Sml Paine

Role of routine neuropathological examination for determining cause of death in sudden unexpected deaths in infancy (SUDI)

Background Current guidelines for the investigation of sudden unexpected death in infancy (SUDI) include full neuropathological examination with recommendations for brain fixation for 1–2u2005weeks. Little evidence is available regarding the yield of such examination in determining cause of death in clinical practice. This study examines the frequency of neuropathological findings determining cause of death at postmortem examination in SUDI in relation to clinical and macroscopic features. Methods All postmortem examinations performed for the indication of SUDI at a single specialist centre over a 14-year period were reviewed, including clinical history, macroscopic and neuropathological findings. Results 6% of postmortem examinations performed for cases of SUDI demonstrated a neuropathological cause of death; in almost all (>90%) the clinical history and/or macroscopic examination suggested the cause of death. In 2% of all cases the cause of death was determined by histological neuropathological examination, but there were no cases in which histological neuropathological examination of a macroscopically normal brain revealed the cause of death in the absence of a ‘neurological history’. Macroscopic brain abnormalities and the presence of a ‘neurological history’ were significantly more likely to yield histological brain abnormalities (11-fold and fourfold, respectively). Conclusions Histological neuropathological examination rarely determines the cause of death in SUDI in the absence of macroscopic abnormalities or neurological clinical history. A macroscopically abnormal brain and the presence of a clinical history of possible neurological disease or of inflicted injury are significantly more likely to be associated with significant histological brain abnormalities.

The neuropathological consequences of CDKL5 mutation

A wide range of mutations in the X-linked gene cyclindependent kinase-like 5 (CDKL5), causing either frameshifts or interfering with the splice sites, have been described in children of both sexes with early-onset epileptic encephalopathy, infantile spasms and a Rett syndromelike phenotype [1–4]. In the majority of mutation carriers, brain MRI is normal but non-specific abnormalities including cerebral atrophy and reduced white matter bulk or myelination have been reported [2,5–16]. The neuropathological consequences of CDKL5 mutations have not been previously described. We present the neuropathology of a child with infantile spasms and a Rett-like syndrome who carried a de novo, novel CDKL5 mutation and who suffered a sudden unexpected death at the age of 5 years. We found malformations and striking ongoing degeneration in the cerebellum. It is likely that some of these features are attributable to the gene mutation. Following an uneventful pregnancy, a girl was born at 35 weeks’ gestation to non-consanguineous parents. Her birth weight was 2.47 kg.The child’s mother and maternal grandfather have fatigable right ptosis. At the age of 11 weeks, she presented with focal clonic seizures, which subsequently became generalized. EEG did not show any epileptiform activity. At 18 months, her seizures evolved in to infantile spasms, which were treated with steroids and vigabatrin. EEG showed multifocal polymorphic spike waves, suggestive of epileptic encephalopathy. At 2 years of age her infantile spasms resolved and she developed clusters of tonic seizures that were refractory to several antiepileptic drugs. EEG showed marked abnormality with frequent central and fronto-central epileptiform activity. Her development was delayed: she sat at 16 months and achieved supported standing at 20 months. After a period of poor seizure control at 20 months she significantly regressed and stopped sitting and talking. These skills were not recovered. She had been hyperkinetic since infancy with mixed dystonic and choreoathetoid movements and occasional opisthotonus. Her vision was severely restricted and she was unable to fix or follow. It was not possible to test her hearing. She had a poor swallow and had frequent aspirations. There were no dysmorphic features but her head circumference was >2 SD below the mean. Brain MRI between the ages of 2 and 4 years demonstrated progressive cerebral and cerebellar atrophy without any focal lesions. Brainstem-evoked responses were normal but her visual evoked potentials demonstrated significant impairment of visual cortical function. Extensive metabolic investigations and respiratory chain studies were normal. A skeletal muscle biopsy showed a mild excess of lipid but no diagnostic features. Mutation analyses for SCN1A, Angelman syndrome (UBE3A) and Rett syndrome (MECP2) were negative. Array-CGH was negative and a karyotype normal. Analysis of CDKL5 showed a novel heterozygous mutation c.2277-2A>G which is predicted to destroy the splice acceptor site of exon 16. At the age of 5 years, she was found dead in bed in the early hours of the morning, having been well the previous day. A careful review of her history showed that at no point had she received phenytoin. A detailed post mortem examination was undertaken, according to a standard protocol, which involved histological examination of all major organ systems, detailed microbiology and toxicology. The only significant abnormalities were in the central nervous system. The fixed brain weighed 1010 g and the structures of the posterior fossa weighed 118 g (11.7% of total brain weight). The occipital poles were flattened, giving a brachycephalic appearance (Figure 1). On the base of the brain, the temporal poles were drawn inwards and directed towards the midline. From the exterior, both superior temporal gyri appeared small but on coronal section they were of normal size but deeply buried. The lateral and third ventricles were enlarged throughout. The cerebellar vermis and hemispheres were macroscopically normal. Microscopically, the main findings were in the vermis and cerebellum where there were a small number of short

Antenatal neurodevelopmental defects in ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) is a mitochondrial enzyme that catalyses the production of citrulline from ornithine and carbamoyl phosphate. Mutations in the gene, which is encoded on the X chromosome, result in reduced enzyme function and accumulation of ammonia. It is the commonest inherited defect of the urea cycle. Depending upon the precise genetic mutation, presentation can be either in the neonatal period with vomiting, seizures and coma or later in life with a range of problems including neuropsychiatric disorders, chronic encephalopathy and stroke-like episodes. The neuropathological findings in a small number of cases of OTC deficiency (OTCD) with neonatal onset have been reported. These are typically destructive insults causing progressive degeneration, resulting in ulegyria with cystic degeneration, global cerebral atrophy, neuronal loss and astrocytic gliosis [1–5]. We describe a case of OTCD with neonatal onset in which there are coexisting hippocampal, dentato-olivary and cerebellar malformations that have not been previously described together, suggesting an in utero teratogenic effect of the gene defect. Following an entirely uneventful pregnancy, a boy was born at 39 weeks gestation to non-consanguineous parents. His birth weight was 3.77 kg. At 2 days of age, he became lethargic and unresponsive. He was found to have a compensated metabolic acidosis with a blood ammonia level of 397 mmol/l. This peaked at 651 mmol/l, requiring continuous venovenous haemofiltration. On the fourth post-natal day he showed abnormal posturing which resolved promptly. Genetic analysis confirmed a mutation in the OTC gene (c.1028 C > A p.Thr343Lys) on exon 10 and confirmed that his mother was a carrier. He was managed with a low-protein diet and ammonia scavenger drugs. His motor development was age appropriate but he had cognitive delay, communication difficulties and challenging behaviour that were thought to be part of the autism spectrum. He had very few and rather mild episodes of metabolic decompensations and had no further neurological sequelae, in particular no seizures or visual symptoms. At the age of 5 years, he became acutely unwell with a febrile illness and rapidly became comatose. Blood ammonia on admission to hospital was 279 mmol/l and peaked later that day at 474 mmol/l. He was treated with antibiotics, sodium benzoate and sodium phenylbutyrate and was sedated and ventilated. Over the next 2 days he was treated with mannitol and haemofiltration with rapid normalization of the blood ammonia level. Despite this, diffuse cerebral oedema developed causing tonsillar herniation and he died 48 h after becoming acutely unwell. Extensive anteand post mortem microbiological investigations for possible bacterial and viral agents were negative. Consent was given for a limited post mortem examination. The whole fixed brain weighed 1710 g and the cerebellum and brainstem weighed 183 g (10.7% of whole brain weight). The leptomeninges were clear. The gyral patterning was normal but the gyri were swollen, effacing the sulci. Both cerebellar tonsils were necrotic. Coronal sectioning revealed symmetrical swelling of the cerebral hemispheres with squaring of the lateral angles of the body of the lateral ventricles. The mammillary bodies were at the level of the Greenhall line. Microscopic examination of the brain revealed two types of lesion. First, there was evidence of acquired pathology including widespread neuronal hypoxia/ ischaemia. Throughout the normally formed cerebral cortex there was neuronal eosinophilia with neuropil breakdown and microgliosis. In the hippocampus there was neuronal eosinophilia and cell loss, particularly in sectors CA1 and CA3 where there was accompanying microgliosis. The neuropil of the subiculum and CA1 was vacuolated and there was endfolial astrocytic gliosis. In addition, on either side of the crest of both gyri on either side of the calcarine sulcus there were symmetrical areas of subtle myelin loss in the striae of Gennari. In this region, there was both microglial and astrocytic gliosis without pronounced neuronal loss (Figure 1). Elsewhere cortical astrocytic gliosis was limited to the subpial region (Chaslin’s gliosis). The cerebral white matter and optic nerves were normally myelinated. In the cerebellar hemispheres, there was patchy loss of Purkinje cells with very occasional axonal torpedoes that were immunoreactive for phosphorylated neurofilament. The cerebellar tonsils