Color Atlas of Neurology

Pathogenesis

Pathogens usually reach the CNS by local extension from a nearby infectious focus (e. g. sinusitis, mastoiditis) or by hematogenous spread from a distant focus. The ability of pathogens to spread by way of the bloodstream depends on their virulence and on the immune status of the host. They use special mechanisms to cross or circumvent the blood–brain barrier (p. 8). Some pathogens enter the CNS by centripetal travel along peripheral nerves (herpes simplex virus type I, vari- cella-zoster virus, rabies virus), others by endocytosis (Neisseria meningitidis), intracellular transport (Plasmodium falciparum via erythrocytes, Toxoplasma gondii via macrophages), or intracellular invasion (Haemophilus influenzae). Thosethatenterthe subarachnoid space probably do so by way of the choroid plexus, venous sinuses, or cribriform plate (p. 76). Having entered the CSF spaces, pathogens trigger an inflammatory response characterized by the release of complement factors and cytokines, the influx of leukocytes and macrophages, and the activation of microglia and astrocytes. Disruption of the blood–brain barrier results in an influx of fluids and proteins across the vascular endothelium and into the CNS, causing vasogenic cerebral edema (p. 162), which is accompanied by both cytotoxic cellular edema and interstitial edema due to impaired CSF circulation. Cerebral edema causes intracranial hypertension. These processes, in conjunction with vasculitis, impairment of vascular autoregulatory mechanisms, and/or fluctuations of systemic blood pressure, lead to the development of ischemic, metabolic, and hypoxic cerebral lesions (focal necrosis, territorial infarction).

porting (as specified by local law), prevention of exposure (isolation of sources of infection, disinfection, sterilization), and prophylaxis in persons at risk (active and passive immunization, chemoprophylaxis).

Treatment. Patients with bacterial or viral meningoencephalitis must be treated at once. The treatment strategy is initially based on the clinical and additional findings. Antimicrobial therapy is first given empirically in a broadspectrum combination, then specifically tailored in accordance with the species and drug sensitivity pattern of the pathogen(s) identified. Causative organisms may be found in the CSF, blood, or other bodily fluids (e. g., throat smear, urine or stool samples, bronchial secretions, gastric juice, abscess aspirate).

Bacterial Infections

! Meningitis/Meningoencephalitis

For an overview of the most common pathogens, cf. Table 29 (p 376). Immune prophylaxis: Vaccines are available against Haemophilus influenzae type B infection (for infants, small children, and children over 6 years of age at increased risk), Pneumococcus (children over 2 years of age and adults with risk factors such as immunosuppression or asplenia), and meningococcus (travel to endemic regions, local outbreaks). Chemoprophylaxis is indicated for close contacts of persons infected with

Haemophilus influenzae (rifampicin) or meningococcus (rifampicin, ciprofloxacin, or ceftriaxone).

! Brain Abscess

Brain abscess begins as local cerebritis and is then transformed into an encapsulated region of purulent necrosis with perifocal edema. The pathogenic organisms may reach the brain by local or hematogenous spread (mastoiditis, otitis media, sinusitis, osteomyelitis; endocarditis, pneumonia, tooth infection, osteomyelitis, diverticulitis), or by direct inoculation (trauma, neurosurgery). The clinical manifestations include headache, nausea, vomiting, fever, impairment of consciousness, and focal or generalized epileptic seizures, neck stiffness, and focal neurological signs. The diagnosis is made by MRI and/or CT (which should include bone windows, as the infection may have originated in bony structures) and confirmed by culture of the pathogenic organism.

! Bacterial Vasculitis (p. 180)

Veins. Bacterial thrombophlebitis of the cerebral veins or venous sinuses may arise as a complication of meningitis or by local spread of infection from neighboring structures.

! Ventriculitis

Infection of the ventricular system (perhaps in connection with an intraventricular catheter for internal or external CSF drainage). The clinical findings are often nonspecific (somnolence, impairment of concentration and memory). Abdominal complaints (peritonitis) may predominate if the infection has spread down a ventriculoperitoneal shunt to the abdomen. Diagnosis: CSF examination and culture.

! Septic Encephalopathy

Bacteremia leads to the release of endotoxins, which, in turn, impair cerebral function. Septic encephalopathy can produce findings suggestive of meningoencephalitis such as impairment of consciousness, epileptic seizures, paresis, and meningismus, despite the absence of CSF inflammatory changes and a sterile CSF culture. Diagnosis: EEG changes consistent with the diagnosis (general changes, triphasic complexes, burst suppression) in the setting of known systemic sepsis with sterile CSF. CT and MRI are normal.

! Lyme Disease (Neuroborreliosis)

Pathogenesis. The spirochete Borrelia burgdorferi sensu lato (Europe: B. garinii, B. afzelii; North America: B. burgdorferi sensu stricto) is transmitted to man by ticks (Europe: Ixodes ricinus; North America: Ixodes pacificus, I. scapularis). The probability of infection is low unless the infected tick remains attached to the skin for at least 24–48 hours. Only 1–2% of individuals bitten by ticks become infected. The incubation time ranges from 3–30 days. The disease occurs in three stages, as described below.

Clinical manifestations. Stage I (localized infection). Up to 90% of all patients develop a painless, erythematous macule or papule that gradually spreads outward from the site of the tick bite in a ringlike or homogeneous fashion (erythema chronicum migrans). This is commonly accompanied by symptoms due to hematogenous spread of the pathogen, such as fever, fatigue, arthralgia, myalgia, or other types of pain, which may be the chief complaint, rather than the skin rash. Regional or generalized lymphadenopathy (lymphadenosis benigna cutis) is a less common presentation. All of these findings may resolve spontaneously.

Stage II (disseminated infection). Generalized symptoms such as fatigue, anorexia, muscle and joint pain, and headache develop in 10–15% of patients within ca. 3–6 weeks, sometimes accompanied by mild fever and neck stiffness. Cardiac manifestations: Myocarditis or pericarditis with AV block. Neurological manifestations:

Cranial nerve palsies, painful polyradiculitis and lymphocytic meningitis (Bannwarth syndrome, meningopolyneuritis) are commonly seen in combination. One or more cranial nerves may be affected; the most common finding is unilateral or bilateral facial palsy of peripheral type. Neu- roborreliosis-related polyradiculoneuropathy

(which may be mistaken for lumbar disk herniation) is characterized by intense pain in a radicular distribution, most severe at night, with accompanying neurological deficits (motor, sensory, and reflex abnormalities, focal muscle atrophy). Borrelia-related meningitis (Lyme meningitis) usually causes alternating headache and neck pain, but the headache is mild or absent in some cases. It may be worst at certain times of day. CSF studies reveal a mononuclear

pleocytosis with a high plasma cell count and an elevated protein concentration, while the glucose concentration is normal. Encephalitis occurs relatively rarely and may cause focal neurological deficits as well as behavioral changes (impaired concentration, personality changes, depression). MRI reveals cerebral white-matter lesions, and the CSF findings are consistent with meningitis. Myelitis, when it occurs, often affects the spinal cord at the level of a radicular lesion.

Stage III (persistent infection). The latency from clinical presentation to the onset of stage III disease varies from 1 to 17 years (chronic Lyme neuroborreliosis). Few patients ever reach this stage, characterized by neurological deficits such as ataxia, cranial nerve palsies, paraparesis or quadriparesis, and bladder dysfunction (Lyme encephalomyelitis). Encephalopathy causing impairment of concentration and memory, insomnia, fatigue, personality changes, and depression has also been described. Myositis and cerebral vasculitis may also occur. In stage III of Lyme disease, acrodermatitis chronica atrophicans of the extensor surface of the limbs may be seen along with a type of polyneuropathy specific to Borrelia afzelii.

Diagnosis. Many patients have no memory of a tick bite. The diagnosis of Lyme disease is based on the presence of erythema chronicum migrans, the immunological confirmation of Borrelia infection (e. g., by ELISA, indirect immunofluorescence assay, Western blot, or specific IgG antibody–CSF-serum index) and/or the identification of the causative organism (e. g., by culture, histology, or polymerase chain reaction). By definition, the diagnosis also requires the presence of lymphocytic meningitis (with or without cranial nerve involvement or painful polyradiculoneuritis), encephalomyelitis, or encephalopathy.

Treatment. Local symptoms: Antibiotic such as doxycycline or amoxicillin (p.o.) for 3 weeks. Neuroborreliosis: Ceftriaxone or cefotaxime (i. v.) for 2–3 weeks. A vaccine has been approved for use in the United States, and another is being developed for use in Europe.

! Neurosyphilis

Pathogenesis. Syphilis is caused by the spirochete (bacterium) Treponema pallidum (TP) ssp. pallidum and is transmitted by direct exposure to infected lesions, usually on the skin or mucous membranes, during sexual contact. Other routes of transmission, such as the sharing of needles by intravenous drug users, are much less common. The disease has three clinical stages. In the primary and secondary stages, nonspecific tests (VDRL and RPR) and specific tests (TPHA, FTA-ABS, and 19S-(IgM-)FTA-ABS tests) yield positive results. Tertiary stage (currently rare): After an asymptomatic period of a few months to years (latent syphilis), organ manifestations develop, such as gummata (skin, bone, kidney, liver) and cardiovascular lesions (aortic aneurysm). The first year of the tertiary stage is designated the early latency period and is characterized by a high likelihood of recurrence and, thus, recurrent infectivity.

Clinical manifestations. TP may invade the nervous system at any stage of syphilis without necessarily producing signs or symptoms.

Early meningitis. A variably severe meningitic syndrome may be accompanied by deficits of CN VIII (sudden hearing loss), VII (facial palsy), or II (visual impairment). Meningopolyradiculitis is rare. CSF examination reveals lymphocytic pleocytosis (up to 400 cells/µl) and an elevated protein concentration. Meningitis resolves spontaneously, but late complications may occur. Asymptomatic meningitis (CSF changes in the absence of a meningitic syndrome) occurs in 20–30% of all infected persons.

Meningovascular neurosyphilis. Fluctuating symptoms such as headache, visual disturbances, and vertigo occur 5–12 years after the initial infection. Vasculitis (von Heubner angiitis) causes stroke, particularly in the territory of the middle cerebral artery, and may also affect small perforating vessels as well as cranial nerves (VIII, VII, V). Hydrocephalus, personality changes, epileptic seizures, and spinal cord signs (paraparesis, bladder dysfunction, anterior cord syndrome) round out the kaleidoscopic clinical picture. Gummata are rarely seen. CT and MRI findings suggest the diagnosis, and CSF examination reveals a mononuclear pleocytosis (up to 100 cells/µl), elevated protein concentra-

tion, elevated oligoclonal IgG, and VDRL positivity (up to 80%).

Progressive paralysis. Chronic meningoencephalitis with progressive paralysis occurs 10–25 years after the initial infection. The “preparalytic” stage, characterized by personality changes and mild impairment of concentration and memory, later evolves into the “paralytic” stage, characterized by more severe cognitive changes, dysarthria, dysphasia, tremor (mimic tremor), apraxia, gait impairment, urinary incontinence, and abnormal pupillary reflexes (roughly 25% of patients have Argyll–Robertson pupils, p. 92). The CSF findings resemble those of meningovascular syphilis.

Tabes dorsalis. This late meningovascular complication (25–30 years after the initial infection) produces ocular manifestations (Argyll–Robert- son pupils, strabismus, papillary atrophy), pain (lightning pains = lancinating pain mainly in the legs; colicky abdominal pain), gait impairment (due to loss of acrognosis and proprioception), and autonomic dysfunction (impotence, urinary dysfunction). Joint deformities (Charcot joints) in the lower limbs are occasionally seen. The CSF cell count is relatively low, as in meningovascular syphilis.

Antibiotic therapy. The efficacy of treatment depends on the stage of disease in which it is instituted (the earlier, the better). Penicillin is the agent of choice.