Infectious Myelopathies REVIEW ARTICLE


By Anita M. Fletcher, MD; Shamik Bhattacharyya, MD, FAAN C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
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ABSTRACT
OBJECTIVE: Infectious myelopathy of any stage and etiology carries the
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potential for significant morbidity and mortality. This article details the
clinical presentation, risk factors, and key diagnostic components of
infectious myelopathies with the goal of improving the recognition of these
disorders and guiding subsequent management.

LATEST DEVELOPMENTS: Despite our era of advanced multimodal imaging and

laboratory diagnostic technology, a causative organism often remains
unidentified in suspected infectious and parainfectious myelopathy cases.
To improve diagnostic capability, newer technologies such as CITE AS:
metagenomics are being harnessed to develop diagnostic assays with a CONTINUUM (MINNEAP MINN)
2024;30(1, SPINAL CORD
greater breadth of data from each specimen and improvements in DISORDERS):133–159.
infection identification. Conventional assays have been optimized for
improved sensitivity and specificity. Address correspondence to
Dr Anita M. Fletcher, 265 E
Rollins St, Ste 600, Orlando, FL
ESSENTIAL POINTS: Prompt recognition and treatment of infectious 32804, [email protected].
myelopathy decreases morbidity and mortality. The key diagnostic tools
RELATIONSHIP DISCLOSURE:
include serologies, CSF analysis, and imaging; however clinical
Dr Fletcher reports no
presentation, epidemiologic risk factors, and history of recent illness are disclosure. Dr Bhattacharyya
all vital to making the proper diagnosis because current laboratory and has received personal
compensation in the range of
imaging modalities are often inconclusive. The cornerstone of $500 to $4999 for serving as a
recommended treatment is targeted antimicrobials with appropriate consultant for Alexion
immune modulation, surgical intervention, supportive care, and Pharmaceuticals, Inc, and as a
second opinion for Teladoc
interdisciplinary involvement, all of which further improve outcomes for Health, Inc, and in the range of
patients with infectious myelopathy. $5000 to $9999 for serving as
an editor, associate editor, or
editorial advisory board
member for the American
Academy of Neurology, and
INTRODUCTION publishing royalties from a

M
publication relating to health
yelopathy is defined as dysfunction of the spinal cord. Spinal care. The institution of Dr
cord dysfunction caused by inflammation is termed myelitis. Bhattacharyya has received
Clinical manifestations of dysfunction depend on the anatomic research support from Alexion
Pharmaceuticals, Inc, the
lesion location and extent. Clinical symptoms or syndromes National Institutes of Health,
that present concurrently with infection are termed and UCB S.A.
parainfectious whereas symptoms appearing after infection are termed
UNLABELED USE OF
postinfectious. The temporal relationship between the manifestation of PRODUCTS/INVESTIGATIONAL
constitutional symptoms and spinal dysfunction plays a key role in diagnosis. USE DISCLOSURE:
Drs Fletcher and
Bacteria, viruses, and fungi may cause myelopathy either by direct infection of Bhattacharyya report no
the spinal cord or secondarily by several possible mechanisms including spinal disclosure.
cord compression from vertebral body fracture, epidural abscess with cord
compression, inflammatory vasculitis of spinal arteries and veins, arachnoiditis © 2024 American Academy
with subsequent syringomyelia and cord tethering, and immune response to of Neurology.

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 INFECTIOUS MYELOPATHIES

infection with secondary spinal cord injury.1 Distinguishing which of these

pathologic mechanisms is causing clinical symptoms is difficult in individual
cases and often results in the use of antimicrobial and immunomodulatory
therapies simultaneously along with spinal surgical intervention for
compressive lesions.
To determine the cause of infectious myelopathy, the clinical presentation,
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radiologic evaluation, serology, and CSF analysis are used in conjunction with
medical and social histories. Social risk factors, travel to or origin in endemic
regions, and professional and recreational history are important to early
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differential diagnosis development, which serves to both avoid unnecessary

testing and, conversely, identify investigations for uncommon organisms.
Infectious myelopathies are seen in both pediatric and adult patients. Some
myelopathies, such as enterovirus D68, which is associated with acute flaccid
myelitis, manifest more commonly in pediatric patients. It is important to
remember that not all cases have a characteristic imaging pattern or even
abnormal imaging, nor can all organisms be identified with conventional
laboratory techniques such as polymerase chain reaction (PCR) or culture. Basic
immunologic assays may lack sensitivity. Many newer assays are now available
commercially but remain costly, and some are unavailable outside of academic
medical centers, limiting their use in acute and resource-limited settings.
The following discussion includes clinical presentation, risk factors, and key
components of imaging and laboratory evaluation. Recommended treatments such
as antimicrobials, immune modulation, intervention, and innovative treatments
(where appropriate) are reviewed; however, most treatments are not based on
rigorous trials in specific myelopathies. Newer technologies to improve diagnoses
and outcomes for patients with infectious myelopathy are also discussed.

BACTERIAL MYELOPATHIES
Bacterial infections can lead to vertebral, epidural, intradural extramedullary,
and intramedullary infections. Bacterial infections of the spinal column typically
occur from hematogenous spread. Direct regional spread from adjacent soft
tissue infections or after invasive spinal procedures can also occur. Infection of
the vertebral column usually causes spondylodiscitis (simultaneous infection of
the intervertebral disk and vertebral body) and much less commonly isolated
vertebral body osteomyelitis. The most common causative organism is
Staphylococcus aureus although other pathogens such as Escherichia coli infection
following urinary tract instrumentation can also be found in susceptible hosts.
Patients typically present with localized pain, which is exacerbated by vertebral
body percussion.2 Progression of infection subsequently causes nerve root
irritation (radiculopathy) or spinal cord dysfunction from either epidural abscess
formation or compression of the vertebral canal from vertebral body fracture.
Fever is present in less than 50% of cases, but erythrocyte sedimentation rates
and C-reactive protein levels are elevated in 80% of cases.3 For diagnosis,
maintaining clinical suspicion is key, and assessment of risk factors including
progressive back pain in older adults, history of cancer or immunosuppression,
recent surgical intervention, diabetes, and IV drug use help triage risk. Patients
with these risk factors for infection should have spinal MRI with gadolinium
contrast. MRI sequences should include T2-weighted, T1-weighted, and short tau
inversion recovery (STIR) imaging. Gradient echo sequences identify bleeding
and calcifications, and diffusion-weighted image (DWI) sequences help

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 characterize abscesses, infarcts, and tumors. Postcontrast imaging shows KEY POINTS
inflammation in acute lesions as seen in FIGURE 6-1.4,5 Infectious Diseases Society
● Staphylococcus aureus is
of America (IDSA) guidelines suggest delaying treatment in cases of vertebral the most common cause of
osteomyelitis until biopsy culture results are available if a patient is stable; pyogenic vertebral
however, treatment should be initiated as early as possible in cases of instability osteomyelitis.
and include IV antibiotics with broad coverage (TABLE 6-15,6).1 Blood and urine
● Risk factors for vertebral
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cultures should be obtained in all cases. Treatment is typically tailored to

osteomyelitis include older
microbial tissue culture from biopsy. age, history of cancer or
Intramedullary lesions are rare and can result from bacterial seeding of the immunosuppression,
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spinal cord through hematogenous spread or direct infection. Compared with diabetes, recent surgical
spondylodiscitis and epidural abscess, intramedullary spinal cord abscess is much intervention, and IV drug
use.
rarer. Patients typically present with rapidly progressive weakness with imaging
showing an enlarging spinal cord lesion usually with gadolinium enhancement on ● Neurosyphilis can present
MRI. Bacterial causes include Mycobacterium tuberculosis, Streptococcus species, with meningitis, stroke, gait
and Staphylococcus species. Treatment is typically tailored to the causative and balance dysfunction,
loss of vibratory sensation,
organism, and the majority require surgical drainage. and bladder dysfunction.

Spirochetes
Treponema pallidum is a bacterium of the Spirochaetaceae order, which causes
syphilis and which can lead to neurosyphilis when the central nervous system
(CNS) is affected. The spinal cord can be affected within the first year or very

FIGURE 6-1
Sagittal MRI of an intramedullary spinal cord abscess. A, A T2-weighted image shows a long
segment of spinal cord swelling and hyperintensity adjacent to the intramedullary abscess. B,
A fat-suppressed T1-weighted image shows a contrast-enhancing lesion with a nonenhancing
center. C, A diffusion-weighted image of an intramedullary abscess is hyperintense on MRI;
this image, inverted for clarity, demonstrates a dark area indicating the pyogenic abscess.
The intramedullary spinal cord abscess is indicated by the arrow in each image.
Reprinted with permission from Yokota H and Tali ET, Neuroimaging Clin N Am.5 © 2023 Elsevier Inc.

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 INFECTIOUS MYELOPATHIES

late in the disease course, up to 50 years after infection. Myelopathy in the early
stages of infection (meningovascular syphilis) may present with meningeal signs
including headache and meningismus, as well as sudden-onset paraparesis
associated with vasculitis. Other neurologic symptoms such as hearing deficits,
otosyphilis, or panuveitis (ocular syphilis) can also develop. Meningovascular
syphilis is characterized by meningitis and strokes that result from endarteritis of
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blood vessels supplying the leptomeninges, brain, and spinal cord.

Meningovascular syphilis can be seen after 1 month; however, it is more often
encountered in the late stage.7
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Late neurologic manifestations typically occur more than 5 years after

infection (tertiary syphilis). Tabes dorsalis affects the dorsal spinal cord tracts
and dorsal root ganglion and is characterized by radicular or severe, lancinating
abdominal pain along with sensory gait ataxia and bladder dysfunction. Loss of
vibratory sensation and gait and balance dysfunction are common features of this
presentation (CASE 6-1).8
In all stages of syphilis, serum treponemal tests are used to initially screen for
syphilis; common available options include fluorescent treponemal assay
antibody absorption, T. pallidum particle agglutination, or enzyme-linked
immunosorbent assay (ELISA). The nontreponemal tests of Venereal Disease
Research Laboratory (VDRL) or rapid plasma reagin can inform active infection
but can be negative especially in later stages of syphilis. After a confirmatory

TABLE 6-1 MRI Recommendations for Evaluation of Possible Bacterial Myelopathy

or Myelitisa

MRI series Image findings Enhancement

Spondylitis T2-weighted image (T2WI), short tau Variable Possible

inversion recovery (STIR), gradient
echo, gadolinium indicated

Pyogenic Fat-suppressed T2WI, T1-weighted Hyperintense on T2WI in pyogenic Yes, in acute lesions,
spondylitis image (T1WI), diffusion-weighted infections of the soft tissue and surrounding soft tissue or
image (DWI), gadolinium indicated intervertebral disk; abscess intervertebral enhancement
narrowing the intervertebral space may be seen

Arachnoiditis T2WI and T1WI, gadolinium indicated Thickening of cord surface, nerve Yes, late infections may
roots, or cauda equina; pockets of show enhancement in the
CSF or pus may be seen in later spinal cord
stages of infection

Meningitis T2WI and T1WI, gadolinium indicated Thickening of cord surface, nerve Yes, late infections may
roots, or cauda equina show enhancement in the
spinal cord

Empyema T1WI and T2WI, gadolinium indicated Long-segment lesions, meningeal Yes, meningeal
thickening enhancement (central
empyema does not enhance)

Intramedullary T2WI and T1WI, gadolinium indicated Varies based on stage of Varies; mild to none in
abscess development myelitis stage; ringlike once
abscess forms

a
Data from Yokota H and Tali ET, Neuroimaging Clin N Am5 and Modic MT et al, Radiol.6

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 serum screening test, neurologic involvement is tested for by CSF analysis.
Typical CSF findings in neurosyphilis include lymphocytic pleocytosis and
elevated protein levels. A finding of positive CSF VDRL essentially secures the
diagnosis of neurosyphilis (>99% specificity) but has low sensitivity.
Neurosyphilis is diagnosed in the setting of neurologic dysfunction consistent
with neurosyphilis, positive serum testing for syphilis, and CSF demonstration of
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inflammation (with or without positive CSF VDRL).9,10 Treatment should be

given to all patients diagnosed with neurosyphilis and typically consists of 4 g
penicillin G administered intravenously every 4 hours for 10 to 14 days. Steroids
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can be used to ameliorate symptoms related to a Jarisch-Herxheimer reaction.11

The Jarisch-Herxheimer reaction most commonly manifests as chills,
temperature fluctuations, and skin eruptions following antibiotic treatment in
patients with spirochete infections. The reaction mechanism is thought to be
mediated by leukocytes. Steroids may be administered prior to antibiotic
administration to decrease or ameliorate the reaction.12

Lyme Disease
Borrelia burgdorferi, a bacterium in the Spirochaetaceae order, causes Lyme
disease in the United States. In Europe, Borrelia afzelii and Borrelia garinii

A 62-year-old man presented with 3 years of progressive walking CASE 6-1

difficulty. He was falling more often, typically in a forward direction, and
felt that it was due to an inability to lift his legs high, and he noted that his
shoes wore out quickly. He denied loss of muscle mass or cramps but
endorsed stiffness and frequent episodes of abdominal pain. Erectile
dysfunction began about 3 years before presentation, and significant
constipation began 2 years before presentation. He did not have visual
problems, word-finding difficulties, memory or personality changes,
vivid or active dreams, hearing changes, facial weakness, dysarthria,
dysphagia, or dizziness on standing. He had a normal cranial nerve
examination, a spastic paraparesis with 4+/5 strength in his hip flexors,
knee extension, and foot dorsiflexion bilaterally. His biceps brachii
reflexes were normal, and patellar reflexes were brisk. He had
diminished proprioception and cutaneous pain perception in his feet.
Laboratory diagnostic evaluation was negative for human
immunodeficiency virus (HIV) and human T-cell lymphotropic virus type 1
(HTLV-1). Serum treponemal antibody and Venereal Disease Research
Laboratory (VDRL) were positive, and VDRL was positive in CSF.
Prednisone was administered 3 days before initiation of a 14-day course
of IV penicillin.

This case exemplifies chronic syphilitic myelopathy with posterior and COMMENT
lateral column involvement. The patient had weakness, spasticity, and pain
and proprioception deficit in his lower extremities. This case demonstrates
that syphilis can present as a myelopathy across a broad span of time after
initial infection.

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 INFECTIOUS MYELOPATHIES

infections are also associated with Lyme disease. Lyme disease is a tick-borne
infection and is transmitted by the Ixodes scapularis tick found throughout the
United States and Ixodes pacificus tick found on the Pacific Coast of the United
States. Erythema migrans, a targetoid cutaneous lesion, is the characteristic
initial manifestation of Lyme disease. Lyme disease affects the nervous system in
up to 15% of cases; this is termed neuroborreliosis.12 The typical neurologic
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manifestations are cranial neuropathies (most commonly facial nerve palsy),

meningitis, and radiculoneuritis (painful radiculitis typically in multiple
dermatomes).13 Very rarely, Lyme disease has been reported to cause isolated
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myelitis usually with evidence of robust CSF inflammation. Lesions on MRI have
been seen in the cervical, thoracic, and lumbar spinal cord.14 Patients with
evidence of neurologic disease consistent with Lyme disease and plausible
exposure to ticks infected with B. burgdorferi should be tested for Lyme disease.
The Centers for Disease Control and Prevention recommends a two-step
serologic testing procedure for the diagnosis of Lyme disease as follows:
1 Total IgM/IgG immunoassay to screen for B. burgdorferi

A If negative, the patient does not have Lyme disease

B If positive or borderline, proceed to step 2

2 There are two separate approaches:

A Standard two-tiered testing: perform Western blot for both IgM and IgG
antibodies. IgM immunoblot is considered positive if two of the following three
bands are present: 24 kDa (OspC), 39 kDa (BmpA), and 41 kDa (Fla). IgG
immunoblot is considered positive if 5 of the following 10 bands are present:
18 kDa, 21 kDa (OspC), 28 kDa, 30 kDa, 39 kDa (BmpA), 41 kDa (Fla), 45 kDa, 58 kDa
(not GroEL), 66 kDa, and 93 kDa15,16
B Modified two-tiered testing: second-tier IgG and IgM immunoassays. Positivity by
this second assay results in an overall positive test.

Patients with active neuroborreliosis demonstrate CSF pleocytosis. Borrelia

antibodies can be passively transferred from serum to CSF; thus, CSF antibodies
do not necessarily indicate a CNS infection. The CSF-to-serum antibody index
should be used to determine if intrathecal production of antibodies to Borrelia has
occurred. The antibody index is defined in the following equation:

anti-Borrelia IgG in CSF=anti-Borrelia IgG in serum

total IgG in CSF=total IgG in serum

The antibody index is considered positive when the result is greater than 1.3 to 1.5.
The algorithm in FIGURE 6-2 can be used to guide clinical decision making.13
In 2020, new clinical practice guidelines were released by the American
Academy of Neurology, IDSA, and American College of Rheumatology.17
Treatment for neuroborreliosis consists of IV ceftriaxone, cefotaxime, or
penicillin G or oral doxycycline. In cases involving the spinal cord, IV
ceftriaxone, cefotaxime, or penicillin G for 10 to 14 days is recommended.18

MYCOBACTERIUM TUBERCULOSIS. Tuberculosis (TB) is a worldwide pandemic

caused by the bacterium M. tuberculosis. An estimated 10.6 million people

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 KEY POINTS

● CSF Venereal Disease

Research Laboratory (VDRL)
has specificity greater than
99% but low sensitivity for
neurosyphilis.
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● Patients with positive

treponemal serology, CSF
inflammation, and
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symptoms of neurosyphilis
should receive treatment
with penicillin G.

● Patients with evidence of

neurologic disease
consistent with Lyme
disease and have had
plausible exposure to ticks
infected with Borrelia
burgdorferi should be
tested for Lyme disease.
FIGURE 6-2
An algorithm for Lyme disease treatment decisions based on the presence or absence of ● The serologic diagnosis of
erythema migrans, duration of symptoms, and results of Western blots for IgM and IgG if the Lyme disease includes
enzyme-linked immunosorbent assay (ELISA) is positive or borderline. standard or modified
Reprinted with permission from Halperin JJ, Continuum (Minneap Minn).4 © 2012 American Academy of two-tiered testing usually
Neurology. consisting of a screening
test followed by a
confirmatory test (either
Western blot or second
became ill with TB in 2021, which is equivalent to 134 cases per 100,000 people.19 immunoassay).
Among all TB cases, 6.7% were among people living with human
● Xpert MTB/RIF Ultra
immunodeficiency virus (HIV). The highest rates of TB infection in 2021 were in assay is assay recommended
Southeast Asia followed by Africa and the Western Pacific, with lower rates in by the World Health
the Eastern Mediterranean region, the Americas, and Europe. In contrast to the Organization for suspected
past 2 decades, the incidence of TB increased in 2021, which was attributed to M. tuberculosis.
fewer people seeking care during the COVID-19 pandemic.19
● Acute flaccid myelitis
Although TB frequently causes pulmonary disease, neurologic infection and occurs more often in
symptoms can occur without concurrent pulmonary symptoms. TB can cause children than adults and
varying CNS infectious syndromes including meningitis, masslike lesions presents with weakness,
(tuberculoma), myelitis, and spinal arachnoiditis. TB spreads to the nervous decreased muscle stretch
reflexes, and hypotonicity
system hematogenously and causes a focus of infection or tuberculoma (Rich after viral or gastrointestinal
focus). Rupture of this tubercle subsequently spreads the infection to the illness.
subarachnoid space, causing manifestations such as meningitis or spinal
arachnoiditis.20-22 Tuberculomas can occur throughout the CNS including the
spinal cord. TB can also cause myelopathy by progressive vertebral osteomyelitis
(Pott disease) and subsequent compromise of the spinal canal from kyphotic
vertebral deformity (gibbous deformity).
On MRI, tuberculomas are often isointense on T1-weighted imaging with rim
or homogeneous contrast enhancement and hypointense or hyperintense on
T2-weighted imaging (depending on the degree of necrosis). Intramedullary
tuberculomas are round on MRI, and extramedullary tuberculomas are often
elongated; however, DWI and enhancement patterns can vary based on stage
and progression of central necrosis.23 Patients with suspected TB in the CNS,

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 INFECTIOUS MYELOPATHIES

particularly TB meningitis, should have MRI protocols including precontrast

T1-weighted and T2-weighted sequences, DWI, and gradient echo.24 TB myelitis
typically appears as a longitudinally extensive T2-hyperintense lesion with
gadolinium T1 postcontrast enhancement of the lesion. Spinal meningeal
gadolinium enhancement frequently occurs, as well.
CSF testing is an important step in diagnosis. CSF analysis may demonstrate
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pleocytosis and hypoglycorrhachia. Although the definitive diagnostic test

remains culture for Mycobacteria, nucleic acid-based testing is an important part
of diagnostic strategy. Xpert MTB/RIF (Cepheid) and Xpert MTB/RIF Ultra
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(Cepheid) assays are rapid nucleic acid amplification tests for the detection of M.
tuberculosis. Xpert MTB/RIF can provide insight into rifampin resistance and is
recommended by the World Health Organization (WHO) for diagnosis of TB.
However, a 2021 Cochrane review of Xpert MTB/RIF and Xpert MTB/RIF Ultra
assays for extrapulmonary TB showed that Xpert MTB/RIF had a 71.1%
sensitivity and 96.9% specificity for mycobacterial detection. The Xpert
MTB/RIF Ultra assay showed 89.4% sensitivity and 91.2% specificity.25
Treatment of tuberculous spinal involvement typically is with rifampin,
pyrazinamide, isoniazid, and ethambutol for 2 months, followed by isoniazid and
rifampin for 7 to 10 months. Corticosteroids may be used in cases with a
significant inflammatory component.26

VIRAL MYELOPATHIES
Viruses can cause spinal cord injury from direct infection in addition to initiation
of secondary immune cascade contributing to further cellular damage or tissue
destruction. Viral myelopathies may lead to a range of clinical outcomes from
complete resolution of symptoms to permanent severe impairment.

Acute Flaccid Myelitis

Acute flaccid myelitis is a clinical syndrome that presents with flaccid limb
weakness following a viral infection. Neurologic examination in these patients
demonstrates weakness, decreased muscle stretch reflexes, and decreased tone in
the affected limbs. The disease has been associated with different pathogens such
as enteroviruses D68 and 71, poliovirus, and flaviviruses.
The antecedent infection in acute flaccid myelitis can be either an upper
respiratory illness or a gastrointestinal illness with preceding nausea, vomiting,
or diarrhea. Acute flaccid myelitis occurs more often in children; however, adults
can present with a similar picture. In 2021, the acute flaccid myelitis working
group published diagnostic criteria based on combined clinical presentation, MRI
findings, and CSF analysis.27 A definite diagnosis requires core clinical features,
MRI with spinal cord gray matter–predominant lesions or nerve root
enhancement, and CSF pleocytosis (CASE 6-2). A probable diagnosis requires
core clinical features and MRI findings, but CSF pleocytosis is not required. A
possible acute flaccid myelitis diagnosis requires mild clinical syndrome and MRI
findings. A classification of uncertain requires only core clinical features.27
Treatment options for acute flaccid myelitis have included the use of early IV
immunoglobulin (IVIg). Other immunomodulatory options are steroids and
plasma exchange, with IV steroids used in cases of spinal cord edema. There is a
theoretical risk of increased viral titer with steroids, as seen in preclinical models
of disease, so steroids must be used judiciously (TABLE 6-227). Prospective
controlled series for treatment outcomes are lacking in acute flaccid myelitis.

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 West Nile Virus
West Nile virus (WNV) is a neuroinvasive flavivirus transmitted by Culex
mosquito species and is most often seen in summer months. Originally, WNV
was found in Africa, the Middle East, Asia, and Australia and was not associated
with severe human disease. Neurologic manifestations of WNV infection were
first reported in the 1990s. Over the past 2 decades, WNV has circulated
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throughout North America, Mexico, the Caribbean, and South America. WNV
acts on the nervous system through direct infection and immune-mediated
mechanisms,28 and the factors that determine disease severity may reflect
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polymorphisms in key host genes. The majority of WNV infections are

asymptomatic or associated with self-limiting flulike febrile illnesses with full

A 15-year-old boy with anxiety, asthma, migraines, and attention deficit CASE 6-2
disorder presented with rapidly progressive lower extremity weakness.
One month before presentation, he felt weakness in his legs on waking and
when walking down the stairs. He had headache, myalgia in both legs, and
a fever to 39°C (102°F) before the onset of weakness. He recalled using the
handrails with stairs and difficulty when he stepped up on a curb. He had a
few falls, and his left leg became weaker more rapidly than the right. The
weakness persisted despite resolution of the flulike symptoms. In the
emergency department, whole-spine MRI showed a linear T2
hyperintensity in the gray matter from T11 to L1 and a possible lesion at T7;
no enhancement was seen, and the lumbar lesion was associated with
cord expansion. At his 6-week follow-up neurology visit, his left leg
weakness persisted, and his right leg was weak. EMG showed fibrillation
potentials with reduced recruitment of motor unit potentials in the lower
limbs, which was the worst in the left quadriceps muscles. Repeat MRI
showed improvement in his linear lumbar lesion, but enhancement of
multiple ventral nerve roots was seen. A lumbar puncture was performed,
and CSF analysis showed 8 white blood cells/mm3 and 730 red blood
cells/mm3 (79% lymphocytes, 17% neutrophils, 4% macrophages), protein
of 121 mg/dL, and glucose of 60 mg/dL. Enterovirus polymerase chain
reaction (PCR) was negative in the CSF, oligoclonal bands were absent,
and the myelin basic protein level was normal. His IgG index was elevated
at 0.77. A nasopharyngeal swab and stool test were negative for
enterovirus. Antibodies to West Nile virus were absent in his blood. He
followed up with neurologic-focused rehabilitation.

This case demonstrates clinical, imaging, and laboratory evidence that COMMENT
meets criteria for acute flaccid myelitis based on criteria set forth by the
acute flaccid myelitis working group: prodromal illness with fever that
preceded the weakness in his left leg with characteristic physical
examination findings, a linear lesion in the low thoracic cord on initial
imaging, ventral root enhancement on subsequent imaging, and CSF
pleocytosis. Early involvement of multidisciplinary rehabilitation teams is
important to optimizing outcomes.

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 INFECTIOUS MYELOPATHIES

TABLE 6-2 Diagnostic Criteria for Acute Flaccid Myelitisa,b

Diagnostic items Definite Probable Possible Uncertain

c
H1: acute onset of limb weakness Present Present Present Present
(period from onset to nadir: hours to
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10 days)

H2: prodromal fever or illnessd Presence is Presence is Presence is Present

supportive but supportive but supportive but not
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not required not required required

E1: weakness involving one or more Present Present Presentc Present

limbs, neck, face, or cranial nerves

E2: decreased muscle tone in at Present Present Presence is Present

least one weak limb supportive but not
required

E3: decreased or absent muscle Present Present Presence is Present

stretch reflexes in at least one weak supportive but not
limbe required

MRI: spinal cord lesion with Present Present Present Not done
predominant gray matter
involvement, with or without nerve
root enhancementf

CSF: pleocytosis (white cell Present Absent or not Presence is Presence is

count > 5 cells/mm3)g done supportive but not supportive but not
required or not done required or not done

Factors that might suggest an alternative diagnosis

1. Encephalopathy that cannot be explained by fever, illness, respiratory distress, metabolic abnormalities, or medications
2. Presence of sensory deficits on examinationh
3. Presence of lesions in supratentorial white matter or cortex, which should prompt consideration of acute disseminated
encephalomyelitis (ADEM), myelin oligodendrocyte glycoprotein (MOG)–antibody–associated disease, neuromyelitis optica
spectrum disorder, encephalomyelitis, and others
4. Absence of CSF pleocytosis, which should prompt consideration of Guillain-Barré syndrome, botulism, ischemic cord
lesions, and others
5. Positive serum aquaporin 4 antibody, which would exclude acute flaccid myelitis
6. Positive serum MOG antibody, which would suggest MOG-antibody–associated diseaseh

E = examination; H = history.
a
Modified with permission from Murphy OC, et al, Lancet.27 © 2021 Elsevier Ltd.
b
These criteria apply to the acute stage of the disease.
c
Subjective (H1) or objective (E1) weakness must be present in any of the limbs, neck, or cranial nerves.
d
Prodromal illness can include respiratory, gastrointestinal, or other symptoms of viral illness.
e
Normal or increased reflexes can be found in other limbs.
f
If the MRI obtained very early (within hours of neurologic onset) appears normal, repeat MRI after clinical evolution might show diagnostic
findings. MRI obtained at late stages (≥4 weeks) might be normal.
g
CSF may be normal at very early (hours) or late (≥4 weeks) stages of acute flaccid myelitis.
h
At present, there are no data describing the frequency of these features in patients with acute flaccid myelitis.

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 recovery.29 Neuroinvasive disease occurs in less than 1% of people infected and KEY POINTS
presents with meningitis, encephalitis, and parkinsonian features.
● West Nile virus IgM in
Myelitis develops in an estimated 5% to 10% of cases of WNV neuroinvasive serum can remain positive
disease and most often presents as an acute flaccid paralysis with weakness, for months to years. Paired
decreased reflexes, and possible bowel and bladder dysfunction.30 MRI may be acute and convalescent
normal or demonstrate T2 hyperintensity with or without contrast enhancement plasma IgM and IgG
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antibodies can be used to

in the ventral spinal cord or gray matter; longitudinally extensive myelitis has
establish acute infection.
also been reported. CSF analysis in affected patients demonstrates neutrophilic
pleocytosis with later lymphocytic pleocytosis. Viral replication in blood and CSF ● Neuroinvasive West Nile
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is brief and can occur before symptom onset, which renders WNV PCR less virus may present with
useful for a diagnosis with a low sensitivity of 25% to 30% despite a specificity of encephalitis, parkinsonian
features, and acute flaccid
100%. CSF IgM is more sensitive than CSF PCR. IgM does not normally cross the myelitis.
blood-brain barrier; therefore, a positive WNV IgM in the CSF indicates
intrathecal synthesis and is diagnostic of West Nile neuroinvasive disease. CSF ● Japanese encephalitis
IgM can remain positive for months to years and cannot be used to inform a virus causes an estimated
50,000 to 175,000
possible recent infection. Paired acute and convalescent plasma IgM and IgG symptomatic human
antibodies can be used to establish acute infection.31 Treatment for West Nile infections per year and is the
myelitis is primarily supportive. A randomized controlled trial did not show most common
efficacy for IVIg in WNV.32-34 vaccine-preventable cause
of encephalitis in Asia. Rare
cases of myelitis or acute
Japanese Encephalitis Virus flaccid myelitis have been
Japanese encephalitis virus, a flavivirus whose vector is Culex tritaeniorhynchus, reported in endemic areas.
causes human infection during rainy seasons in endemic areas of Asia and the
Western Pacific region. Japanese encephalitis virus causes an estimated 50,000 to ● In chikungunya-
associated myelopathy, MRI
175,000 symptomatic infections per year and is the most common vaccine- of the spinal cord shows
preventable cause of encephalitis in Asia.35 Rare cases of myelitis or acute flaccid multiple punctate and T2
myelitis have also been reported in endemic areas.36,37 The number of cases is longitudinal hyperintense
likely underreported because of limited access to laboratory resources to lesions with associated T1
contrast enhancement,
complete WHO diagnostic recommendations, which include testing for Japanese primarily in the peripheral
encephalitis virus–specific IgM antibody in a single sample of CSF or serum and regions of the spinal cord.
using an IgM-capture ELISA. A CSF sample is preferred. It is important to
remember that serum analysis can lead to false positives from a previous
infection or vaccination.38 Treatment for Japanese encephalitis virus myelopathy
is supportive. No antiviral medications have evidence of efficacy in Japanese
encephalitis virus myelopathy. A few case reports have described the use of
steroids and IVIg in affected patients.36,39

Chikungunya Virus
Chikungunya virus, an arbovirus found in Asia, Africa, Europe, and the
Americas, typically causes a self-limited syndrome of high fever, malaise,
arthralgias, and often skin rash. Chikungunya has been associated with
parainfectious and postinfectious presentation of meningoencephalitis, myelitis,
myelopathy, acute inflammatory demyelinating polyradiculoneuropathy
(AIDP), and acute disseminated encephalomyelitis (ADEM). Whether these
represent direct neurotropism or likely secondary immune response is unclear.
MRI of the spinal cord in affected patients shows multiple punctate and
longitudinal T2 hyperintense lesions with associated T1 contrast enhancement,
primarily in the peripheral regions of the spinal cord.40 In acute settings (the first
week of symptoms), chikungunya is diagnosed by reverse transcription PCR of
viral RNA from blood. After the first week, serologic testing by IgM and IgG is

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 INFECTIOUS MYELOPATHIES

more sensitive.41 With neurologic involvement, CSF typically shows evidence of

inflammation without necessarily showing direct evidence of chikungunya viral
products. Treatment is informed by expert opinion and typically includes
steroids, but relapsing neurologic dysfunction can occur.42

Human Immunodeficiency Virus (HIV)

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HIV is a retrovirus associated with myelopathy that can present early at the time
of seroconversion as acute myelitis or later in infection with a vacuolar
myelopathy. Opportunistic infections may occur with suboptimal HIV control
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(FIGURE 6-343), and HIV-related myelopathy may be seen after initiation of

combination antiretroviral therapy because of chronic immune dysregulation
(TABLE 6-3).44 Vacuolar myelopathy is the most widely recognized spinal cord
complication of HIV and typically affects patients with long-standing disease.
Patients typically present with progressive myelopathy causing spastic
paraparesis with significant sensory loss in the legs primarily affecting the dorsal
columns. The clinical features are similar to subacute combined degeneration as

FIGURE 6-3
Syphilitic myelitis in a 50-year-old man with human immunodeficiency virus (HIV). Sagittal
short tau inversion recovery (STIR) (A) and T2-weighted (B) noncontrast MRI of the spine
shows a longitudinally extensive central cord hyperintense lesion (A, B, arrows). Peripheral
striplike enhancement at the thoracic spinal cord surface is seen on T1-weighted imaging with
fat saturation with contrast (C); this image shows a candle-guttering appearance (C, arrows).
Reprinted with permission from Corrêa DG, et al, J Neuroradiol.43 © 2023 Elsevier Masson SAS.

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 Human Immunodeficiency Virus–associated Spinal Cord Diseases TABLE 6-3
Organized by Immune Statusa,b

Disease Prevalence Pathophysiology Key diagnostic tests Treatmentc

CD4+ count
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> 500 cells/mm3

Primary human Case HIV-mediated CSF HIV RNA, excluding Combination

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immunodeficiency virus reports immunotoxicity other diseases antiretroviral therapy

(HIV)–associated acute (cART)
myelitis

Immune-mediated Case Unknown MRI, CSF oligoclonal Corticosteroids

myelitis reports bands

HIV-associated motor Case Unknown MRI, electromyography IV immunoglobulin

neuron disease reports and nerve conduction (IVIg)
studies

CD4+ count
< 500 cells/mm3

HIV myelitis 8-10% by HIV-mediated CSF HIV RNA, excluding cART

pathology immunotoxicity other diseases

Vacuolar myelopathy 7-55% by Unknown Excluding other diseases Supportive

pathology

Primary central nervous Case Intramedullary or CSF cytology, biopsy of Steroids, radiation,
system lymphoma reports leptomeningeal spread mass lesion systemic
chemotherapy

Cytomegalovirus (CMV) 3-8% by Necrosis, small to medium CSF CMV polymerase IV ganciclovir with or
radiculomyelitis pathology vessel vasculitis chain reaction (PCR) without foscarnet

Herpes simplex virus Case Necrosis, small to medium CSF HSV PCR IV acyclovir
(HSV) sacral reports vessel vasculitis
radiculomyelitis

Varicella-zoster virus Case Necrosis, medium vessel CSF VZV PCR or VZV IV acyclovir
(VZV) myelitis reports vasculitis IgM/IgG

Spinal cord syphilisd Case Large vessel vasculitis, CSF Venereal Disease IV penicillin
reports meningomyelitis, gummas, Research Laboratory
tabes dorsalis

Spinal cord tuberculosis Case Vertebral compression, CSF acid-fast bacilli stain, First-line tuberculosis
reports paravertebral abscess, cultures or PCR, biopsy of antibiotics and
radiculomyelitis, mass lesion corticosteroids
tuberculomas

a
Reprinted with permission from Levin SN and Lyons JL, Handb Clin Neurol.44 © 2018 Elsevier B.V.
b
Fungal and parasitic infections not included in this table.
c
Treatment for all conditions includes cART. The therapies for myelitis and HIV-associated motor neuron disease are based on case reports.
d
May also occur with CD4+ count >500 cells/mm3.

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 INFECTIOUS MYELOPATHIES

caused by vitamin B12 deficiency, although vitamin levels are normal. The
pathophysiology of this disease is unclear. Pathologically, viral invasion by HIV is
typically absent, as is significant degree of inflammation. Treatment generally
consists of antiretroviral therapy combined with potential immune modulation
such as with IV immunoglobulin. Patients with HIV-associated vacuolar
myelopathy should also be tested for other infections such as syphilis, human
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T-cell lymphotropic virus type 1 (HTLV-1), and cytomegalovirus (CMV), as well

as noninfectious nutritional causes.
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Human T-Cell Lymphotropic Virus Type 1

HTLV-1 is a retrovirus that causes HTLV-1–associated myelopathy, also known
as tropical spastic paraparesis, a progressive myelopathy occurring in up to 3% of
people infected with HTLV-1.45 Approximately 20 million to 40 million people
are infected worldwide, and most infected individuals remain lifelong
asymptomatic carriers. Endemic areas of HTLV-1 infection include the
Caribbean, southern Japan, Central and South America, the Middle East,
southwest Pacific islands, and equatorial Africa.46 HTLV-1 is transmitted from
mother to child through breast milk, by sexual contact, and through infected
blood.47 The incidence is higher in women than men with onset reported most
often in the third or fourth decade of life. However, a 2020 report from Peru
characterized HTLV-1–associated myelopathy in children with a median age of
onset of 14 years.48
HTLV-1–associated myelopathy is characterized by higher HTLV-1 proviral
loads in blood and CSF (calculated as fraction of infected mononuclear cells)
compared with asymptomatic control values.49 In patients with HTLV-1–
associated myelopathy, the HTLV-1 proviral load is twofold or threefold higher
in CSF cells compared with peripheral blood mononuclear cells.50 Activated
immune cells and spontaneous lymphoproliferation of infected T cells are also
characteristic of HTLV and serve as a focus for possible therapeutic
intervention.51 HTLV-1–associated myelopathy includes considerable mononuclear
cell inflammation with lymphocytic perivascular cuffing, capillary proliferation,
demyelination, and reactive astrocytosis. In the early phase of disease, CD4+ and
CD8+ lymphocytes are seen in spinal cord inflammatory lesions with a shift to CD8+
lymphocyte predominance in chronic disease.52 Demyelination and axonal damage
affect the spinal cord most severely in the lateral columns with thoracic spinal cord
atrophy seen on MRI. However, in early disease, spinal cord imaging may be
normal, and atrophy is seen only later with disease progression.53,54
The most common presentation of HTLV-1–associated myelopathy starts with
lower extremity weakness with progression to spastic paraparesis and disability
within 2 years of onset, urinary retention, lumbar pain, and loss of vibratory
sensation with constipation and erectile dysfunction presenting later in the
disease course.55,56 Rapid progression of disease occurs in some cases, leading to
the use of assistive devices within 3 months of initial symptoms. FIGURE 6-4 shows
disease progression in HTLV-1–associated myelopathy. CASE 6-3 represents a
characteristic HTLV-1–associated myelopathy presentation. HTLV-1–associated
myelopathy diagnosis requires the clinical syndrome and an HTLV-1 antibody–
positive two-step immunoassay (ELISA for HTLV-1/2 followed by confirmation
of HTLV-1 with antibody banding with p19 or p24 encoded protein in
combination with banding for rgp21 or rgp46env on Western blot).57

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 A 45-year-old woman presented with 1 year of progressive gait difficulty, CASE 6-3
aching in the lower back and thighs, and urinary retention. Neurologic
examination showed normal upper extremity strength, sensation, and
reflexes with 4/5 strength in hip flexion, hyperreflexia in bilateral lower
extremities with sustained ankle clonus, and a mildly spastic gait. Her
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history included dengue fever as a child in Honduras and no family history

of similar conditions. MRI of her brain was normal. MRI of her cervical and
thoracic spine showed atrophy of the thoracic spinal cord (FIGURE 6-4).
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Complete blood cell counts and metabolic panel were normal; CD4+ and
CD8+ counts were normal; HIV and hepatitis C serologies were negative;
hepatitis B testing was positive for hepatitis B surface antibody only;
copper, vitamin B12, and vitamin E levels were normal; human T-cell
lymphotropic virus type 1 or 2 (HTLV 1/2) was positive on ELISA; and a
Western blot was positive for HTLV-1. Anti–aquaporin 4 antibodies were
negative. CSF analysis showed normal protein and glucose concentrations,
and paired oligoclonal bands were positive in CSF and serum.

FIGURE 6-4
Sagittal T1-weighted MRI of the cervical and thoracic spinal cord of the patient in CASE 6-3
who has human T-cell lymphotropic virus type 1 (HTLV-1)–associated myelopathy, also known
as tropical spastic paraparesis, 2 years after onset (A), 4 years after onset (B), and 6 years after
onset (C). The sequential imaging findings demonstrate progressive spinal cord atrophy.

This case exemplifies HTLV-1–associated myelopathy, also known as COMMENT

tropical spastic paraparesis. World Health Organization criteria for HTLV-1–
associated myelopathy were met through HTLV-1/2 ELISA with a
confirmatory line assay and the progressive nature of clinical presentation.
The patient’s earlier-onset urinary retention led to extensive urologic
evaluation that included ureteral stent placement; only later did the gait
disturbance manifest and lead the patient to seek a neurologic
consultation. Because modes of transmission include sexual contact and
vertical transmission, it is important to counsel patients regarding possible
asymptomatic carrier status in partners and children who received breast
milk for early nutrition.

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 INFECTIOUS MYELOPATHIES

There is no effective antiviral treatment for HTLV-1 infection. Observational

studies showed evidence for the use of high-dose methylprednisolone, 1 g IV for 3
to 5 days, for induction and low-dose oral prednisolone, 5 mg/d to 10 mg/d, as
maintenance therapy.58-61 A phase 2 randomized controlled trial that compared
placebo with prednisolone in rapid, slow, and very slow progressors showed
improvement in Osame Motor Disability Score values with 1 g/d IV
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methylprednisolone for 3 days and 0.5 mg/kg/d oral prednisolone for rapid
progressors.62 A consensus review by the International Retrovirology Association
stated there is insufficient evidence to recommend antiviral drugs and
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immunomodulators, specifically cyclosporin A and interferon alfa.63

Mogamulizumab is a humanized anti-CCR4 (chemokine receptor type 4)
monoclonal antibody that targets HTLV-1–infected CCR4+ T cells and has shown
promise in early phase trials, but further studies are required.64

Herpesviruses
Herpesviruses are large, enveloped, double-stranded DNA viruses. Eight
herpesviruses affect humans; herpes simplex virus 1 (HSV-1), herpes simplex
virus 2 (HSV-2), and varicella-zoster virus (VZV) are neuroinvasive and
establish lifelong latent infection in ganglia and can give rise to recurrent
reactivations responsible for significant morbidity and mortality.

HERPES SIMPLEX VIRUS. HSV-1 is acquired by oral mucosa infection and is the most
common cause of sporadic viral encephalitis worldwide.65 HSV-1 and HSV-2 may
both affect the spinal cord, typically manifesting as inflammatory myelitis.
HSV-2 is mainly responsible for meningoencephalitis in newborns and
meningitis in adults.66 HSV-2 myelitis can present as a mild syndrome with full
recovery, as a recurrent meningomyelitis, or as a devastating acute necrotizing
myelitis, especially in immunocompromised hosts. Most commonly, patients
have radiculomyelitis affecting the conus and lumbosacral dermatomes causing
clinical symptoms of urinary sphincteric dysfunction with pain, numbness, and
weakness in the legs. CSF usually shows lymphocytic pleocytosis but may be
neutrophilic very early in the disease. Detection of HSV-1 and HSV-2 DNA by
PCR is the gold standard method for diagnosing HSV infection of the CNS.
Estimates of sensitivity and specificity are unclear because some patients with
radiculomyelitis typical of HSV-2 infection may not show positive PCR results
but were not tested early in the disease course when PCR is most sensitive. MRI
may show spinal cord T2 hyperintensities with edema and contrast enhancement
of the cord and roots or smooth, linear enhancement of the cord surface and
cauda equina.67 Treatment for HSV-1 or HSV-2 CNS infection is 10 mg/kg IV
acyclovir every 8 hours for 14 to 21 days.

VARICELLA-ZOSTER VIRUS. The most common presentation of VZV is chickenpox

in children and zoster, or shingles, in adults. VZV has tropism for dorsal root
ganglia where the virus remains latent. VZV myelitis is rare and may be seen with
primary VZV infection but more often presents with reactivation of latent
virus.68 Patients can present with regional, dermatomal pain and acute or
subacute focal neurologic dysfunction including paraparesis and bladder
dysfunction. VZV myelitis has been associated with lesions throughout the spinal
cord and nerve roots and can present as meningitis, radiculitis, myelitis, and focal
vasculopathies. Myelitis is often preceded by painful cutaneous vesicular lesions

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 in a dermatomal pattern but can present at the same time as the cutaneous lesions KEY POINTS
or occasionally without any vesicular skin eruptions.69,70 Like HSV-2 and CMV,
● A diagnosis of human
VZV also can cause a syndrome of acute radiculomyelitis of the conus T-cell lymphotropic virus
(sometimes called Elsberg syndrome).70,71 VZV angiopathy is a rare complication type 1 (HTLV-1)–associated
that can result in spinal cord infarction. VZV PCR on CSF has limited sensitivity; myelopathy, also known as
therefore, testing for IgG antibodies in CSF is recommended. The CSF VZV tropical spastic paraparesis,
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requires positive HTLV-1/2

antibody index reveals intrathecal synthesis of VZV-specific IgG. The antibody ELISA and confirmatory
index is defined in the following equation: HTLV-1 Western blot.
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● Detection of herpes
anti-VZV IgG in CSF=anti-VZV IgG in serum
simplex virus 1 (HSV-1) and
total IgG in CSF=total IgG in serum herpes simplex virus 2 (HSV-
2) DNA by polymerase chain
reaction is the gold standard
CSF antibody index is considered elevated for values greater than 1.5. Treatment method for diagnosing HSV
can include IV acyclovir 10 mg/kg every 8 hours for 14 to 21 days, corticosteroids infection.
if cord edema is present, and symptomatic and supportive care.
● VZV myelopathy is not
always preceded by herpes
EPSTEIN-BARR VIRUS. Epstein-Barr virus (EBV) is a common virus with >80% zoster.
seropositivity in adults in the United States. EBV presents most commonly as
acute mononucleosis associated with pharyngitis, cervical lymphadenopathy, ● HSV-2, varicella-zoster
virus, and cytomegalovirus
fever, and malaise. CNS involvement includes encephalopathy, myelitis, and
(CMV) can present with a
myeloradiculitis, with presentations that include myelitis or longitudinally painful lumbosacral
extensive myelitis. MRI may show intramedullary, central T2 hyperintensity radiculitis and myelitis
with a longitudinally extensive or transverse pattern. CSF analysis usually shows known as Elsberg syndrome.
mononuclear pleocytosis. EBV DNA PCR is typically positive in the CSF; EBV
● VZV polymerase chain
IgM and IgG should be tested to show intrathecal production.72-75 reaction on CSF has low
sensitivity; therefore,
CYTOMEGALOVIRUS AND HUMAN HERPESVIRUS 6 AND 7. CMV, human herpes virus 6 testing for IgG antibodies in
(HHV-6), and human herpes virus 7 (HHV-7) myelopathy are rare and CSF is recommended. The
CSF VZV antibody index
associated with posttransplantation viral activation or immunocompromised reveals intrathecal synthesis
patients. CMV myelitis should be considered in patients with spinal cord of VZV-specific IgG.
dysfunction and HIV with CD4+ counts less than 100 cells/mm3. CMV can cause
lumbosacral polyradiculitis or myeloradiculitis76 or longitudinally extensive ● CMV myelitis should be
considered in patients with
myelitis.77 CMV myelitis can be treated with IV ganciclovir 5 mg/kg every
CD4+ counts less than 100
12 hours or a combination of ganciclovir and IV foscarnet 90 mg/kg every cells/mm3 and myelopathy.
12 hours. The duration of treatment varies. Newer antiviral drugs, including
letermovir and maribavir, were US Food and Drug Administration (FDA) ● Longitudinally extensive
approved for CMV infection, and adoptive T-cell therapies have shown promise myelitis is the most
frequently reported
in posttransplantation patients with CMV infection.71 myelopathy associated with
severe acute respiratory
Severe Acute Respiratory Syndrome Coronavirus 2 syndrome coronavirus 2
(SARS-CoV-2).
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly
transmissible and pathogenic coronavirus, a single-stranded RNA virus, that
caused the recent pandemic of acute respiratory disease, COVID-19.78 Clinical
series have reported that 33% to 73% of infected patients experienced neurologic
symptoms. Longitudinally extensive myelitis is the most frequently reported
myelopathy. It has been postulated that SARS-CoV-2–associated spinal cord
demyelination can be a para- or postinfectious process; this is partially based on a
variable time interval between exposure and onset of myelitis symptoms
and improvement with immune therapy.79 MRI may show lesions in both the

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 INFECTIOUS MYELOPATHIES

cervical and thoracic cord, with isolated lesions and diffuse demyelination
patterns seen. New-onset paraplegia with anterior horn lesions seen on MRI have
also been reported, reigniting questions about neurotropism and the
neuroinvasive potential of SARS-CoV-2. CSF may show an elevated protein
concentration and lymphocytic pleocytosis. Reverse transcription–PCR assays of
CSF samples are negative for SARS-CoV-2. Clinical series have described the use
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of IV corticosteroids, oral corticosteroids, plasma exchange, and IVIg in the

treatment of these patients.80,81
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FUNGAL MYELOPATHIES
Fungal infections occur more frequently in immunocompromised people. Fungal
infections may affect the spinal cord or nerve roots and can result in the
formation of abscesses or granulomas. CSF analysis characteristically shows an
elevated opening pressure and protein concentration with lymphocytic
pleocytosis and hypoglycorrhachia. Gram stain and culture may demonstrate the
fungi. Testing for fungus-specific antigens and antibodies in body fluids
including the CSF, serum, and urine and (1,3)-β-D-glucan assays should be part
of the diagnostic evaluation.72 Fungal myelopathy and myelitis usually present
with abnormal imaging.

Aspergillus
Myelitis is an uncommon manifestation of disseminated Aspergillus, an
angioinvasive mold. Aspergillus typically causes brain abscess with inflammatory
vasculopathy causing infarction. Aspergillus myelitis or myelopathy should be
considered in immunocompromised individuals who present with back pain and
spinal cord dysfunction. Symptoms can result from cord compression due to
granuloma formation or from direct fungal myelitis. Spinal cord infarction can
occur as well. Galactomannan antigen testing detects Aspergillus in
immunocompromised patients with serum and CSF sensitivity greater than 85%
and specificity greater than 95%.82 Piperacillin-tazobactam therapy, concomitant
bacterial infection, transfusion, and dialysis can result in a false positive. The
(1,3)-β-D-glucan antigen test is also positive for invasive aspergillosis but is not
specific for the diagnosis.82 Similar antifungal therapies can be used in adults and
pediatric patients; however, the dosing may be different and is not well
established in pediatrics.83 Current treatment recommendations for CNS
aspergillosis include voriconazole (oral or IV) with an IV load of voriconazole
6 mg/kg every 12 h for two doses followed by 4 mg/kg every 12 hours. The oral
loading dose is 400 mg every 12 hours for two doses, followed by 200 mg orally
every 12 hours. The therapy duration typically continues for several months,
depending on the clinical and radiologic response and ongoing
immunosuppression. In addition to antifungal therapy, immunosuppression
should be reduced or reversed whenever possible.83

Coccidioides
Coccidioidomycosis is caused by Coccidioides immitis and Coccidioides posadasii,
dimorphic fungi endemic to California and southwest United States, Mexico, and
Central America. Most cases are asymptomatic or manifest as a mild, self-
resolving respiratory infection, but 1% to 3% of cases disseminate to the skin,
bones, lymph nodes, or CNS.84 Meningitis is the most common CNS
manifestation. Rarely, myelitis, spondylitis, and spondylodiscitis have also been

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 reported. Patients typically present with back pain, sensory disturbance, KEY POINTS
weakness, and bladder dysfunction, reporting prior headache in some cases.
● CSF in patients with
Onset is usually insidious. Immunocompromised patients are more likely to have fungal infections
dissemination. Diagnosis typically requires demonstration of systemic characteristically shows an
coccidioidal infection by serology, testing of CSF, and usually MRI. CSF analysis elevated opening pressure
shows mixed or lymphocytic pleocytosis, hypoglycorrhachia, and elevated and protein concentration
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with lymphocytic
protein. More specific diagnosis requires culture or antibody testing for
pleocytosis and
complement fixing anticoccidioidal antibodies. Culture or PCR for coccidioides is hypoglycorrhachia.
insensitive and does not sufficiently exclude the diagnosis. CSF coccidioidal
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antigen testing supplements serologic testing and can improve sensitivity of ● Galactomannan antigen
diagnosis. MRI typically shows variable abnormalities. A 2022 MRI study showed testing detects Aspergillus
in immunocompromised
53% of infected patients had leptomeningeal enhancement, 53% had patients with serum and CSF
arachnoiditis, 23% had syringomyelia, 10% had cord signal abnormalities, and 7% sensitivity of 88% and
had osteomyelitis.85 Treatment recommendations include fluconazole at doses specificity of 96%.
ranging from 400 mg/d to 1200 mg/d and surgery in some cases.86 Piperacillin-tazobactam
therapy, concomitant
bacterial infection, blood
Histoplasma transfusion, and dialysis can
Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys. result in a false positive test.
Infection is most often asymptomatic but can present with pulmonary findings,
particularly in immunocompromised people. Subacute or chronic meningitis,
intramedullary brain and spinal cord lesions, stroke syndromes, or encephalitis
can be seen in 5% to 10% of cases with progressive disseminated histoplasmosis.
Diagnostic evaluation includes CSF culture, anti-Histoplasma antibodies in serum
and CSF, and Histoplasma antigen tests.87 Treatment with liposomal
amphotericin B followed by itraconazole for at least 1 year and until resolution of
CSF abnormalities, including Histoplasma antigen levels, is recommended;
however, this is based on moderate evidence.88

Cryptococcus
Cryptococcus neoformans, a neurotropic fungus, is an important opportunistic
infection that causes meningoencephalitis, radiculitis, and inflammatory
myelopathy. Spinal cord compression can also occur from a cryptococcoma,
which occurs more often with Cryptococcus gattii than C. neoformans. Spinal cord
dysfunction is much less frequent than meningoencephalitis. Patients can
present with headache, neck stiffness or pain, radicular pain, and focal deficits
dependent on anatomic location.89,90 Nearly half of patients who present with
cryptococcal meningitis are HIV positive.91 Cryptococcal-specific antigen in CSF
and serum is used for diagnosis. CSF typically demonstrates low glucose and
elevated protein concentrations and high IgG indices; the white blood cell count
in CSF may be normal.92 Treatment includes liposomal amphotericin B and
flucytosine with a careful immune-reconstitution strategy given the propensity
for immune reconstitution inflammatory syndrome (IRIS) in patients with
cryptococcal meningitis.93 In addition, elevated intracranial pressure in patients
with cryptococcus infection may require multiple lumbar punctures or
ventricular drainage for CSF decompression.

Candida
Candidiasis is the most frequent invasive fungal infection. Compared with
Candida spp. meningitis and microabscess, myelitis is rare but has been reported
in hematologic malignancies with neutropenia, HIV, postsurgical intervention,

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 INFECTIOUS MYELOPATHIES

diabetes, and CARD9 deficiency (caused by variations in the CARD9 gene). Focal
lesions or meningeal enhancement can be seen on MRI, and (1,3)-β-D-glucan is
positive in serum and CSF. A CSF Candida mannan antigen test should be
included in the diagnostic workup. Treatment is a combination of liposomal
amphotericin B and flucytosine followed by fluconazole, per IDSA guidelines.94,95
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PARASITIC MYELOPATHIES
Globally, parasitic infections are an important cause of myelopathy, especially
for space-occupying spinal cord lesions. Even in areas without endemic parasitic
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infections, thoughtful evaluation for spinal cord masses should include

assessment for exposure to the more common parasitic infections.

Neurocysticercosis
Neurocysticercosis is caused by Taenia solium, a tapeworm larva, and is the most
common parasitic infection of the CNS. Infection occurs when humans ingest
food contaminated with T. solium eggs. Cysticerci subsequently develop in
different tissue sites after ingestion. Taenia is endemic to Latin America,
sub-Saharan Africa, and large regions of Asia, including the Indian subcontinent,
most of southeast Asia, and China. Global travel contributes to the
neurocysticercosis cases in the United States.96 Neurocysticercosis occurs in the
brain parenchyma, spinal cord, and meninges. Spinal neurocysticercosis is rare,
occurring in only 3% of cases of neurocysticercosis and more commonly involve
the spinal subarachnoid space rather than the spinal cord.97 The most common
clinical presentations of spinal neurocysticercosis are focal motor deficits,
radicular pain, sensory deficits from spinal subarachnoid disease. With rarer
spinal cord involvement, subacute or chronic myelopathy develops.98 MRI is the
preferred imaging modality for cysticercosis of the spine.97 Leptomeningeal cysts
are seen on MRI as cystic lesions or areas of arachnoiditis, and intramedullary

FIGURE 6-5
Intramedullary cystic cysticercosis. Sagittal gadolinium-enhanced T1-weighted (A) and
T2-weighted (B) MRI shows an intramedullary cystic lesion located at the T3 to T4 level. The
lesion has a thick wall and contrast enhancement, which is associated with adjacent
vasogenic edema.
Reprinted with permission from Almeida C, et al, Neurology.113 © 2018 American Academy of Neurology.

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 cysticerci are rounded cysts. MRI may show internal scolex (as in FIGURE 6-5), but KEY POINTS
without the scolex, cysts could be mistaken for tumors.99 Pericystic edema and a
● The most common clinical
ringlike pattern of abnormal enhancement may also be seen on MRI.100 Serologic presentations of spinal
testing with enzyme-linked immunotransfer blot as a confirmatory test in neurocysticercosis are focal
patients with suspected neurocysticercosis is recommended. CSF may show an motor deficits, radicular
increased protein level and eosinophilia or mononuclear pleocytosis, although pain, and sensory deficits
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from spinal subarachnoid

eosinophilia is not always present. Albendazole is an option for therapy of
lesions. Myelopathy may
intramedullary spinal cord cysts in conjunction with corticosteroids.101 Although occur with rarer spinal cord
medical treatment had similar outcomes compared with surgery, a combined lesions.
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approach may be appropriate, and removal of intramedullary cysts and cysts in

the spinal subarachnoid space may be required in some cases.102 ● In patients with
neurocysticercosis, therapy
for intramedullary cysts and
Neuroschistosomiasis cysts in the spinal
Schistosomiasis is caused by Schistosoma japonicum, Schistosoma haematobium, subarachnoid space is
and Schistosoma mansoni in Asia, Sub-Saharan Africa, and Central and South surgical resection,
albendazole, and steroids
America, respectively. Risk factors include contact with contaminated water in when edema is present.
which larvae gain entry through skin penetration. Patients acutely present with
an itchy rash at the site of larval entry or a systemic hypersensitivity reaction ● In areas with endemic
following hematogenous spread. Neurologically, spinal cord spread is more schistosomiasis, up to 5% of
myelopathy cases have
common than spread to the brain. Up to 5% of myelopathy cases in endemic
been attributed to infection
areas, including acute myelitis and subacute myeloradiculopathy of the with this parasite.
lumbosacral region, have been attributed to schistosomiasis, associated most
with S. mansoni or S. haematobium.103 Patients can present with lumbar pain,
lower limb radicular pain, muscle weakness, sensory loss, and
bladder dysfunction.
Diagnosis typically begins with testing for systemic infection. In early
infection, schistosome eggs are typically sought in stool or urine samples.
Microscopic evaluation is highly dependent on available expertise and insensitive
in individuals with a low burden of disease. For individuals past the acute phase
of infection, systemic infection is established by serology and urine antigen
testing. CSF testing can show eosinophilia and may show positive antibody
testing. Patients are often treated empirically at this stage when there is a
compatible neurologic syndrome, supportive imaging, and evidence of systemic
disease. For atypical cases, biopsy is obtained to demonstrate infection.
Praziquantel and steroids are currently used for the treatment of
neuroschistosomiasis. Surgery may also be required in cases of spinal cord
compression from schistosomal lesions.104

Sparganosis
Sparganosis is caused by the Spirometra tapeworm and results from ingestion of
undercooked meat. Although most cases have been documented in Asia,
sparganosis has been seen globally. Most Spirometra infections are ocular or
subcutaneous, with rare cases in the brain and spinal cord. Reported cases
presented acutely or insidiously, with up to a 20-year latency period reported.105
The clinical presentation is dependent on the location in the spinal cord but
usually creates a space occupying lesion. MRI may show ring-enhancing lesions
and tubular linear enhancement (called tunnel sign) from migration of larvae.106
Eosinophilic pleocytosis may be present, and specific antisparganum antibodies
may be positive in CSF and serum. Surgical removal of the tapeworm serves as
the confirmation of the diagnosis and the treatment. The use of albendazole

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 INFECTIOUS MYELOPATHIES

15 mg/kg once a day, praziquantel 50 mg/kg once a day, and dexamethasone

0.1 mg/kg once a day for 1 month to reduce recurrence of infection has shown
improved outcomes in individual cases.106

PATHWAYS TO PATHOGEN IDENTIFICATION

In an era of advanced multimodal imaging and laboratory diagnostic technology,
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patients who present with myelitis remain undiagnosed in approximately 15% of

suspected infectious or inflammatory causes with currently available
techniques.107 In addition, an observational study using conventional diagnostic
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tools in the United Kingdom reported no organism was identified in 42% of

patients with meningitis.108 Conventional microbiological, molecular, and
serologic assays require the neurologist to suspect specific organisms based on
the patient history and presentation. Although this process is a foundational
component of the practice of medicine and explicitly directed in the
introduction, standard assays lack the ability to identify an organism in many
cases. The lack of identification sets forth a pathway that leads to increased
morbidity and mortality.
With the focus on more recent technologic applications that demonstrate
progress in the field of pathogen discovery, an important advancement is the
increased availability of metagenomic sequencing in the clinical setting.
Metagenomic next-generation sequencing is a nonbiased, agnostic diagnostic
modality that consists of sequencing all DNA in a single patient sample (body
fluid or tissue) followed by computational analysis to identify possible
pathogenic organisms.30 A small study of 51 patients with TB meningitis
compared acid-fast bacilli stain and culture, Xpert-MTB/RIF, quantitative
reverse transcription–PCR, and metagenomic next-generation sequencing of
CSF and found that metagenomic next-generation sequencing was the most
sensitive method (84%) for detecting M. tuberculosis DNA.109 A second study
using metagenomic next-generation sequencing in a population of patients with
TB not only reported high sensitivity and specificity for TB detection but also
predicted the use of a multiple-pathogen discovery tool in a low-resource
setting.110 Technologies that use phage immunoprecipitation sequencing to
profile human antiviral antibodies and inform on viral exposures are being
optimized to gain insight into postviral immune-mediated pathology.111
VIRRION (virus capture with rapid Raman spectroscopy detection and
identification), a diagnostic technique that analyzes enriched biofluids coupled
with Raman spectroscopy to identify influenza virus at very low concentrations
in nasopharyngeal swab samples, is currently being studied to improve virus
detection in CSF samples.112

CONCLUSION
Infectious myelopathies present in many ways. The patient’s immune status,
history of travel and exposures, and temporal relationship to prior illness all need
to be considered. Although methods for identifying the causative organism are
improving, making a definitive diagnosis can be challenging. Thus, any patient
presenting with a clinical picture consistent with myelopathy needs to be
evaluated carefully with a consideration for tropism, imaging patterns, and often
a combination of laboratory assay results. The general treatment approach to

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 infectious myelopathy may involve antimicrobials, corticosteroids, and
neurosurgical intervention as indicated in cases of cord compression. Immune
therapies can also be helpful to modulate immune response. However, in many
cases, the treatment may be supportive. A multidisciplinary approach to
recovery improves functional outcomes.
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