Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome.

OBJECTIVE: The aim of this study is to describe the long-term neurological, neuropsychological and neuroradiological sequelae and to determine prognostic factors for neurological outcome in children with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome. METHODS: Data on medical history were collected for the study patients. Examinations with grading of neurological signs, neuropsychological tests and brain magnetic resonance imaging with spectroscopy were performed during a follow-up clinic. RESULTS: Fourteen subjects entered the study. All had localized neuroblastoma and they were evaluated after a median of 7.8 years. Patients with a chronic/multiphasic neurological course received steroids combined with intravenous immunoglobulins in the majority of cases. 71% presented neurological sequelae and 62% had a full-scale IQ below the normal range. All patients showed at least some deficit in the neuropsychological functions assessed (language, visual-motor integration, memory, attention and motor ability). Long-term deficits were more frequently detected in patients with an interval of more than 2 months between OMA onset and its diagnosis, even if in most comparisons statistical significance was not reached. Cerebellar atrophy, observed in 36% of patients, was not associated with the neurological outcome. CONCLUSIONS: Persisting disability is present in most children with neuroblastoma-associated OMA. However, our results support the role of an early diagnosis of OMA in reducing sequelae and encourage the use of new immunosuppressive therapies.

MR imaging findings in 2 cases of late infantile GM1 gangliosidosis.

SUMMARY: Late infantile GM1 gangliosidosis is a rare lysosomal disorder characterized by mental deterioration and progressive spastic, cerebellar, and extrapyramidal signs, without facial dysmorphisms and organomegaly. Neuroimaging findings have been reported in only a few cases. Here we report on predominant globus pallidus MR signal-intensity abnormalities in 2 patients with the late infantile form of GM1 gangliosidosis.

Enhancing cranial nerves and cauda equina: an emerging magnetic resonance imaging pattern in metachromatic leukodystrophy and krabbe disease.

We report on three cases of infantile Krabbe disease and one case of infantile metachromatic leukodystrophy showing magnetic resonance (MR) imaging findings of diffuse and coexistent cranial nerve and cauda equina nerve roots enhancement. Such findings may be simultaneous, or even precede, typical white matter abnormalities and, in the appropriate clinical context, may facilitate an earlier diagnosis. There is a rational for the use of contrast agents and craniospinal MR imaging during the first imaging of children with a history of psychomotor regression and clinical evidence of peripheral nerve involvement to exclude differential diagnoses.

Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy.

Aicardi-Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi-Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease.

GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease.

Alexander disease (AD), a rare neurodegenerative disorder of the central nervous system, is characterized by the accumulation of cytoplasmic protein aggregates (Rosenthal fibers) composed of glial fibrillary acidic protein (GFAP) and small heat-shock proteins within astrocytes. To date, more than 40 different GFAP mutations have been reported in AD. The present study is aimed at the molecular diagnosis of Italian patients suspected to be affected by AD. By analyzing the GFAP gene of 13 unrelated patients (eight with infantile form, two with juvenile form and three with adult form), we found 11 different alleles, including four new ones. Among the novel mutations, three (p.R70Q, p.R73K, and p.R79P) were identified in exon 1 and p.L359P in exon 6. The sequence analysis also detected six different single nucleotide polymorphic variants, including two previously unreported ones, spread throughout non-coding regions (introns 2, 3, 5, 6, and 3'UTR) of the gene. All patients were heterozygous for the mutations, thus confirming their dominant effect.

Different molecular mechanisms leading to white matter hypomyelination in infantile onset lysosomal disorders.

Hypomyelinating leukoencephalopathies may be related to a primary disturbance in the formation of myelin or may be caused by neuronal, oligodendrocytic or astrocytic dysfunction, leading to a failure of myelination. Abnormal myelination related to a direct metabolic damage on oligodendrocytes has been shown to occur in some animal models of lysosomal storage diseases. To demonstrate that cerebral white matter hypomyelination may occur also in humans affected by early-onset lysosomal storage diseases, we report three cases with infantile-onset lysosomal storage disorders (type 1 GM1 gangliosidosis, globoid cell leukodystrophy or Krabbe's disease, and type A Niemann-Pick disease) showing white matter hypomyelination. Hypomyelinating leukoencephalopathy may therefore represent a feature of lysosomal storage disorders with onset in the first months of life, when the process of myelination is particularly active, indicating that neuronal storage disorders may be primarily responsible for central nervous system hypomyelination.

Long-lasting myopathy as a major clinical feature of sarcoidosis in a child: case report with a 7-year follow-up.

Muscle involvement in sarcoidosis is rarely described as the predominant feature and muscular symptoms are seldom observed. In recent pediatric series, sarcoid myopathy was no longer considered a typical aspect of sarcoidosis. The authors report a case of sarcoidosis in a patient presenting predominant muscular symptoms since childhood, due to biopsy-proven muscle localization. A seven-year follow-up has demonstrated a slow improvement of symptoms with persistency of electromyography (EMG) and biochemical abnormalities. Mild and transient pulmonary involvement was demonstrated only after diagnosis. Clinical improvement associated with a decrease in serum muscular enzyme levels with no changes in EMG was observed after a six-month course of systemic corticosteroid therapy. In childhood, skeletal muscle symptoms may be the presenting feature of sarcoidosis.

Presence of delayed myelination and macrocephaly in the sister of a patient with vacuolating leukoencephalopathy with subcortical cysts.

Leukoencephalopathy with swelling and a discrepantly mild clinical course ("van der Knaap disease") is a recently identified syndrome. It is characterised by macrocephaly occurring during the first year of life, initially normal or nearly normal development, and slowly progressive ataxia and spasticity with initial preservation of intellectual functions. MRI shows diffuse abnormality in signal intensity, as well as swelling of the hemispheral white matter with subcortical cyst-like spaces in the fronto-parietal and anterior temporal areas. It is thought to have an autosomal recessive mode of inheritance, since many patients have consanguineous parents and more than one affected patient is often present within the same family. We report on two sibs: a 5-year old boy affected with "van der Knaap disease" and his macrocephalic sister whose first MRI (2 years 6 months) showed delayed myelination, which led us to suspect the same disease as her brother, however with subsequent normalisation at the second MRI (3 years 6 months).

[Aplasia and hypoplasia of the optic nerve. Comparison of 2 cases]. / Aplasia ed ipoplasia del nervo ottico. Comparazione di due casi.

Hypoplasia and aplasia of the optic nerve are congenital anomalies characterized respectively by a marked volume reduction (very small papilla, often identifiable only as a rosy-yellowish area from which the retinal vessels emerge) and by the absence of the optic disk (absence of the nerve and mainly of its vessels) and of the visual functions. These anomalies are often associated with malformations of the central nervous system and of the ocular structures. The defects originate in the embryonal period due to the arrested development of the mesodermal component towards the head of the optic nerve. The aim of this study is to try to interpret the different clinical manifestations of the disease by observing two cases (a female and a male) with a clinical picture of aplasia and hypoplasia of the optic nerve respectively. Both cases presented the following clinical characteristics: developmental defects of the optic nerve, severe microcephaly, positive IgG antibodies against CMV. The association of the optic nerve defect with microcephaly is due to the embryogenic origin of the optic vescicle by prosencephalon. The resulting clinical picture is probably the outcome of an interfering process that the authors have presumed in CMV intrauterine infection, after having excluded the most frequent teratogenic agents (maternal diabetes, tabagism, intake of alcohol ad drugs). Moreover, the different degree of ocular involvement and the different time of onset of the intrauterine pathogenic insult in the two cases could account for the different clinical pictures.

Pharmacokinetics of the peritoneal-plasma barrier after systemic mitomycin C administration.

The peritoneal plasma barrier (PPB) is a pharmacologic entity of importance for treatment planning in patients with malignant tumors confined to the abdominal cavity. We have examined the pharmacokinetics of the PPB by sampling abdominal fluid following intravenous mitomycin C (MMC) administration. The study included 15 cycles of treatment in seven patients with peritoneal carcinomatosis from colorectal cancer. Five patients were studied twice and one patient was studied three times for a total of 15 cycles. Patients were treated with intraperitoneal 5-fluorouracil (5-FU) at 20 mg/m2 in 11 of fluid. Between 250 and 500 ml of ascites remained after the 23 hour intraperitoneal dwell. On day 3, MMC (12 mg/m2) was administered intravenously as a 2-hour continuous infusion in 200 ml of dextrose solution. The concentration of MMC was determined in plasma, peritoneal fluid, and urine by high performance liquid chromatolography (HPLC) at frequent intervals for 8 hours. The area under the curve (AUC) for plasma as related to peritoneal fluid was three times greater for plasma in one cycle, two times greater for plasma in three cycles, 1.5 times greater for plasma in five cycles, and the same in six cycles. AUC ratios showed a correlation with the extent of peritoneal stripping at the prior surgical procedure 6 weeks to 14 weeks previously. We conclude that malignant ascites may be less exposed to chemotherapy than systemic tumor nodules when the intravenous route of drug administration is used. This inadequacy is even more pronounced in patients who have had extensive abdominal surgery.

Treatment of electrical status epilepticus by short diazepam (DZP) cycles after DZP rectal bolus test.

The effects of rapid rectal diazepam introduction (DZP test) were investigated in 43 patients (age range 5 months-14 years) with electrical status epilepticus (ESE) undergoing EEG monitoring. A remission of the paroxysmal activity was obtained in 58% of cases, a negative response in 42%, particularly in hypsarrhythmic patterns. DZP test responders were aged over 12 months with organized paroxysmal EEG patterns, in particular with ESE during sleep (ESES). The patients who responded to the DZP test underwent short cycles (3-4 weeks) of relatively high dosage DZP (0.5-0.75 mg/kg). The response to treatment was positive in 64%, particularly in ESES conditions. 56% of responders to the DZP test but not to DZP therapy (five out of nine patients) presented a significant mental retardation; maturational factors were also likely to be present.

SPECT and epilepsy with continuous spike waves during slow-wave sleep.

Ten cases of epilepsy with continuous spike waves in slow-wave sleep (CSWS) were evaluated using single photon emission computed tomography (SPECT); in eight patients the EEG paroxysmal abnormalities showed a predominant localization. SPECT carried out using 99mTc-HMPAO allows study of cerebral blood flow (CBF); the examination was performed during phases of drowsiness and the results compared to the EEG data. In four cases SPECT revealed areas of low CBF in sites corresponding to those of the prevalent EEG discharges; in two cases the areas of hypoperfusion did not correspond to those indicated by the EEG; lastly, in four cases SPECT results were negative. The areas of hypoperfusion were predominantly located in the frontal, temporal, and parietal regions. Furthermore, the percentage of positive SPECT results was significantly higher (five cases out of six) in the group in which the CSWS phase was prolonged for at least 1 year, compared to the group in which this phase lasted less than 1 year. Thus, in this type of epilepsy, SPECT reveals focal cortical areas of decreased CBF which correlated generally to the predominant sites of EEG abnormalities. A longer duration of the CSWS phase seems to be associated with a more significant cortical disorder, documented by the presence of areas of hypoperfusion.

[Role of extracorporeal circulation in reversible acute cardiorespiratory insufficiency in neonatal and pediatric intensive care]. / Ruolo della circolazione extracorporea nell'insufficienza cardiorespiratoria acuta reversibile in terapia intensiva neonatale e pediatrica.

In the present study we try to analyze indications, contra-indication, side effects and limits of the use of extracorporeal circulation in neonatal and pediatric patients affected by reversible acute cardiorespiratory failure. The greatest experience on this technique has been achieved in the neonatal age (about 6000 newborns have been treated until now), while the employment in the pediatric age appears more recent (about 500 patients). Moreover, we focused on the drop-in criteria for neonatal and pediatric patients and on the clinical aspects and laboratory findings which can anticipate the surviving rate; the latter appears in any case much greater in the neonatal patient compared to the other pediatric ages.

Familial white matter hypoplasia, agenesis of the corpus callosum, mental retardation and growth deficiency: a new distinctive syndrome.

We have observed in two different families two pairs of male siblings born from normal, non-consanguineous parents having the same syndrome, characterized by severe cerebral white matter hypoplasia, agenesis or extreme hypoplasia of the corpus callosum, mental retardation, failure to thrive and minor midline facial abnormalities. This seems to be a previously unreported genetic syndrome.

[The clinical assessment and intensive treatment of meningoencephalitis in newborns and children of subsequent ages]. / Valutazione clinica e trattamento intensivo delle meningo-encefaliti in età neonatale e successive età pediatriche.

We focused on the best timing and management when admitting into intensive care unit a pediatric patient with central nervous system infection. The modified scales for pediatric patients did not prove satisfactory and reliable for making such decision. In fact the final score is obtained by adding the partial scores regarding the different clinical aspects. That bears a loss of informations. For this reason we think that the cardiorespiratory and metabolic parameters, assessed in a period of time, may indicate the moment when it is necessary to start an intensive care in these patients, regardless of consciousness. We therefore discussed the monitoring precociously required in these patients after assessing the initial clinical status. We also discussed the intensive care procedure employed in severely ill patients with cardio-circulatory and metabolic problems due to septic shock caused by bacterial meningoencephalitis (infants) and meningitis (other pediatric ages). In patients affected by infectious or post-infective encephalitis with respiratory failure and/or brain edema, it is essential to apply the organ protection procedures and particularly neuroprotection.

Oculocerebral syndrome with hypopigmentation (Cross syndrome): report of a new case.

A syndrome of ocular and cutaneous hypopigmentation, severe mental retardation with spastic tetraplegia and athetosis was first observed by Cross in three siblings of an inbred Amish family. Since then, seven other patients, three sporadic and four with familial recurrence, have been reported in the literature, confirming the autosomal recessive inheritance. The clinical spectrum of the syndrome has been expanded to include true developmental defects of the CNS such as cystic malformation of the posterior fossa of the Dandy-Walker type. We report a new case of Cross syndrome.

Rapid diazepam introduction (venous or rectal) in childhood epilepsy: taxonomic and therapeutic considerations.

Rapid diazepam (DZP) introduction was investigated in 24 children with different types of cryptogenic or symptomatic generalized epilepsy and EEG epileptic "status" with EEG and pharmacologic monitoring. In 12 cases DZP was given intravenously and in another 12 by the rectal route. In general, intravenous administration proved more rapid and more effective as to high blood levels of DZP and the arrest of the paroxysmal activity. However, when the results were correlated to the different forms of paroxysmal EEG activity it was apparent that cases with a typical hypsarrhythmic EEG pattern under the age of 12 months and cases with unorganized paroxysmal activity over the age of 12 months are insensitive or only slightly sensitive to both intravenous and rectal introduction. A number of taxonomic and therapeutic considerations are presented.