Emilio Franzoni

A new leukoencephalopathy with vanishing white matter

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

Unusual variants of Alexander's disease.

The purpose of this study was to describe unusual variants of Alexanders disease. We studied 10 patients who did not meet previously established magnetic resonance imaging (MRI) criteria for Alexanders disease, but for whom this diagnosis was considered because of Rosenthal fibers at histological examination or presence of some MRI features suggestive of Alexanders disease. Sequence analysis of the GFAP gene was performed. In eight patients, MRI results showed predominantly posterior fossa lesions, especially multiple tumor‐like brainstem lesions. One patient had asymmetrical frontal white matter abnormalities and basal ganglia abnormalities. One patient (Patient 10) developed degeneration of the frontal white matter. In nine patients, a mutation was found that was concluded to be pathogenic, because the mutation was de novo (five patients), a known mutation was found (two patients), or assembly of the glial fibrillary acidic protein was abnormal in cultured cells (two patients). In Patient 10, a DNA variation was found that was also present in the patients clinically unaffected father and was concluded to be a polymorphism. In conclusion, DNA diagnostics is warranted in patients who display MRI features suggestive of Alexanders disease, even if they do not meet the full set of previously established MRI criteria. Ann Neurol 2005;57:327–338

EARLY PREDNISONE TREATMENT IN DUCHENNE MUSCULAR DYSTROPHY

The purpose of this long‐term, open parallel‐group, double‐consent study of alternate‐day, low‐dose prednisone in 2–4‐year‐old patients with Duchenne muscular dystrophy (DMD) was to determine whether prednisone produces a beneficial effect when given earlier than usual. Muscle function was evaluated by timed tests, and muscle strength with a hand‐held myometer. After 55 months of treatment, the five patients (mean age 8.3 years) in the prednisone group were still able to get up from the floor, whereas two of the three in the control group had lost this ability. Side effects included a decline in growth rate in the prednisone‐treated patients and excessive weight gain in one control and three treated patients. Because steroids are effective in prolonging function, but not in recovering lost function, we propose that treatment be started with low‐dose prednisone in DMD patients as soon as the diagnosis is definite. Muscle Nerve 27: 222–227, 2003

Early corticosteroid treatment in 4 Duchenne muscular dystrophy patients: 14-year follow-up.

Corticosteroid treatment is the standard of care in Duchenne muscular dystrophy (DMD), but the optimal age to initiate treatment and dosage pattern remain a matter of discussion.

Increased oxidative stress in epileptic children treated with valproic acid

PURPOSE To determine influence of Valproic Acid (VPA) treatment on oxidative status in non-obese and overweight epileptic children. METHODS A prospective study was conducted at the Departments of Pediatrics, University of Chieti and Bologna. Thirty-one epileptic children were studied before and after 1 year of therapy with VPA. Also 31 sex-, age- and BMI-matched healthy controls were evaluated. Insulin and glucose serum levels and plasma Vitamin E, Lag phase and Malondialdehyde (MDA) levels were determined. RESULTS Before the beginning of VPA therapy, insulin and glucose serum values and plasma Vitamin E, Lag phase and MDA levels were normal in all subjects. At the end of follow-up, 11 (35.5%) epileptic patients developed obesity. In obese VPA treated patients, we found lower serum levels of antioxidant (Vitamin E, p<0.001) and higher levels of oxidant markers (MDA, p<0.001; Lag phase, p<0.001) compared to VPA-treated non-obese patients and controls. CONCLUSION After 1 year of VPA therapy oxidative stress occurs only in overweight children. This increase in the levels of oxidant markers, probably caused by obesity, might contribute to the development of endothelial dysfunction and atherosclerosis later in life.

Total Cholesterol, High‐Density Lipoprotein Cholesterol, and Triglycerides in Children Receiving Antiepileptic Drugs

Summary: The influence of antiepileptic drug (AED) therapy on total cholesterol (TC), high‐density lipoprotein (HDL) cholesterol, and triglycerides was studied in 208 epileptic children compared with 175 normal children. A significant increase in TC plasma levels was observed with carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT). The patients receiving valproate (VPA) showed levels very similar to those of the control population. The results may be explainable by the different biotransformation pathway of these drugs. HDL cholesterol and triglycerides were not altered by any of the AEDs. We recommend monitoring TC level in patients receiving CBZ, PB, and PHT and prescription of diet treatment, at least during the time of AED treatment.

Efficacy and safety of levetiracetam: An add-on trial in children with refractory epilepsy

The aim of this multicentric, prospective and uncontrolled study was to evaluate the efficacy and safety of levetiracetam in 110 children with refractory epilepsy, of whom 21 were less than 4 years old. After a median follow-up period of 7 months, levetiracetam administration was effective (responders with >50% decrease in seizure frequency) in 39% of children, of whom 10 (9%) became seizure-free. The efficacy was higher in patients with localization-related epilepsy (58% of responders) than in those with generalized epilepsy (37% of responders). Levetiracetam was well tolerated. The main side effects of somnolence and irritability occurred in 14% of patients. In one patient acute choreoathetosis occurred after few doses of levetiracetam. Overall, the adverse effects were not severe. Children younger than 4 years were particularly tolerant. In conclusion, the present study confirms that levetiracetam is effective and well tolerated as an add-on treatment in children with refractory epilepsy. Our preliminary data also indicate that levetiracetam may be a valid therapeutic option for epilepsy in infants and young children.

Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate.

OBJECTIVE This study evaluates the effects of long-term carbamazepine (CBZ) and valproate acid (VPA) therapy on thyroid function in epileptic children. DESIGN A prospective study performed in 32 newly diagnosed pediatric patients, subdivided into two groups: 18 patients treated with CBZ and 14 patients treated with VPA. Thirty-two sex- and age- matched subjects served as controls. METHODS Serum TSH, thyroxine (T(4)), triiodothyronine (T(3)), free thyroxine (fT(4)), free triiodothyronine (fT(3)), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Ab) were evaluated at baseline and at the 3rd, 6th, and 12th month in all patients and in the control group. A TRH stimulation test was performed in all epileptic patients at baseline and at the 3rd, 6th, and 12th month evaluations while in controls only baseline assessment was carried out. RESULTS At baseline evaluation, thyroid function was normal in all epileptic children. After 3 months, CBZ-treated patients showed serum T(4) and fT(4) levels significantly lower than baseline evaluation and control subjects. Serum T(4) and fT(4) concentrations were unaffected by VPA monotherapy. Serum T(3) and fT(3) were normal in both CBZ-treated and VPA-treated patients. TRH test was normal in all patients. At 6th and 12th month evaluations, the same alterations were present in CBZ-treated patients while thyroid function remained normal in VPA-treated patients. TRH test responses were normal in all epileptic patients. TPO-Ab and TG-Ab were always absent in all patients. CONCLUSIONS Our data suggest that VPA monotherapy does not alter thyroid hormones. On the contrary, alterations of thyroid hormones occur in CBZ-treated children. However, the patients are euthyroid and thyroid hormone alterations are not associated with clinical or subclinical hypothyroidism.

Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.