Deep medullary vein damage correlates with small vessel disease in small vessel occlusion acute ischemic stroke.

OBJECTIVES: We aim to investigate whether cerebral small vessel disease (cSVD) imaging markers correlate with deep medullary vein (DMV) damage in small vessel occlusion acute ischemic stroke (SVO-AIS) patients. METHODS: The DMV was divided into six segments according to the regional anatomy. The total DMV score (0-18) was calculated based on segmental continuity and visibility. The damage of DMV was grouped according to the quartiles of the total DMV score. Neuroimaging biomarkers of cSVD including white matter hyperintensity (WMH), cerebral microbleed (CMB), perivascular space (PVS), and lacune were identified. The cSVD score were further analyzed. RESULTS: We included 229 SVO-AIS patients, the mean age was 63.7 ± 23.1 years, the median NIHSS score was 3 (IQR, 2-6). In the severe DMV burden group (the 4th quartile), the NIHSS score grade (6 (3-9)) was significantly higher than other groups (p < 0.01). The grade scores for basal ganglia PVS (BG-PVS) were positively correlated with the degree of DMV (R = 0.67, p < 0.01), rather than centrum semivole PVS (CS-PVS) (R = 0.17, p = 0.1). In multivariate analysis, high CMB burden (adjusted odds ratio [aOR], 25.38; 95% confidence interval [CI], 1.87-345.23) was associated with severe DMV scores. In addition, BG-PVS was related to severe DMV burden in a dose-dependent manner: when BG-PVS score was 3 and 4, the aORs of severe DMV burden were 18.5 and 12.19, respectively. CONCLUSION: The DMV impairment was associated with the severity of cSVD, which suggests that DMV burden may be used for risk stratification in SVO-AIS patients. CLINICAL RELEVANCE STATEMENT: The DMV damage score, based on the association between small vessel disease and the deep medullary veins impairment, is a potential new imaging biomarker for the prognosis of small vessel occlusion acute ischemic stroke, with clinical management implications. KEY POINTS: • The damage to the deep medullary vein may be one mechanism of cerebral small vessel disease. • Severe burden of the basal ganglia perivascular space and cerebral microbleed is closely associated with significant impairment to the deep medullary vein. • The deep medullary vein damage score may reflect a risk of added vascular damage in small vessel occlusion acute ischemic stroke patients.

Deep medullary vein abnormalities impact white matter hyperintensity volume through increases in interstitial free water.

BACKGROUND: Our intent was to explore the mediating role of interstitial free water (FW) linking deep medullary vein (DMV) score to white matter hyperintensity (WMH) volume. METHODS: Our research team conducted a forward-looking analysis of initial clinical and imaging information gathered from 125 patients with cerebral small vessel disease. We identified six anatomic DMV regions on susceptibility weighted imaging (SWI) studies. Each region earned a score of 0-3, determined by the visual conditions of vessels, summing all six to generate a DMV score. We utilized fluid-attenuated inversion recovery (FLAIR) sequences to measure the volume of WMH. Additionally, we employed diffusion tensor imaging (DTI) to assess FW value. RESULTS: DMV score significantly positively correlated with FW value and with WMH volume (p < 0.05), and value of FW positively correlated with WMH volume (p < 0.05). The indirect effect of DMV score on WMH volume was mediated by FW (ß = 0.281, 95% confidence interval [CI]: 0.178-0.388), whether adjusted for age and gender (ß = 0.142, 95% CI: 0.058-0.240) or for age, gender and vascular risk factors (ß = 0.141, 95% CI: 0.054-0.249). CONCLUSION: DMV score correlate with WMH volume by virtue of FW increases in white matter.

VLM catecholaminergic neurons control tumor growth by regulating CD8+ T cells.

It is known that tumor growth can be influenced by the nervous system. It is not known, however, if tumors communicate directly with the central nervous system (CNS) or if such interactions may impact tumor growth. Here, we report that ventrolateral medulla (VLM) catecholaminergic (CA) neurons in the mouse brain are activated in tumor-bearing mice and the activity of these neurons significantly alter tumor growth in multiple syngeneic and spontaneous mouse tumor models. Specific ablation of VLM CA neurons by a dopamine-ß-hydroxylase (DBH) promotor-activated apoptosis-promoting caspase-3 in Dbh-Cre mice as well as inhibition of these neurons by a chemogenetic method slowed tumor progression. Consistently, chemogenetic activation of VLM CA neurons promoted tumor growth. The tumor inhibition effect of VLM CA neuron ablation is mitigated in Dbh-Cre;Rag1-/- mice, indicating that this regulatory effect is mediated by the adaptive immune system. Specific depletion of CD8+ T cells using an anti-CD8+ antibody also mitigated the tumor suppression resulting from the VLM CA neuron ablation. Finally, we showed that the VLM CA neuronal ablation had an additive antitumor effect with paclitaxel treatment. Collectively, our study uncovered the role of VLM CA neurons in the mouse brain in controlling tumor growth in the mouse body.

Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Midlateral medullary infarction presenting with isolated thermoanaesthesia: a case report.

BACKGROUND: A small lateral medullary lesion could produce isolated impairment of temperature sensation without concomitant impaired pain sensation. However, only one such case has ever been reported, and there are no reports on subjective symptoms and detailed somatosensory testing. CASE PRESENTATION: Herein, we report the case of a 53-year-old female patient presenting with impaired temperature sensation on the left half of her body, from the neck down, following a small infarction of the right midlateral medulla. The chronological changes in the patient's introspection regarding impairment of thermoception and the results of detailed somatosensory tests, including thermal sense, are shown in this report. CONCLUSIONS: Thorough somatosensory tests, personal descriptions of symptoms, and electrophysiological quantification of similar cases are needed to improve our understanding of the neurological separation of the sensations of pain and temperature at the medullary level.

The stroke mechanism, clinical presentation, and radiological feature of bilateral medial medullary infarction.

BACKGROUND: Bilateral medial medullary infarction (BMMI) is a rare type of posterior circulation stroke. The aim of this study is to characterize its stroke mechanisms, clinical manifestations, neuroradiological features, and prognosis. METHODS: From January 2015 to June 2021, a retrospective review of 15 patients diagnosed with BMMI was conducted. The clinical and neuroradiological features were summarized by our experienced neurologists. RESULTS: Fifteen patients (12 male, 3 female), ranging in age from 48 to 72 years, satisfied the inclusion criteria. The common clinical presentations included motor weakness (100%), deep sensory disturbance (93.3%), vertigo/dizziness (80%), dysarthria (93.3%), and dysphagia (66.7%). Vertically, infarct lesions in the rostral medulla were observed in all included patients. Horizontally, "heart appearance," "Y appearance," and "fan appearance" infarcts occurred in 9 cases (60%), 5 cases (33.3%), and 1 (6.7%) case, respectively. Patients (53.3%) had severe stenosis or occlusion in unilateral vertebral artery (VA), and 33.3% had normal findings in the vertebrobasilar artery. Patients (93.3%) achieved poor prognosis. CONCLUSION: BMMI is more frequently located in the rostral medulla and comprises three forms of infarction. The two main stroke etiologies of BMMI are large-artery atherosclerosis (LAA) and small vessel disease (SVD). BMMI is always associated with bad clinical outcome.

Brain and spinal cord lesions in 28 inbred strains of aging mice.

Brain and spinal cord histopathology findings in male and female 20-month-old mice in a large-scale aging study of 28 inbred Jackson Laboratory mouse strains from 7 genetic families are described. Brain sections from selected strains at 12 and 24 months of age or older were also reviewed. Common lesions include axonal dystrophy in the gracile and/or cuneate nucleus in the sensory tract of the dorsal medulla and in the spinal cord in all strains. Hirano-like bodies were seen in 24/28 strains, and mineralization was observed in the thalamus of 9/28 strains. Less common lesions were also seen in the cerebellum, cerebral cortex, and other brain areas. No brain or spinal cord tumors were found. Evidence of an impairment of the ubiquitin-proteasome system (UPS) and/or suspected autophagy was manifested as medullary axonal dystrophy with intra-axonal granular eosinophilic bodies and LC3B immunohistochemistry in most strains. RIIIS/J, the most severely affected strain, showed moderate axonal dystrophy at 12 months, which progressed to severe lesions at 20 months. Comparative pathology in various species is discussed.

In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.

Baroreflex dysfunction in Parkinson's disease: integration of central and peripheral mechanisms.

The incidence of Parkinson's disease (PD) is increasing worldwide. Although the PD hallmark is the motor impairments, nonmotor dysfunctions are now becoming more recognized. Recently, studies have suggested that baroreflex dysfunction is one of the underlying mechanisms of cardiovascular dysregulation observed in patients with PD. However, the large body of literature on baroreflex function in PD is unclear. The baroreflex system plays a major role in the autonomic, and ultimately blood pressure and heart rate, adjustments that accompany acute cardiovascular stressors on a daily basis. Therefore, impaired baroreflex function (i.e., decreased sensitivity or gain) can lead to altered neural cardiovascular responses. Since PD affects parasympathetic and sympathetic branches of the autonomic nervous system and both are orchestrated by the baroreflex system, understanding of this crucial mechanism in PD is necessary. In the present review, we summarize the potential altered central and peripheral mechanisms affecting the feedback-controlled loops that comprise the reflex arc in patients with PD. Major factors including arterial stiffness, reduced number of C1 and activation of non-C1 neurons, presence of central α-synuclein aggregation, cardiac sympathetic denervation, attenuated muscle sympathetic nerve activity, and lower norepinephrine release could compromise baroreflex function in PD. Results from patients with PD and from animal models of PD provide the reader with a clearer picture of baroreflex function in this clinical condition. By doing so, our intent is to stimulate future studies to evaluate several unanswered questions in this research area.

Dorsolateral medullary infarction registry: a study protocol for a prospective, multicentric registry.

BACKGROUND: Dorsolateral medullary infarction is a typical cerebral infarction which is characterized by Wallenberg's syndrome. Neurotrophic keratopathy is an uncommon consequence of dorsolateral medullary infarction. At present, the protocol is aimed to study the dynamic changes in corneal innervation and the ocular surface environment after dorsolateral medullary infarction. METHODS: This study will involve consecutive data from all medical records of patients within 7 days of acute dorsolateral medullary infarction onset at the Departments of Neurology from 10 collaborating stroke centers. Eligible patients will mainly be characterized based on detailed physical examinations, multimodal imaging, and corneal related examinations and patients will be followed-up for 2 years. Neurotrophic keratopathy after dorsolateral medullary infarction is the primary endpoint. The dynamic histological corneal innervation and ocular surface environment after dorsolateral medullary infarction will be observed during the follow-up period. DISCUSSION: This multicentric, prospective registry is the first to identify and characterize the dynamic changes of corneal innervation and the ocular surface environment after acute dorsolateral medullary infarction. The significance of the study is to emphasize that the curative effect is based on the doctors' identification of the disease in the earliest stage before irreversible damage occurs to the cornea. TRIAL REGISTRATION: The registry was registered ( ChiCTR-OPC-17,011,625 ) on June 11, 2017.

Primary intracranial germ cell tumour originating from right brachium Pontis with hypertrophic Olivary degeneration: a case report.

BACKGROUND: Primary right brachium pontis germinoma with hypertrophic olivary degeneration (HOD) is extremely rare. A preoperative diagnosis is challenging due to the absence of characterized clinical and neuroimaging features, and biopsy should be considered. CASE PRESENTATION: A 20-year-old male patient presented with a case of primary intracranial germinoma originating from right brachium pontis with HOD manifesting as ocular myoclonus, nystagmus in both eyes, ataxic gait and incoordination of the limbs. Magnetic resonance imaging (MRI) revealed an irregular patchy lesion with hyperintensity on T2-weighted images (T2WI) and T2 fluid-attenuated inversion recovery (FLAIR) without enhancement by gadolinium (Gd). Furthermore, a focal hyperintense nodule on T2WI in the left inferior olive nucleus (ION) of the medulla oblongata was considered hypertrophic olivary degeneration (HOD) based on the patient's symptoms and neuroimaging findings. Due to suspected demyelinating disease and low-grade glioma (LGG), a biopsy was planned. The pathological diagnosis was germinoma. Subsequently, he received chemoradiation therapy, resulting in the improvement of neurological deficits and the disappearance of the lesion on MRI. CONCLUSION: A case of "Primary right brachium pontis germinoma with HOD" is reported for the first time. A preoperative diagnosis is challenging due to the fact of absence of clinical signs and symptoms and neuroimaging characteristics. However, patients can have favourable prognoses with appropriate evaluation and treatment.

Thymoquinone has a neuroprotective effect against inflammation, oxidative stress, and endoplasmic reticulum stress in the brain cortex, medulla, and hippocampus due to doxorubicin.

Although doxorubicin (DOX) is used in many cancer treatments, it causes neurotoxicity. In this study, the effect of thymoquinone (THQ), a powerful antioxidant, on DOX-induced neurotoxicity was evaluated. In total, 40 rats were used and 5 groups were formed. Group I: control group (n = 8); Group II: olive oil group (n = 8); Group III: the THQ group (n = 8); THQ 10 mg/kg per day was given intraperitoneally (i.p.) throughout the experiment; group IV: DOX group (n = 8); On Day 7 of the experiment, a single dose of 15 mg/kg intraperitoneally DOX injected; group V: DOX + THQ group (n = 8); Throughout the experiment, 10 mg/kg THQ per day and intraperitoneally 15 mg/kg DOX on Day 7 were injected. Immunohistochemically, tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), hypoxia-inducible factor 1α (HIF1-α), glucose regulatory protein 78 (GRP78), and the gene inducible by growth arrest and DNA damage 153 (GADD153) proteins were evaluated in the brain cortex, medulla, and hippocampus regions. Total oxidant status (TOS) levels and total antioxidant status (TAS) in the brain tissue were measured. TNF-α, IL-17, HIF1-α, GRP78, and GADD153 immunoreactivities significantly increased in the DOX group in the study. THQ significantly reduced these values. THQ increased the TAS level significantly and decreased the TOS level significantly compared to the DOX group. THQ may play a role as a neuroprotective agent in DOX-induced neurotoxicity in the cortex, medulla, and hippocampus regions of the brain.

Horizontal Gaze Palsy, Scoliosis, and Split Pons Sign in a 6-Year-Old Girl.

ABSTRACT: A 6-year-old girl presented with complaints of absent horizontal eye movements since birth. There was also associated progressive scoliosis for past 1 year. Neuroimaging revealed split pons sign, butterfly-shaped medulla, and prominent inferior olivary nuclei. The presence of congenital horizontal gaze palsy, childhood onset progressive scoliosis, and abnormal neuroimaging findings confirmed the diagnosis of horizontal gaze palsy with progressive scoliosis. This case highlights the importance of neuroimaging in a child presenting with horizontal gaze palsy and scoliosis that helped for starting early rehabilitation of the child, prevention of permanent vision loss, and parental counseling for future pregnancies.

Extensive craniospinal disseminated metastasis after the resection of intradural extramedullary ependymoma in the craniocervical junction: a case report and literature review.

PURPOSE/AIM: Intradural extramedullary (IDEM) ependymomas are very rare, and IDEM ependymomas with craniospinal disseminated metastasis are exceptionally rare; only 2 preoperative cases have been confirmed, and postoperative cases have not been reported. CASE REPORT: We present a case of a 21-year-old female with an IDEM ependymoma of the craniocervical junction who experienced head and neck pain for more than 1 month. Magnetic resonance imaging (MRI) of the cervical spine revealed a large IDEM cystic lesion located in the medulla oblongata and the upper cervical spinal cord. The patient underwent surgery without complications, and the tumor was completely removed. Histopathological examination revealed a diagnosis of aplastic ependymoma, World Health Organization (WHO) grade III. The patient failed to follow-up with radiotherapy for one month after discharge. Nearly three months after surgery, craniospinal disseminated metastasis was found in the patient; subsequently, chemoradiotherapy was administered to prolong the survival time of the patient. Unfortunately, the patient underwent radiotherapy and chemotherapy for only 7 days; then, the patient gave up treatment and died 5 months later. CONCLUSIONS: To the best of our knowledge, no other cases of craniocervical junction anaplastic ependymomas with craniospinal disseminated metastasis have been reported in the literature. Total resection does not completely prevent recurrence and metastasis, and MRI of the entire neuraxis and timely postoperative craniospinal radiotherapy are necessary for the treatment of this disease.

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia.

BACKGROUND: Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear. METHODS: The stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope. RESULTS: We showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia. CONCLUSIONS: Collectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM.

Giant "heart appearance-like sign" on MRI in bilateral ponto-medullary junction infraction: case report.

BACKGROUND: Bilateral medial medullary infarction (MMI) is uncommon and bilateral medial pons infarction (MPI) is even rarer. "Heart appearance" on magnetic resonance imaging (MRI) is a characteristic presentation of bilateral medial medullary infarction (MMI). CASE PRESENTATION: We present 67-year-old Chinese diabetic and hypertensive female patient affected with "heart appearance-like" infarction in bilateral ponto-medullary junction on MRI. Abnormal signal was observed in the bilateral ponto-medullary junction on T1, T2, fluid-attenuated inversion recovery and apparent diffusion coefficient (ADC). The whole brain digital subtraction angiography (DSA) showed the basilar artery and vertebral artery remained intact. Therefore, we speculated that the bilateral ponto-medullary junction infarction might be caused by the deep perforating branch of the basilar artery. CONCLUSIONS: As far as we know, the "heart appearance-like" infraction in bilateral ponto-medullary junction was not reported. Our case also suggests that bilateral ischemic infraction involvement of the medulla and pon is possible even in the context of an intact basilar artery.

Stress cardiomyopathy associated with area postrema syndrome as a presentation of neuromyelitis optica: case report.

BACKGROUND: Stress cardiomyopathy (Takotsubo cardiomyopathy) is very rare in the central nervous system (CNS) demyelinating disorders. Although this dysfunction of the heart-brain axis has been reported in several case series related to multiple sclerosis (MS), stress cardiomyopathy by neuromyelitis optica (NMO), which is rarer CNS demyelinating disorder than MS, is extremely rare. Herein, we report a case of stress cardiomyopathy associated with a medullary lesion as a presentation of NMO. CASE PRESENTATION: A 30-year-old woman was treated by veno-arterial extracorporeal membrane oxygenation due to catastrophic cardiopulmonary dysfunction after prolonged and unexplained nausea, vomiting, and cough. Myoclonus on the limbs developed afterward. Taken with suspicion of area postrema syndrome (APS), the brain MRI showed a demyelinating lesion in the medulla oblongata. APS and severe heart failure by stress cardiomyopathy were completely resolved by ECMO and hydrocortisone therapy. However, the CNS demyelinating lesion recurred after 1 month. The patient was diagnosed with NMO evident by the presence of aquaporin-4 antibody; Steroid therapy improved her symptoms. CONCLUSION: NMO should be considered as one of the differential diagnoses in patients with APS preceding severe cardiopulmonary distress.

Fabry disease presenting as bilateral medial medullary infarction with a "heart appearance" sign: a case report.

BACKGROUND: The etiologic determinants of cryptogenic stroke remain a diagnostic challenge in clinical practice. Fabry disease (FD) is one of the monogenic causes of stroke that may remain unrecognized as a potential contributing causative factor, because of its rarity and difficulty in diagnosis. We report a case with rare bilateral medial medullary infarction manifesting as "heart appearance" who was diagnosed with FD. CASE PRESENTATION: A 51-year-old Chinese man presented with acute dysarthria and mild tetraparesis. In the 24 h following admission, the patient rapidly developed progressive flaccid quadriplegia and tongue weakness, necessitating ventilator support. Immediate magnetic resonance imaging of the brain showed heart-shaped appearance of bilateral medial medullary infarction. The patient suffered two new subcortical infarcts 40 days after the first. Detailed Family history and physical examination indicated symptoms consistent with FD, which was confirmed by very low alpha galactosidase A levels and a missense mutation of the alpha-galactosidase A gene. CONCLUSIONS: We report what appears to be the first case of FD manifesting as bilateral medial medullary infarction. Our case suggests that clinicians should consider the possibility of FD in patients with cryptogenic stroke, especially when combined with infarction in the vertebrobasilar artery system, renal insufficiency, or cardiomyopathy. A detailed analysis of subtle historical clues and performing a complete physical examination on stroke patients would help promote earlier diagnosis of FD.

Spontaneous Axonal Dystrophy in the Brain and Spinal Cord in Naïve Beagle Dogs.

Axonal dystrophy (AD) is a common age-related neurohistological finding in vertebrates that can be congenital or induced by xenobiotics, vitamin E deficiency, or trauma/compression. To understand the incidence and location of AD as a background finding in Beagle dogs used in routine toxicity studies, we examined central nervous system (CNS) and selected peripheral nervous system (PNS) tissues in twenty 18- to 24-month-old and ten 4- to 5-year-old control males and females. Both sexes were equally affected. The cuneate, gracile, and cochlear nuclei and the cerebellar white matter (rostral vermis) were the most common locations for AD. Incidence of AD increased with age in the cuneate nucleus, cerebellar white matter (rostral vermis), trigeminal nuclei/tracts, and lumbar spinal cord. Axonal dystrophy in the CNS was not accompanied by neuronal degeneration/necrosis, nerve fiber degeneration, and/or glial reaction. Axonal dystrophy was not observed in the PNS (sciatic nerve, vagus nerve branches, or gastrointestinal mural autonomic plexuses).

Oral repeated-dose toxicity studies of BIA 10-2474 in cynomolgus monkeys.

BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys. Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10-2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards. Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanized during the up-titration period after receiving 9 administrations of 75 mg/kg as a result of bleeding erosion on the feet and hands and ulceration on the tongue. These signs were not seen in any other monkeys during these studies. Doses of 10, 50 or 100 mg/kg/day were administered during the 4-week study and clinical signs related to the pharmacological action of BIA 10-2474 (e.g., tremors and weakness, incoordination and loss of balance, reduction in food intake and reduced body weight) were observed in several monkeys from the intermediate and high dose. Histological alterations consisted of axonal dystrophy in the fasciculus cuneatus (dorsal medulla oblongata) characterized by swollen axons and myelin sheath edema, edema in the pars nervosa of the pituitary gland and vacuolation of Meissner's plexus ganglia in all gastrointestinal segments. All lesions recovered and a dose of 100 mg/kg/day was considered to be the NOAEL. In the 13-week oral study the monkeys received BIA 10-2474 daily by gavage at a dose of 6.25, 37.5 or 75 mg/kg/day. Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL.