Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH.

Endosomes have emerged as a central hub and pathogenic driver of Alzheimer's disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aß), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aß clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aß in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.

Bosley-Salih-Alorainy syndrome in patients from India.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.

Eye movement abnormalities are associated with brainstem atrophy in Wilson disease.

BACKGROUNDS: This study aims to characterize eye movement abnormalities in Wilson disease and examine their association with the degree of brainstem atrophy. METHODS: Twenty patients (10 males, mean age 46.8, SD 8.9 years) with genetically confirmed neurological WD on stable anti-copper treatment and 20 age- and sex-matched healthy subjects were examined. Eye movements, including prosaccade and antisaccade tasks, were evaluated using infrared videooculography. MRI was performed using 1.5 T system, and T2-weighted images were used for the measurement of midbrain and pontine area on mid-sagittal slices. Clinical severity was assessed using the Unified Wilson's Disease Rating Scale (UWDRS). RESULTS: Compared to healthy controls, WD patients showed prolonged latencies of horizontal prosaccades and hypometry of both horizontal (p = 0.04) and vertical (p = 0.0046) prosaccades. In the antisaccade task, WD patients showed prolonged latency of both horizontal (p = 0.04) and vertical antisaccades (p = 0.047) and increased error rate of vertical antisaccades (p = 0.04). There is a significant association between midbrain area and horizontal latencies (r = -0.53; p = 0.02) and vertical maximum speed in prosaccades (r = 0.47; p = 0.04). The pons area inversely correlated with horizontal prosaccade and antisaccade latencies (p = 0.007). CONCLUSIONS: We showed impairments of ocular saccades such as prolonged latencies, hypometry, and increased error rate in antisaccades. The strong association between prolonged latencies of prosaccades and the brainstem atrophy suggests that VOG might serve as a sensitive electrophysiological marker of brainstem dysfunction in WD.

A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome.

Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.

Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments.

Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.

MRI findings in Parinaud's syndrome: a closer look at pineal masses.

PURPOSE: The association between MRI findings in patients with pineal lesions and the presence or absence of Parinaud's syndrome (PS) remains poorly described. We sought to better understand what MRI characteristics of a pineal lesion make PS more likely. Can these features predict prognosis for clinical resolution? Based on the anatomical relationship of the pineal gland and midbrain, we hypothesized that the degree of midbrain injury by a pineal mass as assessed by abutment, displacement, or intrinsic midbrain signal abnormality (IMSA) may predict PS. METHODS: We reviewed our institution's databases to find patients with MRI evidence of an intrinsic lesion of the pineal gland. Seventy-seven patients with intrinsic pineal gland lesions, 26 with PS and 51 without PS (NPS), were identified. Data regarding clinical history were collected, and an experienced neuroradiologist reviewed all MRI studies and recorded mass size, midbrain abutment, displacement by the pineal lesion, and presence or absence of IMSA. RESULTS: IMSA occurred with increased frequency in pineal lesions with PS (85%) when compared with NPS (39.2%) (p = 0.0001). Midbrain abutment, compression, and displacement occurred with similar frequencies in both groups, with no statistically significant difference. Hydrocephalus was present in 80.8% of patients with PS and 84% without PS (p = 0.75). CONCLUSION: IMSA in a patient with an intrinsic pineal gland mass is associated with PS. Other findings such as hydrocephalus and midbrain displacement are common in patients with pineal masses both with and without PS and do not have any predictive value.

Infratentorial immature teratoma of congenital origin can be associated with a 20-year survival outcome: a case report and review of literature.

BACKGROUND: Congenital intracranial tumors are very rare and account for less than 2% of all childhood brain tumors. Teratomas constitute about one third to one half of these, predominantly located midline in the supratentorial region. Posterior fossa location rarely occurs and, based on the cases reported in the literature, commonly has a poor prognosis. CASE PRESENTATION: A newborn female, diagnosed prenatally with hydrocephalus, is presented at birth with increasing head circumference and Parinaud's syndrome. Magnetic resonance imaging scans demonstrated a huge posterior fossa tumor with obstructive hydrocephalus. At surgery, through a suboccipital craniotomy, complete excision was achieved of a histological-proven immature teratoma. The infant received adjuvant chemotherapy for 1 year. She had normal neurological development and remained tumor-free through her 20-year follow-up. CONCLUSION: The authors report this rare case of congenital posterior fossa teratoma with long-term outcome, and the literature is reviewed.

Surgical treatment of pineal cysts in non-hydrocephalic and neurologically intact patients: selection of surgical candidates and clinical outcome.

PURPOSE: Management of patients presenting for various nonspecific complaints without clear neurological abnormalities and with normal ventricular size remains highly controversial. We intended to share our rationale for surgical treatment of patients who show symptoms of transient increase of intracranial pressure owing to the presence of the cyst. MATERIALS AND METHODS: We have retrospectively analyzed 28 cases of patients who presented without Parinaud syndrome nor ventricular enlargement and underwent pineal cyst removal in our centre between 2007 and 2015. We analyzed patients' age, sex, symptoms, preoperative cyst size, perioperative course, treatment outcome and neurologic status at discharge and at follow-up visits 4 and 12 months afterwards. RESULTS: Main complaints included paroxysmal headaches, nausea, vomiting, visual disturbances, syncope and transient depression of consciousness. Mean age of patients was 31 years (17-55); there were 24 females and 4 males. Mean cyst diameter was 17 mm (10-26). Decision about surgical treament was based on signs of transient increases of intracranial pressure. All patients underwent complete cyst excision via midline suboccipital craniotomy and infratentorial supracerebellar route. Short-lasting perioperative neurological signs (notably upgaze palsy) were noted in 22 cases and uniformly resolved within the observation period of 12 months. CONCLUSION: Abnormal neurological findings and ventricular enlargement are not indispensable to justify surgical treatment of pineal cysts. Judicious selection of surgical candidates based predominantly on clinical grounds can lead to excellent operative results.

Oculomotor abnormalities in children with Niemann-Pick type C.

Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions.

Parinaud syndrome: Any clinicoradiological correlation?

INTRODUCTION: The significance of MRI findings of patients with Parinaud syndrome (PS) with respect to clinical characteristics is poorly defined. Over the past decades, all patients with PS undergo magnetic resonance imaging which allows a better identification of the lesion localization. We compared the neuro-ophthalmological findings of patients with PS caused by intrinsic (intra-axial) vs extrinsic (pineal gland tumor) brainstem lesions. METHODS: Medical records of patients with PS evaluated between 2000 and 2016 were retrospectively reviewed. RESULTS: Twenty-six patients with PS were included. Eight patients had pineal gland tumors and hydrocephalus. Two patients had hydrocephalus due to aqueduct stenosis and fourth ventricle tumor. Sixteen patients suffered from an intrinsic brainstem lesion and seven associated with hydrocephalus. The neuro-ophthalmological findings did not differ between patients with extrinsic and intrinsic brainstem lesions. No correlation was found between the grade of hydrocephalus and number of clinical findings except for more findings in low-grade hydrocephalus in intrinsic (40%) vs extrinsic (0%) lesions (P=.003). Patients with moderate brainstem lesions and hydrocephalus had more clinical findings (65%) than patients with the same grade of brainstem involvement without hydrocephalus (29%) (P=.03). The resolution rate of ophthalmological findings was comparable in all groups of patients. CONCLUSIONS: Our results did not show differences in neuro-ophthalmological findings between intra- and extra-axial lesions causing PS. However, the presence of hydrocephalus was an important factor influencing clinical findings. The prognosis of PS was less favorable than generally reported.

Patterns of Eye Movement Impairment Correlate with Regional Brain Atrophy in Neurodegenerative Parkinsonism.

BACKGROUND: One common feature of neurodegenerative parkinsonism including Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) is altered eye movement control. Characteristic regional structural atrophy patterns in MRI can be observed in PD, MSA, and PSP. OBJECTIVE: To investigate the association between eye movement disturbances and regional brain atrophy in patients with PD, MSA, and PSP. METHODS: High-resolution 3-dimensional T1-weighted MRI images and video-oculographic recordings (EyeLink®) were obtained from 39 PD, 32 PSP, and 18 MSA patients and 24 matched healthy control subjects. Automatic regional volumetric assessment was performed using atlas-based volumetry (ABV). RESULTS: The prevalence of saccadic intrusions as a measure of inhibitory control was significantly increased in PD patients compared to controls (p < 0.001) and negatively correlated with whole brain volume, cerebral brain volume, and occipital lobe volume (p = 0.0057, p = 0.0049, and p = 0.0059, respectively; all p values are false discovery rate corrected). In MSA, smooth pursuit was disturbed by characteristic "catch-up" saccades (p < 0.001) and it was significantly correlated with cerebellar volume (p = 0.004) and pontine volume (p < 0.001). The hallmark of PSP was pathologically slowed vertical peak eye velocities (p < 0.001); the lower the peak eye velocity, the more marked midbrain atrophy (p = 0.007). CONCLUSIONS: Foci of regional atrophy correlated with disease-specific eye movement alterations in all investigated parkinsonian syndromes. Oculomotor impairment in PD, predominantly the result of executive dysfunction, was linked to cerebral atrophy. Impairment in the corresponding oculomotor pathways was associated with atrophy of pontocerebellar oculomotor structures in MSA and midbrain atrophy in PSP.

An Evaluation of Educational Neurological Eye Movement Disorder Videos Posted on Internet Video Sharing Sites.

BACKGROUND: Internet video sharing sites allow the free dissemination of educational material. This study investigated the quality and educational content of videos of eye movement disorders posted on such sites. METHODS: Educational neurological eye movement videos were identified by entering the titles of the eye movement abnormality into the search boxes of the video sharing sites. Also, suggested links were followed from each video. The number of views, likes, and dislikes for each video were recorded. The videos were then rated for their picture and sound quality. Their educational value was assessed according to whether the video included a description of the eye movement abnormality, the anatomical location of the lesion (if appropriate), and the underlying diagnosis. RESULTS: Three hundred fifty-four of these videos were found on YouTube and Vimeo. There was a mean of 6,443 views per video (range, 1-195,957). One hundred nineteen (33.6%) had no form of commentary about the eye movement disorder shown apart from the title. Forty-seven (13.3%) contained errors in the title or in the text. Eighty (22.6%) had excellent educational value by describing the eye movement abnormality, the anatomical location of the lesion, and the underlying diagnosis. Of these, 30 also had good picture and sound quality. The videos with excellent educational value had a mean of 9.84 "likes" per video compared with 2.37 for those videos without a commentary (P < 0.001). The videos that combined excellent educational value with good picture and sound quality had a mean of 10.23 "likes" per video (P = 0.004 vs videos with no commentary). There was no significant difference in the mean number of "dislikes" between those videos that had no commentary or which contained errors and those with excellent educational value. CONCLUSIONS: There are a large number of eye movement videos freely available on these sites; however, due to the lack of peer review, a significant number have poor educational value due to having no commentary or containing errors. The number of "likes" can help to identify videos with excellent educational value but the number of "dislikes" does not help in discerning which videos have poor educational value.

Neural mechanisms of smooth pursuit eye movements in schizotypy.

Patients with schizophrenia as well as individuals with high levels of schizotypy are known to have deficits in smooth pursuit eye movements (SPEM). Here, we investigated, for the first time, the neural mechanisms underlying SPEM performance in high schizotypy. Thirty-one healthy participants [N = 19 low schizotypes, N = 12 high schizotypes (HS)] underwent functional magnetic resonance imaging at 3T with concurrent oculographic recording while performing a SPEM task with sinusoidal stimuli at two velocities (0.2 and 0.4 Hz). Behaviorally, a significant interaction between schizotypy group and velocity was found for frequency of saccades during SPEM, indicating impairments in HS in the slow but not the fast condition. On the neural level, HS demonstrated lower brain activation in different regions of the occipital lobe known to be associated with early sensory and attentional processing and motion perception (V3A, middle occipital gyrus, and fusiform gyrus). This group difference in neural activation was independent of target velocity. Together, these findings replicate the observation of altered pursuit performance in highly schizotypal individuals and, for the first time, identify brain activation patterns accompanying these performance changes. These posterior activation differences are compatible with evidence of motion processing deficits from the schizophrenia literature and, therefore, suggest overlap between schizotypy and schizophrenia both on cognitive-perceptual and neurophysiological levels. However, deficits in frontal motor areas observed during pursuit in schizophrenia were not seen here, suggesting the operation of additional genetic and/or illness-related influences in the clinical disorder.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

Axonal conduction in multiple sclerosis: A combined magnetic resonance imaging and electrophysiological study of the medial longitudinal fasciculus.

OBJECTIVE: The objective of this paper is to inform the pathophysiology of medial longitudinal fasciculus (MLF) axonal dysfunction in patients with internuclear ophthalmoplegia (INO) due to multiple sclerosis (MS), and develop a composite structural-functional biomarker of axonal and myelin integrity in this tract. METHODS: Eighteen patients with definite MS and clinically suspected INO underwent electrical vestibular stimulation and search-coil eye movement recording. Components of the electrically evoked vestibulo-ocular reflex (eVOR) were analyzed to probe the latency and fidelity of MLF axonal conduction. The MLF and T2-visible brainstem lesions were defined by high-resolution MRI. White matter integrity was determined by diffusion-weighted imaging metrics. RESULTS: eVOR onset latency was positively correlated with MLF lesion length (left: r = 0.66, p = 0.004; right: r = 0.75, p = 0.001). The mean conduction velocity (±SD) within MLF lesions was estimated at 2.72 (±0.87) m/s. eVOR onset latency correlated with normalized axial diffusivity (r = 0.66, p < 0.001) and fractional anisotropy (r = 0.44, p = 0.02) after exclusion of cases with ipsilateral vestibular root entry zone lesions. CONCLUSIONS: Axonal conduction velocity through lesions involving the MLF was reduced below levels predicted for natively myelinated and remyelinated axons. Composite in vivo biomarkers enable delineation of axonal from myelin processes and may provide a crucial role in assessing efficacy of novel reparative therapies in MS.

Considerations on the etiology of congenital Brown syndrome.

PURPOSE OF REVIEW: Brown syndrome is an ocular motility disorder characterized by limited volitional and passive elevation of the eye in adduction. Although originally thought due to abnormalities in the trochlea or tendon sheath (limiting the free movement of the tendon through the trochlea), recent evidence suggests that some cases of congenital Brown syndrome may be related to neurodevelopmental abnormalities of the extraocular muscles (congenital cranial dysinnervation disorders, CCDD). RECENT FINDINGS: CCDD is a term encompassing congenital abnormalities of eye movements caused by congenital innervational abnormalities. The abnormal development of cranial nerve nuclei or abnormalities in cranial nerve axonal transport affects the development of the extraocular muscle(s). Currently, congenital fibrosis of the extraocular muscles, Duane syndrome, Moebius syndrome, Horizontal gaze palsy and progressive scoliosis, and synergistic divergence are included as CCDDs. In addition, congenial ptosis, Jaw Wink ptosis, and congenital superior oblique palsy are also included. Recently, it has been suggested that some cases of congenital Brown syndrome and congenital superior oblique paresis are related, and these entities may be part of the CCDDs spectrum. SUMMARY: Important findings regarding the cause of congenital Brown syndrome will be reviewed.

The great imitator--still today! A case of meningovascular syphilis affecting the posterior circulation.

Cerebral ischemia due to meningovascular syphilis is rare and more frequently affects the anterior circulation than the posterior circulation. We describe clinical features and imaging studies of a 50-year-old patient with Parinaud syndrome and a syphilitic dorsal midbrain infarction. Brain magnetic resonance imaging indicated vasculitis of the posterior circulation. The diagnosis of meningovascular syphilis was established by serum and cerebrospinal fluid examinations. Although rare, because of the high impact on treatment, clinicians should always be aware of meningovascular syphilis in the differential diagnosis of stroke, particularly in young and male patients with cryptogenic stroke.

Tendinous muscle insertions (scleromuscular junctions of the recti muscles) in patients with ocular alignment problems.

BACKGROUND: The purpose of this study was to prove the hypothesis whether the scleromuscular junction of extraocular recti muscle is tendinous. PATIENTS AND METHODS: Muscle samples of the 41 extraocular recti muscles of 33 patients and 4 muscle-/eye-matched samples from 2 postmortem eyes, were processed for light/electron microscopy and immunohistochemistry with antibodies against desmin, smooth-muscle actin and muscle regulating proteins like myf3 and myf4 (myogenin), tenascin C and for 8 samples against collagens I to IV. RESULTS: Histological examination of the muscle samples confirmed a thick collagen-structured tissue, specific for muscle tendon; without appearance of muscle tissue. This was confirmed by immunohistochemistry with antibodies against desmin, smooth-muscle actin, myf3 and myf4 (myogenin) and for eight samples with collagens I to IV. Anti-tenascin C marker was only strongly positive in the connective tissue of the blood vessel walls. Electron microscopy demonstrated collagen bundles composed of parallel oriented fibrils with a moderate amount of ground substance. CONCLUSIONS: The absence of contractile fibers at the sclerotendinous junction is an entirely normal finding in humans and cannot be related to ocular alignment pathogenesis.

[Brown syndrome: clinical and radiological correlation].

OBJECTIVE: Brown syndrome is characterized by limitation of elevation in adduction, with complex mechanisms involving muscle, tendon, and trochlea. Here, we investigated mechanisms of Brown syndrome by magnetic resonance (MR) imaging. METHODS: It was a retrospective case series study. Fourteen patients with unilateral Brown syndrome between 3 and 54 years of age (10 cases of congenital and 4 cases with acquired disease) were included in the study. All patients underwent complete ophthalmic and orthoptic evaluation. Imaging of the ocular motor nerves at the brainstem was performed on 3D-FIESTA sequence, the orbits were imaged with FSE T1, T2WI using surface coils. RESULTS: Nine of 10 with congenital Brown syndrome demonstrated hypoplasia of the superior oblique (SO) of the affected side. Abnormal low signal intensity in the trochlea area was found in one patient. Three of 4 acquired patients had a history of trauma and were demonstrated fracture of the trochlea, extensive scarring, and superior orbital fracture. One acquired case was demonstrated scarring of anterior part of the SO and hypoplasia of the posterior part. CONCLUSION: Brown syndrome consists of a series of diseases. Their clinical features are quite similar while their anatomical mechanism varies in numerous ways. Therefore, based on patient's individual pathophysiology, the management in Brown syndrome should be personalized.

Retinal ganglion cells projecting to the accessory optic system in optokinetic blind albinotic rats are direction-selective.

The optokinetic deficits in albinotic rats and ferrets are caused by the loss of direction selectivity in the accessory optic system (AOS). However, the underlying mechanisms for this loss are still not clear. Here we tested the hypothesis that, in albino rats, the retinal input to the AOS lacks direction selectivity and, as a consequence, neurons in the AOS are direction non-selective. We investigated ON-center direction-selective retinal ganglion cells, the major input to the AOS, in pigmented Long Evans and albino Wistar rats using extracellular in vitro patch-clamp techniques. To visualise putative AOS-projecting direction-selective ganglion cells, we retrogradely labeled them by injection of the infrared-sensitive dye indocyanine green into the medial terminal nucleus of the AOS. The present study is the first to present physiological evidence for retinal ON-center direction-selective ganglion cells in rat. Our results show that, in albinotic and pigmented rats, ON-center retinal ganglion cells projecting to the AOS are similarly direction-selective, suggesting that the optokinetic deficit must be caused by the abolition of direction selectivity in the AOS itself.