Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Titin related myopathy with ophthalmoplegia. A novel phenotype.

Titin-related myopathy is an emerging genetic neuromuscular disorder with a wide spectrum of clinical phenotypes. To date, there have not been reports of patients with this disease that presented with extraocular muscle involvement. Here we discuss a 19-year-old male with congenital weakness, complete ophthalmoplegia, thoracolumbar scoliosis, and obstructive sleep apnea. Muscle magnetic resonance imaging revealed severe involvement of the gluteal and anterior compartment muscles, and clear adductor sparing, while muscle biopsy of the right vastus lateralis showed distinctive cap-like structures. Trio Whole Exome Sequencing (WES) showed compound heterozygous likely pathologic variants in the TTN gene. (c.82541_82544dup (p.Arg27515Serfs*2) in exon 327 (NM_001267550.2) and c.31846+1G>A (p.?) in exon 123 (NM_001267550.2). To our knowledge, this is the first report of a TTN-related disorder associated with ophthalmoplegia.

A Treatment Approach in Congenital Fibrosis of Extraocular Muscles.

Background: Congenital fibrosis of extraocular muscles ( CFEOM) is a group of genetically defined eye-moving disorders. The syndrome is clinically characterized by congenital non-progressive ophthalmoplegia caused by dysinervation of the cranial nerves with or without ptosis. As a main sign of a CFEOM, extraocular muscles get shrunken and fibrotic, which makes surgery more technically demanding and the result more unpredictable, which makes the treatment challenging and highly customized. Our paper presents variations of the clinical picture and treatment cases of CFEOM1. Objective: To outline the importance of the clinical examination with the exact measurement of deviations for the patients with ocular fibrosis and passive duction test under general anesthesia, establishing them as the main criteria for treatment. Methods: We treated seven patients (14 eyes) with CFEOM1. The decision of the treatment was based on the measurement of the eye position in the primary position (PP), the severity of compensatory head position (CHP), restriction of motility, and passive motility test performed before surgery in general anesthesia. In 3 cases, patients were treated conservatively with the treatment of refractive error and amblyopia. However, in 4 patients, CHP and position of the eyes in PP were not acceptable, motility was severely impaired, and patients underwent surgery. The first surgery was performed on eye muscles: recession of inferior rectus muscle (IRM), anteposition, and resection of superior rectus muscle (SRM). As a second step procedure, ptosis surgery was performed. When the muscle was too tight, and it wasn't possible to have a satisfying result with conventional surgery, we used a tissue expander to improve the position and motility of the affected eyes. Results: In all operated cases, CHP has significantly improved and the position of the eyes in PP. Conclusion: Exact eye and head position measurements and a passive motility test during general anesthesia should guide the surgery. In the case when conventional surgery is not possible, implantation of a bovine pericard is a safe and effective method.

Blindness and ophthalmoplegia from metastatic breast carcinoma.

SUMMARY: We report a very rare complication from metastatic breast cancer of right-sided blindness and ophthalmoplegia in a 70-year-old female. Cavernous sinus syndrome, superior orbital fissure syndrome and complicated sinusitis were considered in the differential diagnosis but involvement of cranial nerves II, III, IV, VI and the ophthalmic division of V were consistent with an orbital apex syndrome. She had been diagnosed with breast carcinoma 10 years previously. This report highlights the correct clinical and diagnostic pathway with computed tomography (CT) scan of the brain and paranasal sinuses to evaluate for the presence and extent of pathology and biopsy route for any causative mass. In this patient, the mass in the right parasellar region and orbital apex with extension into the sphenoid sinus was amenable to transsphenoidal biopsy which showed features suggestive of metastatic breast carcinoma. She was treated with palliative whole brain radiotherapy without resolution of symptoms.

Novel Mutations of the TYMP Gene in Mitochondrial Neurogastrointestinal Encephalomyopathy: Case Series and Literature Review.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multi-system disorder caused by several homozygous or compound heterozygous mutations, mostly in the nuclear gene of TYMP. Our current knowledge on the underlying pathology of the disease is derived through the study of about 200 cases of different ethnicities. Clinical presentations include severe cachexia, weakness, ptosis, diplopia, abdominal cramps or digestive tract disorders, hearing impairment, and paresthesia.Herein, we aim to present five novel mutations of the nuclear gene of TYMP in six Iranian patients diagnosed with MNGIE. In our population, age at the time of diagnosis was 18 to 49 years, while the onset of the symptoms varied from 13 to 20 years. We detected two pathogenic non-frameshift nonsense premature stop codon mutations (c.1013C > A, and c.130C > T), one variant of uncertain significance (VUS) non-frameshift missense mutation (c.345G > T), one likely pathogenic frameshift insertion (c.801_802insCGCG), and one likely benign homozygous non-frameshift deletion (c.1176_1187del) from two siblings. Our findings also confirm the autosomal recessive inheritance pattern of MNGIE in the Iranian population. The lack of knowledge in the area of nuclear gene-modifier genes shadows the genotype-phenotype relationships of MNGIE.

Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE.NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and ß tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

Disseminated lymphoblastic lymphoma revealed by an isolated third cranial nerve palsy.

Dysfunction of the third cranial nerve can be provoked by a number of different conditions. An isolated cranial neuropathy as a first clinical sign of a non-Hodgkin lymphoma is very infrequent. We represent here an atypical case of lymphoblastic lymphoma revealed by an isolated third cranial nerve palsy. The patient was managed by alternating cycles of cyclophosphamide, vincristine, and prednisone. She made a full recovery with a complete resolution of the symptomatology.

The Wide Spectrum of Pathophysiologic Mechanisms of Paraproteinemic Neuropathy.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

The recurrent TUBB3 Gly98Ser substitution is the first described to inconsistently result in CFEOM3.

Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G>A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of TUBB3 syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype-specific to the TUBB3 Gly98Ser substitution.

TUBB3 E410K syndrome: Case report and review of the clinical spectrum of TUBB3 mutations.

The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The ß-tubulin isotype III (TUBB3) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron-specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype-phenotype correlations have been proposed. We report on a 3-year-old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow-up.

A review of the histopathological findings in myasthenia gravis: Clues to the pathogenesis of treatment-resistance in extraocular muscles.

In myasthenia gravis autoantibodies target components of the neuromuscular junction causing variable degrees of weakness. In most cases, autoantibodies trigger complement-mediated endplate damage and extraocular muscles may be most susceptible. A proportion of MG cases develop treatment-resistant ophthalmoplegia. We reviewed publications spanning 65 years reporting the histopathological findings in the muscles and extraocular muscles of myasthenic patients to determine whether pathological changes in extraocular muscles differ from non-ocular muscles. As extraocular muscles represent a unique muscle allotype we also compared their histopathology in myasthenia to those in strabismus. We found that in myasthenia gravis, the non-ocular muscles frequently demonstrate neurogenic changes regardless of myasthenic serotype. Mitochondrial stress/damage was also frequent in myasthenic muscles and possibly more evident in muscle-specific kinase antibody-positive MG. Although myasthenia-associated paralysed extraocular muscles demonstrated prominent fibro-fatty replacement and mitochondrial alterations, these features appeared commonly in paralysed extraocular muscles of any cause. We postulate that extraocular muscles may be more susceptible than limb muscles to poor contractility as a consequence of myasthenia, resulting in a cascade of atrophy signaling pathways and altered mitochondrial homeostasis which contribute to the tipping point in developing treatment-resistant myasthenic ophthalmoplegia. Early strategies to improve force generation in extraocular muscles are critical.

Altered White Matter Organization in the TUBB3 E410K Syndrome.

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.

Clinical signs, imaging findings, and outcome in twelve cats with internal ophthalmoparesis/ophthalmoplegia.

OBJECTIVE: To retrospectively evaluate the clinical signs, imaging findings, and outcome of feline internal ophthalmoparesis/ophthalmoplegia. PROCEDURE: Medical records were reviewed from 2008 to 2015. Inclusion criteria included cats that presented with internal ophthalmoparesis/ophthalmoplegia, underwent diagnostic imaging, and had follow-up information available. RESULTS: Twelve cases of feline internal ophthalmoparesis/ophthalmoplegia were identified. Nine cats were unilaterally affected, and three cats were bilaterally affected. Affected cats had a median age of 10.54 years (range 5.75 to 13.17), and both sexes of varying breeds were affected (nine males; three females). Clinical signs including abnormal mental status (n = 9; 75%) and additional neurologic abnormalities (n = 10; 83%) were observed. Magnetic resonance imaging and/or computed tomography (MRI/CT) of the head were performed in ten cats, revealing a mass lesion in all cases with varying locations. Multicentric lymphoma was diagnosed in two cats via abdominal ultrasound and cytology. All twelve cats were euthanized due to deterioration of clinical signs and/or quality-of-life concerns. Median time from diagnosis to euthanasia was 3.5 days (range 0 to 80 days). CONCLUSIONS: Feline internal ophthalmoparesis/ophthalmoplegia rarely presents as the sole clinical sign in a referral hospital. Advanced imaging (MRI/CT) may be necessary to reach a definitive diagnosis in these cases. However, abdominal ultrasound would be advocated in cats with systemic clinical signs as a less expensive and less invasive diagnostic test to further investigate the possible etiology of internal ophthalmoparesis/ophthalmoplegia prior to advanced imaging. Feline cases with internal ophthalmoparesis/ophthalmoplegia associated with other intracranial signs and/or systemic clinical signs have a poor prognosis.

A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects.

Individuals with inclusion body myopathy type 3 (IBM3) display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro motility, reduced muscle power output and focal myofibrillar disorganization similar to that seen in individuals with IBM3.

Tolosa-Hunt Syndrome - Case Report.

This case report presents a patient diagnosed with Tolosa-Hunt syndrome (THS) after an extensive neuro-diagnostic and neuroimaging evaluation. Diagnostic work-up included thorough physical and neurological examination, complete laboratory serum assessments, neuroendocrine and immunohistochemistry analysis, cerebrospinal fluid analysis, neurophysiology assessment, ophthalmologist examination and neuroimaging. Th e most important diagnostic tool in deriving the diagnosis of THS was neuroimaging evaluation that included baseline and follow-up cranial contrast enhanced magnetic resonance imaging (MRI). Baseline cranial contrast enhanced MRI detected a nonspecific inflammatory granulomatous lesion in the right cavernous sinus extending basally towards the right trigeminal cave (Meckel's cave) and anteriorly towards the apex of the right orbit. Systemic intravenous high-dose corticosteroid therapy was administered for 3 consecutive days and then tapered down to lower oral steroid doses. Following therapy, the patient experienced complete regression of symptoms. Follow-up cranial contrast enhanced MRI showed significant regression of inflammatory lesion in the area of right cavernous sinus, thus verifying the efficacy of the treatment applied. This paper shows that an extensive diagnostic schedule for THS must be conducted prior to therapeutic treatment, for the possibility of alternative diagnosis. Patients suspected of having THS require careful evaluation, appropriate treatment, and follow-up.

The African-387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis.

Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling. We screened the regulatory region of the transforming growth factor beta-1 (TGFB1) gene encoding the cytokine pivotal in muscle healing responses. We show the frequency of an African-specific polymorphism TGFB1 c.-387 T (rs11466316) among South Africans with African-genetic ancestry is higher than 1000 Genomes African controls (17.2% vs 4.8%; P<1 × 10(-7)), and associates with juvenile OP-MG (28%; P=0.043). Further, TGFB1 -387 C>T is functional because it represses the TGFB1 promoter construct basal activity by fivefold, and OP-MG fibroblasts (-387 C/T or T/T) have lower basal TGFB1 mRNA transcripts compared with controls (-387 C/C)(P=0.001). Co-transfections with Sp1 show less responsiveness of the -387 T promoter compared with wild-type -387 C (P=0.015). Our findings suggest that population-specific alleles may lower TGFB1 expression, thereby influencing OP-MG susceptibility by inhibiting extraocular muscle CD55 upregulation and/or altered endplate remodeling.

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.

Saccadic palsy following cardiac surgery: a review and new hypothesis.

The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN.