INTRODUCTION
There are a seemingly insurmountable number of infections that can affect the nervous system. However, as in all areas of neurology, the principles of a neurologic history and exam are essential to diagnosis. Focusing on the localization of the syndrome and the patient’s infectious risk factors (e.g., travel history, animal exposures, occupational exposures, immune status) narrows the differential diagnosis sufficiently to make infections of the nervous system approachable. This chapter highlights common infections of the nervous system, “do-not-miss” infections of the nervous system, and infections that are more prevalent in patients who are immunocompromised but is far from a comprehensive list of all possible nervous system infections.
CENTRAL NERVOUS SYSTEM
Meningitis
Meningitis refers to inflammation of either the pachymeninges (dura mater) or leptomeninges (pia mater and arachnoid) with infectious meningitis typically predominantly affecting the leptomeninges. Multiple types of organisms can cause meningitis and the spectrum of meningitis can range from a true neurologic emergency (bacterial meningitis) to a relatively mild presentation (some cases of viral meningitis).
Bacterial Meningitis
The most feared type of meningitis, and perhaps most feared neurologic infection, is bacterial meningitis. Bacterial meningitis in the pre–antibiotic era had a mortality rate approaching 100%, but even in the modern era mortality from Streptococcus pneumoniae remains as high as 30%. Because mortality is so high, prompt recognition and initiation of treatment is vital. The classic triad of fever, neck stiffness, and altered mental status has been shown to be relatively insensitive, occurring in 41%–44% of patients, although having two of either fever, neck stiffness, altered mental status, or headache has been shown to have a sensitivity as high as 95%. Bacterial meningitis should be considered in any patient with at least two or more of those symptoms.
All patients suspected of having meningitis should have blood cultures drawn and undergo urgent lumbar puncture for CSF analysis to evaluate for meningitis and to attempt to isolate the causative organism. Lumbar puncture should only be delayed to obtain imaging (head CT without contrast) in the subset of patients at risk of herniation: those who are immunocompromised, have a history of mass lesion in the brain (e.g., tumor, stroke, focal infection), have new-onset seizures, have papilledema on examination, have an abnormal level of consciousness, or have a focal neurologic deficit. Opening pressure should be measured and CSF should be sent for cell count with differential, protein, glucose, gram stain, and culture at minimum. Multiplex PCR has also become increasingly available with high sensitivity and specificity for common organisms (including Neisseria meningitides , S. pneumoniae , Haemophilus influenzae ) and the added benefit of rapid turnaround time. Cerebrospinal fluid values can be variable, but generally in bacterial meningitis the nucleated cell count is often >1000 cells/μL with a neutrophil predominance of ≥80%, protein is often elevated >200 mg/dL, and glucose is often decreased <40 mg/dL with a CSF to serum glucose ratio of ≤0.4.
Prompt initiation of treatment is crucial as soon as bacterial meningitis is suspected. Lumbar puncture should ideally be performed prior to antibiotic administration so as to not decrease the yield of the CSF culture, but antibiotics should not be delayed if lumbar puncture cannot be performed immediately. Empiric antibiotics should include a third-generation cephalosporin to cover for Streptococcus species, N. meningitides , and H. influenzae , the three most common causative organisms for community-acquired bacterial meningitis, as well as vancomycin to cover for cephalosporin-resistant S. pneumoniae . Ampicillin should be added to cover for Listeria monocytogenes in neonates, adults over age 50, and those who are otherwise immunocompromised. Antimicrobial therapy should be tailored based on Gram stain, culture, and/or PCR results.
In addition to antibiotics, patients suspected of having bacterial meningitis should be treated with dexamethasone concurrently with antibiotics based on data showing both a mortality benefit among patients with S. pneumoniae and a lower rate of hearing loss. Dexamethasone should only be continued if S. pneumoniae is found to be the causative organism, as dexamethasone was not found to be as beneficial in meningitis caused by other organisms. Dexamethasone should not be started after antibiotics have already been given, as this timing has been associated with worse outcomes.
Patients with bacterial meningitis are at risk for numerous complications and often require an ICU level of care with a multidisciplinary team including infectious disease, neurology, and neurosurgery. Neurologic complications to monitor for include increased intracranial pressure (from cerebral edema and/or hydrocephalus), seizure, ischemic stroke, venous sinus thrombosis, and subdural empyema. Patients who survive bacterial meningitis may be left with a spectrum of neurologic sequela including cognitive impairment, cranial neuropathies, hearing loss, and paresis.
In addition to meningitis, Listeria can additionally lead to a rhombencephalitis in 17% of cases, with progressive cranial nerve palsies, cerebellar signs, weakness, and decreased level of arousal. Development of abscess from Listeria is uncommon but does occur.
Viral Meningitis
Viruses are the most common cause of “aseptic” meningitis, which would be more accurately called nonbacterial meningitis. Viral meningitides tend to be much less severe than bacterial meningitis and are often self-limited. The typical presentation includes a combination of headache, neck stiffness, and/or photophobia.
All patients presenting with concern for viral meningitis should undergo lumbar puncture as there are no specific clinical features for viral meningitis, and it is prudent to rule out other causes, specifically bacterial meningitis. Typical CSF findings include moderate lymphocytic pleocytosis (in the range of 100–1000 cells/μL; may be neutrophilic early in the course), moderately elevated total protein (in the range of 100–1000 mg/dL), and normal or only mildly reduced glucose, although wide variations may be seen for each of these.
The most common causative viruses include enteroviruses, herpes simplex virus–2 (HSV-2), varicella zoster virus (VZV), and arboviruses. PCR testing for enteroviruses, HSV, and VZV are routinely available and should be performed. Multiplex PCR is also available but may be less sensitive and specific than the individual PCR tests so should be used cautiously. Primary infection with HIV can also present as a self-limited meningitis and can present before antibodies are present. Patients with risk factors for HIV infection should have HIV serum viral load tested.
Most causes of viral meningitis do not have specific treatments and self-resolve with supportive care. Patients with HSV or VZV meningitis should be treated with IV acyclovir, which can be transitioned to oral valacyclovir. There is stronger evidence to support treatment in immunocompromised patients, although the risk/benefit ratio is likely also favorable for immunocompetent patients. HSV-2 can cause a recurrent lymphocytic meningitis (Mollaret meningitis) characterized by repeated, self-limited attacks of meningitis. Suppressive valacyclovir is often used although one small randomized trial did not find a benefit and showed a higher risk of recurrence after stopping valacyclovir.
Fungal Meningitis
Yeast and fungi can cause a more indolent meningitis, typically presenting with days to weeks of meningismus and signs of intracranial pressure such as fever, headache, neck stiffness, photophobia, malaise, vomiting, and cranial nerve palsies. Cryptococcosis is the most common cause of fungal meningitis, although the endemic dimorphic fungi can also cause meningitis.
Cryptococcosis most commonly occurs in patients who are immunocompromised, with HIV/AIDS being the predominant risk factor, though patients without any known immunodeficiency can also develop cryptococcal meningitis. Typical CSF findings include lymphocytic pleocytosis, normal to elevated protein levels, low glucose, and elevated opening pressure, although the nucleated cell count and protein may be normal in patients with HIV. Culture is insensitive; diagnosis is typically made via testing the CSF for cryptococcal antigen. Treatment follows an induction, consolidation, maintenance paradigm (typically with amphotericin B and flucytosine followed by fluconazole) and should be done with infectious disease consultation. Patients are at high risk for elevated intracranial pressure and may require serial lumbar punctures or CSF diversion (e.g., ventriculoperitoneal shunt or lumbar drain).
Histoplasmosis, blastomycosis, and coccidiomycosis can each additionally present with meningitis within their respective geographic territories. These dimorphic fungi can additionally present with mass lesions and can cause a basilar meningitis and/or vasculitis leading to infarcts. Treatment typically involves at least 12 months of an antifungal agent.
Encephalitis
Encephalitis refers to inflammation of the brain parenchyma itself and is typically infectious or autoimmune in etiology. Infectious and autoimmune encephalitis can be very difficult to distinguish clinically. Fever, prominent findings on MRI, and/or marked CSF abnormalities may be a clue to an infectious rather than autoimmune etiology. Most infectious causes of encephalitis are viral, although in 60%–70% of viral encephalitides no virus is identified.
HSV Encephalitis
HSV is the most common cause of infectious encephalitis, accounting for 35%–55% of infections with an identified organism. Over 90% of HSV encephalitis (HSVE) results from HSV-1 with less than 10% from HSV-2, which is more associated with meningitis. HSVE is thought to result both from primary infection with entry through the nose leading to infection of olfactory bulb neurons and retrograde spread to the mesial temporal lobes as well as from reactivation of latent virus in the trigeminal ganglia. HSVE typically presents with altered mental status, fever, headache, focal neurologic deficits, and/or seizures which develop over days. Focal neurologic deficits may include aphasia, apraxia, memory impairment, visual field impairment, cranial nerve deficits, hemiparesis, and/or ataxia.
Diagnosis of HSVE was historically made via brain biopsy, but in the current era is almost exclusively made by CSF PCR. All patients suspected of having HSVE should undergo lumbar puncture to evaluate for the HSV PCR, which is extremely sensitive and specific for HSVE. However, some experts have suggested that false negatives are more likely when the lumbar puncture is performed within 72 hours of symptom onset, in which case a repeat lumbar puncture should be performed. Additionally, the sensitivity of the HSV PCR decreases with time, to as low as 30% from 11 to 20 days after symptom onset and 19% from 21 to 40 days after symptom onset. CSF HSV antibodies are generally not useful and should not be sent in the acute setting. There are rare instances where they may be useful to make a delayed or retrospective diagnosis. General examination of the CSF typically shows a lymphocytic pleocytosis (which may be neutrophilic early in the course of the infection) of 10–500 cells/μL, red blood cells of 10–500 cells/μL, elevation in total protein that may be mild or in the 100s of mg/dL, and may show mild hypoglycorrhachia. MRI typically shows T2 and/or diffusion-weighted imaging (DWI) changes in the temporal lobes early in the course of the infection which may extend into other lobes of the brain ( Fig. 9.1 ).
All patients suspected of having HSVE should be started on IV acyclovir as soon as the diagnosis is suspected. Delay in treatment initiation is the only modifiable risk factor shown to affect prognosis. There is no need to wait for lumbar puncture as starting acyclovir should not meaningfully affect the sensitivity of HSV PCR in the short term. Treatment is with IV acyclovir at a dose of 10 mg/kg (which may need to be adjusted for renal insufficiency) every 8 hours for 14–21 days. Even with treatment HSVE has a mortality rate between 6% and 15% and moderate to severe morbidity including cognitive deficits, aphasia, seizures, and/or weakness in 32–56%. Recently, it has become clear that as many as 27% of patients with HSVE will develop a secondary autoimmune encephalitis, most commonly with positive NMDA receptor antibodies, within 2 months of their treatment for HSVE. These patients should be treated with immunotherapy as would any other patient with autoimmune encephalitis.
Arboviral Encephalitis
Arboviruses refer to viruses spread through the bite of an arthropod, typically a tick or mosquito. In the United States, the most common arboviral infection is West Nile Virus (WNV), which is transmitted via the bite of the Culex mosquito, with birds as the amplifying host. It has been reported in all 50 US states with almost 28,000 neuroinvasive cases reported through 2021. WNV leads to an asymptomatic infection in most people, a febrile illness in approximately 25%, and neuroinvasive disease (encephalitis) in less than 1%. Among those who develop neuroinvasive disease, three syndromes are most common: meningitis, encephalitis, and acute flaccid paralysis, which can develop in isolation or in combination. Testing for WNV is via IgM in the serum and/or CSF. PCR-based testing has limited utility as the viremia generally clears early in the course of the infection. Among the almost 28,000 neuroinvasive cases reported through 2021, the mortality rate was 9%.
Powassan virus is an emerging tick-borne virus in the northern and northeastern US with cases also reported in Canada and Russia. Powassan is carried by the same tick, Ixodes scapularis , as Lyme disease but can be transmitted in as little as 15 minutes from time of tick attachment. In the United States, 189 neuroinvasive cases have been reported as of 2021 with a mortality rate of 13%. Powassan encephalitis can present with fever, encephalopathy, decreased level of arousal, seizures, and focal neurological deficits. Diagnosis is via IgM from the serum and/or CSF. Historically this has only been available in the United States through the CDC, but has recently become available through other clinical labs. PCR testing should be reserved for patients who would not be expected to mount an antibody response (e.g., those receiving anti-CD20 therapies like rituximab).
Other arboviral infections include Eastern Equine Encephalitis (EEE), which is rare (46 cases reported in the United States from 2012 to 2021), but has a mortality rate over 40%; La Crosse virus; and St. Louis encephalitis, although others also exist. Imaging in arboviral infections can be variable, although many patients will have symmetric deep T2-hyperintense lesions (i.e., T2 hyperintensity of the basal ganglia). No specific treatments beyond supportive care have been proven to be effective for any of the arboviral encephalitides.
Brain Abscesses
Infectious abscesses are typically bacterial, although other types of organisms, such as fungi and toxoplasma, can also form abscesses. Bacterial abscesses arise from contiguous sites of infection (i.e., otitis, mastoiditis, or sinusitis) in over 40% of cases, hematogenous spread of a distant infection in about 33% of cases, and are related to recent trauma or neurosurgery in 23% (14% and 9%, respectively). The most common organisms are Streptococcus (34%), Staphylococcus (18%), and enteric gram-negative rods (15%). Abscesses can cause variable neurologic deficits depending on their location in the brain and their size. Most patients (69%) have a headache, but only about half have fever or a focal neurologic deficit. Initial workup for an abscess is largely with urgent imaging, with contrast-enhanced MRI preferred over CT if available. Typical findings on MRI include peripheral enhancement and diffusion restriction. Lumbar puncture is typically not performed due to the theoretical risk of herniation (if there is a large mass lesion) and because CSF culture is insensitive. All patients with suspicion for brain abscess should have neurosurgical consultation as most patients should undergo neurosurgical aspiration or resection, although medical treatment alone can be considered for those with small abscess(es), who are clinically stable, and who have a known etiologic organism. Empiric treatment is generally with 4–8 weeks of a third-generation cephalosporin plus metronidazole with modifications based on risk factors (e.g., adding vancomycin if there are risk factors for methicillin-resistant Staphylococcus aureus ). If clinically stable, empiric antibiotics can be delayed until after neurosurgical drainage to increase the yield of the culture, although many experts advise continuing anaerobic coverage regardless of the culture result as >30% of abscesses are polymicrobial. Although historically brain abscesses have had a mortality rate of 40%, modern series show this has declined to approximately 10%.
Neurocysticercosis
Cysticercosis is caused by the tapeworm Taenia solium and can lead to both neurocysticercosis and extraneural cysticercosis. Ingestion of undercooked pork leads to gastrointestinal tapeworm infection; ingestion of tapeworm eggs via the fecal-oral route is required for cysticercosis (although those with tapeworm infection are at risk for autoinoculation). The most important sequela of neurocysticercosis is epilepsy and neurocysticercosis is one of the leading causes of epilepsy globally. Although not endemic in the United States, it has been shown to be the cause of 2% of new-onset seizures. Neurocysticercosis can manifest in the brain parenchyma itself or can be intraventricular or subarachnoid and can be single or multiple. While parenchymal lesions are more associated with seizures, intraventricular lesions can lead to obstructive hydrocephalus and subarachnoid lesions can lead to communicating or obstructive hydrocephalus. Lesions progress through multiple stages, starting out as viable cysts, then degenerating cysts, and finally as calcified lesions. Although they can present at any stage, most present during the degenerative stage. Diagnosis is largely based on a compatible clinical history and imaging, with visualization of a scolex within a cyst sufficient to make the diagnosis. Antibody, antigen, and PCR-based testing may also be useful, although antigen and PCR testing are not widely available. All patients with suspected or confirmed neurocysticercosis should undergo ophthalmologic exam for evaluation of ocular cysticercosis, which generally requires surgical removal. All patients should similarly be evaluated for evidence of hydrocephalus (obstructive or communicating), which may require neurosurgical intervention. Patients with viable or degenerating cysts may be candidates for treatment with antiparasitic therapy with albendazole or albendazole plus praziquantel depending on the burden of disease. All patients should receive corticosteroids prior to , concurrent with, and following antiparasitic therapy to decrease the risk of seizures.
Infectious Myelopathies
Infections of the spine are relatively infrequent but do occur. Infections can occur within the spinal cord itself or can be extramedullary, such as spinal epidural abscesses, and cause extrinsic compression of the spinal cord. A wide variety of infectious agents including viruses, bacteria, fungi, and parasites may cause spinal cord infection.
Among immunocompetent people, herpesviruses are the most common cause of viral myelitis with VZV and HSV being the most common. Both VZV and HSV can reactivate from the dorsal root ganglia and travel anterograde to cause rash or retrograde to, less commonly, cause myelitis. Both HSV and VZV myelitis can occur concurrently with typical HSV or VZV rashes (i.e., anogenital vesicular rash or dermatomal shingles rash, respectively) in which case the etiology of the myelitis can be presumed, but they can also occur without rash. HSV and VZV PCR may be useful but are more specific than sensitive. Both HSV and VZV myelitis should be treated with IV acyclovir. Other herpesviruses including CMV, EBV, and HHV-6 have also been associated with infectious myelopathy, typically in immunocompromised individuals. HIV infection is known to cause HIV-associated vacuolar myelopathy with the white matter of the dorsal columns and corticospinal tracts predominantly affected in a pattern similar to that seen in subacute combined degeneration from B12 deficiency.
Human T-cell lymphotropic virus type I (HTLV-I) is an important cause of infectious myelopathy worldwide, and particularly in specific populations within Central and South America, Africa, and Japan. It is transmitted vertically mother-to-child (likely predominantly through breastfeeding), via sexual contact, and via contaminated blood products. Although most people infected will remain asymptomatic, approximately 2%–4% develop HTLV-I-associated myelopathy (HAM; also known as tropical spastic paraparesis). HAM is characterized by slowly progressive hyperreflexia, spasticity, and weakness of the legs with resulting gait impairment. Patients often additionally describe urinary dysfunction, lower back pain, and sensory dysfunction. Progression is usually over years to decades. Imaging may be normal or may reveal cord atrophy without specific signal change in the cord. Diagnosis is made based on a compatible clinical syndrome and the presence of HTLV-I antibodies in the serum and CSF. HTLV-I proviral load in the CSF may be useful but is not clinically available. There are no proven disease-modifying therapies for HAM although there is preliminary evidence for mogamulizumab.
Syphilis, caused by Treponema pallidum , was historically a common cause of infectious myelopathy (tabes dorsalis), although this manifestation has become less common in the modern era. Tabes dorsalis, when it does occur, tends to occur in chronic, untreated infection and manifests with demyelination of the dorsal cord with resulting impaired proprioception and gait impairment. More common in the modern era, although still uncommon, is syphilitic meningomyelitis, manifesting as spastic weakness and generally responsive to treatment with penicillin. Early neurosyphilis can manifest as a meningitis, presenting with headache, neck stiffness, encephalopathy; ocular syphilis with uveitis, vitreitis, retinitis, and/or optic neuropathy; or otosyphilis. Patients with suspected early neurosyphilis should have lumbar puncture and if there is a CSF pleocytosis, elevated CSF total protein, or reactive CSF VDRL assay should generally be treated with IV penicillin.
Bacterial abscesses can occur in the spine and are most commonly located in the epidural space. Spinal epidural abscesses result from hematogenous spread of infection in approximately half of cases and from contiguous infection in approximately one-third of cases with Staphylococcus aureus accounting for about two-thirds of cases. Epidural abscesses can cause both mechanical compression of the spine as well as ischemia via septic thrombophlebitis. Patients can present with pain, weakness, sensory changes, and bowel and/or bladder dysfunction. The triad of back pain, fever, and neurologic deficit may only be present in 13% of patients. MRI with contrast is the diagnostic modality of choice. CSF culture is insensitive and is generally only positive in patients with positive blood cultures, so CSF analysis is generally not recommended. All patients should have urgent neurosurgical consultation for consideration of surgical drainage which can be both diagnostic and therapeutic. Antibiotics should be tailored to the causative organism, if known. Empiric antibiotics should cover methicillin-resistant S. aureus and Gram-negative bacilli; usually vancomycin plus a third or fourth generation cephalosporin.
Infectious Causes of Stroke
The most important infectious cause of stroke is infective endocarditis (IE), where microorganisms, most commonly staphylococci or streptococci, form a vegetation on a cardiac valve. Pieces of this vegetation may embolize and occlude cerebral blood vessels, leading to ischemic strokes. Approximately 25% of patients with IE will have a clinically apparent stroke and a higher proportion have clinically asymptomatic strokes visible on imaging. The other major neurovascular complication of IE is mycotic aneurysm formation where the arteries themselves become infected and are high risk for hemorrhage. Both ischemic strokes from septic emboli and mycotic aneurysms carry a high risk of hemorrhage, so anticoagulation and antiplatelet therapy should generally be avoided in patients with either complication. A common clinical dilemma is when or if to offer cardiac surgery to a patient with neurovascular complications of IE due to the need for intraoperative anticoagulation. This decision is best made with multidisciplinary input from cardiac surgery, neurology, and infectious disease.
Any infection that causes a meningitis and, especially meningitis at the skull base (basilar meningitis), can also lead to ischemic strokes. This is particularly well described in bacterial and tuberculous meningitis. In tuberculous meningitis, antiplatelet therapy has been shown to reduce risk of ischemic stroke, although not mortality. VZV can also infect cerebral arteries and lead to ischemic strokes and/or hemorrhage, a syndrome termed VZV vasculopathy. VZV vasculopathy is often associated with a typical VZV rash, and especially with herpes zoster ophthalmicus, but there is no rash in almost 40% of cases. Diagnosis is generally via CSF PCR for VZV DNA or elevation of VZV IgG in the CSF (ideally with an increased CSF:serum IgG index). Patients should be treated with high-dose IV acyclovir and experts also recommend a short course of glucocorticoids to reduce inflammation although there is no trial data to support this recommendation.
Central Nervous System Tuberculosis
Although the incidence of tuberculosis (TB) in the United States has been decreasing, there are still almost 8000 new diagnoses annually, with almost 1700 of those presenting with extrapulmonary tuberculosis. Approximately 5% of those with extrapulmonary disease will have tuberculous meningitis, a severe neurologic infection resulting in death or permanent disability in about half of those affected. People living with HIV are at higher risk for tuberculous meningitis and for more severe disease. CNS TB most commonly presents as tuberculous meningitis which often starts subacutely with nonspecific symptoms such as fever, headache, nausea, and anorexia before progressing to focal neurologic symptoms such as cranial neuropathies, paresis, encephalopathy, and/or seizures. Imaging may show evidence of a skull base predominant meningitis ( Fig. 9.2 ) and CSF analysis typically shows a lymphocytic pleocytosis with elevated protein and low glucose. CNS TB can also manifest with tuberculomas with or without meningitis. Tuberculomas can occur throughout the brain or spine and can be asymptomatic, cause neurologic deficits associated with their location, or cause seizures. Prompt recognition and initiation of treatment are important to minimize morbidity and mortality, but diagnostic evaluation of CNS TB is complex with multiple diagnostic tests with varying sensitivity and specificity available. Treatment of CNS is similarly complex with multiple complex considerations including choosing an adequate drug regimen and duration, ensuring adequate drug dosing, considering whether to add corticosteroids and at which dose/duration, and, in people living with HIV, when to start antiretroviral therapy. Additionally, patients with CNS TB are at risk for multiple complications including hydrocephalus, strokes, seizures, and paradoxical worsening. Because of the complexities of diagnosis and management of CNS TB, infectious disease and neurology consultation should be sought as soon as the diagnosis is being considered.
