Neurogenic bladder as a lurking complication in Moebius syndrome.

Moebius syndrome (MBS) is a congenital disorder characterized by facial and abducens palsy, sometimes accompanied with other cranial nerve palsies and comorbid conditions. Anatomical anomalies of the brainstem are assumed to be major etiologies of MBS. Its phenotypic presentation can be variable. We report a female patient with MBS who presented with neurogenic bladder (NB). She was born via normal vaginal delivery. At birth, she showed bilateral abducens palsy and right facial palsy. We diagnosed MBS by cranial computed tomography scan and magnetic resonance imaging. She had recurrent urinary tract infection. Hydronephrosis was noted on ultrasonography and bilateral vesicoureteral reflux (grade 5) on voiding cystourethrography. Urodynamic investigation showed detrusor overactivity and detrusor-sphincter dyssynergia, which follow the pattern of NB resulting from infrapontine-suprasacral lesions. Patients with MBS have lower brainstem dysfunction, and accordingly we should be aware of NB.

Motor Organization in Schizencephaly: Outcomes of Transcranial Magnetic Stimulation and Diffusion Tensor Imaging of Motor Tract Projections Correlate with the Different Domains of Hand Function.

OBJECTIVE: Schizencephaly is a rare congenital malformation that causes motor impairment. To determine the treatment strategy, each domain of the motor functions should be appropriately evaluated. We correlated a color map of diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS) with the hand function test (HFT) to identify the type of hand function that each test (DTI and TMS) reflects. Further, we attempted to demonstrate the motor neuron organization in schizencephaly. METHOD: This retrospective study was conducted on 12 patients with schizencephaly. TMS was conducted in the first dorsal interosseous (FDI), biceps (BB), and deltoid muscles of the upper extremity, and contralateral MEP (cMEP) and ipsilateral MEP (iMEP) were recorded. The HFT included the grip strength, box and block (B&B), and 9-hole peg test. The schizencephalic cleft was confirmed using magnetic resonance imaging, and the corticospinal tract (CST) was identified using the color map of DTI. The symmetry indices for the peduncle and CST at pons level were calculated as the ratios of the cross-sectional area of the less-affected side and that of the more-affected side. RESULT: In the more-affected hemisphere TMS, no iMEP was obtained. In the less-affected hemisphere TMS, the iMEP response was detected in 9 patients and cMEP in all patients, which was similar to the pattern observed in unilateral lesion. Paretic hand grip strength was strongly correlated with the presence of iMEP (p = 0.044). The symmetry index of the color map of DTI was significantly correlated with the B&B (p = 0.008, R 2 = 0.416), whereas the symmetry index of the peduncle was not correlated with all HFTs. CONCLUSION: In patients with schizencephaly, the iMEP response rate is correlated with the hand function related to strength, while the symmetricity of the CST by the color map of DTI is correlated with the hand function associated with dexterity. Additionally, we suggest the possible motor organization pattern of schizencephaly following interhemispheric competition.

Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case.

BACKGROUND: Since the nineteenth century, a great variety of crossed brainstem syndromes (CBS) have been described in the medical literature. A CBS typically combines ipsilateral cranial nerves deficits to contralateral long tracts involvement such as hemiparesis or hemianesthesia. Classical CBS seem in fact not to be so clear-cut entities with up to 20% of patients showing different or unnamed combinations of crossed symptoms. In terms of etiologies, acute brainstem infarction predominates but CBS secondary to hemorrhage, neoplasm, abscess, and demyelination have been described. The aim of this study was to assess the proportion of CBS caused by a bleeding episode arising from a brainstem cavernous malformation (BCM) reported in the literature. CASE PRESENTATION: We present the case of a typical Foville syndrome in a 65-year-old man that was caused by a pontine BCM with extralesional bleeding. Following the first bleeding episode, a conservative management was decided but the patient had eventually to be operated on soon after the second bleeding event. DISCUSSION: A literature review was conducted focusing on the five most common CBS (Benedikt, Weber, Foville, Millard-Gubler, Wallenberg) on Medline database from inception to 2020. According to the literature, hemorrhagic BCM account for approximately 7 % of CBS. Microsurgical excision may be indicated after the second bleeding episode but needs to be carefully weighted up against the risks of the surgical procedure and openly discussed with the patient. CONCLUSIONS: In the setting of a CBS, neuroimaging work-up may not infrequently reveal a BCM requiring complex multidisciplinary team management including neurosurgical advice.

Sympathetic hyperactivity, hypertension, and tachycardia induced by stimulation of the ponto-medullary junction in humans.

OBJECTIVE: The purpose of this study is to investigate changes in autonomic activities and systemic circulation generated by surgical manipulation or electrical stimulation to the human brain stem. METHODS: We constructed a system that simultaneously recorded microsurgical field videos and heart rate variability (HRV) that represent autonomic activities. In 20 brain stem surgeries recorded, HRV features and sites of surgical manipulation were analyzed in 19 hypertensive epochs, defined as the periods with transient increases in the blood pressure. We analyzed the period during electrical stimulation to the ponto-medullary junction, performed for the purpose of monitoring a cranial nerve function. RESULTS: In the hypertensive epoch, HRV analysis showed that sympathetic activity predominated over the parasympathetic activity. The hypertensive epoch was more associated with surgical manipulation of the area in the caudal pons or the rostral medulla oblongata compared to controls. During the period of electrical stimulation, there were significant increases in blood pressures and heart rates, accompanied by sympathetic overdrive. CONCLUSIONS: Our results provide physiological evidence that there is an important autonomic center located adjacent to the ponto-medullary junction. SIGNIFICANCE: A large study would reveal a candidate target of neuromodulation for disorders with autonomic imbalances such as drug-resistant hypertension.

Absence of pontine perforators in vertebrobasilar dolichoectasia on ultra-high resolution cone-beam computed tomography.

BACKGROUND: Vertebrobasilar dolichoectasia (VBDE) is a rare type of non-saccular intracranial aneurysm, with poor natural history and limited effective treatment options. Visualizing neurovascular microanatomy in patients with VBDE has not been previously reported, but may yield insight into the pathology, and provide important information for treatment planning. OBJECTIVE: To carry out a retrospective analysis of ultra-high resolution cone-beam computed tomography (UHR-CBCT) in patients with fusiform basilar aneurysms, visualizing neurovascular microanatomy of the posterior circulation with a special focus on the pontine perforators. METHODS: UHR-CBCT was performed in seven patients (mean age 59 years; two female) with a VBDE, and in 14 control patients with unrelated conditions. RESULTS: The mean maximum diameter of the fusiform vessel segment was 28 mm (range 19-36 mm), and the mean length of the segment was 39 mm (range 15-50 mm). In all patients with VBDE, UHR-CBCT demonstrated an absence of perforating arteries in the fusiform arterial segment and a mean of 3.7 perforators arising from the unaffected vessel segment. The network of interconnected superficial circumferential pontine arteries (brainstem vasocorona) were draping around the aneurysm sac. In controls, a mean of 3.6, 2.5, and 1.2 perforators were demonstrated arising from the distal, mid-, and proximal basilar artery, respectively. CONCLUSIONS: The absence of pontine perforators in the fusiform vessel segment of VBDE is counterbalanced by recruitment of collateral flow from pontine perforators arising from the unaffected segment of the basilar artery, as well as collaterals arising from the anterior inferior cerebellar artery/posterior inferior cerebellar artery and superior cerebellar artery. These alternative routes supply the superficial brainstem arteries (brainstem vasocorona) and sustain brainstem viability. Our findings might have implications for further treatment planning.

Brain activation patterns of female multiple sclerosis patients with voiding dysfunction.

AIMS: We compared brain activation patterns between female multiple sclerosis (MS) patients with voiding dysfunction (VD) and those without. We aim to expand current knowledge of supraspinal correlates of voiding initiation within a cohort of female MS patients with and without VD. MATERIALS AND METHODS: Twenty-eight ambulatory female MS patients with stable disease and lower urinary tract dysfunction were recruited for this study. Subjects were divided into group 1, without VD (n = 14), and group 2, with VD (n = 14), defined as postvoid residual urine of ≥40% of maximum cystometric capacity or need for self-catheterization. We recorded brain activity via functional magnetic resonance imaging (fMRI) with simultaneous urodynamic testing. Average fMRI activation maps (the Student t test) were created for both groups, and areas of significant activation were identified (P < .05). A priori regions of interest (ROIs), identified by prior meta-analysis to be involved in voiding, were selected. RESULTS: Group-averaged blood-oxygen level-dependent (BOLD) activation maps demonstrated significant differences between groups 1 and 2 during initiation of voiding with group 2 showing significantly lower levels of activation in all ROIs except for the left cerebellum and right cingulate gyrus. Interestingly, group 2 displayed negative BOLD signals, while group 1 displayed positive signals in the right and left pontine micturition center, right periaqueductal gray, left thalamus, and left cingulate gyrus. The activation map of group 1 was similar to healthy controls. CONCLUSIONS: Our results support the hypothesis that distinct supraspinal activation patterns exist between female MS patients with VD and those without.

Intraoperative facial motor evoked potential monitoring for pontine cavernous malformation resection.

OBJECTIVE: The aim of this study was to predict postoperative facial nerve function during pontine cavernous malformation surgery by monitoring facial motor evoked potentials (FMEPs). METHODS: From 2008 to 2017, 10 patients with pontine cavernous malformations underwent total resection via the trans-fourth ventricle floor approach with FMEP monitoring. House-Brackmann grades and Karnofsky Performance Scale (KPS) scores were obtained pre- and postoperatively. The surgeries were performed using one of 2 safe entry zones into the brainstem: the suprafacial triangle and infrafacial triangle approaches. Six patients underwent the suprafacial triangle approach, and 4 patients underwent the infrafacial triangle approach. A cranial peg screw electrode was used to deliver electrical stimulation for FMEP by a train of 4 or 5 pulse anodal constant current stimulation. FMEP was recorded from needle electrodes on the ipsilateral facial muscles and monitored throughout surgery by using a threshold-level stimulation method. RESULTS: FMEPs were recorded and analyzed in 8 patients; they were not recorded in 2 patients who had severe preoperative facial palsy and underwent an infrafacial triangle approach. Warning signs appeared in all patients who underwent the suprafacial triangle approach. However, after temporarily stopping the procedures, FMEP findings during surgery showed recovery of the thresholds. FMEPs in patients who underwent the infrafacial triangle approach were stable during the surgery. House-Brackmann grades were unchanged postoperatively in all patients. Postoperative KPS scores improved in 3 patients, decreased in 1, and remained the same in 6 patients. CONCLUSIONS: FMEPs can be used to monitor facial nerve function during surgery for pontine cavernous malformations, especially when the suprafacial triangle approach is performed.

Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.

Pre-clinical research in rodents provides evidence that the central nervous system (CNS) has functional lymphatic vessels. In-vivo observations in humans, however, are not demonstrated. We here show data on CNS lymphatic drainage to cervical lymph nodes in-vivo by magnetic resonance imaging (MRI) enhanced with an intrathecal contrast agent as a cerebrospinal fluid (CSF) tracer. Standardized MRI of the intracranial compartment and the neck were acquired before and up to 24-48 hours following intrathecal contrast agent administration in 19 individuals. Contrast enhancement was radiologically confirmed by signal changes in CSF nearby inferior frontal gyrus, brain parenchyma of inferior frontal gyrus, parahippocampal gyrus, thalamus and pons, and parenchyma of cervical lymph node, and with sagittal sinus and neck muscle serving as reference tissue for cranial and neck MRI acquisitions, respectively. Time series of changes in signal intensity shows that contrast enhancement within CSF precedes glymphatic enhancement and peaks at 4-6 hours following intrathecal injection. Cervical lymph node enhancement coincides in time with peak glymphatic enhancement, with peak after 24 hours. Our findings provide in-vivo evidence of CSF tracer drainage to cervical lymph nodes in humans. The time course of lymph node enhancement coincided with brain glymphatic enhancement rather than with CSF enhancement.

Saccadic Palsy following Cardiac Surgery: Possible Role of Perineuronal Nets.

OBJECTIVE: Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements - saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy. METHODS: Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses. RESULTS: Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation. INTERPRETATION: Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.

Diffuse intrinsic pontine glioma: time for therapeutic optimism.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive tumor that is universally fatal, and to-date we are at a virtual standstill in improving its grim prognosis. Dearth of tissue due to rarity of biopsy has precluded understanding the elusive biology and frustration continues in reproducing faithful animal models for translational research. Furthermore the intricate anatomy of the pons has forestalled locoregional therapy and drug penetration. Over the last few years, biopsy-driven targeted therapy, development of vitro and xenograft animal models for therapeutic testing, profiling immunotherapeutic strategies and locoregional infusion of drugs in brain stem tumors, now provide a sense of hope in the years ahead. This review aims to discuss current status and advances in the management of these tumors.

Human pontine glioma cells can induce murine tumors.

Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.

Pattern of voiding dysfunction after acute brainstem infarction.

BACKGROUND: The purpose of this study is to compare the patterns of voiding dysfunction according to the locations of brainstem lesions. METHODS: Between November 2008 and December 2011, a total of 30 patients participated in this study. All 30 subjects, consisting of 16 men and 14 women, aged between 41 and 82 years (mean age, 63.0±11.0 years) underwent a urodynamic study within 7 days after the onset of a stroke. RESULTS: Twenty-one (70%) patients had a pontine lesion and 9 (30%) had a medullary lesion. Fourteen of these patients (46.7%) had bladder storage disorder, 7 patients (23.3%) had bladder emptying disorder, and 9 patients (30%) had a normal report. Five of the patients who had a medullary lesion (55.6%) had bladder emptying disorder, whereas only 2 patients who had a pontine lesion (9.5%) had bladder emptying disorder. Thirteen patients who had a pontine lesion (61.9%) showed bladder storage disorder. DISCUSSION: The descending pathway from the midbrain tegmentum is inhibitory, and the pathway from the pontine tegmentum is stimulatory. Because of their location pontine lesions could disrupt the descending fibers of the midbrain tegmentum and medullary lesions could disrupt the descending fibers of the pontine tegmentum.

Neurons of the A5 region are required for the tachycardia evoked by electrical stimulation of the hypothalamic defence area in anaesthetized rats.

In order to assess the possible interactions between the pontine A5 region and the hypothalamic defence area (HDA), we have examined the pattern of double staining for c-Fos protein immunoreactivity (c-Fos-ir) and tyrosine hydroxylase, throughout the rostrocaudal extent of the A5 region in spontaneously breathing anaesthetized male Sprague-Dawley rats during electrical stimulation of the HDA. Activation of the HDA elicited a selective increase in c-Fos-ir with an ipsilateral predominance in catecholaminergic and non-catecholaminergic A5 somata (P < 0.001 in both cases). A second group of experiments was done to examine the importance of the A5 region in modulating the cardiorespiratory response evoked from the HDA. Cardiorespiratory changes were analysed in response to electrical stimulation of the HDA before and after ipsilateral microinjection of muscimol within the A5 region. Stimulation of the HDA evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (P < 0.001) due to a decrease in expiratory time (P < 0.01). The respiratory response was accompanied by a pressor response (P < 0.001) and tachycardia (P < 0.001). After muscimol microinjection within the A5 region, pressor and heart rate responses to HDA stimulation were reduced (P < 0.01 and P < 0.001, respectively). The respiratory response persisted unchanged. Finally, to confirm functional interactions between the HDA and the A5 region, extracellular recordings of putative A5 neurones were obtained during HDA stimulation. Seventy-five A5 cells were recorded, 35 of which were affected by the HDA (47%). These results indicate that neurones of the A5 region participate in the cardiovascular response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

Ocular vestibular evoked myogenic potentials induced by air-conducted sound in patients with acute brainstem lesions.

OBJECTIVE: The ocular vestibular-evoked myogenic potential (oVEMP), a recently documented otolith-ocular reflex, is considered to reflect the central projections of the primary otolithic afferent fibers to the oculomotor nuclei. The aim of our study is to define air-conducted sound oVEMP abnormality in patients with acute brainstem lesions and to determine the brainstem structures involved in the generation of oVEMPs. METHODS: In response to air-conducted tone burst sounds (ACS), oVEMP was measured in 52 patients with acute brainstem lesions. Individualized brainstem lesions were analyzed by means of MRI-based voxel-wise lesion-behavior mapping, and the probabilistic lesion maps were constructed. RESULTS: More than half (n=28, 53.8%) of the patients with acute brainstem lesions showed abnormal oVEMP in response to ACS. The majority of patients with abnormal oVEMPs had lesions in the dorsomedial brainstem that contains the medial longitudinal fasciculus (MLF), the crossed ventral tegmental tract (CVTT), and the oculomotor nuclei and nerves. CONCLUSION: MLF, CVTT, and the oculomotor nuclei and nerves appear to be responsible for otolith-ocular responses in the brainstem. SIGNIFICANCE: Complemented to cervical VEMP for the uncrossed otolith-spinal function, oVEMP to ACS may be applied to evaluate the crossed otolith-ocular function in central vestibulopathies.

Evolution of abnormal eye movements in Wernicke's encephalopathy: correlation with serial MRI findings.

A 33-year-old woman with Wernicke's encephalopathy (WE) due to poor oral intake after allogeneic stem cell transplantation for acute myeloid leukemia showed a sequential development of bilateral gaze-evoked nystagmus (GEN), rightward gaze palsy, and upbeat nystagmus. Initial MRIs obtained when she had GEN only showed a lesion involving the medullary tegmentum, and follow-up MRIs revealed additional lesions in the pontine and midbrain tegmentum along with development of rightward gaze palsy, and finally bilateral medial thalamus lesions in association with upbeat nystagmus. The evolution of abnormal ocular motor findings and serial MRI changes in our patient with WE provide imaging evidence on relative vulnerability of the neural structures, and on the progression of lesions and ocular motor findings in thiamine deficiency.

Guillain-Barré syndrome following sepsis after stereotactic aspiration for spontaneous pontine hemorrhage.

A 52-year-old female was treated with CT-guided stereotactic aspiration for acute spontaneous pontine hemorrhage. On postoperative day 7, the patient was complicated by Acinetobacter baumannii sepsis. As sepsis was stabilized, she developed flaccid weakness and autonomic dysfunction on postoperative day 21. Investigations including neurophysiological studies and cerebral spinal fluid analysis prompted the diagnosis of acute motor axonal neuropathy, a variant of Guillain-Barré syndrome. Intravenous administration of immunoglobulin resolved her potentially life-threatening autonomic instability. At 1-year follow-up, she was able to stand with significant assistance. Although Guillain-Barré syndrome rarely occurs, clinicians should be alert to the possibility of this potentially life-threatening consequence after cranial surgery with severe respiratory infection.

Neural mechanisms for smooth pursuit in strabismus.

The visual and oculomotor systems of primates are immature at birth and sensitive to injury. If synergistic interactions between visual and oculomotor systems are compromised during the first months of life, disorders in eye alignment, gaze holding, and smooth pursuit (SP) follow. Here we consider some potential neural mechanisms supporting SP and associated vestibular ocular reflex (VOR) behavior in normal and strabismic monkeys. Experimental strabismus was created by prism goggle wearing or eye muscle surgery in rhesus monkeys (Macaca mulatta). SP and cancellation of the VOR were highly asymmetric in strabismic monkeys during monocular viewing conditions. Similar asymmetric SP and VOR cancellation could be produced in normal monkeys by delivering unilateral muscimol injections to the dorsolateral pontine nucleus (DLPN). We suggest that failure to develop balanced cortical-brainstem circuits in strabismus accounts for many of the components of infantile strabismus syndrome.

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.