Agata Polizzi

MULTIPLE SCLEROSIS IN CHILDREN UNDER 6 YEARS OF AGE

Objectives: To characterize MS patients with the earliest onset of disease. Background: MS—primarily a disease of young adulthood—begins in childhood in 3 to 5% of cases. However, onset before 10 years of age is considered exceptional. Accordingly, inclusion age at onset is generally between 10 and 59 years. Methods: Information was obtained on patients with MS treated at our institution (n = 6) or from reports in Medline or bibliographies. Onset of disease was before 6 years of age, for a total of 49 patients (29 girls, 20 boys). Results: All patients had clinically defined MS according to Poser’s criteria; 22 were also laboratory supported. The female/male ratio (1.4) was lower than that usually recorded for adult onset MS (2.0) and that of MS with onset between 6 and 15 years (2.2 to 3.0). The group of patients (n = 5) with onset before 24 months of age showed the lowest ratio (0.6) and carried the most unfavorable prognosis. Among initial symptoms, ataxia was preponderant (61%). Optic nerve involvement became more frequent with age. Generalized or partial seizures occurred in 22% of cases. First inter-attack interval was less than 1 year in 63% of the cases. The yearly relapse rate ranged from 1.1 at disease onset to 0.2 after 9 years from disease onset. At follow-up (mean length 6.8 years), the disease was relapsing-remitting in 84% patients and the grade of recovery was complete in 64%. Conclusions: Definite MS can be consistently diagnosed by current criteria for adult onset MS in patients with the earliest onset of disease who show peculiar clinical features and natural history. These findings may suggest a reconsideration of current lower limits for MS diagnostic criteria.

Antibodies in Myasthenia Gravis and Related Disorders

Abstract: Acetylcholine receptor (AChR) antibodies are present in around 85% of patients with myasthenia gravis (MG) as measured by the conventional radioimmunoprecipitation assay. Antibodies that block the fetal form of the AChR are occasionally present in mothers who develop MG after pregnancy, especially in those whose babies are born with arthrogryposis multiplex congenita. The antibodies cross the placenta and block neuromuscular transmission, leading to joint deformities and often stillbirth. In these mothers, antibodies made in the thymus are mainly specific for fetal AChR and show restricted germline origins, suggesting a highly mutated clonal response; subsequent spread to involve adult AChR could explain development of maternal MG in those cases who first present after pregnancy. In the 15% of “seronegative” MG patients without AChR antibodies (SNMG), there are serum factors that increase AChR phosphorylation and reduce AChR function, probably acting via a different membrane receptor. These factors are not IgG and could be IgM or even non‐Ig serum proteins. In a proportion of SNMG patients, however, IgG antibodies to the muscle‐specific kinase, MuSK, are present. These antibodies are not found in AChR antibody‐positive MG and are predominantly IgG4. MuSK antibody positivity appears to be associated with more severe bulbar disease that can be difficult to treat effectively.

Multiple sclerosis in children under 10 years of age.

Abstract.Despite the consistent amount of information accumulated in recent years on multiple sclerosis (MS) in childhood, many clinicians still view this condition as an exclusively young adult-onset disease and do not consider that it may occur and manifest even during infancy and pre-school age, suggesting that the number of MS cases in the paediatric age group may have been underestimated. Thus, the need to have practical parameters for therapeutic, counselling and educational purposes in such settings as caring for patients whose onset of disease is at very early ages may increasingly arise for practising clinicians. In addition, the clinical and radiographic criteria for the diagnosis of MS have not been validated in a paediatric MS population; accordingly, inclusion age at onset (such as for research purposes) is generally over 10 years. To highlight the peculiarities that characterise MS when it begins at this young age we have reviewed the literature and summarised our preliminary results with the national registry of the Italian Society of Paediatric Neurology (SINP) Study Group on Childhood MS in the group of MS patients with the earliest onset of disease (i. e., <10 years of age).

Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenita causes deformities in mice.

Arthrogryposis multiplex congenita (AMC) is characterized by fixed joint contractures and other deformities, sometimes resulting in fetal death. The cause is unknown in most cases, but some women with fetuses affected by severe AMC have serum antibodies that inhibit fetal acetylcholine receptor (AChR) function, and antibodies to fetal antigens might play a pathogenic role in other congenital disorders. To investigate this possibility, we have established a model by injecting pregnant mice with plasma from four anti-AChR antibody-positive women whose fetuses had severe AMC. We found that human antibodies can be transferred efficiently to the mouse fetus during the last few days of fetal life. Many of the fetuses of dams injected with AMC maternal plasmas or Ig were stillborn and showed fixed joints and other deformities. Moreover, similar changes were found in mice after injection of a serum from one anti-AChR antibody-negative mother who had had four AMC fetuses. Thus, we have confirmed the role of maternal antibodies in cases of AMC associated with maternal anti-AChR, and we have demonstrated the existence of pathogenic maternal factors in one other case. Importantly, this approach can be used to look at the effects of other maternal human antibodies on development of the fetus.

Two Novel SCN1A Missense Mutations in Generalized Epilepsy with Febrile Seizures Plus

) for muta-tions in SCN1A, SCN1B, and GABRG2 genes (1–3).Probands were ascertained from the clinical practice inthree epilepsy centers in southern Italy. Detailed familypedigrees were constructed, including maternal and pa-ternal lines extending as far back as possible. In the ninefamilies, we investigated 110 members of whom 37 indi-viduals were determined to be affected. Most patients hadfebrile seizures (FSs) or FS plus (FS

Ohtahara syndrome with emphasis on recent genetic discovery

Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brains neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.

Acute Disseminated Encephalomyelitis: A Long-Term Prospective Study and Meta-Analysis

BACKGROUND There are only a few series in the literature on acute disseminated encephalomyelitis (ADEM) in children. OBJECTIVES AND METHODS the aims of this study were to perform (i) a prospective clinical/imaging study (1992-2009) on ADEM in children consecutively referred to our institution in Catania, Italy, and (ii) to undertake a systematic review and meta-analysis of published ADEM pediatric cohorts (>10 cases). RESULTS We identified 17 patients with ADEM (incidence <10 years of age=1.1 per 100 000 person-years). 15 previously published cohorts were compared with our cohort: (i) systematically reviewed (750 cases); and (ii) meta-analyzed (492/750 cases). The 17 patients had the following characteristics: (a) male-to-female ratio, 1.4 (vs. 1.2-1.3 in previous cohorts); (b) mean age at presentation, 3.6 years (vs. 7.1 years in previous cohorts); (c) specific preceding triggering factor, 88% (vs. 69-79% in previous cohorts); (d) the most common initial signs were ataxia, seizures, headache, and thalamic syndrome; (e) brain imaging revealed >3 lesions in 100% (vs. 92% in previous cohorts); (f) the outcome was good in 94% (vs. 70-75% in previous cohorts); and (g) 12% relapsed once (vs. 18% in previous cohorts). CONCLUSIONS ADEM is generally a benign condition that mosly affects boys more than girls and rarely recurs.

Ophthalmological manifestations in segmental neurofibromatosis type 1

Aims: To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1. Methods: Visual acuity and colour tests, visual field examination, slit lamp biomicroscopy of the anterior segment, and a detailed examination of the retina by indirect ophthalmoscopy were performed at diagnosis and follow up in 72 consecutive subjects (29 males, 43 females; aged 1–64 years; mean age 14.6 years) seen at the university departments of paediatrics in Catania and Rome, Italy, during years 1990–2003, who had in restricted body areas: (1) typical pigmentary manifestations of NF1 (café au lait spots and freckling) only (n = 48); (2) NF1 pigmentary manifestations and neurofibromas alone (n = 2); (3) neurofibromas only (n = 15); and (4) plexiform neurofibromas only (n = 7). Results: None of the 72 patients had Lisch nodules in the iris irrespective of age at eye examination or hypertelorism (a “minor” NF1 feature) and none developed typical associated ophthalmological NF1 complications. An additional child had an isolated optic pathways glioma (OPG), which behaved both biologically and radiographically as an NF1 associated OPG. Conclusions: This represents the first systematic study reporting on eye involvement in the largest series of individuals at different ages having segmental NF1. As one of the postulated mechanisms to explain segmental NF1 is somatic mosaicism for the NF1 gene (so far demonstrated only in two patients) the present findings could be explained either by the fact that the eye is too far from the mutated area with NF1 lesions in most cases or by the NF1 (or other “predisposing” or “cooperating”) gene mutation restricted to too few cellular clones or to tissues embryologically different from the eye.

Thalamic Syndrome in Children With Measles Infection and Selective, Reversible Thalamic Involvement

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Recurrent peripheral neuropathy in a girl with celiac disease

The involvement of the peripheral nervous system (PNS) in children with celiac disease is particularly rare. Furthermore, in both children and adults with celiac disease, neurological complications are chronic and progressive.1 We report on a 12 year old girl affected by celiac disease, who on two separate occasions presented with an acute peripheral neurological syndrome after accidental reintroduction of gluten in her diet. This patient was born uneventfully to healthy non-consanguineous parents with no family history of neurological or metabolic diseases. At the age of 6 months she was diagnosed as having celiac disease according to the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) criteria. Since then she was on a strict gluten free diet and was asymptomatic until the age of 10 years when severe diarrhoea, vomiting, and abdominal pain manifested 6 days after the intake of corn flakes erroneously thought to be gluten free. No previous infections had been noticed. One week after the onset of these symptoms she experienced acute weakness and pins and needles sensation confined to her legs. At that time her parents stopped her intake of corn flakes on the suspicion that these were responsible for the symptoms. Despite this, symptoms worsened during the next 2 days, confining her to bed. At hospital admission, she was alert and mentally stable. Results of general physical examination were unremarkable. Neurological examination disclosed symmetric, predominantly distal, weakness of the legs; …