Posterior Lissencephaly Associated with Subcortical Band Heterotopia Due to a Variation in the CEP85L Gene: A Case Report and Refining of the Phenotypic Spectrum

Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo–occipito–parietal regions of both hemispheres with “double-cortex” (Dobyns’ 1–2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the CEP85L gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic CEP85L variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with CEP85L variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.

Lost in Transition: The Long and Winding Road Toward Epilepsy Surgery—An Analysis of Obstacles Prior to Surgery and Call for Orchestrated Health Care Efforts in Epilepsy

Difficult-to-treat epilepsy is defined as ongoing seizures despite adequate pharmacological treatment. This condition is affecting a significant percentage of epilepsy patients and is estimated to be as high as one-third of all patients. Epilepsy surgery, targeting the removal of the key parts of cerebral convolutions responsible for seizure generation and often including a structural lesion, can be a very successful approach. However, this necessitates careful patient selection by comprehensive investigations, proving the localization of the epileptogenic zone as well as measures to make such surgeries safe. With careful selection as a prerequisite, the percentage of patients achieving seizure freedom by neurosurgical intervention is high, approximating two-thirds of all epilepsy surgeries performed. In contrast, the average duration of a patient's pharmacoresistant focal epilepsy prior to surgery anywhere around the globe is around 20 years. Given that typical patients are ∼30 to 40 years of age at the time of surgery, many patients have been living with chronic seizures since childhood or adolescence. This means that most of these patients have been going through several stages of medical care for years or even decades, both as children and adults, without ever being fully investigated and/or selected for surgery which is concerning. Yet, there is no set standard for a timeline leading toward successful surgery in epilepsy. It is obvious that the average transit period from the moment of first seizure manifestation until the day of successful surgery takes much too long. This is the reason why we see these patients lost in transition.

Gliogenesis in the outer subventricular zone promotes enlargement and gyrification of the primate cerebrum

The primate cerebrum is characterized by a large expansion of cortical surface area, the formation of convolutions, and extraordinarily voluminous subcortical white matter. It was recently proposed that this expansion is primarily driven by increased production of superficial neurons in the dramatically enlarged outer subventricular zone (oSVZ). Here, we examined the development of the parietal cerebrum in macaque monkey and found that, indeed, the oSVZ initially adds neurons to the superficial layers II and III, increasing their thickness. However, as the oSVZ grows in size, its output changes to production of astrocytes and oligodendrocytes, which in primates outnumber cerebral neurons by a factor of three. After the completion of neurogenesis around embryonic day (E) 90, when the cerebrum is still lissencephalic, the oSVZ enlarges and contains Pax6+/Hopx+outer (basal) radial glial cells producing astrocytes and oligodendrocytes until after E125. Our data indicate that oSVZ gliogenesis, rather than neurogenesis, correlates with rapid enlargement of the cerebrum and development of convolutions, which occur concomitantly with the formation of cortical connections via the underlying white matter, in addition to neuronal growth, elaboration of dendrites, and amplification of neuropil in the cortex, which are primary factors in the formation of cerebral convolutions in primates.

Paul Broca and the first craniotomy based on cerebral localization

✓ Paul Broca (1824–1880) was a well-known French surgeon-anthropologist-neurologist. Best known for his work on cerebral cortical localization and speech mechanisms, Broca also carefully worked out skull and scalp localization for underlying cortical regions. In 1871, Broca treated a man who had sustained a scalp laceration from a blow to the head without loss of consciousness or skull fracture. The patient exhibited a nonfluent aphasia about 1 month after injury and became progressively obtunded and eventually comatose. Suspecting an intracranial abscess, Broca trephined at the region of the left third frontal convolution and drained an epidural abscess. The patient improved transiently but died a few days later. Autopsy showed a left-sided, predominantly frontal purulent meningoencephalitis. Broca's other neurosurgical contributions included various surgical cases, methods for scalp localization of the cerebral convolutions, extensive studies of skull and brain abnormalities, thermoencephalography, and the stimulation of younger surgical colleagues and neurologists to make practical use of cerebral localization.