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PubMed1987

Nephropathic cystinosis with central nervous system involvement.

Nephropathic cystinosis is associated with end-stage renal failure, retinal damage, and hypothyroidism. Patients may now survive past the first decade of life with the use of dialysis and renal transplantation. Examination of a 24-year-old woman with this disorder revealed ovarian failure, mildly abnormal results on a glucose tolerance test, intermittent confusion, short-term memory loss, and cerebral atrophy on computerized axial tomography. Autopsy examination at age 25 years revealed cystine storage in multiple tissues including the atrophic ovaries, pancreatic islet cells, the aorta, and the brain. Dysfunction of multiple organ systems may develop in patients with cystinosis who survive into adulthood. This emphasizes the need for a systemic therapy for cystinosis.

Adult↗
PubMed1988

[Multiple neurologic manifestations of Borrelia burgdorferi infection].

The neurological spectrum of Borrelia burgdorferi infections is still enlarging. We review epidemiological, pathological and serological data of Lyme disease. The course of the disease is divided in three stages: stage 1 during the first month is characterised by erythema chronicum migrans and associated manifestations; stage 2 includes not only the classical European meningoradiculitis but also less specific neurological symptoms: isolated lymphocytic meningitis with an acute or even relapsing course, apparently idiopathic facial palsy, neuritis of other cranial nerves, polyneuritis cranialis, Argyll-Robertson sign, peripheral nerve involvement, acute transverse myelitis, severe encephalitis, myositis. During stage 3, three to five months or longer after the onset of the disease, chronic arthritis, acrodermatitis chronica atrophicans and various neurological symptoms can be observed: chronic neuropathy with mainly sensory or motor signs, recurrent strokes due to cerebral angiopathy and progressive encephalomyelitis; this third stage the central nervous system involvement is characterised by slowly progressive or fluctuating course during months or years, ataxic or spastic gait disorder, bladder disturbances, cranial nerve dysfunction including optic atrophy and hypoacusia, dysarthria, focal and diffuse encephalopathy. This chronic central nervous system disease can mimic multiple sclerosis, anorexia nervosa, psychic disorders or subacute presenile dementia. It is often associated with pleiocytosis, abnormal EEG and evoked potentials, sometimes multifocal and mainly periventricular white matter lesions visualised by CT or MRI, and as a rule high antibody titers against Borrelia burgdorferi. High doses of penicillin can halt the disease, sometimes induce spectacular regression of symptoms or sometimes be inefficient; ceftriaxone could be a more powerful therapy. Similarities between syphilis and Borreliosis are multiple: both of these spirochetes contain plasmids, can be transmitted through the placenta and progress for many years through successive stages, with multiorgan symptoms, including parenchymatous and vascular lesions of the central nervous system. Borrelia burgdorferi is the new great imitator.

Animals↗
PubMed2005

Behavioral heterogeneity in an animal model of neuropsychiatric lupus.

BACKGROUND: Various psychiatric manifestations of unknown etiology are common in systemic autoimmune disease lupus erythematosus (SLE). Profound heterogeneity at clinical and neuropathological levels suggests distinct subpopulations of SLE patients and multiple mechanisms in the pathogenesis of aberrant behavior. Using inbred mice prone to SLE-like condition, we presently examine whether subpopulations of diseased mice can be identified on the basis of their behavioral performance. METHODS: Hierarchical cluster analysis was used to classify 105 MRL-lpr males into clusters. Multivariate analysis of variance (MANOVA) and discriminant function analysis were used to detect overall differences and identify discriminative variables. RESULTS: Cluster 1 was characterized by blunted responsiveness to palatable stimulation, as well as increased spleen mass and serum levels of interleukin-1. Cluster 2 comprised of animals with reduced ambulation speed and enlarged spleen. Mice from cluster 3 showed profound dilatation of brain ventricles, reduced brain mass, impaired nutrition and performance in task reflective of emotional reactivity. CONCLUSIONS: Present results suggest that systemic autoimmunity compromises brain function via non-Mendelian mechanisms. Although neuroactive cytokines may impair reward systems, brain atrophy seems to underlie deficits in ingestive behavior and emotional reactivity. This study supports the hypothesis that multiple neuroimmunological pathways are involved in the etiology of aberrant behavior during SLE-like disease.

Analysis of Variance↗
PubMed1998

Vecuronium dose requirement and pupillary response in a patient with olivopontocerebellar atrophy (OPCA).

PURPOSE: Olivopontocerebellar atrophy (OPCA), a variant of spinocerebellar degeneration (Shy-Drager syndrome), is a systemic degenerative disorder affecting the neurons of multiple nuclei. We investigated the sensitivity to vecuronium and the pupillary responses to various stresses in a patient with OPCA. CLINICAL FEATURES: A 65-yr-old woman with a six-month history of OPCA underwent a left upper lobectomy for lung cancer under propofol-N2O anaesthesia. She had symptoms of dysarthria, bulbar palsy, cerebellar ataxia, Parkinsonism, myosis, pyramidal signs and muscular atrophy of the distal extremities. A cumulative dose-response curve for vecuronium was constructed, and pupillary changes in response to various noxious stimuli were evaluated with concomitant recording of the Spectral-Edge-Frequency 90% (SEF90; the frequency below which 90 percent of the EEG power is located). The dose-response curve for vecuronium and the estimated ED50 value (the 50% blocking dose of vecuronium) in this patient with OPCA were almost identical with those of five ASA I-II patients (27 micrograms.kg-1 vs 31 micrograms.kg-1). The pupil size and the SEF90 did not change after tracheal intubation or surgical stimulation in this patient, while in the control subjects (n = 3), these measures increased in response to both stresses. CONCLUSIONS: The absence of pupillary and SEF90 responses to noxious stimuli suggests a sensitivity to propofol and/or central autonomic dysfunction in patients with OPCA. Although the dose requirement of vecuronium in this patient was similar to that of the control patients, the effects of neuromuscular blockers may vary depending on the severity of muscle atrophy.

Aged↗
PubMed2004

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.

Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin-induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair-fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin-1/MAFbx and MuRF-1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down-regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up-regulated (lipin, metallothionein, AMP deaminase, RNA helicase-related protein, TG interacting factor) and several growth-related mRNAs were down-regulated (P311, JUN, IGF-1-BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.

Adenosine Triphosphate↗
PubMed2001

Blepharoclonus in multiple sclerosis.

OBJECTIVE: Keane described 2 patients with gaze-evoked blepharoclonus (BLC), a form of reflex BLC, and multiple sclerosis (MS). A search for common areas of demyelination and focal axonal atrophy (T1 black holes) of the central nervous system (CNS) in 11 patients with MS exhibiting eyelid closure BLC was conducted employing magnetic resonance imaging (MRI). Finding lesions in common CNS locations on these patients can help to elucidate the pathogenesis of this restricted movement disorder. MATERIALS AND METHODS: Eleven adult patients with relapsing-remitting, primary or secondary progressive MS were studied. MRI views were completed employing a 1.5-tesla scanner. Contrast Axial T1 imaging was obtained in 9 patients. RESULTS: TL blackholes were not identified. Ten patients had multiple, scattered periventricular (PV) areas of demyelination. Four patients exhibited brainstem lesions of diverse but inconsistent locations including midbrain, cerebellar peduncle, pons and medulla. In 2 of the patients the brainstem lesions were transient but BLC persisted after the lesions regressed. CONCLUSION: No common areas of CNS demyelination or focal axonal atrophy were identified on these patients with MS and BLC. The pathogenesis and clinical significance of BLC in MS remains to be elucidated.

Adult↗
PubMed2005

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Adult↗
PubMed2000

Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a.

Brain atrophy is a relevant surrogate marker of the disease process in multiple sclerosis (MS) because it represents the net effect of various pathological processes leading to brain tissue loss. There are various approaches to quantifying central nervous system atrophy in MS. We have focused on a normalized measure of whole brain atrophy, the brain parenchymal fraction (BPF). BPF is defined as the brain parenchymal volume, divided by the volume within the surface of the brain. We applied this method to an MRI data set generated during a phase III clinical trial of interferon beta-1a (AVONEX). The purpose of the current study is to further explore clinical and MRI correlates of the BPF, particularly as they relate to relapse rate and Kurtzke's Expanded Disability Status Score (EDSS); and to further explore the therapeutic effects observed in interferon beta-1a recipients. Of all demographic and disease measures in the clinical trial data base, T2 lesion volume most closely correlated with BPF in cross sectional studies, and was the baseline factor most closely correlated with progressive brain atrophy in the subsequent 2 years. We also observed that change in T2 lesion volume was the disease measure most closely correlated with change in BPF during 2 years of observation. Of interest, relapse number and EDSS change during 2 years were only weakly correlated with BPF change during the same period. Disability progression, defined as sustained worsening of at least 1.0 EDSS points from baseline, persisting at least 6 months, was associated with significantly greater brain atrophy progression. We observed a therapeutic effect of interferon beta-1a in the second year of the clinical trial, and this beneficial effect was not accounted for by change in gadolinium enhanced lesion volume, or by corticosteroid medication within 40 days of the final MRI scan. The BPF is an informative surrogate marker for destructive pathological processes in relaping MS patients, and is useful in demonstrating treatment effects in controlled clinical trials. The significance of progressive brain atrophy during relapsing MS will be assessed by measuring clinical and MRI changes in prospective follow up studies.

Adjuvants, Immunologic↗
PubMed2001

Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia.

We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.

Aged↗
PubMed2000

[Protection of the mucosal barrier by nutritional strategies. What are the therapeutic options?].

The dysfunction of intestinal barrier allows the translocation of both endotoxin and whole bacterial organisms. It plays an important role in the development of multiple organ failure (MOF). The mucosa ia one component of this barrier. Trauma, atrophy and the "systemic inflammatory response syndrome" increase gastrointestinal permeability. These abnormalities may contribute to the pathophysiology of sepsis. Malnutrition per se compromises the gut's barrier function. Maintenance of gastrointestinal blood flow may be facilitated by (glutamine-enriched?) enteral diets. The most important conclusions of the majority of controlled trials support the concept of the very early enteral nutrition (within 24 hours after trauma): the outcome of seriously ill patients is improved, the rate of complications and infections is reduced. Gastrointestinal motility disorders may interfere with the initiation and tolerance of early enteral nutrition. They may be managed by prokinetic agents (cisapride, erythromycin) or by bypassing the stomach with a nasoenteric tube.

Gastrointestinal Diseases↗
PubMed2006

Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases.

We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1alpha and PGC-1beta coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.

Animals↗
PubMed2005

Magnetic resonance imaging in multiple sclerosis.

Magnetic resonance imaging (MRI) has played a central role in the clinical management and scientific investigation of multiple sclerosis (MS) and has become the most important ancillary tool for diagnosing and monitoring the disease. Conventional MRI techniques are used to assess overt lesions and atrophy in the central nervous system and include spin-echo T2-weighted, pre- and post-gadolinium-enhanced spin-echo T1-weighted, and fluid-attenuated inversion-recovery images. Advanced MRI techniques such as diffusion-weighted imaging, magnetization transfer imaging, magnetic resonance spectroscopy, and functional MRI have increased our understanding of the pathogenesis of MS. The role of these newer techniques in clinical practice remains under investigation. In this review, we will focus on the role of MRI in the diagnosis and management of MS. We will also review how advanced MRI techniques contribute to our understanding of MS.

Atrophy↗
PubMed2005

Anesthetic approach to the Dyke-Davidoff-Masson syndrome--a case report.

The so-called Dyke-Davidoff-Masson syndrome (DDMS) is a rare disorder of cerebral hemiatrophy. The clinical presentation may consist of facial asymmetry, contralateral atrophy (including the trunk, and the extremities) and hemiparesis, speech difficulties, mental retardation, and epilepsy. Because it involves multiple systems, especially problem of the airway, occult myopathy, and seizure disorder, anesthesia for such a patient is a challenge to any anesthesiologist. However, there are no clinical reports which concern the anesthetic management of such patients in the literature. We herein report a 5-year-old girl, a sufferer of DDMS, scheduled for burr trephination. The successful anesthetic management is brought forward with highlights of inference from the experience.

Anesthesia↗
PubMed2003

Delleman (oculocerebrocutaneous) syndrome: few variations in a classical case.

Delleman syndrome involves a group of congenital abnormalities affecting the eye, skin and central nervous system. It is a rare and sporadic disorder. We report on a 4-year-old male child who presented to us with oculocerebrocutaneous syndrome featuring: focal alopecia on the left side of the scalp, left periorbital skin appendages, a left-sided orbital dermoid, a large left-sided intracranial cyst,optic atrophy. About 35 such cases have been reported in the literature so far. To our knowledge optic atrophy associated with oculocerebrocutaneous syndrome has not been reported previously. Our patient had only a single seizure and his IQ was normal.

Abnormalities, Multiple↗
PubMed1999

Quantitation of spinal cord demyelination, remyelination, atrophy, and axonal loss in a model of progressive neurologic injury.

Spinal cord pathology, such as demyelination and axonal loss, is a common feature in multiple models of central nervous system (CNS) injury and disease. Development of methods to quantify spinal cord pathology objectively would aid studies designed to establish mechanisms of damage, correlate pathology with neurologic function, and assess therapeutic interventions. In this study, we describe sensitive methods to objectively quantify spinal cord demyelination, remyelination, atrophy, and axonal loss following the initiation of a progressive inflammatory demyelinating disease with Theiler's murine encephalomyelitis virus (TMEV). Spinal cord demyelination, remyelination, and atrophy were quantified from representative 1-microm-thick cross sections embedded in Araldite plastic using interactive image analysis. In addition, this study demonstrates novel, automated methodology to quantify axonal loss from areas of normal-appearing white matter, as a measure of secondary axonal injury following demyelination. These morphologic methods, which are applicable to various models of CNS injury, provide an innovative way to assess the benefits of therapeutic agents, to determine mechanisms of spinal cord damage, or to establish a correlation with sensitive measures of neurologic function. J. Neurosci Res 58:492-504.

Animals↗