Clinical spectrum of the anti-GQ1b antibody syndrome: a case series of eight patients.

Anti-GQ1b antibodies can be detected in the serum of patients with Miller Fisher syndrome (MFS) and its incomplete forms such as acute ophthalmoparesis (AO), acute ptosis, acute mydriasis, acute oropharyngeal palsy and acute ataxic neuropathy (AAN), as well as in pharyngeal-cervical-brachial weakness, Bickerstaff brainstem encephalitis (BBE) and in overlap syndromes with Guillain-Barré syndrome (MFS-GBS, BBE-GBS). We searched the laboratory medicine database at University Hospitals Leuven between 2002 and 2017 for serum samples with anti-GQ1b IgG antibodies. We identified eight patients with anti-GQ1b antibodies: 4 MFS, 2 AO, 1 MFS-GBS and 1 AAN. Mean age was 57 years and five patients were males. Preceding illness was present in all patients. At nadir, we observed most frequently gait disturbance, external ophthalmoplegia and absent/decreased reflexes. Albumino-cytological dissociation was present in four patients. Mean time between onset and nadir was 4 days, between onset and recovery 2.5 months. Five patients recovered completely and three had minor residual symptoms. Interestingly, one patient with AO experienced a second identical episode, approximately 1 year after the first one. Our data confirm the broad clinical spectrum associated with the presence of anti-GQ1b IgG antibodies. Incomplete MFS subtypes such as AO are a challenge for diagnosis, because of the limited (though invalidating) clinical presentation and the lack of confirming ancillary tests. Subacute onset of ophthalmoplegia and/or ataxia should urge the clinician to include the anti-GQ1b antibody syndrome in the differential diagnosis.

Expanding the clinical relevance of the 5'-nucleotidase cN-II/NT5C2.

Purine metabolism is depending on a large amount of enzymes to ensure cellular homeostasis. Among these enzymes, we have been interested in the 5'-nucleotidase cN-II and its role in cancer biology and in response of cancer cells to treatments. This protein has been cited and studied in a large number of papers published during the last decade for its involvement in non-cancerous pathologies such as hereditary spastic paraplegia, schizophrenia, and blood pressure regulation. Here, we review these articles in order to give an overview of the recently discovered clinical relevance of cN-II.

Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1.

Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy.

Profiling the immunity status of children with non-polio acute flaccid paralysis who had not received any doses of oral polio vaccine in the South-South region, Nigeria 2011-2014.

OBJECTIVES: To demonstrate the immunity status of children with non-polio acute flaccid paralysis (NP AFP) reported through the AFP surveillance system in the South-South region of Nigeria. STUDY DESIGN: A retrospective study was conducted using AFP surveillance data collected routinely between January 2011 and December 2014 by the Disease Surveillance Department of the regional health service and the World Health Organization (WHO)-accredited regional reference polio laboratory. All cases of AFP reported to the Disease Surveillance Network from all six zones during this period were included in the study. METHODS: In total, 5111 cases of AFP in children aged ≤15 years were reported between 2011 and 2014. These cases were investigated and verified by WHO surveillance officers using a standard questionnaire, which captured the number of doses of oral polio vaccine (OPV) received by the child. Two stool samples were collected for each case, 24-48 h apart, within 14 days of the onset of paralysis, and transported to the national polio laboratory under reverse cold chain storage. Data retrieved were stored in an AFP database hosted by the WHO server. EPIINFO software was used to query the database and extract the information required for analysis in this study. RESULTS: The percentage of children who had received at least three doses of OPV (which serves as a threshold to measure immunity status) decreased from 87% in 2011 to 82% in 2014. The percentage of children who had not received any doses of OPV decreased from 2% in 2011 to 1% in 2014. Forty-eight percent of the children who had not received any doses of OPV were aged <1 year. CONCLUSION: Given the decrease in OPV immunity status, the region risks re-introduction of poliovirus. Swift steps should be taken to improve the immunization coverage, which would boost immunity status in Nigeria.

Paediatric Active Enhanced Disease Surveillance inaugural annual report, 2014.

INTRODUCTION: The Paediatric Active Enhanced Disease Surveillance (PAEDS) network is a hospital-based active surveillance system employing prospective case ascertainment of selected uncommon vaccine preventable diseases and potential adverse events following immunisation (AEFI). PAEDS enhances other Australian surveillance systems by providing prospective detailed clinical and laboratory data for the same child. METHODS: Specialist surveillance nurses screen hospital admissions, emergency department records, laboratory and other data, to prospectively identify hospitalised children aged under 15 years in 5 paediatric tertiary referral hospitals in New South Wales, Victoria, South Australia, Western Australia and Queensland. Standardised protocols and case definitions are used across all sites. Conditions under surveillance include vaccine preventable diseases: acute flaccid paralysis, varicella, pandemic and seasonal influenza and pertussis, and potential AEFIs: febrile seizures and intussusception. PAEDS also conducts surveillance for acute childhood encephalitis. RESULTS: Since August 2007, PAEDS has recruited a total of 6,227 hospitalised cases in total, for all conditions. From January to December 2014, there were 1,220 cases recruited across all conditions. Key outcomes include: enhanced acute flaccid paralysis surveillance to reach World Health Organization targets; supporting varicella and influenza vaccination in children; confirmation of a known low risk of febrile seizures following the 1st dose of measles-mumps-rubella vaccine but no increased risk of febrile seizures after measles-mumps-rubella-varicella vaccine, and a slightly increased risk of developing intussusception 1-7 days after rotavirus vaccination in infants aged less than 3 months. Acute childhood encephalitis data facilitated rapid investigation and response to the enterovirus 71 outbreak in 2013-2014. CONCLUSIONS: PAEDS provides unique policy-relevant data. This is the first of planned PAEDS annual reports to Communicable Diseases Intelligence.

Serum IgG and IgA levels in polio and non-polio acute flaccid paralysis cases in western Uttar Pradesh, India.

OBJECTIVE: IgG and IgA immunocompetence of children with wild poliovirus poliomyelitis and non-polio acute flaccid paralysis. METHODS: 932 cases of acute flaccid paralysis, reported in 2008-2009, were tested for presence of polio and non-polio enteroviruses according to the WHO standards. Serum IgA and IgG levels were determined by sandwich ELISA. RESULTS: Mean (SD) IgA levels [0.87 (0.62)g/L; n=28] of virologically confirmed poliomyelitis cases were lower than those of virus negative [1.21 (0.83)g/L; n=612] and non-polio Enterovirus positive [1.22 (0.79)g/L; n=240] cases of acute flaccid paralysis. No significant difference was observed in the concentration of IgG among these groups. CONCLUSIONS: IgA plays an important role in protection against poliomyelitis.

Status of immunity against poliomyelitis in the acute flaccid paralysis (AFP) cases in Romania between 2009-2012.

Poliovirus (PV), a member of the Enterovirus genus, is the etiological agent of poliomyelitis, an acute paralytic disease. No poliovirus strain has been isolated in Romania since 2009. A serosurvey study carried out between 2009-2012, that involved 76 serum samples from acute flaccid paralysis (AFP) cases, showed a low protection level in the examined subjects against type 1 (80%), type 2 (79%) and type 3 (71%) poliovirus Sabin strains. Samples with titers ≥ 1:8 were considered positive. Suboptimal seroprevalence in the AFP cases confirmed that a high level of immunization against polio must be assured in our country, because the risk of importation and subsequent transmission of the poliovirus remains until polio is globally eradicated.

Autoreactivity against myelin basic protein in patients with chronic paraplegia.

INTRODUCTION: Previous studies have shown the existence of either cellular or humoral MBP-reactive elements up to 5 years after spinal cord injury (SCI), but not the presence of both after 10 years. MATERIALS AND METHODS: Twelve SCI patients, with more than 10 years of evolution, and 18 healthy blood donors were studied. Lymphocyte proliferation (colorimetric-BrdU ELISA assay) and antibody titers against MBP (ELISA Human IgG MBP-specific assay) were assessed. RESULTS: SCI patients presented a significant T-cell proliferation against MBP (lymphocyte proliferation index: 3.7 ± 1.5, mean ± SD) compared to control individuals (0.7 ± 0.3; P < 0.001). Humoral response analysis yielded a significant difference (P < 0.0001) between the antibody titers of controls and SCI patients. A significant correlation between cellular and humoral responses was observed. Finally, patients with an ASIA B presented the highest immune responses. CONCLUSION: This work demonstrates, for the first time, the existence of both cellular and humoral responses against MBP in the chronic stages (>10 years) of injury.

Vaccine-associated paralytic poliomyelitis in an infant with perianal abscesses.

We describe a case of vaccine-associated paralytic poliomyelitis (VAPP) in a 7-month-old infant with perianal abscesses. The infant had suffered from perianal abscesses from 3 weeks after birth. The abscesses repeatedly developed and spontaneously drained through the orifice. Twenty-seven days before admission, a live attenuated oral poliovirus vaccine (OPV) was given to the infant for the first time for routine immunization. His body temperature rose to 38°C 19 days after receiving the OPV and fell 4 days later. Flaccid paralysis of the right leg appeared 26 days after receipt of the OPV. A Sabin type 3 poliovirus was isolated from a stool obtained at admission. The DNA sequences of the VP1 region of the isolated virus were more than 99% identical with those of the vaccine strain. Mild muscle atrophy with moderate motor impairment in the right leg persisted at 18 months of age. One VAPP case provoked by a perianal abscess has been reported from the United Kingdom. Database search revealed that one of nine VAPP cases reported during 2003-2008 in Japan had a perianal abscess. Taken together, these reports and our case imply that we should give OPV with caution to infants with a perianal abscess.

Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury.

OBJECTIVE: To determine the serum cytokine profiles of patients with spinal cord injury (SCI) and varying clinical presentations relative to healthy, able-bodied, age-matched control subjects. DESIGN: Cross-sectional study. SETTING: Clinical research unit. PARTICIPANTS: People with SCI (N=56) and different clinical presentations, and healthy, able-bodied, age-matched control subjects (N=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Serum levels of the proinflammatory cytokines interleukin (IL) 1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), the anti-inflammatory cytokines IL-4 and IL-10, the regulatory cytokine IL-2, the IL-1 receptor antagonist (IL-1RA), and autoantibodies against myelin-associated glycoprotein and GM(1) ganglioside (anti-GM(1)) immunoglobulin (IgG and IgM), as determined by enzyme-linked immunosorbent assay. The relationship between elevated serum cytokine levels and clinical variables was also studied. RESULTS: SCI subjects exhibited serum concentrations of IL-6, TNF-alpha, IL-1RA, and anti-GM(1) (IgG) that were greater (P<.05) than control group values. Elevated cytokine concentrations were not associated with high white blood cell counts, level of injury, or American Spinal Injury Association classification; they were evident in SCI subjects who were asymptomatic for medical complications, but were further elevated in subjects with pain, urinary tract infection (UTI), and pressure ulcers. CONCLUSIONS: Elevated levels of circulating proinflammatory cytokines and autoantibodies are present in the serum of SCI subjects without medical complications, and are further elevated in SCI subjects with neuropathic pain, UTI, or pressure ulcers, relative to healthy, able-bodied control subjects. These findings may be indicative of a protective autoimmunity, simply a consequence of occult or evident infection, or evidence of cytokine dysregulation that may contribute to an immune-mediated impairment of axonal conduction.

Purine nucleoside phosphorylase deficiency in a patient with spastic paraplegia and recurrent infections.

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disease. The characteristic features of the disease include severe T cell immune defects with recurrent infections, a failure to thrive, and progressive neurological findings. To date, 35 cases of purine nucleosidase phosphorylase deficiency have been reported worldwide. A 2-year-old female patient was hospitalized due to recurrent infections starting from 6 months and a fever that had continued for a month. The parents were first cousins. Physical examination showed a failure to thrive, herpetic lesions around the lips, painful lesions on the tongue and the buccal mucosa, lung infection, and spastic paraparesis in the lower extremities. She had motor and mental retardation. Laboratory tests revealed lymphopenia; low CD3, CD4, and CD8 counts; normal immunoglobulin levels; low uric acid; and very low purine nucleoside phosphorylase enzyme activity (1.4 nmol/h/mg; normal range, 490-1530). DNA sequencing of the purine nucleosidase phosphorylase gene revealed a missense homozygous mutation, a G to A transition at exon 4 position 64 (349G>A transition), which led to a substitution of alanine by threonine at codon 117 (Ala117Thr). Both parents were heterozygous for the mutation. This is the second purine nucleosidase phosphorylase deficient case to have been presented and carrying this mutation worldwide. Various antibiotics, antifungal drugs, and intravenous immunoglobulin were used to treat the infections during her 3 months. This form of treatment proved to be unresponsive, resulting in her subsequent death at 26 months of age.

Protective efficacy of a monovalent oral type 1 poliovirus vaccine: a case-control study.

BACKGROUND: A high-potency monovalent oral type 1 poliovirus vaccine (mOPV1) was developed in 2005 to tackle persistent poliovirus transmission in the last remaining infected countries. Our aim was to assess the efficacy of this vaccine in India. METHODS: We estimated the efficacy of mOPV1 used in supplementary immunisation activities from 2076 matched case-control pairs of confirmed cases of poliomyelitis caused by type 1 wild poliovirus and cases of non-polio acute flaccid paralysis in India. The effect of the introduction of mOPV1 on population immunity was calculated on the basis of estimates of vaccination coverage from data for non-polio acute flaccid paralysis. FINDINGS: In areas of persistent poliovirus transmission in Uttar Pradesh, the protective efficacy of mOPV1 was estimated to be 30% (95% CI 19-41) per dose against type 1 paralytic disease, compared with 11% (7-14) for the trivalent oral vaccine. 76-82% of children aged 0-23 months were estimated to be protected by vaccination against type 1 poliovirus at the end of 2006, compared with 59% at the end of 2004, before the introduction of mOPV1. INTERPRETATION: Under conditions where the efficacy of live-attenuated oral poliovirus vaccines is compromised by a high prevalence of diarrhoea and other infections, a dose of high-potency mOPV1 is almost three times more effective against type 1 poliomyelitis disease than is trivalent vaccine. Achieving high coverage with this new vaccine in areas of persistent poliovirus transmission should substantially improve the probability of rapidly eliminating transmission of the disease.

[Coeliac disease an spastic paraplegia]. / Maladie coeliaque et paraplégie spasmodique.

INTRODUCTION: Celiac disease (CD) is an immune-mediated disease triggered by the ingestion of gluten in genetically susceptible individuals. Neurological manifestations are rare and severe and must be sought systematically. CLINICAL CASES: Two non related patients each from a consanguineous marriage developed progressive spastic paraplegia 2 and 8 years respectively after onset of CD. The radiological and biological findings were normal except for the presence of abnormalities related to CD. CONCLUSION: The relationship between spastic paraplegia and CD is not well established. Autoimmune, metabolic and genetic mechanisms could be considered but the probability of a fortuitous association should not be ruled out.

Paraplegic mice are leading to new advances in spinal cord injury research.

STUDY DESIGN: Experimental laboratory investigations with paraplegic mouse models. OBJECTIVES: To review the most recent advances in the field of spinal cord injury research; immune system response, regeneration, and functional recovery. SETTINGS: Laval University and Laval University Medical Center, Quebec, Canada. METHODS: Assessment of regenerative processes and locomotor function recovery induced by a variety of treatments and approaches in wild-type and genetically engineered mice with complete or incomplete lesions of the spinal cord. RESULTS: Recent studies have reported a number of significant observations providing additional insight into the role and mechanism of regeneration, immune system response, and functional recovery after spinal cord injury (SCI) using incomplete paraplegic mice with Nogo-A, NgR, EphA4, GFAP/vimentime, LIF, or Fas gene knock-out. A novel antibody called CXCL10 was also recently found to increase tissue sparing and angiogenesis after SCI. In an attempt to explore the possibilities of reactivating spared neurons below the injury level, researchers have found that pharmacological activation of specific subtypes of serotonin receptors (eg, 5-HT1A/2A/7) can sustain the production of basic locomotor-like movements in complete paraplegic mice. CONCLUSION: The growing availability of genetically engineered and mutant mouse strains along with molecular biology tools has led scientists to increasingly use murine models in SCI research. These new tools and models may assist scientists in understanding further the complex pathological consequences of SCI.

Preserved granulocyte formation and function, as well as bone marrow innervation, in subjects with complete spinal cord injury.

Patients with a spinal cord injury are at risk of infections and is partly attributed to immobilization. Their lymphocyte-mediated immunity is impaired and the growth of blood progenitor cells is reduced. An adequate immune response depends on granulocytes being mobilized rapidly and activated properly, at the inflammatory site. Possibly this requires a coordinated interaction between the autonomous nervous system and cells within the haematopoietic bone marrow. Granulocyte function in the spinal cord injured has not been evaluated. Although there is evidence that the bone marrow in rodents is innervated, it is uncertain whether human bone marrow is similarly affected. Microscopy and immunolabelling followed by flow cytometry, showed that blood and bone marrow counts of leucocyte subsets were similar in paraplegic, tetraplegic and control subjects (P > 0.05). Neutrophilic migration and oxygen consumption, as well as eosinophil activation, assayed as release of eosinophilic cationic protein or CD69 expression, were not altered after spinal cord injury (P > 0.05). Cryostat sections of human bone marrow biopsies stained positive with glyoxylic acid, indicating the presence of catecholamine-containing nerves in both the patients and the controls. We conclude that terminal differentiation and formation of granulocytes, as well as their functional capacity, do not depend appreciably on supraspinal nervous regulation.

The role of CD4(+) T cells in biphasic hind limb paralysis induced by the D variant of encephalomyocarditis virus (EMC-D) in DBA/2 mice.

DBA/2 CrSlc mice infected with the D variant of encephalomyocarditis virus (EMC-D) (10 PFU/head) developed biphasic hind limb paralysis due to spinal cord lesion. The early phase lesion was characterized by demyelination with infiltration of macrophages in the funiculus lateraris and the late phase lesion by degeneration of motor neurons with infiltration of CD4(+) T cells in the cornu ventrale. In the present study, treatment with anti-Mac1 monoclonal antibody (MAb) or anti-CD4 MAb prior to virus infection (-3 to -1 days) reduced the early phase lesion and the incidence of the first paralysis. Signals of viral RNAs were observed only in a few oligodendrocytes in the funiculus lateraris. Treatment with anti-CD4 MAb from 31 to 33 days post infection when mice showed recovery from the first paralysis reduced the late phase lesion and prevented the second paralysis. Signals of viral RNAs were still detected in a few degenerated neurons in the cornu ventrale. These results indicate that while macrophages and CD4(+) T cells participate in the early phase lesion and paralysis and only CD4(+) T cells in the late phase lesion and paralysis.

Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection.

The neuromuscular aspects of West Nile virus (WNV) infection have not been characterized in detail. We have studied a group of six patients with proven WNV infection. All cases presented with acute, severe, asymmetric, or monolimb weakness, with minimal or no sensory disturbance after a mild flu-like prodrome. Four cases also had facial weakness. Three of our cases had no encephalitic signs or symptoms despite cerebrospinal fluid pleocytosis. Electrophysiological studies showed severe denervation in paralyzed limb muscles, suggesting either motor neuron or multiple ventral nerve root damage. This localization is supported further by the finding of abnormal signal intensity confined to the anterior horns on a lumbar spine magnetic resonance imaging. Muscle biopsies from three patients showed scattered necrotic fibers, implicating mild direct or indirect muscle damage from the WNV infection. In summary, we describe a group of patients with acute segmental flaccid paralysis with minimal or no encephalitic or sensory signs. We have localized the abnormality to either the spinal motor neurons or their ventral nerve roots. It will be important for physicians to consider WNV infection in patients with acute asymmetric paralysis with or without encephalitic symptoms.

Activation of natural killer cell function in recreational athletes with paraplegia during a wheelchair half-marathon race.

OBJECTIVE: To investigate a part of the immune homeostasis in recreational athletes with spinal cord injury (SCI) during and after a wheelchair half-marathon race. DESIGN: Case-control study in an actual race. SETTING: The half-marathon division of an international wheelchair marathon race in Japan. PARTICIPANTS: Seven male wheelchair racers with SCI between T7 and L1. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Changes in the number and function of natural killer (NK) cells and the endocrine effects, including plasma catecholamines and cortisol in blood samples obtained the day before the race, immediately after it, and 1 day after the race. RESULTS: Both the percentage and absolute number of peripheral NK cells did not change significantly throughout the experiment. Mean NK cell cytotoxic activity +/- standard deviation increased significantly, from 45.5%+/-7.5% to 56.1%+/-5.1% (P<.01) immediately after the race and remained increased until the next day. Plasma adrenaline levels were increased (P<.05) immediately after the race and recovered 1 day later; the plasma concentration of cortisol did not change throughout the experiment. CONCLUSIONS: The wheelchair half-marathon race induced activation of NK cell function in recreational athletes with SCI between T7 and L1.