Filippo Arrigoni

Early Cerebral Lesions in Cytomegalovirus Infection: Prenatal MR Imaging

PURPOSE To assess the diagnostic and prognostic value of fetal cerebral magnetic resonance (MR) imaging of congenital cytomegalovirus (CMV) infection in comparison with that of level II ultrasonography (US). MATERIALS AND METHODS Institutional review board approval and informed consent for fetal MR imaging and data collection were obtained. Thirty-eight fetuses with CMV infection, examined by using serial level II US, underwent fetal MR imaging (mean gestational age, 25 weeks; age range at first fetal MR examination, 20-34 weeks). The frequency of pathologic findings at US (29 cases with transabdominal examination and nine cases with both transabdominal and transvaginal examination) and MR imaging was calculated, and a comparison between techniques by considering number (paired Student t test) and type (McNemar test) of finding was made. A comparison (paired Student t test) in cases of repeated fetal (nine of 38) and/or postnatal (14 of 38) MR imaging was obtained. Diagnostic and prognostic sensitivity was calculated for both techniques. RESULTS US and MR imaging findings were both normal in 47% of cases (18 of 38). Abnormal studies were reported in 26% (10 of 38) of US and 53% (20 of 38) of MR imaging cases. In 47% of cases (18 of 38), MR imaging provided additional information (P = .0002). MR imaging had better results than US in detecting polar temporal lesions (P = .0001), microencephaly (P = .03), and cortical anomalies (P = .06). In 44.5% of cases (four of nine), the second fetal MR examination results showed new findings (P = .05). In 79% of cases, postnatal MR imaging results confirmed prenatal findings (P = .08). MR imaging had higher sensitivity than US in detecting brain anomalies (92% vs 38%) and in predicting symptomatic infection (83% vs 33%). US and MR imaging revealed low positive predictive values (29% vs 36%). CONCLUSION Fetal MR imaging results can show abnormalities in the fetal brain after CMV infection, even when US results are normal. The early detection of some brain abnormalities, such as microencephaly and cortical anomalies, may substantially influence the prognosis of fetal infection.

Mutations in α- and β-tubulin encoding genes: Implications in brain malformations

The tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this family encode dimeric proteins consisting of two closely related subunits (α and β), representing the major constituents of microtubules. Tubulin genes play a crucial role in the mechanisms of the Central Nervous System development such as neuronal migration and axonal guidance (axon outgrowth and maintenance). Different mutations in α/β-tubulin genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, and TUBB) might alter the dynamic properties and functions of microtubules in several ways, effecting a reduction in the number of functional tubulin heterodimers and causing alterations in GTP binding and disruptions of the binding of other proteins to microtubules (motor proteins and other microtubule interacting proteins). In recent years an increasing number of brain malformations has been associated with mutations in tubulin genes: malformations of cortical development such as lissencephaly and various grades of gyral disorganization, focal or diffuse polymicrogyria and open or closed-lips schizencephaly as likely consequences of an altered neuronal migration process; abnormalities or agenesis of the midline commissural structures (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, dysmorphisms of the hind-brain as expression of axon guidance disorders. Dysmorphisms of the basal ganglia (fusion between the caudate nucleus and putamen with absence of the anterior limb of the internal capsule) and hippocampi were also observed. A rare form of leukoencephalopathy characterized by hypomyelination with atrophy of the basal ganglia an cerebellum (H-ABC) was also recently described. The present review, describing the structural and functional features of tubulin genes, aims to revise the main cerebral associated malformations and related clinical aspects, suggesting a genotype-phenotype correlation.

A novel mutation in the β-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice‐site mutations in the genes encoding α‐ and β‐tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G > C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open‐lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine‐rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the β‐tubulin gene TUBB2B, supporting its critical role in migration/organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly.

Brain malformations and mutations in α- and β-tubulin genes: a review of the literature and description of two new cases

The aim of this study was to determine the frequency of mutations in tubulin genes (TUBB2B, TUBA1A, and TUBB3) in patients with malformations of cortical development (MCDs) of unknown origin.

Is fetal magnetic resonance imaging indicated when ultrasound isolated mild ventriculomegaly is present in pregnancies with no risk factors?: Role of MR in fetuses with mild isolated ventriculomegaly on US

Ventriculomegaly (VM) is the most common brain anomaly in prenatal ultrasound (US) diagnosis. There is a general trend to perform fetal magnetic resonance imaging (MRI) when VM is severe (greater than 15 mm) and/or it is not isolated. The role of MRI is debated when VM is borderline (between 10 and 15 mm) and isolated. Some authors have subdivided borderline VM into mild (10 to 12 mm) and moderate (>12 to15 mm). The aim of the study was to evaluate the role of MR in the imaging protocol of fetal cases characterized by mild isolated VM and no risk factors.

A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors’ density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy.

Deep Medullary Vein Involvement in Neonates with Brain Damage: An MR Imaging Study

These investigators report a new finding that may lead to the development of periventricular leukomalacia in premature infants. They analyzed conventional T1 and T2 images in 21 babies who showed areas of low T2 signal corresponding to the deep medullary veins. These abnormalities were found in association with cavities or cysts and, when followed, about 25% of patients developed typical MRI indications of periventricular leukomalacia. The authors suggest these findings may be related to venous thrombosis or engorgement and precede the onset of periventricular leukomalacia. BACKGROUND AND PURPOSE: Different and specific MR imaging patterns of lesions involving WM are widely defined in neonatal encephalopathy. The aim of this study was to describe a novel MR imaging pattern of damage characterized by the abnormal prominence of DMVs in premature and full-term neonates. MATERIALS AND METHODS: Twenty-one (11 premature and 10 full-term) neonates with MR imaging evidence of linear radially oriented fan-shaped lesions in the periventricular WM and without dural venous thrombosis were enrolled in this retrospective study. A total of 37 MR imaging examinations were performed at ages ranging from day 0 to 24 months. RESULTS: According to the appearance of linear anomalies on T2-weighted images, we identified 2 main patterns: T2 hypointense lesions without WM cavitations and T2 hypointense lesions associated with linear cysts. The first pattern was found in 17 examinations performed between 0 and 44 days of life; the second pattern was found in another 14 examinations performed between 6 days and 4 months of life. Five examinations performed between 9 and 24 months of life showed a reduction in volume and hyperintense signal intensity of the periventricular WM on T2-weighted and FLAIR images. CONCLUSIONS: Subtle linear WM lesions with the same anatomic distribution of DMVs may be evident in premature and full-term neonates without signs of major venous thrombosis, both in the acute and subacute phases. Their appearance and evolution suggest that transient DMV engorgement/thrombosis may be responsible for WM damage that can lead to a PVL-like pattern.

Prenatal MR Imaging of the Normal Pituitary Stalk

BACKGROUND AND PURPOSE: Prenatal imaging data of the normal pituitary gland and in vivo information on the development of the pituitary region are lacking; however, we noticed that the pituitary stalk (PS) is visible occasionally in utero on MR images. Our main purpose was to establish the detection rate of the PS in healthy fetuses at various gestational ages (GAs) by using single-shot fast spin-echo T2-weighted images. MATERIALS AND METHODS: We selected 73 fetal cases with normal findings on prenatal MR imaging and clinical postnatal follow-up. The GA ranged between 19 and 37 weeks. The 3 planes of MR imaging sections were 4 mm thick with 1.25 × 1.25 mm in-plane resolution. Two pediatric neuroradiologists evaluated in consensus whether the PS was present as a linear isointense structure connecting the hypothalamic region with the floor of sella turcica. In those cases in which the PS was visible on the sagittal section, the angle formed by the intersection of the PS and the sellar plane (SP) was measured (PS-SP angle). RESULTS: The PS was detectable on at least 1 coronal or sagittal section from 19 to 25 weeks’ GA in 30/42 fetuses (71.4% sensitivity); from 26 to 37 weeks’ GA, the PS was detected in all 31 fetuses (100% sensitivity). The PS-SP angle decreased significantly with GA, being <90° in all fetuses after gestational week 25. CONCLUSIONS: At the current spatial resolution of clinical prenatal MR imaging, PS can be reliably detected after 25 weeks’ GA, so in case of a missing visualization, a strong suspicion of pituitary region anomaly could be raised.

Investigation of negative BOLD responses in human brain through NIRS technique. A visual stimulation study

Despite negative blood oxygenation level dependent (BOLD) responses to visual stimuli have recently gained considerable interest, the explanation for their underlying neuronal and vascular mechanisms is still controversial. In the present study, a multimodal experimental approach is presented to shed light on the negative BOLD phenomenon in the human brain. In particular, information from functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS) was integrated to confirm and gain insight into the phenomenon of negative BOLD responses (NBRs) to unpatterned intermittent photic stimulation (IPS) in healthy subjects. Eight healthy subjects participated in the study. Consistent findings emerged from the activation analysis of fMRI and NIRS data and the comparison of BOLD and hemoglobin responses at the single channel level showed that NBRs are related to a decrease in oxyhemoglobin (HbO) combined with a lower increase in deoxyhemoglobin (HHb), corresponding to a decrease in total hemoglobin (THb) and estimated cerebral blood volume (CBV). The HbO and HHb variations were significant in at least one channel in six subjects out of eight (p<0.05). The NIRS technique allowed obtaining valuable information on the vascular determinants of the NBRs, since the discrimination between HbO, HHb and THb information provided a more comprehensive view of the negative BOLD phenomenon. The within and between subject heterogeneous BOLD-Hb temporal relations pave the way to further investigations into the neurovascular properties of NBRs.

A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern

Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-year-old boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of “STXBP1-related encephalopathy” suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects.