Causality Assessment Score Research Articles

Acute Dystonia Associated with Low-Dose Aripiprazole in a Male Child: A Case Report

Aripiprazole is a newer anti-psychotic agent with low liability for Extrapyramidal Symptoms (EPS). Acute dystonia develops due to a lack of dopamine, resulting in a relative overactivity of cholinergic neurons. In the past, cases of Aripiprazole-induced acute dystonia have been reported more frequently among adults than children. Here, the authors present a case in which acute dystonia developed at a very low dose (2 mg) of Aripiprazole. The case involves a 10-year-old boy diagnosed with Oppositional Defiant Disorder (ODD) who exhibited aggressive behaviour and irritability. Aripiprazole (2 mg) was initiated for treatment, but after five days, the patient developed excessive sleepiness, slurred speech, oculogyric crisis, and torticollis, indicative of acute dystonia. To rule out any organic causes, a detailed assessment and investigations were conducted, including complete blood counts, liver and kidney function tests, serum calcium, electrolytes, ceruloplasmin, blood copper levels, slit-lamp examination for Kayser-Fleischer ring, and electroencephalography, which did not reveal any significant organic conditions. Aripiprazole was discontinued, and Promethazine was administered. The dystonia score on the Unified Dystonia Rating Scale (UDRS) decreased from 10 to 0 in 5 days, indicating complete resolution of dystonia. Naranjo’s causality assessment score was seven, reflecting the probable association of aripiprazole with acute dystonia. This case emphasises the importance of monitoring for adverse reactions to anti-psychotic medications, particularly in paediatric patients, and the need for prompt recognition and management of adverse effects to ensure patient safety and treatment efficacy. To the best of our knowledge, this is the first case report of acute dystonia in a child at such a low dose of Aripiprazole. Clinicians should be vigilant for the emergence of such significant adverse effects of commonly used drugs.

Acute generalized exanthematous pustulosis induced by duloxetine

AbstractDuloxetine is a serotonin and norepinephrine reuptake inhibitor. Some rare duloxetine‐induced hypersensitivity skin reactions have been reported. We report a case of acute generalized exanthematous pustulosis potentially induced by duloxetine. Skin pustules appeared 8 days after the introduction of duloxetine. Treatment with topical clobetasol propionate led to gradual remission of the lesions. As there are no cases of duloxetine‐induced acute generalized exanthematous pustulosis(AGEP) in the literature, we did a research in the World Health Organization (WHO) pharmacovigilance database (21 March 2022) and found three cases of duloxetine‐induced AGEP. The French causality assessment score for our case of duloxetine‐induced AGEP was 15 (C2S3). The Naranjo score was 7, indicating a possible correlation between AGEP and the use of duloxetine. This was consistent with the WHO causality score. We inform clinicians of the possibility of AGEP following therapy with duloxetine.

Skin Rash and Mild Bruising: Is Montelukast a Safe Drug?

Montelukast is one of the commonly used drugs in asthma patients. It is prescribed along with inhalational corticosteroids. Although a relatively safe drug, there is a probability of occurrence of skin rashes and skin bruising. Authors present a case report of a 64-year-old chronic asthmatic woman, reporting widespread erythematous eruptions with mild skin bruising and generalized pruritus mostly affecting her lower abdomen and upper extremities. The rash appeared 28 days after introduction of montelukast (10 mg OD). The physician excluded other attributable factors such as trauma, autoimmune disorders such as Churg-Strauss syndrome, and food allergy. Reappearance of rashes after montelukast introduction and complete resolution of the skin rashes after discontinuing it confirms montelukast as offending drug. Naranjo causality assessment score also revealed a “certain/definite” relationship to the montelukast. Long-term safety of montelukast needs to be reviewed by prescribing physicians to prevent adverse reaction.

Amoxycillin-clavulanic Acid Induced Stevens Johnson Syndrome: A Pediatric Case Report

Stevens Johnson Syndrome is an unlikely, lethal, severe skin and mucosal hypersensitive reaction of delayed type, identified by detachment of epidermis, necrosis of mucosa with stomatitis and purulent conjunctivitis requiring prompt medical intervention. Drugs like antibiotics, anticonvulsants and oxide inhibitors are the vital cause of developing Stevens Johnson syndrome. A 12 year old female patient was admitted in pediatric department with the chief complaints of oral lesions on the bilateral buccal mucosa and hard palate causing difficulty in opening mouth and swallowing since 10 days. Past medical history revealed that the patient had fever and sore throat and was prescribed tablet amoxyclav (amoxicillin – clavulanic acid) by a local medical practitioner, after that patient developed ulcer in the buccal cavity and around the lips. The patient was managed with cephalosporin antibiotic (ceftriaxone), betadine mouthwash, candid ointment, nutritional supplements and systemic steroids (dexamethasone). Naranjo causality assessment score was 6 in our patient and amoxicillin clavulanic acid induced Stevens Johnson syndrome was probable and moreover on severity assessment by Hartwigs Severity Assessment Scale the severity level for the suspected adverse drug reactions was 5 therefore amoxicillin clavulanic acid induced Stevens johnson syndrome was a severe adverse drug reaction. Early detection of symptoms of Stevens johnson syndrome followed by prompt withdrawal of offending drug and timely management can improve the clinical condition of patients. Key words: Amoxicillin - clavulanic acid, Hartwigs Severity Assesment Scale, Stevens Johnson Syndrome, Hypersensitivity reaction, Naranjo Causality Assessment.

ISOPROPYL ALCOHOL (70%)-BASED HAND SANITIZER-INDUCED CONTACT DERMATITIS: A CASE REPORT AMID COVID-19

Indiscriminate use of alcohol-based hand sanitizers during the coronavirus-19 pandemic has led to adverse effects on the skin across the globe. We present the case of a 12-years-old child, who developed a skin rash on the dorsal aspect of the hands with overapplication of 70% isopropyl alcohol-based hand sanitizer. On examination, inflamed dark-colored skin with itching was noticed.  Based on the history and examination, a diagnosis of “Isopropyl alcohol-based sanitizer-induced irritant contact dermatitis” was made. The application of offending sanitizer was immediately stopped. An improvement was seen 2 weeks after the application of topical corticosteroids and oral antihistamines. No re-challenge was subjected to the child. The Naranjo causality assessment score of six suggested probable association of adverse effect with the use of 70% isopropyl alcohol. It can be concluded that alcohol-based hand sanitization to be reserved for outdoor use, whereas only soap and water should be promoted to be used at home for sanitizing hands. The risk of adverse reactions can be minimized by following the manufacturer’s instructions and reducing the frequency of use of single hygiene products.

2.6 CATATONIA AND AUTOIMMUNE CONDITIONS IN CHILDREN AND ADOLESCENTS: A DIAGNOSTIC AND THERAPEUTIC CHALLENGE

Pediatric catatonia is a rare and life-threatening syndrome. Approximately 20 percent of juvenile catatonia is associated with such organic causes as genetic, neurometabolic, and autoimmune disorders. Specific treatments are available for some of these conditions and can drastically improve catatonic symptoms if high-dose benzodiazepines or ECT are insufficient. Systemic autoimmune disorders (lupus, Hashimoto encephalopathy, anti-N-methyl-d-aspartate [anti-NMDA], and anti-gamma-aminobutyric acid [anti-GABA] autoimmune encephalitis) are likely to include catatonia associated with other severe mental illness symptoms (psychosis, mania). Some autoimmune disorders may occur in the context of genetic disorders. Autoantibody-negative but probable autoimmune encephalitis may also be associated with these symptoms. Catatonia may be a marker of a more severe and resistant form of autoimmune encephalitis. To facilitate decision making, we formulated a causality assessment score (CAUS) using a stepwise approach and an immunosuppressive therapeutic challenge. Our objectives were to validate the CAUS and define its threshold, retrospectively, for an accurate distinction between organic catatonia and nonorganic catatonia and specifically between autoimmune catatonia and nonorganic catatonia.

Case report on Fluconazole Induced stevens -Johnson Syndrome

Stevens-Johnson syndrome (SJS) is a rare cutaneous reaction characterised by mucosal erosions and epidermal detachment of about less than 10% of the total area of body skin. The incidence of SJS is approximately 1–6 cases per million person-years. The incidence of fluconazole induced SJS is less than 1%. Here the patient came with complaints of scaly lesions over chest and axilla following which he was started on topical antifungals (Lulliconazole) and antihistamines with the suspicion of Tinea versicolor. Though few lesions resolved on treatment, the patient later developed a small scaly macule over the left upper arm. Thus the patient upon further evaluation was given a stat dose of Tablet Fluconazole 400mg. Following this, the patient developed swelling of lower lips and tip of the glans and erythema over palms. This was later confirmed as Stevens-Johnson syndrome. The reaction was suspected to have occurred in association with Fluconazole. Fluconazole had a probable causal relationship with Stevens Johnson Syndrome as per ALDEN Algorithm in the EuroSCAR study. As per the Naranjo ADR probability scale, the causality assessment score for this reaction was found to be 5 which indicates a probable causal relationship. Clinicians must be more vigilant while prescribing Fluconazole by conducting regular monitoring of such patients and carrying out early diagnosis of such reactions.

Tramadol withdrawal psychosis.

Sir, Tramadol is a synthetic 4-phenyl-piperidine analog of codeine, and it is effective in mild-to-moderate analgesia. Tramadol acts on μ-opioid receptor mainly and to a lesser extent on δ-opioid receptor and κ-opioid receptor. It also has action as a serotonin and norepinephrine reuptake inhibitor.[1] In addition to typical withdrawals of opiate, tramadol can also have atypical withdrawals in the form of anxiety, paranoia, depersonalization, derealization, and auditory hallucinations.[1] Tramadol has relatively less potential for abuse and dependency than morphine.[2] In literature, there is handful of case reports of psychosis emerging from tramadol withdrawal which were managed with antipsychotic and without antipsychotic.[34] Here, the authors have reported a case of tramadol withdrawal having predominant auditory hallucinations and responded to the management of opioid withdrawals without use of antipsychotic. CASE REPORT A 42-year-old male presented with acute onset of symptoms of aggressive behavior, difficulty in sleeping, self-muttering, severe and diffuse leg pain for the past 3 days. The patient accepted that he could hear the voices of his demised father and grandfather. He would hear these voices 8–10 times throughout the day, from outer objective space. The patient had a history of opioid dependence and was treated with tablet tramadol. However, he continued to use tablet tramadol 50 mg, 5–10 tablets per day in a dependent fashion continuously for the last 3 years, and the last dose was 36–48 h before onset of current complaints. There is no history of delirium or seizure and no history of psychiatric illness. General physical examination and neurological examination were within normal limits. Mental status examination revealed second-person auditory hallucinations, and higher mental functions were within normal limits and absent insight. All routine blood investigations and contrast-enhanced computed tomography of the head were within normal limit. Urine screening with poly-kit for substance was positive for tramadol (>100 ng/ml). However, it was negative for benzodiazepines and cannabis. Baseline clinical opiate withdrawal scale (COWS)[5] score was 19 and subjective opiate withdrawal scale[6] was 30. The patient was managed for opioid withdrawal with tablet clonidine, benzodiazepines, and painkillers and the COWS score came down to 6 within a week. Auditory hallucination disappeared completely in 2 weeks of abstinence. Naranjo scale for causality assessment score came out to be 9 which suggests a definite correlation.[7] The patient is coming for follow-up and maintaining abstinent from tramadol and free from auditory hallucination. Since tramadol binds to opioid μ-receptors, it is expected that its cessation after chronic use causes withdrawal symptoms and signs like the other opioid drugs. However, there are instances in which tramadol withdrawal symptoms are similar to serotonin reuptake inhibitor withdrawal symptoms.[18] This has a direct correlation to tramadol's mechanism of action as a serotonin and norepinephrine reuptake blocker, which explains the auditory hallucinations in the index case. Index case was managed without use of antipsychotic which is similar to another case report[3] but contrary to the case report by Lakhal et al.[4] Hence, atypical withdrawal of tramadol can appear in the form of psychosis, and one should manage such patients solely by treating the opioid withdrawal and do not require the addition of an antipsychotic. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature.

Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

A causality algorithm to guide diagnosis and treatment of catatonia due to autoimmune conditions in children and adolescents

ObjectivesPediatric catatonia is a rare and life-threatening syndrome. Around 20% of juvenile catatonia is associated with organic condition (Consoli et al., 2012). Autoimmune conditions represent a diagnostic and therapeutic challenge since specific antibodies can be missed. To facilitate decision making, we recently formulated a causality assessment score (CAUS) using a stepwise approach and an immunosuppressive therapeutic challenge (Ferrafiat et al., 2016). Our objectives were to validate retrospectively CAUS and to define its threshold for an accurate distinction between organic catatonia and non-organic catatonia, and specifically between autoimmune catatonia and non-organic catatonia. MethodTo obtain a sufficient number of cases with organic catatonia, we pooled two samples (N=104) – one from a child psychiatry center, the other from neuro-pediatrics center – expert in catatonia and autoimmune conditions. Organic conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. Given the binary classification needs, we used receiver operating characteristic (ROC) analysis (Peacock and Peacock, 2010) to calculate the best classification threshold. ResultsThe cohort included 67 cases of non-organic catatonia and 37 cases of organic catatonia. ROC analysis showed that the CAUS performance in discriminating both organic catatonia vs. non-organic catatonia, and autoimmune catatonia vs. non-organic catatonia was excellent (Area Under the Curve=0.99). In both analyses, for a CAUS threshold≥5, accuracy equaled to 0.96. ConclusionRegarding juvenile catatonia, the use of the CAUS score algorithm combining a therapeutic challenge and a threshold≥5 may help to diagnose and treat autoimmune conditions even without formal identification of auto-antibodies.

Catatonia and Autoimmune Conditions in Children and Adolescents: Should We Consider a Therapeutic Challenge?

Catatonia as a result of autoimmune conditions offers new therapeutic opportunities for patients that child and adolescent psychiatrists should consider. However, the diagnosis is sometimes challenging when an autoimmune signature is not identified. In this study, we aim to summarize seven cases from a 20-year series of 84 youths with catatonia, including three cases that represented a diagnostic challenge because of the absence of positive autoimmune testing. Immunosuppressive/modulatory treatment improved catatonic and psychotic features in all cases. To facilitate treatment decision-making, we propose a causality assessment score and a treatment algorithm, which may help clinicians consider whether an autoimmune condition is associated with catatonia.

Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury

BackgroundIdiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in...

Drug-induced immune thrombocytopenia: A descriptive survey in the French PharmacoVigilance database

The aim of this survey was to describe drug-induced immune thrombocytopenia (ITP) reported in the French PharmacoVigilance database (FPVD) and to discuss the drugs involved. The request to the FPVD used the seven most accurate diagnosis codes to identify ITP. The study was restricted to cases reported from 2007 to 2010 and at least “possible” according to the French causality assessment score. We then described the population's characteristics, the drugs involved, the clinical symptoms, and the course of ITP. For each drug, we estimated the causality assessment score developed by George for drug-induced ITP. We included 59 drug-induced ITP. Among them, 45.8% were post-vaccinal: they mainly occurred in children (median age: 16 years). Main vaccines were diphtheria–tetanus–poliomyelitis (DTP, 9 cases), influenza (n = 8) and measles, mumps, and rubella (MMR, n = 7). Regarding the 33 non-vaccinal cases: some drugs are well-known as triggering ITP (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), n = 5; abciximab, n = 4, acetaminophen, n = 2). Other drugs inducing ITP were involved, like serotonin reuptake inhibitors or bevacizumab. Mean age was 57.1 ± 21.7; 60.6% of the patients were male and 25% had autoimmune antecedents. Among the 55 suspected drugs, three were classified as “probable” and 28 as “possible” according to George scale. In both vaccinal and other cases, median delay was 14 days, median platelet value at nadir was < 10 000 µl−1 and hemorrhagic symptoms were rarely severe (only 2 gastrointestinal hemorrhages). Specific treatment was introduced in 45 (76.3%) patients. Five drug-induced cases led to chronicity. Among them, ezetimibe was suspected in two reports. In the FPVD, DTP, MMR, and influenza vaccines are the most often reported vaccines inducing ITP, perhaps because of their wide use. Our study confirmed that NSAIDs, abciximab, and acetaminophen frequently trigger ITP. It also allows to suspect other drugs like serotonin reuptake inhibitors or bevacizumab. Ezetimibe may induce chronic ITP. Drug-induced ITP is rarely severe. Finally, this study also shows that chronicity of ITP does not rule out the possibility of an iatrogenic cause.

An Overview of Drug-induced Liver Injury

Drug-induced liver injury (DILI) represents liver damage from various therapeutic drugs, herbal medicines, plants, or nutritional supplements. DILI is the most frequent reason for drug withdrawal and may lead to acute liver failure, liver transplant, or fatality. Its pathophysiology includes direct hepatotoxicity and idiosyncratic immune reactions. The diagnosis requires serum alanine aminotransferase or alkaline phosphatase elevation > 2-fold above the upper limit of normal, a causality assessment score ≥ 3, and exclusion of other possible causes of liver disease. While early diagnosis and drug discontinuation are imperative to recovery, continued drug exposure may lead to serious undesirable outcomes.

Chimioprophylaxie de longue durée à la méfloquine : étude des effets indésirables

To estimate the relative frequency of reported adverse drug reactions during the malaria chemoprophylactic period of the Moroccan contingent in Democratic Republic of Congo (DRC). The transversal survey involved all military personnel of the Moroccan contingent and was carried out using a questionnaire to be filled out by a multidisciplinary medical team. It was performed in all the military sites and the advanced posts accessible during the period of the study. The study involved 362 male military subjects. Ninety-four adverse drug reactions were described: neuropsychiatric (anxiety, irritability, dizziness...) [n=76], digestive (anorexia, diarrhea, nausea...) [n=42], cardiovascular (tachycardia, palpitation, precordialgia...) [n=5], musculoskeletal (arthralgia, cramps) [n=4], cutaneous (redness, purpura) [n=2], and other (n=13). No "unexpected" or "serious" adverse drug reaction was reported. The causality assessment score was determined in 94 cases. Two of these reports were rated "likely", 12 "possible" and 80 doubtful. More adverse drug reactions were reported by subjects having medical and paramedical functions. During our study, mefloquine induced adverse drug reactions in a quarter of the treated subjects. Most of the adverse drug reactions were neuropsychiatric. No "serious" adverse drug reactions were reported underlying the interest of its use, even for long-term chemoprophylaxis.

Adverse Drug Reactions to Local Anaesthetics

Some evidence of significant patient morbidity or mortality has been reported with the use of local anaesthetics (LAs). The most common adverse drug reactions (ADRs) to LAs are neurological (seizures) and cardiac (conduction disorders, cardiac arrests). However, little is known about other adverse drug reactions (ADRs). The aim of this study was to characterize the safety profile of the LAs lidocaine, bupivacaine, mepivacaine, ropivacaine and levobupivacaine. We studied ADRs occurring between 1995 and 2006 reported to the French Pharmacovigilance System. For each ADR, we noted type of LA, type of ADR, its seriousness and the causality assessment score. We identified 727 reports (corresponding to 0.3% of patients in the database) in which LA was suspected as the cause of 1157 different ADRs. Sixty-one patients (8.7%) were children aged<18 years. Lidocaine (36.0%) and bupivacaine (35.4%) were the LAs most often involved. The most frequently reported ADRs were failure of the block (27.7%), followed by neurological (22.1%), allergic (19.4%) and cardiovascular (15.3%) complications. Eight patients died. Spinal anaesthesia performed with bupivacaine represented 90% of failed blocks. Seizures were the most frequent neurological complications, leading to death in four cases. Twenty-two of 111 cardiovascular complications were cardiac arrest (three of which were fatal). To our knowledge, this is the first analysis of safety profiles of LAs in a non-selected population, using data collected in a pharmacovigilance database. The present study confirmed the frequency and seriousness of both neurological and cardiovascular complications. Other less well documented ADRs were identified, such as spinal anaesthesia failures with bupivacaine and allergic reactions following LA injections.

Accuracy of a Pharmacovigilance Algorithm in Diagnosing Drug Hypersensitivity Reactions

This study was performed to evaluate the diagnostic accuracy of a pharmacovigilance algorithm in patients with 1 or more histories suggestive of drug hypersensitivity. We performed a retrospective analysis of a clinic case series. We analyzed patients with suspected clinical reactions of drug hypersensitivity. Patients with severe skin reactions were excluded. Patients with history of drug allergy were subjected to additional testing to validate this history. Following a detailed clinical history, skin tests were performed. If skin tests were not available or validated, drug provocation tests were conducted. Assessment of causality was established by an investigator unaware of drug testing results using a pharmacovigilance algorithm that was then compared with the final diagnosis. A total of 677 consecutive patients with 1001 reactions were analyzed. No score could be given because of the absence of 1 of the criteria required for 204 reactions (20.4%). For 720 reactions (71.9%), a dubious causality assessment score was given. Drug hypersensitivity was confirmed by drug testing in 175 reactions (17.5%) and eliminated in 826 reactions (82.5%). Sensitivity of the algorithm was 10.3% and specificity was 76.9%. Although there were 1.7% false-positive scores, there were no false-negative scores. The logistic regression that was performed to look for independent clinical risk factors linked to the drug hypersensitivity diagnosis found 3 parameters: likely causality assessment score, drug reintroduction in clinical history, and delay between reaction and last drug intake of less than 1 hour. A pharmacovigilance algorithm is not accurate for the diagnosis of drug hypersensitivity reactions and cannot replace drug allergy testing.