Letter to the Editor
Encephalopathy secondary to lamotrigine toxicity
Encefalopatía secundaria a intoxicación por lamotrigina
Á. Lambea Gil
, R. Caldú Agud, D. Rodríguez Gascón, V. Garayoa Irigoyen
Corresponding author
Servicio de Neurología, Hospital Universitario Miguel Servet, Zaragoza, Spain
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Lambea Gil, R. Caldú Agud, D. Rodríguez Gascón, V. Garayoa Irigoyen" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Á." "apellidos" => "Lambea Gil" "email" => array:1 [ 0 => "alvarolambea@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Caldú Agud" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Rodríguez Gascón" ] 3 => array:2 [ "nombre" => "V." "apellidos" => "Garayoa Irigoyen" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Neurología, Hospital Universitario Miguel Servet, Zaragoza, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Encefalopatía secundaria a intoxicación por lamotrigina" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Voluntary ingestion of drugs with suicidal intent is more frequent in patients with epilepsy or psychiatric disorders than in the general population.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> In this way, drugs prescribed for those conditions are susceptible to cause intoxication.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Lamotrigine, a broad-spectrum antiepileptic drug (AED), is approved for treating epilepsy (both in monotherapy and in polytherapy) and also bipolar disorder, due to its action as a mood stabiliser.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> It is widely used due to its good tolerability.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> However, given its high toxicity index compared to other AEDs,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">2</span></a> we must be familiar with its pharmacological profile and other possible adverse effects.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a 38-year-old man with personal history of arterial hypertension and migraine. In the previous year and a half, the patient had experienced sudden episodes of loss of consciousness without prodrome or abnormal movements. A brain magnetic resonance imaging scan and long-term video-EEG revealed no pathological findings, despite the clinical events observed. However, he was receiving treatment with lamotrigine at 150<span class="elsevierStyleHsp" style=""></span>mg/12 hours, with limited treatment adherence. He presented no history of using or abusing drugs.</p><p id="par0020" class="elsevierStylePara elsevierViewall">These episodes led to medical leave from work, and given the increasing number of events and the possibility of having to stop work permanently, the patient attempted suicide by taking lamotrigine (total dose of approximately 1000<span class="elsevierStyleHsp" style=""></span>mg). His family found him on the floor, nearly unconscious, and he was transferred to hospital.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Upon arrival, 8 hours after the last time he was seen without symptoms, he presented arterial blood pressure values of 148/70, tachycardia at 110<span class="elsevierStyleHsp" style=""></span>bpm, oxygen saturation of 95%, axillary temperature of 36.2<span class="elsevierStyleHsp" style=""></span>°C, and a blood glucose level of 182<span class="elsevierStyleHsp" style=""></span>mg/dL. The edges of the tongue were bitten and the patient presented nausea and vomiting. Neurological examination revealed somnolence, bradypsychia, and partial orientation; a Glasgow Coma Scale score of 13 points (eye opening: 3; verbal response: 4; motor response: 6); reactive, mildly miotic pupils; dysarthria with no language alterations and intelligible speech; ability to follow instructions; no visual field alterations; and vertical nystagmus in all gaze positions, with a horizontal component. He presented no limitations when performing extrinsic eye movements or involvement of other cranial nerves, and showed preserved muscular balance and sensitivity in the limbs; ataxia predominantly affecting the upper limbs; generalised hyperreflexia with spontaneous and sustained bilateral ankle clonus and bilateral Hoffman sign; bilateral flexor plantar reflex; and no neck rigidity or other sign of meningeal involvement. The patient also presented mild oppressive headache of parietal predominance. The general examination identified no other abnormalities.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Emergency studies revealed metabolic acidosis, with lactate at 8.9<span class="elsevierStyleHsp" style=""></span>mmol/L; isolated leukocytosis (21<span class="elsevierStyleHsp" style=""></span>700<span class="elsevierStyleHsp" style=""></span>cells/mm<span class="elsevierStyleSup">3</span>); normal renal and liver function; calcium and magnesium ions within normal levels; and normal urinalysis results, with negative results in the urine toxicology test. A brain CT scan and baseline EEG study yielded no pathological results, and a lumbar puncture revealed an opening pressure of 22.5<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleInf">2</span>O and cerebrospinal fluid with no alterations.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Awaiting results for the concentration of lamotrigine in the blood (sample extracted 8-12 hours after ingestion), we started fluid replacement therapy to promote renal excretion in the event of intoxication and maintained clinical and haemodynamic monitoring until the drug was eliminated. Telemetry showed no alterations in cardiac conduction or repolarisation, and an isolated episode of fever (37.8<span class="elsevierStyleHsp" style=""></span>°C) with no infectious focus. The patient progressively improved, remaining asymptomatic after 48 hours. Results for blood lamotrigine concentration were 17.2<span class="elsevierStyleHsp" style=""></span>mg/L, leading us to diagnose metabolic encephalopathy secondary to lamotrigine intoxication.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Lamotrigine is a phenyltriazine derivative that acts by inhibiting voltage-gated calcium and sodium channels. It also reduces neuronal glutamate release, which affects the serotonergic pathway, inhibiting serotonin reuptake.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">It presents a bioavailability of 98% and reaches peak concentration (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>) in the 1-3 hours after ingestion.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> The half-life of lamotrigine is approximately 33 hours (22-36<span class="elsevierStyleHsp" style=""></span>h), with considerable variations between individuals<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">3</span></a>; half-life may decrease by as much as 25% in chronically treated patients as the drug induces its own metabolism.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> During its degradation it undergoes hepatic inactivation, with the metabolite finally being excreted by the kidneys. The recommended therapeutic range for patients with epilepsy is 1-4<span class="elsevierStyleHsp" style=""></span>mg/L. However, adverse reactions are rare in patients with concentrations < 10<span class="elsevierStyleHsp" style=""></span>mg/L, and this value has been proposed as the upper bound of the therapeutic range, according to response.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">3</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The main adverse reactions affect the central nervous system and the cardiovascular system, due to the drug's action on the channels responsible for initiating and propagating the action potential in nerves and muscles. Its inhibition of serotonin reuptake would explain the risk of serotonin syndrome. Other reactions include hypersensitivity syndrome with pronounced skin involvement. These side effects have been observed at concentrations from 15.5<span class="elsevierStyleHsp" style=""></span>mg/L, but with no clear correlation between blood lamotrigine concentration and clinical toxicity. Furthermore, the concentrations observed seem to differ in patients ingesting the same amount of the drug<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">3</span></a>; some patients may not present toxic effects despite the overdose.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The most frequent neurological presentations are decreased level of consciousness and ataxia, followed by vertigo, confusion, agitation, dysarthria, nystagmus, headache, seizures, and other findings associated with serotonin syndrome. Cardiac effects, which are less frequent, include sinus tachycardia and QRS and QTc widening, with the subsequent risk of arrhythmia.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">1</span></a> Nausea, vomiting, and exanthema are also frequent.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In the case of our patient, altered level of consciousness and sustained spontaneous clonus may be considered part of a serotonin syndrome, fulfilling the Hunter criteria for this diagnosis,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">4</span></a> in addition to lactic acidosis, slight fever with no apparent focus, and isolated leukocytosis, which normalised in the first 24 hours. He also presented other polymorphic neurological symptoms, particularly nystagmus, ataxia, and dysarthria. In terms of cardiac manifestations, he only presented self-limited sinus tachycardia. Although it was not witnessed, the tongue biting and the limited reactivity at baseline may have been associated with a seizure, which is consistent with the paroxysmal convulsive action of overdoses of certain AEDs.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Our treatment was exclusively symptomatic due to the time elapsed. However, gastrointestinal decontamination is possible when patients are examined early, although previous protection of the airway is essential due to the risk of decreased level of consciousness and presence of seizures. Other treatments used are alkalinisation with sodium bicarbonate, intravenous lipid emulsions, and even haemodialysis, although published experience is limited.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion, our case exemplifies the polymorphic presentation of lamotrigine intoxication. Due to the wide array of neurological symptoms and the association with serotonin syndrome, we consider it a good example to illustrate the adverse effects of a frequently used drug that, in the absence of suspicion, may be life-threatening.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Lambea Gil Á, Caldú Agud R, Rodríguez Gascón D, Garayoa Irigoyen V. Encefalopatía secundaria a intoxicación por lamotrigina. Neurología. 2020;35:439–440.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:4 [ 0 => array:3 [ "identificador" => "bib0025" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety profile of lamotrigine in overdose" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Alabi" 1 => "A. Todd" 2 => "A. Husband" 3 => "J. 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Stromberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s13181-014-0384-5" "Revista" => array:6 [ "tituloSerie" => "J Med Toxicol" "fecha" => "2014" "volumen" => "10" "paginaInicial" => "254" "paginaFinal" => "260" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24515527" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0035" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute lamotrigine overdose: a systematic review of published adult and pediatric cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "B. Alyahya" 1 => "M. Friesen" 2 => "B. Nauche" 3 => "M. Laliberté" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Toxicol (Phila)" "fecha" => "2018" "volumen" => "56" "paginaInicial" => "81" "paginaFinal" => "89" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0040" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "E.J.C. Dunkley" 1 => "G.K. Isbister" 2 => "D. Sibbritt" 3 => "A.H. Dawson" 4 => "I.M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 29 | 0 | 29 |
| 2024 October | 185 | 10 | 195 |
| 2024 September | 186 | 12 | 198 |
| 2024 August | 154 | 8 | 162 |
| 2024 July | 166 | 8 | 174 |
| 2024 June | 151 | 11 | 162 |
| 2024 May | 204 | 10 | 214 |
| 2024 April | 201 | 6 | 207 |
| 2024 March | 243 | 5 | 248 |
| 2024 February | 255 | 12 | 267 |
| 2024 January | 234 | 8 | 242 |
| 2023 December | 149 | 16 | 165 |
| 2023 November | 273 | 24 | 297 |
| 2023 October | 271 | 16 | 287 |
| 2023 September | 190 | 12 | 202 |
| 2023 August | 199 | 7 | 206 |
| 2023 July | 183 | 12 | 195 |
| 2023 June | 140 | 7 | 147 |
| 2023 May | 228 | 8 | 236 |
| 2023 April | 145 | 3 | 148 |
| 2023 March | 230 | 14 | 244 |
| 2023 February | 168 | 10 | 178 |
| 2023 January | 159 | 4 | 163 |
| 2022 December | 124 | 10 | 134 |
| 2022 November | 106 | 10 | 116 |
| 2022 October | 116 | 15 | 131 |
| 2022 September | 114 | 10 | 124 |
| 2022 August | 138 | 13 | 151 |
| 2022 July | 114 | 10 | 124 |
| 2022 June | 91 | 8 | 99 |
| 2022 May | 83 | 22 | 105 |
| 2022 April | 97 | 11 | 108 |
| 2022 March | 93 | 9 | 102 |
| 2022 February | 84 | 3 | 87 |
| 2022 January | 114 | 4 | 118 |
| 2021 December | 76 | 11 | 87 |
| 2021 November | 99 | 8 | 107 |
| 2021 October | 111 | 15 | 126 |
| 2021 September | 103 | 17 | 120 |
| 2021 August | 84 | 7 | 91 |
| 2021 July | 88 | 7 | 95 |
| 2021 June | 77 | 16 | 93 |
| 2021 May | 59 | 12 | 71 |
| 2021 April | 131 | 7 | 138 |
| 2021 March | 76 | 14 | 90 |
| 2021 February | 44 | 13 | 57 |
| 2021 January | 25 | 16 | 41 |
| 2020 December | 20 | 8 | 28 |
| 2020 November | 12 | 5 | 17 |
| 2020 October | 15 | 6 | 21 |
| 2020 September | 10 | 14 | 24 |
| 2020 August | 19 | 14 | 33 |
| 2020 July | 8 | 5 | 13 |
| 2020 June | 7 | 12 | 19 |
| 2020 May | 0 | 1 | 1 |
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