Bilateral temporal arachnoid cysts associated with tuberous sclerosis complex

The association between tuberous sclerosis complex and intracranial abnormalities such as hemimegalencephaly, schizencephaly, intracranial arterial aneurysms, and corpus callosum agenesis/dysplasia has been reported in the recent literature. However, the association between tuberous sclerosis complex and bilateral temporal arachnoid cysts has not been reported. A case of an 8-year-old boy with a mental impairment and epileptic seizures that began 5 years earlier is presented. The neuro-radiological findings are consistent with tuberous sclerosis complex associated with bitemporal arachnoid cysts. His epileptic seizures were treated with antiepileptic medications. To the authors' knowledge, this is the first reported case of tuberous sclerosis complex associated with bilateral arachnoid cysts of the temporal region. In such cases, arachnoid cysts may exacerbate the clinical picture.     

A case of neonatal tuberous sclerosis with large calcified lesions in the brain parenchyma]

A patient was reported, who was diagnosed as having tuberous sclerosis in neonatal period. He began to have complex partial seizures at 3 weeks of age. At 27 days of age, brain CT revealed a large high density lesion from the left temporal cortex to the left posterior horn, in addition to periventricular nodules. These lesions were not enhanced after injection of contrast medium. Brain MRI demonstrated more nodular lesions, the intensity pattern of which was different form those in previously reported cases. Ictal EEG showed secondary generalization from left temporal focus, which was compatible with complex partial seizures. In English literature, neonatal cases of tuberous sclerosis with large parenchymal lesions on brain CT were reported by only a few authors, and only two cases of neonatal MRI findings were documented. The neonate with tuberous sclerosis should be carefully evaluated because of the atypical appearance of MRI in rare cases.     

Aberrant cellular differentiation and migration in renal and pulmonary tuberous sclerosis complex

This review is focused on pathways and mechanisms that might provide molecular links between the pathogenesis of renal and pulmonary disease in tuberous sclerosis complex and the pathogenesis of the neurologic manifestations of tuberous sclerosis complex. Tuberous sclerosis complex is an autosomal dominant disorder in which the manifestations can include seizures; mental retardation; autism; benign tumors of the brain, retina, skin, and kidneys; and pulmonary lymphangiomyomatosis. Lymphangiomyomatosis is a life-threatening lung disease affecting almost exclusively young women. Genetic data have demonstrated that the cells giving rise to renal angiomyolipomas, the most frequent tumor type in patients with tuberous sclerosis complex, exhibit differentiation plasticity. Genetic studies have also shown that the benign smooth muscle cells of angiomyolipomas and pulmonary lymphangiomyomatosis have the ability to migrate or metastasize to other organs. These findings indicate that hamartin and tuberin play functional roles in the regulation of cell migration and differentiation. The biochemical pathways responsible for these effects are not yet fully understood but might involve dysregulation of the small guanosine triphosphatase Rho. Similar pathways might contribute to aberrant neuronal differentiation and migration in tuberous sclerosis complex.     

Molecular genetic basis of tuberous sclerosis complex: from bench to bedside

Tuberous sclerosis complex is an autosomal dominant disease of benign tumors occurring in multiple organ systems of the body. Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype. The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways. Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. Numerous pathogenic mutations have been elucidated in individuals affected with tuberous sclerosis complex. Information on the type and distribution of nearly 1000 mutations in the two genes is discussed. Mosaicism for tuberous sclerosis complex mutations has been documented, complicating provision of genetic counseling to families. Emerging genotype-phenotype correlations should provide guidance for better medical care of individuals with tuberous sclerosis complex.     

Current management for epilepsy in tuberous sclerosis complex

PURPOSE OF REVIEW: This article reviews the most significant advances in the field of epilepsy associated with tuberous sclerosis complex, with emphasis on new advances in the knowledge of the pathophysiological mechanisms of epileptogenicity, progress in identifying the epileptogenic zone, and the rationale for surgical management in individuals with intractable seizures. RECENT FINDINGS: Advances in our understanding of the mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with tuberous sclerosis complex may facilitate more effective interventions. Early effective seizure control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice in the short-term treatment of infantile spasms. Some individuals, however, develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with tuberous sclerosis complex remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. Epilepsy surgery is often associated with significant improvement of the neurologic outcome. SUMMARY: Epilepsy in tuberous sclerosis seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition. Understanding the mechanisms of epileptogenesis might increase the availability of development of a more specific and efficacious treatment. New evidence suggests that it is possible to noninvasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment.     

Cortical tubers, cognition, and epilepsy in tuberous sclerosis

Tuberous sclerosis complex is an autosomal-dominant genetic disorder characterized by hamartomatous growth in various organs. Patients who have this disorder exhibit a high rate of epilepsy and cognitive problems. We investigated number of tubers, location, seizure types, and cognitive outcome, and we analyzed the relationships among them in our tuberous sclerosis patients in the Comprehensive Epilepsy Program at the University of Alberta. We also examined the seizure outcome after tuber resection. Our study cohort included 24 patients with tuberous sclerosis complex. We obtained seizure history, electroencephalogram, and neuropsychologic parameters. Magnetic resonance imaging was used to examine tuber numbers and locations. Ten patients underwent surgical removal of tubers responsible for intractable epilepsy. A negative correlation was found between the number of tubers and intelligent quotient score. Epilepsy surgery led to freedom from seizures in this patient group. We demonstrated that the total number and location of cortical tubers play a significant role in the extent of mental retardation in patients with tuberous sclerosis complex. In addition, patients with intractable seizures and well-defined epileptic focus had excellent surgical outcome.     

Vagal nerve stimulation in tuberous sclerosis complex patients

This is an open-label, retrospective, multicenter study to determine the outcome of intermittent stimulation of the left vagal nerve in children with tuberous sclerosis complex and medically refractory epilepsy. The records of all children treated with vagal nerve stimulation were reviewed in five pediatric epilepsy centers to locate those with tuberous sclerosis complex who had been treated with vagal nerve stimulation for at least 6 months. These patients were compared with (1) a series of patients obtained from the literature, (2) 10 similar control patients with epilepsy obtained from a registry of patients receiving vagal nerve stimulation, and (3) four published series of tuberous sclerosis complex patients whose epilepsy was surgically managed. Ten tuberous sclerosis complex patients with medically refractory epilepsy treated with vagal nerve stimulation were found. Nine experienced at least a 50% reduction in seizure frequency, and half had a 90% or greater reduction in seizure frequency. No adverse events were encountered. Comparison with published and registry patients revealed improved seizure control in the tuberous sclerosis complex patients. Comparison with the group undergoing seizure surgery demonstrated improved outcomes after surgery. Vagal nerve stimulation appears to be an effective and well-tolerated adjunctive therapy in patients with tuberous sclerosis complex and seizures refractory to medical therapy. Resective surgery has a better prospect for improved seizure control.     

Development, behaviour and seizures in 300 cases of tuberous sclerosis

Three hundred cases of tuberous sclerosis were surveyed by postal questionnaire, including 240 cases with learning difficulties. People who have tuberous sclerosis and severe learning disabilities also have a higher frequency of epileptic seizures than people with learning difficulties from all causes. Pervasive developmental disorder and hyperactive behaviour are behavioural features of the disorder. Sleep problems and the level of vigilant care required because of seizures or behaviour have implications on the level of service needed to support people with tuberous sclerosis in the community.     

SISCOM in Children with Tuberous Sclerosis Complex-Related Epilepsy

Identification of a single epileptogenic focus in patients with tuberous sclerosis complex is a challenge. Noninvasive imaging modalities, including subtraction ictal single-photon emission computed tomography coregistered to magnetic resonance imaging (SISCOM), have been used to determine the dominant epileptogenic focus for surgical resection. We assessed whether complete resection of SISCOM hyperperfusion abnormality correlates with seizure-free outcome in 6 children with tuberous sclerosis complex-related epilepsy. The median seizure onset age was 4 months (range 1 day to 16 months). The age at surgery ranged from 8 months to 13 years. A dominant SISCOM hyperperfusion focus was identified in 5 patients with multiple tubers. SISCOM provided additional localizing information for epilepsy surgery in 3 patients with nonlocalizing or discordant electrophysiologic and neuroimaging findings. At a minimum of 2 years’ follow-up, 3 patients were free of seizures overall. Freedom from seizures was associated with complete resection of SISCOM abnormality in 2 patients. These findings demonstrate that SISCOM can be useful in identifying the epileptogenic zone and in guiding the location and extent of epilepsy surgery in children with tuberous sclerosis complex and multifocal abnormalities. In children with tuberous sclerosis complex and intractable epilepsy, complete resection of the SISCOM hyperperfusion abnormality is associated with freedom from seizures.     

Autism and tuberous sclerosis

The co-occurrence of autism spectrum disorder and tuberous sclerosis complex has been recognized for decades. The prevalence of tuberous sclerosis complex in the autism spectrum disorder population is 1 to 4%, whereas features of autism spectrum disorder are present in 25 to 50% of individuals with tuberous sclerosis complex. The underlying reason for this association might be a nonspecific disruption of brain function owing to tuberous sclerosis complex, including tuber location, seizures and their effect on brain development, cognitive impairment, a disturbance in brain development in regions associated with autism spectrum disorder, or, less likely, a linkage between a TSC gene and an autism susceptibility gene. Awareness of the relationship between autism spectrum disorder and tuberous sclerosis complex is important during the evaluation of individuals with either disorder. Better delineation of the association and its causative factors is needed for the development of possible interventions.     

Surgical treatment for epilepsy in 17 children with tuberous sclerosis-related West syndrome

The efficacy of surgery for the treatment of epilepsy in patients with West syndrome secondary to tuberous sclerosis is unclear. The charts of 17 patients with tuberous sclerosis and secondary West syndrome who underwent a one-stage surgical resection with a combined palliative operative procedure were reviewed. Engel classification was used to classify the patients with regard to seizure status following surgery. After surgery, 11 patients were in Engel class I, 4 in class II, and 2 in class III. The EEG after surgery was normal in 8 patients, significantly improved in 8, and without significant improvement in 1 patient. Six patients had a recurrence of seizures after surgery, which included 3 patients with continuing spasms and 3 patients where the spasms had resolved but had developed either partial seizures or generalized tonic-clonic seizures. There were significant improvements in the Gesell Developmental Schedules for motor field (P=0.003), adaptive field (P=0.003), language field (P=0.033), and personal-social field (P=0.007). Thus, a one-stage surgical approach can be used to produce satisfactory outcomes in young children with tuberous sclerosis who have secondary West syndrome and seizures that do not respond to conventional antiepileptic therapy, even in when there are multiple epileptogenic foci.     

Efficacy of Thyrotropin-Releasing Hormone in the Treatment of Intractable Epilepsy

Purpose : The ictal EEG and magnetoencephalogram (MEG) for gelastic seizures were recorded in a 4-year-old girl with tuberous sclerosis. The sites of origin for the seizure activities were investigated by using an equivalent current dipole (ECD) with the MEG.
Methods : EEG and MEG were recorded simultaneously under the administration of diazepam (DZP). The MEG recording was performed on a system consisting of an array of 64 sensors uniformly distributed over the patient's whole head (CTF, Canada), and the estimated ECDs were superimposed on the magnetic resonance imaging (MRI) images (Siemens, 1.5 Tesla).
Results : Two laughing attacks lasting 5 s each were documented. The ictal EEG showed gradually increasing 11–Hz rhythmic α activities with dominance over the frontocentral areas bilaterally, followed by irregular spike-and-wave discharges. The ictal MEG detected bilateral frontal rhythmic sharp waves before the appearance of the activities on the EEG. The estimated ECDs were localized in the deep white matter of the right frontal lobe on the MRI. However, those dipoles did not coincide with the locations of her cortical tubers.
Conclusions : Although gelastic seizures accompanied with hypothalamic hamartomas are well known, several reports have suggested a temporal or frontal lobe origin for gelastic seizures. In this patient, the ECD indicated that the seizures originated in the frontal lobe, although ictal scalp EEG recordings could not determine the precise focus. Thus, in cases in which the use of ictal scalp EEG fails to show the sites of origin for the seizures, it is recommended that the origins be estimated by using the non-invasive method of ictal MEG analysis.     

Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review

The purpose of this report is to review the efficacy and safety of vigabatrin in the treatment of infantile spasms in infants suffering from tuberous sclerosis complex. We reviewed all studies published in the English-language literature investigating the use of vigabatrin in the treatment of infantile spasms. Ten studies gave results for the efficacy of vigabatrin in infantile spasms for infants both with and without underlying diagnoses of tuberous sclerosis. Of the 313 patients without tuberous sclerosis complex, 170 (54%) had complete cessation of their infantile spasms; of the 77 patients with tuberous sclerosis complex, 73 (95%) had complete cessation of their seizures. We conclude that vigabatrin should be considered as first-line monotherapy for the treatment of infantile spasms in infants with either a confirmed diagnosis of tuberous sclerosis or those at high risk, ie, those with a first-degree relative with tuberous sclerosis complex. Paradoxically, in those without tuberous sclerosis complex, vigabatrin might be less efficacious than suggested by studies including patients with tuberous sclerosis complex.     

Neonatal diagnosis of tuberous sclerosis

Intracranial tumors are rare in the neonatal period, and generally the most common histological types are astrocytoma, medulloblastoma, choroid plexus papilloma and neuroectodermal tumors. The early diagnosis of these tumors is often very difficult. The authors report a case of a full-term newborn who presented with opisthotonus. A subependymal mass was detected by cerebral ultrasonography, and when the child was 1 month of age depigmentations appeared on the trunk and on the right leg, confirming the suspicion of tuberous sclerosis. At 3 months of age the child suffered infantile spasm with hypsarrhythmia. The developmental delay, the marked progressive neurological deterioration and the daily seizures suggested surgical resection. Histologic studies showed a subependymal giant cell astrocytoma such as typically occurs in tuberous sclerosis.     

Occlusive hydrocephalus complicating tuberous sclerosis: report of two cases

Two patients—6 and 14 years old—with tuberous sclerosis are presented. Both developed a subependymal giant cell astrocytoma from nodules located near to the foramen of Monro. They caused obstruction of the cerebrospinal fluid pathways. Signs of raised intracranial pressure were detected in both patients, and one of them had also developed infantile spasm—Blitz-Nick-Salaam seizures. Cutaneous stigmata being characteristic for this entity were observed in both cases, but their mental development was unaffected. Diagnosis was based on computed tomography. Angiography did not reveal pathological vessels. The tumours were completely excised through transcallosal exposure in both cases. The patients have been symptom-free during the follow-up time of 1 and 2 years. Although the incidence of malignant transformation of tuberous sclerosis is less than 15% the disease generally has a poor prognosis which can be ascribed to sudden increase of intracranial pressure caused by obstruction of cerebrospinal fluid pathways by paraventricular tumours. However, regular follow-up of paraventricular nodules and maintenance of patency of cerebrospinal fluid pathways by microsurgical methods in patients suffering from mild cerebral disorders offers a better chance of survival.     

Epilepsy surgery for children with tuberous sclerosis complex

Tuberous sclerosis complex is associated with medically refractory seizures and developmental delay in children. These epilepsies are often resistant to antiepileptic drugs, can be quite severe, and usually have a negative impact on the child's neurologic and cognitive development. It is believed that functional outcome is improved if seizures can be controlled at an early age. The surgical treatment of intractable epilepsy in children and adults with tuberous sclerosis complex has gained significant interest in recent years. Previously published studies have shown a potential benefit from resection of single tubers, with most of the results noted in relatively older children. All of these reports support the idea that if a single primary epileptogenic tuber or region can be identified, then a surgical approach is appropriate. However, most children with tuberous sclerosis complex have multiple potentially epileptogenic tubers, rendering localization challenging, and they are therefore rejected as possible surgical candidates. We have used a novel surgical approach using invasive intracranial monitoring, which is typically multistaged and bilateral. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in patients with tuberous sclerosis complex with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected patients. Long-term follow-up will determine whether this approach has durable effects. We await better methods for identifying the epileptogenic zone, both noninvasive and invasive.     

Long-term prognosis of tuberous sclerosis with epilepsy in children

A follow-up study was performed on 40 children with tuberous sclerosis and epilepsy. In 68% of the patients with infantile spasms and 73% of those without them, complex partial seizures were observed. Thus, patients with tuberous sclerosis are subject to not only infantile spasms but also complex partial seizures. Patients with infantile spasms showed mental retardation more often than those without. Seizures which had evolved from infantile spasms were more difficult to control than those which had not. The prognosis of infantile spasms associated with tuberous sclerosis was better than that of prenatal group other than tuberous sclerosis. Forty percent of the 40 cases showed asymmetry on EEG, and the asymmetry tended to disappear as the patients grew up.     

Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.

At the recent Tuberous Sclerosis Consensus Conference, a subcommittee proposed recommendations to guide the rational use of diagnostic studies in patients with tuberous sclerosis complex. Recommendations were made for diagnostic evaluation at the time of diagnosis, when testing helps both to establish the diagnosis and to identify potential complications. Additional guidelines were proposed for the ongoing surveillance of established patients to detect later complications of tuberous sclerosis complex. In the absence of comprehensive population studies to govern the use of diagnostic studies in individuals with tuberous sclerosis complex, the panel developed guidelines based on the disorder's natural history, concentrating on complications that are common, clinically significant, and more easily managed when found early. Finally, the group made suggestions for the use of diagnostic tests to identify family members who have tuberous sclerosis complex. Although these recommendations should standardize and improve our use of diagnostic studies in individuals with tuberous sclerosis complex, the clinical approach in a given patient must remain flexible enough to meet the needs of individual patients and families.     

Mesial temporal sclerosis after status epilepticus due to milk alkali syndrome.

Seizures induced by hypercalcemia are rare. A few case reports of seizures associated with hypercalcemia have been published, but none due to the milk alkali syndrome. This is the first report regarding seizures associated with calcium carbonate overuse. The two patients described in this article, who had no risk factors for developing epilepsy, suffered from status epilepticus probably induced by hypercalcemia. Subsequently, they both developed complex partial seizures, and were later found to have mesial temporal sclerosis on MRI. There are no reports linking hypercalcemia to mesial temporal sclerosis. While this may be a coincidence, there is reason to suspect that the development of persistent epilepsy, possibly due to mesial temporal sclerosis, was caused by prolonged seizures induced by hypercalcemia.     

Unusual presentation of hypothalamic hamartoma with hypersomnia in an adult patient

We report a patient with polysomnography findings related to hypersomnia, as a primary presenting symptom, who was shown to have stereotypical gelastic seizures. Her cranial magnetic resonance imaging revealed a hypothalamic hamartoma in the posterior region of the hypothalamus. The patient had no previous history of gelastic seizures. We suggest that patients who present with hypersomnia should be investigated for gelastic seizures in order to avoid misdiagnosis and receive appropriate treatment.