Anticonvulsant Hypersensitivity Syndrome Research Articles

Pharmacokinetic Simulation Study: Exploring the Impact of Clinical Parameters on Lamotrigine for Different Patient Populations with Implications for Liver Function Assessment and Therapeutic Drug Monitoring

Lamotrigine, widely used for managing epilepsy and bipolar disorder, carries potential side effects, including severe anticonvulsant hypersensitivity syndrome (AHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which may lead to hepatotoxicity. Patients with Type 2 Diabetes (TD2) and Non-Alcoholic Fatty Liver Disease (NAFLD) are identified as more susceptible to these adverse reactions. This exploratory analysis aims to identify clinical parameters influencing lamotrigine pharmacokinetics across diverse populations, shedding light on toxicity and therapeutic drug monitoring (TDM) considerations. Starting with a retrospective analysis of 41 lamotrigine-treated patients at Hospital Santo António reveals changes or deviations from normal levels in various blood parameters and significant correlations between these parameters. Serum level changes, including creatinine, albumin, gamma-glutamyl transferase, total bilirubin, and Vitamin B12, are observed, with strong negative correlations between Vitamin B12 and creatinine. Then, we used GastroPlus and DILIsym to explore the impact of clinical parameters on lamotrigine for different patient populations. We constructed a Physiologically Based Pharmacokinetic (PBPK) model for lamotrigine in GastroPlus, based on ADMET predictions and data from the literature, to simulate the pharmacokinetic variability of lamotrigine in different populations, and we visualized the impact of increasing lamotrigine dose on its plasma concentration–time profiles (200 mg, 400 mg, 600 mg, 1200 mg) and reduced bioavailability. At higher doses, it is possible that the saturation of metabolic pathways leads to the formation of toxic metabolites or intermediates. These metabolites may exert inhibitory effects on drug-metabolizing enzymes or disrupt normal physiological processes, thereby impeding the drug’s clearance and potentially lowering its bioavailability. In DILIsym, we investigated lamotrigine’s DILI potential for individuals with diabetes and NAFLD. The results demonstrated an increased risk, emphasizing the need for careful monitoring. This study underscores the importance of understanding lamotrigine’s pharmacokinetics for tailored treatment decisions, improved outcomes, and minimized adverse reactions.

Dermatological adverse drug reactions with particular reference to Steven-Johnson syndrome and toxic epidermal necrolysis

Background: Drug therapy is an inevitable cause of cutaneous adverse reactions. Aims and Objectives: The primary aim was to identify the incidence and magnitude of various dermatological adverse reactions including Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Moreover, secondary aim was to quantify the risks associated with the use of specific medications. Materials and Methods: A prospective and hospital-based study was conducted in the department of dermatology SMHS hospital on hospitalized cases of cutaneous adverse drug reactions (CADRs). Informed consent was sought and reactions were reported on validated questionnaire based on adverse drug reaction (ADR) monitoring form provided by Central Drug Standard Control organization Ministry of Health and Family Welfare, Government of India. These dermatological reactions were assessed for the clinical pattern, causative agents, and prognosis. The WHO-Uppsala Monitoring centre system for standardized case was used for causality assessment of all cases identified. Results: A total of 101 hospitalized patients with varied dermatological ADRs were reported during the study period. Cases were found more in females (n=75, 74.25%) than in males (n=26, 25.75%). CADRs that were reported in our study were exanthematous rash, fixed drug eruptions, urticarial rashes, SJS, TEN, urticarial vasculitis, anticonvulsant hypersensitivity syndrome, erythema multiforme, contact dermatitis, exfoliative dermatitis, mucosal hyperpigmentation, and nail pigmentation, respectively. After a meticulous drug history, the drugs implicated in causing the cutaneous reactions were anticonvalscents such as phenytoin, carbamazepine, lamotrigine, and phenobarbitone. Other drugs identified were non-steroidal anti-inflammatory drugs such as oxicam, antibiotics such as sulfasalazine, cefixime, cefpodoxime, amoxicillin, fluoroquinolones such as levofloxacin and ciprofloxacin, chemotherapeutic agents such as cyclophosphamide, 5FU, and hydroxurea. Conclusion: The present study concluded that skin is most common target for ADRs. Drug-induced cutaneous reactions can be as simple as a mild rash to rare life-threatening SJS and TEN. Moreover, certain group of patients is at increased risk for developing CADR’s as women are more susceptible than men.

A CASE REPORT ON WELL KNOWN BUT HAS TO BE REPORTED ADVERSE EFFECT OF PHENYTOIN-INDUCED RASH AND ASSESSMENT OF ITS SEVERITY BASED ON ADVERSE DRUG REACTION REPORTING SCALES

Phenytoin is an aromatic antiepileptic drug, commonly used for the purpose of treating generalized tonic clonic and partial seizures. The drug has been known to cause hypersensitivity reaction, which can be life-threatening by involving internal organs, and is referred as anticonvulsant hypersensitivity syndrome. The treatment in such cases is the immediate discontinuation of the agent causing the reaction and replacing the treatment with other non-aromatic anticonvulsant agent. This case report presents an adverse drug reaction and occurs within 1 week of starting the treatment, a well-known but has to report this adverse effect.

Idiosyncratic reaction of topiramate in a Maine Coon cat

AbstractA 1.5‐year‐old Main Coon neutered male cat was presented for cluster epileptic seizures. The cat was first treated with phenobarbital; however, it had to be discontinued due to anticonvulsant hypersensitivity syndrome. Topiramate was then initiated. Shortly thereafter, a persistent neutropenia developed and the topiramate was stopped. The epileptic seizures are now adequately controlled by levetiracetam extended release 500 mg every 12 hours and the neutropenia had resolved. This is the first report of adverse drug reaction of topiramate in cats.

Suspected phenobarbital-induced anticonvulsant hypersensitivity syndrome in a cat

A six-month-old, uncastrated, male American shorthair cat was diagnosed with most likely primary epilepsy by history, laboratory examination and MRI. After 10 days of treatment with phenobarbital and levetiracetam, the...

A 14-year-old female with fever, rash, lymphadenopathy, and pancytopenia: a case report

BackgroundAnticonvulsant hypersensitivity syndrome is a rare adverse drug reaction associated with aromatic anticonvulsant drugs. This syndrome can range from mild cutaneous rash to drug reaction with eosinophilia and systemic symptoms that include fever, rash, lymphadenopathy, pancytopenia, and involvement of multiple internal organs. We aimed to report this case in the literature and make physicians aware of the uncommon symptoms of this syndrome when they prescribe antiepileptic medications in particular.Case presentationA 14-year-old Middle Eastern female patient from Iran with free past medical and allergic history was admitted to hospital because of fever, rash, lymphadenopathy, and pancytopenia after taking anticonvulsants due to new-onset seizure. High fever and cutaneous rash along with lymphadenopathy following administration of anticonvulsant medications that could not be explained by other causes alerted the physician to the possibility of this syndrome. Our investigation revealed no further diagnosis and 1 week after discontinuation of the drugs, her symptoms were resolved. Anticonvulsant hypersensitivity syndrome is a diagnosis of exclusion and immediate discontinuation of the suspicious drugs is necessary. Hence, early recognition can prevent permanent multiorgan damage.ConclusionsChlorpheniramine as a simple treatment was provided for this syndrome.

Revisión del síndrome de hipersensibilidad a anticonvulsivantes, a propósito de un caso clínico complejo

Anticonvulsant hypersensitivity syndrome (AHS) is a rare (incidence: 1 in 1,000 to 1 in 10,000 patients exposed to anticonvulsants), but potentially serious (approximate mortality rate: 10%) entity. We present the case of a patient diagnosed with left focal epilepsy due to post-radiotherapy leukoencephalopathy with several episodes of generalised rash after the introduction of antiepileptic treatment. After several episodes, the patient is diagnosed with Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome. He was then treated with a benzodiazepine to control the seizures until resolution of rash and eosinophilia.AHS should be suspected in all patients under antiepileptic treatment who present: fever, rash, lymphadenopathies and increased transaminases. In this situation, the drug should be suspended. Knowledge of this entity can avoid fatal outcomes.

Phenobarbital-induced anticonvulsant hypersensitivity syndrome in a cat.

In this study, we document a case of phenobarbital-induced anticonvulsant hypersensitivity syndrome (AHS), which has been rarely reported in veterinary medicine. A 2-year-old, 5.4 kg, neutered male Russian Blue cat was diagnosed with idiopathic epilepsy and started on phenobarbital treatment. Eight days after initiation of phenobarbital treatment, the cat showed tachypnea and hyperthermia. CBC and serum biochemistry were unremarkable. However, the patient showed high serum amyloid A (SAA). On abdominal ultrasonography, generalized enlargement of abdominal lymph nodes and splenic multiple hypo-echoic nodules, which were consistent with reactive lymphadenopathy were found. The cat was diagnosed with AHS, and phenobarbital was discontinued. After 10 days of cessation, the patient had normal SAA, and clinical signs were resolved.

Anticonvulsant hypersensitivity syndrome or drug rash with eosinophilia and systemic symptoms (DRESS) induced by anticonvulsants

Anticonvulsant hypersensitivity syndrome or drug rash with eosinophilia and systemic symptoms (DRESS) induced by anticonvulsants

Anticonvulsant Hypersensitivity Syndrome Secondary to Carbamazepine

Anticonvulsant hypersensitivity syndrome (AHS) is a potentially fatal multiorgan drug reaction that presents with various cutaneous eruptions. There is a genetic predisposition to such reactions. We present a young woman with AHS due to carbamazepine that presented as an atypical erythema multiforme with elevated liver enzymes.

Anticonvulsant hypersensitivity syndrome

AbstractHere a rare but clinically important adverse reaction to anticonvulsant medication is presented in the form of an original case report. This report discusses the epidemiology, pathophysiology and management of anticonvulsant hypersensitivity syndrome (AHS). AHS is estimated to occur in one in every 1000–10 000 exposures. However, its true incidence is unknown due to variable presentations. Given the frequent use of anticonvulsants and the potentially fatal complications of this adverse event, it is important all clinicians are aware of this presentation. Potential for cross‐reactivity must be considered when selecting anticonvulsant drug therapy in a patient who has a history of AHS. Clinical pharmacists play a vital role in identifying potential adverse reactions and advising on their management.

Lamotrigine-Induced Disseminated Intravascular Coagulation With Anticonvulsant Hypersensitivity Syndrome: A Case Report

Received January 15, 2016; revised February 24, 2016; accepted February 26, 2016. From Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan (MT, HI, TS); Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine, Akita, Japan (AT, MM). Send correspondence and reprint requests to Masahiro Takeshima, M.D., Ph.D., Department of Neuropsychiatry, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita-shi, Akita 010-8543, Japan; e-mail: m. takeshima@med.akita-u.ac.jp & 2016TheAcademy of PsychosomaticMedicine. Published by Elsevier Inc. All rights reserved. Dr Shimizu has received research support from KAKEN (15K09821). Dr Manabe has received research support from KAKEN (26461679). Case Report

Carbamazepine Induced Ebstein-Barr Virus Reactivation: A Rare Manifestation of Anticonvulsant Hypersensitivity Syndrome

Carbamazepine (CBZ) is an antiepileptic drug which has multiple mechanisms of action including stabilization of the inactivated stage of the voltage-gated sodium channels, potentiating gamma-amino butyric acid (GABA) receptors as a GABA antagonist, as well as the serotonin releasing affect. It is effective in neuropathic pain syndromes such as post-herpetic neuralgia and trigeminal neuralgia, as well as epilepsy. We presented a 29-year-old female patient with the diagnosis of trigeminal neuralgia (TN) who experienced a reactivation of the latent Ebstein-Barr Virus (EBV) infection in terms of anticonvulsant hypersensitivity syndrome after CBZ use, who gave her approval to publish her data. Since the clinical and serological findings of EBV re-infection resolved after the discontinuation of the drug, this clinical and serological manifestation was attributed to CBZ. Since common side-effects of CBZ are drowsiness, dizziness, headaches, skin reactions, cognitive dysfunctions, we reported an activation of EBV infection due to CBZ consumption as a rare side-effect of the drug.

Carbamazepine induced anticonvulsant hypersensitivity syndrome

Anticonvulsant hypersensitivity syndrome (AHS) is a potentially fatal drug-induced, multi-organ syndrome. The syndrome has been reported with anticonvulsants such as carbamazepine, phenytoin, phenobarbitone, and lamotrigine. A 17-year-old female who presented with papules and desquamation all over was diagnosed with AHS. She gave a history of fever, earache, peripheral edema, and erythematous papular eruptions 3 days prior. She gave a history of carbamazepine treatment since 15 days for generalized tonic-clonic seizures. On examination, there was cervical lymph node enlargement without tenderness. Investigations revealed elevated absolute eosinophil count at 550/mm 3 and positive C-reactive protein tests. Carbamazepine was immediately withdrawn. Symptomatic treatment was administered, and resolution of the symptoms was observed. In this case, causalty assessment using Naranjo adverse drug reaction probability scale showed that carbamazepine was a probable cause for the AHS (Score - 7).

Anticonvulsant hypersensitivity syndrome associated with carbamazepine administration: Case series

Hypersensitivity reactions are common adverse drug reactions (ADRs) associated with antiepileptics. Carbamazepine is one of the routinely prescribed drugs for the treatment of epilepsy and neuropathic pain. ADRs due to carbamazepine range from mild maculopapular rash to severe anticonvulsant hypersensitivity syndrome (AHS). AHS is the triad of fever, rash, and internal organ involvement occurring 1-8 weeks after exposure to an anticonvulsant (1 in 1,000 to 10,000 exposures). Spontaneously reported three cases of AHS-drug hypersensitivity reactions induced by carbamazepine are discussed here. Seven to ten days after starting therapy, patients developed maculopapular skin rashes, fever and liver or kidney involvement. The causal relationship between drug and ADR was found to be ‘certain’ in one case and ‘probable’ in other two cases with both WHO-UMC and Naranjo causality assessment scale. All the three cases show category 4a according to Hartwig's severity scale as ADR was the cause for hospital admission. On assessing preventability of ADRs by modified Schumock and Thorntons’ scale, one case was falling into category of ‘definitely preventable’ and other two were ‘not preventable’. AHS is rare but serious reaction with carbamazepine which requires vigilant monitoring by physicians to avoid major consequences.

Injudicious use of anticonvulsants leading to life-threatening event

Epilepsy is common childhood problem and advent of newer anticonvulsant drugs has led to injudicious uses. Anticonvulsant hypersensitivity syndrome (AHS) has been previously described developing secondary to aromatic anticonvulsants such as phenytoin and carbamazepine. AHS developing secondary to non-aromatic anticonvulsant agents such as lamotrigine (LTG) and valproic acid (VPA) is rare. We present a case of an 11-year-old girl with known epilepsy on VPA, LTG and carbamazepine therapy that developed fever with the clinical pattern of Steven-Johnson syndrome/toxic epidermal necrolysis requiring pediatric intensive care. Judicious use of anticonvulsant should be done in appropriate dose especially in pediatric population and when used in combination to prevent AHS like life-threatening event.

Ketamine Continuous Infusion for Refractory Status Epilepticus in a Patient With Anticonvulsant Hypersensitivity Syndrome

Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis.

Levetiracetam following liver and kidney failure in late-onset anticonvulsant hypersensitivity syndrome

Anticonvulsant hypersensitivity syndrome is an adverse drug reaction usually occurring from 1 to 8weeks after exposure to antiepileptic drugs. It can threaten life by affecting the liver, kidneys, central nervous system or lungs. We present a 47-year-old patient treated with phenytoin, lamotrigine and clobazam for 7years. He presented with hepatic and renal failure in relation to this syndrome demonstrated by renal biopsy. Prognosis was excellent due to an early diagnosis leading to cessation of the causative agents. Levetiracetam was started with a good response.

Nevirapine-induced rash with eosinophilia and systemic symptoms (DRESS)

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse reaction commonly occurring with antiepileptic agents. It was earlier referred to by various names such as dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome. It is characterized by the triad of fever, skin eruption, and systemic involvement. DRESS syndrome has also been reported with a number of other drugs including allopurinol, minocycline, terbinafine, sulfonamides, azathioprine, dapsone, and antiretroviral agents such as abacavir and nevirapine. We describe a rare case of nevirapine-induced hypersensitivity syndrome that was successfully treated with oral steroids.

Phenytoin Hypersensitivity Syndrome Associated with Glutathione S-Transferase, N-Acetyltransferase, Cytochrome P450 Polymorphisms

Observation: The anticonvulsant hypersensitivity syndrome is rare complication that occurs with the use of antiepileptic medications. All of the aromatic anticonvulsant drugs are metabolised by the cytochrome P-450 enzyme to a common arene oxide metabolite that is normally detoxified by epoxide hydrolase. A genetically determined inability to detoxify the toxic metabolites due to a defect in the enzyme epoxide hydrolase has been observed in patients with this hypersensitivity syndrome. We present a patient with severe phenytoin-induced hypersensitivity syndrome associated with glutathione S-transferase, N-acetyltransferase, and cytochrome P450 polymorphisms.