Article 1: Acute Bacterial Meningitis
Larry E. Davis, MD, FAAN. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1264–1283.
PURPOSE OF REVIEW
While acute bacterial meningitis is becoming less common in developed countries because of the widespread use of vaccines against Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae, bacterial meningitis still occurs worldwide, with peak incidence in young children and the elderly. Bacterial meningitis is usually lethal unless appropriate antibiotics that cross the blood-brain barrier are given. Clinical suspicion of bacterial meningitis begins when patients present with the abrupt onset of fever, headache, and meningismus.
New technologies are being developed for more rapid identification of the bacterial species causing meningitis. When appropriate, administration of adjunctive dexamethasone with the antibiotics often lessens neurologic sequelae in survivors, which may include aphasia, ataxia, paresis, hearing loss, and cognitive impairment.
Confirmation of the diagnosis of bacterial meningitis comes mainly from examination and culture of CSF obtained from a lumbar puncture. Typically, the CSF shows an elevated neutrophil count, elevated protein, depressed glucose, positive Gram stain, and growth of the bacteria on appropriate culture media. Antibiotic sensitivities of the bacteria determine the appropriate antibiotics, although an educated guess of the best antibiotics to be given promptly must be made until the antibiotic sensitivities return, usually in a few days.
- Acute bacterial meningitis is a severe life-threatening inflammation of the meninges and subarachnoid space caused by bacteria. The meningeal inflammation can cause vasospasm and even thrombosis of cerebral arterioles, arteries, and draining veins.
- Acute bacterial meningitis causes up to 16 million infections worldwide each year.
- In infants, the symptoms of meningitis may be nonspecific, with lethargy, fussiness, sleepiness, jitteriness, anorexia, hypotonia, apnea, jaundice, diarrhea, and general weakness.
- Because many maternal immunoglobulins do not cross the placenta before 32 weeks, very premature infants are at a higher risk for infections than other children.
- In older children, classic meningitis features include fever, severe headache, lethargy, irritability, confusion, photophobia, nausea, vomiting, stiff neck, and back pain.
- In adults, communityacquired bacterial meningitis may present with headache, neck stiffness, fever, and impairment of consciousness. However, patients may not have all these clinical features.
- Adults older than 65 years of age can have an atypical presentation of meningitis. Fever is not a constant finding, headache and nuchal rigidity may not be present, and nonspecific confusion is common.
- More patients are developing health care–associated bacterial meningitis. This meningitis differs from communityacquired bacterial meningitis in that it typically develops in patients with chronic illnesses or following trauma or neurosurgical procedures.
- When meningitis is suspected, the key to diagnosis and establishing the etiology is examination and culture of CSF.
- In lumbar puncture, if a patient has a severe bleeding tendency or is anticoagulated, a risk of causing a spinal hematoma exists if the lumbar puncture needle hits a radicular vein within the lumbar subarachnoid space.
- A small risk of brain herniation exists following removal of CSF from the lumbar space. This usually develops from downward shifting of one temporal lobe through the midline tentorial opening, producing a herniation syndrome.
- New CSF diagnostic tests are being developed to improve on the standard method of culturing CSF on agar plates.
- Streptococcus pneumoniae is the most common cause of community-acquired acute bacterial meningitis in the United States.
- The case fatality rate of pneumococcal meningitis is 10% to 20% in developed countries but much higher (30% to 40%) in developing countries.
- Neisseria meningitidis is a major cause of meningitis in sub-Saharan Africa.
- Listeria monocytogenes causes about 9% of acute bacterial meningitis cases worldwide, with the highest incidence in infants, the elderly, and individuals with a malignancy or who are immunocompromised or posttransplantation.
- Staphylococcus aureus accounts for about 5% of meningitis but has a mortality rate of about 30%. It is classified as a major cause of health care–associated bacterial meningitis.
- Bacterial meningitis caused by anaerobic bacteria is uncommon but appears tomainly develop in infants whose mothers had amnionitis or other delivery problems and in children and adults with otitis media, sinusitis, pulmonary infections, CNS shunt infections or who have had recent neurosurgery.
- Despite rapid diagnosis and appropriate antibiotic treatment, acute bacterial meningitis still has a complication rate of up to 20%.
- For maximum benefit, adjunctive dexamethasone must be given early in the meningitis course when administering antibiotics and must be in high dose, and the administered antibiotics must cross the blood-brain barrier and kill the meningitis bacteria.
- The incidence of neurologic sequelae of acute bacterial meningitis is substantial. The most commonly reported sequelae are hearing loss, cognitive impairment, and epilepsy.
Article 2: Viral Meningitis and Encephalitis
Jennifer L. Lyons, MD. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1284–1297.
PURPOSE OF REVIEW
This article discusses meningitis and encephalitis infections caused by viruses, excluding herpes family and human immunodeficiency virus (HIV).
The viral infections of the nervous system detailed in this article have no specific treatment other than supportive care. However, many of the viruses discussed are highly preventable by vaccination, proper skin protection against transmitting vectors, and postexposure prophylaxis.
While meningitis and encephalitis caused by viruses may have some clinical overlap, the management and outcomes can be highly disparate, making distinction between the two imperative. Furthermore, despite their relative rarity in terms of clinical disease, many of the viral infections discussed herein are highly preventable. Given the morbidity and mortality attached to such infections, provider and patient education are the best approach available to prevent these potentially devastating illnesses.
- Differentiating between viral meningitis and viral encephalitis is arguably more important than determining which virus caused disease, as the prognosis differs greatly between the two infections, even when occurring by the same organism.
- Immediacy of rabies postexposure prophylaxis initiation is paramount, and in remote or rural places where availability is an issue, preexposure prophylaxis should be considered.
- Review preventive measures for vector-borne illnesses with patients who are traveling to or living in endemic areas prior to exposure.
- Asymptomatic West Nile virus infection in the United States is quite common, which means that discovering IgG in the blood is not diagnostic of acute disease.
- Japanese encephalitis virus and tick-borne encephalitis virus are both vaccine preventable, yet they still cause tens of thousands of symptomatic infections each year.
- Enterovirus is thought to be the most common etiology of viral meningitis.
- Postexposure prophylaxis for measles is recommended for the unvaccinated who come into contact with this highly contagious disease.
- Although extremely rare, encephalitides caused by measles can be devastating and fatal.
- Subacute sclerosing panencephalitis occurs years after the initial infection and is progressive and fatal. Presentation is notable for progressive cognitive impairment over months that is eventually accompanied by additional focal neurologic deficits and myoclonus, which also progress.
- Many viral infections of the meninges and brain parenchyma are preventable, and given the lack of specific antidote for disease, preemptive education of patients on both preventing exposure and seeking immediate attention where postexposure prophylaxis is available is the best approach to these infections.
Article 3: Chronic Meningitis
Kiran T. Thakur, MD; Michael R. Wilson, MD, MAS. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1298–1326.
PURPOSE OF REVIEW
This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and noninfectious etiologies of chronic meningitis.
Identification of the etiology of chronic meningitis remains challenging, with no cause identified in at least one-third of cases. Often, several serologic, CSF, and neuroimaging studies are indicated, although novel diagnostic platforms including metagenomic deep sequencing may hold promise for identifying organisms. Infectious etiologies are more common in those at risk for disseminated disease, specifically those who are immunocompromised because of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), transplantation, or immunosuppressant medications. An important step in identifying the etiology of chronic meningitis is assembling a multidisciplinary team of individuals, including those with specialized expertise in ophthalmology, dermatology, rheumatology, and infectious diseases, to provide guidance regarding diagnostic procedures.
Chronic meningitis is defined as inflammation involving the meninges that lasts at least 4 weeks and is associated with a CSF pleocytosis. Chronic meningitis has numerous possible infectious and noninfectious etiologies, making it challenging to definitively diagnose patients. Therefore, a multifaceted approach that combines history, physical examination, neuroimaging, and laboratory analysis, including novel diagnostic platforms, is needed. This article focuses on key aspects of the evaluation of and approach to patients with chronic meningitis. Specific infectious etiologies and differential diagnoses of subacute and chronic meningitis, including noninfectious etiologies, are addressed.
- Establishing a cause of chronic meningitis and providing timely targeted treatment are major challenges for clinicians as many identified infectious agents are rare, and noninfectious etiologies, including medications, neuroinflammatory conditions, toxins, and malignancies, can mimic infections.
- Diagnostic testing should be guided by a thorough history, including assessment of epidemiologic factors and physical examination findings. Often, several serologic, CSF, and neuroimaging studies are indicated.
- The development of novel noninvasive diagnostic techniques, including multiplex polymerase chain reaction; 16s, 18s, and 28s ribosomal RNA polymerase chain reaction; and metagenomic deep sequencing, allows for broad pathogen testing and is an exciting scientific frontier.
- Because of the frequently indolent nature of the symptoms associated with chronic meningitis, the rare and diverse infectious causes, and the significant number of noninfectious etiologies, empiric treatment for chronic meningitis is not broadly recommended. Instead, it is recommended that empiric therapy be initiated on a case-by-case basis after weighing the risks and benefits associated with antimicrobial therapy and the potential for a worsening clinical course.
- Cryptococcus remains the most common fungal etiology of chronic meningitis globally.
- Aggressive measures to decrease intracranial pressure improve survival in cryptococcal meningitis by up to 70%. Despite this, therapeutic lumbar punctures are underutilized. Despite antifungal treatment, studies have shown that the long-term mortality in cryptococcal meningitis is at least 25%.
- CSF (1,3)-β-D-glucan was evaluated as a diagnostic assay in the US fungal meningitis outbreak associated with steroid injections. Elevated levels of CSF (1,3)-β-D-glucan were an important diagnostic aid during the outbreak, and serial CSF (1,3)-β-D-glucan levels correlated with CNS disease outcome. CSF (1,3)-β-D-glucan is now routinely used in cases of suspected fungal meningitis, except for meningitis caused by cryptococcal species.
- The US fungal meningitis outbreak had important implications with respect to medication administration safety as well as the evaluation and treatment of emerging fungal meningitis cases.
- Several viral etiologies of chronic meningitis and meningoencephalitis exist, including primary human immunodeficiency virus type 1 infection, cytomegalovirus, herpes simplex virus type 1 and type 2, polyomaviruses, enteroviruses, lymphocytic choriomeningitis virus, and mumps virus. In addition, metagenomic deep sequencing has identified a number of unusual causes of chronic viral meningoencephalitis in patients who are immunocompromised.
- Most chronic meningitis cases in individuals with human immunodeficiency virus (HIV) infection occur in the context of opportunistic infections, namely tuberculous meningitis and cryptococcal meningitis. Chronic meningitis as a manifestation of primary HIV infection, although rare, has most frequently been described around the time of seroconversion.
- Herpes simplex virus type 2 is a common cause of acute, chronic, and recurrent meningitis.
- Although bacteria are most commonly associated with acute meningitis, several bacteria species can lead to a more indolent clinical course. Both Treponema pallidum and Mycobacterium tuberculosis are important etiologies of chronic meningitis.
- Tick-borne organisms, including Ehrlichia, Babesia, and Anaplasma species, constitute an important group of bacteria that can cause chronic meningitis. Other bacterial organisms in the differential include Nocardia, Leptospira, Brucella species, and Listeria monocytogenes.
- Parasitic etiologies are important to consider in patients with a pertinent epidemiologic history, including individuals who have lived in or traveled to tropical and subtropical regions. Typically, parasitic infections are rare causes of chronic meningitis, but they are important to include in the differential diagnosis. Organisms to consider include Echinococcus, Strongyloides, Acanthamoeba, Angiostrongylus, Taenia solium, Baylisascaris, and Toxoplasma species.
- The main categories of medications associated with chronic meningitis include nonsteroidal anti-inflammatory medications, IVIg, antimicrobial medications, immunosuppressant medications, chemotherapy agents, and anticonvulsants.
- Several autoimmune and inflammatory conditions that mimic an infectious process can lead to a chronic meningitis. These cases are particularly challenging to clinicians as patients are often on chronic immunosuppressant medications for treatment of their underlying immune-mediated condition, placing them at risk for serious central nervous system infections.
- The most common neurologic manifestations of IgG4-related disease include a pachymeningitis or pituitary gland involvement.
- Vogt-Koyanagi-Harada syndrome is one of several syndromes known to involve the ocular system and meninges.
- Metastatic spread of certain solid and hematologic malignancies to the leptomeninges and pachymeninges are important considerations when evaluating a patient with chronic meningitis.
Article 4: Brain and Spinal Epidural Abscess
Felicia Chow, MD, MAS. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1327–1348.
PURPOSE OF REVIEW
Brain abscesses and spinal epidural abscesses are serious, potentially life-threatening infections of the central nervous system. This article outlines the clinical presentation, evaluation, and management of brain abscesses and spinal epidural abscesses, with a specific focus on bacterial infections.
The overall incidence of brain abscesses has declined, in part because of fewer brain abscesses associated with otogenic infections. However, emerging patient populations at high risk for brain abscess include those with a history of penetrating head trauma, neurosurgery, or immunodeficiency. Improved mortality rates for brain abscess are attributable to modern diagnostic imaging, stereotactic-guided aspiration, and newer antimicrobials that readily penetrate into the central nervous system and abscesses. Brain MRI is more sensitive than CT for brain abscess, particularly in the early stages, but CT remains more widely available and can adequately identify potential abscesses and confirm response to treatment. With the advent of minimally invasive neurosurgical techniques, surgical excision is often employed only for posterior fossa, multiloculated, or superficial well-circumscribed abscesses. In select clinical scenarios, conservative medical management may be a safe alternative to a combined surgical and medical approach. Unlike brain abscess, the incidence of spinal epidural abscess is on the rise and has been attributed to higher prevalence of predisposing factors, including spinal procedures and instrumentation.
Successful diagnosis and management of brain abscess and spinal epidural abscess requires a collaborative approach among neurologists, neurosurgeons, radiologists, and infectious disease physicians. The foundation of management of brain abscess includes surgical intervention for diagnostic purposes if a pathogen has not been identified or for decompression of larger abscesses or those with mass effect and significant surrounding edema; appropriate dosing and adequate duration of an antimicrobial regimen tailored to the presumptive source of infection and available culture data, and eradication of the primary source of infection. For spinal epidural abscesses, neurologic status at the time of presentation is directly related to outcomes, underscoring the importance of prompt recognition and intervention.
- Common mechanisms of infection in brain abscess include contiguous spread from a local site (eg, otitis media, mastoiditis, sinusitis) or hematogenous seeding from a distant source (eg, endocarditis, pulmonary, abdominal, or skin infection).
- Abscesses related to infection at a contiguous site are usually solitary, while hematogenous infection often results in multiple abscesses, commonly at the gray-white junction and borderzone vascular territories.
- Headache is the single most frequent symptom of brain abscess, whereas fever may be absent in more than half of cases. The classic triad of fever, headache, and focal neurologic deficit may be suggestive of an abscess but is neither sensitive nor specific.
- Patients presenting with purulent otorhinogenic, sinus, or dental infections with encephalopathy or focal neurologic deficits should undergo brain imaging with contrast.
- Although intense and homogeneous diffusion restriction in the core of a rim-enhancing brain lesion is highly suggestive of a pyogenic infection, high-grade neoplasms and other mimics can demonstrate a similar pattern on diffusion-weighted imaging.
- The degree of restricted diffusion within infectious nonbacterial brain abscesses is variable but typically less intense and more heterogeneous compared with pyogenic abscess or may be altogether absent.
- Given the low microbiological yield of CSF culture, except in situations of abscess rupture into the ventricle or concomitant meningitis, lumbar puncture is generally considered to play a marginal role in the diagnosis of abscess.
- Blood cultures can be positive in 25% to 50% of cases of brain abscess and should be drawn before initiation of empiric antimicrobial therapy.
- Surgical excision (versus stereotactic-guided aspiration) is increasingly reserved for abscesses in the posterior fossa, multiloculated abscesses, or superficial solitary abscesses that are well circumscribed, especially if high clinical suspicion exists for a fastidious, difficult-to-culture pathogen.
- A lower threshold for surgical excision of cerebellar abscess is recommended because of the high risk of precipitous decline from mass effect or effacement of the fourth ventricle, resulting in obstructive hydrocephalus.
- Early neurosurgical consultation should be considered for an abscess adjacent to the ventricular system, with or without focal ependymitis, because of high case-fatality rates associated with intraventricular rupture.
- In select cases of a smaller abscess (less than 2.5 cm) without mass effect, with intact mental status and absence of risk factors for poor outcome (eg, immunodeficiency), conservative management with antimicrobial therapy alone may be a safe alternative to a combined surgical and medical approach.
- The combination of a third-generation cephalosporin and metronidazole is the standard backbone of empiric therapy for brain abscesses, with the addition of vancomycin for patients at risk for staphylococcal infection (eg, after neurosurgery).
- Brain abscess is generally treated with antimicrobial therapy for a minimum of 4 to 8 weeks, with a longer course for abscesses managed with medical therapy alone and a briefer course when adjunctive antimicrobial therapy follows surgical excision.
- The duration of deficits at the time of presentation is directly related to neurologic outcome in spinal epidural abscess, underscoring the importance of prompt diagnosis and intervention.
- The sensitivity of the classic triad for spinal epidural abscess (fever, back pain, and neurologic deficits) is poor, and fever may be absent in 50% or more of cases.
- Urgent surgical drainage and decompression are the first-line approach for cases of spinal epidural abscess with acute or progressive neurologic deficits. Conservative management is considered only in select cases, including individuals at high risk for surgery who have none of the risk factors associated with a higher likelihood of failed medical therapy (eg, neurologic deficit, diabetes mellitus, methicillin-resistant Staphylococcus aureus infection).
- Use of a risk factor–based algorithm and serum inflammatory markers to risk-stratify patients presenting with back pain may aid in more prompt diagnosis of spinal epidural abscess.
Article 5: Herpesvirus Infections of the Nervous System
Kelly J. Baldwin, MD; Christopher L. Cummings, MD. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1349–1369.
PURPOSE OF REVIEW
This article reviews the spectrum of neurologic disease associated with human herpesvirus infections.
As more patients are becoming therapeutically immunosuppressed, human herpesvirus infections are increasingly common. Historically, infections with human herpesviruses were described as temporal lobe encephalitis caused by herpes simplex virus type 1 or type 2. More recently, however, additional pathogens, such as varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6 have been identified to cause serious neurologic infections. As literature emerges, clinical presentations of herpesvirus infections have taken on many new forms, becoming heterogeneous and involving nearly every location along the neuraxis. Advanced diagnostic methods are now available for each specific pathogen in the herpesvirus family. As data emerge on viral resistance to conventional therapies, newer antiviral medications must be considered.
Infections from the herpesvirus family can have devastating neurologic outcomes without prompt and appropriate treatment. Clinical recognition of symptoms and appropriate advanced testing are necessary to correctly identify the infectious etiology. Knowledge of secondary neurologic complications of disease is equally important to prevent additional morbidity and mortality. This article discusses infections of the central and peripheral nervous systems caused by herpes simplex virus type 1 and type 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6. The pathophysiology, epidemiology, clinical presentations of disease, diagnostic investigations, imaging characteristics, and treatment for each infectious etiology are discussed in detail.
- The most common reason for delay in acyclovir therapy is the failure to consider herpes simplex virus in the differential diagnosis, despite suggestive clinical features.
- Patients who are immunocompromised can have an absence of pleocytosis and a false-negative polymerase chain reaction early in herpes encephalitis. Repeat CSF testing for herpes simplex virus polymerase chain reaction at 72 hours is recommended.
- Clinicians should consider acyclovir resistance in patients with herpes simplex virus encephalitis when, despite antiviral treatment, they have notable clinical deterioration, ongoing pleocytosis and imaging progression.
- Recent literature suggests that as many as 20% of patients with herpes simplex virus encephalitis may go on to subsequently develop an autoimmune encephalitis that can mimic herpes simplex virus encephalitis relapse.
- Reactivation of varicella-zoster virus without a visible rash is known as zoster sine herpete, and symptoms may respond to antiviral therapy.
- Herpes zoster ophthalmicus is a particularly concerning manifestation of varicella-zoster virus as it can lead to a variety of orbital complications and is associated with ischemic and hemorrhagic stroke and myocardial infarction.
- Auricular distribution zoster (known as zoster oticus or Ramsay Hunt syndrome) involves reactivation of varicella-zoster virus in the geniculate ganglion of the facial nerve and may cause ipsilateral facial weakness, loss of taste or hearing, or vestibular symptoms.
- Varicella-zoster virus–associated transient ischemic attack, stroke, or arteritis may be considered more likely when there has been a recent manifestation of varicella-zoster infection or when neuroimaging demonstrates stroke (ischemic more often than hemorrhagic), CSF analysis reveals a mononuclear pleocytosis (typically <100 cells), or angiography confirms focal arterial stenosis or arterial beading.
- In cases of cerebral vasculitis due to varicella-zoster virus, the CSF polymerase chain reaction for varicella-zoster virus DNA is only 30% sensitive. Diagnostic sensitivity is improved to 93% with the addition of varicella-zoster virus IgG in the CSF, and the addition of CSF varicella-zoster virus IgM may also improve diagnostic sensitivity.
- For herpes zoster in patients older than 50 years of age, who are immunocompromised, or who have herpes zoster ophthalmicus or oticus, systemic treatment with antiviral therapy for 7 to 10 days is recommended. In patients with central nervous system manifestations of varicella-zoster virus, including vasculopathy, or those with zoster sine herpete or disseminated varicella-zoster virus, IV acyclovir is recommended for 14 days.
- Epstein-Barr virus infections of the nervous system occur almost exclusively from reactivation of latent virus in the setting of severe immunosuppression and transplantation.
- Progressive sensorineural hearing loss is the most common disability caused by congenital cytomegalovirus infection and the second most common cause of sensorineural hearing loss in children.
- Cytomegalovirus brain lesions restrict diffusion for long periods of time in locations with ongoing cytotoxicity.
- Status epilepticus and anterograde amnesia are hallmark findings in human herpesvirus 6 encephalitis due to the viral predilection for mesial temporal lobe involvement.
Article 6: Central Nervous System Infections Complicating Immunosuppression and Transplantation
Amy A. Pruitt, MD. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1370–1396.
PURPOSE OF REVIEW
This article reviews infections associated with cancer treatments and immunosuppressive/immunomodulatory therapies used in both neoplastic and non-neoplastic conditions, including hematopoietic cell transplantation and solid organ transplantation. It provides a clinical approach to the most commonly affected patient groups based on clinicoanatomic presentation and disease-specific risks resulting from immune deficits and drugs received.
The clinical presentations, associated neuroimaging findings, and CSF abnormalities of patients with central nervous system infections who are immunocompromised may differ from those of patients with central nervous system infections who are immunocompetent and may be confused with noninfectious processes. Triggering of brain autoimmunity with emergence of neurotropic antibodies has emerged as a recognized parainfectious complication. New unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity.
Despite evidence-based prophylactic regimens and organismspecific antimicrobials, central nervous system infections continue to cause significant morbidity and mortality in an increasing range of patients who are immunocompromised by their conditions and therapies. Multiple new drugs put patients at risk for progressive multifocal leukoencephalopathy, which has numerous imaging and clinical manifestations; patients at risk include those with multiple sclerosis, for whom infection risk is becoming one of the most important factors in therapeutic decision making. Efficient, early diagnosis is essential to improve outcomes in these often-devastating diseases.
- Central nervous system infections in patients who are immunocompromised can be difficult to diagnose because they can present with minimal signs of inflammation and without fever. Multiple infections may be present simultaneously, and laboratory and imaging findings may be ambiguous.
- Groups of patients with cancer at high risk for central nervous system infection include those who have undergone neurosurgery or hematopoietic cell transplantation or who have had multiple aggressive chemotherapy regimens.
- Immunosuppressive therapies predispose patients to a wide range of bacterial, fungal, and viral pathogens, whereas immunomodulatory therapies that target one or just a few immune system components make patients susceptible to a restricted range of infections.
- While fewspecific clinical syndromes are unique to specific pathogens, focal deficits suggest abscess or infarction from fungi or varicella-zoster virus, posterior fossa focal symptoms raise the possibility of infection by Listeria monocytogenes, and progressive white matter lesions with minimal enhancement suggest progressive multifocal leukoencephalopathy.
- Paralytic spinal cord syndromes suggest several viral infections including West Nile virus, Powassan virus, enterovirus, poliovirus, varicella-zoster virus, or cytomegalovirus, although radiation-related toxicity, autoimmune disorders such as neuromyelitis optica, and chemotherapy for carcinomatous meningitis can have a similar clinical and radiographic appearance.
- Important clues to infectious processes, such as Epstein-Barr virus–associated primary central nervous system lymphoma, varicella-zoster virus, cytomegalovirus, cryptococcosis, or aspergillosis, can sometimes be found through examination of the eyes, skin, sinuses, and lungs.
- All patients who are immunocompromised should have at least a screening head CT or preferably MRI before undergoing lumbar puncture.
- Diffusion-weighted imaging can help distinguish between abscesses, which typically show restricted diffusion, and cystic tumors or pseudoprogression, which do not exhibit restricted diffusion.
- Patients who have had neurosurgery represent one-fourth of all central nervous system infections in patients with cancer, often due to intracranial infection through barrier breakdown after steroids, radiation therapy, vascular endothelial growth factor inhibitors, or repeat craniotomies. Infections can be delayed for many months or even years after surgery.
- Most central nervous system infections occur within the first 6 months after transplantation, but patients remain vulnerable to varicella-zoster virus, progressive multifocal leukoencephalopathy, and other infectious complications throughout their lives.
- The older multiple sclerosis platform therapies, such as glatiramer acetate and interferons, are not associated with significant central nervous system infection risk, but fingolimod, dimethyl fumarate, and, especially, natalizumab have been associated with cases of progressive multifocal leukoencephalopathy and other opportunistic infections.
- No therapy has been found to be effective for natalizumab-associated progressive multifocal leukoencephalopathy except for withdrawal of the drug, and the benefit of plasma exchange remains unconfirmed.
- Rituximab, a CD20 monoclonal antibody, has been used in a wide variety of oncologic and autoimmune conditions and is associated with increased severity of enterovirus infection and West Nile infection. Epstein-Barr virus–positive primary central nervous system lymphoma and progressive multifocal leukoencephalopathy have both been associated with rituximab.
- One-fourth of community-dwelling patients with bacterial meningitis due to Streptococcus pneumoniae have an immunocompromising condition. Treatment of patients with suspected bacterial meningitis who are immunocompromised must include coverage for Listeria monocytogenes, gram-negative aerobic organisms, and methicillin-resistant Staphylococcus aureus.
- Aspergillus species and Candida species thrive in neutropenic environments. The usual portal of entry is the lung or sinus, and aspergillosis can present with either a chronic meningitis or a catastrophic hemorrhage because of its angioinvasive properties.
- Progressive multifocal leukoencephalopathy can have a variable clinical appearance, including vividly enhancing lesions, cerebellar atrophy, and spinal cord involvement.
- Patients who have recently received corticosteroids may require supplementation when they are stressed by central nervous system and other infections.
- A non–enzyme-inducing antiepileptic drug with little protein binding is the best choice for seizure treatment in patients who are immunocompromised.
- Immune reconstitution inflammatory syndrome occurs in numerous situations in the non–HIV-infected but immunocompromised population, including cryptococcal immune reconstitution inflammatory syndrome after withdrawal of alemtuzumab for treatment of lymphoma.
Article 7: Neurologic Complications of Human Immunodeficiency Virus Infection
Deanna Saylor, MD, MHS. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1397–1420.
PURPOSE OF REVIEW
Widespread use of antiretroviral therapy (ART) has led to near-normal life expectancy in people with human immunodeficiency virus (HIV) infection. However, neurologic complications of HIV remain common; can affect any part of the neuraxis; and are due to direct effects of the virus, immunosuppression because of untreated HIV infection, aberrant immune responses in the setting of ART initiation, and ART toxicities.
HIV-associated neurocognitive disorder (HAND) remains one of the most common neurologic complications of HIV encountered today, but milder forms predominate in people on ART. No specific treatments for HAND exist, but small trials and epidemiologic evidence suggest paroxetine, intranasal insulin, and maraviroc may have utility in its treatment; further trials of these agents are ongoing. Widespread ART use has decreased the incidence of central nervous system opportunistic infections, but prognosis often remains poor in those who develop opportunistic infections. High-titer positive serum cryptococcal antigen is strongly predictive of cryptococcal meningitis and provides a tool to enhance diagnosis in areas with limited resources. HIV is an independent risk factor for stroke, and accelerated aging associated with HIV infection results in neurologic diseases of older age occurring at much younger ages in individuals infected with HIV. Ongoing HIV replication in the CSF despite peripheral virologic suppression may contribute to the development of HAND and may not improve despite adjusting the ART regimen to increase central nervous system penetrance.
Neurologists are likely to encounter patients infected with HIV in clinical practice. This article reviews the presentation, diagnosis, and management of the most common neurologic conditions associated with HIV infection and ART.
- Neurologic complications of human immunodeficiency virus (HIV) infection affect every part of the neuraxis and stem primarily from four mechanisms: (1) direct effects of HIV, (2) opportunistic infections secondary to immunocompromise, (3) aberrant immune responses in the setting of antiretroviral therapy initiation, and (4) antiretroviral toxicity.
- HIV-associated neurocognitive disorder represents a spectrum of conditions of varying severity, including asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia.
- HIV-associated neurocognitive disorder affects up to 50% of patients who are HIV infected today. This is largely unchanged from the pre–antiretroviral therapy era, but milder stages predominate in the antiretroviral therapy era.
- HIV-associated neurocognitive disorder is a subcortical cognitive disorder that can occur at any point in the course of HIV infection, but lower nadir CD4+ T-cell count is a risk factor for its development.
- Diagnosis and classification of HIV-associated neurocognitive disorder is based on the magnitude of deficits on neuropsychological testing and functional status assessments.
- Before diagnosing a patient with HIV-associated neurocognitive disorder, a careful workup, including laboratory and radiologic investigations, should be undertaken as the diagnosis should only be considered when alternative causes of cognitive impairment have been excluded.
- All individuals with HIV-associated neurocognitive disorder should be on antiretroviral therapy, and modifiable risk factors for cognitive impairment should be identified and treated to minimize their deleterious effects on cognitive function.
- Currently, no specific treatments for HIV-associated neurocognitive disorder have been identified, but studies of paroxetine, intranasal insulin, and maraviroc are ongoing.
- Distal symmetric polyneuropathy remains one of the most common neurologic complications of HIV encountered today.
- HIV-associated distal symmetric polyneuropathy presents with slowly progressive numbness, tingling, and paresthesia in a stocking-glove distribution.
- A clinical diagnosis of HIV-associated distal symmetric polyneuropathy is sufficient, with additional testing used only for atypical presentations, but a standard workup for additional causes of distal symmetric polyneuropathy should also be completed.
- The primary goals of treatment for HIV-associated distal symmetric polyneuropathy are to prevent progression with optimal virologic suppression and to alleviate pain using standard neuropathic pain agents, nonpharmacologic strategies such as acupuncture, or both.
- Central nervous system opportunistic infections tend to occur at particular levels of immunosuppression but may have overlapping presentations and may occur concurrently.
- Cryptococcal meningitis is the most common cause of meningitis in people who are HIV infected and accounts for approximately one-fifth of acquired immunodeficiency syndrome–related mortality worldwide.
- Cryptococcal meningitis usually occurs at CD4+ T-cell counts of less than 100 cells/mm3 and initially presents as a slowly progressive nonspecific headache with or without fever.
- A serum cryptococcal antigen titer greater than 1:160 is highly sensitive and specific for a diagnosis of cryptococcal meningitis.
- Treatment of cryptococcal meningitis includes antifungal agents to sterilize the CSF and management of increased intracranial pressure.
- Progressive multifocal leukoencephalopathy usually occurs at CD4+ T-cell counts of less than 100 cells/mm3 and presents with slowly to subacutely progressive focal neurologic deficits.
- A definitive diagnosis of progressive multifocal leukoencephalopathy requires clinical, radiographic, and virologic evidence.
- In the setting of clinical suspicion and a negative CSF JC virus polymerase chain reaction, brain biopsy should be pursued to confirm a diagnosis of progressive multifocal leukoencephalopathy.
- No JC virus–specific treatment exists, so the mainstay of treatment for progressive multifocal leukoencephalopathy remains immune reconstitution with immediate antiretroviral therapy initiation.
- Immune reconstitution inflammatory syndrome manifests as clinical deterioration in the setting of immune recovery after an immunocompromised state.
- In the central nervous system, immune reconstitution inflammatory syndrome is most commonly seen in response to cryptococcal meningitis and progressive multifocal leukoencephalopathy.
- Management of immune reconstitution inflammatory syndrome includes continuation of antiretroviral therapy, initiation of specific antimicrobials for the underlying infection (if available) and use of corticosteroids in people with significant clinical deterioration due to cerebral edema.
- A complete antiretroviral therapy history is important as many people who are HIV infected encountered in clinical practice today were exposed to neurotoxic antiretroviral therapy agents in the past.
- Conditions often associated with older age, including stroke and dementia, are occurring at earlier ages in people with chronic HIV infection.
- HIV is an independent risk factor for stroke.
- CSF escape (undetectable plasma HIV RNA with detectable CSF HIV RNA) may develop in 5% to 10% of individuals who are HIV infected and may lead to higher rates of HIV-associated neurocognitive disorder and limit emerging HIV cure strategies.
- With a large population of people who are HIV infected in the United States and globally who are aging, neurologists should be aware of the neurologic complications of HIV and comfortable with their diagnosis and management.
Article 8: Tuberculosis of the Central Nervous System
Joseph R. Zunt, MD, MPH. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1422–1438.
PURPOSE OF REVIEW
This article details the epidemiology and clinical manifestations of central nervous system (CNS) tuberculosis (TB), provides guidance for diagnostic imaging and CSF testing, and recommends treatment strategies for tuberculous meningitis and other forms of CNS TB, illustrating key aspects of diagnosis and management with case presentations.
Although improvements in our understanding of the pathogenesis and management of CNS TB have occurred over the past 50 years, the emergence of multidrug-resistant and extensively drug-resistant TB, the advent of acquired immunodeficiency syndrome (AIDS), and the subsequent availability of highly active antiretroviral therapy that can produce the immune reconstitution inflammatory syndrome have complicated the diagnosis and treatment of CNS TB. Advances in diagnostic assays promise to increase the speed of diagnosis as well as the percentage of people with a confirmed rather than a presumptive diagnosis. Advances in precision medicine have identified polymorphisms in the LTA4H gene that influence the risk for inflammation in patients with tuberculous meningitis.
CNS TB continues to be a major cause of morbidity and mortality, with the majority of people affected living in low-income and middle-income countries. Newer diagnostic assays promise to increase the speed of diagnosis and improve appropriate selection of antituberculous therapy and anti-inflammatory medications. Despite these advances, CNS TB remains difficult to diagnose, and clinicians should have a low threshold for initiating empiric therapy in patients with presumptive infection.
- Although central nervous system tuberculosis (TB) occurs most often as a complication of pulmonary TB, imaging of the lungs may reveal what appears to be quiescent infection; it is not uncommon to have central nervous system TB manifest in individuals who were treated for pulmonary TB years or even decades previously.
- More than 50% of people with human immunodeficiency virus (HIV)/TB coinfection develop extrapulmonary TB, and individuals who are HIV positive are up to 5 times more likely to develop central nervous system involvement during TB infection than individuals who are HIV negative.
- Given the higher likelihood of developing TB in the setting of HIV infection as well as the association of HIV infection with worse outcome of TB, HIV testing should be performed in all patients diagnosed with TB.
- The most common symptoms of tuberculous meningitis include fever, vomiting, and apathy. Given the frequent involvement of the basilar meninges and ambient cistern in tuberculous meningitis, cranial nerve dysfunction is frequent. On neuroimaging, a common triad of findings includes basilar meningeal enhancement, hydrocephalus, and infarctions in the supratentorial brain parenchyma and brainstem.
- On neuroimaging, tuberculomas are typically space-occupying lesions; as the center of the tuberculoma caseates and becomes liquefied, neuroimaging characteristics change from hypointense to isointense to hyperintense.
- The immune reconstitution inflammatory syndrome is an inflammatory response to previous or undiagnosed infection that can develop in patients with HIV infection shortly after starting highly active antiretroviral therapy.
- Hyponatremia is present in almost half of patients with tuberculous meningitis and should alert the practitioner to not only the possible diagnosis of tuberculous meningitis but also the need for addressing hyponatremia to avoid potential complications.
- Compared to other central nervous system infections, tuberculous meningitis typically produces a mild pleocytosis similar to that caused by viral or fungal meningitis but with a protein level higher than most other forms of central nervous system infection.
- CSF culture typically takes 2 to 4 weeks to become positive, so when central nervous system TB is suspected, empiric treatment for presumptive central nervous system TB should be initiated before confirmation.
- Given the multiple potential interactions and complications of medications used for the treatment of tuberculous meningitis and HIV infections, consultation with an infectious diseases specialist is recommended to provide expert management of these treatments.
- In 2017, the World Health Organization reconfirmed its recommendations regarding HIV therapy in patients with TB coinfection: (1) HIV treatment should be started regardless of CD4+ T-cell count; (2) TB treatment should be initiated first, followed by antiretroviral therapy as soon as possible within the first 8 weeks of treatment; and (3) patients with profound immunosuppression should receive antiretroviral therapy within the first 2 weeks of initiating TB treatment.
- Paradoxical expansion of tuberculomas despite adequate therapy is uncommon but can produce marked worsening of symptoms; it typically responds well to continuing steroid treatment.
- The World Health Organization recommends initial adjuvant corticosteroid therapy with dexamethasone or prednisolone tapered over 6 to 8 weeks for all patients with tuberculous meningitis.
- The most common complications of tuberculosis treatment include hearing impairment (streptomycin) and vision loss (ethambutol).
Article 9: Neuroborreliosis and Neurosyphilis
John J. Halperin, MD, FAAN, FIDSA. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1439–1458.
PURPOSE OF REVIEW
This article presents an overview of the current diagnosis and management of two spirochetal infections of the nervous system, neuroborreliosis (Lyme disease) and neurosyphilis, focusing on similarities and differences. Although neuroborreliosis was first identified almost a century ago, much confusion remains about how to accurately diagnose this quite treatable nervous system infection. Well-established diagnostic tools and therapeutic regimens exist for neurosyphilis, which has been well-known for centuries.
Serologic testing targeting the C6 antigen may simplify diagnostic testing in neuroborreliosis while improving accuracy. Historically, screening for syphilis has used a reaginic test followed by a treponeme-specific assay; alternative approaches, including use of well-defined recombinant antigens, may improve sensitivity without sacrificing specificity. In neuroborreliosis, measurement of the chemokine CXCL13 in CSF may provide a useful marker of disease activity in the central nervous system.
Lyme disease causes meningitis, cranial neuritis, radiculitis, and mononeuropathy multiplex. Cognitive symptoms, occurring either during (encephalopathy) or after infection (posttreatment Lyme disease syndrome) are rarely, if ever, due to central nervous system infection. Posttreatment Lyme disease syndrome is not antibiotic responsive. Syphilis causes meningitis, cranial neuritis, chronic meningovascular syphilis, tabes dorsalis, and parenchymal neurosyphilis. The organism remains highly sensitive to penicillin, but residua of chronic infection may be irreversible.
- Overall, 10% to 15% of patients, both in Europe and in the United States, develop nervous system involvement from Borrelia infection, which is generally referred to as Lyme neuroborreliosis.
- Although a CSF lymphocytic pleocytosis often occurs with other components of the triad of lymphocytic meningitis, cranial neuritis, and radiculoneuritis, symptoms of meningitis are highly variable.
- Bilateral seventh nerve palsies are not uncommon in Lyme neuroborreliosis; because facial nerve palsies in children occur much less commonly than in adults, unilateral facial nerve palsy in a child with potential exposure should certainly raise a suspicion of Lyme disease; bilateral involvement in a child is exceptionally unusual except with Lyme disease.
- Radiculoneuritis from Lyme neuroborreliosis is probably the diagnosis most often missed.
- All neuropathic manifestations of Lyme neuroborreliosis, including radiculitis and cranial neuritis, are varying presentations of a mononeuropathy multiplex.
- As in European patients, US patients very rarely may develop parenchymal central nervous system inflammation (encephalomyelitis) from Lyme neuroborreliosis.
- Because exposures to novel antigens typically lead to increasing amounts of antibodies over time, follow-up serologic testing in 2 to 4 weeks is entirely reasonable in situations with a strong index of suspicion of early acute neuroborreliosis (symptom duration of just a few weeks) but negative initial serology.
- In patients in whom Lyme disease has been active for more than 3 to 6 weeks, IgM reactivity is largely irrelevant (and actually more likely to be a false positive than a true positive).
- If the enzyme-linked immunosorbent assay is negative, a Western blot should not be performed; by the same token, a Western blot should not be performed without knowing the results of the enzyme-linked immunosorbent assay.
- In patients with no evidence of any nervous system involvement of any sort or in whom involvement is strictly limited to the peripheral nervous system, there is no reason to think CSF will be abnormal or informative.
- Cognitive difficulties occurring in the context of systemic Borrelia burgdorferi infection are a nonspecific, likely cytokine-mediated remote neurobehavioral effect of infection and should not be considered evidence of neuroborreliosis, ie, nervous system infection with B. burgdorferi.
- It is unclear if posttreatment Lyme disease syndrome exists or if it largely reflects misattribution of a very common symptom complex to sequelae of the infection.
- Approximately 95% of patients with Lyme meningitis, radiculitis, cranial neuritis, and other forms of peripheral nerve involvement will respond well to 2- to 4-week courses of appropriate antibiotics (now typically doxycycline 100 mg orally, 2 times a day for 2 to 4 weeks).
- Unless the patient has clear evidence of Lyme disease at presentation, idiopathic facial nerve palsies should be treated with steroids, absent other contraindications.
- The similarities between Lyme disease and syphilis are intriguing and informative.
- Antibiotic resistance has not been a substantial problem with either Lyme disease or syphilis. Both are fastidious in vitro; Treponema pallidum remains impossible to culture, and culturing Borrelia burgdorferi is impractical for clinical purposes.
- Just as in Lyme borreliosis, early meningeal seeding is quite common in syphilis, sometimes in the absence of any apparent immune reaction.
- About one-third of untreated patients with latent infection will progress to symptomatic late (tertiary) syphilis.
- While specific antitreponemal antibodies, as with IgG antibodies in most other infections, remain elevated long after successful treatment, high-titer nonspecific reaginic antibodies are present primarily in active infection and fall with successful treatment of syphilis.
- Both reaginic and treponemal assays are often negative in primary syphilis.
- Sera screening positive for reaginic antibodies should be confirmed with a specific antitreponemal antibody test.
- Testing of CSF has long played an essential role in the diagnosis of neurosyphilis. Given that treatment of patients with neurosyphilis differs from that in patients without nervous system infection, this will continue to be important.
- Meningovascular syphilis presents as strokes, occurs several years into the illness, and represents about 10% to 15% of neurosyphilis cases.
- Treponema pallidum remains highly sensitive to penicillin.
- In patients with human immunodeficiency virus and syphilis, very close follow-up is prudent.
Article 10: Tetanus, Botulism, and Diphtheria
Aaron L. Berkowitz, MD, PhD. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1459–1488.
PURPOSE OF REVIEW
This article reviews the pathophysiology, epidemiology, clinical manifestations, diagnosis, and treatment of tetanus, botulism, and diphtheric neuropathy.
Tetanus is most common in lower-income settings, but rare cases are seen in higher-income settings because of the inadequate maintenance of vaccination status. Foodborne botulism remains rare, but botulism can also be caused by IV drug use (wound botulism) and medical use of botulinum toxin (iatrogenic botulism); botulinum toxin has also been considered a potential agent of bioterrorism. Diphtheric neuropathy is rare but has been seen in recent epidemics in the former Soviet Union, and vaccination status is inadequate in a significant proportion of older individuals, creating the potential for subsequent epidemics.
Tetanus, botulism, and diphtheric neuropathy are rare in higher-resource settings where most neurologists practice; however, familiarity with the unique clinical manifestations of and laboratory evaluation for these disorders is essential for the rapid diagnosis and treatment of patients with these conditions.
- Neonatal tetanus is most often due to infection of the umbilical stump in infants born to unvaccinated women.
- Maternal tetanus is most commonly due to unhygienic birth or abortion practices.
- Non-neonatal, nonmaternal tetanus (referred to in this article simply as tetanus) can be caused by infections of major or minor wounds, chronic otitis media, injection drug use, or surgery.
- The clinical presentation of tetanus can be classified as generalized, local (affecting a single limb at the site of wound infection), or cephalic (affecting only muscles innervated by cranial nerves after a head wound infection).
- Disinhibition of motor neurons of peripheral and cranial nerves due to tetanus leads to increased motor activity and manifests clinically as muscle spasms. In the cranial nerve–innervated muscles, this leads to the classic features of risus sardonicus, trismus, and laryngospasm. In extremity and axial musculature, this leads to muscle rigidity with superimposed painful spasms of the limbs and abdominal and paraspinal muscles and opisthotonos.
- Attempting to elicit the gag reflex results in spasm of the masseter muscles, causing the patient to bite down (the “spatula test”).
- As a result of disinhibited sympathetic overactivity in patients with tetanus, autonomic instability can occur several days into the illness and becomes more prominent in the second week.
- When intensive care unit facilities capable of mechanical ventilation are not available, the most common cause of death in patients with tetanus is respiratory failure. When intensive care unit management of respiration and spasms is available, cardiovascular complications related to autonomic instability emerge as the main cause of death.
- Neonatal tetanus presents similarly to adult tetanus except that refusal to feed is an early sign and the disease tends to progress more rapidly.
- Tetanus is a clinical diagnosis. Since clostridial culture from wounds may be negative in cases of tetanus and can be positive in patients without tetanus, culture is considered neither sensitive nor specific.
- The EMG features of tetanus result from disinhibition of motor neurons.
- Treatment of tetanus must address several elements in parallel: airway management, neutralization of tetanus toxin, treatment of spasms, treatment of the infected wound believed to be the portal of entry, treatment of autonomic instability, and meticulous supportive care.
- IM injection of antitoxin in the form of human tetanus immunoglobulin or equine antitoxin (where tetanus immunoglobulin is not available) is recommended to neutralize circulating toxin and prevent further neurologic toxicity.
- Benzodiazepines are considered the standard of care for the treatment for tetanus spasms. Despite limited evidence, diazepam is used most commonly because of its widespread availability in regions of highest incidence.
- If spasms from tetanus cannot be adequately controlled with sedating agents, neuromuscular blocking agents may be required.
- If a wound is present, it should be cleaned and debrided to reduce the source of toxin production. Antibiotic therapy consists of oral or IV metronidazole or IV penicillin G for 7 to 10 days.
- All individuals should be vaccinated against tetanus.
- Vaccination of pregnant women can prevent both maternal tetanus and neonatal tetanus, since tetanus IgG is transferred to the fetus transplacentally.
- For patients with wounds of any type who have received fewer than three doses of tetanus toxoid vaccine or do not know their tetanus vaccine status, a dose of tetanus toxoid should be given. Patients with major wounds or unclean wounds should also receive tetanus immunoglobulin.
- For patients who are fully vaccinated against tetanus (three or more prior doses) with clean, minor wounds, tetanus toxoid vaccine is only indicated if it has been 10 or more years since the last vaccine dose. For major or unclean wounds, tetanus toxoid vaccine should be given if the last vaccine dose was 5 or more years prior; tetanus immunoglobulin is not recommended in these scenarios.
- Botulism is classified as infant botulism, foodborne botulism, wound botulism, adult intestinal colonization botulism, and iatrogenic botulism.
- Although botulism infection can complicate any wound, nearly all cases of wound botulism in the United States occur in injection drug users, particularly patients who inject black tar heroin subcutaneously (skin-popping).
- Infant botulism should be considered in the differential diagnosis of the hypotonic infant.
- Foodborne botulism presents as a rapidly progressive descending paralysis involving the cranial nerves innervating the eyes and bulbar musculature followed by the extremities.
- The classic pentad of symptoms and signs in botulism is dry mouth, nausea/vomiting, dysphagia, diplopia, and fixed, dilated pupils, although it is uncommon to observe the full pentad.
- Although dilated pupils are thought to distinguish botulism from Miller Fisher syndrome, this should not be relied upon, as many series demonstrate the low sensitivity of this finding in botulism.
- Type A botulism is associated with a more severe illness than types B and E with respect to need for mechanical ventilation and length of hospitalization, although no difference appears to exist in mortality rates between types of botulism that are treated with adequate supportive care.
- Wound botulism presents similarly to foodborne botulism, although gastrointestinal symptoms are typically absent and fever may be present (attributable to other bacteria in the cutaneous abscess rather than to botulism).
- The differential diagnosis for botulism includes Guillain-Barré syndrome (in particular, Miller Fisher syndrome and the pharyngeal-cervical-brachial variant), myasthenia gravis, and acute brainstem stroke.
- As a presynaptic neuromuscular disorder, botulism shares many electrophysiologic features with Lambert-Eaton myasthenic syndrome on nerve conduction studies and EMG: decreased compound muscle action potential amplitudes, decremental response to low-frequency repetitive stimulation, incremental response (facilitation) to high-frequency repetitive stimulation, short-duration low-amplitude motor unit potentials, and increased jitter on single fiber EMG. Sensory nerve action potentials, sensory and motor velocities, and distal latencies are normal.
- Nerve conduction study and EMG findings that that may distinguish botulism from other presynaptic disorders such as Lambert-Eaton myasthenic syndrome include less post-tetanic facilitation with high frequency repetitive stimulation compared to Lambert-Eaton myasthenic syndrome and persistence of post-tetanic facilitation for several minutes in botulism.
- In both infant botulism and foodborne botulism, antitoxin should be administered as early as possible.
- Human-derived botulism immunoglobulin is used for the treatment of infant botulism, whereas equine-derived heptavalent botulinum antitoxin (containing antitoxin against toxin types A, B, C, D, E, F, and G) is used in the treatment of all other forms of botulism and is available through the Centers for Disease Control and Prevention.
- Prevention of foodborne botulism relies on safe food preparation procedures including adequate heating, refrigeration, and safe home canning methods.
- The only known preventable source of infant botulism is honey, which should not be given to children younger than 1 year of age.
- The most common manifestation of diphtheria is pharyngitis characterized by pharyngeal pseudomembranes (adherent gray patches on the pharynx that bleed if manipulated) accompanied by low-grade fever.
- Diphtheric neuropathy is usually biphasic. Within several weeks after pharyngeal infection, lower cranial neuropathies develop, leading to dysphonia; dysphagia; and numbness of the face, tongue, and gingiva. Polyneuropathy affecting the extremities emerges several weeks later as cranial neuropathies improve.
- In one study, administration of antitoxin within 48 hours of pharyngeal symptom onset led to better outcomes for patients with diphtheric neuropathy, although it did not prevent severe disability at nadir. No difference was found in the outcome between patients who received antitoxin after day 3 of pharyngeal infection and patients who did not receive antitoxin.
- Nerve conduction studies in diphtheric polyneuropathy demonstrate slowed conduction velocities, prolonged distal latencies, conduction block, and prolonged F waves with preserved amplitudes, consistent with a demyelinating polyneuropathy.
- Acute pharyngeal diphtheria is treated with antibiotics and antitoxin.
Article 11: Helminthic Infections of the Central Nervous System
Tracey A. Cho, MD, FAAN. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1489–1511.
PURPOSE OF REVIEW
This article discusses select helminthic parasitic infections that may affect the central nervous system and reviews the epidemiology, neurologic presentation, recommended diagnostic testing, and treatment approach to these infections.
Emigration from and travel to areas endemic for helminthic infections that affect the nervous system has led to increased incidence of parasitic neurologic disease in developed countries, necessitating that neurologists be familiar with the diagnostic and therapeutic approach to these diseases. Evidence is emerging on the optimal treatment for neurocysticercosis, which varies based on the form of the disease in the nervous system.
Parenchymal neurocysticercosis is a leading cause of acquired epilepsy worldwide, and extraparenchymal neurocysticercosis is responsible for many cases of hydrocephalus. Recognition of the different stages and locations of neurocysticercosis is essential for proper management. Similarly, schistosomiasis constitutes a major cause of myelopathy in endemic areas and requires prompt diagnosis and treatment to avoid permanent deficits.
- Larval cysts of Taenia solium may persist in a viable form for many years but eventually begin to degrade, losing their ability to avoid the host’s immune response.
- Patients from Latin America with neurocysticercosis often present with multiple viable brain cysts, whereas patients from India and patients presenting in high-resource, nonendemic countries more commonly present with a solitary degenerating cyst.
- While travelers to endemic regions may be infected with cysticercosis, prolonged exposure (months to years) to high numbers of eggs is usually necessary; therefore, most casual travelers or those visiting only urban areas will be at low risk for acquiring neurocysticercosis.
- Seizures are the most common neurologic presentation of neurocysticercosis.
- As neuroimaging has become more widespread, asymptomatic neurocysticercosis is increasingly recognized in the form of multiple small calcifications on CT or MRI obtained for other reasons.
- Extraparenchymal neurocysticercosis typically presents with symptoms and signs of intracranial hypertension.
- Diagnosis of neurocysticercosis relies predominantly on the combination of plausible exposure and characteristic neuroimaging features; direct histopathologic confirmation of Taenia solium is rarely needed or pursued.
- Viable cysts may show a visible scolex and will have little to no surrounding edema or rim enhancement; the fluid within the cyst has the consistency of CSF.
- Visualization of a scolex on CT or MRI is strong evidence for neurocysticercosis.
- In some cases, a scolex may not be visible on routine MRI sequences, but diffusion-weighted imaging and highly T2-weighted sequences, such as fast imaging employing steady state acquisition (FIESTA) and constructive interference in steady state (CISS), may help identify the scolex.
- Degenerating cysts have uniform or irregular and multilobulated rim enhancement, CSF-isointense or -hyperintense cyst fluid, and surrounding edema.
- Some patients present with a calcified lesion with surrounding edema, which is thought to represent a reaction to late antigen release from the nonviable parasite remnants.
- Extraparenchymal neurocysticercosis involving the subarachnoid space around the cerebral convexity often behaves radiographically (and clinically) similarly to parenchymal neurocysticercosis.
- Neurocysticercosis involving the ventricles, basal cisterns, or sylvian fissure are best visualized with multiplanar highly T2-weighted MRI sequences (eg, FIESTA, CISS) to highlight the contrast between the cyst wall and the CSF.
- A large proportion of patients with basal subarachnoid neurocysticercosis will also have spinal canal involvement on MRI.
- Cysticercosis enzyme-linked immunoelectrotransfer blot is less sensitive in CSF than in serum, so lumbar puncture is not required for serologic testing in most cases of parenchymal neurocysticercosis.
- Serologic tests for neurocysticercosis are poorly sensitive when a single cyst is present or when the cysts are calcified.
- Serologic testing is not helpful in monitoring response to therapy once the diagnosis of neurocysticercosis is established.
- In neurocysticercosis, seizure control and reducing intracranial hypertension take priority and should be addressed before deciding on the need for antiparasitic therapy.
- Prior to antiparasitic treatment, patients with neurocysticercosis should undergo an ophthalmologic evaluation to assess for ocular involvement.
- Patients presenting with seizures in the setting of calcified neurocysticercosis should be considered to have epilepsy and are at a high risk for recurrent seizures.
- Based on randomized controlled trials, antiparasitic treatment of viable and degenerating parenchymal neurocysticercosis can hasten the radiographic resolution of cysts and lower the risk of developing epilepsy.
- For intraventricular neurocysticercosis, endoscopic surgical excision is the optimal treatment when feasible.
- For calcified neurocysticercosis, antiparasitic treatment has no role.
- Corticosteroids should be started at least 1 day prior to antiparasitic treatment and continued as a taper after completion of antiparasitic treatment.
- Neurologic involvement in schistosomiasis occurs when the worms or eggs migrate in retrograde fashion from the portal venous system through the valveless vertebral epidural plexus.
- Schistosoma mansoni is endemic in sub-Saharan Africa and parts of Brazil, Venezuela, and the Caribbean.
- Neurologists in developed countries may encounter neuroschistosomiasis in travelers to and emigrants from these regions who usually present with symptoms within weeks to months of their last exposure; however, in rare cases, the latency may be years.
- Most patients presenting with neuroschistosomiasis do not have concurrent symptoms of systemic illness, as central nervous system involvement typically occurs after acute infection.
- The most frequent initial symptoms of the myeloradicular form of schistosomiasis are back pain (with or without radicular shooting pain) or asymmetric pain in the lower limbs.
- MRI in the myeloradicular form of schistosomiasis typically reveals enlargement of the conus medullaris and cauda equina nerve roots, intrinsic cord T2 hyperintense signal, and heterogeneous cord and nerve root enhancement.
- Cerebral neuroschistosomiasis typically presents with a syndrome of one or more slowly expanding intracranial mass lesions (pseudotumor).
- CT and MRI of cerebral neuroschistosomiasis typically shows a solitary lesion or multiple subcortical mass lesions with surrounding hypodense or T2 hyperintense edema and heterogeneous contrast enhancement with irregular borders.
- Neuroschistosomiasis should be suspected in patients who originated from or traveled to an endemic area and present with a compatible clinical syndrome, ie, acute/subacute lumbosacral myeloradiculopathy or cerebral pseudotumor.
- Because the granulomatous reaction to eggs drives the edema and venous congestion in neuroschistosomiasis, corticosteroids are a mainstay of treatment for both cerebral and spinal cord forms.
- Praziquantel is an effective antiparasitic for all Schistosoma species; it destroys mature worms and thereby eliminates ongoing egg deposition.
Article 12: Zika Virus and Other Emerging Arboviral Central Nervous System Infections
James J. Sejvar, MD. Continuum (Minneap Minn). October 2018; 24 (5 Neuroinfectious Disease):1512–1534.
PURPOSE OF REVIEW
In recent years, we have observed the emergence and reemergence of a number of arthropod-borne viruses (arboviruses). Zika virus is the most recent addition to this group, first causing sporadic cases of uncomplicated febrile illness followed by sizeable outbreaks in the Pacific. However, the epidemiology and clinical features of Zika virus infection have changed rapidly and dramatically; it is now recognized as causing Guillain-Barré syndrome (GBS) in children and adults and congenital abnormalities in infected fetuses. This article reviews the epidemiology, clinical features, and diagnosis of Zika virus–associated neurologic illness and briefly reviews features of West Nile virus and Japanese encephalitis virus.
Zika virus has emerged as a significant human pathogen in recent years. In 2015, it began to cause large outbreaks of febrile rash illness in South America and the Caribbean. During these large Zika virus outbreaks, a significant increase in the incidence of GBS was also observed in multiple countries/territories. Zika virus–associated GBS has several unique features, including a relatively short interval between febrile illness and GBS onset, an unusually high incidence among older people, and prominent cranial nerve abnormalities. Congenital Zika syndrome includes a myriad of abnormalities, including microcephaly, lissencephaly, hydrocephalus, arthrogryposis, and parenchymal calcifications. Currently, no treatment has been identified for Zika virus, although work on vaccines is under way.
Arboviruses continue to surprise us with unexpected emergence in various locations, the nature of clinical illness, and outcomes. Zika virus presents a classic example of this type of emergence. Ongoing surveillance will be needed to evaluate the long-term pattern of Zika virus and related arboviruses.
- Zika virus is a member of the genus Flavivirus, which includes several medically important neurotropic viruses such as Japanese encephalitis virus, West Nile virus, and St. Louis encephalitis virus.
- In urban and suburban environments, Aedes mosquitoes transmit the Zika virus to humans in a mosquito-human-mosquito cycle in which an infected Aedes mosquito feeds on a blood meal on a human and transmits the virus, after which an infected human, still viremic with the virus, is bitten by another mosquito, thus continuing the cycle of transmission.
- Recently published studies seem to indicate a strong, if not causal, association between Zika virus and Guillain-Barré syndrome.
- The pattern of mosquito-human transmission of Zika virus continues until sufficient amplification of the virus has occurred to lead to sustained transmission, and, in areas in which people are naïve to the virus, epidemics can occur.
- Perinatal transmission, presumably through the placenta, has been considered to be the cause of congenital Zika virus syndrome; evidence also exists that Zika virus can be transmitted through breast milk or by a blood-borne route. Sexual transmission, primarily from the semen of infected men with one report of transmission from a woman to a man, has also been documented.
- Zika virus appears to be able to cause sustained infection of the testes, which can then cause semen to carry the virus. This has led to recommendations that males who have traveled to a Zika virus–infected area use condoms or abstain from sex for 6 months.
- Women who are pregnant or are considering becoming pregnant should avoid traveling to Zika virus–endemic areas and use condoms with partners or abstain from sex for 8 weeks after returning from travel.
- Nearly all of the phenotypes of Guillain-Barré syndrome have been described in association with Zika virus infection, including acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, Fisher syndrome, and uncommon variants such as acute motor-sensory axonal neuropathy and pure sensory illness.
- Several investigations have alluded to a short latency between the onset of Zika virus signs and symptoms and the onset of Guillain-Barré syndrome.
- The incidence of Guillain-Barré syndrome increases with age, but an investigation in Brazil found that in age-stratified cases, the age group–specific incidence increased with age, most dramatically in older age groups.
- A notable feature of Zika virus–associated Guillain-Barré syndrome is prominent cranial nerve palsies, in particular, bilateral facial nerve palsies.
- In addition to microcephaly, a wide range of congenital abnormalities have been observed in infants prenatally affected by Zika virus, including decreased brain parenchymal volume, lissencephaly, ventriculomegaly, cerebral calcifications, choriomeningitis, arthrogryposis, and various ocular findings.
- An association seems to exist between the time of Zika virus infection during the pregnancy and the severity of congenital malformations, with infection of the mother during the first or second trimester having more serious consequences for the infant.
- Acute-phase diagnosis of Zika virus relies on molecular testing; reverse transcriptase polymerase chain reaction testing may be able to detect viral nucleic acids early in the course of illness and should be performed on paired serum and urine specimens within 14 days of illness onset for individuals who are symptomatic.
- Treatment of Zika virus–associated Guillain-Barré syndrome is the same as for Guillain-Barré syndrome associated with any other antigenic stimulus; currently no evidence shows that treatment efficacy is any different for Zika virus–associated Guillain-Barré syndrome than for any other form of Guillain-Barré syndrome.
- IV immunoglobulin or plasma exchange should be initiated as soon as the diagnosis of Guillain-Barré syndrome is made; these treatments are more efficacious when given early in the course of Guillain-Barré syndrome.
- Japanese encephalitis virus is the most common cause of arboviral epidemic encephalitis worldwide.
- Humans are considered to be dead-end hosts for Japanese encephalitis virus, as viremia generally never gets high enough to permit human-mosquito-human transmission.
- In endemic areas, children are most susceptible to Japanese encephalitis virus illness, although adult cases can and do occur; adults seem to have less severe illness than children.
- Symptomatic infection with Japanese encephalitis virus may include a prodromic illness of fever, headache, arthralgia or myalgia, and gastrointestinal symptoms. In persons progressing to severe neurologic illness, altered mental status, sometimes progressing to coma, will follow, with features of encephalitic illness.
- A distinctive feature of Japanese encephalitis (and other flaviviral encephalitides) is prominent extrapyramidal signs, including facial masking, tremor, generalized hypertonia, and, in some cases, choreoathetosis and dystonia.
- A poliomyelitislike anterior myelitis has also been described with Japanese encephalitis virus, although less commonly than encephalitis. Anterior myelitis may occur in the absence of encephalitis.
- Definitive diagnosis of Japanese encephalitis virus infection can be made by detection of viral nucleic acid by reverse transcription polymerase chain reaction of serum or CSF (or brain tissue in fatal cases); however, viremia in Japanese encephalitis is transient, and thus polymerase chain reaction is insensitive.
- Most diagnoses of Japanese encephalitis virus rest on detection of Japanese encephalitis virus–specific IgM antibodies in serum or CSF by enzyme-linked immunosorbent assay or a fourfold rise in antibody titers between acute and convalescent sera collected 2 to 3 weeks apart.
- West Nile virus is spread via an enzootic cycle involving Culex species as the principal mosquito vector, with avian (and, to a lesser extent, equine) principal amplifying hosts. As in Japanese encephalitis virus infection, humans are considered dead-end hosts for West Nile virus, as human infection does not result in human-mosquito-human transmission.
- Most infections with West Nile virus are thought to be asymptomatic, with approximately 20% of infected people developing mild febrile illness (West Nile fever) and less than 1% going on to develop severe neurologic illness (West Nile neuroinvasive disease).
- The small percentage of people who go on to develop West Nile neuroinvasive disease may present with aseptic meningitis, including meningeal signs of nuchal rigidity, Kernig sign, Brudzinski sign, and photophobia or phonophobia.
- West Nile neuroinvasive disease is characterized by decreased or altered mental status, often with cranial nerve abnormalities. As in Japanese encephalitis, patients with West Nile encephalitis may develop an extrapyramidal syndrome, including masked facies, tremor, and myoclonus.
- A subset of patients with West Nile neuroinvasive disease may develop a poliomyelitislike anterior myelitis, with acute flaccid paralysis that is typically asymmetric.
- Older individuals and persons with compromised immune status are more likely to develop West Nile neuroinvasive disease than other individuals.