Clinical Central Nervous System Manifestations Research Articles

Distinct spatial profile of inflammatory gene expression in the brain of a mouse model of neuropsychiatric lupus

Abstract Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease that results in central nervous system (CNS) involvement in up to 80% of patients, with clinical manifestations ranging from anxiety and fatigue to overt psychosis. However, the mechanisms and cellular components underlying these neuropsychiatric symptoms (NPSLE) remain largely unknown. An elevated type 1 interferon (IFN) signature has been commonly observed in SLE patients, particularly within the CNS of NPSLE patients (Crow et. al., 2014, Shiozawa et. al., 1992). Given the diversity of clinical CNS manifestations, we hypothesized that type 1 interferon-mediated inflammation occurs in spatially distinct regions within the CNS, resulting in differential behavioral outcomes depending on the impacted brain region. To test this hypothesis, we first characterized behavioral phenotypes in the Sle1, Yaa mouse model, and show that these mice exhibit anxiety-like, and fatigue-like behaviors consistent with the major clinical manifestations of NPSLE. To assess the spatial distribution of inflammatory gene expression, we utilized MERFISH (Moffitt et. al., 2016), a multiplexed spatial transcriptomics platform, and observed strikingly distinct patches of interferon stimulated gene (ISG) expression within the subcortical regions of Sle1, Yaa mouse brains. Preliminary single nucleus sequencing (sNuc-Seq) and in situ hybridization results implicate astrocytes and oligodendrocytes as the major cell classes enriched in these ISG patches. In summary, our results validate a mouse behavioral model of NPSLE, and show spatially distinct regions of ISG expression within the CNS, opening up a new avenue of investigation into the fundamental mechanisms of NPSLE.

Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Report of 26 patients and review of the literature.

Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36months, 11 patients died including 5 from intracerebral hemorrhages. EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.

Four novel connexin 32 mutations in X-linked Charcot–Marie–Tooth disease. Phenotypic variability and central nervous system involvement

Charcot–Marie–Tooth (CMT) disease, the most common hereditary neuropathy, is clinically and genetically heterogeneous. X-linked CMT (CMTX) is usually caused by mutations in the gap junction protein b 1 gene (GJB1) coding for connexin 32 (Cx32). The clinical manifestations of CMTX are characterized by significant variability, with some patients exhibiting central nervous system (CNS) involvement. We report four novel mutations in GJB1, c.191G>A (p.Cys64Tyr), c.508G>T (p.Val170Phe), c.778A>G (p.Lys260Glu) and c.300C>G (p.His100Gln) identified in four unrelated Greek families. These mutations were characterized by variable phenotypic expression, including a family with the Roussy–Lévy syndrome, and three of them were associated with mild clinical CNS manifestations.

Leukoencephalopathies in Mitochondrial Disorders: Clinical and MRI Findings

The second most frequently affected organ in mitochondrial disorders (MIDs) is the central nervous system (CNS). One of the most frequent CNS abnormalities on imaging is the affection of the white matter (WMLs) for which the term, leukoencephalopathies in mitochondrial disorders (LEM), is proposed. The morphology of LEM on imaging is quite variable even within the same type of MID and the same family. LEM can be a subtle or prominent feature on imaging and may go along with or without clinical neurologic or neuropsychological manifestations. WMLs are most likely due to the underlying metabolic defect of the respiratory chain or concomitant oxidative stress, resulting in neuronal death and replacement of neurons by glial cells. WMLs in MIDs frequently give rise to misinterpretation, particularly if the mitochondrial defect is not evident in organs other than the CNS or if the presence of WMLs does not induce consideration of a MID as a differential. The diagnosis of a LEM requires the diagnosis of an MID, the detection of WMLs on imaging, and the exclusion of all possible differentials. Because the presence of LEM has an impact on the prognosis of an MID, all MID patients should undergo cerebral imaging even in the absence of clinical CNS manifestations.

Possible Association Between Alice In Wonderland Syndrome And Influenza A Infection

Possible Association Between Alice In Wonderland Syndrome And Influenza A Infection

CT und MRT des Zerebrums bei mitochondrialen Erkrankungen

The central nervous system (CNS) is the second most frequently affected organ in mitochondrial disorders (MD). In the majority of the cases, clinical CNS manifestations correlate with the CNS lesions on imaging and vice versa. The most important method to demonstrate CNS abnormalities in MD is the MRI. This imaging technique can demonstrate structural lesions, such as strokelike lesions, focal or diffuse atrophy, cysts or lacunas, focal or diffuse white matter lesions, grey matter lesions of the cortex or deep grey matter, and increased iron deposition. Functional abnormalities such as increased lactate in the white and grey matter or increased cholin in the white matter can be demonstrated by proton spectroscopy. Abnormlities of the intracerebral vessels can also be documented by MRI. Calcification and bleeding, however, are still more easily accessible by CT. Differentiation between disseminated, focal MD lesions of the white matter from nonactive MS plaques requires inclusion of the individual and family history and all instrumental investigations which are usually necessary to establish the diagnosis of a MD.

G.P.12.04 Clinical features, particularly those of the central nervous system of patients with Becker muscular dystrophy, including autopsied cases

There are no detailed reports about the clinical and pathological findings in the central nervous system (CNS) of patients with Becker’s muscular dystrophy (BMD), although dysfunctions of the skeletal and cardiac muscles are well known in BMD. Since dystrophin is present in the CNS, and usual medical treatment is often influenced by CNS manifestations in patients, we studied the clinical and pathological features of BMD, with particular focus on the CNS manifestations, and also examined the relationships of these features with skeletal and cardiac muscle dysfunctions. We examined eight BMD patients aged 24-77 years who were admitted to our hospital, and six autopsied BMD patients aged 39-58 years. In addition to family histories of the patients, clinical findings, and disease progression, BMD was diagnosed based on the presence of dystrophin revealed by immunohistochemical examination and examination of the dystrophin gene. Brain computed tomography (CT), magnetic resonance imaging (MRI), and CNS pathohistology were also performed. Gene analyses by multiplex PCR revealed that exons 3-4, 3-6, 12-19, 45-47,45-49, and 45-52 were deleted; all the deletions occurred in hot spots in the dystrophin gene. With regard to the clinical CNS manifestations of BMD, 2 of the 14 patients experienced hallucinations, but there was no patient with severe mental retardation. Brain CT and MRI scans revealed various grades of mild atrophy of the front-parietal lobe for all the patients. Low-magnification microscopy images of the brain of three autopsied patients with mild BMD showed that the gyri of the brain were separated, suggesting brain atrophy. The nerve cells of the frontal lobe, however, seemed to be unaffected histologically. These results show that there are mild abnormalities in the CNS of BMD patients. It is well known that BMD patients demonstrate different levels of skeletal and cardiac muscle dysfunctions. In the current study as well, the BMD patients demonstrated CNS abnormalities, although these abnormalities were mild compared to the skeletal and cardiac muscle dysfunctions.

Central nervous system manifestations of mitochondrial disorders

The central nervous system (CNS) is, after the peripheral nervous system, the second most frequently affected organ in mitochondrial disorders (MCDs). CNS involvement in MCDs is clinically heterogeneous, manifesting as epilepsy, stroke-like episodes, migraine, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, or hypophysial abnormalities. CNS involvement is found in syndromic and non-syndromic MCDs. Syndromic MCDs with CNS involvement include mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome, myoclonic epilepsy and ragged red fibers syndrome, mitochondrial neuro-gastrointestinal encephalomyopathy syndrome, neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome, mitochondrial depletion syndrome, Kearns-Sayre syndrome, and Leigh syndrome, Leber's hereditary optic neuropathy, Friedreich's ataxia, and multiple systemic lipomatosis. As CNS involvement is often subclinical, the CNS including the spinal cord should be investigated even in the absence of overt clinical CNS manifestations. CNS investigations comprise the history, clinical neurological examination, neuropsychological tests, electroencephalogram, cerebral computed tomography scan, and magnetic resonance imaging. A spinal tap is indicated if there is episodic or permanent impaired consciousness or in case of cognitive decline. More sophisticated methods are required if the CNS is solely affected. Treatment of CNS manifestations in MCDs is symptomatic and focused on epilepsy, headache, lactacidosis, impaired consciousness, confusion, spasticity, extrapyramidal abnormalities, or depression. Valproate, carbamazepine, corticosteroids, acetyl salicylic acid, local and volatile anesthetics should be applied with caution. Avoiding certain drugs is often more beneficial than application of established, apparently indicated drugs.

Basal Ganglia Calcification in Mitochondrial Disorders

Though basal ganglia calcification (BGC) has been recognized as a feature of mitochondriopathy, little is known about its frequency in a larger cohort. The aim of this work was to assess the frequency of BGC, type and frequency of clinical and additional imaging central-nervous-system (CNS) abnormalities and of non-CNS abnormalities in mitochondriopathy patients with BGC. Retrospectively reviewed were the records of all mitochondriopathy patients in whom BGC was found on cerebral CT during 10 years. Among those who underwent cerebral CT, thirty-six, 24 women, 12 men, aged 33-93 years, showed BGC. The most frequent clinical CNS manifestations in these patients were epilepsy (n = 9), Parkinson syndrome (n = 9), dementia (n = 7), dysarthria (n = 5), spasticity (n = 4), tremor (n = 4), or stroke (n = 4). Additional cerebral CT-findings were atrophy (n = 10), lacunas (n = 6), leucaraiosis (n = 6), focal gliosis (n = 4), or stroke (n = 1). MR imaging, carried out in 12 patients, confirmed BGC in one. The 36 patients presented with involvement of the CNS (n = 32), endocrine system (n = 29), peripheral nervous system (n = 28), heart (n = 23), inner ear (n = 16), eyes (n = 15), guts (n = 11), blood (n = 9), kidney (n = 2), or dermis (n = 2). BGC occurs in one sixth of non-selected patients with mitochondriopathy and is associated with clinical and imaging CNS abnormalities and multisystem disease in the majority of them.

Cellular mechanisms of connexin32 mutations associated with CNS manifestations.

Both oligodendrocytes and myelinating Schwann cells express the gap junction protein connexin32 (Cx32). Mutations in the gene encoding Cx32 (GJB1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX). Although most CMTX patients do not have clinical central nervous system (CNS) manifestations, subclinical evidence of CNS dysfunction is common. We investigated the cellular effects of a subgroup of GJB1/Cx32 mutations that have been reported to cause clinical CNS dysfunction. We hypothesized that these mutants have dominant-negative effects on other connexins expressed by oligodendrocytes, specifically Cx45. We expressed these and other Cx32 mutants in communication-incompetent as well as Cx45-expressing HeLa cells, and analyzed the transfected cells by immunocytochemistry and immunoblotting. In communication-incompetent cells, the mutants associated with CNS phenotypes failed to reach the cell membrane and were instead retained in the endoplasmic reticulum (A39V, T55I) or Golgi apparatus (M93V, R164Q, R183H), although rare gap junction plaques were found in cells expressing M93V or R183H. In HeLa cells stably expressing Cx45, these Cx32 mutants showed a similar expression pattern, and did not alter the pattern of Cx45 expression. These results indicate that Cx32 mutants that are associated with a CNS phenotype do not interact with Cx45, but may instead have other toxic effects in oligodendrocytes.

Brain protein kinase in synaptic vesicles is inhibited by a factor in sera from systemic lupus erythematosus patients with central nervous system manifestations

Sera from systemic lupus erythematosus patients with clinical central nervous system manifestations had a high mean percent of brain synaptic vesicle protein kinase inhibition ( 62 ± 9.3, P < 0.001). This conclusion was derived from screening sera of a total of 287 patients with heterogeneous diseases and from 12 healthy controls. Low levels of synaptic vesicle protein kinase inhibition also were detected in the sera of patients with certain autoimmune, inflammatory, neurological and/or psychiatric symptoms. Because 87.5% of the patients whose sera showed strong synaptic vesicle protein kinase inhibition (over 50%) had neuropsychiatric manifestations, we postulate this relationship may be due to the presence of an inhibitor factor, of which the etiology and molecular characteristics were investigated.

A Study of the Allergic Phenomena in the Central Nervous System.

These experiments were designed to study the allergic response of the central nervous system and to determine what part this phenomena might play in certain types of meningitis and encephalitis. Tuberculous animals were first employed because it is known that their tissues are sensitive to tuberculin. Guinea pigs were inoculated subcutaneously in the groin with a known quantity of virulent human tubercle bacilli sufficient to give rise to an extensive generalized tuberculosis within 3 to 6 weeks. At varying intervals, up to 5 weeks, following the initial inoculation different animals had injected in their subarachnoid spaces by the way of the basal cisterns 0.3 cc. of a 1/10, 1/100, and 1/1000 dilution of old tuberculin. If the animals failed to develop fatal central nervous system disturbances they were killed by means of decapitation under ether anesthesia. Gross and microscopic studies were made of the brain and viscera. Cultures were prepared of the brains for the presence of the tubercle bacilli and other pathogenic organisms. As controls, both tuberculous and non-tuberculous animals were employed in each experiment. In this investigation 112 guinea pigs were employed, 42 of which were controls. Following the subarachnoid injection of tuberculin the animals with advanced visceral tuberculosis showed definite and constant clinical central nervous system manifestations as well as a striking histological response in the leptomeninges. Restlessness, ruffled hair, progressive weakness, twitching and loss of sphincter control occurred 3 to 4 hours after the inoculation of tuberculin. Death usually occurred within 6 to 12 hours. Histological studies of the brains revealed an extensive polymorphonuclear exudate in the subarachnoid space. In the more advanced cases there was a definite perivascular extension and some glial proliferation around the vessels of the cerebral parenchyma.