Color Atlas of Neurology (Thieme 2004)

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.

Normal PrPc synthesis

Infectious prion disease

Continuous sharp wave complexes (CJD)

Creutzfeldt-Jakob disease (CJD)

Spontaneous conversion of 6PrP zu PrPsc

Hereditary prion disease

Dementia,

ataxia,

myoclonus, visual disturbances, behavioral changes

Symptoms and Signs

The clinical manifestations of a brain tumor may range from a virtually asymptomatic state to a constellation of symptoms and signs that is specific for a particular type and location of lesion. The only way to rule out a brain tumor for certain is by neuroimaging (CT or MRI).

! Nonspecific Manifestations

Tumors whose manifestations are mainly nonspecific include astrocytoma, oligodendroglioma, cerebral metastasis, ependymoma, meningioma, neoplastic meningitis, and primary CNS lymphoma.

Behavioral changes. Patients may complain of easy fatigability or exhaustion, while their relatives or co-workers may notice lack of concentration, forgetfulness, loss of initiative, cognitive impairment, indifference, negligent task performance, indecisiveness, slovenliness, and general slowing of movement. Such manifestations are often mistaken for signs of depression or stress. Apathy, obtundation, and somnolence worsen as the disease progresses. There may also be increasing confusion, disorientation, and dementia.

Headache. More than half of patients with brain tumors suffer from headache, and many headache patients fear that they might have a brain tumor. If headache is the sole symptom, the neurological examination is normal, and the headache can be securely classified as belonging to one of the primary types (p. 182 ff), then a brain tumor is very unlikely. Neuroimaging is indicated in patients with longstanding headache who report a change in their symptoms. The clinical features of headache do not differentiate benign from malignant tumors.

Nausea, vertigo, and malaise are frequent, though often vague, complaints. The patient feels unsteady or simply “different.” Vomiting (sometimes on an empty stomach) is less common and not necessarily accompanied by nausea; there may be spontaneous, projectile vomiting.

may be present earlier in milder form. Hemiparesis, aphasia, apraxia, ataxia, cranial nerve palsies, or incontinence may occur depending on the type and location of the tumor.

Intracranial hypertension (elevated ICP) (p. 158) may arise without marked focal neurological dysfunction because of a medulloblastoma, ependymoma of the fourth ventricle, cerebellar hemangioblastoma, colloid cyst of the 3rd ventricle, craniopharyngioma, or glioblastoma (e. g. of the frontal lobe or corpus callosum). Cervical tumors very rarely cause intracranial hypertension. Papilledema, if present, is not necessarily due to a brain tumor, nor does its absence rule one out. Papilledema does not impair vision in its acute phase.

! Specific Manifestations

Some tumors produce symptoms and signs that are specific for their histological type, location, or both. These tumors include craniopharyngioma, olfactory groove meningioma, pituitary tumors, cerebellopontine angle tumors, pontine glioma, chondrosarcoma, chordoma, glomus tumors, skull base tumors, and tumors of the foramen magnum. In general, these specific manifestations are typically found when the tumor is relatively small and are gradually overshadowed by nonspecific manifestations (described above) as it grows.

Early papilledema

(irregular margins, disk elevation, reduced venous pulsation)

Peripapillary hemorrhage

Advanced papilledema

Incontinence, focal neurological signs

Hemorrhage

Blurring of disk

Fully developed margins papilledema

Nausea, vomiting

Vertigo, unsteady gait

Benign Brain Tumors

! Astrocytoma (WHO grades I and II)

Astrocytomas arise from blastomatous astrocytes. They are classified as benign (WHO grade I) or semibenign (WHO grade II) according to their histological features (p. 377).

Pilocytic astrocytoma (WHO grade I) is a slowly growing tumor that mainly occurs in children and young adults and usually arises in the cerebellum, optic nerve, optic chiasm, hypothalamus, or pons. It is not uncommonly found in the setting of neurofibromatosis I. There may be a relatively long history of headache, abnormal gait, visual impairment, diabetes insipidus, precocious puberty, or cranial nerve palsies before the tumor is discovered.

Low-grade astrocytoma (WHO grade II). Fibrillary astrocytoma is more common than the gemistocytic and protoplasmic types. These tumors most commonly arise in the frontal and temporal lobes and often undergo malignant transformation to grades III and IV over the course of several years. They may be calcified. They may produce epileptic seizures and behavioral changes.

Oligodendroglioma (WHO grade II) usually appears in the 4th or 5th decade of life. It tends to arise at or near the cortical surface of the frontal and temporal lobes and may extend locally to involve the leptomeninges. Oligodendrogliomas are often partially calcified. Tumors of mixed histology (oligodendrocytoma plus astrocytoma) are called oligoastrocytomas.

Pleomorphic xanthoastrocytoma (WHO grade II) is a rare tumor that mainly arises in the temporal lobes of children and young adults and is associated with epileptic seizures in most cases. It can progress to a grade III tumor.

! Meningioma (WHO grade I)

CNS but are most often found in supratentorial (falx, parasagittal region, sphenoid wing, cerebral convexities), infratentorial (tentorium, cerebellopontine angle, craniocervical junction), and spinal locations. Multiple or intraventricular meningioma is less common. Extracranial meningiomas rarely arise in the orbit, skin, or nasal sinuses. Familial meningioma is seen in hereditary disorders such as type II neurofibromatosis.

! Choroid Plexus Papilloma (WHO grade I)

This rare tumor most commonly arises in the (left) lateral ventricle in children and in the 4th ventricle in adults. Signs of intracranial hypertension, due to obstruction of CSF flow, are the most common clinical presentation and may arise acutely.

! Hemangioblastoma (WHO grade I)

These solid or cystic tumors usually arise in the cerebellum (from the vermis more often than the hemispheres) and produce vertigo, headache, truncal ataxia, and gait ataxia. Obstructive hydrocephalus may occur as an early manifestation. 10% of cases are in patients with von Hip- pel–Lindau disease (p. 294).

! Ependymoma (WHO grades I–II)

Ependymomas most commonly arise in children, adolescents, and young adults. They may arise in the ventricular system (usually in the fourth ventricle) or outside it; they may be cystic or calcified. Subependymoma of the fourth ventricle (WHO grade I) may appear in middle age or later. Spinal ependymomas may arise in any portion of the spinal cord.