Infections of the Spine and Spinal Cord.

PURPOSE OF REVIEW: Infections of the spine and spinal cord are associated with a high risk of morbidity and mortality and, therefore, require prompt clinical recognition, efficient diagnostic evaluation, and interdisciplinary treatment. This article reviews the pathophysiology, epidemiology, clinical manifestations, diagnosis, and treatment of infections of the spine and spinal cord to help practicing clinicians recognize, evaluate, and manage patients with such infections. RECENT FINDINGS: Aging of the population, increasing use of immunosuppressive medications, and other factors have contributed to increasing rates of spinal infections. Although the most common agents responsible for spinal infections remain bacteria and viruses, fungal infections occur in individuals who are immunocompromised, and parasitic infections are common in endemic regions, but patterns are in evolution with migration and climate change. Recent outbreaks of acute flaccid myelitis in children have been associated with enteroviruses A71 and D68. SUMMARY: Infections of the spine and spinal cord can be challenging to diagnose, requiring a thorough history and neurologic examination, laboratory studies of serum and CSF, neuroimaging (particularly MRI), and, in some instances, biopsy, to establish a diagnosis and treatment regimen. Interdisciplinary management including collaboration with experts in internal medicine, infectious disease, and neurosurgery is important to improve clinical outcomes.

Acute flaccid myelitis and enterovirus D68: lessons from the past and present.

Acute flaccid myelitis is characterized by the combination of acute flaccid paralysis and a spinal cord lesion largely restricted to the gray matter on magnetic resonance imaging. The term acute flaccid myelitis was introduced in 2014 after the upsurge of pediatric cases in the USA with enterovirus D68 infection. Since then, an increasing number of cases have been reported worldwide. Whereas the terminology is new, the clinical syndrome has been recognized in the past in association with several other neurotropic viruses such as poliovirus.Conclusion: This review presents the current knowledge on acute flaccid myelitis with respect to the clinical presentation and its differential diagnosis with Guillain-Barré syndrome and acute transverse myelitis. We also discuss the association with enterovirus D68 and the presumed pathophysiological mechanism of this infection causing anterior horn cell damage. Sharing clinical knowledge and insights from basic research is needed to make progress in diagnosis, treatment, and prevention of this new polio-like disease. What is Known: • Acute flaccid myelitis (AFM) is a polio-like condition characterized by rapid progressive asymmetric weakness, together with specific findings on MRI • AFM has been related to different viral agents, but recent outbreaks are predominantly associated with enterovirus D68. What is New: • Improving knowledge on AFM must increase early recognition and adequate diagnostic procedures by clinicians. • The increasing incidence of AFM urges cooperation between pediatricians, neurologists, and microbiologists for the development of treatment and preventive options.

Acute Flaccid Myelitis Among Children - Washington, September-November 2016.

In October 2016, Seattle Children's Hospital notified the Washington State Department of Health (DOH) and CDC of a cluster of acute onset of limb weakness in children aged ≤14 years. All patients had distinctive spinal lesions largely restricted to gray matter detected by magnetic resonance imaging (MRI), consistent with acute flaccid myelitis (AFM). On November 3, DOH issued a health advisory to local health jurisdictions requesting that health care providers report similar cases. By January 24, 2017, DOH and CDC had confirmed 10 cases of AFM and excluded two suspected cases among residents of Washington during September-November 2016. Upper respiratory tract, stool, rectal, serum, buccal, and cerebrospinal fluid (CSF) specimens were tested for multiple pathogens. Hypothesis-generating interviews were conducted with patients or their parents to determine commonalities between cases. No common etiology or source of exposure was identified. Polymerase chain reaction (PCR) testing detected enterovirus D68 (EV-D68) in nasopharyngeal swabs of two patients, one of whom also tested positive for adenovirus by PCR, and detected enterovirus A71 (EV-A71) in the stool of a third patient. Mycoplasma spp. immunoglobulin M (IgM) titer was elevated in two patients, but both had upper respiratory swabs that tested negative for Mycoplasma spp. by PCR. Clinicians should maintain vigilance for AFM and report cases as soon as possible to state or local health departments.

Aumento inusual de casos de mielitis en un hospital pediátrico en Argentina / Unusual increase of cases of myelitis in a pediatric hospital in Argentina

Introducción: La asociación entre enterovirus D68 y cuadros de mielitis aguda fláccida ha sido descrita en Estados Unidos, en 2014. Desde ese año, se han reportado casos esporádicamente en Canadá y Europa. Se describe, en este estudio, una serie de casos con mielitis aguda fláccida en el Hospital de Pediatría "Prof. Dr. Juan P. Garrahan" en Buenos Aires, Argentina, en 2016. Métodos: Estudio descriptivo, retrospectivo. Se incluyeron todos los pacientes internados desde el 1/04/2016 al 1/07/2016 con mielitis fláccida aguda con lesiones en la médula espinal que comprometieran la sustancia gris en la resonancia magnética nuclear. Se procesaron, para la búsqueda etiológica, muestras de secreciones nasofaríngeas, hisopados de materia fecal y líquido cefalorraquídeo. Resultados: Se incluyeron 10 pacientes. La mediana de edad fue 4 años (rango de 3 meses a 5 años). Ocho pacientes tuvieron una enfermedad febril autolimitada antes del inicio de los síntomas neurológicos. Los hallazgos neurológicos fueron debilidad fláccida de, al menos, un miembro, cervicoplejia (n= 2) y parálisis facial (n= 2). Todos los pacientes presentaron lesiones longitudinales en la médula espinal, con compromiso de sustancia gris, predominantemente, en el asta anterior. En todos los casos, se realizó una punción lumbar. En 7 pacientes, se observó pleocitosis. En cuatro niños, se identificó enterovirus D68 en secreciones nasofaríngeas y, en uno, se identificó el enterovirusD68 en el líquido cefalorraquídeo. Todos los pacientes persistieron con déficits neurológicos al momento del alta. Conclusiones: Se reporta el primer brote de mielitis aguda fláccida asociada a enterovirusD68 en Argentina. La vigilancia epidemiológica activa permitirá conocer la verdadera incidencia, epidemiología y etiología de esta enfermedad.

Introduction: The association between enterovirus D68 and acute flaccid myelitis was first described in the United States in 2014. Since then, sporadic cases have been reported in Canada and Europe. This study describes a series of cases of acute flaccid myelitis at Hospital de Pediatría "Prof. Dr. Juan P. Garrahan," in Buenos Aires, Argentina, during 2016. Methods: Descriptive, retrospective study. All patients with acute flaccid myelitis and lesions in the spinal cord involving the gray matter, as observed in the magnetic resonance imaging (MRI) scan, hospitalized from 04/01/2016 to 07/01/2016, were included in the study. Samples of nasopharyngeal secretions, fecal swabs and cerebrospinal fluid were collected and processed to look for the causative agent. Results: Ten patients were included. The median age was 4 years old (range from 3 months to 5 years old). Eight patients had a self-limiting febrile condition before the onset of neurological symptoms. Neurological findings were flaccid weakness in, at least, one limb, cervical paralysis (n= 2) and facial paralysis (n= 2). All patients had longitudinal lesions in the spinal cord, with gray matter involvement, mainly in the anterior horn. In all cases, a lumbar puncture (spinal tap) was performed. Pleocytosis was observed in 7 patients. In four children, enterovirus D68 was identified in nasopharyngeal secretions, and in one, it was detected in the cerebrospinal fluid. Neurological deficit persisted in all patients at the time of discharge. Conclusions: The first outbreak of acute flaccid myelitis associated to enterovirus D68 is reported in Argentina. Active epidemiological surveillance will help to determine the true incidence, epidemiology and etiology of this disease.

Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) encephalitis/myelitis is now a well-known complication after allogeneic stem cell transplantation (allo-HSCT), particularly after cord blood transplantation (CBT). In this study, we evaluated the risk factors of HHV-6 encephalitis/myelitis. METHODS: We evaluated 253 patients who received allo-HSCT from 2007 to 2015 at our institute. HHV-6 encephalitis/myelitis was defined as HHV-6 DNA detection in the cerebrospinal fluid or peripheral blood by polymerase chain reaction in the presence of typical manifestations without other concurrent condition that led to the manifestations. RESULTS: HHV-6 encephalitis/myelitis occurred in 11 patients (4.5%) (9 encephalitis, 3.7%; 2 myelitis, 0.8%). Multivariate analysis showed that CBT, mycophenolate mofetil (MMF) for graft-versus-host disease prophylaxis, history of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and engraftment syndrome (ES) were significantly associated with incidence of HHV-6 encephalitis/myelitis (P=.025, P=.017, P=.017, and P=.014, respectively). CONCLUSION: Although it has been shown that CBT, ES, and history of allo-HSCT are risk factors for HHV-6 encephalitis/myelitis, our study demonstrated MMF is also a risk factor for the disease.

Etiological, clinical, and radiological features of longitudinally extensive myelopathy in Chinese patients.

Longitudinally extensive myelopathy (LEM) is a rare spinal syndrome, and was mostly assessed in western populations. In order to investigate the etiological, clinical, and radiological features of LEM in Chinese patients, we retrospectively analyzed eighty-nine (40 men and 49 women, median age 45.9±15.7years) patients with LEM hospitalized in China-Japan Friendship Hospital. LEM comprised autoimmune inflammatory myelitis (n=53), metabolic and compressive disorders (n=13), vascular diseases (n=10), neoplastic diseases (n=7), infectious diseases (n=4), and syringomyelia (n=2). Neuromyelitis optica spectrum disorders (NMOSD) was the most common cause of transverse myelopathy identified in LEM (38/89 [42.7%]) characterized by intractable vomiting and hiccups and painful tonic spasms. Subacute combined degeneration and anterior spinal artery syndrome accounted for the largest non-transverse LEM, which selectively affected the spinal dorsal and/or lateral columns and the spinal anterior region, respectively. Radicular pain was common in anterior spinal artery syndrome. Postrema (n=15, 39.5%) and cervical (n=31, 81.6%) lesions were significantly increased in NMOSD versus non-NMOSD (n=7, 13.7% and n=34, 66.7%, respectively, p<0.05]. Axial T2-weighted MRI indicated that 46 (51.7%) patients exhibited complete lesions; 43 (48.3%) patients exhibited non-transverse lesions, mainly unilateral or symmetrical tract lesions. Twenty-four (51.1%) LEM patients exhibited distinct gadolinium contrast enhancement. In this Chinese cohort, LEM was primarily attributed to NMOSD. While the etiological distribution in the non-NMOSD group was different from western populations, clinical and imaging features may facilitate a differential diagnosis.

A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study.

BACKGROUND: Enterovirus D68 was implicated in a widespread outbreak of severe respiratory illness across the USA in 2014 and has also been reported sporadically in patients with acute flaccid myelitis. We aimed to investigate the association between enterovirus D68 infection and acute flaccid myelitis during the 2014 enterovirus D68 respiratory outbreak in the USA. METHODS: Patients with acute flaccid myelitis who presented to two hospitals in Colorado and California, USA, between Nov 24, 2013, and Oct 11, 2014, were included in the study. Additional cases identified from Jan 1, 2012, to Oct 4, 2014, via statewide surveillance were provided by the California Department of Public Health. We investigated the cause of these cases by metagenomic next-generation sequencing, viral genome recovery, and enterovirus D68 phylogenetic analysis. We compared patients with acute flaccid myelitis who were positive for enterovirus D68 with those with acute flaccid myelitis but negative for enterovirus D68 using the two-tailed Fisher's exact test, two-sample unpaired t test, and Mann-Whitney U test. FINDINGS: 48 patients were included: 25 with acute flaccid myelitis, two with enterovirus-associated encephalitis, five with enterovirus-D68-associated upper respiratory illness, and 16 with aseptic meningitis or encephalitis who tested positive for enterovirus. Enterovirus D68 was detected in respiratory secretions from seven (64%) of 11 patients comprising two temporally and geographically linked acute flaccid myelitis clusters at the height of the 2014 outbreak, and from 12 (48%) of 25 patients with acute flaccid myelitis overall. Phylogenetic analysis revealed that all enterovirus D68 sequences associated with acute flaccid myelitis grouped into a clade B1 strain that emerged in 2010. Of six coding polymorphisms in the clade B1 enterovirus D68 polyprotein, five were present in neuropathogenic poliovirus or enterovirus D70, or both. One child with acute flaccid myelitis and a sibling with only upper respiratory illness were both infected by identical enterovirus D68 strains. Enterovirus D68 viraemia was identified in a child experiencing acute neurological progression of his paralytic illness. Deep metagenomic sequencing of cerebrospinal fluid from 14 patients with acute flaccid myelitis did not reveal evidence of an alternative infectious cause to enterovirus D68. INTERPRETATION: These findings strengthen the putative association between enterovirus D68 and acute flaccid myelitis and the contention that acute flaccid myelitis is a rare yet severe clinical manifestation of enterovirus D68 infection in susceptible hosts. FUNDING: National Institutes of Health, University of California, Abbott Laboratories, and the Centers for Disease Control and Prevention.

[History of the radiation damage in occupations].

In the year following Röntgen`s discovery of X-rays in 1895, approximately 60 cases of hand dermatitis and hair loss induced by radiation were reported. People using X-rays in their occupation, including X-ray tube manufacturers, physicians, and engineers, experienced chronic radiation dermatitis and were the first to be diagnosed with occupational radiation exposure. Reports of later appearing disorders, including skin cancer, suffered by doctors and engineers, were regarded as serious occupational diseases. In the 1910's, blood disorders, including leukemia, in people with occupational exposure to radiation came into focus. Dial painters applying radium to watches with a luminous dial clock face suffered osteomyelitis from about 1914. Other radiation damage reports include radiation death and carcinogenesis in the Chernobyl nuclear power plant accident in 1986, and radiation death in the Tokai-mura JCO accident in 1999. The details of radiation damage in the Fukushima Daiichi Nuclear Power Plant in 2011 have not yet been reported, but must be followed in the future.

An analysis of cervical non-infectious inflammatory myelitis risk factors.

BACKGROUND: Non-infectious inflammatory myelitis or non-infectious myelitis (NIM) is an inflammatory condition that occurs following an immune response in the central nervous system (CNS). In cases of spinal disc degeneration, multiple factors converge to cause pathologic changes in disc structure. To date, no studies have examined the potential relationship between disc degeneration and NIM. OBJECTIVES: To investigate the relationship between cervical NIM and cervical disc degeneration. METHODS: Magnetic resonance imaging (MRI) was used to examine 85 patients with cervical NIM. Peripheral levels of the pro-inflammatory cytokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were also measured. Non-infectious myelitis occurrence rates and TNF-alpha and IL-6 levels were compared between patients with cervical disc degeneration and a control group. The relationship between cervical NIM and cervical disc degeneration was analyzed with logistic regression and a receiver operating characteristic (ROC) curve. RESULTS: Magnetic resonance imaging showed that 78.8% of patients with myelitis exhibited disc degeneration compared to only 18.9% of the control group. Moreover, IL-6 and TNF-alpha levels in patients with NIM were significantly higher than those in the control group; levels of these inflammatory cytokines were even higher in NIM patients with cervical disc degeneration than in those without. CONCLUSIONS: Our results suggest that patients with cervical NIM have a higher incidence of cervical disc degeneration, indicating that cervical disc degeneration is likely a possible risk factor in cervical NIM progression. Future quantitative studies are required to confirm this observation.

[Clinical diversity of HAM/TSP].

HTLV-I is a human retrovirus and causes adult T cell leukemia and several inflammatory diseases such as HAM/TSP. The infection occurs via HTLV-I-infected cells and the main transmission rout is mother-to-child infection via breast-feeding. In Japan, total numbers of HTLV-I carriers and HAM/TSP patients are recently estimated to be 1.08 million and 3,600, respectively, which exhibit no reduction in numbers. Although the main lesion is in the thoracic cord of patients with HAM/TSP, the inflammatory regions characterized by mononuclear cells infiltration are disseminated throughout the central nervous system (CNS). The patients show higher proviral load compared to the carries and are frequently complicated with HTLV-I-associated inflammatory diseases in other organs, including uveitis, bronchoalveolitis, arthritis, and Sjögren syndrome. Pathologically, HTLV-I-infected lymphocytes and HTLV-I-specific cytotoxic T lymphocytes infiltrate the CNS from the peripheral blood and induce an inflammation without HTLV-I infection of CNS resident cells, leading to bystander damage in the resident cells. Inhibition of mother-to-child infection via breast-feeding is most important to prevent HTLV-I spread and a treatment to eliminate HTLV-I-infected cells should urgently be established.

High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation.

Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB.

Neural damage associated with atopic diathesis: a nationwide survey in Japan.

BACKGROUND: We previously reported the occurrence of myelitis in patients with atopic disorders (atopic myelitis [AM]). To uncover the spectrum of neural damage associated with atopy, we conducted a cross-sectional nationwide survey of AM and atopy-related peripheral neuritis (APN), including Churg-Strauss syndrome (CSS), in individuals with atopic diathesis. METHOD: Cases with AM diagnosed between 1996 and 2006 and cases with APN between 2000 and 2006 were collected from all over Japan. Detailed data on 109 patients with AM and 133 patients with APN were collated. RESULTS: Patients with APN showed a preponderance of women, higher age at onset, and greater eosinophil counts than patients with AM. Patients with AM most commonly showed cervical cord involvement, whereas patients with APN preferentially exhibited mononeuritis multiplex predominantly affecting the lower limbs. Among patients with AM, motor weakness and muscle atrophy were significantly more frequent in those with bronchial asthma than in those with other atopic disorders. Patients with APN who met the criteria for CSS showed a higher age at onset, higher frequencies of systemic organ involvement, and greater disability than those who did not. Abnormalities suggesting peripheral nervous system involvement were seen in 25.7% of patients with AM, whereas 18.8% of patients with APN had abnormalities indicating CNS involvement. Multiple logistic regression analyses revealed that atopic dermatitis increased the risk of myelitis, whereas high age at onset and bronchial asthma decreased that risk. CONCLUSIONS: Atopy-related neural inflammation multifocally affects CNS and peripheral nervous system tissues. Both preceding atopic disorders and age seem to influence the distribution of neural damage.

Meningomyelitis in dogs: a retrospective review of 28 cases (1999 to 2007).

OBJECTIVES: To characterise dogs with meningomyelitis and to compare signalment, body temperature and vaccination status to a representative control group. METHODS: Dogs with meningomyelitis were identified retrospectively. Signalment, history, vaccination status, body temperature, severity of neurological dysfunction (modified Frankel score), diagnostic procedures, aetiology, survival to discharge and long-term survival were analysed. RESULTS: Affected dogs were younger (P<0.05) and more frequently hound or toy breeds (P<0.05) when compared with controls. Hound and toy breed dogs less than or equal to three years of age had a 13 times higher odds of meningomyelitis compared with other breeds (P<0.001). General proprioceptive ataxia, limb paresis and paraspinal hyperaesthesia were the most common clinical signs. Meningomyelitis of unknown aetiology and granulomatous meningomyelitis were the most common diagnoses. The median time to death or continued follow-up in dogs alive at discharge was 213 days. Meningomyelitis resulted in death or euthanasia in 14 of 28 dogs. Clinical signs improved or resolved in seven of 28 dogs. CLINICAL SIGNIFICANCE: Meningomyelitis is a differential diagnosis for dogs with clinical signs of myelopathy. Young dogs and toy or hound breeds seem to be predisposed. Clinical signs of meningomyelitis improve or resolve in some dogs.

Patterns of in vitro lymphoproliferative responses among HTLV-1-infected subjects: upregulation by HTLV-1 during HIV-1 co-infection.

The present study evaluated the in vitro response to different mitogens and a candidin antigen (CMA) in Human T-cell lymphotropic virus type 1 (HTLV-1) and co-infected HIV-1/HTLV-1 patients, to identify if this co-infection may modify the spontaneous lymph proliferative response. Peripheral blood mononuclear cells from 72 healthy seronegative controls, 75 asymptomatic HTLV-1-infected carriers, 42 HAM/TSP cases, 33 solely HIV-1-infected subjects and 24 HIV-1/HTLV-1 patients were assayed in the presence and absence of mitogens (PHA, PWM and OKT3) and CMA. The HAM/TSP group had the highest proliferation rate at 3 and 6 days after culture. HAM/TSP cases showed decreased response to PHA, compared with asymptomatic HTLV-1 subjects, and most important, the co-infected HIV-1/HTLV-1 cases presented a similar response to HTLV-1-infected subjects after 3 days of culture. The singles HIV-1-infected group had decreased in vitro response. It appears that during co-infection, the HTLV-1 regulatory proteins overwhelm the action of HIV-1 regulatory proteins.

Meningoencefalite e polioencefalomalacia causadas por Herpesvírus bovino-5 no estado do Pará / Meningoencephalitis and polioencephalomalacia caused by bovine herpesvirus-5 in the state of Pará, northern Brazil

O presente trabalho relata quatro casos de meningoencefalite por BHV-5 em quatro municípios no estado do Pará afetando bovinos de 1-2 anos, criados extensivamente. Três casos ocorreram de forma isolada e em um caso foram atingidos 3 animais do rebanho. Os principais sinais clínicos observados foram incoordenação, depressão acentuada, cegueira, decúbito lateral, opistótono e morte. O curso clínico foi de 3-4 dias. Macroscopicamente observaram-se áreas amolecidas, amareladas e cavitações no córtex cerebral. Microscopicamente observaram-se poliencefalomalacia no córtex cerebral, tálamo e núcleos da base, encefalite e meningite não supurativa e corpúsculos de inclusão intranucleares eosinofílicos em astrócitos. O diagnóstico foi realizado com base nos achados histológicos característicos.

Myasthenia gravis and hypothyroidism in a dog with meningomyelitis.

A 12-year-old, spayed female miniature poodle was evaluated because of a 4-day history of paraparesis, dysuria, and tenesmus. Neurological assessment suggested peripheral nervous system dysfunction, predominantly pelvic limb weakness with a possible concurrent sixth lumbar (L(6)) to second sacral (S(2)) myelopathy. Further studies supported the diagnoses of myasthenia gravis, hypothyroidism, and meningomyelitis. To the authors' knowledge, this is the first reported case of concurrent myasthenia gravis and meningomyelitis in the dog. It was unclear whether the identified conditions evolved from a shared etiopathogenesis or were merely coincidental.