CSF Protein Research Articles

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Biallelic variants in PLEKHG5 have been reported so far associated with different clinical phenotypes including Lower motor neuron disease (LMND) [also known as distal hereditary motor neuropathies (dHMN or HMN) or distal spinal muscular atrophy (DSMA4)] and intermediate Charcot-Marie-Tooth disease (CMT). We report four patients from two families presenting with intermediate CMT and atypical clinical and para-clinical findings. Patients presented with predominant distal weakness with none or mild sensory involvement and remain ambulant at last examination (22–36 years). Nerve conduction studies revealed, in all patients, intermediate motor nerve conduction velocities, reduced sensory amplitudes and multiple conduction blocks in upper limbs, outside of typical nerve compression sites. CK levels were strikingly elevated (1611–3867 U/L). CSF protein content was mildly elevated in two patients. Diffuse bilateral white matter lesions were detected in one patient. Genetic analysis revealed three novel frameshift variants c.1835_1860del and c.2308del (family 1) and c.104del (family 2). PLEKHG5-associated disease ranges from pure motor phenotypes with predominantly proximal involvement to intermediate CMT with predominant distal motor involvement and mild sensory symptoms. Leukoencephalopathy, elevated CK levels and the presence of conduction blocks associated with intermediate velocities in NCS are part of the phenotype and may arise suspicion of the disease, thus avoiding misdiagnosis and unnecessary therapeutics in these patients.

Developing a Prognostic Model to Predict Mortality in Patients with Acute Bacterial Meningitis.

Bacterial meningitis is one of the harmful and deadly infectious diseases, and any delay in its treatment will lead to death. In this paper, a prognostic model was developed to predict the risk of death amongst probable cases of bacterial meningitis. Our prognostic model was developed using a decision tree algorithm on the national meningitis registry of the Iranian Center for Disease and Prevention (ICDCP) containing 3,923 records of meningitis suspected cases in 2018-2019. The most important features have been selected for the model construction. This model can predict the mortality risk for the meningitis probable cases with 78% accuracy, 84% sensitivity, and 73% specificity. The identified variables in prognosis the death included age and CSF protein level. CSF protein level (mg/dl) <= 65 versus > 65 provided the first branch of our decision tree. The highest mortality risk (85.8%) was seen in the patients >65 CSF protein level with 30 years < of age. For the patients <=30 year of age with CSF protein level >137 (mg/dl), the mortality risk was 60%. The prognostic factors identified in the present study draw the attention of clinicians to provide early specific measures, such as the admission of patients with a higher risk of death to intensive care units (ICU). It could also provide a helpful risk score tool in decision-making in the early phases of admission in pandemics, decrease mortality rate and improve public health operations efficiently in infectious diseases.

Clinical Character of CASPR2 Autoimmune Encephalitis: A Multiple Center Retrospective Study.

ObjectiveTo examine the clinical characteristics of autoimmune encephalitis associated with the contactin-associated protein-2 (CASPR2) antibody.Materials and MethodsMedical records of all patients diagnosed with CASPR2 antibody-associated encephalitis were retrospectively analysed. Data regarding demographic features, neurological symptoms and signs, laboratory tests, imaging results, treatments, and prognosis were collected.ResultsA total of 25 patients aged from 3 to 79 years old were enrolled in this study, with a median age of 43. Eight of 25 (32%) were female, and 17 of 25 (68%) were male. The median age of symptom onset was 42 years old with the course of disease from onset to hospital admission ranging from 2 days to 6 months (median was 17 days). Six patients (6/25) had fever as an onset symptom. During the course of disease, cognitive disturbance was the most common symptom, which was observed in 17 patients (17/25) in total. Eight patients (8/25) met the criteria for limbic encephalitis. Epileptic seizure occurred in six of these eight patients. Four patients (4/25) were diagnosed as Morvan syndrome. All patients were positive for anti-CASPR2 antibody in the serum (1:10–1:300). In six patients, antibodies were detected both in the blood and CSF (1:32–1:100). White blood cell (WBC) counts in the CSF were elevated in eight patients (8/25). The concentration of proteins in CSF increased in 10 patients (ranging from 480 to 1,337.6 mg/dl), decreased in seven patients (ranging from 23.2 to 130.5 mg/dl) and remained at a normal range in the other eight patients (ranging from 150 to 450 mg/dl). Abnormal electroencephalogram (EEG) activities included slow background activity and epileptic patterns. Abnormal signals in the bilateral hippocampus were detected by magnetic resonance imaging (MRI) in three patients presenting cognitive disturbance. In one patient who had limbic encephalitis, increased metabolism of bilateral basal ganglia and the mesial temporal lobe was revealed by PET-CT. Eleven of 15 patients receiving immunotherapy experienced varying degrees of improvement. Relapse occurred in four of 25 patients (4/25) after 2 months.ConclusionCASPR-antibody-mediated autoimmune encephalitis is characterized by diverse clinical manifestations. The most prominent conclusion revealed by this retrospective analysis is the involvement of both central and peripheral nerve systems, as well as a lower relapse rate, a good response to immunotherapy, and favorable short-term prognosis after treatment was also demonstrated. Besides, additional work is necessary to evaluate the long-term prognosis.

CSF shunt valve occlusion-does CSF protein and cell count matter?

Shunt obstruction is a common cause of shunt failure in the treatment of hydrocephalus. Valve occlusion is traditionally believed to originate from elevated CSF protein or cellular components, although detailed evidence is scarce and contradictory. Therefore, this study aimed to examine CSF protein and cell count as risk factors for valve obstruction. We retrospectively examined 274 patients who underwent shunt placement for hydrocephalus between 2009 and 2018 and had at least 1year follow-up. Age, aetiology of hydrocephalus, valve type, occurrence of revision, reason for revision and CSF protein and cell count at the time of shunt insertion and revision surgery were analysed. Thirty-two of 274 patients (11.7%) required revision surgery due to valve occlusion. Mean time to revision was 143days. CSF white blood cell (WBC) count but not protein was associated with valve occlusion overall. Of all obstructed valve patients, 25% showed CSF protein level within the normal range, whereas 13.6% of the patients overall showed greatly elevated CSF protein level without evidence of valve obstruction. Persistently elevated CSF protein level at the time of shunt revision was significantly associated with valve obstruction within 90days of initial insertion (early occlusion). Children with congenital malformations and post-haemorrhagic patients were significantly overrepresented in the occlusion group, particularly in the early occlusion group. Pathological CSF values such as WBC count and persistently elevated protein level serves as a risk factor for early valve obstruction. Late obstruction occurs independent of normal CSF values. Infants are particularly prone to early and late valve obstructions. CSF protein level at shunt insertion is not predictive of valve occlusion.

A case series of intracranial dural arteriovenous fistulae mimicking cervical myelitis: a diagnosis not to be missed

ObjectiveTo describe the diagnostic features of intracranial dural arteriovenous fistulae (DAVF) presenting with cervical cord or brainstem swelling.MethodsRetrospective case note and neuroimaging review of patients with angiographically confirmed DAVF diagnosed during January 2015–June 2020 at a tertiary neuroscience centre (Walton Centre NHS Foundation Trust, Liverpool, UK).ResultsSix intracranial DAVF causing cervical cord or brainstem oedema (all males aged 60–69 years) and 27 spinal DAVF (88% thoracolumbar) were detected over a 5.5-year period. Significantly more patients with intracranial DAVF received steroids for presumed inflammatory myelitis than those with spinal DAVF (5/6 vs 1/27, p = 0.0001, Fisher’s exact test). Several factors misled the treating clinicians: atypical rostral location of cord oedema (6/6); acute clinical deterioration (4/6); absence (3/6) or failure to recognise (3/6) subtle dilated perimedullary veins on MRI; intramedullary gadolinium enhancement (2/6); and elevated CSF protein (4/5). Acute deterioration followed steroid treatment in 4/5 patients. The following features may suggest DAVF rather than myelitis: older male patients (6/6), symptomatic progression over 4 or more weeks (6/6) and acellular CSF (5/5).ConclusionIntracranial DAVF are uncommon but often misdiagnosed and treated as myelitis, which can cause life-threatening deterioration. Neurologists must recognise suggestive features and consider angiography, especially in older male patients. Dilated perimedullary veins are an important clue to underlying DAVF, but may be invisible or easily missed on routine MRI sequences.

Atypical Neurologic Complications Post Autologous Stem Cell Transplantation

We describe the case of a patient with high grade, triple hit, Non-Hodgkin’s Lymphoma (NHL) who underwent high-dose chemotherapy and Autologous Stem Cell Transplantation (ASCT) as a consolidation. Patient received BEAM conditioning regimen. She engrafted after usual post ASCT course. However, 2 months post ASCT she developed atypical neurologic symptoms and findings leading to general weakness mainly in the lower extremities with multiple falls, mental status changes and high CSF protein with severe sensorimotor neuropathy. She initially failed treatment with IVIg but responded to high dose steroids. More than one year after transplant, she has maintained her neurological improvement, but unable to walk, while her NHL continues to be in remission.

IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

BackgroundFosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.ObjectivesTo generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.MethodsThe NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed.ResultsIn total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347–0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272–0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio.ConclusionsThrough this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant’s PMA, PNA and weight.

Oligoclonal IgG bands in chronic inflammatory polyradiculoneuropathies

BackgroundCerebrospinal fluid (CSF) albumincytologic dissociation represents a supportive diagnostic criterion of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Few studies have investigated possible systemic or intrathecal humoral immune response activation in CIDP.Aim of...

CIDP PRESENTING AS MYELORADICULOPATHY

Chronic inammatory demyelinating polyradiculoneuropathy (CIDP) is a relapsing or chronic progressive disorder which is one of the causes of hypertrophic neuropathy. Enlarged nerve roots were identied in few patients. We now report a case of CIDP with highly thickened or enlarged nerve roots severe enough to cause cord compression and myelopathy. A 38 year old woman presented with weakness and sensory disturbances in lower limbs with sensory level at L1 and bladder disturbances in form of urgency and urge incontinence . MRI showed a non enhancing isointense mass lesion from L1 to S1 causing compression over conus . During surgery the cauda equina nerve roots were found to be thickened , entangled with ' bag of worms' appearance. Nerve conduction studies showed all her peripheral nerves to be inexcitable. Her CSF protein was mildly elevated. Diagnosis of CIDP with thickened nerve roots was considered and she was started on steroids and subsequently showed improvement. Thus, CIDP may present with symptoms of myeloradiculopathy due to thickened nerve roots causing cord compression.

Risk factors for death in suspected severe bacterial infection in infants aged

BackgroundYearly, about two million infants die during the first 28 days of life. Most of these deaths occur in sub-Saharan Africa and a third of those are caused by severe infections. The early identification of infants at risk of death is important when trying to prevent poor outcomes. ObjectiveThe aim of this study was to identify risk factors for death among young infants with possible serious bacterial infection (pSBI) at hospital admission. MethodsThis prospective, observational, single-site, descriptive study forms part of a larger study on bacterial meningitis in infants <90 days of age admitted to the Pediatric Hospital of Luanda, the capital of Angola, from February 1, 2016 to October 23, 2017. Infants with pSBI, a known outcome, and a final diagnosis were included. ResultsOf 574 young infants with pSBI, 115 (20%) died in hospital. An altered level of consciousness, absence of spontaneous movements, dyspnea, CSF that is not clear, low CSF glucose, high CSF protein, heart rate over the median, and seizures were identified as risk factors for death in the univariate analysis. In the multivariate analysis, only heart rate over the median and seizures were independent predictors of death. ConclusionsEasily recognizable clinical signs – tachycardia and seizures – may guide clinicians to identify infants at high risk of death due to severe bacterial infections in sub-Saharan Africa.

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS.

BackgroundAmyotrophic lateral sclerosis is a clinical syndrome with complex biological determinants, but which in most cases is characterized by TDP-43 pathology. The identification in CSF of a protein signature of TDP-43 network dysfunction would have the potential to inform the identification of new biomarkers and therapeutic targets.MethodsWe compared CSF proteomic data from patients with ALS (n = 41), Parkinson’s disease (n = 19) and healthy control participants (n = 20). Weighted correlation network analysis was used to identify modules within the CSF protein network and combined with gene ontology enrichment analysis to functionally annotate module proteins. Analysis of module eigenproteins and differential correlation analysis of the CSF protein network was used to compare ALS and Parkinson’s disease protein co-correlation with healthy controls. In order to monitor temporal changes in the CSF proteome, we performed longitudinal analysis of the CSF proteome in a subset of ALS patients.ResultsWeighted correlation network analysis identified 10 modules, including those enriched for terms involved in gene expression including nucleic acid binding, RNA metabolism and translation; humoral immune system function, including complement pathways; membrane proteins, axonal outgrowth and adherence; and glutamatergic synapses. Immune system module eigenproteins were increased in ALS, whilst axonal module eigenproteins were decreased in ALS. The 19 altered protein correlations in ALS were enriched for gene expression (OR 3.05, p = 0.017) and membrane protein modules (OR 17.48, p = 0.011), including intramodular hub proteins previously identified as TDP-43 interactors. Proteins decreasing over longitudinal analysis ALS were enriched in glutamatergic synapse and axonal outgrowth modules. Protein correlation network disruptions in Parkinson’s disease showed no module enrichment.ConclusionsAlterations in the co-correlation network in CSF samples identified a set of pathways known to be associated with TDP-43 dysfunction in the pathogenesis of ALS, with important implications for therapeutic targeting and biomarker development.

Editor's Note: A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City.

Editor's Note: A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City.

Author Response: A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City.

We appreciate the comments by Kumar et al. on our article.1 The referenced Kremer study2 was a retrospective case series and included patients with positive MRI findings only. It is unclear whether the patients with the diagnosis of “encephalitis” met diagnostic or causal criteria outlined by the International Encephalitis Consortium3 and others.4 Indeed, CSF SARS-CoV-2 RT-PCR was negative in 20 patients. In 2 of 3 with CSF pleocytosis (>5 cell/mm3), imaging was performed >2 weeks from symptom onset, possibly representing postinfectious autoimmune encephalitis and not infectious encephalitis. Many of the MRI findings described are nonspecific and can be seen in hypoxic/ischemic brain injury, metabolic encephalopathy, or postseizure. Notably, 100% of “encephalitis” patients required oxygen and 75% had ARDS, suggesting that a proportion of the MRI changes may represent hypoxic/ischemic injury (defined as a global insult due to hypoxemia, hypotension, or cardiac arrest). Although we detected elevated CSF protein in some patients,1 this is nonspecific and can be found in stroke, hemorrhage (or traumatic tap), hypoxic/ischemic injury, diabetes, uremia, tumor, neuropathy, and many other conditions. Because the implications of SARS-CoV-2 neurotropism are far reaching, we believe that it is critical to follow the most rigorous standards and criteria when ascribing encephalitis/meningitis/myelitis to SARS-CoV-2 infection.

Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment.

Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined. The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s < 0.05). PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

ObjectiveSensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features.MethodsCISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986–2019).ResultsWe identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46).ConclusionThe recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

CLINICAL AND INVESTIGATIVE FEATURES OF SEIZURE IN CHILDREN ADMITTED IN TERTIARY CARE HOSPITAL OF NORTHERN INDIA

Introduction: Convulsions are one of the most common paediatric neurological disorders worldwide, with its incidence being highest among children younger than 3 years of age. It is also one of the most frequent causes for visit to the pediatric emergency department and could either be idiopathic or secondary to disease process of brain. Seizures lead to alterat Aims and objectives: ions in the laboratory values and reect changes in different organ systems. This study was done to evaluate the clinical, laboratory, EEG and CT ndings in cases of seizure among children between 1month to15years of age. It was a descriptive study conducted in patients admitt Materials and methods: ed in emergency and indoor of department of paediatrics, Patna Medical College and Hospital, over a period of 2 years from October 2014 to September 2016. Children from 1 month to 15 years of age with seizures were studied to know the proportion of idiopathic or secondary seizures and to evaluate various laboratory, EEG and CT ndings in these cases. During study period, 200 children between ages Results: 1 month to 15 years, with convulsion, were enrolled. Seizures were found to be more common in males (67.5%). Secondary seizures were present in 90% cases and idiopathic epilepsy accounted only for 10%. GTCS was the commonest type of seizure both in idiopathic epilepsy (100%) as well as in secondary seizure group (87.77%). Family history of seizure disorders was present in 13% of cases. Developmental delay was found in 11.5% cases, whereas 88.5% children were developmentally normal. Commonest symptoms associated with secondary seizures were fever (86.11%), altered sensorium (77.22%), and cough (38.89%). Headache, vomiting, ear discharge, rashes were other symptoms. Altered sensorium (69.5%), neck stiffness (33%), cranial nerve involvement (16%) were commonest signs. Hypocalcemia, hyponatremia and hypoglycaemia were found in 4.5%, 1.67% and 1.11% cases respectively, in cases of secondary seizures. CSF analysis was done in all 200 cases and was found to be normal in all cases (100%) of idiopathic epilepsy, whereas it was abnormal in 81% cases of secondary seizures. Abnormal CSF ndings included low CSF glucose (24.69% cases), high CSF proteins (100%) and CSF pleocytosis in 82.71% cases. EEG was also done in all cases, and was found to be abnormal in 85% cases of idiopathic epilepsy, whereas 43.89% cases of secondary seizures had abnormal recordings. Abnormal EEG recordings were abnormal background activity in 60.41%, generalised interictal discharges (IED) in 77.08% and focal IED in 21.87%. Abnormal CT scan ndings were seen in 60(45.8%) cases. Out of these 60 cases, commonest CT scan abnormalities seen were cerebral oedema (45%), cerebral atrophy (20%), and hydrocephalus (16.7%). Other CT ndings were ring enhancing lesions, basal exudates, infarcts etc.

MMSE is an independent prognostic factor for survival in primary central nervous system lymphoma

IntroductionTo assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients.MethodsIn the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable.ResultsIn univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01–1.08; OS 1.06 (95% CI 1.02–1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02–2.35); OS 1.68 (1.05–2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value.ConclusionNeurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.

Sensory neuronopathies: A case series and literature review.

Sensory neuronopathies are heterogeneous disorders of dorsal root ganglia. The clinical and laboratory features in a single-centre series, including response to treatment and outcome have been described. They retrospectively included 54 patients meeting Camdessanché et al (2009) criteria for sensory neuronopathy. The patients were classified according to their likely aetiology and analysed their demographic, clinical, neurophysiological, histological and spinal MRI features. The outcome with the modified Rankin Scale (mRS) was evaluated, and the response to treatment was assessed. About 54 patients were included (18 male; median age 54.5 years). The most common initial symptoms were hypoaesthesia, paraesthesia, ataxia and pain. Half of patients had a slow onset, greater than 12 months before seeing a neurologist. The aetiology as possibly inflammatory (meaning nonspecific laboratory evidence of immune abnormality) in 18 patients (33%), paraneoplastic 8 (15%), autoimmune 7 (13%) and idiopathic 6 (11%) was classified. About 31 patients received immune therapy of which 11 (35%) improved or stabilised. Corticosteroids were the most used treatment (24 patients) and cyclophosphamide had the highest response rate (3/6, 50%). At the final follow up (median 24 months) 67% had mRS ≥3 and 46% mRS ≥4, including 15% who died. Worse outcome was associated with generalised areflexia and pseudoathetosis by logistic regression, and with motor involvement and raised CSF protein by univariate analysis. Sensory neuronopathies caused severe disability, especially in patients with generalised areflexia and pseudoathetosis. Of those without an obvious cause, most had some evidence of dysimmunity. Some patients had a positive response to immunotherapy, but rarely enough to improve disability much.

A meta-analysis on RT-QuIC for the diagnosis of sporadic CJD

Creutzfeld-Jakob disease (CJD) is a fatal neurodegenerative disease which belongs to the family of transmissible spongiform encephalopathies (TSEs), or prion diseases. Historically, CJD diagnosis has been based on the combination of clinical features and in vivo markers, including CSF protein assays, MRI and EEG changes. Brain-derived CSF proteins, such as 14-3-3, t-tau and p-tau have been largely used to support the diagnosis of probable CJD, although with certain limitations concerning sensitivity and specificity of these tests. More recently, a new method for the pre-mortem diagnosis of sporadic CJD has been developed, based on the ability of PrPsc to induce the polymerization of protease-sensitive recombinant PrP (PrPsen) into amyloid fibrils, and is known as Real-Time Quaking- Induced Conversion (RT-QuIC) assay allows the detection of > 1fg of PrPsc in diluted CJD brain homogenate and a variety of biological tissues and fluids. In the present study, we did a meta-analysis on the liability of RT-QuIC method in the diagnosis of sporadic CJD, in comparison to 14-3-3 and Tau protein. Twelve studies were finally included in the statistical analysis which showed that RT-QuIC has a very high specificity and comparable sensitivity to 14-3-3 protein and Tau protein in the CSF, and hence can be used as a reliable biomarker for the diagnosis of sporadic CJD.

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

BackgroundMucolipidosis type IV (MLIV), an ultra-rare neurodevelopmental and neurodegenerative disorder, is caused by mutations in the MCOLN1 gene, which encodes the late endosomal/lysosomal transient receptor potential channel TRPML1 (mucolipin 1). The precise pathophysiogical pathways that cause neurological disease in MLIV are poorly understood. Recently, the first post-mortem brain sample became available from a single MLIV patient, and in the current study we performed mass spectrometry (MS)-based proteomics on this tissue with a view to delineating pathological pathways, and to compare with previously-published data on MLIV, including studies using the Mcoln1−/− mouse.ResultsA number of pathways were altered in two brain regions from the MLIV patient, including those related to the lysosome, lipid metabolism, myelination, cellular trafficking and autophagy, mTOR and calmodulin, the complement system and interferon signaling. Of these, levels of some proteins not known previously to be associated with MLIV were altered, including APOD, PLIN4, ATG and proteins related to interferon signaling. Moreover, when proteins detected by proteomics in the human brain were compared with their orthologs detected in the Mcoln1−/− mouse by RNAseq, the results were remarkably similar. Finally, analysis of proteins in human and mouse CSF suggest that calbindin 1 and calbindin 2 might be useful as biomarkers to help chart the course of disease development.ConclusionsDespite the sample size limitations, our findings are consistent with the relatively general changes in lysosomal function previously reported in MLIV, and shed light on new pathways of disease pathophysiology, which is required in order to understand the course of disease development and to determine the efficacy of therapies when they become available for this devastating disease.