Bacterial Infections

Bacterial meningitis involving the spinal meninges are more common than spinal parenchymal infections and may be due to hematogenic spread of microorganisms or direct spread from an infectious source or may occur following surgery, trauma, and other manipulations. On the other hand, myelitis is a rare manifestation or occurrence of bacterial infections. Most bacterial myelitis also involves the paraspinal soft tissues and/or the vertebrae. Most common bacterial pathogens for myelitis and spinal meningitis and their pathologic features are described below.

Streptococcus pneumoniae , Neisseria meningitidis , Haemophilus influenza , and Listeria monocytogenes are among the most common causes of meningitis in children as well as adults. In the neonatal period, group B Streptococci , Escherichia coli , and, in adults, gram-negative bacilli can be added to this list. These organisms more commonly involve the cranial meninges. In addition, many other species can be isolated from spinal meninges. Common and uncommon pathogens are also reported as the cause of abscess and meningitis following surgery or trauma to the spinal cord. Bacterial meningitis, especially streptococcal meningitides, can also be seen in the setting of immune deficiency, such as human immunodeficiency virus (HIV)/AIDS. Diabetes mellitus, surgical procedures, malignancies such as multiple myeloma, and liver disease are among the conditions that constitute risk factors for the development of meningitis. Inflammatory conditions, such as collagen vascular diseases or inflammatory bowel diseases, can also predispose to myelomeningitis and/or spinal cord abscesses.

Histologically, the acute meningitides are characterized by an intense infiltration of polymorphonuclear leukocytes admixed with necrotic debris constituting the purulent material. Rarely, lymphocytes, macrophages, and plasma cells may also be observed. Special stains are most helpful in the acute inflammatory phase for the identification of intracellular or extracellular bacteria. Gram stain and its modifications are most useful in this phase when the neutrophilic infiltration is prominent.

Chronic meningitis can be caused by several bacterial pathogens that include Mycobacteria spp, Treponema pallidum , Borrelia burgdorferii , Brucella abortus , L monocytogenes , Rickettsia spp, Chlamydia , and Bartonella henselae .

Detection and identification of bacteria in tissues can often be performed using routine Gram stains followed by microbiological tests or cultures. In some circumstances, tissue recognition even with special stains may not be possible and serologic testing, wherever available, can be useful in diagnosis. Serologic or DNA testing for brucella, listeria, rickettsia, and other bacterial species can be used if there is sufficiently high suspicion clinically.

Tuberculosis incidence appears to be on the increase in some developed and developing countries, and there is an expanding number of mycobacterial species showing resistance to standard antibiotic treatment. Tuberculous meningitis or myelitis is often a secondary extension from pulmonary or other primary sites. One of the most common forms of myelopathy associated with tuberculosis is the tuberculous spondylitis, otherwise known as the Pott disease. The infection results in an abscess formation, compressing the spinal cord, and occasionally causing obstruction of the anterior spinal artery. Occasionally, granulomatous inflammation associated with tuberculosis involves spinal meninges and parenchyma without bony involvement. Histologically, the destruction is due to well-formed granulomata with necrosis (ie, caseating granuloma) and multinucleated giant cells. The infectious process can involve any tissue type, including spinal cord parenchyma, meninges, disc and cartilage, soft tissue, and bone. Tissue diagnosis of tuberculosis can be made with the acid-fast stains such as Ziehl-Nielsen, Fite, Ellis-Zabrowarny, or the Kinyoun method or using the fluorescence auramine-rhodamine staining technique. In addition, polymerase chain reaction (PCR)-based detection techniques for various mycobacteria species can also be applied in both fresh and formalin-fixed paraffin-embedded tissues.

T pallidum causing syphilis can involve the meninges and the spinal cord parenchyma as well as brain parenchyma. Approximately 5% of all patients with syphilis develop neural involvement in the form of meningitis or meningomyelitis. Tabes dorsalis had been historically the most common presentation of in the spinal cord and is characterized by incoordination, pain, anesthesias, and visceral trophic abnormalities. Before effective antibiotic treatment, Tabes dorsalis had been one of the more common presentations of neurosyphilis and seemed to be the only manifestation of neurosyphilis that was been markedly reduced during the antibiotic era. Histologically, there is often inflammation within the leptomeninges and either atrophy or parenchymal destruction of the spinal cord. Tabes dorsalis is associated with demyelination of the posterior columns along with reactive gliosis. There is often thickening of the vessels, and meninges and the nerve tissue within the posterior nerve roots are often replaced by fibrosis and reactive changes. Meningomyelitis is often characterized by lymphoplasmacytic inflammation, dense fibrosis, and scattered granulomata with giant cells. Occasionally, there is clear necrotizing vasculitis with prominent perivascular inflammation. A gumma is a well-circumscribed mass defined macroscopically and is a massive necrotizing granulomatous reaction composed of giant cells, epithelioid macrophages, and lymphoplasmacytic infiltrates. Gumma is most often localized to the meninges but can also involve the parenchyma. The dura is often markedly thickened near the gummae. Detection of Treponema species can be performed with the Dieterle stain, but the yield is not often satisfactory. Therefore, in suspected cases, serologic testing such as rapid plasma reagin and the antibody test (FTA-ABS [fluorescent treponemal antibody absorption]), immobilization reaction can be used to confirm the infectious agent. In recent years, PCR-based methods are preferred over standard serologic testing.

B burgdorferi is the causative agent for Lyme disease and is transmitted often through ticks, most commonly in the northeastern United States, Wisconsin, and Michigan as well as the forested regions in California and Oregon. The clinical features can be quite variable, and their description is beyond the scope of this article; the reader is referred to more comprehensive review of the subject. Typically, there is cerebrospinal fluid (CSF) pleocytosis with normal glucose and protein levels. CSF can be used for Western blot detection of antibodies or PCR detection of Borrelia DNA. Histologically, the spinal cord parenchyma and meninges can be affected and show lymphoplasmacytic infiltrates, microglial nodules, and astrocytosis. Nerve roots may show scarring, gliosis, and chronic inflammatory infiltrates. Nevertheless, spinal cord involvement in Lyme disease is extremely rare and may be in the form of acute transverse or posterior myelitis. There is no useful special stain for the detection of borrelia in tissues, and serologic testing is not often specific, which necessitates detection by Western blotting.

Other chronic infectious agents listed above often demonstrate nonspecific pathologic features, and their identification often relies on the level of suspicion for the agent and the availability of special stains, serologic, or molecular testing.

Mycoplasma pneumoniae is a common bacterial pathogen associated with respiratory infections and can occasionally cause infectious myelitis. Myelitis due to mycoplasma is extremely rare compared with infection in other sites and constitutes one of the most severe central nervous system (CNS) complications associated with this organism. In addition, many studies suggested an immune-mediated mechanism leading to acute transverse myelitis because of systemic mycoplasma infection or mycoplasma encephalitis. Mycoplasma myelitis can have a wide range of clinical presentations, and the use of highly sensitive molecular diagnostic tests in the serum or the CSF may help to clearly define the cause. Histologic sampling (ie, an open biopsy) is often not needed and, when performed, typically demonstrates nonspecific inflammatory changes. Histologic diagnosis of mycoplasma is often not possible, and serologic methods have yielded variable results, making PCR-based detection the method of choice.

Other bacterial myelitides include common and uncommon pathogens such as bartonella , rickettsiae , and chlamydia species.

Fungal Infections

Although fungal infections involving the spinal cord or the meninges are rare, they have become more common in the HIV/AIDS era because of opportunistic agents such as Candida , Aspergillus , and Zygomycetes . Other fungal organisms such as Cryptococcus, Coccidioides, Blastomyces , and Histoplasma can primarily infect the spinal cord and cause myelitis or meningomyelitis as well as localized abscesses. Most of the organisms in this group, such as coccidioidomycosis, cryptococccosis, aspergillosis, and blastomycosis, cause granulomatous inflammation. In most fungal infections, there is CSF pleocytosis, and cultures and serologic studies from CSF are better initial attempts at identifying the organism before biopsy. In tissue samples, H&E stains may reveal the organisms such as Candida or Aspergillus , but others such as Histoplasma or Cryptococci may be elusive and require PAS stain or silver stains, such as Gomori methenamine silver (GMS) or immunohistochemistry. Most fungal organisms can be readily identified using special stains and will not require further analysis if appropriate tissue is obtained. For some fungal organisms, identification of the species using microbiological methods is indicated.

Aspergillus species often cause myelitis or meningomyelitis in the spinal cord through hematogenous spread and are typically angioinvasive, causing vasculitis or vascular occlusion. Immune suppression such as HIV/AIDs, transplantation, or malignancies is a predisposing factor, and intracranial involvement with Aspergillus is equally prevalent. Histologically, there is suppurative inflammation and often destruction of the vascular elastic lamina, vasculitis, and/or thrombosis. Abscess formation can be seen and typical granulomas form. The organism has septate hyphae that branch out in acute angles.

Cryptococci are encapsulated spherical yeastlike fungi causing granulomatous inflammation and are often associated with immune suppression. The fungus reaches the spinal cord hematogenous dissemination. Histologically, the fungi cause granulomatous inflammation and abscess formation particularly along the meninges. The organism is a small, round, budding yeast surrounded by a thick capsule and is easily identified by GMS, India ink, mucicarmine, or PAS stains.

Coccidioides are endemic in semiarid regions in the world, such as southwestern United States and certain regions of the South American continent. Meningitis due to coccidioidomycosis is often in the setting of immune suppression leading to myelomeningitis and abscesses along the spinal cord. The endospores are contained in large (20–60 μn) thick spherules that can be recognized on H&E stains; however, endospores are best identified on GMS and PAS stains. Inflammation is often accompanied by vasculitis and/or luminal occlusion of affected blood vessels. The granulomatous disease is often similar to tuberculous meningitis and abscess with well-formed granulomata containing the microorganisms.

Candida species are common throughout the world and are often opportunistic, causing significant pathologic abnormality in the setting of reduced immunity or immune suppression. The organismisthe most common fungus associated with hospital-borne infections. Spinal and meningeal involvement often follows hematogenous dissemination, but they are distinctly rare and much less common than cerebral involvement. Histologically, the organisms form pseudohyphae and true hyphae and are visible on H&E stains. However, most fungal stains such as GMS and PAS highlight both the pseudohyphae and the hyphae. The inflammation is often composed of microabscesses and acute and chronic inflammatory cells.

Histoplasma species are more common around river valleys, but are seen almost everywhere in the world, and the infection is often through inhalation. Dissemination and spinal involvement often occur in the setting of immune deficiency and often manifest as a meningeal inflammation. The organism is rather small and is typically contained within the macrophages. Identification often requires special stains such as GMS and PAS. There is often a necrotizing chronic inflammation containing lymphocytes, plasma cells, macrophages, and giant cells.

Parasitic Infections

Myelitis and myelopathy can be caused by several parasitic organisms, but the incidence of such lesions is distinctly low. Typically, spinal cord involvement with parasitic infections is seen in tropical regions with poor sanitary conditions. However, with the increase of global travel and transactions, many such cases are also seen in the developed countries. Echinococcus species released from the canine tapeworm can cause spinal cysts or destructive paraspinal lesions leading to spinal cord compression; spinal involvement by cysticercosis caused by Taenia solium is seen in a minority of patients infected with this parasite in the tropics, but the brain is by far the most preferred site for cysticercosis. Finally, in patients with HIV/AIDS, toxoplasmosis can cause spinal abscesses and necrotizing myelitis. The reader is referred to more comprehensive reviews for a more detailed discussion of the parasitic infections of the CNS. Identification of most parasitic infections usually requires well-sampled tissue and a simple H&E stain. Occasionally, such as in toxoplasmosis, identification may require immunohistochemical stains or serologic methods.

Viral Infections

Numerous viruses can involve the spinal cord and cause myelitis or myelopathy. Most often, viral organisms are associated with an acute myelitis, but many also cause a chronic infection that progresses like noninfectious chronic myelopathies. Viral myelitis can be either gray matter poliomyelitis or a white matter transverse/longitudinal myelitis. A comprehensive review of all the viruses associated with myelitis is beyond the scope of this article; however, some of the critical species associated with myelitis are mentioned.

Herpesviruses , HSV, varicella zoster virus (VZV), and CMV have been reported to cause significant myelitis. VZV myelitis and typically radiculitis and myeloradiculitis have been well-recognized for a long time and are often the result of reactivation of the virus that remains latent within the dorsal ganglia as well as the sacral ganglia ; this occurs in individuals with diminished immune capacity or with frank immunosuppression, and the myelitis sometimes coexists with genital lesions. Histologic examination is often unnecessary, but rare samples obtained for other purposes demonstrate a variable amount of acute and chronic inflammatory cells with focal necrosis; intranuclear inclusions, known as Cowdry type A inclusions, are seen in glial, neuronal, and endothelial cells and can be detected serologically, histologically, or ultrastructurally. HSV-2 can cause radiculitis or myelitis in rare instances and is often accompanied by infection elsewhere. There may be coagulative necrosis of the spinal cord parenchyma and chronic inflammatory infiltrates within the leptomeninges, especially in immunosuppressed patients. Likewise, CMV has been known to cause transverse myelitis as a secondary site of involvement following primary infection. Immunosuppression is the hallmark for all cases of myelitis caused by herpesviruses.

Enteroviruses , including polioviruses, cause myelitis, and until recently, polioviruses were the classic cause of acute flaccid paralysis. The virus had been nearly eradicated from the world because of an aggressive vaccination program by the World Health Organization (WHO). Both inactivated (Salk) and active (Sabin) vaccines have been used effectively to virtually reduce the incidence to near zero. However, several factors have prevented children in many countries from getting the vaccine. Recently, based on the advice of the International Health Regulations Emergency Committee and its expert advisors, the WHO declared that the situation related to the international spread of wild poliovirus constitutes a Public Health Emergency of International Concern. Histologically, poliovirus is associated with a low level of inflammatory infiltrate and loss of anterior neuron cells in the spinal cord. Other motor nuclei in the pons and medulla may also be affected. In the acute phase, there may be intense inflammation composed of neutrophils and lymphocytes, particularly involving the leptomeninges and the gray matter. The inflammation converts to a chronic inflammatory infiltrate composed of lymphocytes and macrophages with microscopic hemorrhages and neuronophagia. In the chronic phase, the inflammation subsides and there is loss of neurons, decrease of tissue, and atrophy in the anterior nerve roots. There are numerous enterovirus species that can present in atypical forms as aseptic meningitis, and molecular analyses in such cases may be necessary to identify the causative agent.

Lentiviridae are a group of retroviruses (lenti for slow) that deliver RNA into the host cell and can have long incubation periods. These viruses also have the ability to infect nondividing cells. The HIV is the most notorious species in this family. HIV/AIDS is currently accepted as the term that represents the entire range of pathologic processes and the clinical manifestation of HIV infection in humans. Transmission is typically via contact with contaminated blood, sexual intercourse, pregnancy, and transfusions. Spinal cord disease associated with HIV infection includes a long list of secondary pathogens in addition to direct infection by the virus. HIV-associated vacuolar myelopathy had been one of the most common spinal cord pathologic abnormalities during the HIV/AIDS epidemic. Vacuolar myelopathy has been assumed to occur in the setting of advanced immunosuppression, and the incidence has declined with the use of effective multiple drug regimens. The histologic features of HIV-associated vacuolar myelopathy are often characterized by loss of myelin and spongy degeneration involving the lateral and posterior columns. The white matter has a vacuolar appearance with scattered macrophages and rare lymphocytic cells. Inflammation is typically very sparse and rare perivascular multinucleated giant cells can be seen. Because there is no correlation between the severity and location of vacular myelopathy with the HIV burden, mechanisms other than direct viral cytopathic effect have been suggested.

Detection of viral infections can rarely be done using light microscopic stains and often require ultrastructural analysis of the tissue using electron microscopy (EM). Analysis of tissues using EM requires special fixation and processing, so tissue must be specifically submitted for ultrastructural evaluation. In many cases, sampling of the tissue is critical in correct identification. Recently, more effective and faster techniques using either single-probe or multiplex PCR-based techniques have been quite successful in the identification of viral pathogens. These techniques not only are effective for the diagnosis of common viruses but also greatly improve the ability to detect emerging viral infections. Recent studies using next-generation sequencing seem quite promising in the identification of elusive pathogens.