Francis J. DiMario

Tuberous Sclerosis Consensus Conference: Recommendations for Diagnostic Evaluation

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 disorders 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. (J Child Neurol 1999;14:401-407).

Global cognitive function in children with epilepsy: A community‐based study

Purpose: To determine the frequency and determinants of subnormal global cognitive function in a representative, community‐based sample of children prospectively identified at the time of initial diagnosis of epilepsy.

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Background Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Trial Registration Clinicaltrials.gov NCT00126672

Brain abnormalities in tuberous sclerosis complex.

Tuberous sclerosis complex is an autosomal dominant multisystem disorder. Spontaneous mutations occur in up to 60% of patients with gene loci located on chromosomes 9q34 ( TSC1) and 16p13 (TSC2). Diagnosis is established with the identification of various neurocutaneous markers and multiple organ system hamartomas. The variable expression of severity, the potential for cognitive dysfunction, and epilepsy compound the clinical picture. The intracranial abnormalities include the identification of migration and hamartomatous brain lesions, such as tubers, subependymal nodules, and subependymal giant cell astrocytomas. A number of other neuroimaging and morphometric abnormalities coexist, which can be identified with current neuroimaging techniques. This review examines the spectrum of brain abnormalities encountered in tuberous sclerosis complex and presents them as not merely a collection of lesions but more cohesively in the context of a global neuronal migration disorder. (J Child Neurol 2004;19:650—657).

Neurofibromatosis Type 1: Magnetic Resonance Imaging Findings

The purpose of this study was to determine the locations and characterize the types of brain abnormalities noted on brain magnetic resonance imaging in patients with probable and definite neurofibromatosis type 1. Patients with definite neurofibromatosis type 1 (n = 17) were studied when clinically indicated, and patients with probable neurofibromatosis type 1 (n = 9) were studied to evaluate for asymptomatic optic pathway glioma. Of the 26 patients evaluated, 14 (53%) had high-intensity signal abnormalities and 11 (42%) had significant structural abnormalities. Subsequent clinical follow-up has confirmed conversion to a definite neurofibromatosis type 1 diagnosis in three of the four cases of probable neurofibromatosis type 1 who had high-intensity signal abnormalities. The most common locations of high-intensity signal lesions were in the globus pallidus of the basal ganglia and cerebellar white matter. Tortuous or thickened optic nerves and/or optic chiasm were seen in eight cases. Brain magnetic resonance imaging scans frequently reveal high-intensity signal lesions and structural abnormalities in selected patients with both probable and definite neurofibromatosis type 1. These findings may allow for a definitive diagnosis in clinically probable cases. (J Child Neurol 1993;8:32-39).

Family pedigree analysis of children with severe breath-holding spells☆☆☆★

We examined family pedigrees of children with severe breath-holding spells (SBHS). There were 57 probands (27 males, 30 females; 44 cyanotic, 13 pallid) whose families comprised 1683 individuals. We found that 31 (27%) of 114 proband parents and 9 (21%) of 43 proband siblings had current or prior SBHS. Father-to-son transmission was observed in 7 instances. There were 7 families with 2 or more affected siblings and 5 families with 3 or more affected members. From 85 nuclear families, 130 individuals had current or prior SBHS (59 males, 71 females; male/female ratio, 1:12). These data suggest that the most likely underlying genetic inheritance pattern in SBHS is an autosomal dominant trait with reduced penetrance.

Residual cognitive effects of uncomplicated idiopathic and cryptogenic epilepsy

We assessed residual cognitive deficits in young people with idiopathic and cryptogenic epilepsy. In the setting of an ongoing prospective study, we invited participants initially diagnosed and enrolled in the cohort 8-9 years earlier to undergo standardized neuropsychological assessment. Sibling controls were invited when available. We analyzed 143 pairs in which cases had idiopathic or cryptogenic epilepsy and both case and control had normal intelligence. Compared with that for siblings, the Full Scale IQ for cases was 3.3 points lower (P=0.01) mainly due to slower processing speed, which was 5.6 points lower (P=0.0004). Word reading (P=0.04) and spelling (P=0.01), but not other scores, were also lower in cases. Remission status and drug use did not influence findings. In young people of normal intelligence with idiopathic or cryptogenic childhood-onset epilepsy, substantial residual effects of epilepsy appear to be confined largely to slower processing speed.

Behavior and social competency in idiopathic and cryptogenic childhood epilepsy

Behaviroal and related disorders are frequently reported in association with childhood epilepsy but the reasons for this are unclear. In a long‐term prospective, community‐based study of newly‐diagnosed childhood epilepsy, behavioral assessments (Child Behavior Checklist) were performed in children 8 to 9 years after the initial diagnosis of epilepsy to determine the impact of remission and medication status on behavioral problems. Children with epilepsy were also compared with sibling controls. A total of 226 children (108 females, 118 males; mean age 13y 1mo [SD 2y 8mo], range 8‐17y) with idiopathic or cryptogenic epilepsy were included in the analyses. One hundred and twenty‐eight matched pairs were included in analyses of case‐sibling differences. Lack of remission and current medication use were associated with worse behavioral problem and competency scores. Lack of remission generally had a greater effect than medication use, except for attention problems; medication status had the more deleterious effect (p<0.001). Children with epilepsy had significantly worse behavioral problems and competency scores relative to sibling controls. Even in paris in which the patient was seizure‐free and off medication, significant case‐sibling differences persisted for most scales (p=0.05 to p=0.001). Lack of remission and continued use of antiepileptic drugs have a negative influence on behavioral problems in children with epilepsy but do not fully explain the worse scores relative to siblings. This suggests an independent effect associated with the epilepsy itself.

Evolution of Cardiac Rhabdomyoma in Tuberous Sclerosis Complex

The objective of the study was to define the longitudinal evolution of cardiac rhabdomyomas (CR) in patients with tuberous sclerosis complex (TSC). A cohort of patients with TSC who had undergone videotaped echocardiographic (ECHO) examination during the 10-year interval (1984-1994) were retrospectively studied by reviewing and quantifying the CR appearance and associated cardiac abnormalities in sequentially obtained ECHO examinations. Sixteen patients with TSC (8 males) underwent a total of 35 recorded studies. Ten of the 16 (62.5%) had CR identified at initial study; none were found in the atria. Localization was the ventricular walls as compared with the ventricular septum by a ratio of 2:1. The number of CRs sequentially studied declined as follows; initial study: 23 lesions in 10 patients; second study: 16 lesions in 8 patients; third study: 12 lesions in 5 patients; and fourth study: 4 lesions in 2 patients. Total CR size index declined at each study as follows: initial index of 2,684; second index of 1,746 (-35% from initial); third index 1,141 (-57% from initial); and fourth index 705 (-74% from initial). Complete spontaneous regression of CR was seen by age 6 years with prolonged gradual resolution thereafter. Two patients had bicuspid aortic valves and two had conduction defects. Patients with TSC who have CR can be expected to experience a decline in both the number and size of CR over time; early complete regression on ECHO occurs before age 6 years.

Autonomic nervous system function in severe breath-holding spells

This study attempted to determine noninvasively whether a dysregulation of autonomic nervous system reflexes exists in children with severe cyanotic breath-holding spells (BHS). This was a cross-sectional study performed in the neurophysiology laboratory at a tertiary care hospital. Patients, 18 months of age and older taken from a referral population of children with severe cyanotic BHS and normal controls, were studied. Fourteen children with cyanotic BHS and 12 controls were evaluated. Several noninvasive measures of parasympathetic and sympathetic reflex functions were assessed and statistically analyzed using analysis of variance and covariance, and Fishers exact tests. The cyanotic BHS group had a significantly greater increase in pulse rate at 15 s of standing after rising from the supine position (P < .06), with a trend toward a concomitant higher mean arterial pressure (P < .09). After adjusting for age, sex, and mean supine systolic and diastolic blood pressures, breath-holders had a greater decrease in diastolic blood pressure (P < .02) without an increase in systolic blood pressure after standing from the supine position. Breath-holders also had significantly abnormal 30:15 R-R interval ratios compared with controls (P < .002). These results support the hypothesis that children with cyanotic BHS have underlying autonomic nervous system dysregulation. This dysregulation may contribute to the pathophysiology of severe BHS in these children.