Introduction
Prion diseases are uncommon and occur as Creutzfeldt-Jakob disease (CJD), the juvenile vari-ant of CJD (vCJD), Gerstmann-Sträussler syn-drome, fatal familial insomnia, and kuru in humans, scrapie in sheep, and bovine spongiform encephalopathy (mad cow disease) in cattle. These prion diseases are discussed because the infectious agent (prion) breaks the conventional rules for infectious agents and may represent a new class of misfolding diseases. First, the infectious particle is a single unique protein molecule (prion) of 27 to 30 kd whose DNA resides in host chromosome 20.
No nucleic acid has been identified that is attached to the protein. Second, the infectious particle is not killed by formalin, ethanol, or boiling but can be destroyed by autoclaving. Third, patients with the illness do not present with typical signs of an infection. They lack fever or elevated WBC counts
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and have normal-appearing CSF. Fourth, the host makes no immune response to the infectious pro-tein, so the brain lacks inflammatory cells typical of encephalitis.
Pathophysiology
Prion diseases occur by three different routes: spo-radic, infectious, and hereditary, and all share an abnormal brain protein called a prion. The PRNP gene on human chromosome 20 produces a nor-mal cellular protein (PrPc) that has a specific 3-dimensional (3-D) configuration that is found in membranes of neurons and other cells. The nor-mal function of the PrPcprotein is poorly under-stood. In prion diseases, the normal cellular protein somehow alters its 3-D configuration to become a family of abnormal prion proteins, com-monly called PrPsc, that all contain the same amino acid sequence. The normal PrPcprotein has a high α-helical structure content while abnormal prions have in common a high β-sheet content, but each has a different 3-D configuration. Each different 3-D configuration causes a human dis-ease that has a different clinical picture (pheno-type). The probability of the protein misfolding increases if genetic mutations are present at spe-cific DNA sites. The abnormal protein not only causes neurologic disease but also is infectious.
When the abnormal prion enters a normal cell containing only normal PrPcproteins, the prion causes PrPc proteins to reconfigure their 3-D structure to become identical to the 3-D structure of the abnormal prion. Prions are poorly catabo-lized by the host cell, accumulate, and eventually kill the cell. While systemic cells dying from prions can be replaced, neurons cannot divide, leading to neurologic disease from a progressive loss of neu-rons. The abnormal prion is structurally so close to the normal cell protein that the host does not recognize prions as foreign and hence produces no immune response. As such, prion diseases appear like a degenerative disease without inflammatory cells or the production of a specific antibody.
The most common form of CJD is sporadic, in which many neurons have prions. How the body first developed prions remains unclear, but it could begin following spontaneous transformation of a normal PrPcprotein into a prion. Once CJD devel-ops from any cause, the nervous system becomes infectious. Infectious transmission producing CJD
in the recipient has been shown to occur following transplantation of corneas, pituitary extracts, and dural grafts. There is considerable evidence that the vCJD seen in the United Kingdom can develop, though rarely, from oral consumption of the meat of infected cattle. Finally, CJD as well as other human prion diseases can be autosomal dominant hereditary diseases occurring in families with spe-cific single-site mutations in the PRNP gene.
Again, these patients are infectious should the above tissues be donated to others.
The pathologic hallmarks of CJD are generalized brain atrophy, spongiform degeneration ( “tiny holes” in the cortex), and widespread gliosis without inflammation. Amyloid plaques are seen in the juvenile variant of CJD and Gerstmann-Sträussler syndrome. Antibody to prions specifically stains amyloid plaques, brain cortex, cerebellum, and ton-sils from vCJD patients. Systemic organs are histo-logically normal.
Prion diseases may represent the first of a new class of misfolding diseases. It is known that yeasts and fungi, when environmental conditions war-rant, have some proteins that can alter their 3-D configuration normally to acquire unique proper-ties for the new environment. If vertebrate pro-teins also can change their 3-D structures normally, then misfolding can occur and lead to disease that would not necessarily be infectious.
Currently, Huntington’s, Alzheimer’s, and Parkin-son’s disease are potential candidates for this new disease mechanism.
Major Clinical Features
CJD is the most common prion disease, with an incidence of 1/1 million adults. The majority of cases are sporadic, developing in previously healthy adults with a mean age of 65 years (CJD from a genetic or infectious cause has an earlier age of onset). The onset is insidious but then patients develop a rapidly progressive dementia. Myoclonus appears in over 1/2 of patients as the dementia progresses. Occa-sionally patients also develop ataxia, visual loss (cor-tical blindness or homonymous hemianopia), and extrapyramidal or pyramidal signs. Patients lack sys-temic symptoms of fever, aches, and myalgia. Within 4 to 6 months, patients are severely demented, rigid, mute, and unresponsive.
vCJD appears in children and young adults who have eaten beef of British origin years earlier.
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These patients often present with psychiatric symptoms (anxiety, withdrawal, behavior changes, and depression) shortly before dementia and myoclonus develop.
Major Laboratory Findings
Routine blood tests are normal. Cerebrospinal fluid is under normal pressure and contains no cells and normal glucose and protein. Oligoclonal bands are not seen. The CSF contains a nonprion, chaperone protein called 14-3-3. When seen on electrophoresis, it is characteristic, but not diag-nostic, for CJD. An EEG may show characteristic abnormalities, particularly later in the illness. MRI shows progressive brain atrophy and often demon-strates increased signal in the basal ganglia and cortex on a diffusion-weighted image. The later finding is diagnostically helpful.
The prion infectious agent is complicated to isolate and requires incubation in small laboratory animals for months. However, CSF, brain, pitu-itary, and peripheral nerves that innervate cornea and dura contain infectious prions. Tonsils are infectious in vCJD. The infectious agent does not appear to be present in saliva, urine, sweat, or stool, so isolation of the patient is not necessary.
Blood should be considered infectious, but no documented human cases have occurred from blood transfusions.
Principles of Management and Prognosis Currently, there is no available treatment to stop disease progression. Death in CJD usually occurs within 6 months of diagnosis and within 2 years
for vCJD and other genetic prion diseases. Since the infectious agent is present in tissues, patients suspected of a prion disease should not donate blood or autopsy organs.
RECOMMENDED READING
Davis LE, Kennedy PGE. Infectious Diseases of the Nervous System. Oxford, England: Butterworth-Heinemann; 2000. (Comprehensive review of many different CNS infections.)
Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis 1997;25:763–781. (Good overall review that includes pathophysiology, clinical features, and treatment.)
Peterson LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002;137:
173–179. (Nice review of the clinical features of West Nile encephalitis.)
Saez-Llorens X, McCracken GH. Bacterial menin-gitis in children. Lancet 2003;361:2139–2148.
(Reviews pathogenesis, diagnosis, and treatment of bacterial meningitis in children and, by exten-sion, adults.)
Sy MS, Gambetti P, Wong BS. Human prion dis-eases. Med Clin North Am 2002;86:551–571.
(Good review of prions and the human diseases they cause.)
Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: thera-peutic and diagnostic considerations. Clin Infect Dis 1995, 20:414–420. (Excellent review of clinical features, pathogenesis theories, diagnosis, and treatment.)
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Overview
The term “brain tumor” refers to a collection of neoplasms of differing cell types, biology, progno-sis, and treatment arising as a primary tumor or metastasis. Each year over 17,000 new primary brain tumors are diagnosed in the United States and about 13,000 people die from their disease. Pri-mary brain tumors mainly occur in adults, with a peak incidence in the elderly. Most of these adult neoplasms occur above the tentorium in the hemi-spheres. Primary tumors develop in infants and children, mainly in the posterior fossa (especially cerebellum), and have different histologic types from those in adults. Most CNS tumors are of glial (astrocytoma more often than oligodendroglioma) origin (>90%) and rarely of neuronal origin (1%).
Brain tumors produce signs and symptoms by 3 mechanisms. The first of these is the tumor loca-tion. Since the hemispheres are most commonly affected, common signs include hemiparesis, hemisensory loss, aphasia, and visual field deficits.
When the cerebral gray matter is involved, seizures are common and may be either focal or secondar-ily generalized. As the tumor spreads, cognitive dysfunction is common.
Second, the mass of the tumor can produce signs and symptoms as it expands in a closed intracranial
space. In addition, many tumors release unknown substances that affect the surrounding blood–brain barrier, allowing vasogenic edema to develop. As such, tumors and their surrounding cerebral edema soon produce gradually increasing intracranial pressure (ICP). Increased ICP causes headaches, psychomotor retardation (slowing in amount and speed of cognitive functions coupled with a slowing of motor activities), nausea, vomiting, and papilledema (blurring of optic discs, retinal edema, and flame hemorrhages without loss of vision). The headache is ill defined, intermittent, and may be lat-eralizing. As the tumor expands, the headache becomes more intense, constant, and increases with coughing or straining at stool. The papilledema results from increased pressure on both optic nerves that impedes axonal flow and venous return from the retina.
Third, as the mass expands, the resulting increased ICP may shift intracranial structures downward enough to produce brain herniation.