Acute seizures due to a probable interaction between valproic acid and meropenem

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.     

Evaluation of a first seizure

Seizure is a common presentation in the emergency care setting, and new-onset epilepsy is the most common cause of unprovoked seizures. The patient history and physical examination should direct the type and timing of laboratory and imaging studies. No single sign, symptom, or test dearly differentiates a seizure from a nonseizure event (e.g., syncope, pseudoseizure). Electroencephalography is recommended for patients presenting with a first seizure, and neuroimaging is recommended for adults. Neuroimaging also should be performed in children with risk factors such as head trauma, focal neurologic deficits, or a history of malignancy. Magnetic resonance imaging is preferred over computed tomography except when acute intracranial bleeding is suspected. The most common laboratory findings associated with a seizure are abnormal sodium and glucose levels. Patients with a normal neurologic examination, normal test results, and no structural brain disease do not require hospitalization or antiepileptic medications. Treatment with antiepileptic medications reduces the one- to two-year risk of recurrent seizures but does not reduce the long-term risk of recurrence and does not affect remission rates. Regardless of etiology, a seizure diagnosis severely limits a patient's driving privileges, although laws vary by state.     

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem

A 55-year-old woman was diagnosed with pneumonia and was treated with meropenem; 5 days later she developed epileptic seizures. She had been treated with valproic acid for 16 years to control her epileptic seizures. Her serum valproic acid concentration was low during treatment with meropenem than previously recorded despite an increase of valproic dose. As soon as administration of meropenem was withdrawn, valproic acid concentration increased to previous levels and her seizures stopped. Meropenem decreases valproic acid concentration, and may promote the development of epileptic seizures in previously controlled epileptic patients. The acute lowering of serum valproate produced by meropenem probably precludes their concomitant use.     

Unrecognized valproic acid intoxication

We report the case of a patient with schizophrenia who presented to the emergency department (ED) with a mental status change. He was initially treated for nonconvulsive seizures until a valproic acid (VPA) serum concentration test was performed and indicated acute intoxication.     

MELAS误诊为单纯疱疹病毒性脑炎一例

线粒体脑肌病伴高乳酸血症和卒中样发作（MELAS）是母系遗传性线粒体疾病,临床表现多样,易与单纯疱疹病毒性脑炎（HSE）混淆。该文报道1例初诊时误诊为HSE的MELAS患者,该例患者因反复发热、头痛、肢体抽搐1个月,再发头痛1周就诊,入院时初步疑诊为HSE,予以抗病毒治疗无效,进一步行血液和尿液基因检测确诊为MELAS。MELAS可与不典型的HSE表现相似,应谨慎鉴别。脑脊液和（或）血清乳酸升高和基底节钙化有助于诊断MELAS,MELAS的线粒体DNA突变可通过血液和尿液基因检测,而不需要采用肌肉活组织检查这样的有创检查。     

Valproic acid-induced hyperammonemia and thrombocytopenia in an elderly woman

OBJECTIVE: To describe a case of oral valproic acid-induced hyperammonemia and thrombocytopenia in an elderly patient. CASE SUMMARY: A 76-year-old white woman presented to the emergency department with generalized weakness, confusion, nausea, and vomiting. She was taking sodium divalproex 750 mg 3 times daily, with valproic acid concentration 144 mg/L. She was admitted to the medical ward. The dose of sodium divalproex was decreased and discontinued. During her hospital stay, the woman's ammonia level rose to 211 microg/dL despite a normal valproic acid concentration. She was confused, somnolent, and had decreased mobility. Her platelet count decreased from 133 to 86 x 10(3)/mm(3). Gabapentin was prescribed for seizure control. The patient's mental status, ammonia level, and platelet count returned to baseline following discontinuation of valproic acid. DISCUSSION: It has been reported that valproic acid can interfere with the enzyme carbamoylphosphate synthetase, which is responsible for incorporating ammonia into the urea cycle. It has also been reported that valproic acid can increase the transport of glutamine across the mitochondrial membrane in the kidney, thereby increasing the production of ammonia. The etiology of valproic acid-induced thrombocytopenia has not been elucidated. Using the Naranjo probability scale, a probable relationship between hyperammonemia and valproic acid and a possible relationship between thrombocytopenia and valproic acid were determined. CONCLUSIONS: Valproic acid can be associated with hyperammonemia and thrombocytopenia. Clinicians should be aware of changes in patients' cognitive and functional capacity, especially elderly patients on sodium divalproex.     

Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management

A review of US poison center data for 2004 showed over 9000 ingestions of valproic acid. A guideline that determines the conditions for emergency department referral and prehospital care could potentially optimize patient outcome, avoid unnecessary emergency department visits, reduce health care costs, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected ingestion of valproic acid by 1) describing the process by which an ingestion of valproic acid might be managed, 2) identifying the key decision elements in managing cases of valproic acid ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to the acute ingestion and acute-on-chronic ingestion of immediate-release and extended-release dosage forms of valproic acid, divalproex, and valproate sodium alone. Co-ingestion of additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This review focuses on the ingestion of more than a single therapeutic dose and the effects of an overdose. Although therapeutic doses of valproic acid can cause adverse effects in adults and children, some idiosyncratic and some dose-dependent, these cases are not considered. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions might be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in whom a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) Patients who are symptomatic (more than somnolence or exhibiting coma or seizures) after a valproic acid ingestion should be referred to an emergency department (Grade C). 3) Asymptomatic patients with an unintentional acute ingestion of 50 mg/kg or more or asymptomatic patients who are taking the drug therapeutically and who take an additional single acute ingestion of 50 mg/kg or more of any valproic acid formulation should be referred to an emergency department for evaluation (Grade C). 4) Patients with unintentional ingestions of immediate-release valproic acid formulations, who are asymptomatic, and more than 6 hours has elapsed since the time of ingestion, can be observed at home (Grade C). 5) Patients with unintentional ingestions of delayed-release or extended-release formulations of valproic acid who are asymptomatic, and more than 12 hours has elapsed since the time of ingestion, can be observed at home (Grade C). 6) Pregnant women who ingest below the dose for emergency department referral and do not have other referral conditions should be directed to their primary care obstetrical provider for evaluation of potential maternal and fetal risk. Routine referral to an emergency department for immediate care is not required (Grade D). 7) Do not induce emesis (Grade C). 8) Activated charcoal can be administered to asymptomatic patients who have ingested valproic acid within the preceding hour (Grade C). Prehospital activated charcoal administration, if available, should only be carried out by health professionals and only if no contraindications are present. Poison centers should follow local protocols and experience with its use. Do not delay transportation in order to administer activated charcoal (Grades D). 9) In patients who have ingested valproic acid and who are comatose, naloxone can be considered for prehospital administration in the doses used for treatment of opioid overdose, particularly if the patient has respiratory depression (Grade C). 10) A benzodiazepine can be administered by EMS personnel if convulsions are present and if authorized by EMS medical direction, expressed by written treatment protocol or policy, or if there is direct medical oversight (Grade C).     

Headache and mitochondrial disorders

We report on 2 patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These 2, and 9 other, reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from 2 other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns–Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these 3 clinical syndromes remain to be elucidated.     

Contraindications to phenytoin in emergency department patients with seizures

The objective of this study was to determine what contraindications to phenytoin exist in Emergency Department (ED) patients with a medical history of seizures. We conducted a retrospective chart review using ED medical records from 2005 at two network health care EDs. We identified potential patients through ICD-9 (International Classification of Diseases, Ninth Revision) codes, selected only adult patients with a prior documented history of seizures, and reviewed these charts. From 201 charts reviewed, the three most common antiepileptic drugs taken by patients were: phenytoin (38%), levetiracetam (17%), and valproic acid (15%). For absolute contraindications to phenytoin, 4.5% of seizure patients had a known hypersensitivity to phenytoin and 1.5% were pregnant; however, no pregnant patients were taking phenytoin and only 1 person with hypersensitivity to phenytoin was taking phenytoin. For relative contraindications, 6% of seizure patients had liver disease, 8% had kidney disease, 9% had alcohol use/dependence, and 16% had diabetes. However, 55% of those with liver disease, 44% with kidney disease, 77% with alcohol use/dependence, and 53% with diabetes were currently taking phenytoin. Very few seizure patients in the ED have absolute contraindications to the use of phenytoin, and most with absolute contraindications are taking other antiepileptic drugs. Conversely, a greater proportion of seizure patients have relative contraindications and many are continuing to use phenytoin.     

Seizures in patients with multiple sclerosis seen at Mayo Clinic, Rochester, Minn, 1990-1998

OBJECTIVE: To evaluate seizure type, electroencephalographic findings, and response to antiepileptic drug (AED) treatment in patients with multiple sclerosis (MS) and coexistent seizure activity. PATIENTS AND METHODS: We reviewed the medical records of all patients seen at the Mayo Clinic in Rochester, Minn, with the diagnosis of MS and seizures between 1990 and 1998. RESULTS: During the study period, 5715 patients with MS were identified. Of these 5715 patients, 51 (0.89%) experienced seizure activity. The most common ictal behavior was a generalized tonic-clonic seizure in 35 patients (68.6%). Simple or complex partial seizures occurred in 11 patients (21.6%), and 18 patients (35.3%) had only 1 seizure episode. Focal motor status epilepticus, ie, epilepsia partialis continua, occurred in 3 patients (5.9%) and was associated with cognitive impairment. In 37 patients (72.5%), the initial seizure presentation was after the diagnosis of MS. A seizure resulted in the diagnosis of MS or occurred before the diagnosis of MS but after other symptoms or signs of demyelinating disease in 14 patients (27.4%). Electroencephalography was performed in 43 patients. Electroencephalographic findings included diffuse or localized nonspecific background slowing in 19 patients (44.2%), unilateral or bilateral frontotemporal spike discharges in 9 (20.9%), generalized atypical spike-and-wave or multifocal independent epileptiform alterations in 6 (14.0%), and normal results in 11 (25.6%). Of the 45 patients who received AED therapy, 35 (77.8%) had an excellent response, ie, they were seizure free. Five treated patients (11.1%) had an intractable seizure disorder. CONCLUSION: Most of the patients with MS who experienced seizure activity had a benign and transient disorder that was responsive to AED treatment or required no therapy.     

Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms

Study objectives: Muscle is one of the most commonly affected organs in mitochondrial disorders, and the symptoms are often exercise related. The cardiopulmonary exercise test with the determination of lactic acid formation could give supplementary information about the exercise‐induced metabolic stress and compensatory mechanisms used in these disorders. The aim of this study was to evaluate the exercise capacity and lactate kinetics related to exercise in subjects with two genetically characterized mitochondrial disorders (multiple mitochondrial DNA deletions with PEO, MELAS) compared with lactate kinetics in subjects with metabolic myopathy (McArdle's disease) and in the healthy controls. Design: The subjects were consecutive, co‐operative patients of Department of Neurology of Helsinki University Hospital. Molecular genetic analyses were used for group classification of the mitochondrial myopathy. Study subjects: The study groups consisted of 11 patients with multiple deletions (PEO) and five patients with a point mutation in the mitochondrial DNA (MELAS), four patients with a muscle phosphorylase enzyme deficiency (McArdle's disease) and 13 healthy controls. The clinical disease of the patients was relatively mild. Measurements and results: A graded exercise test with ventilatory gas analyses and venous blood lactic acid analyses was performed. The main finding was the prolonged accumulation of blood lactate after the exercise in the PEO and MELAS groups compared with the controls. An overcompensation in ventilation was found in the MELAS and PEO group. Conclusions: The blood lactate accumulation after exercise occurs in patients with multiple mitochondrial DNA deletions or MELAS even in patients with only mild exercise intolerance. Cardiopulmonary exercise can be used in the diagnostic process of patients with mitochondrial myopathies.     

Effect of concomitant administration of meropenem and valproic acid in an elderly chinese patient

Background: Meropenem is a carbapenem with a broad spectrum of activity against β-lactamase-producing organisms. Valproic acid is widely used in the treatment of generalized tonic-clonic and partial seizures. Concomitant administration of meropenem and valproic acid reportedly leads to a rapid decline in serum concentrations of valproic acid, which is sometimes associated with seizures.Case summary: This report describes an 85-year-old Chinese male inpatient who twice received concomitant administration of meropenem and valproic acid for the treatment of pneumonia and poststroke epilepsy, respectively. Rapid declines in valproic acid concentrations were observed both times after meropenem administration. No seizures occurred in the first treatment period; however, when the patient suffered pneumonia again 3 months later, the same concomitant therapy was prescribed, and seizures occurred. It is difficult to identify a single etiology of the seizures. Based on a score of 7 on the Naranjo adverse drug reaction probability scale, the seizures were considered to be probably related to the concomitant administration of meropenem and valproic acid.Conclusions: Various factors make the effect of concomitant administration of meropenem and valproic acid unpredictable, even in the same patient. Caution should be used when administering meropenem and valproic acid concomitantly, especially in elderly patients with central nervous system disorders, even if the patient has had a successful prior experience with these 2 drugs. If concomitant administration is essential, very close serum concentration monitoring and clinical observation are necessary.     

Seizure disorders in the elderly

Seizure disorders become increasingly common after the age of 60 years and can have a significant impact on functional status. The goal of antiepileptic drug therapy is to control seizures but preserve quality of life. If possible, seizure control should be achieved with one agent given in the lowest effective dosage. Clinical response, rather than drug levels, should guide dosage changes. All antiepileptic drugs can cause dose-dependent sedation and cognitive impairment. Although the newer agents may have theoretical advantages over standard antiepileptic agents, higher cost may limit their use. Drugs for first-line monotherapy of seizures in elderly patients include carbamazepine, valproic acid, oxcarbazepine, gabapentin, and lamotrigine.     

Valproic acid-associated pancreatitis: report of three cases and a brief review

We describe three patients with seizure disorders in whom pancreatitis or pancreatic injury was probably caused by valproic acid, a widely used anticonvulsant drug. Trivial or no increases of serum amylase (EC 3.2.1.1) but striking increases of serum lipase (EC 3.1.1.3) were common to all patients, as assayed in the Kodak Ektachem. In vitro, valproic acid does not cause any change in serum lipase. In patients with symptoms suggestive of pancreatitis and abnormal values for amylase and (or) lipase, treatment with valproic acid should be discontinued.     

Benign juvenile myoclonic epilepsy

Two patients with long-standing, poorly controlled seizures presented to a university hospital emergency department. Both patients had myoclonic jerks on waking and evidence of absence seizures as well as generalized tonic-clonic seizures. A diagnosis of benign juvenile myoclonic epilepsy was made, and the seizures were controlled with valproic acid.     

Seizure prophylaxis in patients with brain tumors: a meta-analysis

OBJECTIVE: To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS: We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS: Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS: No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.     

Evaluation and management of pediatric febrile seizures in the emergency department

Febrile seizures are common in children, who are often brought to the nearest emergency department (ED). Patients who meet the case definition of simple febrile seizure are not at higher risk for serious bacterial illness than clinically similar febrile children who have not experienced a convulsion. Children who have had complex febrile seizures must be evaluated on a case-by-case basis, and treated with diagnostic and therapeutic measures based on the differential diagnosis. Round-the-clock prophylactic administration of antipyretics has not been demonstrated to affect recurrence of simple febrile seizure. Parents should be informed that recurrence is common, and that these convulsions are benign with an excellent prognosis. Care-givers should be informed that the risk of developing epilepsy after a simple febrile seizure is low, but that complex febrile seizures carry a significantly higher risk.     

Common emergent pediatric neurologic problems

Although there are a variety of neurologic disease processes that the emergency physician should be aware of the most common of these include seizures, closed head injury, headache, and syncope. When one is evaluating a patient who has had a seizure, differentiating between febrile seizures, afebrile seizures, and SE helps to determine the extent of the work-up. Febrile seizures are typically benign, although a diagnosis of meningitis must not be missed. Educating parents regarding the likelihood of future seizures, and precautions to be taken should a subsequent seizure be witnessed, is important. The etiology of a first-time afebrile seizure varies with the patient's age at presentation, and this age-specific differential drives the diagnostic work-up. A follow-up EEG is often indicated, and imaging studies can appropriate on a nonurgent basis. Appropriate management of SE requires a paradigm of escalating pharmacologic therapy, and early consideration of transport for pediatric intensive care services if the seizure cannot be controlled with conventional three-tiered therapy. Closed head injury frequently is seen in the pediatric emergency care setting. The absence of specific clinical criteria to guide the need for imaging makes management of these children more difficult. A thorough history and physical examination is important to uncover risk factors that prompt emergent imaging. Headaches are best approached by assessing the temporal course, associated symptoms, and the presence of persistent neurologic signs. Most patients ultimately are diagnosed with either a tension or migraine headache; however, in those patients with a chronic progressive headache course, an intracranial process must be addressed and pursued with appropriate imaging. Syncope has multiple causes but can generally be categorized as autonomic, cardiac, or noncardiac. Although vasovagal syncope is the most common cause of syncope, vigilance is required to identify those patients with a potentially fatal arrhythmia or with heart disease that predisposes to hypoperfusion. As such, all patients who present with syncope should have an ECG. Additional work-up studies are guided by the results of individual history and physical examination.     

一种新的线粒体DNA基因突变:线粒体脑肌病伴高乳酸血症和卒中样发作综合征1例基因与残障特征分析

背景线粒体脑肌病伴高乳酸血症和卒中样发作综合征(MELAS)是线粒体脑肌病中最常见的一种临床类型,多种线粒体基因突变均可导致MELAS.目的探讨1例MELAS患者的临床表现和线粒体基因突变的关系.设计临床、病理和基因分析对照研究.地点和对象实验在解放军济南军区总医院神经内科病房、神经病理实验室和神经分子生物学实验室进行.患者,男,13岁,因发作性头痛、呕吐,肢体抽搐1个月于2001-06-04入院,入院后逐渐出现失明和智能减退.血乳酸和丙酮酸水平升高,临床诊断MELAS.干预对患者行头颅MRI检查、脑活检病理检查和线粒体基因分析.主要观察指标临床表现特点、MRI病变特征、脑组织病理改变特点以及线粒体基因突变类型.结果患者不存在能引起MELAS的较常见的突变,但在线粒体3314～3589之间有276 bp的碱基缺失.结论线粒体DNA 3314～3589位点之间276 bp的碱基缺失可能是能够导致MELAS的一种新的基因突变类型,也是导致患者出现失明、癫痫和痴呆的原因.     

Seizures in the elderly: Nuances in presentation and treatment

Acute symptomatic seizures and epilepsy are two of the most common neurologic complaints in the elderly. Stroke is the leading underlying etiology for both. Because clinical seizure manifestations in the elderly often differ from those in younger adults, they may be difficult to recognize or may be misdiagnosed. Interpretation of diagnostic tests in elderly patients with seizures is often complicated by comorbidities, and treatment decisions require careful consideration in the context of age-related physiologic changes, comorbidities, and the use of concomitant medications. Treatment of an acute seizure with a clear precipitating cause involves correcting the underlying etiology; antiepileptic drug (AED) therapy is generally reserved for patients with epilepsy (recurrent unprovoked seizures). The prognosis for elderly epilepsy patients treated with AEDs is generally good. Both older and newer AEDs are efficacious but have respective advantages and disadvantages; no ideal AED yet exists. Status epilepticus is a neurologic emergency that is particularly frequent in the elderly and associated with high mortality, although treatment can be effective.