Carbamazepine and benzodiazepines in combination--a possibility to improve the efficacy of treatment of patients with 'intractable' infantile spasms?

Therapeutical efforts in epilepsies with infantile spasms (IS) often show unsatisfying results, especially if neurological impairments are found. In a clearly negatively selected group of 24 children with IS and 10 patients with symptomatic myoclonic-astatic epilepsies--pretreated without success with ACTH and/or benzodiazepines (BDZ) alone or combined with other anticonvulsants--we tried a two-drug therapy of BDZ with carbamazepine (CBZ). Dosage of both drugs was within the usual range. In a follow-up period of 1-5 years, 8 of the IS patients and 4 of those with myoclonic-astatic seizures became seizure-free; furthermore, 6 children showed a marked reduction in their seizure frequency: 3 more than 80%, 3 more than 50%. Besides the fact that the patients did not develop a so-called escape-phenomenon--as often seen in therapy with benzodiazepines--they also showed fewer and less intensive side-effects. Without optioning for antiepileptic polytherapy in general, we conclude that in cases of "intractable" IS the combination of BDZ with CBZ might be more successful than the single drug. To confirm these preliminary findings further controlled studies have to be carried out.     

Decreased cerebrospinal fluid levels of β-endorphin and ACTH in children with infantile spasms

Summary. To investigate the pathophysiology of infantile spasms (IS), we measured the cerebrospinal fluid (CSF) levels of β-endorphin (β-EP), adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone (CRH) in 20 patients with IS, including 11 with the secondary form and 9 with the cryptogenic form of the disease. The findings were compared with those obtained in age-matched controls without neurologic disease. The CSF levels of β-EP and ACTH were significantly lower in patients with IS than those in the controls. The CSF levels of CRH in patients with IS were lower, although, this trend was not significant. These reductions in the CSF levels of these neuropeptides could explain the impairment of the brain-adrenal axis in such patients. These results might support the hypothesis that, instead of originating from an increased abundance of CRH, which can act as a rapid and potent convulsant, some infantile seizures could be caused by an ACTH deficiency. Received March 7, 2000; accepted September 13, 2000     

Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: how valid is the GABAergic hypothesis?

Acquired nystagmus occurs frequently in patients with multiple sclerosis and is often the cause of illusory motion of the environment (oscillopsia), and blurring of vision. Based primarily on the beneficial effect of gabapentin on acquired pendular nystagmus (APN), a GABAergic mechanism in controlling nystagmus has been hypothesised. If increasing GABA concentrations in the CNS are critical for the treatment of nystagmus, then a selective GABAergic drug should be highly successful. However, as gabapentin is not a selective GABAergic agent, vigabatrin, a "pure" GABAergic medication, and gabapentin, were compared in a single blind cross over trial in eight patients with definite multiple sclerosis.Patients were randomly assigned to begin with gabapentin (1200 mg daily) or vigabatrin (2000 mg daily). Neuro-ophthalmological and electro-oculographic (EOG) evaluations were performed four and three times, respectively. Treatment efficacy was based on improving visual acuity and EOG indices (amplitude or frequency of nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects.In the remaining five patients gabapentin improved symptomatic pendular or gaze evoked jerk nystagmus in four. Three patients decided to continue gabapentin therapy. Importantly, vigabatrin proved useful in only one out of five patients, suggesting that gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action. Interaction with cerebral glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of gabapentin.     

The gut or the brain?—gastrointestinal misdiagnoses of infantile brain tumors

Purpose

Central nervous system tumors account for the largest number of cancer deaths in childhood. Brain tumors in infants less than 3 years of age are rare; symptoms and signs are often non-specific. Patent anterior fontanelles/unfused cranial sutures in infants can accommodate rising intracranial pressure without acutely compromising the neurological status. We hypothesize that vomiting as the initial symptom, in infants with brain tumors, can possibly lead to extensive gastrointestinal evaluation, delaying the diagnosis of intracranial pathology.

Methods

We conducted a retrospective chart review of infants less than 3 years of age diagnosed with brain tumors over the period of 4.7 years from February 2008 to October 2012 at Inova Children’s Hospital, Virginia.

Results

We identified three of 21 patients (14.3 %) who presented with vomiting and underwent initial or extensive abdominal imaging investigations. All patients were relatively young (median age, 5.4 months). Working diagnoses were pyloric stenosis, viral gastritis, or gastroesophageal reflux. All patients eventually had computed tomography of the head to rule out increased intracranial pressure and were found to have large brain tumors with obstructive hydrocephalus. Tumor locations were cerebral hemispheres (2/3) and posterior fossa (1/3). All patients had biologically aggressive high-grade tumors (glioblastoma multiforme, atypical teratoid rhabdoid tumor, and anaplastic/large cell medulloblastoma) and died within weeks of diagnosis.

Conclusions

Our study highlights a clinical challenge of persistent vomiting in infants, which in the absence of convincing gastrointestinal pathology after evaluation should raise the physician’s suspicion of an underlying intracranial pathology even if neurological features are absent.     

Does the absence or presence of sleep spindles on EEG have prognostic value for cognitive outcome in children with infantile epileptic spasms syndrome? A systematic literature review

Infantile Epileptic Spasms Syndrome (IESS) is an epileptic encephalopathy in childhood that affects infants under the age of two years. When spasm series occur, prognosis for cognitive outcome is poor in the majority of cases. The encephalopathy in IESS includes delayed maturation of normal sleep phenomena in the EEG, such as sleep spindles. Children with intellectual disabilities often have abnormal sleep, and children with sleep problems have difficulties learning at school. We examined whether there is evidence of prognostic value of detection of sleep spindles in the EEG of children with IESS on their future cognitive development. A systematic literature search yielded five studies touching this question. They were evaluated by two scorers independently. The lack of normal sleep patterns including lack of sleep spindles was used as a biomarker of poor cognitive outcome. Positive (PPV) and Negative (NPV) prognostic values were calculated. A summary of all five studies indicates a PPV of 82% and an NPV of 45%. Given the small amount of data, the retrospective quality of most studies, and the differences in the outcome parameters reported, it is prudent to say that currently available data do not allow us to conclude whether spindles have a specific and independent role in the cognitive prognosis of affected children. Since sleep spindles are needed for memory consolidation and demonstrate the active role of sleep for learning and memory, the hypothesis remains that their absence in the EEG may indicate an increased risk of cognitive delay, but more supporting data are needed to reach such a firm conclusion.     

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age-dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug-resistant IESS.     

Surgery or γ -knife for the treatment of arteriovenous malformations?

Decision making for either surgery or γ-knife for the treatment of arteriovenous malformations (AVMs) cannot be uniform. The skill of the neurosurgeon in operating on AVMs is now being compared with that of the γ-knife. The decision varies from case to case and is to be taken by the neurosurgeon. This report presents three cases in which such decision making was not easy. Case 1 was a non-ruptured cingulate AVM of 2.5 cm diameter in the cingulate cortex. The operative field was anticipated to be very narrow between the parietal bridging veins. Case 2 was a tiny ruptured AVM in the speech-motor area which was buried underneath the cortex. Case 3 was a large ruptured thalamo-stiriate-capsular AVM with feeders from the anterior and posterior choroidal arteries. All cases were operated without serious morbidity. A combination of pre-operative intravascular surgery (cases 1 and 3) or postoperative γ-knife (case 3) was adopted. In conclusion, there is no unitary rule to decide on surgery or γ-knife for the treatment of AVMs. It depends on what good or harm the responsible surgeon or the γ-knife does.     

Which children receive vigabatrin? Characteristics of pediatric patients enrolled in the mandatory FDA registry

Vigabatrin (Sabril®) is an antiepileptic drug (AED) currently indicated in the US as a monotherapy for patients 1 month to 2 years of age with infantile spasms (IS) and as adjunctive therapy for patients ≥ 10 years of age with refractory complex partial seizures (rCPS) whose seizures have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. The approval required an FDA mandated registry. This article describes 5 years of demographic and treatment exposure data from US pediatric patients (< 17 years). Participation is mandatory for all US Sabril® prescribers and patients. A benefit–risk assessment must be documented for patient progression to maintenance therapy. This includes demographic diagnosis and reports of ophthalmologic assessments (where available). Patient data were grouped by age as proxies for indication (IS: < 3 years, rCPS: ≥ 3 to < 17 years). As of August 26, 2014, 5546/6823 enrolled patients were pediatric/total; 4472 (81%) were vigabatrin-naïve. Seventy-one percent of patients were < 3 years of age; 29% were ≥ 3 to < 17 years of age. Etiologies of IS were identified as cryptogenic (21%), symptomatic tuberous sclerosis (17%), and symptomatic other (42%). The majority of patients with IS (56%) attempted no prior treatments; 16% received adrenocorticotropic hormone prior to vigabatrin. A third of patients with IS were receiving 1 concomitant treatment with vigabatrin. For patients with rCPS, 39% attempted 1–3 prior treatments; 27% were receiving 2 concomitant treatments at enrollment. A total of 1852 (41%) patients did not undergo baseline ophthalmological assessment; 25% of patients with IS and 42% of patients with rCPS were exempted for neurologic disabilities. Kaplan–Meier estimates predict that 71% and 65% of vigabatrin-naïve patients with IS and rCPS, respectively, would remain in the registry at 6 months. Most pediatric vigabatrin patients have IS as an underlying diagnosis, especially those < 3 years of age. A proportion of those with rCPS remain on long-term vigabatrin despite the risk of adverse events.     

The treatment of infantile hydrocephalus: ”differential-pressure” or ”flow-control” valves

The choice of shunt valve in the treatment of hydrocephalus in children remains controversial. We embarked on a pilot study to determine the differences in outcome between differential-pressure and flow-regulating valves. Prospective data collected on 50 consecutive first-time shunt insertions, performed between June 1993 to June 1996, was analysed. Children with tumour- related hydrocephalus and Dandy-Walker malformations as well as children who had external ventricular drainage prior to definitive shunt insertion were excluded from the study. The defining event was the first complication necessitating surgery, including obstruction, over-drainage and infection. Of the 50 children (31 males), 23 had differential pressure (medium-pressure) and 27 had Delta (performance level 2) valves inserted. The mean age at shunt insertion was 26.4 months. The mean follow-up was 53.8 months. The overall cumulative shunt survival at 5 years was 58.6% for the differential pressure and 58.7% for the Delta valves. The mean shunt life was 37.1 months for the differential pressure group and 34.6 months for the Delta group. This difference was not statistically significant (P=0.72, t-test). Both valves had a similar outcome with respect to obstruction (including proximal, valve, distal). The main differences between the two valves were with respect to the incidence of over-drainage and infection. Amongst the differential pressure valves, there were 4 instances of overdrainage (3 slit-ventricle syndrome, 1 bilateral subdural collection) – all occurring within the first 36 months. The Delta valve group had only one instance of over-drainage (bilateral subdural collection). There were no infections in the differential pressure valve group, whereas 3 of the Delta valve shunts got infected, all within the first month. Whereas both shunt types seemed to have a similar overall survival, there was a relatively higher incidence of over-drainage amongst the differential pressure valves. The Delta valves, on the other hand, had higher rates of infection. Similar studies with larger numbers could suggest whether the choice of shunt type will ultimately have to be a compromise accepting one or the other complication. Received: 12 October 1999