ "nombre" => "P.E." "apellidos" => "Jiménez Caballero" "email" => array:1 [ 0 => "pjimenez1010j@yahoo.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Neurología, Hospital San Pedro de Alcántara, Cáceres, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Epilepsia mioclónica progresiva: Descripción de un caso de enfermedad de Lafora con autopsia" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2475 "Ancho" => 947 "Tamanyo" => 498815 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Axillary skin biopsy (PAS stain, 2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>400 magnification) showing round-shaped intensely PAS-positive formations in the epithelial cells of the apocrine glands and in the ducts of the eccrine glands which correspond to Lafora bodies. (B) Heart (PAS stain, 1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>200 magnification). Multiple Lafora bodies in myocytes.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The term ‘progressive myoclonus epilepsy’ (PME) refers to an array of clinical entities with heterogeneous causes. They are characterised by different types of epileptic seizures (mainly myoclonic), intellectual impairment, and other clinical manifestations mainly involving the cerebellum.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a 15-year-old male whose gestation and birth were uneventful. Psychomotor development and educational level were also normal until the age of 11. He had a healthy brother 3 years older. Their parents were not consanguineous, although both were from the same village of some 1000 inhabitants.</p><p id="par0015" class="elsevierStylePara elsevierViewall">At the age of 12, the patient began to suffer episodes of disorientation lasting a few seconds, which were interpreted as absence seizures. During the following months, he presented several generalised tonic-clonic seizures. Cranial CT yielded normal results; EEG revealed overall slowing of the background activity plus some diffuse spike-wave complexes. Intermittent light stimulation generated a photoparoxysmal response at low frequencies. Epileptic activity did not increase during stages of drowsiness.</p><p id="par0020" class="elsevierStylePara elsevierViewall">He was initially diagnosed with juvenile myoclonus epilepsy and treated with valproic acid (1500<span class="elsevierStyleHsp" style=""></span>mg per day) associated with clonazepam (40<span class="elsevierStyleHsp" style=""></span>mg per day). Given the lack of response to medication, doctors added phenobarbital (90<span class="elsevierStyleHsp" style=""></span>mg per day) and ethosuximide (1000<span class="elsevierStyleHsp" style=""></span>mg per day) to reduce generalised seizures and absence seizures, respectively.</p><p id="par0025" class="elsevierStylePara elsevierViewall">During the following 2 years, the patient's epilepsy progressed unfavourably with increasingly frequent seizures. His different types of epileptic seizures were classified as atypical absence seizures, multifocal cortical myoclonus, and generalised tonic-clonic seizures. Doctors also observed declining academic performance with multiple cognitive deficits mainly affecting visuospatial and literacy abilities. The patient was finally diagnosed with progressive myoclonus epilepsy based on the above symptoms.</p><p id="par0030" class="elsevierStylePara elsevierViewall">General physical examination revealed no cutaneous stigmata (phacomatosis), visceromegalies, or retinal cherry-red spots. Neurological examination revealed bradypsychia and amnestic deficit for recent events. Cranial nerves were normal, except for horizontal nystagmus with quick phase following the direction of the gaze. There were no relevant changes in the motor system or in sensitivity. The patient presented truncal ataxia, tremor in both hands that could be increased voluntarily, dysarthria, and bilateral dysmetria (finger-to-nose test).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Analytical tests, including a haemogram, renal, liver, and thyroid profiles, copper, ceruloplasmin, creatine kinase, antineuronal antibodies, and baseline and post-exercise lactate levels, all yielded normal results. Blood and urine amino acid levels were normal. Results from the lysosomal enzyme study were also unremarkable.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Brain MRI showed moderate overall cerebral and cerebellar atrophy.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The EEG showed slow background activity with generalised epileptiform discharges manifesting as spike/polyspike wave complexes of variable duration that persisted throughout the reading. Intermittent light stimulation generated a photoparoxysmal response at low frequencies. Epileptic activity did not increase during stages of drowsiness.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Striated muscle biopsy revealed no structural changes; fibre diameters were moderately variable. The basophilic intermyofibrillar network was increased by multiples fibres forming small round basophilic deposits, which were PAS-positive according to enzymatic oxidation methods.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Axillary skin biopsies (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A) showed rounded intensely PAS-positive formations in the epithelial cells of the apocrine glands and in the ducts of the eccrine glands. Both biopsies were compatible with Lafora disease.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Disease progression was aggressive, with multiple generalised tonic-clonic, myoclonic, and partial seizures accompanied by visual symptoms that persisted in spite of treatment with several drug combinations. He lost functional abilities to the point of becoming completely disabled; nasogastric feeding was required since his frequent palatal myoclonias provoked difficulty swallowing. He presented bladder and bowel incontinence and tetraparesis, and became confined to bed and armchair. He died of aspiration pneumonia 8 years after disease onset.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Autopsy revealed typical Lafora bodies in several areas of the central nervous system (especially the thalamus and cerebellum), the liver, and the heart (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B).</p><p id="par0070" class="elsevierStylePara elsevierViewall">The most frequent causes of PME affecting most of the cases are Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinoses, sialidosis, and mitochondrial cytopathies (myoclonus epilepsy with ragged red fibres, MERRF) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Dr Rodríguez Lafora was the first to describe Lafora disease in 1911.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It consists of a degenerative and progressive disorder of the central nervous system with a recessive autosomal inheritance pattern. This disease presents no sex-related differences and it is predominantly found in southern European countries.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Lafora disease is clinically characterised by generalised tonic-clonic seizures, myoclonias, progressive mental decline, and pyramidal, extrapyramidal, and cerebellar signs.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It appears at the end of childhood or during adolescence (6 to 20 years) and it leads to death 10 years after the onset of the first symptoms. The disease is caused by a homozygous EPM2 mutation linked to chromosome 6q23-25, which codifies tyrosine phosphatase (laforin), a protein involved in the metabolic control of glycogen.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">From a histological point of view, it is characterised by the presence of intracytoplasmic inclusion bodies in organs such as the liver, heart, and brain. They are especially common in biopsies of axillary skin.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These bodies include glucose polymers (polyglucosan) and their presence in an axillary skin biopsy is considered nearly pathognomonic.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Myoclonias become continuous during waking hours; they are resistant to antiepileptic medication and usually associated with occipital lobe seizure. Occipital seizures are characterised by simple visual hallucinations that are sometimes complex. These hallucinations are typical of Lafora disease. The onset of myoclonias coincides with progressive deterioration of cortical function and ataxia.</p><p id="par0095" class="elsevierStylePara elsevierViewall">On rare occasions, electroencephalographic manifestations may appear prior to symptom onset. They are characterised by increasingly frequent spike- or polyspike-wave paroxysms. Subsequently, the baseline record becomes slower and more disorganised. Paroxysms caused by intermittent light stimulation grow more frequent and gradually become continuous; photoparoxysmal response is typical at low frequencies.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Unlike in juvenile myoclonus epilepsy, epileptic anomalies do not increase during sleep in initial stages of Lafora disease.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Brain MRI shows no relevant changes in initial and intermediate stages of the disease; final stages are characterised by cerebral and cerebellar atrophy.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In theory, doctors can offer genetic counselling and establish a prenatal diagnosis when the genetic anomaly has been detected in a family member.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion, doctors should assign a suspected diagnosis of Lafora disease when a young patient (in late childhood or adolescence) begins experiencing myoclonias followed by ataxia and progressive cognitive decline with no evidence of structural changes in neuroimaging tests and no metabolic changes in the analytical study.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-02-08" "fechaAceptado" => "2012-04-22" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Jiménez Caballero PE. Epilepsia mioclónica progresiva: Descripción de un caso de enfermedad de Lafora con autopsia. Neurología. 2013;28:584–586.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2475 "Ancho" => 947 "Tamanyo" => 498815 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Axillary skin biopsy (PAS stain, 2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>400 magnification) showing round-shaped intensely PAS-positive formations in the epithelial cells of the apocrine glands and in the ducts of the eccrine glands which correspond to Lafora bodies. (B) Heart (PAS stain, 1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>200 magnification). Multiple Lafora bodies in myocytes.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">AD: autosomal dominant; AR: autosomal recessive; MERRF: myoclonus epilepsy with ragged red fibres.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Progressive myoclonic epilepsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Inheritance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Age at onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Indicative symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Pathological patterns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unverricht-Lundborg disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6–15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Slow progression, mild and late-onset cerebellar impairment; absence of dementia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSTB (PME) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lafora disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6–19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Visual symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polyglucosan inclusions (Lafora bodies) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EMP2AEMP2B \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MERRF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maternal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Any age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactic acidosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ragged red fibres \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MT-TK (tRNALys) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neuronal ceroid lipofuscinoses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AR or AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macular degeneration and visual impairment (except in the adult form) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipopigment deposits: granular osmiophilic, curvilinear, or fingerprint-like shapes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Various \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sialidosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8–15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gradual cerebellar changes; maculopathy with cherry-red spot \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oligosaccharide deficiency in urine and neuraminidase deficiency in fibroblasts \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NEU1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab431360.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of progressive myoclonic epilepsies.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epilepsia mioclónica progresiva: caracterización clínica de 18 pacientes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. 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| Year/Month | Html | Total | |
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| 2024 November | 7 | 4 | 11 |
| 2024 October | 38 | 4 | 42 |
| 2024 September | 61 | 12 | 73 |
| 2024 August | 42 | 18 | 60 |
| 2024 July | 26 | 10 | 36 |
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| 2024 May | 35 | 12 | 47 |
| 2024 April | 44 | 12 | 56 |
| 2024 March | 64 | 11 | 75 |
| 2024 February | 42 | 8 | 50 |
| 2024 January | 43 | 12 | 55 |
| 2023 December | 42 | 9 | 51 |
| 2023 November | 48 | 16 | 64 |
| 2023 October | 44 | 27 | 71 |
| 2023 September | 20 | 10 | 30 |
| 2023 August | 31 | 9 | 40 |
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| 2023 June | 37 | 6 | 43 |
| 2023 May | 39 | 16 | 55 |
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| 2022 April | 48 | 8 | 56 |
| 2022 March | 46 | 5 | 51 |
| 2022 February | 44 | 4 | 48 |
| 2022 January | 62 | 9 | 71 |
| 2021 December | 64 | 15 | 79 |
| 2021 November | 49 | 12 | 61 |
| 2021 October | 62 | 20 | 82 |
| 2021 September | 36 | 11 | 47 |
| 2021 August | 60 | 7 | 67 |
| 2021 July | 27 | 9 | 36 |
| 2021 June | 28 | 10 | 38 |
| 2021 May | 35 | 8 | 43 |
| 2021 April | 128 | 9 | 137 |
| 2021 March | 91 | 34 | 125 |
| 2021 February | 33 | 8 | 41 |
| 2021 January | 53 | 14 | 67 |
| 2020 December | 49 | 10 | 59 |
| 2020 November | 47 | 14 | 61 |
| 2020 October | 54 | 13 | 67 |
| 2020 September | 42 | 7 | 49 |
| 2020 August | 41 | 14 | 55 |
| 2020 July | 39 | 9 | 48 |
| 2020 June | 37 | 18 | 55 |
| 2020 May | 48 | 19 | 67 |
| 2020 April | 42 | 9 | 51 |
| 2020 March | 51 | 6 | 57 |
| 2020 February | 43 | 12 | 55 |
| 2020 January | 50 | 16 | 66 |
| 2019 December | 48 | 5 | 53 |
| 2019 November | 29 | 16 | 45 |
| 2019 October | 26 | 8 | 34 |
| 2019 September | 43 | 9 | 52 |
| 2019 August | 28 | 6 | 34 |
| 2019 July | 39 | 16 | 55 |
| 2019 June | 92 | 30 | 122 |
| 2019 May | 228 | 55 | 283 |
| 2019 April | 60 | 21 | 81 |
| 2019 March | 20 | 9 | 29 |
| 2019 February | 23 | 7 | 30 |
| 2019 January | 31 | 5 | 36 |
| 2018 December | 22 | 9 | 31 |
| 2018 November | 36 | 10 | 46 |
| 2018 October | 28 | 15 | 43 |
| 2018 September | 18 | 3 | 21 |
| 2018 August | 21 | 6 | 27 |
| 2018 July | 22 | 4 | 26 |
| 2018 June | 13 | 2 | 15 |
| 2018 May | 23 | 10 | 33 |
| 2018 April | 23 | 0 | 23 |
| 2018 March | 45 | 1 | 46 |
| 2018 February | 16 | 6 | 22 |
| 2018 January | 20 | 4 | 24 |
| 2017 December | 20 | 1 | 21 |
| 2017 November | 20 | 5 | 25 |
| 2017 October | 16 | 6 | 22 |
| 2017 September | 17 | 4 | 21 |
| 2017 August | 24 | 3 | 27 |
| 2017 July | 17 | 1 | 18 |
| 2017 June | 29 | 22 | 51 |
| 2017 May | 17 | 8 | 25 |
| 2017 April | 12 | 4 | 16 |
| 2017 March | 30 | 24 | 54 |
| 2017 February | 10 | 2 | 12 |
| 2017 January | 15 | 5 | 20 |
| 2016 December | 21 | 4 | 25 |
| 2016 November | 11 | 7 | 18 |
| 2016 October | 35 | 8 | 43 |
| 2016 September | 28 | 5 | 33 |
| 2016 August | 30 | 7 | 37 |
| 2016 July | 22 | 1 | 23 |
| 2016 June | 19 | 7 | 26 |
| 2016 May | 20 | 17 | 37 |
| 2016 April | 23 | 18 | 41 |
| 2016 March | 16 | 14 | 30 |
| 2016 February | 15 | 12 | 27 |
| 2016 January | 11 | 4 | 15 |
| 2015 December | 11 | 8 | 19 |
| 2015 November | 21 | 6 | 27 |
| 2015 October | 22 | 8 | 30 |
| 2015 September | 22 | 6 | 28 |
| 2015 August | 14 | 9 | 23 |
| 2015 July | 7 | 3 | 10 |
| 2015 June | 5 | 0 | 5 |
| 2015 May | 17 | 7 | 24 |
| 2015 April | 22 | 5 | 27 |
| 2015 March | 29 | 6 | 35 |
| 2015 February | 13 | 7 | 20 |
| 2015 January | 24 | 5 | 29 |
| 2014 December | 36 | 13 | 49 |
| 2014 November | 17 | 5 | 22 |
| 2014 October | 33 | 6 | 39 |
| 2014 September | 22 | 3 | 25 |
| 2014 August | 29 | 3 | 32 |
| 2014 July | 29 | 2 | 31 |
| 2014 June | 15 | 3 | 18 |
| 2014 May | 8 | 1 | 9 |
| 2014 April | 13 | 4 | 17 |
| 2014 March | 30 | 3 | 33 |
| 2014 February | 37 | 9 | 46 |
| 2014 January | 34 | 15 | 49 |
| 2013 December | 47 | 17 | 64 |
Show all
