Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets.

Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and germinate into a vegetative bacterium that releases a toxin, termed tetanus neurotoxin (TeNT). TeNT enters the general circulation, binds to peripheral motor neurons and sensory neurons, and is transported retroaxonally to the spinal cord. It then enters inhibitory interneurons and blocks the release of glycine or GABA causing a spastic paralysis. This review attempts to correlate the metalloprotease activity of TeNT and its trafficking and localization into the vertebrate body to the nature and sequence of appearance of the symptoms of tetanus.

Central nervous system and spinal cord tuberculosis: Revisiting an important disease.

Tuberculosis is a worldwide pandemic. Estimated that about 25% humans are colonized by Mycobacterium tuberculosis and about 1% are believed to develop the infection in the central nervous system (CNS-TB). Given the importance of this disease and its high levels of morbidity and mortality, it is imperative that every radiologist must be reminded of the most common findings of CNS-TB as there are several related differential diagnoses for this disease. The most common form CNS-TB is tuberculous meningitis (TBM), characterized mostly by basal meningitis, but infarction, hydrocephalus and tuberculomas could be present. Intracerebral tuberculosis is characterized by tuberculomas that can have different imaging features according to their stage. Vascular and spinal complications of tuberculosis are also reported. This review compiles the classic and unusual findings regarding CNS-TB together with new diagnostic scores in which neuroimaging have an important role.

C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.

Cryptococcal meningitis presenting as acute flaccid paralysis: A case report.

Cryptococcus is a cosmopolitan fungus with tropism for the nervous system and a higher prevalence of infection in immunosuppressed patients. Neurological compromise caused by this microorganism mainly debuts as a meningeal syndrome (headache, fever, neck stiffness) with predominant encephalic involvement. In this report we present the rare case of a non-HIV patient with flaccid paralysis and peripheral nerve involvement due to crytpococcal meningitis. This is a 53-years-old woman, with a past-medical history of diabetes, who presented with dysarthria, unilateral peripheral facial paralysis, asymmetric ascending quadriparesis, generalized hyporeflexia and urinary retention. Neuroimaging was initially reported as negative for vascular or demyelinating diseases. Electrophysiological studies were performed, and acute flaccid paralysis of undetermined etiology was defined as a temporal clinical diagnosis. Cerebrospinal fluid molecular analysis confirmed the presence of Cryptococcus neoformans var. gatti; posteriorly, antifungal treatment with amphotericin B and fluconazole was started. Polyneuroradiculopathy symptoms significantly improved over the in-hospital stay. In conclusion, spinal cord and peripheral nerve involvement by Cryptococcus is an infrequent cause of acute flaccid paralysis that should be considered in the differential diagnosis even in HIV-negative patients.

Infectious Myelitis.

Myelitis refers to inflammation of the spinal cord which can result in a spectrum of neurologic impairment. Infectious pathogens are an important etiologic category, and can result in myelitis through direct pathogenic effect or through immune-mediated parainfection; this review focuses on the former category. The spectrum of clinical manifestations is summarized and a diagnostic workup provided to aid clinicians in developing an approach to patients presenting with symptoms suggestive of infectious myelitis. This is followed by an overview of the important viral, bacterial, parasitic, and fungal causes of infectious myelitis. The typical presentations, diagnostic modalities, and treatment approaches are outlined for key pathogens culprit in infectious myelitis to allow clinicians to promptly recognize and diagnose specific infectious etiologies of myelitis.

Fusarium species intramedullary spinal cord fungus ball: case report.

The Fusarium species are one of the most common opportunistic fungal infections occurring in immunocompromised patients and are associated with high morbidity and mortality. Common sites of infection include blood, skin, nasal passages, lungs, bone, and other visceral organs. There is a paucity of literature on Fusarium infections in the brain, and the true nature and extent of central nervous system involvement is not well described. To the authors' knowledge, there have been no reported cases of Fusarium infection of the spine. The authors report the case of a man with acute myeloblastic leukemia and resultant pancytopenia who presented with fungal sinusitis, upper- and lower-extremity weakness, and cardiopulmonary arrest. Imaging studies revealed a spinal cervical intramedullary ring-enhancing lesion. Because of the progressive nature of his symptoms, neurosurgical intervention involving a C2-3 laminectomy and drainage of the lesion was performed. Intraoperative cultures and histopathology results were positive for Fusarium species and, along with intraoperative findings, were consistent with a fungus ball. The patient was placed on a regimen of intravenous and intrathecal antifungal therapy. Unfortunately, his clinical condition declined postoperatively, and he ultimately died of disseminated infection.

Contribution of spinal cord glial cells to L. amazonensis experimental infection-induced pain in BALB/c mice.

BACKGROUND: The cellular and molecular pathophysiological mecha\nisms of pain processing in neglected parasitic infections such as leishmaniasis remain unknown. The present study evaluated the participation of spinal cord glial cells in the pathophysiology of pain induced by Leishmania amazonensis infection in BALB/c mice. METHODS: Mice received intra-plantar (i.pl.) injection of L. amazonensis (1 × 105) and hyperalgesia, and paw edema were evaluated bilaterally for 40 days. The levels of TNF-α and IL-1ß, MPO activity, and histopathology were assessed on the 40th day. ATF3 mRNA expression was assessed in DRG cells at the 30th day post-infection. Blood TNF-α and IL-1ß levels and systemic parasite burden were evaluated 5-40 days after the infection. At the 30th day post-infection L. amazonensis, the effects of intrathecal (i.t.) treatments with neutralizing antibody anti-CX3CL1, etanercept (soluble TNFR2 receptor), and interleukin-1 receptor antagonist (IL-1ra) on infection-induced hyperalgesia and paw edema were assessed. In another set of experiments, we performed a time course analysis of spinal cord GFAP and Iba-1 (astrocytes and microglia markers, respectively) and used confocal immunofluorescence and Western blot to confirm the expression at the protein level. Selective astrocyte (α-aminoadipate) and microglia (minocycline) inhibitors were injected i.t. to determine the contribution of these cells to hyperalgesia and paw edema. The effects of i.t. treatments with glial and NFκB (PDTC) inhibitors on spinal glial activation, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation were also evaluated. Finally, the contribution of TNF-α and IL-1ß to CX3CL1 mRNA expression was investigated. RESULTS: L. amazonensis infection induced chronic mechanical and thermal hyperalgesia and paw edema in the infected paw. Mechanical hyperalgesia was also observed in the contralateral paw. TNF-α, IL-1ß, MPO activity, and epidermal/dermal thickness increased in the infected paw, which confirmed the peripheral inflammation at the primary foci of this infection. ATF3 mRNA expression at the ipsilateral DRG of the infected paw was unaltered 30 days post-infection. TNF-α and IL-1ß blood levels were not changed over the time course of disease, and parasitism increased in a time-dependent manner in the ipsilateral draining lymph node. Treatments targeting CX3CL1, TNF-α, and IL-1ß inhibited L. amazonensis-induced ongoing mechanical and thermal hyperalgesia, but not paw edema. A time course of GFAP, Iba-1, and CX3CR1 mRNA expression indicated spinal activation of astrocytes and microglia, which was confirmed at the GFAP and Iba-1 protein level at the peak of mRNA expression (30th day). Selective astrocyte and microglia inhibition diminished infection-induced ipsilateral mechanical hyperalgesia and thermal hyperalgesia, and contralateral mechanical hyperalgesia, but not ipsilateral paw edema. Targeting astrocytes, microglia and NFκB diminished L. amazonensis-induced GFAP, Iba-1, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation in the spinal cord at the peak of spinal cord glial cells activation. CX3CL1 mRNA expression was also detected in the ipsilateral DRG of infected mice at the 30th day post-infection, and the i.t. injection of TNF-α or IL-1ß in naïve animals induced CX3CL1 mRNA expression in the spinal cord and ipsilateral DRG. CONCLUSIONS: L. amazonensis skin infection produces chronic pain by central mechanisms involving spinal cord astrocytes and microglia-related production of cytokines and chemokines, and NFκB activation contributes to L. amazonensis infection-induced hyperalgesia and neuroinflammation.

Brain and Spinal Cord Lesions in Leprosy: A Magnetic Resonance Imaging-Based Study.

Neurotropism and infiltration by Mycobacterium leprae of peripheral nerves causing neuropathy are well established, but reports of central nervous system (CNS) damage are exceptional. We report CNS magnetic resonance imaging (MRI) abnormalities of the brain and spinal cord as well as lesions in nerve roots and plexus in leprosy patients. Eight patients aged between 17 and 41 years underwent detailed clinical, histopathological, and MRI evaluation. All had prominent sensory-motor deficits with hypopigmented and hypo/anesthetic skin patches and thickened peripheral nerves. All demonstrated M. Leprae DNA in affected peripheral nerve tissue. All received multidrug therapy (MDT). Two patients had brainstem lesions with enhancing facial nuclei and nerves, and one patient had a lesion in the nucleus ambiguus. Two patients had enhancing spinal cord lesions. Follow-up MRI performed in four cases showed resolution of brainstem and cord lesions after starting on MDT. Thickened brachial and lumbosacral plexus nerves were observed in six and two patients, respectively, which partially resolved on follow-up MRI in the two cases who had reimaging. The site and side of the MRI lesions corresponded with the location and side of neurological deficits. This precise clinico-radiological correlation of proximal lesions could be explained by an immune reaction in the gray matter corresponding to the involved peripheral nerves, retrograde axonal and gray matter changes, or infection of the CNS and plexus by lepra bacilli. Further study of the CNS in patients with leprous neuropathy is needed to establish the exact nature of these CNS MRI findings.

Paradoxical reaction in HIV-negative tuberculous meningitis patients with spinal involvement.

OBJECTIVE: The aim of this study was to investigate the occurrence of paradoxical reaction (PR) in HIV-negative tuberculous meningitis (TBM) patients with spinal involvement, as well as its possible risk factors. METHODS: Fifty TBM patients with spinal involvement were studied retrospectively and divided into a PR group and a non-PR group according to the presence of PR. Their demographic, clinical, radiological, and laboratory data, and status at follow-up were collected and compared. RESULTS: PR developed in 26 patients (52%), with the median time to the development of PR being 30days (range 15-330 days) after the initiation of tuberculosis therapy. At initial diagnosis, age, documented acid-fast bacilli (AFB), and the cerebrospinal fluid protein level were found to differ significantly between the two groups. After multivariate analysis, age, documented AFB, and vertebral involvement were significantly associated with the development of PR. CONCLUSIONS: PR was common in TBM patients with spinal involvement. Age, documented AFB, and musculoskeletal involvement may be predictors of PR development.

Multiple sclerosis and mixed microbial infections. Direct identification of fungi and bacteria in nervous tissue.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS), leading to multifocal demyelination and neurodegeneration. The etiology of this incurable disease is unknown and remains a matter of intensive research. The possibility that microbial infections, such as viruses or bacteria, can trigger an autoimmune reaction in CNS tissue has been suggested. However, the recent demonstration that bacteria are present in CNS tissue points to a direct involvement of microbial infections in the etiology of MS. In the present study, we provide the first evidence of fungal infection in CNS tissue of MS patients, and demonstrate that fungal DNA from different species can be detected in the CNS. We used, nested PCR assays together with next-generation sequencing to identify the fungal species in the nervous tissue of 10 patients with MS. Strikingly, Trichosporon mucoides was found in the majority of MS patients, and particularly high levels of this fungus were found in two patients. Importantly, T. mucoides was not detected in the CNS of control subjects. We were also able to visualize fungal structures in CNS tissue sections by immunohistochemistry using specific antifungal antibodies, which also revealed the accumulation of a number of microbial cells in microfoci. Again, microbial structures were not observed in CNS sections from controls. In addition to fungi, neural tissue from MS patients was also positive for bacteria. In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury.

Cranial Computed Tomography, Lumbar Puncture, and Clinical Deterioration in Bacterial Meningitis: A Nationwide Cohort Study.

Background: It is unclear how often lumbar puncture (LP) is complicated by cerebral herniation in patients with bacterial meningitis and whether cranial computed tomography (CT) can be used to identify patients at risk for herniation. Methods: We performed a nationwide prospective cohort study of patients with community-acquired bacterial meningitis from 2006 to 2014 and identified patients with clinical deterioration possibly caused by LP. For systematic evaluation of contraindications for LP on cranial CT, these patients were matched to patients in the cohort without deterioration. Four experts, blinded for outcome, scored cranial CT results for contraindications for LP. A Fleiss' generalized κ for this assessment was determined. Results: Of 1533 episodes, 47 (3.1%) had deterioration possibly caused by LP. Two patients deteriorated within 1 hour after LP (0.1%). In 43 of 47 patients with deterioration, cranial CT was performed prior to LP, so CT results were matched with 43 patients without deterioration. The interrater reliability of assessment of contraindications for LP on cranial CT was moderate (Fleiss' generalized κ = 0.47). A contraindication for LP was reported by all 4 raters in 6 patients with deterioration (14%) and in 5 without deterioration (11%). Conclusions: LP can be performed safely in the large majority of patients with bacterial meningitis, as it is only very rarely complicated by cerebral herniation. Cranial CT can be considered a screening method for contraindications for LP, but the interrater reliability of this assessment is moderate.

Rare and unusual presentation of Cladophialophora infection in a pulmonary transplant cystic fibrosis patient.

A 35-year-old woman with severe cystic fibrosis was admitted for sudden loss of strength in both legs, revealing a myelitis. The medullary lesion biopsy revealed phaeohyphomycosis caused by Cladophialophora species. Myelitis caused by Cladophialophora bantiana is a rare disease associated with high mortality.

Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS. Some fungal structures were localized intracellularly and even intranuclearly, indicating that this infection is not the result of post-mortem colonization. By contrast, this burden of fungal infection cannot be observed in several CNS areas of control subjects. PCR analysis and next generation sequencing of DNA extracted from frozen neural tissue identified a variety of fungal genera including Candida, Malassezia, Fusarium, Botrytis, Trichoderma and Cryptococcus. Overall, our present observations provide strong evidence for mixed fungal infections in ALS patients. The exact mixed infection varies from patient to patient consistent with the different evolution and severity of symptoms in each ALS patient. These novel findings provide a logical explanation for the neuropathological observations of this disease, such as neuroinflammation and elevated chitinase levels, and could help to implement appropriate therapies.

The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex.

Metabotropic glutamate receptor 5 (mGluR5) activation in the infralimbic cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals. Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat-evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats. The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.

Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus.

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

Disseminated mucormycosis (DM) after pneumonectomy: a case report.

BACKGROUND: Mucormycosis is a kind of rare opportunistic fungal disease and the incidence of which has gradually increased. Disseminated mucormycosis (DM) is a life-threatening infection that mostly occurs in immunocompromised patients. The lung and brain are usually involved in disseminated mucormycosis, and other sites are scare. We report the first case of disseminated mucormycosis whose infection sites included lung, skin, liver, vertebra, and spinal cord that ensued after a right lung pneumonectomy in an immunocompetent patient. CASE PRESENTATION: A 20-year-old female underwent a right lung pneumonectomy for "lung cancer" presented with an intermittent fever for two years. A computed tomography (CT) scan showed an enclosed outstanding mass in the right chest wall. The patient also suffered from lower limb numbness and weakness, difficulty walking, and dysuria. Medical examination showed superficial feeling of the abdominal wall was decreased from the T7 and T8 level; muscle strength for both lower limbs was decreased; muscle tension of both lower limbs was also diminished. A biopsy through the right chest wall mass and thoracic mass by fistula of chest wall showed broad nonseptate hyphae with right-angle branching, consistent with mucormycosis. With titration of amphotericin B and its lipid complex, the patient recovered. CONCLUSIONS: Our case showed an unusual clinical presentation of disseminated mucormycosisin an immunocompetent patient.

Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation.

Infection with Burkholderia pseudomallei causes melioidosis, a disease with a high mortality rate (20% in Australia and 40% in Southeast Asia). Neurological melioidosis is particularly prevalent in northern Australian patients and involves brain stem infection, which can progress to the spinal cord; however, the route by which the bacteria invade the central nervous system (CNS) is unknown. We have previously demonstrated that B. pseudomallei can infect the olfactory and trigeminal nerves within the nasal cavity following intranasal inoculation. As the trigeminal nerve projects into the brain stem, we investigated whether the bacteria could continue along this nerve to penetrate the CNS. After intranasal inoculation of mice, B. pseudomallei caused low-level localized infection within the nasal cavity epithelium, prior to invasion of the trigeminal nerve in small numbers. B. pseudomallei rapidly invaded the trigeminal nerve and crossed the astrocytic barrier to enter the brain stem within 24 h and then rapidly progressed over 2,000 µm into the spinal cord. To rule out that the bacteria used a hematogenous route, we used a capsule-deficient mutant of B. pseudomallei that does not survive in the blood and found that it also entered the CNS via the trigeminal nerve. This suggests that the primary route of entry is via the nerves that innervate the nasal cavity. We found that actin-mediated motility could facilitate initial infection of the olfactory epithelium. Thus, we have demonstrated that B. pseudomallei can rapidly infect the brain and spinal cord via the trigeminal nerve branches that innervate the nasal cavity.