Felbamate

Summary: After the first year of clinical experience, felbamate (FBM) appears to be a valuable antiepileptic drug (AED) for the treatment of intractable epilepsy. However, many patients experience side effects that may discourage continued usage. These may be decreased by using a slower dose-escalation schedule and/or by being more aggressive in decreasing co-medication. The most common troublesome side effects are nausea and insomnia. With the recent observation of aplastic anemia, FBM should be considered only for persons with intractable epilepsy under the care of a physician familiar with FBM. Nevertheless, many patients have benefited significantly from FBM and have made a decision to continue receiving FBM at the presently known risk profile. A few more years of experience may be needed to more accurately determine the final place of FBM in the treatment of epilepsy.     

Felbamate-induced apoptosis of hematopoietic cells is mediated by redox-sensitive and redox-independent pathways

Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug shown to be effective in a variety of seizure disorders refractory to other treatments. However, its use has been restricted because of association with occurrence of rare cases of aplastic anemia and hepatic failure. Since it was shown that FBM metabolism requires glutathione (GSH), we used two experimental protocols to determine if the effects of specific metabolites were sensitive to redox pathways. FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate), at 0.1 mg/ml, induced increased apoptosis of bone marrow cells from B10.AKM mice as compared with B10.BR mice. Study of the effects of the drug on human promonocytic cell line U937 cells showed that FBM and the metabolite W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate], at higher concentrations (0.5 mg/ml), induced apoptosis in this cell line. We also observed that while FBM and its metabolites induced increased apoptosis of B cells with reduced intracellular GSH levels, addition of exogenous GSH decreased apoptosis induced by W873 but did not significantly affect apoptosis induced by FBM or W2986. Our results suggest that, at concentrations used during the present investigations, FBM metabolites induce apoptosis via redox-sensitive and redox-independent pathways.     

Risk of aplastic anemia in patients using antiepileptic drugs

PURPOSE: To assess the association between exposure to antiepileptic drugs (AEDs) and the occurrence of aplastic anemia. METHODS: A retrospective case-control study was conducted using data from the U.K. General Practitioners Research Database (GPRD). Cases were defined as patients diagnosed with aplastic anemia. For each case, up to three control patients were matched on age, sex, and medical practice. Cases and controls were compared with respect to AED use. The effects of duration of AED use were assessed. Characteristics of individual cases with AED use were reviewed. RESULTS: The study population comprised 173 cases and 497 controls. AED use was more prevalent among cases (9.2%) than among controls (0.8%). After adjustment for confounders, the use of AEDs was significantly associated with aplastic anemia (adjusted odds ratio (OR), 9.5; 95% confidence interval (CI), 3.0-39.7). The most frequently used AEDs were carbamazepine (CBZ), valproic acid (VPA), and phenytoin. The 16 exposed cases were heterogeneous with respect to patient and exposure characteristics: the age of these patients varied from 1 to 92 years, and the duration of AED use varied from 17 days to 6.8 years. CONCLUSIONS: This study indicates that use of AEDs, in particular CBZ and VPA, is associated with a ninefold increased risk of aplastic anemia. Physicians should be alert to the possibility of AED-associated aplastic anemia.     

Increased incidence of axonal Guillain‐Barré syndrome in La Spezia area of Italy: A 13‐year follow‐up study

Guillain‐Barré syndrome (GBS) is an acute immune‐mediated polyradiculoneuropathy with a worldwide incidence of 0.81‐1.89 per 100 000 person‐years. In Europe and North America only 5% of patients with GBS have axonal subtypes, which in South America and Asia account for 30%‐47% of cases. The aim of our study is to assess the annual incidence and clinical features of GBS in La Spezia area in Italy. A retrospective (from 1 January 2003 to 31 December 2011) followed by a prospective (from 1 January 2012 to 31 December 2015) analysis was carried out on patients admitted to La Spezia hospital who fulfilled the GBS diagnostic criteria. A total of 86 patients (58 men), mean age of 62.7 years (range 21‐90), were included. The mean annual incidence rate was 3/100 000 (range: 0.9/100 000‐5.37/100 000) significantly higher than the European incidence (P < 0.001). Forty‐seven percent were classified as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 35% as acute motor and motor‐sensory axonal neuropathy (AMAN‐AMSAN), 13% as variant forms, and 5% were not defined. AIDP was most common in “Golfo dei Poeti” (50%) and “Val di Magra” (63.2%), whereas AMAN/AMSAN prevailed in “Val di Vara” (63.6%) and “Riviera Spezzina” (62.5%) (P = 0.024). In La Spezia area GBS incidence (especially the AMAN subtype) is significantly higher than the incidence reported in Europe. AIDP predominates in the eastern area whereas AMAN/AMSAN in the western, with a significantly different incidence rate (P = 0.003). Prospective studies to assess possible predisposing environmental factors are needed.     

Anticonvulsant drugs and hematological disease

Many antiepileptic drugs (AEDs) are associated with hematological disorders that range from mild thrombocytopenia or neutropenia to anemia, red cell aplasia, until bone marrow failure. Fortunately, potentially fatal hematological disorders such as aplastic anemia are very rare. This review investigates hematological effects associated with classic and newer AEDs: a PubMed search indexed for MEDLINE was undertaken to identify studies in adults, children and animals using the name of all anticonvulsant drugs combined with the terms “hematological disease” and “hematological abnormalities” as key words. The most common hematological alterations occur with older AEDs than newer. Indeed, careful hematological monitoring is needed especially using carbamazepine, phenytoin and valproic acid. The pathogenetic mechanisms are still unknown: they seem to be related to an immunological mechanism, but drugs pharmacokinetics and pharmacodynamics interactions may also play an important role. Further research is needed to assess the real pathogenetic mechanism at the basis of hematological complications caused by AEDs.     

Parent experiences of variations in service delivery of Rapid Syllable Transition (ReST) treatment for childhood apraxia of speech

Purpose: To understand parents’ perceptions of Rapid Syllable Transition (ReST) treatment and their experience of either telehealth or combined parent-clinician delivery of speech–language pathology. Method: Thematic analyses of semi-structured interviews were conducted with 10 parents (5 telehealth, 5 parent-clinician) after their child completed 12 sessions of ReST treatment. Results: Three themes were unique to telehealth: “telehealth was a million times easier,” “technical problems weren’t deal breakers,” and “telehealth therapy has different boundaries.” Three themes were unique to parent-clinician delivery: “therapy is something to get over and done with,” “I wasn’t very good at doing therapy,” and “my child doesn’t like me as his therapist.” Both groups had themes related to the significance of childhood apraxia of speech, the importance of specialist treatment, and ReST being a “different way forward.” Conclusions: Speech–language pathologists should carefully consider the suitability of caregiver-provided ReST treatment, and increase telehealth delivery of ReST treatment.     

Felbamate-Induced Headache

We prospectively investigated drug-induced headaches (HA) among 60 epileptic patients receiving felbamate (FBM). Twenty patients (33%) experienced HA. HA was pounding in 11 (55%), steady in 9 (45%), moderate or severe in 19 (95%), occurred at least once a week in all patients, and was relieved by nonnarcotic analgesics in 14 (70%). Mean duration on FBM before HA onset was 19 days. HA occurred with higher FBM doses and was relieved in 8 of 13 patients (62%) with FBM dose reduction. FBM was discontinued in most cases because of risks of anemia or hepatitis; not because of HA. Other side effects included insomnia (25%), gastrointestinal symptoms (27%), and agitation or restlessness (23%). HA is a common dose-related complication of FBM, occurs early after initiation of FBM treatment, and is relieved by dose reduction.