Autoimmune glial fibrillary acidic protein astrocytopathy mimicking acute disseminated encephalomyelitis: A case report.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an increasingly recognized type of steroid-responsive autoimmune disease of the nervous system. Defined in 2016, it is associated with the presence of anti-GFAP immunoglobulinG in the serum or cerebrospinal fluid (CSF) of affected patients. PATIENT CHARACTERISTICS: Herein, we report a case of acute neurological symptoms, including headache, fever, confusion, and paralysis of the lower extremities. CSF analysis revealed lymphocytic pleocytosis and elevated protein levels, indicating acute disseminated encephalomyelitis, and the patient was given immunotherapy. Cranial magnetic resonance imaging showed multifocal T2/fluid-attenuated inversion recovery hyperintense signal changes in the periventricular white matter, and electromyography testing showed changes consistent with severe sensorimotor neuropathy, indicating the involvement of the brain and peripheral nerves. DIAGNOSES: Finally, a diagnosis of autoimmune GFAP astrocytopathy was confirmed due to the presence of GFAP-immunoglobulinG in the patient's CSF. INTERVENTIONS: The patient was treated with one course of intravenous immunoglobulin therapy, then followed with intravenous methylprednisolone (1.0 g/d for 3 days) and oral prednisolone. OUTCOMES: At 1 week after intravenous immunoglobulin therapy, his level of consciousness improved. However, flaccid paralysis persisted without substantial improvement. CONCLUSION: In conclusion, the provision of an accurate early diagnosis and appropriate treatment are crucial for improving the prognosis of patients with autoimmune GFAP astrocytopathy. Further, this case highlights the importance of recognizing the role of peripheral nerve involvement in GFAP autoimmunity.

Patients with chronic autoimmune demyelinating polyneuropathies exhibit cognitive deficits which might be associated with CSF evidence of blood-brain barrier disturbance.

BACKGROUND: Chronic autoimmune demyelinating polyneuropathies (CADP) result in impaired sensorimotor function. However, anecdotal clinical observations suggest the development of cognitive deficits during the course of disease. METHODS: We tested 16 patients with CADP (11 patients with chronic inflammatory demyelinating polyneuropathy, 4 patients with multifocal motor neuropathy and 1 patient with multifocal acquired demyelinating sensory and motor neuropathy) and 40 healthy controls (HC) with a neuropsychological test battery. Blood-brain-barrier dysfunction (BBBd) in patients was assessed retrospectively by analysing the cerebral spinal fluid (CSF) status at the time the diagnosis of CAPD was established. RESULTS: CADP patients failed on average in 1.7 out of 9 neuropsychological tests (SD ± 1.25, min. 0, max. 5). 50% of the CADP patients failed in at least two neuropsychological tests and 44.3% of the patients failed in at least two different cognitive domains. CADP patients exhibiting BBBd at the time of first diagnosis failed in more neuropsychological tests than patients with intact integrity of the BBB (p < 0.05). When compared directly with the HC group, CADP patients performed worse than HC in tests measuring information processing ability and speed as well as phonemic verbal fluency after adjusting for confounding covariates. CONCLUSIONS: Our results suggest that mild to moderate cognitive deficits might be present in patients with CAPD. One possible tentative explanation, albeit strong evidence is still lacking for this pathophysiological mechanism, refers to the effect of autoimmune antibodies entering the CNS via the dysfunctional blood-brain barrier typically seen in some of the CADP patients.

PAPP-A activity is increased in cerebrospinal fluid from patients with diabetic polyneuropathy and correlates with peripheral nerve impairment.

OBJECTIVE: Insulin-like growth factors (IGFs) have neuroprotective effects. IGF activity is partly controlled by pregnancy-associated plasma protein-A (PAPP-A), an enzyme which enhances IGF-action by cleavage of IGF-binding protein-4 (IGFBP-4). To study the role of PAPP-A and the IGF system in diabetic polyneuropathy (DPN), we measured immunoreactive (total) concentrations of IGF-I and IGF-II, bioactive IGF by cell-based bioassay, PAPP-A, as well as intact and PAPP-A-cleaved IGFBP-4 in cerebrospinal fluid (CSF) and serum from patients with type 2 diabetes (T2D) with and without DPN. DESIGN: Twenty-three patients with T2D were included. Based on clinical examination, vibratory perception thresholds and nerve conduction studies, patients were diagnosed with (n = 9) or without (n = 14) DPN. RESULTS: In CSF, PAPP-A activity, as estimated by IGFBP-4 fragment levels, was higher in patients with than without DPN (34.57 vs 13.79 µg/L, p = .003) and concentrations correlated with peripheral nerve impairment measures (r = 0.73, p < .01). Furthermore, serum bioactive IGF was lower in patients with than without DPN (0.8 vs 1.3 µg/L, p = .006) and correlated inversely to the severity of DPN (r = -0.67, p < .01). CONCLUSIONS: In both CSF and serum, members of the IGF system correlated with measures of peripheral nerve impairment in patients with T2D. This supports a relationship between the IGF system and the development of DPN. Further studies are needed to clarify if these changes are causally linked to the pathogenesis of DPN.

IL-8 as a potential biomarker in Guillain-Barre Syndrome.

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis.

Polineuropatías agudas en un hospital del sur de España: diez años de experiencia / Acute polyneuropathies in a hospital in the south of Spain: ten years’ experience

Introducción. El síndrome de Guillain-Barré es la causa más frecuente de parálisis flácida aguda en niños. Objetivo. Describir características de los pacientes diagnosticados de polineuropatías agudas y su evolución a largo plazo. Pacientes y métodos. Análisis descriptivo retrospectivo de los menores de 14 años ingresados en nuestro hospital entre enero de 2004 y diciembre de 2014. Se recogieron variables clínicas, demográficas, neurofisiológicas y otras pruebas de imagen. Resultados. Veintiséis pacientes, con una mediana de edad de 3,83 años, fueron diagnosticados de polineuropatías agudas, cuatro de ellos de origen marroquí. Veinte (76%) tenían antecedentes de infección previa. El tiempo medio desde el inicio de los síntomas hasta su ingreso fue de 9,2 días y, desde éste hasta el inicio de gammaglobulinas, de 1,6 días. La sintomatología que precedió al diagnóstico fue de carácter muy heterogéneo. Todos presentaron debilidad muscular; el 90%, arreflexia; y el 30%, afectación de los pares craneales. El 100% recibió gammaglobulinas intravenosas, y el 38,4%, corticoides sistémicos. Presentaron cronificación de la patología dos pacientes. No hubo mortalidad en la serie. Conclusiones. Los pacientes incluidos en nuestro estudio presentaron en fases tempranas síntomas muy inespecíficos que llevaron a diagnósticos alternativos iniciales; para evitar este retraso diagnóstico, resulta fundamental realizar una exhaustiva exploración física que incluya los reflejos osteotendinosos y mantener un alto índice de sospecha de la enfermedad aun con normalidad en las pruebas complementarias si éstas son precoces. Detectamos un mayor número de polineuropatía axonal, posiblemente explicado por el elevado número de pacientes atendidos de origen marroquí (AU)

Introduction. Guillain-Barré syndrome is the most frequent cause of acute flaccid paralysis in children. Aim. To describe the characteristics of patients diagnosed with acute polyneuropathies and their long-term progress. Patients and methods. We conducted a retrospective descriptive analysis of children under 14 years of age admitted toour hospital between January 2004 and December 2014. Clinical, demographic and neurophysiological variables were collected together with other imaging tests. Results. Twenty-six patients, with a mean age of 3.83 years, were diagnosed with acute polyneuropathies, four of them of Moroccan origin. Twenty of them (76%) had a history of previous infection. The mean time elapsed since the onset of the symptoms until admission to hospital was 9.2 days, and from admission until beginning with gamma globulins it was 1.6 days. The clinical signs and symptoms prior to diagnosis were of a very heterogeneous nature. They all presented muscular weakness; 90% displayed areflexia; and 30% showed involvement of the cranial nerves. All of them (100%) received intravenous gamma globulins, and 38.4% were given systemic corticosteroids. Two patients presented chronification of the pathology. There was no mortality in the series. Conclusions. The patients included in our study presented very unspecific symptoms in the early phases, which initially led to alternative diagnoses. To avoid this delay in the diagnosis, it is essential to perform an exhaustive physical examination that includes the myotatic reflexes and to maintain a high level of suspicion of the disease even with normal results in the complementary tests if they are performed at an early stage. We detected a greater number of cases of axonal polyneuropathy, which can possibly be explained by the high number of patients of Moroccan origin who were treated (AU)

Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: Neurofilament Light Chain Levels in Definite Subtypes of Disease.

Importance: A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. Objectives: To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. Design, Setting, and Participants: In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department. Main Outcomes and Measures: Levels of NFL. Results: The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS. Conclusions and Relevance: This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

Cystatin C in cerebrospinal fluid as a biomarker of ALS.

Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 +/- 0.3, 6.7 +/- 0.4, and 6.9 +/- 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy.

Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies.

BACKGROUND: Pain is a common symptom in polyneuropathies (PNPs), although it is still not known why some PNPs are painful and others are painless. Increased pro-inflammatory cytokines have been found in conditions resulting in exaggerated pain states in animal studies. Recently, elevated pro-inflammatory cytokine levels have also been found in the cerebrospinal fluid (CSF) of patients suffering from complex regional pain syndrome. Pro-inflammatory cytokines have been shown to induce or increase inflammatory or neuropathic pain. METHODS: Using chemiluminescent enzyme immunometric assays, cytokine levels in 36 patients with painful and painless non-inflammatory PNPs in serum and CSF were investigated. The severity of PNPs was measured with electroneurography (ENG). In subjects with normal results using conventional ENG, quantitative thermo-testing was performed to investigate small-nerve-fibre function. RESULTS: Interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in serum or CSF did not differ between patients with (n = 18) or without (n = 18) painful PNPs, whereas patients with mechanical allodynia (n = 5) had elevated serum TNF-alpha levels compared to those without allodynia. TNF-alpha and IL-6 serum levels were higher in patients with severe (n = 21) compared to those with mild neuropathy (n = 15), and showed a positive correlation with severity of neuropathy. CONCLUSIONS: Results suggest that nerve fibre degeneration and presence of mechanical allodynia in peripheral non-inflammatory neuropathy determine cytokine expression in serum.

Motor variant of chronic inflammatory demyelinating polyneuropathy in a child.

Only 2 cases of pure motor chronic demyelinating inflammatory polyneuropathy in the pediatric age group have been reported in the literature. We report on a motor variant of chronic demyelinating inflammatory polyneuropathy with anti-ganglioside antibodies, diagnosed in a 5-year-old girl who presented with progressive motor weakness over a period of 12 months with no sensory involvement. She initially responded partially to intravenous immunoglobulin therapy (1 gm/kg/month for 6 months), and then demonstrated sustained but incomplete improvement on chronic prednisone therapy (1-2 mg/kg/day), on which she has continued since 1 year and 4 months after her initial presentation 3 years ago.

Chronic polyneuropathy and Lyme disease.

Infection of the peripheral nervous system with Borrelia burgdorferi can present as a cranial neuropathy or radiculopathy with cerebrospinal fluid (CSF) pleocytosis and intrathecal antibody production against B. burgdorferi, or as an asymmetric peripheral neuropathy with acrodermatitis chronica atrophicans (ACA) and normal CSF findings. According to North American studies, it can also present as a symmetric chronic polyneuropathy without ACA or other Lyme manifestations. Our purpose was to investigate the prevalence of B. burgdorferi antibodies in patients presenting with isolated chronic polyneuropathy (PN) in a European region with high incidence of Lyme disease. Sera from 209 PN patients and 247 healthy blood donors from Vest-Agder County, Norway, were examined. Borrelia burgdorferi antibodies were detected in 43 (21%) PN patients and in 45 (18%) healthy blood donors (P = 0.553). The prevalence of B. burgdorferi antibodies was similar (P = 0.311) in cryptogenic PN (24/102, 24%) and PNs of identified etiologies (19/107, 18%). PN patients with B. burgdorferi antibodies had normal spinal fluid white cell count and they did not differ clinically or electrophysiologically from PN patients without antibodies. None of 20 antibody-positive PN patients responded to antimicrobial treatment. The study shows that, in Europe, chronic distal PN without ACA or other Lyme manifestations is very rarely caused by a B. burgdorferi infection.

Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers.

The side chain oxidized oxysterol 24S-hydroxycholesterol (24-OH-chol) is formed almost exclusively in the brain, and there is a continuous passage of this oxysterol through the circulation to the liver. 27-Hydroxycholesterol (27-OH-chol) is produced in most organs and is also taken up by the liver. The 27-OH-chol-24-OH-chol ratio is about 0.1 in the brain and about 2 in the circulation. This ratio was found to be about 0.4 in cerebrospinal fluid (CSF) of asymptomatic patients, consistent with a major contribution from the circulation in the case of 27-OH-chol. In accordance with this, we demonstrated a significant flux of deuterium labeled 27-OH-chol from plasma to the CSF in a healthy volunteer. Patients with a defective blood-brain barrier were found to have markedly increased absolute levels (up to 10-fold) of both 27-OH-chol and 24-OH-chol in CSF, with a ratio between the two sterols reaching up to 2. There was a significant positive correlation between the levels of both oxysterols in CSF and the albuminCSF-albuminplasma ratio. The 27-OH-cholCSF-24-OH-cholCSF ratio was found to be about normal in patients with active multiple sclerosis and significantly increased in patients with meningitis, polyneuropathy, or hemorrhages. Results are discussed in relation to the possible use of 24-OH-cholCSF as a surrogate marker of central nervous system demyelination and/or neuronal death.

[Central nervous system damage in inflammatory demyelinating polyneuropathies]. / Porazhenie tsentral'noi nervnoi sistemy pri vospalitel'nykh demieliniziruiushchikh polinevropatiiakh.

The results of subclinical brain damage study of 20 patients with inflammatory demyelinating polyneuropathy, aged 46.5 +/- 3.7 years, are presented. Eleven patients were diagnosed to have Guillain--Barre syndrome and 9--chronic inflammatory demyelinating polyneuropathy. No clinical systems for central nervous system damage were found. Magnetic resonance tomography defected demyelination foci in periventricular and sub-cortical brain regions in 35% of the patients and diffuse atrophic process--in 55%. Registration of brainstem acoustic-evoked potentials showed bilateral latency increase and a change of a signal shape in 60% of the patients. Possible mechanisms of combined damage of central and peripheral nervous system in this pathology are discussed.

[The immunosorption of the cerebrospinal fluid in the treatment of inflammatory demyelinating polyneuropathies]. / Immunosorbtsiia spinnomozgovoi zhidkosti v lechenii vospalitel'nykh demieliniziruiushchikh polinevropatii.

Immunosorption of cerebrospinal fluid with updated "Pall" immunofilters (Germany) was successfully performed in 3 patients with progressing hormone-resistant Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. It was proved that clinical improvement in the patients' state correlated with a decrease in the contents of both total protein and immunoglobulins G, A, M in cerebrospinal fluid. It was suggested that the removal of these humoral factors had decreased a degree of inflammatory and demyelinating processes in inflammatory demyelinating polyneuropathies and had improved, thereby, the results of the treatment.

Cerebrospinal-fluid ciliary neurotrophic factor in neurological patients.

We developed a double sandwich immunoassay for the dosage of ciliary neurotrophic factor (CNTF) in cerebrospinal fluid (CSF). The detection limit was 100 pg/ml. This assay was applied to human CSF samples from 14 normal subjects, 26 patients with multiple sclerosis (MS), 17 with Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and 22 with tumours of the central nervous system (CNS) or leucaemic meningosis (LM). Samples from normal control subjects and from patients with tumours did not contain detectable CNTF. Only 2 patients with LM were positive, and all the patients with inflammatory diseases of the CNS and peripheral nervous system were positive. The MS group presented a mean value of 240 pg/ml CNTF and the GBS/CIDP group a value of 430 pg/ml.

Serum and CSF anti-GM1 antibodies in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

High titers of antibodies directed against gangliosides, especially GM1, are found in the serum of patients with a variety of polyneuropathies, including those of the inflammatory type. We assayed anti-GM1 IgG and IgM levels in the serum and cerebrospinal fluid (CSF) of 23 patients with Guillain-Barré syndrome (GBS) and 10 with chronic inflammatory demyelinating polyneuropathy (CIDP) to investigate whether this immune response may also be localized within the intrathecal compartment and correlate with clinical parameters such as time interval since disease onset, disability score, preceding infectious episodes, and GM1 therapy. When compared to the control group, anti-GM1 IgG was increased in the serum of 39% of GBS and 10% of CIDP patients, whereas anti-GM1 IgM was elevated in 17% of GBS and none of the CIDP patients. In both patient groups, however, anti-GM1 antibody levels were more frequently elevated in CSF than paired sera: they belonged to the IgG class in 48% of GBS and 50% of CIDP patients, and to the IgM class in 48% of GBS and 55% of CIDP patients. In the GBS group, anti-GM1 IgM serum levels inversely correlated with time elapsed between sample collection and onset of disease (P < 0.05), whereas serum anti-GM1 IgG levels positively correlated with the loss of functional ability (P < 0.005). Increased anti-GM1 antibodies in GBS serum were not associated with clinical or serological evidence of infectious antecedents nor with previous GM1 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Lyme disease meningopolyneuritis simulating malignant lymphoma.

Lyme disease is a multisystem disorder resulting from infection by the tick-borne spirochete, Borrelia burgdorferi. Fever, chills, malaise and headaches; a characteristic rash; and subsequent polyarthritis typically herald the onset of this condition. Neurologic involvement may occur with skin and joint manifestations or present alone as meningitis, cranial neuritis, and radiculopathy known as Bannwarth's syndrome. We report the cerebrospinal fluid (CSF) cytomorphologic and immunocytochemical features of four patients who presented with isolated meningitis, cranial neuritis, and painful neuropathy without initial history of specific skin rash or previous tick bite. Initial CSF findings of significant numbers of markedly atypical plasmacytoid mononuclear cells suggested CSF non-Hodgkin's malignant lymphoma. Immunocytochemical studies on CSF specimens, however, revealed polyclonal surface immunoglobulin patterns consistent with an inflammatory reaction. Follow-up clinical history and/or peripheral blood serologic testing for antibody titers with B. burgdorferi antigen confirmed the diagnosis of Lyme disease in all four cases. We conclude that Lyme disease may present as atypical spinal fluid lymphoplasmacytic cellular infiltrates that simulate malignant lymphoma and that appropriate immunocytochemical studies and peripheral blood serologic testing be performed to establish this diagnosis and direct appropriate therapy.