Neil Stoodley

Clinical and Imaging Heterogeneity of Polymicrogyria: A Study of 328 Patients.

Polymicrogyria is one of the most common malformations of cortical development and is associated with a variety of clinical sequelae including epilepsy, intellectual disability, motor dysfunction and speech disturbance. It has heterogeneous clinical manifestations and imaging patterns, yet large cohort data defining the clinical and imaging spectrum and the relative frequencies of each subtype are lacking. The aims of this study were to determine the types and relative frequencies of different polymicrogyria patterns, define the spectrum of their clinical and imaging features and assess for clinical/imaging correlations. We studied the imaging features of 328 patients referred from six centres, with detailed clinical data available for 183 patients. The ascertainment base was wide, including referral from paediatricians, geneticists and neurologists. The main patterns of polymicrogyria were perisylvian (61%), generalized (13%), frontal (5%) and parasagittal parieto-occipital (3%), and in 11% there was associated periventricular grey matter heterotopia. Each of the above patterns was further divided into subtypes based on distinguishing imaging characteristics. The remaining 7% were comprised of a number of rare patterns, many not described previously. The most common clinical sequelae were epileptic seizures (78%), global developmental delay (70%), spasticity (51%) and microcephaly (50%). Many patients presented with neurological or developmental abnormalities prior to the onset of epilepsy. Patients with more extensive patterns of polymicrogyria presented at an earlier age and with more severe sequelae than those with restricted or unilateral forms. The median age at presentation for the entire cohort was 4 months with 38% presenting in either the antenatal or neonatal periods. There were no significant differences between the prevalence of epilepsy for each polymicrogyria pattern, however patients with generalized and bilateral forms had a lower age at seizure onset. There was significant skewing towards males with a ratio of 3:2. This study expands our understanding of the spectrum of clinical and imaging features of polymicrogyria. Progression from describing imaging patterns to defining anatomoclinical syndromes will improve the accuracy of prognostic counselling and will aid identification of the aetiologies of polymicrogyria, including genetic causes.

Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve Hypoplasia

The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.

Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation.

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain‐imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega‐cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.

Apnoea and brain swelling in non-accidental head injury

Aims: (1) To identify whether infants and young children admitted to hospital with subdural haematomas (SDH) secondary to non-accidental head injury (NAHI), suffer from apnoea leading to radiological evidence of hypoxic ischaemic brain damage, and whether this is related to a poor prognosis; and (2) to determine what degree of trauma is associated with NAHI. Methods: Retrospective case series (1992–98) with case control analysis of 65 children under 2 years old, with an SDH secondary to NAHI. Outcome measures were presenting symptoms, associated injuries and apnoea at presentation, brain swelling or hypoxic ischaemic changes on neuroimaging, and clinical outcome (KOSCHI). Results: Twenty two children had a history of apnoea at presentation to hospital. Apnoea was significantly associated with hypoxic ischaemic brain damage. Severe symptoms at presentation, apnoea, and diffuse brain swelling/hypoxic ischaemic damage were significantly associated with a poor prognosis. Eighty five per cent of cases had associated injuries consistent with a diagnosis of non-accidental injury. Conclusions: Coma at presentation, apnoea, and diffuse brain swelling or hypoxic ischaemia all predict a poor outcome in an infant who has suffered from SDH after NAHI. There is evidence of associated violence in the majority of infants with NAHI. At this point in time we do not know the minimum forces necessary to cause NAHI. It is clear however that it is never acceptable to shake a baby.

Neuroimaging: what neuroradiological features distinguish abusive from non-abusive head trauma? A systematic review

Objectives To identify the evidence base behind the neuroradiological features that differentiate abusive head trauma (AHT) from non-abusive head trauma (nAHT). Design Systematic review. Setting Literature search of 14 databases, websites, textbooks, conference abstracts and references (1970–February 2010). Studies had two independent reviews (three if disputed) and critical appraisal. Patients Primary comparative studies of children <11 years old hospitalised with AHT and nAHT diagnosed on CT or MRI. Main outcome measures Neuroradiological features that differentiated AHT from nAHT. Results 21 studies of children predominantly <3 years old were analysed. Subdural haemorrhages (SDH) were significantly associated with AHT (OR 8.2, 95% CI 6.1 to 11). Subarachnoid haemorrhages were seen equally in AHT and nAHT and extradural haemorrhages (EDH) were significantly associated with nAHT (OR for AHT 0.1, 95% CI 0.07 to 0.18). Multiple (OR 6, 95% CI 2.5 to 14.4), interhemispheric (OR 7.9, 95% CI 4.7 to 13), convexity (OR 4.9, 95% CI 1.3 to 19.4) and posterior fossa haemorrhages (OR 2.5, 95% CI 1 to 6) were associated with AHT. Hypoxic-ischaemic injury (HII) (OR 3.7, 95% CI 1.4 to 10) and cerebral oedema (OR 2.2, 95% CI 1.0 to 4.5) were significantly associated with AHT, while focal parenchymal injury was not a discriminatory feature. SDH of low attenuation were more common in AHT than in nAHT. Conclusion Multiple SDH over the convexity, interhemispheric haemorrhages, posterior fossa SDH, HII and cerebral oedema are significantly associated with AHT and should be considered together with clinical features when identifying the condition.

Mutation in Rab3 GTPase-Activating Protein (RAB3GAP) Noncatalytic Subunit in a Kindred with Martsolf Syndrome

We identified a homozygous missense mutation in the noncatalytic subunit (RAB3GAP2) of RAB3GAP that results in abnormal splicing in a family with congenital cataracts, hypogonadism, and mild mental retardation (Martsolf syndrome). Recently, mutations in the catalytic subunit of RAB3GAP (RAB3GAP1), a key regulator of calcium-mediated hormone and neurotransmitter exocytosis, were reported in Warburg micro syndrome, a severe neurodevelopmental condition with overlapping clinical features. RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively. We performed messenger RNA-expression studies of RAB3GAP1 and RAB3GAP2 orthologues in Danio rerio embryos and demonstrated that, whereas developmental expression of rab3gap1 was generalized (similar to that reported elsewhere in mice), rab3gap2 expression was restricted to the central nervous system. These findings are consistent with RAB3GAP2 having a key role in neurodevelopment and may indicate that Warburg micro and Martsolf syndromes represent a spectrum of disorders. However, we did not detect RAB3GAP2 mutations in patients with Warburg micro syndrome. These findings suggest that RAB3GAP dysregulation may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome.

Neuroradiological aspects of subdural haemorrhages

Aims: To review the neuroimaging of a series of infants and young children admitted to hospital with subdural haemorrhage (SDH). Methods: Neuroradiological investigations of 74 children under 2 years of age, from South Wales and southwest England, in whom an SDH or subdural effusion had been diagnosed between 1992 and 2001, were reviewed. Two paediatric neuroradiologists blinded to the original radiological report reviewed all the relevant images. Results: Neuroradiological review of images identified radiological features which were highly suggestive of non-accidental head injury (NAHI). Interhemispheric haemorrhages and SDHs in multiple sites or of different densities were almost exclusively seen in NAHI. MRI was more sensitive in identifying SDHs of different signal characteristics, posterior and middle cranial fossa bleeds, and parenchymal changes in the brain. CT scans, if performed with suboptimal protocols, were likely to miss small subdural bleeds. Conclusions: Guidelines for neuroimaging in suspected NAHI are recommended. A radiologist with experience in NAHI should report or review these scans. The initial investigation should be CT, but MRI will also be necessary in most cases. Head CT should be an integral part of the skeletal survey in all infants less than 6 months of age referred for child protection investigation, and in children less than 2 years where child abuse is suspected and there are neurological signs, retinal haemorrhages, or fractures.

A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly

We describe a three generation family with recurrent strokes and cataracts. The index case, a 14 year old boy presented with stroke at the age of 14 years and again 6 months later. His mother had long standing episodic headaches diagnosed as migraine. Grandmother was initially diagnosed with multiple sclerosis and had recurrent strokes at age 18 years and 49 years. MRI scanning showed a diffuse leukoencephalopathy with microhaemorrhages in all three individuals. All of the family members had cataracts but did not have retinal arterial changes. Sequence analysis of COL4A1 revealed the heterozygous missense mutation c.2263G-->A in exon 30, responsible for a glycine-to-arginine substitution (p.Gly755Arg) in both the index case and mother. Grandmother died at the age of 73 years and DNA analysis was not possible. Mutation in COL4A1 should be considered in families with a history of autosomal dominant cerebral vasculopathy, even in the absence of porencephaly.

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients—two male–female sibling pairs, one pair born to consanguineous parents, and an unrelated female—with a distinct pattern of band‐like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post‐natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable “pseudo‐TORCH” phenotype inherited as an autosomal recessive trait.

Childhood presentation of COL4A1 mutations

Aim  To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation.