Color Atlas of Neurology

Opportunistic Fungal Infections

CNS mycosis is sometimes found in otherwise healthy persons but mainly occurs as a component of an opportunistic systemic mycosis in persons with immune compromise due to AIDS, organ transplantation, severe burns, malignant diseases, diabetes mellitus, connective tissue diseases, chemotherapy, or chronic corticosteroid therapy. Certain types of mycosis (blastomycosis, coccidioidmycosis, histoplasmosis) are endemic to certain regions of the world (North America, South America, Africa).

! Cryptococcus neoformans (Cryptococcosis)

Cryptococcus, a yeastlike fungus with a polysaccharide capsule, is a common cause of CNS mycosis. It is mainly transmitted by inhalation of dust contaminated with the feces of pet birds and pigeons. Local pulmonary infection is followed by hematogenous spread to the CNS. In the presence of a competent immune system (particularly cell-mediated immunity), the pulmonary infection usually remains asymptomatic and self-limited. Immune-compromised persons, however, may develop meningoencephalitis with or without prior signs of pulmonary cryptococcosis. Its manifestations are heterogeneous and usually progressive. Signs of subacute or chronic meningitis are accompanied by cranial nerve deficits (III, IV, VI), encephalitic syndrome, and/or signs of intracranial hypertension. Diagnosis: MRI reveals granulomatous cystic lesions with surrounding edema. Lung infiltrates may be seen. The nonspecific CSF changes include a variable (usually mild) lymphomonocytic pleocytosis as well as elevated protein, low glucose, and elevated lactate concentrations. An india ink histological preparation reveals the pathogen with a surrounding halo (carbon particles cannot penetrate its polysaccharide capsule). Identification of pathogen: demonstration of antigen in CSF and serum; tests for anticryptococcal antibody yield variable results. Treatment: initially, amphotericin B + flucytosine; subsequently, fluconazole or (if fluconazole is not tolerated) itraconazole.

! Candida (Candidiasis)

Candida albicans is a constituent of the normal body flora. In persons with impaired cell-medi-

ated immunity, Candida can infect the oropharynx (thrush) and then spread to the upper respiratory tract, esophagus, and intestine. CNS infection comes about by hematogenous spread (candida sepsis), resulting in meningitis or meningoencephalitis. Ocular changes: Candida endophthalmitis. Diagnosis:

Candida abscesses can be seen on CT or MRI. The CSF changes included pleocytosis (several hundred cells/µl) and elevated concentrations of protein and lactate. Pathogen identification: Microscopy, culture, or detection of specific antigens or antibodies. Local treatment: Amphotericin B or fluconazole. Systemic tratment: Amphotericin B + flucytosine.

! Aspergillus (Aspergillosis)

The mold Aspergillus fumigatus is commonly found in cellulose-containing materials such as silage grain, wood, paper, potting soil, and foliage. Inhaled spores produce local inflammation in the airways, sinuses, and lungs. Organisms reach the CNS by hematogenous spread or by direct extension (e. g., from osteomyelitis of the skull base, otitis, or mastoiditis), causing encephalitis, dural granulomas, or multiple abscesses. Diagnosis: CT and MRI reveal multiple, sometimes hemorrhagic lesions. The CSF findings include granulocytic pleocytosis and markedly elevated protein, decreased glucose, and elevated lactate concentration. Pathogen identification: Culture; if negative, then lung or brain biopsy. Treatment: Amphotericin B + flucytosine or itraconazole.

! Mucor, Absidia, Rhizopus (Mucormycosis)

Inhaled spores of these molds enter the nasopharynx, bronchi, and lungs, where they mainly infect blood vessels. Rhinocerebral mucormycosis is a rare complication of diabetic ketoacidosis, lymphoproliferative disorders, and drug abuse; infection spreads from the paranasal sinuses via blood vessels to the retro-orbi- tal tissues (causing retro-orbital edema, exophthalmos, and ophthalmoplegia) and to the brain (causing infarction with secondary hemorrhage). Diagnosis: CT, MRI; associated findings on ENT examination. Pathogen identification: Biopsy, smears. Treatment: Surgical excision of infected tissue if possible; amphotericin B.

Protozoan and Helminthic Infections

! Toxoplasma gondii (Toxoplasmosis)

This protozoan goes through three stages of development. Tachyzoites (endozoites; acute stage) are crescent-shaped, rapidly replicating forms that circulate in the bloodstream and are spread from one individual to another through contaminated blood or blood products. These develop into bradyzoites (cystozoites; latent stage), which aggregate to form tissue cysts (e. g., in muscle) containing several thousand organisms each. Oocysts are found only in the intestinal mucosa of the definitive host (domestic cat). Infectious sporozoites (sporulated oocysts) appear 2–4 days after the oocysts are eliminated in cat feces. Reuptake of the organism by the definitive host, or infection of an intermediate host (human, pig, sheep), occurs by ingestion of sporozoites from contaminated feces, or by consumption of raw meat containing tissue cysts. In the intermediate host, the sporozoites develop into tachyzoites, which then become bradyzoites and tissue cysts. Placental transmission (congenital toxoplasmosis hydrocephalus, intracellular calcium deposits, chorioretinitis) occurs only if the mother is initially infected during pregnancy. In immunocompetent persons, acute toxoplasmosis is usually asymptomatic, and only occasionally causes symptoms such as lymphadenopathy, fatigue, low-grade fever, arthralgia, and headache. IgG antibodies can be detected in latent toxoplasmosis (bradyzoite stage). In immunodeficient persons (p. 240), however, latent toxoplasmosis usually becomes symptomatic on reactivation. The central nervous system is most commonly affected (mainly encephalitis; myelitis is rare); other organs that may be affected include the eyes (chorioretinitis, iridocyclitis), heart, liver, spleen, PNS (neuritis) and muscles (myositis).

Diagnosis: EEG (slowing, focal signs), CT/MRI (solitary or multiple ring-enhancing abscesses), CSF (lymphomonocytic pleocytosis, mildly elevated protein concentration). Treatment: pyrimethamine/sulfadiazine or clindamycin/ folinic acid.

! Taenia solium (Neurocysticercosis)

tomatic infection of the human gut. Tapeworm segments that contain eggs (proglottids) are eliminated in the feces of pigs (the intermediate host) or humans with intestinal infection and then reingested by humans (or pigs) under poor hygienic conditions. The oval-shaped larvae pass through the intestinal wall and travel to multiple organs (including the eyes, skin, muscles, lung, and heart) by hematogenous, lymphatic, or direct spread. The CNS is often involved, though manifestations such as epileptic seizures, intracranial hypertension, behavioral changes (dementia, disorientation), hemiparesis, aphasia, and ataxia are uncommon. Spinal cysts are rare. Diagnosis: CT (solitary or multiple hypodense cysts with or without contrast enhancement, calcification and/or hydrocephalus), MRI (demonstration of cysts and surrounding edema), CSF examination (low-grade lymphocytic pleocytosis, occasional eosinophilia). Treatment: Praziquantel or albendazole; neurosurgical excision of intraventricular cysts; ventricular shunting in patients with hydrocephalus.

! Plasmodium falciparum (Cerebral Malaria)

This protozoan is most commonly transmitted by the bite of the female anopheles mosquito. Primary asexual reproduction of the organisms takes place in the hepatic parenchyma (preerythrocytic schizogony). The organisms then invade red blood cells and develop further inside them (intraerythrocytic development). The repeated liberation of merozoites causes recurrent episodes of fever. P. falciparum preferentially colonizes the capillaries of the brain, heart, liver, and kidneys. Pathogen identification: Blood culture. Treatment: See current topical literature for recommendations.

Transmissible Spongiform

Encephalopathies

The transmissible spongiform encephalopathies (TSEs) are characterized by spongiform histological changes in the brain (vacuoles in neurons and neuropil), transmissibility to humans by way of infected tissue or contaminated surgical instruments, and, in some cases, a genetic determination. TSEs are transmitted by nucleic acidfree proteinaceous particles called prions and are associated with mutations in prion protein (PrP); they are therefore referred to as prion diseases.

Normal cellular prion protein (PrPc) is synthesized intracellularly, transported to the cell membrane, and returned to the cell interior by endocytosis. Part of the PrPc is then broken down by proteases, and another fraction is transported back to the cell surface. The physiological function of PrPc is still unknown. It is found in all mammalian species and is especially abundant in neurons. PRNP, the gene responsible for the expression of PrPc in man, is found on the short arm of chromosome 20. PRNP mutations yield the mutated form of PrP ( PrP) that causes the genetic spongiform encephalopathies. Another mutated form of PrP (PrPsc) causes the infectious spongiform encephalopathies. PrPsc induces the conversion of PrPc to PrPsc in the following manner: PrPsc enters the cell and binds with PrPc to yield a heterodimer. The resulting conformational change in the PrPc molecule (α-helical structure) and its interaction with a still unidentified cellular protein (protein X) transform it into PrPsc (#-sheet structure). Protein X is thought to supply the energy needed for protein folding, or at least to lower the activation energy for it. PrPsc cannot be formed in cells lacking PrPc. Mutated PrPsc presumably reaches the CNS by axonal transport or in lymphatic cells; these forms of transport have been demonstrated in forms of spongiform encephalopathies that affect domestic animals, e. g., scrapie (in sheep) and bovine spongiform encephalopathy (BSE). PrP and PrPsc cannot be broken down intracellularly and therefore accumulate within the cells. Partial proteolysis of these proteins yields a protease-resistant molecule (PrP 27–30) that polymerizes to form amyloid, which, in turn, induces further neu-

ropathological changes. PrP and amyloid have been found in certain myopathies (such as inclusion body myositis, p. 344); others involve an accumulation of PrP (PrP overexpression myopathy).

! Creutzfeldt–Jakob Disease (CJD)

CJD is a very rare disease, arising in ca. 1 person per 106 per year. It usually affects older adults (peak incidence around age 60). 85–90% of cases are sporadic (due to a spontaneous gene mutation or conformational change of PrPc to PrPsc); 5–15% are familial (usually autosomal dominant); and very rare cases are iatrogenic (transmitted by contaminated neurosurgical instruments or implants, growth hormone, and dural and corneal grafts). It usually progresses rapidly to death within 4–12 months of onset, though the survival time in individual cases varies from a few weeks to several years. Early manifestations are not typically seen, but may include fatigability, vertigo, cognitive impairment, anxiety, insomnia, hallucinations, increasing apathy, and depression. The principal finding is a rapidly progressive dementia associated with myoclonus, increased startle response, motor disturbances (rigidity, muscle atrophy, fasciculations, cerebellar ataxia), and visual disturbances. Late manifestations include akinetic mutism, severe myoclonus, epileptic seizures, and autonomic dysfunction. A new variant of CJD has recently arisen in the United Kingdom; unlike the typical form, it tends to affect younger patients, produces mainly behavioral changes in its early stages, and is associated with longer survival (though it, too, is fatal). It is thought to be caused by the consumption of beef from cattle infected with BSE. Diagnosis: EEG (1 Hz periodic biphasic or triphasic sharp-wave complexes), CT (cortical atrophy), T2/proton-weighted MRI (bilateral hyperintensity in basal ganglia in ca. 80%), CSF examination (elevation of neuron-specific enolase, S100# or tau protein concentration; presence of protein 14–3-3).

!Gerstmann–Sträussler–Scheinker Disease (GSS) and Fatal Familial Insomnia (FFI)

See pp. 114 and 280.