Loredana Dinapoli

Patients with brain tumor-related epilepsy.

Patients with brain tumor-related epilepsy (BTRE) present a complex therapeutic profile and require a unique and multidisciplinary approach. They, in fact, must face two different pathologies at the same time, brain tumor and epilepsy. Therefore, it is necessary to develop a customized treatment plan for each individual with BTRE. This requires a vision of patient management concerned not only with medical therapies related to the oncological disease and to the correct choice of antiepileptic therapies but also with emotional and psychological support for the individual and his/her family. The choice of antiepileptic drugs is challenging for these patients because BTRE is often drug-resistant, has a strong impact on the quality of life, and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered the most important risk factor for long-term disability. The problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control also has a significant impact on the patient’s psychological and relational sphere.

Rash in four patients with brain tumor-related epilepsy in monotherapy with oxcarbazepine, during radiotherapy.

Antiepileptic drug (AED)-related rash is well documented with older AEDs such as carbamazepine, phenobarbital, and phenytoin, and recent studies have implicated newer AEDs such as lamotrigine, oxcarbazepine (OXC), and zonisamide [1–4]. In patients with brain tumor-related epilepsy (BTRE) treated with old AEDs, the appearance of rash may be severe during radiotherapy (RT). The frequency is approximately 20% of cases where traditional AEDs such as carbamazepine, phenobarbital, and phenytoin are used [4]. The appearance of rash during RT among the new AEDs has not yet been described in the literature. Skin rash is an idiosyncratic adverse drug reaction that can vary from mild maculopapular to life-threatening hypersensitivity [2]. According to the FDA, the incidence of OXC-related serious dermatological reactions including Stevens–Johnson syndrome and toxic epidermal necrolysis is estimated to range between 0.5 and 6/10 early in the non-oncological epileptic population [5]. Although rare, this potential life-threatening adverse reaction should be recognized and treated promptly. The toxicity is unpredictable for the most part. The pathogenesis appears to be multi-factorial and has been explained by drug hyper sensitivity, which implies both metabolic and immunological mechanisms [2]. Literature data show that AEDs containing aromatic rings, phenytoin, and carbamazepine, are associated with a higher incidence of adverse cutaneous skin reactions [2, 3]. A lower incidence was found with levetiracetam, gabapentin, valproic acid, primidone, felbamate, topiramate, and vigabatrin. Clobazam, OXC, phenobarbital, tiagabine, and zonisamide produced intermediate reactions [3]. In the literature, descriptions of OXC-induced Stevens–Johnson syndrome are rare [3]. OXC has recently been demonstrated efficacious in reducing seizure frequency in BTRE with scarce appearance of side-effects both mild and severe [6]. Here, we present four patients with BTRE treated with OXC monotherapy, who, during brain radiation therapy, presented a major skin reaction that disappeared after OXC suspension. The study included three males and one female, with a mean age of 54.8 years, affected by epilepsy secondary to cerebral high-grade glioma, with simple partial seizures (n = 3) and simple partial with secondary generalization seizures (n = 1). We introduced OXC monotherapy (mean dose = 1,050 mg/day) with a good effect on seizure control during the treatment period (monthly mean seizure frequency at baseline = 18; monthly mean seizure frequency before OXC withdrawal = 3; responder rate [50%) (see Table 1). For the treatment of oncological disease, patients underwent brain RT (total dose 60 Gy), in association with concomitant temozolomide treatment dose of 75 mg/m per day in three patients (Stupp protocol) [7]. All patients were on steroids. After the start of RT (min 2 days, max 14 days), all patients presented a major skin reaction characterized by macules, papules, and boils at departure from the scalp, which spread to the face, shoulders, and M. Maschio (&) L. Dinapoli Department of Neuroscience and Cervical-Facial Pathology, Center for Tumor-related Epilepsy, National Institute for Cancer ‘‘Regina Elena’’, Via Elio Chianesi 53, 00144 Rome, Italy e-mail: maschio@ifo.it

Effect of pregabalin add-on treatment on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy: a pilot study

ObjectiveAn open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE).Materials and methodsWe recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given.ResultsDuring follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant (p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale “seizureworry” (p=0.004) and a significant decrease in distress scores related to AEDs and social life (p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAMA score (p=0.002) was documented.ConclusionsThese data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

Lecture: profile of risks and benefits of new antiepileptic drugs in brain tumor-related epilepsy

In patients with brain tumor, seizures are the onset symptom in 20–40% of the patients, while a further 20–45% of the patients will present them during the course of the disease. These data are important when considering the choice of antiepileptic drugs for this particular patient population, because brain tumor-related epilepsy (BTRE) is often drug resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered as the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient’s psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, and zonisamide are preferred, because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered as a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each patient with BTRE, whose goals are complete seizure control, minimal or no side effects, and elimination of cognitive impairment and/or psychosocial problems.

Lacosamide on background eeg activity in brain tumor-related epilepsy patients: A case series study

Therapeutic doses of antiepileptic drugs (AEDs) may alter EEG background activity, which is considered an index of the functional state of the brain. Quantitative analysis (qEEG) of EEG background activity is a valid instrument to assess the effects of many centrally active drugs on the central nervous system, including AEDs. Lacosamide (LCM) is a new AED that could be a valid therapeutic choice in patients with brain tumor‐related epilepsy (BTRE).

Neuropsychology of BTRE

Neuropsychological issues and assessment of them in patients with brain tumor-related epilepsy (BTRE) must take into consideration the simultaneous presence of two different illnesses: brain tumor (BT) and epilepsy. In the literature, neuropsychological issues have been amply discussed for either BT, or for epilepsy, but there is little if any data on this topic as it relates to BTRE. The intent of this chapter is to demonstrate that the studies that have been done on BT patients and on epilepsy patients have significant implications for BTRE for neuropsychological assessment, neurocognitive impairments, psychological issues, sexual disturbances, and quality of life.

Cognitive Rehabilitation in Patients with BTRE

Cognitive rehabilitation is as a systematic, functionally oriented service of therapeutic activities that is based on assessment and understanding of the patient’s brain-behavioral deficits. Multiple approaches exist with different goals, depending on patient characteristics and the methodology used. While there has been increasing interest in cognitive rehabilitation for brain tumor (BT) patients and limited data are available for epilepsy patients, at present there are no data on the effects of cognitive rehabilitation for patients with brain tumor-related epilepsy (BTRE). This chapter focuses on the results of cognitive rehabilitation in either BT patients or patients with epilepsy in order to draw implications for future research on BTRE in this area.

In reference to Usery JB et al. (J Neuro-oncol. 2010 Feb 10)

Referring to the article ‘‘A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures.’’ by Usery JB, Michael LM 2nd, Sills AK, Finch CK., published in your journal on 2010 Feb 10 (Epub ahead of print) [1], I am writing to share what we feel are shortcomings concerning the work of both the authors and the reviewers. First, referring to the ‘‘literature review’’ announced in the title, the authors overlooked the two most recent prospective studies on levetiracetam (LEV) used in patients with brain tumors and seizures. Although these studies did not include intravenous LEV (it did not exist at the time of the studies), the data yielded by these studies could be of value to your readership, certainly equal to the data cited by the authors from several retrospective LEV studies. Had they, or the reviewers, performed a web search with ‘‘LEV’’ and ‘‘brain tumor patients’’ as key words, they would most certainly have come up with the article: ‘‘Levetiracetam: preliminary experience in patients with primary brain tumours’’, by Wagner et al. [2], and the article ‘‘Levetiracetam therapy in patients with brain tumour and epilepsy’’, by Maschio et al. [3]; both studies are prospective. As director of one of the world’s only epilepsy centers specifically for brain tumor (BT) patients, and having been one of the first in the world to publish prospective studies on LEV in BT patients, as was Dr Vecht (Department of Neurology, Medical Center Haaglanden, The Hague, The Netherlands), my team and I were surprised to see that neither had been cited in your article. When an article states overtly that ‘‘no other study to date’’ on the article’s pertinent subject has been conducted, reviewers usually check PubMed and all internet medical search engines to confirm that claim and to evaluate all the work that has been cited by the authors. Although the overlooked articles were not a 100% match, the authors also included abstracts from congresses, which are certainly not as valid as prospective studies. Second, going beyond the shortcomings of the literature review, there are also flaws in the structure of the study that the authors performed. Here, we will list them briefly: