Atezolizumab Treatment for Progressive Multifocal Leukoencephalopathy.

Atezolizumab successfully reinvigorated JC virus immunity in a patient in Belgium with progressive multifocal leukoencephalopathy, as demonstrated by clinical, virologic, and radiologic response to treatment. However, the treatment also resulted in immune reconstitution inflammatory syndrome and life-threatening immune-related adverse events. These conditions were treated with corticosteroids, leading to treatment resistance.

Killing Two Birds With One Stone: Effective Control of Both Non-Small Cell Lung Cancer and Progressive Multifocal Leukoencephalopathy With Atezolizumab, A Case Report.

Treating patients with cancer complicated by severe opportunistic infections is particularly challenging since classical cancer treatments, such as chemotherapy, often induce profound immune suppression and, as a result, may favor infection progression. Little is known about the potential place of immune checkpoint inhibitors in these complex situations. Here, we report a 66-year-old man who was concomitantly diagnosed with non-small cell lung cancer and progressive multifocal leukoencephalopathy. The patient was treated with anti-PD-L1 antibody atezolizumab, which allowed effective control of both lung cancer and progressive multifocal leukoencephalopathy, as demonstrated by the patient's remarkable neurologic clinical improvement, JC viral load reduction in his cerebrospinal fluid, regression of the brain lesions visualized through MRI, and the strict radiological stability of his cancer. In parallel, treatment with atezolizumab was associated with biological evidence of T-cell reinvigoration. Hence, our data suggest that immune checkpoint inhibitors may constitute a treatment option for patients with cancer complicated by severe opportunistic infections.

Oligo-astrocytoma in LZTR1-related Noonan syndrome.

Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.

Impact of reimbursement restrictions on the choice of antiepileptic drugs: Belgian Study on Epilepsy Treatment (BESET).

BACKGROUND: In Belgium, new and costly antiepileptic drugs (AEDs) are only reimbursed as second-line treatment, after documented treatment with conventional and cheaper AEDs has failed. The objective of this study was to describe the treatment of epilepsy in Belgium and to analyze the impact of the reimbursement restrictions on the choice of AEDs. METHODS: Between May and June 2003, a sample of 100 neurologists, representative of the entire neurological community in teaching, academic, and regional hospitals in Belgium, were personally interviewed on the basis of a structured questionnaire (modified Rand method). The questionnaire contained questions on treatment choices and strategies in adult epilepsy. RESULTS: Unanimously, initial monotherapy was the preferred treatment strategy in all types of epilepsy. In the opinion of most neurologists, valproate was the first choice for idiopathic generalized and focal epilepsy with/without secondary generalization. Carbamazepine as their first choice for the treatment of focal epilepsy. New AEDs were most often prescribed as second-line therapy. Lamotrigine was the most frequently prescribed new AED and used for both generalized and focal epilepsy. It was followed by levetiracetam, topiramate and oxcarbazepine for focal epilepsy. In the absence of reimbursement restrictions, two new AEDs would be significantly more often prescribed as a first-line therapy: lamotrigine for idiopathic generalized epilepsy and oxcarbazepine for focal epilepsy. CONCLUSIONS: The neurologists reached a high level of consensus on many of the key treatment questions. Monotherapy with valproate and carbamazepine was the standard treatment strategy in Belgium. Lamotrigine and less so levetiracetam, topiramate and oxcarbazepine were commonly prescribed as second-line AEDs. In the absence of reimbursement restrictions, lamotrigine and oxcarbazepine would be more frequently prescribed.

Recommendations for the treatment of epilepsies in general practice in Belgium.

The large choice of antiepileptic drugs (AEDs) in Belgium complicates the selection of the appropriate product for the individual patient. International guidelines on the treatment of epilepsy have been published, but are not tailored to the Belgian situation. This publication presents recommendations from a group of Belgian epilepsy experts for the practical management of epilepsy in general practice in Belgium. It includes recommendations for initial monotherapy and add-on treatment in adult patients (> or = 16 years) and initial monotherapy in paediatric patients (< 16 years). For these three situations a first choice AED is recommended. One or more alternative first choice AEDs are defined for patients in which certain patient- or AED-related factors preclude the use of the first choice product. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence of efficacy, common daily practice and the personal views and experiences of the authors. The paper reflects the situation in 2008. In addition to the treatment recommendations, other relevant points to consider in the treatment of epilepsy with AEDs are addressed, including comorbidity and age of the patient, the interaction potential, pharmacokinetic properties and safety profile of the AEDs, and generic substitution.

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study.

INTRODUCTION: Vagus nerve stimulation (VNS) is a symptomatic add-on treatment for patients with medically refractory epilepsy. It consists of continuous electrical stimulation of the left vagus nerve by means of a helical electrode and an implantable, programmable pulse generator. Currently, over 50,000 patients are treated with VNS worldwide. AIM: This uncontrolled, open-label retrospective study evaluates long-term outcome in patients treated with VNS for refractory epilepsy in seven different epilepsy centres in Belgium. METHODS: For the purpose of this study, a minimum of essential inclusion criteria were defined to collect relevant data. This limited the results to basic findings with regards to efficacy on the long term. Inclusion criteria were a follow-up of at least 12 months and a documented seizure diary before implantation and at maximum follow-up. Primary outcome measures were the reduction in mean monthly seizure frequency and the percentage of patients with a seizure reduction of at least 50% (responder rate). RESULTS: About 138 patients (67M/71F) had a mean age of 30 years (range 4-59) at time of implantation and a mean post-implantation follow-up of 44 months (range 12-120). The mean number of AEDs before implantation was 3 (range 1-5). About 117/138 patients had focal epilepsy, 21 patients had symptomatic generalised epilepsy. About 117/138 patients were older than 16 years, 21 patients were 16 or younger. At maximum follow-up, mean stimulation output current was 1.84mA (range 0-3.25). Mean number of AEDs at maximum follow-up remained unchanged. The overall reduction in mean monthly seizure frequency was 51%. Mean seizure frequency before implantation was 41 seizures/month (SD=61; range 1-300), mean seizure frequency after implantation at maximum follow-up was 7 seizures/month (SD=25; range 0-120). Responder rate was 59%. 13% of patients had a seizure frequency decrease between 30% and 50%. About 28% had a seizure frequency decrease of<30%. Seizure freedom was obtained in 12/138 patients (9%). CONCLUSIONS: The long-term experience with VNS in Belgium confirms that VNS is an efficacious adjunctive antiepileptic treatment for patients with refractory epilepsy.

Standards of care for non-convulsive status epilepticus: Belgian consensus recommendations.

Non-convulsive status epilepticus (NCSE) makes up around one-third of all cases of SE, affecting approximately 1,000 to 4,000 individuals per year in Belgium. Compared with convulsive SE, NCSE has received considerably less attention, is underdiagnosed and undertreated. However, if recognised, NCSE can however be treated successfully. A workshop was convened by neurologists from major Belgian centres to review the latest information on NCSE and to make recommendations on diagnosis and treatment. These recommendations are not only intended for neurologists, but also for primary care physicians and physicians in intensive care units. NCSE should be suspected whenever cases of fluctuating consciousness or abrupt cognitive or behavioural changes are noted. Confirmation of diagnosis by EEG should be obtained wherever possible. In view of the often subtle clinical signs, EEG is also vital for monitoring treatment outcome. Non-comatose patients should generally be treated in a neurology ward since referral to an ICU is unnecessary. First-line treatment should be an intravenous benzodiazepine. For many patients who fail to respond to benzodiazepines, intravenous valproate will successfully abrogate seizure activity. Intravenous phenytoin can be used in patients with focal NCSE in whom valproate is contraindicated or ineffective. Time and care should be spent in identifying an appropriate and effective antiepileptic drug regimen without recourse to anaesthesia. For comatose patients, treatment intensity should be graded according to epilepsy history, general medical state and prognosis. In some patients, intensive remedial measures may allow rapid resolution of NSCE, whereas in more vulnerable patients, such treatment may be counterproductive.

Standards of care for adults with convulsive status epilepticus: Belgian consensus recommendations.

Status epilepticus (SE) is a significant health problem, affecting approximately 1,000 to 4,000 individuals per year in Belgium. A workshop was convened by a panel of neurologists from major Belgian centers to review the latest information relating to the definition, diagnosis and treatment of convulsive SE. The panelists sought to make recommendations for practising neurologists, but also primary care physicians and physicians in intensive care units when initiating emergency measures for patients with convulsive SE. As there is an association between prolonged seizures and a poor outcome, the importance of early (within the first 5 minutes of seizure onset) and aggressive treatment is to be stressed. In addition to general systemic support (airway, circulation), intravenous administration of the benzodiazepines lorazepam or diazepam is recommended as first-line therapy. Intramuscular midazolam may also be used. If SE persists, second-line drugs include phenytoin or valproate, and third-line drugs the barbiturate phenobarbital, the benzodiazepine midazolam, or the anaesthetics thiopental or propofol, or eventually ketamine. If the patient does not recover after therapy, monitoring of seizures should involve an electroencephalogram to avoid overlooking persistence of clinically silent SE. As a general rule, the intensity of the treatment should reflect the risk to the patient from SE, and drugs likely to depress respiration and blood pressure should initially be avoided. If initial treatment with a benzodiazepine fails to control seizures, the patient must be referred to the emergency unit and a neurologist should be contacted immediately.

Belgian consensus on recommendations for standards of care for women with epilepsy before, during and after pregnancy.

Women with epilepsy (WWE) have an increased risk of complications during pregnancy, which however can be minimized by optimal, interdisciplinary patient management. The aim of any therapy is to achieve an optimal balance between avoidance of seizures, which may be harmful to both mother and foetus, and minimization of foetal and neonatal exposure to deleterious influences of antiepileptic drugs. Suitable measures include early and regular counselling of the young WWE about contraception and planning of pregnancy, optimisation of drug treatment (choice of the right drug and dosage also in view of altered pharmacokinetics, avoidance of polytherapy, therapeutic drug monitoring etc.), in-time folate substitution, and close follow-up of the patient during and after pregnancy. Until now, many issues such as underlying factors of malformations have not been clearly elucidated. Nonetheless, chances for an unproblematic pregnancy of WWE are high.

Brain function in the vegetative state.

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.

Impaired automatic and unconscious motor processes in Parkinson's disease.

While it is increasingly recognized that voluntary movements are produced by an interaction between conscious and unconscious processes, the role of the latter in Parkinson's disease has received little attention to date. Here, we administered a subliminal masked prime task to 15 Parkinson's disease patients and 15 age-matched healthy elderly subjects. Compatibility effects were examined by manipulating the direction of the arrows and the interstimuli interval. Analysis of the positive compatibility effect revealed performance differences between the most and the least affected hand in Parkinson's disease patients. Additionally, patients did not show the same tendency toward a negative compatibility effect as compared to elderly controls. These novel findings provide evidence supporting the role of basal ganglia circuits in controlling the balance between automatic motor response facilitation and inhibition.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.

OBJECTIVE: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS: Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS: Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS: We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.

Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. METHODS: Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. FINDINGS: 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. INTERPRETATION: SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time. FUNDING: Commission of European Affairs of the International League Against Epilepsy.

Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update.

In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs.