Symptoms Of Central Nervous System Involvement Research Articles

The lymphocyte populations and their migration into the central nervous system in tick-borne encephalitis

In tick-borne encephalitis (TBE) the cerebrospinal fluid (CSF) cytosis is dominated by T CD3+CD4+ and T CD3+CD8+ lymphocytes, but their pathogenetic roles and mechanisms of migration into central nervous system (CNS) are unclear. Currently, we have studied CSF lymphocyte subsets and chemotactic axes in TBE patients stratified according to the clinical presentation. Blood and CSF were obtained from 51 patients with TBE (presenting as meningitis in 30, meningoencephalitis in 18 and meningoencephalomyelitis in 3), 20 with non-TBE meningitis and 11 healthy controls. We have studied: (1) abundances of the main lymphocyte subsets and (2) CXCR3 and CCR5 expression on CD3+CD4+ and CD3+CD8+ lymphocytes cytometrically with fluorochrome-stained monoclonal antibodies; (3) concentrations of chemotactic cytokines: CCL5 (CCR5 ligand), CXCL10 (CXCR3 ligand), IL-16, CCL2, CCL20 and CXCL5 with ELISA. Cytokine concentrations were additionally studied in 8 pediatric TBE patients. Data were analyzed with non-parametric tests, p < 0.05 considered significant. The higher CSF lymphocyte counts were associated with symptoms of CNS involvement, especially with altered consciousness (B, Th and Tc cells) and focal neurologic deficits (B cells). The minor fraction of double-positive T CD4+CD8+ cells was unique in associating negatively with encephalitis and altered consciousness. CSF CD3+CD4+ and CD3+CD8+ lymphocyte population was enriched in CCR5-positive cells and CCL5 concentration in CSF was increased and associated with a milder presentation. Although CXCL10 was vividly up-regulated intrathecally and correlated with CSF T lymphocyte counts, the CXCR3 expression in CSF T lymphocytes was low. Serum and CSF concentrations of CCL2, CXCL5 and IL-16 were increased in adult TBE patients, CCL2 created a chemotactic gradient towards CSF and both CCL2 and IL-16 concentrations correlated positively with CSF lymphocyte counts. The particular lymphoid cell populations in CSF associate differently with the clinical presentation of TBE, suggesting their distinct roles in pathogenesis. CCR5/CCL5 axis probably contributes to T lymphocyte migration into CNS. CXCL10 mediates the intrathecal immune response, but is probably not directly responsible for T cell migration. Additional chemotactic factors must be involved, probably including CCL2 and IL-16.

Stearoyl-CoA Desaturase (SCD) Enhances Central Nervous System Leukemia

Background: Central nervous system (CNS) involvement by acute lymphoblastic leukemia (ALL) is a major clinical concern. Leukemic cells can be found in the CNS at diagnosis (1-2%) or, more frequently, at relapse (30%). Very little is known about the pathogenesis and therefore there are no targeted therapies. Prophylactic CNS-directed conventional intrathecal chemotherapy or irradiation are required for relapse-free survival. However, they are associated with substantial rates of short and long term toxicity. Therefore, elucidation of molecular mechanisms and pathways mediating leukemia-cell entry and survival in the CNS is needed to develop alternative CNS-directed treatment strategies. Previous studies showed an increased expression of Stearoyl-CoA desaturase (SCD), a key enzyme of the de novo fatty acid synthesis pathway, in B cell precursor (BCP) ALL cells isolated from cerebrospinal fluid (CSF) of patients at the time of CNS relapse. A small SCD positive population was detected in the bone marrow (BM) at leukemia diagnosis in patients who later developed isolated CNS relapse, defining a potential biomarker for CNS relapse. It is unknown, however, if SCD has a functional role in CNS leukemia.Aim: To examine the hypothesis that increased expression of SCD enhances trafficking and survival of human B-ALL cells in the CNSMethods: We analyzed leukemia-cell entry into the CNS using xenografts of human BCP-ALL cell lines. Microarray profile of cells isolated from CNS and BM of transplanted mice was performed. Cell lines were transduced to overexpress human SCD and evaluated in vitro for proliferation kinetics and metabolic SCD activity. In vivo, SCD overexpressing cells were transplanted in NSG mice,sacrificed upon the first symptoms of CNS involvement, e.g. hind limb paralysis. BM, spleen and meninges were collected and analyzed to check human engraftment by FACS. The tumor load was expressed as total amount of leukemic cells in each organ. Competition assays were performed by transplanting SCD overexpressing and WT cells in the same mouse in a 1:1 ratio.Results: BCP-ALL cells transplanted into NSG mice faithfully recapitulated pathological features of meningeal infiltration seen in patients with ALL. Gene expression analysis of cells collected from BM and meninges of leukemic mice revealed up-regulation of the genes belonging to the signaling pathway of sterol regulatory element binding proteins (SREBPs) in ALL cells isolated from the CNS. SCD, whose transcription is controlled by the SREBP family, was significantly upregulated. SCD overexpression did not alter proliferation in vitro. Since SCD introduces a double bond in Stearoyl-CoA, its activity was measured as the ratio of unsaturated/saturated fatty acids in the cells. That ratio was increased in SCD overexpressing cells in vitro, confirming the functionality of the enzyme. In vivo, mice transplanted with SCD overexpressing cells led to a faster onset of CNS disease manifested by a clinical phenotype of earlier hind limb paralysis compared to control and significant increased number of leukemic cells in the CNS (Figure 1A).SCD overexpression also induced CNS engraftment of another B-ALL cell line, REH, which is not naturally prone to invade the central nervous system. Mice transplanted with SCD overexpressing REH cells showed the same phenotype of earlier hind limb paralysis and accumulation of leukemic cells in the CNS as the CNS-prone 018z cells, while WT REH did not show any CNS engraftment but comparable tumor load in BM and spleen (Figure1B). To reproduce the clonal heterogeneity in SCD expression observed previously in patients' BM, we performed a competition assay transplanting SCD overexpressing cells and control cells, expressing different fluorochromes, in the same mouse in a 1:1 ratio. In the CNS, the ratio between SCD overexpressing and WT cells ranged from 2 to 20 fold. This effect was unique to the CNS and not reproducible in the other hematopoietic organs where the 1:1 ratio was maintained (Figure 1C). Moreover, SCD overexpression sensitized leukemic cells to mTOR inhibitors, suggesting a potential therapeutic optionConclusion: SCD has a role in homing and survival of leukemic cells in the CNS and may be used as early predictor of CNS relapse. This study reveals a role for SCD and fatty acid metabolism in the pathogenesis of CNS leukemia suggesting that this pathway maybe targeted for specific therapy of this devastating disease. [Display omitted] DisclosuresHalsey:Jazz Pharmaceuticals: Honoraria, Other: Support for conference attendance.

3158 - SCD Takes Leukemia to the CNS

Background: In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern with no specific therapy. Prophylactic CNS-directed intrathecal chemotherapy or irradiation are required for relapse-free survival but imply long term toxicity. Therefore, mechanisms mediating leukemia-cell entry and survival into the CNS need to be understood to develop alternative CNS-directed treatment strategies. Previous studies showed an increased expression of Steroyl CoA desaturase (SCD) in BCP-ALL cells isolated from cerebrospinal fluid (CSF) of patients at CNS relapse. Aim: Investigate if SCD have a role in leukemia trafficking, homing and survival into the CNS in order to design new diagnostic and reduced toxicity- treatments to prevent relapse. Methods:Microarray profiling of cells isolated from CNS and BM of xeno-transplanted mice was performed.Human BCP-ALL cell line 018z was transduced to knock-down (KD) or overexpress human SCD. In vivo, SCD KD and overexpressing cells were transplanted in NSG mice who were sacrificed upon the first symptoms of CNS involvement. BM, spleen and meninges were collected and analyzed to check human engraftment by FACS. In Competition assays, SCD overexpressing and WT cells were transplanted in the same mouse in a 1:1 ratio. Results: Microarray profiling of cells collected from BM and meninges of leukemic mice revealed up-regulation of the genes belonging to the signaling pathway of sterol regulatory element binding proteins (SREBPs) in ALL cells that had entered the CNS, includingSCD. In vitro, SCD-KD 018z cells showed reduced proliferation than WT while SCD overexpression did not alter proliferation.Mice transplanted with SCD KD cells showed a general lower infiltration whereas SCD overexpression led to a faster onset of CNS disease.Competition assays showed that in the CNS the balance was skewed towards engraftment of SCD overexpressing cells over WT. Conclusion: SCD has a role in homing and survival of leukemic cells in the CNS.The research can lead to innovative therapies that will minimize the need for intensive chemotherapy in the CNS.

P286 Visual and brainstem auditory evoked potentials abnormalities in the patients with systemic lupus erythematosus

Objectives Lupus erythematosus (SLE) is a systemic disease with possible nervous system involvement, regarded as unfavorable prognostic factor. Evoked potentials (EP) are electrophysiological markers of disturbed central nervous system (CNS) function, even in subclinical stage of CNS disorders. The purpose of the study was to evaluate parameters of EP in the patients with SLE with or without neuropsychiatric manifestation (NPSLE). Methods The study comprised 53 patients with SLE (49 women, 4 men, aged 21–62, mean 38.3) and 40 healthy, age- and gender- matched controls. 33 patients were classified as having NPSLE. Visual evoked potentials (VEP) and brainstem auditory evoked potentials (BAEP) were performed in all the subjects. Latencies and amplitudes of VEP and BAEP components were compared between SLE patients and controls and between NPSLE and non-NPSLE patients. Results Mean latency of P100 component of VEP for the right eye was significantly longer (104.3 ms vs 102.06 ms; p = 0.05) and mean amplitude of the I component of BAEP for the right ear was significantly lowered (0.25 μ V vs 0.30 μ V; p = 0.04) in the SLE patients in comparison with the controls. No differences were found between NPSLE and non-NPSLE patients. Discussion Asymmetric abnormalities of EP correspond with multifocal brain damage in the course of SLE, although they are not specific for the background of the disease. Conclusions and significance Parameters of VEP and BAEP show asymmetric abnormalities in SLE patients, regardless of the clinical symptoms of CNS involvement. EP may be considered as electrophysiological markers of early CNS dysfunction in the course of SLE.

Endogenous event-related potentials in patients with primary Sjögren’s syndrome without central nervous system involvement

Objectives: Endogenous cognitive event-related potentials (CERPs) reflect higher-level processing of sensory information and can be used to evaluate cognitive functions. The aim of this paper was to determine whether there are any abnormalities in the electrophysiological parameters of CERPs in patients with primary Sjögren’s syndrome (pSS) but without symptoms of central nervous system (CNS) involvement or mental disorder. The analysis of CERP parameters was then correlated with the clinical status of the patients and with some of the immunological parameters in the patient group.Method: Thirty consecutive patients with pSS (29 females, one male) were included in the study. All the patients underwent CERP examination.Results: There was a significant prolongation of the latency of P300 and N200 potentials in patients with pSS. Abnormalities in electrophysiological parameters of CERPs correlated with the duration of the disease, salivary gland abnormalities, and elevated erythrocyte sedimentation rate (ESR) values. Patients with coexisting chronic fatigue syndrome (CFS) had larger P300 amplitudes. There were no statistically significant changes in the electrophysiological parameters of CERPs in patients with pSS dependent on the presence of peripheral nervous system (PNS) lesions, skin changes, arthritis, abnormalities in white blood cells and the immune system or the levels of blood lipids.Conclusions: The results of the study suggest the presence of a minor cognitive dysfunction in patients with pSS without symptoms of CNS involvement or mental disorder. Cognitive dysfunction correlated with the disease duration time and the severity of inflammatory changes (salivary gland abnormalities and inflammatory markers in the blood). Further and larger longitudinal studies are necessary for confirmation of this correlation.

Hypothalamic–Pituitary Alterations in Patients With Neurosarcoidosis

Sarcoidosis is a non-caseating, granulomatous inflammatory disorder that can affect the central nervous system (CNS), including the hypothalamic–pituitary region, although rarely. The clinical manifestations of hypothalamic–pituitary neurosarcoidosis are heterogeneous and require a prompt diagnosis to ensure the most appropriate treatment. We have reviewed the cases of neurosarcoidosis affecting the hypothalamic–pituitary axis published since 2002 and compared them with the cases reported in the literature up to 2002, which were previously meta-analysed by our research group. Since 2002, 64 cases were identified in the literature: 37 cases presented with diabetes insipidus, 36 were found to have secondary amenorrhoea, 30 with hypogonadotropic hypogonadism, 17 with hyperprolactinaemia, 15 with thyroid-stimulating hormone deficiency, and 8 cases of panhypopituitarism. Uncommon manifestations included hyperphagia, sudden death, and thermodysregulation. We confirm that neurosarcoidosis affecting the hypothalamic–pituitary axis is an uncommon manifestation of sarcoidosis. Neither changes in the clinical manifestations and diagnosis nor significantly novel management options have appeared in the last decade. While it is a rare disorder, the involvement of the CNS is an indication to treat sarcoidosis and as the symptoms of CNS involvement, including hypothalamic–pituitary alterations, may precede the diagnosis of sarcoidosis, it is important to include neurosarcoidosis in the differential diagnosis of hypothalamic–pituitary axis dysfunction in order to facilitate prompt and appropriate treatment.

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Two Rare Cases Of Central Nervous System Opportunistic Mycoses / Oportunističke Mikoze Središnjega Živčanog Sustava – Prikaz Dvaju Bolesnika

Abstract This article presents two cases of opportunistic mycoses (OMs) of the central nervous system (CNS) caused by Cryptococcus neoformans and Aspergillus nidulans, respectively. The patients were hospitalised in local hospitals between 2009 and 2011 because of unspecific symptoms (fever, headache, and/or weight lost). Duration of symptoms varied from 4 days to over 2 weeks. The patients were treated with antibiotics and symptomatically. OM was not suspected in any of them. The patients became critically ill with symptoms of CNS involvement and were transferred to the Intensive Care Unit (ICU) of the University Hospital for Infectious diseases (UHID) in Zagreb. None of the patients belonged to the high-risk population for developing OMs. They were not HIV-infected, had no transplantation of bone marrow or solid organ, and were not on severe immunosuppressive chemotherapy. Fungi were isolated from cerebrospinal fluid (CSF) samples and, in one patient, from aspirate of cerebral abscess. Isolation and mycological identification of all fungal isolates and in vitro antifungal susceptibility testing of these isolates were done at the Reference Centre for Mycological Diagnostics of Systemic and Disseminated Infections (RCMDSDI) in Zagreb. The patient with cryptococcal meningitis was treated with amphotericin B and fluconazole and the patient with cerebral aspergilloma with voriconazole.

Cognitive impairment in non-neuropsychiatric systemic lupus erythematosus

IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease which can cause prominent central nervous system (CNS) involvement. Cognitive dysfunction is one of the major neuropsychiatric syndromes of SLE. Aim of the workTo evaluate cognitive functions in SLE patients without evident neuropsychiatric manifestations and to find out if it is correlated with disease activity and with treatment. Patients & methodsThirty SLE patients without evident neuropsychiatric manifestations were evaluated. The evaluation included full clinical examination, assessment of SLE disease activity index-2k (SLEDAI-2k), routine laboratory investigations, autoantibodies assessment and cognitive function assessment using Montréal cognitive assessment (MoCA) scale and trail making test (TMT) (part A and part B). Twenty apparently healthy individuals were taken as control. ResultsCognitive dysfunction is present in all SLE patients included in our study. During assessment of cognitive functions, a highly statistically significant difference was observed between patients and control subjects, even with equal levels of education. While patients with higher educational levels were as impaired as those with lower levels of education. Cognitive dysfunction was not correlated with disease activity or with the doses of drugs used for treatment. But a statistically significant positive correlation was noted between deterioration of cognitive functions and the disease duration. ConclusionCognitive dysfunction is a prominent feature in SLE patients without symptoms of CNS involvement. Psychological evaluation should be performed for each SLE patient to detect cognitive dysfunctions. Psychological intervention is recommended to prevent further deterioration. Correlation with disease duration should pay attention to the chronicity of disease.

Is lenticulostriated vasculopathy a sign of central nervous system insult in infants with congenital CMV infection?

BackgroundIn previous studies, lenticulostriated vasculopathy (LSV) was detected in 0.4–5.8% of neonates who had undergone brain ultrasound studies during the neonatal period. Most infants were referred from neonatal intensive care...

Important Role of Routine Cerebrospinal Fluid Examination in Diagnosing Central Nervous System Relapse during Maintenance Therapy in Pediatric Acute Lymphoblastic Leukemia.

Despite the success of central nervous system (CNS) preventive therapy in reducing the incidence of CNS recurrence in pediatric acute lymphoblastic leukemia (ALL) on therapy, CNS relapse continues to be a significant cause of treatment failure and is observed in 5–10% of patients. While most pediatric ALL treatment protocols mandate periodic lumbar puncture (LP) surveillance for the length of therapy, some centers have stopped collecting routine CSF samples unless there are suggestive signs or symptoms of CNS involvement. Our objective herein was to assess the value of routine cerebrospinal fluid (CSF) obtained while performing routine LPs for administration of intrathecal chemotherapy in diagnosing CNS relapse in children with ALL in the maintenance phase.Patients and Methods: All children (0–18 years) with ALL, diagnosed and treated at the Hospital for Sick Children, Toronto, Canada between 1994–2004 were subjected to a retrospective analysis. Original reports for CNS relapse during maintenance therapy were examined to determine whether CNS relapse was diagnosed based on routine CSF sample obtained while administering intrathecal chemotherpy or a CSF sample obtained based on signs and symptoms or after a diagnosis of a bone marrow relapse.Results: Four hundred and ninety four children were diagnosed and treated in our institution during the study period. Children were treated based on the children oncology group (COG), pediatric oncology group (POG) and local protocols where applicable. Thirty-one children (6.3%) suffered CNS relapse while on maintenance therapy. Twenty-one had an isolated CNS relapse and ten had a combined bone marrow and CNS relapse. Seventy-six percent (16/21) isolated CNS relapses were diagnosed base on routine CSF samples obtained from asymptomatic children while administering intratheacal chemotherapy. Conversely, all patients with combined bone marrow and CNS relapse presented with symptoms and signs that warranted CSF examination.Conclusion: Routine CSF examinations are important in detecting CNS relapse in children with ALL during maintenance therapy. Furthermore, routine CSF sampling may detect isolated CNS relapse in asymptomatic children with ALL prior to extension into combined relapse where prognosis is less favorable.

MRI analysis on a patient with the V30M mutation is characteristic of leptomeningeal amyloid

We report a characteristic finding in gadolinium-enhanced magnetic resonance images (MRIs) of the central nervous system (CNS) in a 61-year-old man with a homozygous transthyretin (TTR) Val30Met mutation. Although he presented with polyneuropathy accompanied by autonomic dysfunction and vitreous opacities in both eyes, he has shown no overt signs or symptoms of CNS involvement. Total protein level in the cerebrospinal fluid was moderately elevated. In the gadolinium-enhanced T1-weighted MRIs of the brain and spinal cord, leptomeningeal enhancement was seen along the surfaces of the brain stem and more clearly in the spinal cord, suggesting leptomeningeal TTR-related amyloid deposition. Our result indicates that gadolinium-enhanced MRI of the CNS may be a very sensitive and useful method for detecting leptomeningeal amyloid deposition, since abnormal findings can be detected even at a presymptomatic stage of CNS involvement.

The CNS symptoms of rotavirus infections under the age of two.

Since isolation of the Rotavirus (RV), there is rapidly growing concern about the possible involvement of RV in Central Nervous System (CNS) disorders, especially in Japan. We looked for symptomatic CNS involvement in a large series of RV infections and it's possible risk factors in a European setting. Two-year retrospective survey based at the University Children's Hospital of Freiburg, Germany, a secondary and tertiary care centre with a urban and rural catchment area of 400,000 people. First, the case records of all 366 inpatients aged under two years excreting RV were searched for signs and symptoms of CNS involvement. Second, records of all 32 patients hospitalised with meningitis/encephalitis during the study period were checked for evidence of RV infection. In 15 of 366 children signs of CNS involvement (seizures, meningeal and encephalitic signs) were found. They were older (p = 0.023), had higher temperatures (p = 0.001) and CRP values (p = 0.019). Five of the fifteen had underlying neurological diseases, two had an additional salmonella infection and one suffered from hypernatraemic toxicosis. In the remaining seven children, higher temperature (p = 0.037) and older age (p = 0.05) remained significant risk factors. CNS-signs occurred in 2% of RV-excreting children, a rate equal to the prevalence of febrile seizures among all inpatients during the study period (2.2%). Of all 32 patients hospitalised with a diagnosis of meningitis or encephalitis only four had their stools tested for RV, all with a negative result. CNS symptoms in children aged less than two years with rotavirus diarrhoea have the same clinical epidemiology as febrile seizures and thus, in general, don't need additional diagnostic procedures.

Guidelines of care for dermatologic conditions in patients infected with HIV

Guidelines of care for dermatologic conditions in patients infected with HIV

18FDG PET and acetazolamide-enhanced99mTc-HMPAO SPET in systemic lupus erythematosus

In systemic lupus erythematosus (SLE), brain and kidney are the most frequently affected organs. Measurements of cerebral blood flow and metabolism by means of positron emission tomography (PET) and single-photon emission tomography (SPET) can contribute to the diagnostic assessment of the involvement of the central nervous system (CNS) in SLE. Functional imaging has been proven to be more sensitive than morphological imaging (magnetic resonance imaging and computed tomography). In this report, we present the case of a 70-year-old female patient, suffering from SLE without symptoms of CNS involvement. In addition to a SPET study using technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) and a PET scan with fluorine-18 deoxyglucose (18FDG), a SPET study after acetazolamide injection was performed in order to assess the cerebral perfusion reserve. While the PET scan showed no major abnormalities, and the baseline SPET study revealed only minor changes, the acetazolamide-enhanced SPET study revealed a marked reduction of the cortical perfusion reserve, particularly in both frontal lobes. It is concluded that "preclinical" CNS involvement, mainly caused by pathological mechanisms involving the cerebral blood vessels, can be considered to exist in this patient with SLE.