Accepted Manuscript

Title: Infections of the Nervous System

Author: Seth N. Levin, Jennifer L. Lyons

PII: S0002-9343(17)30898-7
DOI: http://dx.doi.org/doi: 10.1016/j.amjmed.2017.08.020
Reference: AJM 14257

To appear in: The American Journal of Medicine

Please cite this article as: Seth N. Levin, Jennifer L. Lyons, Infections of the Nervous System,
The American Journal of Medicine (2017), http://dx.doi.org/doi: 10.1016/j.amjmed.2017.08.020.

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 INFECTIONS OF THE NERVOUS SYSTEM

SETH N. LEVIN, MD1,2,3 AND JENNIFER L. LYONS, MD2,3*

1
Massachusetts General Hospital Department of Neurology, Boston, MA,
2
Brigham and Womens Hospital Department of Neurology, Boston, MA,
3
Harvard Medical School

* Address correspondence to:

Jennifer L. Lyons, MD
Division of Neurological Infections and Inflammatory Diseases
Department of Neurology
Brigham and Womens Hospital
60 Fenwood Road
Boston, MA 02115
jlyons5@partners.org

Text word count: 3,016

Abstract word count: 78

Figures: 4
References: 95

Keywords: meningitis, encephalitis, transverse myelitis, pyogenic abscess, mononeuritis

multiplex

Running Head: Infections of the Nervous System

Disclosures: This manuscript has not been previously published and is not under consideration
in any other peer-reviewed media. All authors listed have contributed sufficiently to the project to
be included as coauthors.

Page 1 of 21
Funding: None

Clinical Significance Statement

Pathogens can attack all areas of the nervous system, causing distinct deficits.

Cerebral spinal fluid analysis and neuroimaging are key diagnostic studies.

Meninigoencephalitis is a neurologic emergency that requires immediate recogni-

tion.

Atypical infections will increase as more patients take immunosuppressant drugs.

Abstract

Microorganisms can affect the entire neuraxis, producing a variety of neurologic complications
that frequently entail prolonged hospitalizations and complicated treatment regimens. The
spread of pathogens to new regions and the reemergence of opportunistic organisms in
immunocompromised patients pose increasing challenges to healthcare professionals. Since
rapid diagnosis and treatment may prevent long-term neurologic sequelae, providers should
approach these diseases with a structured, neuroanatomic framework, incorporating a thorough
history, exam, laboratory analysis, and neuroimaging in their clinical reasoning and decision-
making.

Introduction

The approach to neurologic infections, like systemic infections, necessitates a detailed

knowledge of the patients medical history, demographics and immune status. Pathogens have
the propensity to attack all areas of the nervous system, causing distinct clinical syndromes.
Consequently, a focused neurologic history and exam are fundamental to early and accurate

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diagnosis. We provide a basic neuroanatomical framework, highlighting prevalent infections in
the community and neurologic diseases in the immunocompromised patient.

Infections of the Central Nervous System

Meningitis

Meningitis, most typically an inflammation of the leptomeninges and subarachnoid space, is a

neurologic emergency. Since the clinical triad of fever, neck stiffness, and altered mental
status accounts for only 44% of adult patients with bacterial meningitis, providers should have a
high index of suspicion [1]. Headaches and photophobia are common features. Impaired
sensorium, hemodynamic instability, and respiratory compromise are life-threatening
complications that require intensive care unit monitoring [2]. Gram stain and culture from blood
and cerebrospinal fluid are critical for diagnosis. Immunocompromised patients or adults with
focal neurologic signs, seizures, obtundation, or papilledema should undergo a non-contrast
head CT scan before lumbar puncture [3]. Guidelines recommend initiating antibiotics as soon
as possible, even prior to lumbar puncture if this study is delayed [3].

Bacterial agents cause a fulminant syndrome with high grade fevers, sepsis and/or end organ
damage. Among adults from developed countries, the most common organisms are
Streptococcus pneumoniae followed by Neisseria meningitidis [4]. Immunocompromised hosts
and individuals over 50 are more susceptible to Listeria monocytogenes. The cerebrospinal
fluid opening pressure is frequently elevated. At least one of the following cerebrospinal fluid
markers white blood cell count > 2000 cells/mm3, protein > 2.2 g/L, glucose level less 34
mg/dL, and cerebrospinal fluid to serum glucose ratio of <0.23, are present in 88% of bacterial
meningitis cases [1, 2]. Gram stain has a sensitivity of 60 to 90 percent and a specificity of over
97% [1]. Empiric treatment includes vancomycin and a third-generation cephalosporin to cover
the most common agents, including those resistant to beta-lactam antibiotics. Ampicillin may be
added for Listeria coverage [3]. Intravenous steroids administered with the first dose of
antibiotics likely confer a decreased mortality in S. pneumoniae infection and are recommended
in the bacterial meningitis treatment guidelines [3, 5].

Viruses, the most common cause of meningitis, typically produce a self-limiting and less severe
infection [6]. Since clinical features insufficiently distinguish microorganisms, a lumbar puncture
is still necessary. In Western countries, the most common agents are Enteroviruses, followed
by herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), and arboviruses in order of
prevalence [6, 7]. The cerebrospinal fluid profile usually reveals a mild to moderate lymphocytic
pleocytosis (100-1,000 cells/mm3), moderately elevated protein, and normal glucose [7].
Although molecular testing with polymerase chain reaction has enabled the identification of
common viruses, in many cases, the pathogenic agent remains unknown. The treatment is

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largely supportive, and despite the evidence for acyclovir in HSV encephalitis, its efficacy in
HSV meningitis is unclear [6].

Providers must consider Mycobacterium tuberculosis in immunocompromised patients or

individuals from developing countries. Tuberculous meningitis typically presents as an indolent
illness with headaches, fevers and photophobia over days to weeks [8]. The bacterium
infiltrates the skull base and can cause cranial neuropathies, subcortical strokes, or obstructive
hydrocephalus [8, 9]. Cerebrospinal fluid analysis varies, but usually reveals protein > 100
mg/dL, white blood cell count 50-1000 cells/mm3, mixed neutrophilic and lymphocytic cells, and
glucose < 50% serum concentration [4, 10]. Acid-fast bacilli staining and culture have poor
sensitivity, which causes diagnostic and therapeutic delays [10]. Consequently, the World
Health Organization now recommends gene amplification assays for rapid detection within the
cerebrospinal fluid [11]. Treatment entails antituberculosis chemotherapy for 9-12 months and
adjunctive corticosteroids [12].

Yeasts, molds, and dimorphic fungi are also culprits for meningitis and, similar to M.
tuberculosis, can present more indolently with basilar features and a mixed cerebrospinal fluid
pleocytosis of varying severity [13]. Additional cerebrospinal fluid features are typically
hypoglycorrhachia and elevated protein. Cerebrospinal fluid fungal cultures have a notoriously
low sensitivity but high specificity [14]. Cryptococcus species are the most common cause of
fungal meningitis, especially in the immunocompromised. The diagnosis relies on a positive
cerebrospinal fluid cryptococcal antigen [15]. An elevated opening pressure has important
implications, since guidelines recommend serial lumbar punctures or a neurosurgical drain to
reduce the intracranial pressure [16]. Fungal meningitis treatment varies by organism; for
Cryptococcus, induction with amphotericin B and 5-flucytosine, followed by consolidation with
fluconazole, is standard [17].

Encephalitis

Encephalitis is an inflammation of the brain parenchyma that arises from penetration of the
blood brain barrier or overlying meningitis [18]. Some pathogens have a proclivity for specific
neuroanatomical structures, producing distinct deficits. HSV represents only 10-15% of viral
encephalitis cases, but carries a high morbidity and mortality if untreated early [18]. HSV-1, a
more common cause of encephalitis than HSV-2, remains latent in trigeminal ganglia [19]. In
primary infection or reactivation, the virus spreads via sensory fibers to the meninges
neighboring the orbitofrontal and mesial temporal lobes [20]. Individuals present with
headaches, fevers, and a limbic encephalitis, characterized by behavioral changes and seizures
[18, 20]. Examination may reveal amnesia, aphasia, visual field impairment or altered
sensorium [18]. The brain MRI shows increased T2 signal, hemorrhage or contrast
enhancement in the temporal lobes (Figure 1) [19, 20]. A positive HSV polymerase chain
reaction from the cerebrospinal fluid is diagnostic. Although intravenous acyclovir significantly
reduces the mortality, neurologic sequelae may persist months to years after treatment [20].

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Mosquito and tickborne viruses mediate encephalitis between spring and autumn [21]. West
Nile virus, the most common domestic arbovirus, is endemic to the entire continental United
States and is responsible for over 1700 deaths to date [21]. Fewer than 1% of infected
individuals develop neuro-invasive disease, and adults over 65 are at highest risk [22, 23].
West Nile fever, characterized by fevers, malaise, myalgias and skin rash precedes
meningoencephalitis [24]. An acute flaccid paralysis, a unique manifestation of West Nile virus,
arises from anterior horn cell destruction [25]. Neuroimaging shows abnormal signal in the
basal ganglia, thalami, upper brainstem or anterior spinal cord [24]. Detection of West Nile virus
IgM from the cerebrospinal fluid is diagnostic. Since no specific antiviral agents are available,
the treatment is supportive.

Other neurotropic arboviruses have emerged as prominent causes of encephalitis in North

America. Powassan virus, a tick-borne flavivirus, causes a systemic illness with confusion
and/or focal neurologic deficits primarily in the Great Lakes and Northeast [26, 27]. MRI
findings reveal subcortical grey matter, brainstem or cerebellar involvement [26]. Pathogen
identification requires Powassan antibodies in the serum or cerebrospinal fluid. Since
Powassan serologies may be absent from state arbovirus lab panels, clinicians should request
dedicated testing when suspicion is high.

Bacterial encephalitis often accompanies meningitis, but can occur independently. L.

monocytogenes causes a rhomboencephalitis, characterized by cranial neuropathies, vertigo or
hemiataxia [28]. Respiratory failure from bulbar weakness is a potential complication.
Mycoplasma pneumoniae, a common etiology of community acquired pneumonia, produces an
acute encephalitis in children and young adults, although the mechanism is unclear [29]. A
post-infectious, immune mediated response may explain central nervous system involvement
weeks after respiratory illness [30]. M. pneumoniae specific IgM or a positive M. pneumoniae
polymerase chain reaction from the cerebrospinal fluid support the diagnosis in the appropriate
clinical context [29].

Space Occupying Lesions

Microorganisms penetrate the blood brain barrier, forming single or multiple abscesses or cystic
lesions. In developed countries, the etiologies of brain abscesses include contiguous
infections, hematogenous spread, and open head injury [31]. On MRI, abscesses usually
appear as ring enhancing lesions at the grey-white matter junction [32]. Dental and otogenic
infections tend to produce single, supratentorial mass lesions composed of anaerobic bacteria
and/or Streptococcal species [31, 33]. Hematogenous infections often cause multifocal
abscesses [31]. The management requires antibiotics and urgent neurosurgical intervention for
accessible lesions [33].

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Neurocysticercosis, acquired from fecal-oral contamination, represents the most common
helminthic neurologic infection and a leading cause of epilepsy in endemic countries [34].
Ingested T. solium eggs release embryos, which disseminate to the central nervous system
[35]. Seizures and hydrocephalus ensue from cystic lesions within the parenchyma or
subarachnoid space [35, 36]. Neuroimaging characterizes the cysticercosis stages, which
include small viable lesions with a nodular head or scolex, contrast enhancing cysts with
surrounding edema, and calcified scars [37]. Antiparasitc drugs may generate an inflammatory
reaction that responds to adjunctive steroids [35]. Extraparenchymal cysts sometimes require
surgical intervention instead of anti-helminthic agents [38].

Infectious Myelopathies

Myelitis arises from intrinsic infection and inflammation of the spinal cord. Clinical
manifestations depend on the exact level and location within the cord. The herpesviruses are
ubiquitous, accounting for a substantial number of viral myelitis cases [39]. HSV and VZV
remain latent in the cell bodies of the dorsal root ganglia [20]. When reactivated, the viruses
can spread retrograde along sensory nerve roots to infiltrate the spinal cord. HSV-2 produces a
distinct sacral myeloradiculitis that presents days to weeks after anovaginal rash with perirectal
pain, urinary retention, and reduced rectal tone [40]. Infection of other levels occurs almost
exclusively in immunocompromised patients.

VZV preferentially targets the thoracic cord, causing urinary retention, limb paresthesias, and
weakness [41]. Reactivation in this scenario is usually bidirectional, resulting in both myelitis
and dermatomal rash. MRI shows increased signal and contrast enhancement within the
affected spinal cord that corresponds to demyelinating or vascular injury [41, 42].
Cerebrospinal viral detection via polymerase chain reaction or antibodies enables accurate
diagnosis [20]. Both VZV and HSV-2 myelitis respond to acyclovir. Corticosteroids are
sometimes indicated, although the data is anecdotal [41].

Treponema pallidum, the causative agent of syphilis, is a rare etiology of myelopathy in the
twenty-first century. The bacterium invades the meninges and neurovasculature, causing either
meningomyelitis, vasculitis, or parenchymal mass lesions (gummas) in advanced disease [43].
Tabes dorsalis manifests as dorsal column dysfunction several decades after primary infection
[44]. Patients present with lancinating pains in the abdomen and legs, gait ataxia, spastic
paralysis and autonomic dysfunction. The diagnosis employs cerebrospinal fluid venereal
disease research laboratory (VDRL) test, but this biomarker lacks sensitivity [45, 46]. Treatment
usually entails a two-week course of intravenous penicillin.

Pyogenic epidural abscess, a cause of extrinsic cord compression, requires immediate

recognition, since permanent neurologic deficits may develop within 36 hours of symptom onset
[47]. Abscesses derive from hematogenous spread, local trauma, or post-surgical infection [48].

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Risk factors include intravenous drug use, diabetes mellitus, and chronic immunosuppression
[49]. S. aureus and Streptococcal species account for most cases [50]. Patients present with
subacute fevers and focal back pain, followed by a spinal sensory level, lower extremity
weakness and sphincter dysfunction [49, 50]. MRI often demonstrates vertebral osteomyelitis,
discitis, and a space occupying, enhancing lesion (Figure 2). Neurologic symptoms necessitate
early surgical decompression and empiric antibiotics until pathogen isolation [50].

Strokes

Endocarditis, a cause of septic strokes, arises in patients with heart valve abnormalities or
intravenous drug use [51]. Microorganisms, including S. aureus, form organized vegetations that
embolize to the cerebral vasculature. Inflammation within the distal arteries also promotes focal
outpouchings or mycotic aneurysms, that, if ruptured, produce intracranial hemorrhages [52].
Syphilis, tuberculosis, yeasts, and viruses cause vasculopathy as their primary stroke
mechanism [53]. VZV vasculopathy has received special attention given the increasing number
of reported cases. The disease presents in primary VZV infection or reactivation and
preferentially affects immunocompromised patients [54, 55]. Radiographic features of angiitis
include multisegment artery stenosis and dilatation [56]. Complications range from grey or
white matter infarcts to aneurysms and subarachnoid hemorrhages. The cerebrospinal fluid
profile is often inflammatory [54].

Infections of the Peripheral Nervous System

Infectious Neuropathies and Radiculopathies

Infectious polyneuropathies of axonal or demyelinating subtypes have distinct features.

Hepatitis C virus produces a length dependent sensory axonal neuropathy [57]. Concomitant
cryoglobulinemia causes a small vessel vasculitis with painful distal paresthesias or a
mononeuritis multiplex with asymmetric, focal sensory or motor nerve impairment [57, 58]. The
Zika virus, a mosquito transmitted arbovirus, has garnered public attention for a recent outbreak
in South America, Central America, Mexico and Florida [59]. Neurologic disease in children and
adults manifests as an acute demyelinating polyradiculoneuropathy or Guillain-Barre Syndrome
[60]. Individuals develop rapidly ascending paralysis, sensory loss, and/or respiratory failure.
Serum Zika antibodies are frequently positive, although the exact pathogenesis is unclear.

Reactivation of latent VZV in sensory ganglion produces a radiculitis, accompanied by a painful,

vesicular rash shingles. The thoracic dermatomes are preferentially affected [20]. Segmental
zoster paresis can develop weeks after the rash with weakness in a myotomal distribution [61].
Among the cranial neuropathies, herpes zoster ophthalmicus, which manifests as retinal or optic
nerve lesions, requires urgent evaluation [20, 62]. A delay in antiviral therapy can lead to

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permanent visual deficits. The virus also spreads along the facial and auditory nerves,
producing a clinical triad of facial palsy, otalgia, and vesicular rash, termed Ramsay Hunt
Syndrome [63].

Mycobacterium leprae remains a prevalent cause of neuropathy in developing countries [64].

The intracellular bacterium causes granulomatous inflammation and damages cutaneous
nerves [58, 64]. A predominantly sensory mononeuritis or mononeuritis multiplex develops in
the limbs, especially in cooler body areas [57]. Examination often reveals palpable, painful
nerve enlargement and hypopigmented skin lesions, whose histopathology shows acid fast
bacilli [64]. In Europe and Northeastern United States, B. burgdorferi, the causative agent of
Lyme disease, is a tick-borne spirochete with both central and peripheral nervous system
manifestations [65]. Approximately 15% of untreated patients develop neurologic symptoms
within weeks of initial infection [66]. Facial palsy, sometimes bilateral, is the most common early
neurologic sign. A lymphocytic meningitis and radiculoneuritis, called Bannwarth syndrome,
produces migrating back pain and asymmetric limb weakness [66, 67]. In late infection, a distal,
symmetric sensory polyneuropathy may ensue [68]. The diagnosis of neurologic Lyme entails
cerebrospinal fluid lymphocytic pleocytosis and a positive B. burgdorferi antibody from the
serum and cerebrospinal fluid [65].

HIV and the Immunocompromised Patient

HIV Infection

HIV can affect the entire nervous system through mechanisms that are independent of
opportunistic infections. The virus is thought to infiltrate the central nervous system by primarily
infecting peripheral monocytes, which cross the blood-brain barrier and differentiate into
microglia and macrophages [69]. Central nervous system disease manifests as early as
primary HIV infection with a self-limiting meningoencephalitis or transverse myelitis [70, 71].
Initiation of highly active antiretroviral therapy (HAART) may trigger an immune reconstitution
inflammatory syndrome (IRIS). Although IRIS often exacerbates opportunistic infections, it
sometimes presents as an acute, non-infectious, steroid responsive encephalitis [72].

A thoracic myelopathy, characterized by urinary incontinence, gait ataxia, and spastic lower
extremity weakness develops in individuals with longstanding, uncontrolled infection [73]. This
disorder, termed HIV-associated vacuolar myelopathy, resembles vitamin B12 deficiency both
clinically and histologically, although MRI and cobalamin levels are frequently normal [74, 75].
At least one-third of HIV-infected patients also acquire a gradual, distal, symmetric peripheral
neuropathy [76]. Sensory axon degeneration accounts for the burning, numbness, and tingling
in the feet and hands. Cranial neuropathies, sensorimotor mononeuropathies, and Guillain-
Barre Syndrome are less common peripheral manifestations [72, 76].

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HIV-associated neurocognitive disorders is an umbrella term for cognitive impairment in HIV-
infected individuals of varying severity, not attributed to other conditions [77]. The disorders
remains prevalent despite increasing viral control, implicating longstanding infection and/or
immune dysregulation in the pathogenesis [78]. The diagnosis is clinical, but MRI may reveal
generalized cortical atrophy and symmetric leukoencephalopathy [79]. HIV RNA detection from
the cerebrospinal fluid of a patient with neurologic symptoms, despite peripheral viral
suppression, is diagnostic of cerebrospinal fluid escape encephalitis [80]. Although treatment is
controversial, changing the antiretroviral regimen to intensify therapy or to increase central
nervous system penetration, is common practice [81].

Viral Opportunistic Infections

Progressive multifocal leukoencephalopathy is a feared complication of acquired

immunodeficiency syndrome (AIDS), lymphoproliferative disorders, and the treatment of
autoimmune conditions [82, 83]. Reactivated JC virus targets oligodendrocytes, causing a
fulminant demyelinating illness. The clinical presentation is variable. Common symptoms
include subacute limb weakness, cognitive changes, gait instability, and visual impairment [83].
Subcortical white matter lesions on MRI have a scalloped appearance [84]. Restricted
diffusion, mass effect, and contrast enhancement are often absent on MRI and routine
cerebrospinal fluid studies are frequently normal (Figure 3) [83]. JCV polymerase chain reaction
from the cerebrospinal fluid has a high sensitivity and specificity [85]. Aside from immune
reconstitution, no effective treatment exists and the prognosis is poor if immune reconstitution
cannot be regained quickly [86].

Among the Herpesviridae, cytomegalovirus (CMV) presents almost exclusively in

immunosuppressed individuals and attacks all divisions of the nervous system. Peripheral or
central vision loss from retinitis is the most common neurologic complication in AIDS [87]. CMV
encephalitis manifests as a subacute confusional state with impairments in cognition, attention,
and arousal [88]. Approximately 10% of affected individuals develop an acute necrotizing
ventriculitis with associated cranial neuropathies and hydrocephalus [89]. The MRI may show
periventricular enhancement, infarcts, or hemorrhages [90]. Peripherally, the virus produces an
ascending lumbosacral polyradiculitis resembling Guillain-Barre Syndrome, and a mononeuritis
multiplex [91]. Cerebrospinal fluid analysis reveals a neutrophilic pleocytosis, elevated protein
and hypoglycorrhachia, although these findings are sometimes absent. CMV polymerase chain
reaction from the cerebrospinal fluid is diagnostic [92].

Cerebral toxoplasmosis

Humans acquire Toxoplasma gondii, an intracellular protozoan, from ingestion of oocytes in soil,
contaminated cat litter, or undercooked meat [93]. Initial infection is often asymptomatic, and
the organism remains dormant for many years. In immunosuppressed hosts, reactivated

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parasite spreads through the central nervous system, forming multiple ring-enhancing lesions
with surrounding edema in the basal ganglia and/or corticomedullary junction (Figure 4) [94]. A
subacute course of headaches and somnolence typically precedes focal neurologic deficits and
seizures [87, 93]. Hyperkinetic movement disorders or parkinsonism may arise from basal
ganglia involvement [95]. The diagnosis relies on clinical suspicion, neuroimaging, and T.
gondii serology, although a neurosurgical biopsy is sometimes necessary [87].

Conclusion

Neurologic infections offer many diagnostic and therapeutic challenges to medical

professionals. The diseases, often severe and protracted, cause significant morbidity and
mortality. The spread of new pathogens and reemergence of opportunistic infections further
complicate management. General practitioners should approach all infections using available
guidelines, including rapid screening and referral to specialists in complex cases. A basic
framework incorporating neuroanatomical location, immune status, and other demographic
features will facilitate early and precise diagnosis.

Acknowledgments

The authors have no acknowledgments.

Page 10 of 21
References

1. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in
adults with bacterial meningitis. N Engl J Med 2004;351:1849-1859.
2. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in
adults. N Engl J Med 2006;354:44-53.
3. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of
bacterial meningitis. Clin Infect Dis 2004;39:1267-1284.
4. van de Beek D, Brouwer M, Hasbun R, et al. Community-acquired bacterial meningitis.
Nat Rev Dis Primers 2016;2:16074.
5. de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis
Study I. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556.
6. McGill F, Griffiths MJ, Solomon T. Viral meningitis: current issues in diagnosis and
treatment. Curr Opin Infect Dis 2017;30:248-256.
7. Logan SA, MacMahon E. Viral meningitis. BMJ 2008;336:36-40.
8. Garcia-Monco JC. Tuberculosis. Handb Clin Neurol 2014;121:1485-1499.
9. Leiguarda R, Berthier M, Starkstein S, et al. Ischemic infarction in 25 children with
tuberculous meningitis. Stroke 1988;19:200-204.
10. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still
too few answers. Lancet Neurol 2013;12:999-1010.
11. . Automated Real-Time Nucleic Acid Amplification Technology for Rapid and
Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF Assay for
the Diagnosis of Pulmonary and Extrapulmonary TB in Adults and Children: Policy Update.
Geneva; 2013.
12. . Rapid Advice: Treatment of Tuberculosis in Children. Geneva; 2010.
13. Murthy JM, Sundaram C. Fungal infections of the central nervous system. Handb Clin
Neurol 2014;121:1383-1401.
14. Jacobs CS, Etherton MR, Lyons JL. Fungal infections of the central nervous system.
Curr Infect Dis Rep 2014;16:449.
15. Jackson A, Powderly WG. Cryptococcal infection. Handb Clin Neurol 2007;85:159-167.
16. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial
pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group
and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000;30:47-54.

Page 11 of 21
17. Day JN, Chau TT, Lalloo DG. Combination antifungal therapy for cryptococcal
meningitis. N Engl J Med 2013;368:2522-2523.
18. Greenlee JE. Encephalitis and postinfectious encephalitis. Continuum (Minneap Minn)
2012;18:1271-1289.
19. Whitley RJ. Herpes Simplex Virus Infections of the Central Nervous System. Continuum
(Minneap Minn) 2015;21:1704-1713.
20. Gilden DH, Mahalingam R, Cohrs RJ, et al. Herpesvirus infections of the nervous
system. Nat Clin Pract Neurol 2007;3:82-94.
21. Beckham JD, Tyler KL. Arbovirus Infections. Continuum (Minneap Minn) 2015;21:1599-
1611.
22. Busch MP, Wright DJ, Custer B, et al. West Nile virus infections projected from blood
donor screening data, United States, 2003. Emerg Infect Dis 2006;12:395-402.
23. Jean CM, Honarmand S, Louie JK, et al. Risk factors for West Nile virus neuroinvasive
disease, California, 2005. Emerg Infect Dis 2007;13:1918-1920.
24. Kramer LD, Li J, Shi PY. West Nile virus. Lancet Neurol 2007;6:171-181.
25. Gadoth N, Weitzman S, Lehmann EE. Acute anterior myelitis complicating West Nile
fever. Arch Neurol 1979;36:172-173.
26. Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging Cases of Powassan Virus
Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature. Clin
Infect Dis 2016;62:707-713.
27. Doughty CT, Yawetz S, Lyons J. Emerging Causes of Arbovirus Encephalitis in North
America: Powassan, Chikungunya, and Zika Viruses. Curr Neurol Neurosci Rep 2017;17:12.
28. Bartt R. Listeria and atypical presentations of Listeria in the central nervous system.
Semin Neurol 2000;20:361-373.
29. Daxboeck F. Mycoplasma pneumoniae central nervous system infections. Curr Opin
Neurol 2006;19:374-378.
30. Tsiodras S, Kelesidis I, Kelesidis T, et al. Central nervous system manifestations of
Mycoplasma pneumoniae infections. J Infect 2005;51:343-354.
31. Brook I. Microbiology and treatment of brain abscess. J Clin Neurosci 2017;38:8-12.
32. Haimes AB, Zimmerman RD, Morgello S, et al. MR imaging of brain abscesses. AJR Am
J Roentgenol 1989;152:1073-1085.
33. Patel K, Clifford DB. Bacterial brain abscess. Neurohospitalist 2014;4:196-204.
34. Singh G, Burneo JG, Sander JW. From seizures to epilepsy and its substrates:
neurocysticercosis. Epilepsia 2013;54:783-792.
35. Garcia HH, Nash TE, Del Brutto OH. Clinical symptoms, diagnosis, and treatment of
neurocysticercosis. Lancet Neurol 2014;13:1202-1215.

Page 12 of 21
36. Lobato RD, Lamas E, Portillo JM, et al. Hydrocephalus in cerebral cysticercosis.
Pathogenic and therapeutic considerations. J Neurosurg 1981;55:786-793.
37. Garcia HH, Del Brutto OH. Imaging findings in neurocysticercosis. Acta Trop
2003;87:71-78.
38. Garcia HH, Evans CA, Nash TE, et al. Current consensus guidelines for treatment of
neurocysticercosis. Clin Microbiol Rev 2002;15:747-756.
39. Lyons JL. Myelopathy associated with microorganisms. Continuum (Minneap Minn)
2015;21:100-120.
40. Eberhardt O, Kuker W, Dichgans J, et al. HSV-2 sacral radiculitis (Elsberg syndrome).
Neurology 2004;63:758-759.
41. Gilden DH, Beinlich BR, Rubinstien EM, et al. Varicella-zoster virus myelitis: an
expanding spectrum. Neurology 1994;44:1818-1823.
42. Kenyon LC, Dulaney E, Montone KT, et al. Varicella-zoster ventriculo-encephalitis and
spinal cord infarction in a patient with AIDS. Acta Neuropathol 1996;92:202-205.
43. Berger JR, Dean D. Neurosyphilis. Handb Clin Neurol 2014;121:1461-1472.
44. Berger JR. Neurosyphilis and the spinal cord: then and now. J Nerv Ment Dis
2011;199:912-913.
45. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with
syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-376.
46. Workowski KA, Berman S, Centers for Disease C, et al. Sexually transmitted diseases
treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1-110.
47. Heusner AP. Nontuberculous spinal epidural infections. N Engl J Med 1948;239:845-
854.
48. Shah NH, Roos KL. Spinal epidural abscess and paralytic mechanisms. Curr Opin
Neurol 2013;26:314-317.
49. Patel AR, Alton TB, Bransford RJ, et al. Spinal epidural abscesses: risk factors, medical
versus surgical management, a retrospective review of 128 cases. Spine J 2014;14:326-330.
50. Pradilla G, Ardila GP, Hsu W, et al. Epidural abscesses of the CNS. Lancet Neurol
2009;8:292-300.
51. Holland TL, Baddour LM, Bayer AS, et al. Infective endocarditis. Nat Rev Dis Primers
2016;2:16059.
52. Morris NA, Matiello M, Lyons JL, et al. Neurologic complications in infective endocarditis:
identification, management, and impact on cardiac surgery. Neurohospitalist 2014;4:213-222.
53. Fugate JE, Lyons JL, Thakur KT, et al. Infectious causes of stroke. Lancet Infect Dis
2014;14:869-880.

Page 13 of 21
54. Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies:
clinical, CSF, imaging, and virologic features. Neurology 2008;70:853-860.
55. Gilden D, Cohrs RJ, Mahalingam R, et al. Varicella zoster virus vasculopathies: diverse
clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol
2009;8:731-740.
56. Russman AN, Lederman RJ, Calabrese LH, et al. Multifocal varicella-zoster virus
vasculopathy without rash. Arch Neurol 2003;60:1607-1609.
57. Hehir MK, 2nd, Logigian EL. Infectious neuropathies. Continuum (Minneap Minn)
2014;20:1274-1292.
58. Sindic CJ. Infectious neuropathies. Curr Opin Neurol 2013;26:510-515.
59. Song BH, Yun SI, Woolley M, et al. Zika virus: History, epidemiology, transmission, and
clinical presentation. J Neuroimmunol 2017.
60. Uncini A, Shahrizaila N, Kuwabara S. Zika virus infection and Guillain-Barre syndrome: a
review focused on clinical and electrophysiological subtypes. J Neurol Neurosurg Psychiatry
2017;88:266-271.
61. Thomas JE, Howard FM, Jr. Segmental zoster paresis--a disease profile. Neurology
1972;22:459-466.
62. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical
presentation, and morbidity. Ophthalmology 2008;115:S3-12.
63. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry
2001;71:149-154.
64. de Freitas MR, Said G. Leprous neuropathy. Handb Clin Neurol 2013;115:499-514.
65. Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis-epidemiology, diagnosis and
management. Nat Rev Neurol 2015;11:446-456.
66. Marques AR. Lyme Neuroborreliosis. Continuum (Minneap Minn) 2015;21:1729-1744.
67. Hansen K, Crone C, Kristoferitsch W. Lyme neuroborreliosis. Handb Clin Neurol
2013;115:559-575.
68. Halperin JJ, Little BW, Coyle PK, et al. Lyme disease: cause of a treatable peripheral
neuropathy. Neurology 1987;37:1700-1706.
69. Bell JE. The neuropathology of adult HIV infection. Rev Neurol (Paris) 1998;154:816-
829.
70. Hamada Y, Watanabe K, Aoki T, et al. Primary HIV infection with acute transverse
myelitis. Intern Med 2011;50:1615-1617.
71. Nzwalo H, Anon RP, Aguas MJ. Acute encephalitis as initial presentation of primary HIV
infection. BMJ Case Rep 2012;2012.

Page 14 of 21
72. Lyons J, Venna N, Cho TA. Atypical nervous system manifestations of HIV. Semin
Neurol 2011;31:254-265.
73. Di Rocco A. HIV myelopathy. Handb Clin Neurol 2007;85:123-128.
74. Petito CK, Navia BA, Cho ES, et al. Vacuolar myelopathy pathologically resembling
subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N
Engl J Med 1985;312:874-879.
75. Chong J, Di Rocco A, Tagliati M, et al. MR findings in AIDS-associated myelopathy.
AJNR Am J Neuroradiol 1999;20:1412-1416.
76. Verma S, Simpson DM. Peripheral neuropathy in HIV infection. Handb Clin Neurol
2007;85:129-137.
77. Nightingale S, Winston A, Letendre S, et al. Controversies in HIV-associated
neurocognitive disorders. Lancet Neurol 2014;13:1139-1151.
78. Bhatia NS, Chow FC. Neurologic Complications in Treated HIV-1 Infection. Curr Neurol
Neurosci Rep 2016;16:62.
79. Nath A. Neurologic Complications of Human Immunodeficiency Virus Infection.
Continuum (Minneap Minn) 2015;21:1557-1576.
80. Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal
fluid and plasma HIV replication in patients with neurological symptoms who are receiving
suppressive antiretroviral therapy. Clin Infect Dis 2010;50:773-778.
81. Etherton MR, Lyons JL, Ard KL. HIV-associated Neurocognitive Disorders and
Antiretroviral Therapy: Current Concepts and Controversies. Curr Infect Dis Rep 2015;17:485.
82. Amend KL, Turnbull B, Foskett N, et al. Incidence of progressive multifocal
leukoencephalopathy in patients without HIV. Neurology 2010;75:1326-1332.
83. Berger JR. Progressive multifocal leukoencephalopathy. Handb Clin Neurol
2014;123:357-376.
84. Sahraian MA, Radue EW, Eshaghi A, et al. Progressive multifocal leukoencephalopathy:
a review of the neuroimaging features and differential diagnosis. Eur J Neurol 2012;19:1060-
1069.
85. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement
from the AAN Neuroinfectious Disease Section. Neurology 2013;80:1430-1438.
86. Aksamit AJ. Progressive multifocal leukoencephalopathy. Curr Treat Options Neurol
2008;10:178-185.
87. Bowen LN, Smith B, Reich D, et al. HIV-associated opportunistic CNS infections:
pathophysiology, diagnosis and treatment. Nat Rev Neurol 2016;12:662-674.
88. Holland NR, Power C, Mathews VP, et al. Cytomegalovirus encephalitis in acquired
immunodeficiency syndrome (AIDS). Neurology 1994;44:507-514.

Page 15 of 21
89. Vinters HV, Kwok MK, Ho HW, et al. Cytomegalovirus in the nervous system of patients
with the acquired immune deficiency syndrome. Brain 1989;112 ( Pt 1):245-268.
90. Grafe MR, Press GA, Berthoty DP, et al. Abnormalities of the brain in AIDS patients:
correlation of postmortem MR findings with neuropathology. AJNR Am J Neuroradiol
1990;11:905-911; discussion 912-903.
91. Behar R, Wiley C, McCutchan JA. Cytomegalovirus polyradiculoneuropathy in acquired
immune deficiency syndrome. Neurology 1987;37:557-561.
92. Miller RF, Fox JD, Thomas P, et al. Acute lumbosacral polyradiculopathy due to
cytomegalovirus in advanced HIV disease: CSF findings in 17 patients. J Neurol Neurosurg
Psychiatry 1996;61:456-460.
93. Chirch LM, Luft BJ. Cerebral toxoplasmosis in AIDS. Handb Clin Neurol 2007;85:147-
158.
94. Chang L, Cornford ME, Chiang FL, et al. Radiologic-pathologic correlation. Cerebral
toxoplasmosis and lymphoma in AIDS. AJNR Am J Neuroradiol 1995;16:1653-1663.
95. Cardoso F. HIV-related movement disorders: epidemiology, pathogenesis and
management. CNS Drugs 2002;16:663-668.

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Figure 1. Herpes simplex virus encephalitis. Brain MRI of a patient who presented with
memory impairment, headaches, and fevers. Axial T2 fluid-attenuated inversion
recovery (FLAIR) imaging shows left hemispheric hyperintensity in the anterior and
medial temporal lobe and mass effect approaching the midbrain. HSV DNA was
detected in the cerebrospinal fluid by polymerase chain reaction.
Figure 2. Discitis with associated ventral epidural abscess. Lumbosacral MRI of a patient with
diabetes mellitus who presented with acute on chronic low back pain, fevers and weight loss.
Sagittal T2 fluid-attenuated inversion recovery (FLAIR) imaging (A) and T1 post-contrast
imaging (B) show high T2 signal within the L1-L2 intervertebral disc (arrow) and an associated
ventral epidural fluid collection with peripheral enhancement. Blood cultures grew methicillin
sensitive Staphylococcus aureus.

Figure 3. Progressive multifocal leukoencephalopathy. Brain MRI of a patient with non-

Hodgkins lymphoma who presented with progressive right sided hemiparesis and dysarthria.
Fluid-attenuated inversion recovery (FLAIR) imaging (A) and T1 post-contrast imaging (B) show
subcortical lesions with U-fiber involvement (arrow) characterized by T2 hyperintensity, T1
hypointensity (arrow head) and lack of mass effect or contrast enhancement. JCV DNA was
recovered from cerebrospinal fluid by polymerase chain reaction.

Figure 4. Cerebral toxoplasmosis. Brain MRI of a patient with uncontrolled HIV-1 infection who
presented with seizures and altered mental status. Fluid-attenuated inversion recovery (FLAIR)
sequence (A), T1 post-contrast imaging (B), and diffusion weighted imaging (DWI) (C) reveal
multiple, heterogeneous, peripherally enhancing deep grey and juxtacortical lesions with areas
of low diffusivity, surrounding vasogenic edema, and local mass effect. Toxoplasma IgG from
serum was positive, and the lesions improved with anti-toxoplasmosis antimicrobials, confirming
the diagnosis.

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