Trapped fourth ventricle: to stent, shunt, or fenestrate-a systematic review and individual patient data meta-analysis.

Trapped or isolated fourth ventricle (TFV) is a rare but critical neurosurgical condition, mostly occurring in pediatric patients, caused by a blockage of the in- and outlets of the fourth ventricle. The purpose of this study is to review all available data on the treatment options of TFV and to compare their safety, efficacy, and durability. MEDLINE, Embase, and Google Scholar were searched from inception to September 13, 2022, for prospective or retrospective cohorts, case-control studies, case series or case reports, reporting detailing outcomes of TFV patients, treated with an endoscopic-, microsurgical-, shunt placement,- or hybrid approaches to TFV. All authors were contacted to provide individual patient data. Eighty-seven articles (314 patients) were included in the individual patient data meta-analysis (IPD) and 9 (151 patients) in the cohort meta-analysis. The IPD revealed that primary endoscopic (aOR 0.21; [95% CI 0.08-0.57]) and microsurgical interventions (aOR 0.21; [95% CI 0.05-0.82]) were associated with a significantly lower revision rate, compared to shunt placement, when adjusted for confounders. Endoscopy was also associated with a significantly higher rate of clinical improvement (aOR 4.56; [95% CI 1.2-18]). The meta-analysis revealed no significant difference in revision rate between the endoscopic (0.33 [95% CI 0.0-0.52]) and shunt group (0.44 [95% CI 0.0-1.0]). Endoscopy should be considered as the first-line treatment of TFV due to its superior efficacy, durability, and similar safety, compared to shunt placement and its minimally invasive nature. Microsurgery should be considered as a second treatment option, due to its similar clinical outcomes and revision rate as endoscopy, but it is more invasive in nature.

Newborns with myelomeningocele: their health-related quality of life and daily functioning 10 years later.

OBJECTIVE: Ten years ago, the authors reported on the outcome of their study investigating the degree of discomfort and pain in newborns with myelomeningocele (MMC), using the parameters of unbearable and hopeless suffering. In the current study, they investigated the quality of life, daily functioning, pain and fatigue, ability to communicate, and number of surgeries in the same cohort of patients. They subdivided their study population into severe (Lorber) and less severe (non-Lorber) cases and compared these cases with a healthy population (non-MMC group) and with each other. METHODS: The parents of 22 of 28 patients gave informed consent for this study. The KIDSCREEN-27 and PEDI-CAT (Pediatric Evaluation of Disability Inventory) were used to assess quality of life and daily functioning. Pain and fatigue were self-reported on a 10-point numeric rating scale. Communication and ambulation levels were determined using the Communication Function Classification System (CFCS) and the Hoffer ambulation scale. Using reference data from the KIDSCREEN-27 and PEDI-CAT, the authors created a healthy population comparison group. RESULTS: There was no significant difference in health-related quality-of-life (HRQOL) scores between Lorber and non-Lorber patients, except that school environment domain scores were lower in the Lorber group. When comparing the HRQOL of MMC patients with that of the non-MMC group, the physical well-being and parent relations and autonomy domains scored significantly lower. The daily functioning of MMC patients was lower on all domains of the PEDI-CAT compared with the non-MMC group. Lorber MMC patients scored lower on all domains of the PEDI-CAT when compared with non-Lorber patients. All patients were capable of communicating effectively; most patients (n = 18) were considered CFCS level I, and 4 patients were considered CFCS level II. CONCLUSIONS: This study shows that MMC is a severe, lifelong condition that affects patients' lives in many domains. All the patients in this study are capable of effective communication, irrespective of severity of MMC. Overall, the data show that in newborn MMC patients, future unbearable suffering with respect to pain, mobility, cognition, and communication is hard to predict and may not always occur.

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity.

BACKGROUND: Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. HYPOTHESIS: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. METHODS: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. RESULTS: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. CONCLUSION: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome.

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Differentiating Cerebellar Impact on Thalamic Nuclei.

The cerebellum plays a role in coordination of movements and non-motor functions. Cerebellar nuclei (CN) axons connect to various parts of the thalamo-cortical network, but detailed information on the characteristics of cerebello-thalamic connections is lacking. Here, we assessed the cerebellar input to the ventrolateral (VL), ventromedial (VM), and centrolateral (CL) thalamus. Confocal and electron microscopy showed an increased density and size of CN axon terminals in VL compared to VM or CL. Electrophysiological recordings in vitro revealed that optogenetic CN stimulation resulted in enhanced charge transfer and action potential firing in VL neurons compared to VM or CL neurons, despite that the paired-pulse ratio was not significantly different. Together, these findings indicate that the impact of CN input onto neurons of different thalamic nuclei varies substantially, which highlights the possibility that cerebellar output differentially controls various parts of the thalamo-cortical network.

Corrigendum: Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike-and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy.

[This corrects the article DOI: 10.3389/fncel.2017.00346.].

Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike-and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy.

Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, head-restrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure-related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations.

Controlling Cerebellar Output to Treat Refractory Epilepsy.

Generalized epilepsy is characterized by recurrent seizures caused by oscillatory neuronal firing throughout thalamocortical networks. Current therapeutic approaches often intervene at the level of the thalamus or cerebral cortex to ameliorate seizures. We review here the therapeutic potential of cerebellar stimulation. The cerebellum forms a prominent ascending input to the thalamus and, whereas stimulation of the foliated cerebellar cortex exerts inconsistent results, stimulation of the centrally located cerebellar nuclei (CN) reliably stops generalized seizures in experimental models. Stimulation of this area indicates that the period of stimulation with respect to the phase of the oscillations in thalamocortical networks can optimize its effect, opening up the possibility of developing on-demand deep brain stimulation (DBS) treatments.

Cerebellar output controls generalized spike-and-wave discharge occurrence.

OBJECTIVE: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. METHODS: Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures. RESULTS: We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds. INTERPRETATION: CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated.

Results of early surgery for sagittal suture synostosis: long-term follow-up and the occurrence of raised intracranial pressure.

PURPOSE: Numerous techniques are used to correct sagittal synostosis. Although cosmetic results and operative complications are well documented, little is known about functional outcome. In our institution, the technique for extended strip craniectomy evolved over time. This study compares cosmetic results, complications, and signs of raised intracranial pressure (ICP) between the variants of the extended strip craniectomy. METHODS: Seventy-nine consecutive patients undergoing early extended strip craniectomy for scaphocephaly (2002-2008) were included. Four techniques were used: A, a simple bilateral parietal flap with out-fracturing of the bone flap; B, C, and D included remodeling of the parietal flap by adding triangular cuts and bending or suturing the resulting fingers. In technique D, the sagittal strip was rotated and fixed between the parietal flaps. Data on head circumference (HC), skull X-ray, and fundoscopy were collected prospectively. RESULTS: For all patients, the average cranial index (CI) was 74 after 3 months and 72 after 2 years. Although technique D resulted in the best initial improvement, there was no significant percentage increase in CI after 24 months between the four techniques. Postoperatively, 9 % of the patients developed papilledema, 42 % developed a fontanel bulge, and 57 % had diminished HC. Four patients were reoperated on because of raised ICP. CONCLUSIONS: Postoperative CI is mainly determined by preoperative CI and hardly affected by type of extended strip craniectomy. Signs of raised ICP occurred more frequently than expected, therefore structural follow-up is required to detect such signs. Technique and timing of surgery should aim at creating sufficient intracranial volume.