Infectious Diseases
Although infectious diseases affecting the central nervous system (CNS) are plentiful, there is a subtle misperception that these may have become uncommon to pay much attention. Neuroinfectious disorders that would have been readily recognized by an expert clinician are growingly believed as rare. Regardless, many “classics” have always been fascinating.
Rabies, a zoonotic viral infectious disease, is now effectively controlled with vaccination programs in dogs and other pets, whose bites are the main sources of the virus. The literature sparked our interest with its similarities to vampirism. Spasms of the facial, laryngeal, and pharyngeal muscles give rise to hoarse sounds and the appearance of an “animal with teeth clinched and lips retracted.” As saliva cannot be swallowed, there is frothing at the mouth and vomiting of bloody fluids. The spasms are generally triggered by some stimuli, such as breeze (aerophobia), water (hydrophobia), light (photophobia), noises, odor, a minimal excitement, or “the sight of mirrors.” A man was not considered rabid if he was able to stand the sight of his own image in a mirror.
Tabes dorsalis, a late manifestation of untreated syphilis, and now rarely seen due to comprehensive screening and treatment programs, became readily recognizable with a simple neurologic examination maneuver. Moritz Romberg (circa 1840) reported the observation of increased postural sway upon eye closure in tabetics in what became known as the Romberg sign. Subsequently, New York neurologist William Hammond (circa 1871) emphasized the sign’s independence from muscle weakness and from cerebellar disease. Jean-Martin Charcot (circa 1888) considered the Romberg sign as typical of tabes dorsalis, but was the first to document it also in Friedreich disease.
Postencephalitic parkinsonism was a complication of encephalitis lethargica related to the influenza epidemic, described by Constantin von Economo (1917) and brought to the fore by the movie Awakenings. Postpolio syndrome was also a complication of anterior poliomyelitis, widespread in the 1940s-1950s. Both of these complications required extensive resources and long-term neurologic care. Our history had a giant with postpolio syndrome, Franklin D. Roosevelt (32nd US President), who steered Western democracies through the Great Depression and World War II.
Admissions to or consults by a busy hospital neurology service for any neuroinfectious disease account for less than 3% per year. About one-fourth of patients may have an HIV infection, but almost one-third remain without an identifiable microbiologic etiology and require long hospitalizations, expensive diagnostic tests and treatments, and substantial posthospital rehabilitation and long-term care needs. The burden of recognizable and potentially curable conditions may be shortened by getting to the next few pages time and again while in rounds.
Cerebrospinal Fluid
Cerebrospinal fluid (CSF) is formed in the ventricular choroid plexus at a rate of 500 mL/d. Total volumes (and pressures in mm H2O) are 150 mL (180, 250 if obese) in adults, 60 to 100 mL (150) in children, and 30 to 60 mL (110) in neonates.
Hypoglycorrhachia (below 45 mg/dL or a CSF:serum ratio < 0.6) can be seen in bacterial meningitis, TB meningitis, fungal meningitis, carcinomatous meningitis, sarcoidosis, amebic meningoencephalitis, HSV encephalitis, lymphocytic choriomeningitis, mumps, and GLUT1 deficiency syndrome.
CSF Patterns in Infectious Meningitis
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Lymphocytic pleocytosis with low glucose can be seen in partially treated bacterial meningitis and in bacterial meningitis due to Listeria monocytogenes. Other entities include TB, fungal meningitis, neoplastic meningitis, sarcoidosis, partially treated bacterial meningitis, viral meningitis (e.g., mumps, LCM), and spirochetal meningitis (e.g., lues, leptospirosis).
Lymphocytic pleocytosis with normal glucose can be seen in viral meningitis/encephalitis, postinfectious encephalomyelitis, partially treated bacterial meningitis, parameningeal infections, early phase of TB and fungal meningitis, parasitic diseases, neoplastic meningitis.
PMN pleocytosis typically indicates bacterial infections but may be seen within the first 24 hours in meningitis due to enteroviruses and arthropod-borne viruses (LaCrosse and St. Louis encephalitis), for which reverse transcriptase (RT) PCR and a fourfold increase in virus-specific IgG are diagnostic, respectively.
Persistent PMN pleocytosis suggests HIV-associated CMV polyradiculomyelitis, as well as West Nile virus (WNV) meningoencephalitis; mononuclear pleocytosis occurs in HIV-1 meningitis within 3 to 6 weeks of initial infection, when CD4+ T-lymphocyte count is >400 cells/mm3.
CSF eosinophilia can be seen in a range of parasitic diseases such as from cysticercosis, angiostrongylus cantonensis, echinococcus granulosus, Coccidioides immitis, as well as from Treponema pallidum, Mycobacterium tuberculosis, coxsackie, subacute sclerosing panencephalitis (SSPE), and lymphocytic choriomeningitis.
CSF in Encephalitis
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Fourfold IgG antibody increase between acute and convalescent sera is diagnostic for arboviruses, RMSF, EV, and HHV-6 (HHV-6 DNA is not sufficient since it may be due to latent infection).
Eastern equine encephalitis, the deadliest of the arboviral encephalitis, may uniquely involve the basal ganglia and thalami early and cause xanthochromia, hyponatremia, and raise the CSF leukocyte count above 1,000 (neutrophils). The La Crosse virus accounts for most cases of encephalitis in the pediatric age group. Japanese B encephalitis virus is the most common arthropod-borne human encephalitis worldwide, which does not show the July-to-October seasonal pattern of other arboviral encephalitis. St. Louis encephalitis (SLE) and WNVs are discussed later.
Meningoencephalitis and Rash (Rash Distribution, Diagnosis, and Treatment)
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Viral Encephalitis
Herpes simplex virus (HSV) is responsible for 10% of endemic cases of viral encephalitis in the United States. (Japanese B encephalitis is the most common epidemic infection outside North America.) The typical focal abnormality on brain MRI is T2W-hyperintense signal in the orbitofrontal cortex and hippocampus/medial temporal lobes. When bilateral destruction of the temporal lobes involves the anterior operculum and insular areas, a potential complication is the opercular syndrome (Foix-Chavany-Marie syndrome). It is characterized by loss of voluntary movements of the facio-pharyngo-glosso-masticatory muscles (anarthria, inability to move the tongue or swallow to commands) with preservation of reflex movements (intact cough and swallowing reflexes) and limb strength. Choreoathetosis and refractory seizures may complicate post-HSV and HHV6 encephalitis, most often due to NMDAR (less so, GABAAR) antibodies and respond to immunotherapy.
HSV type 2 is a major cause of nondermatomal genital or truncal vesicular lesions, intermittent radiculopathy, and benign recurrent lymphocytic meningitis (Mollaret meningitis). On pathology, Cowdry type A inclusion bodies are characteristic (Negri bodies are of rabies). Other recurrent meningoencephalitis include VZV reactivation, Behcet disease, and the Vogt-Koyanagi-Harada syndrome (uveomeningoencephalitis with vitiligo of skin, hair, and mucosa).
Varicella zoster virus (VZV), more common in immunocompromised patients, may follow, by days to months, a vesicular rash in a dermatomal distribution. VZV infects endothelial cells and oligodendrocytes causing ischemic and hemorrhagic infarction and demyelination. Zoster may be complicated by postherpetic neuralgia, myelitis, meningoencephalitis, meningoradiculitis, cerebellitis, retinal necrosis, herpes zoster ophthalmicus, and giant cell arteritis. In children, acute cerebellar ataxia, encephalitis, and ischemic stroke are well-recognized complications of chickenpox. Anti-VZV IgG antibody in CSF is the virologic test of choice for diagnosis. Negative VZV DNA PCR and negative anti-VZV IgG antibody in CSF most reliably excludes the diagnosis of VZV vasculopathy.
Selected Clinical Clues Favoring Specific Encephalitides
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Common and Emerging Viral Encephalitides
The three most common causes of viral meningitis and encephalitis in North America are enteroviruses (especially in infants and hypogammaglobulinemic patients), arboviruses (particularly WNV), and HSV. In adolescents and adults, herpes simplex virus 1 (HSV-1) more commonly causes encephalitis, whereas HSV-2 causes meningitis.
The three most common mimics are the autoimmune limbic encephalitis due to LGI1, GABABR, and AMPAR antibodies, all associated with hyponatremia (60% of GABABR are associated with small-cell lung cancer).
Preferential sites of involvement for selected viruses are the frontal and temporal lobes (HSV), the cerebellum (VZV and EBV), and the limbic system (rabies).
Several major viral infections have been associated with a wide range of serious neurological complications including Zika, Chikungunya, and acute flaccid myelitis (AFM).
Zika virus (ZIKV), a single stranded RNA flavivirus related to dengue, yellow fever, WNV, SLE, and Japanese encephalitis, causes vector-borne infectious disease transmitted by Aedes species of mosquitoes. In newborns, ZIKV disease has been associated with microcephaly, encephalitis, and calcifications at the cortical-subcortical junction, with variable ocular findings, including macular lesions, focal mottling of the retina, chorioretinal atrophy, optic nerve abnormalities, cataract, microphthalmia, and strabismus. In adults, the most common presentation is Guillain-Barré syndrome (GBS), but some patients may develop acute transverse myelitis, meningoencephalitis, ADEM, CIDP, seizures, cerebrovascular complications, and transient polyneuritis.
Chikungunya, an alphavirus also transmitted by Aedes mosquitoes, has been associated with a large spectrum of neurological disorders, including encephalopathy, encephalitis, myelopathy, myelitis, GBS, ADEM, and optic neuritis, among others. Brain MRI may show confluent areas of hyperintensity suggestive of demyelination in an ADEM-suggestive pattern, potentially involving the corpus callosum and the frontal and parietal lobes.
AFM, a rare disorder (1-2 cases per million) mostly affecting children, may follow viral infections such as poliovirus, flavivirus (WNV), adenovirus, and nonpolio enteroviruses. AFM is characterized by sudden onset of focal flaccid limb weakness with areflexia, and at times cranial nerve weakness (facial weakness, ophthalmoplegia, often following a respiratory or other febrile illness). Spinal MRI shows hyperintense signal abnormalities or T2 and FLAIR especially involving the ventral horns of the gray matter. CSF studies may show mild pleocytosis and discrete elevation of the protein content.
Imaging of Viral Encephalitis
 Herpes simplex virus encephalitis: 63-year-old woman with a 2-week history of headaches and fever, followed by features suggestive of partial complex seizures (staring and tapping the dorsal aspect of her right hand with her left hand; repeating: “is OK, is OK”; calling a computer, “stove”). Brain MRI showed hyperintense T2/FLAIR signal abnormalities involving both anterior and medial aspects of the temporal lobes, left greater than right, and extending into the inferior left frontal lobe with some hemorrhage and enhancement. A similar pattern may be seen in some autoimmune (due to voltage-gated potassium channel or NMDAR antibodies) and paraneoplastic (limbic) encephalitis. |
 Rhombencephalitis: 28-year-old woman with 2-week history of flu-like symptoms and diplopia. CSF showed lymphocytic pleocytosis. She normalized after a 14-week course with acyclovir. Etiology was not uncovered, but viral entities associated with this presentation are arboviruses (St. Louis and West Nile), enteroviruses (Coxsackie), and adenoviruses. Rhombencephalitis is a form of encephalitis that affects primarily the brainstem and cerebellum (rhombencephalon), presenting with gaze palsy, diplopia, persistent hiccuping, central sleep apnea, or acute respiratory failure. Listeria monocytogenes infection has been a classical etiology. This imaging pattern has also been reported in the setting of infections with human herpes virus; paraneoplastic disorders due to anti-Yo, anti-Hu, anti-Ri, and anti-Ma2 antibodies; lymphoma; vasculitic diseases (systemic lupus erythematosus); Behçet (most common autoimmune etiology) disease; neurosarcoidosis; tuberculosis; multiple sclerosis (MS); and acute disseminated encephalomyelitis. |
Viral Meningoencephalitis: Temporal and Geographical Distribution
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St. Louis Encephalitis and West Nile Virus Encephalitis
The SLE (midwestern and southern United States) and WNV encephalitis (expanding from New York and northeast) are, respectively, the most common and most rapidly spreading arboviral infections during the late summer and early fall and have similar ecology and epidemiology. They belong to the Japanese encephalitis virus complex of antigenically related flaviviruses.
SLE and WNV are primarily avian infections (reservoirs and hosts) that spread to humans via ornithophilic culicine mosquitoes (vectors). The WNV was first identified in Uganda in 1937, and became endemic in the Middle East, Africa, and parts of Europe. It was initially mistaken as SLE in New York in 1999 in two cases of encephalitis associated with muscle weakness, which were preceded by a fatal epizootic among American crows, Corvus brachyrhynchos, a species that remain a sentinel for the spread of this virus.
SLE typically causes mild to moderately severe illness. Meningoencephalitis with myalgia develops in 1 of 100 infected patients. Disease severity is worse in those over 50 years, with tremor, seizures, and hyponatremia from inappropriate antidiuretic hormone secretion (SIADH) complicating the course, associated with T2W hyperintensity in the bilateral substantia nigra and thalamus.
WNV infection causes a mild febrile illness in one out of five infected (3-6 days) with headache, eye pain, nonpruritic macular rash, and gastrointestinal problems. Leukopenia with relative or absolute lymphopenia is unusual in other viral encephalitides. Meningoencephalitis develops in 1 out of 150 infected, often associated with severe muscle weakness in the elderly or immunosuppressed. Parkinsonism, tremor, and myoclonus have been reported. The predominant gray matter lymphocytic infiltration, causing T2W hyperintensity in deep brain and cerebellar nuclei, has the capability of affecting the entire neuroaxis and spinal roots.
The muscle weakness induced by WNV may present in two forms:
Guillain-Barré type syndrome
Poliomyelitis-like syndrome (affecting anterior horn cells)
Diagnosis of arboviral encephalitis can be relied upon the following tests:
Virus-specific CSF IgM is confirmatory; serum IgM is suspicious. The latter requires a fourfold increase in virus-specific IgG in convalescent sera. IgM becomes detectable in 75% of patients with flavivirus encephalitis within the first 4 days of illness and may persist for one or more years after the infection.
Virus-neutralization tests are used to distinguish the antigenically related WNV from SLE infections when serum specimens are available due to the serologic cross-reactions with other flaviviruses.
Qualitative rt-PCR or quantitative PCR have poor sensitivity.
Aseptic Meningitis Syndrome
Infectious causes include enteroviruses, arboviruses, HSV-2, HHV-6, VZV, EBV, fungi, Mycoplasma pneumoniae, Borrelia burgdorferi, and Treponema pallidum. Noninfectious causes include sarcoidosis, carcinomatous meningitis, SLE, granulomatosis with polyangiitis, Behçet disease, and drug-induced.
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